# Patent

## Title
Methods for characterizing and treating cognitive impairment in aging and disease

## Abstract

This invention provides methods for identifying genes associated with cognitive impairment and for identifying compounds useful in the treatment of cognitive impairment. The methods can in particular be used to identify genes associated with, and compounds useful in treating, cognitive impairment in aging.

## Background
BACKGROUND OF THE INVENTION
A major focus of the field of aging and dementia is the investigation of the causes of cognitive impairment. Various conditions, such as dementias (e.g., Alzheimer's Disease, Lewy body dementia, vascular dementia, and HIV associated dementia), neurodegenerative diseases (e.g., Huntington's Disease, Parkinson's Disease, amyotrophic lateral sclerosis), neurological disorders (e.g., schizophrenia, depression), and age-related conditions (e.g., Mild Cognitive Impairment, Age-Related Cognitive Decline), are associated with cognitive impairment. As the understanding of cognitive impairment increases, so does the need to develop sensitive methods to both detect and to treat such impairment.
Accumulating evidence suggests that there is a neurogenetic component to cognitive impairment. For example, changes in the mammalian brain appear to parallel alterations in distinct learning and memory processes. See, e.g., Albert, Philos. Trans. R. Soc. Lond. B. Biol. Sci. 352(1362):1703-09 (1997). In particular, alterations in the hippocampal formation are among the most prominent and consistent features observed in age-related cognitive impairment. Gallagher, Philos. Trans. R. Soc. Lond. B. Biol. Sci. 352(1362):1711-7 (1997). Changes in the aged hippocampus also parallel, to some extent, the hippocampal changes observed in other conditions associated with cognitive impairment, such as Alzheimer's Disease. Whitehouse et al., Science. 215(4537):1237-39 (1982); Bartus et al., Science. 17(4558):408-14 (1982); Rapp and Heindel, Curr. Opin. Neurol. 7(4):294-8 (1994). Thus, the effects of aging on hippocampal function may be related at some level to disease processes in progressive neurodegenerative illnesses.
The mammalian hippocampus is a structure that contains distinct populations of neurons organized into separate anatomical subregions. These subregions include, for example, the dentate gyrus (DG) and the Cornu Ammonis (CA) subfields CA1 and CA3. Each hippocampal subregion is characterized by a unique molecular profile. Lein et al. J. Neurosci. 24(15):3879-89 (2004). These different profiles may account for the differential vulnerability of these regions to various mechanisms of cognitive impairment. See, e.g., Small et al. Proc. Natl. Acad. Sci. USA. 101(18):7181-6 (2004).
Considerable research has examined the correlation between changes in cognitive function and neuronal changes in specific hippocampal subregions. This research suggests that the specific nature and extent of hippocampal damage parallels in some cases the degree and type of cognitive impairment. See, Jarrard, Behav. Neural. Biol. 60(1):9-26 (1993). For example, synaptic alterations specific to the CA1 region correlate with age-related impairments in cellular responsiveness to glutamate receptor stimulation. Barnes et al., Hippocampus. 2(4):457-68 (1992). Likewise, individual differences in spatial learning ability correlate with expression levels of NR1, an N-methyl-D-Aspartate (NMDA) receptor subunit, selectively in CA3 neurons. Adams et al., J. Comp. Neurol. 432(2):230-43 (2001). And, levels of synaptic markers in the DG correlate with individual levels of cognitive impairment in spatial learning capacity among aged rats. Smith et al., J. Neurosci. 20(17):6587-93 (2000). These correlations do not, however, establish that the neuronal changes cause the observed functional changes. Just as, importantly, changes in the hippocampus and cognitive function do not occur solely as a result of aging per se. Thus, comparisons based on chronological age alone often fail to capture the hippocampal changes that correlate with individual levels of cognitive impairment.
Although some impairment in both cognitive function and hippocampal integrity may be a normal consequence of healthy aging, a significant population of elderly adults experiences a decline in cognitive ability that exceeds normal development. Thus, the effect of aging itself on cognition, in the absence of dementia or disease, is important for defining the boundary between illness and normal aging.
Heterogeneous patterns of progressive cognitive impairment are characteristic of mammalian test populations, e.g., aged humans and aged laboratory animals. The increasing preponderance of ‘individual differences’ in cognitive impairment has been used to characterize normal mammalian aging itself. Baxter and Gallagher, Neurobiol. Aging. 17(3):491-95 (1996).
There is, therefore, a need to elucidate the molecular basis of and to treat cognitive impairment, both in aging and in disease. There is also a need to understand the neurogenetic components of cognitive impairment and to develop a range of treatment options for individuals with varying levels of impaired cognition.
The examination of changes in expressed gene products in the hippocampus of the mammalian brain, as described in this invention, may serve to elucidate the genetic or molecular basis of cognitive impairment. Moreover, the examination of changes in expressed gene products in the aged hippocampus may serve to elucidate the genetic or molecular basis of cognitive impairment in aging. The identification of genes, or a plurality of genes, that are associated with cognitive impairment, and particularly that are associated with age-related cognitive impairment, would also allow the identification of compounds for treating such impairment.
SUMMARY OF THE INVENTION
This invention provides methods for identifying genes and their expressed gene products, e.g., RNAs, polypeptides, peptides and proteins, associated with cognitive impairment and for identifying compounds useful in the treatment of cognitive impairment. The methods of this invention can, in particular, be used to identify genes and expressed gene products associated with and compounds useful in treating cognitive impairment in aging.
This invention provides a method of identifying a gene or a plurality of genes associated with cognitive impairment by determining the abundance of expressed gene products in one or more of CA1, CA3 and DG hippocampal tissue of mammals in a population of aged mammals with cognitive impairment (aged impaired or “AI”), aged mammals without cognitive impairment (aged unimpaired or “AU”) and young mammals (“Y”), and selecting the genes based on a significant change—increase or decrease—in the relative abundance of the gene's expressed gene product in the AI population relative to the combined AU and Y populations or based on a significant change—increase or decrease—in the relative abundance of the gene's expressed gene product in the AU population relative to the combined AI and Y populations. The AI genes and their expressed gene products may be related to and markers of cognitive impairment and unhealthy aging. Conversely the AU genes and their expressed genes products may be related to and markers of adaptive aging to preserve and protect cognitive function.
One preferred gene in accordance with this invention, the abundance of whose expressed gene product in the AI population relative to the expressed gene product in the combined AU and Y populations is decreased is the GABA-A α5 receptor gene (corresponding to GENBANK® accession number NM—017295), as shown in Example 36 and Table 36 (CA3 AI ANOVA decrease) and its homologues.
This invention provides a method of correlating the changed abundance—increase or decrease—of a selected gene's or its homologue's expressed gene product with the level of cognitive impairment or age-related cognitive impairment in each mammal of the AU and AI populations and selecting one or more genes, the changed abundance—increase or decrease—of whose expressed gene product(s) significantly correlates with the level of cognitive impairment or age-related cognitive impairment in the mammal. Preferably, one gene whose decreased expressed gene product significantly correlates with the level of cognitive impairment is the GABA-A a5 receptor gene (corresponding to GENBANK® accession number NM—017295), as shown in Example 10 and Table 10 (CA3 AI ANOVA negative correlation).
This invention also provides methods for identifying compounds useful for treating cognitive impairment by determining the abundance or function, either in a mammalian cell or in the hippocampus of a mammal, of the expressed gene product of at least one gene, identified by the above methods of the invention, or listed in Tables 1-48, or their homologues, in the presence or absence of a candidate compound and identifying a compound from among the candidate compounds that significantly changes that abundance or alters the function of those genes or expressed gene products in the appropriate direction as defined herein, either in the mammalian cell or in the hippocampus of the mammal, preferably in the CA1, CA3 or DG hippocampal tissue from which the gene was identified, to whom the candidate compound is administered. The same method may also be used for identifying compounds useful in treating age-related cognitive impairment by testing the candidate compounds in aged mammals. Preferably, compounds useful for treating cognitive impairment are (1) the GABA-A a5 receptor agonist QH-ii-066 (1-methyl-7-acetyleno-5-phenyl-1,3-dihydro-benzo[e]-1,4-diazepin-2-one), see, Platt et al., Contribution of α1GABAA and α5GABAA Receptor Subtypes to the Discriminative Stimulus Effects of Ethanol in Squirrel Monkeys, J. Pharmacol. Exp. Ther. 313: 658-667 (2005); (2) 6,6 dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one, corresponding to compound number 44 in Chambers et al., Identification of a Novel, Selective GABAA α5 Receptor Inverse Agonist Which Enhances Cognition, J. Med. Chem. 46:2227-2240 (2003); and (3) 8-ethylthio-3-methyl-5-(1-oxidopyridin-2-yl)-3,4-dihydronaphthalen-1(2H)-one, corresponding to compound number 19 in Szekeres et al., 3,4-Dihydronaphthalen-1(2H)-ones: novel ligands for the benzodiazepine site of alpha5-containing GABAA receptors. Bioorg. Med. Chem. Lett. 14:2871-2875 (2004).
This invention provides methods for identifying a compound useful in the treatment of cognitive impairment by determining the cognitive status of a mammal in the presence or absence of a candidate compound believed to change the abundance of the expressed gene product of at least one gene, identified by the method of this invention, or listed in Tables 1-48, or their homologues, or to alter the function of those genes or expressed gene products in the appropriate direction, as defined herein, and identifying a compound from among the candidate compounds that beneficially alters the cognitive status of the mammal. The same method may also be used to identify compounds useful for treating age-related cognitive impairment by testing candidate compounds in aged mammals.


DETAILED DESCRIPTION OF THE INVENTION
Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms include pluralities and plural terms include the singular. Generally, nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics and protein and nucleic acid chemistry, described herein, are those well known and commonly used in the art.
The methods and techniques of the present invention are generally performed, unless otherwise indicated, according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e.g. Ausubel et al., “Current Protocols in Molecular Biology”, Greene Publishing Associates (1992, and Supplements to 2003); Cooper and Hausman, “The Cell—A Molecular Approach, 2nd ed.”, Sinauer Associates, Inc., Sunderland, Mass. (2000); Kandel et al., “Principles of Neural Science”, McGraw-Hill Medical, New York, N.Y. (2000); Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4th ed.”, W. H. Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th ed.”, W. H. Freeman & Co., N.Y. (1999); Gilbert et al., “Developmental Biology, 6th ed.”, Sinauer Associates, Inc., Sunderland, Mass. (2000); Sambrook et al., “Molecular Cloning: A Laboratory Manual, 2d ed.”, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989).
Chemistry terms used herein are used according to conventional usage in the art, as exemplified by “The McGraw-Hill Dictionary of Chemical Terms”, Parker S., Ed., McGraw-Hill, San Francisco, Calif. (1985).
All of the above, and any other publications, patents and published patent applications, referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control.
The Specific Terms Used in the Methods of this Invention
The following terms, unless otherwise indicated, shall be understood to have the following meanings.
“Abundance” refers to the level of expression, activity or amount of an expressed gene product of a gene or its homologue from another organism. The abundance of an expressed gene product includes, but is not limited to, the level of expression of the function that the gene performs and the way in which it does so, including chemical or structural differences and/or differences in binding or association with other factors. It also includes the amount of the product whatever its source, e.g., expression or direct addition to the tissue, cell or animal. Abundance can be detected by any method useful in quantitatively measuring the expressed gene product. These include, for example, enzymatic assays, binding assays, immunoassays, structural and chemical assays (e.g., which measure modifications such as phosphorylation status, conformational changes).
The methods for measuring the abundance of an expressed gene product according to this invention include, but are not limited to, microarray analysis, macroarray analysis, in situ hybridization histochemistry, fluorescent in situ hybridization (FISH), immunocytochemistry (ICC), immunofluorescence, enzyme linked immunosorbent assay (ELISA), fluorescence polarization immunoassay (FPIA), nephelometric inhibition immunoassay (NIA), immunoprecipitation, quantitative polymerase chain reaction (PCR), RNase protection assay, reverse-transcription PCR, competitive PCR, real-time quantitative PCR (i.e., TagMan PCR), serial analysis of gene expression (SAGE) analysis, two-dimensional gel electrophoresis, mass spectrometry, MALDI-TOF mass spectrometry, radioimmunoassay (RIA) and blot analysis (e.g. Northern blot, Western blot, protein slot blot, immunoblot, dot blot). If desired, any of the expression and activity assays described above can be used in combination, either sequentially or simultaneously. Such assays can also be partially or completely automated, using methods known in the art.
“Aged” refers to a mammal advanced in years, preferably in or near the latter third of their average lifespan. For example, an aged human would be fifty or more years of age. An aged rat would be fifteen months of age or more.
“Age-related cognitive decline” or “ARCD”, or an equivalent construct such as “age-associated memory impairment”, refers to a diagnosis of mild memory deficit that is not expected to worsen considerably over time. As used herein, ARCD can also be defined as Stage 2 on the Global Deterioration Scale (GDS). The GDS is a seven-point rating system of cognitive and functional capabilities. It is widely used for rating cognitive performance in older adults, with scores ranging from normal aging (Stage 1) to severe dementia (Stage 7). Stage 2 is characterized, for example, by the following clinical characteristics: subjective cognitive complaints in the absence of clinically manifest deficit.
“AI” or “aged impaired” refers to one or more aged mammals with cognitive impairment relative to young mammals of the same species. The preferred species used as models of age impairment in this invention is rats. Most preferably, the rat is from an outbred strain. Aged rats naturally segregate into two populations, with about half of the aged rats being AI and about half being aged unimpaired (AU). To identify these populations, the cognitive ability of young and aged rats is measured. Methods for identifying populations of AI rats are known in the art, e.g., Gallagher and Burwell, Neurobiol. Aging 10:691-708 (1989) and an exemplary method is described in the Example. A number of methods for assessing rat cognitive ability are also known, e.g., the Barnes circular maze, the radial arm maze, the Morris water maze, delayed alternation (delayed nonmatch-to-sample), novel object recognition, conditioned avoidance, and fear conditioning.
“ANOVA” or “analysis of variance” refers to a statistical technique broadly applicable for analyzing data. An ANOVA compares the distribution of two or more populations to determine if one or more of the populations are significantly different from the others. The average variance within each of the populations is factored out from the variance between each of the populations before computing the probability of significant differences between the populations. When an ANOVA tests the difference between the means of two (and not more) populations, it is equivalent to a t-test. As used herein, for example, ANOVA is used to test the hypothesis that the abundance of an expressed gene product of a gene or a plurality of genes is different in mammals with cognitive impairment (e.g., the AI population) relative to mammals without cognitive impairment (e.g., the combined AU and Y populations), by computing the probability that significant differences among populations or treatments are too large to be due to chance.
The statistic calculated by an ANOVA is an F-ratio, which reveals the significance of the hypothesis that Y depends on X. It comprises the ratio of two mean-squares: MS[X]/MS[ε], which is the sum of squared deviations from the mean X or c divided by the appropriate degrees of freedom. One of skill in the art would use standard tables to determine whether the observed F-ratio indicates a significant relationship. When there are two groups, the F-ratio is equivalent to the t as determined by a t-test. As used herein, when the mean abundance of an expressed gene product of a gene or a plurality of genes is being compared between two groups (e.g., between Aged Impaired and Aged Unimpaired with Young) by ANOVA, the F-ratio would be equivalent to the t test statistic, as determined by a t-test.
A “MAS5” statistical analysis produces absolute and comparison analysis results for microarrays and preferably GeneChip microarrays. It is an algorithm for deriving gene expression scores from microarrays based on present or absent calls, where a percentage of transcripts that are considered significantly hybridized to the chip are considered present. The MAS5 analysis also comprises an algorithm, not used in the present invention, that can deduce present, absent and also marginal calls.
A “gcRMA” statistical analysis is another algorithm for deriving gene expression scores from microarrays and preferably GeneChip microarrays. It is an open-source method that is based on robust averaging techniques and sequence-dependent affinity corrections. The robust averaging employed in gcRMA confers a strong immunity to outliers.
“Appropriate direction” refers to the direction of the change in the abundance of the expressed gene product(s) of at least one gene identified by the methods of this invention or listed in Tables 1-48 or their homologues or the change in the function of the gene or expressed gene product. For genes, whose gene products increase in the AI population relative to the combined AU and Y populations, the “appropriate direction” is a decrease or attenuation of function. For genes, whose gene products decrease in the AI population relative to the combined AU and Y population, the “appropriate direction” is an increase or enhancement in function. For genes, whose gene products increase in the AU population relative to the combined AI and Y populations, the “appropriate direction” is an increase or enhancement of function. And, for genes, whose gene products decrease in the AU population relative to the combined AI and Y populations, the “appropriate direction” is a decrease.
“AU” or “aged unimpaired” refers to one or more aged mammals without cognitive impairment relative to young mammals of the same species. The preferred species used as models of age impairment in this invention is rats. Most preferably, the rat is from an outbred strain. As noted above, aged rats naturally segregate into two populations, with about half of the aged rats being AI and about half being AU. To identify these populations, the cognitive ability of young and aged rats can be measured. Methods for identifying populations of AU rats are known in the art, e.g., Gallagher and Burwell, Neurobiol. Aging 10:691-708 (1989), and an exemplary method is described in the Example. A number of methods for assessing rat cognitive ability are known, e.g., the Barnes circular maze, the radial arm maze, the Morris water maze, delayed alternation (delayed nonmatch-to-sample), novel object recognition, conditioned avoidance, and fear conditioning.
“Beneficially alters” refers to the state of promoting, improving, or preserving cognitive function, or of alleviating or attenuating cognitive decline. A beneficial alteration in accordance with this invention also includes the alleviation or amelioration of one or more manifestations of cognitive impairment, or the delay of onset or slowing of the progression of cognitive impairment. A beneficial alteration of this invention includes, but is not limited to, a change in cognitive function sufficient to result in an improved score in a test of cognitive function; the improvement of cognitive function in a subject with impaired cognitive function so that it more closely resembles the function of a control subject, preferably, e.g., a young subject or an aged unimpaired subject; the improvement over an aged cognitively impaired subject or population; and the preservation of cognitive function over time such that it does not decline or fall below the level observed in the subject upon first presentation or diagnosis.
“Candidate compound” or “compound” means a pharmaceutical, chemical or other composition of matter with known or unknown physiological effects. A compound can be any natural or synthetic agent made up of one or more elements, including, but not limited to, a small molecule, peptide, polypeptide, peptidomimetic, carbohydrate, lipid, protein, glycoprotein, lipoprotein, nucleic acid, and antibody. A compound may or may not have been characterized for its target, or mode of action, in cells or animals prior to its use in the methods of this invention.
As used herein, the compound that is identified and selected from among one or more candidate compounds as being useful in treating cognitive impairment refers to a compound that is capable of altering the abundance—increase or decrease—of the expressed gene product of at least one gene identified in accordance with this invention, one or more genes listed in Tables 1-48, or their homologues in the appropriate direction, as defined herein, i.e., in a manner consistent with the beneficial treatment of cognitive function or that is capable of beneficially altering the cognitive status of a mammal to whom it is administered. Preferably, the compound crosses the blood-brain barrier. More preferably, the compound is orally bioavailable.
“Cognitive function” or “cognitive status” refers to any higher order intellectual brain process or brain state, respectively, involved in learning and memory including, but not limited to, attention, information acquisition, information processing, working memory, short-term memory, long-term memory, anterograde memory, retrograde memory, memory retrieval, discrimination learning, decision-making, inhibitory response control, attentional set-shifting, delayed reinforcement learning, reversal learning, the temporal integration of voluntary behavior, and expressing an interest in one's surroundings and self-care.
“Cognitive impairment” or “CI” or an equivalent construct, such as “impaired cognitive function” or “cognitive decline”, refers to a deficit or reduction in cognitive status or cognitive function, as defined above, compared to that same function in an age-matched control subject or more usually a population. Cognitive impairment may be observed as a consequence of aging, as well as in various diseases and conditions, including but not limited to, Alzheimer's Disease, Lewy body dementia, vascular dementia, HIV associated dementia, Huntington's Disease, Parkinson's Disease, amyotrophic lateral sclerosis, schizophrenia, depression, MC1, and ARCD.
“Expressed gene product” refers to any form of expression of a gene that can be detected and measured, for example, RNA, amino acid, peptide, polypeptide or protein. It also includes the product itself, whether or not it was actually derived from expression in the cell or tissues of an animal.
“Hippocampal-dependent function” refers to a cognitive function, more specifically a learning or memory process, that includes the encoding and acquisition of memories for specific facts and events and episodes of experiences. Hippocampal-dependent function includes the processing of memory representations and the maintenance of memories. Hippocampal-dependent function in mammals includes, for example, spatial memory acquisition, long-term spatial memory, and spatial memory retrieval. A mammal with impaired hippocampal-dependent function may display, e.g., anterograde amnesia for newly acquired facts and events, including maze-specific information in a spatial water maze.
“Hippocampal formation” or “hippocampus” or “hippocampal tissue” refers to the whole or part of the hemispheric structure in the brain folded into the ventromedial surface of the temporal lobe, caudal to the amygdaloid complex. Hippocampal tissue comprises hippocampal cells from, without limitation, the CA1, CA3 and DG subregions. Hippocampal cells include, but are not limited to, pyramidal cells of the CA subregions and granule cells of the DG subregion.
“Homologue” refers to a gene that has the same origin and functions in two or more species. Preferably, a mammal's homologue of a gene, as identified by the method of the invention, refers to the mammal's equivalent of a gene identified in another mammalian species, e.g., the genes encoding human and rat growth hormones.
“Level of cognitive impairment” refers to a measure of the degree of cognitive impairment observed in a mammal. In humans, the level of cognitive impairment may be measured by various neuropsychological tests, alone or in combination, including, but not limited to, the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog); Global Deterioration Scale (GDS); the clinical global impression of change scale (CIBIC-plus scale); the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale (ADCS-ADL); the Mini Mental State Exam (MMSE); the Neuropsychiatric Inventory (NPI); the Clinical Dementia Rating Scale (CDR); the Rey Auditory Verbal Learning Test (AVLT), Logical Memory Subtest of the revised Wechsler Memory Scale (WMS-R); the New York University (NYU) Paragraph Recall Test the Cambridge Neuropsychological Test Automated Battery (CANTAB) or the Sandoz Clinical Assessment-Geriatric (SCAG).
In non-human mammalian models, for example, a rat or non-human primate model, the level of cognitive function may be measured by methods including, but not limited to, using a maze in which subjects use spatial information (e.g., Morris water maze, Barnes circular maze, elevated radial arm maze, elevated plus maze, T-maze and others), recognition tests using odor and novel objects, conditioning tests (e.g., fear conditioning, discrimination tasks, active avoidance, illuminated open-field, two-compartment exploratory test, second and third order conditioning tasks), and tests of higher level executive function (e.g., serial reaction time tests, delayed match and non-match to sample, and stimulus-reward associations including choices involving delayed reinforcement).
In addition, the level of cognitive function may be measured in mammals, including humans, using neuroimaging techniques, e.g., Positron Emission Tomography (PET), magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), Single Photon Emission Computed Tomography (SPECT), or any other imaging technique that allows one to measure brain function. The level of cognitive function in aging can be tested by any of the above methods using aged mammals.
“Microarray” or “macroarray” refers to an array (i.e. a matrix) that consist of a surface to which probes (e.g., cDNAs, mRNAs, oligonucleotides, peptides, polypeptides, proteins, antibodies or their equivalents) that correspond or are complementary to in sequence or bind to expressed gene products are bound at known or addressable positions. Each position represents a discrete binding site, e.g., a nucleic acid or nucleic acid analogue, to which a particular expressed gene product can specifically bind. Each array typically, but not necessarily, possesses binding sites for products of most or almost all of the expressed gene products in the mammal's genome. It may also be a representative of such genome. A microarray has a higher density of individual probe species or binding sites per area than a macroarray. A nucleic acid or analogue of a binding site can be, e.g., a synthetic oligomer, a full-length cDNA, a less-than full-length cDNA, an expressed sequence tag (EST) as part of a cDNA molecule, or a gene fragment, e.g., an oligonucleotide corresponding to an overlapping portion of a gene. Preferably, oligonucleotide probes are used. Most preferably, the Affymetrix RAT genome 230-2 array (or an equivalent) is used. The RAT genome 230-2 array contains more than 31,000 probe sets to transcripts from approximately 28,000 genes.
“Mild Cognitive Impairment” or “MCI” refers to a condition characterized by isolated memory impairment accompanied by no other cognitive abnormality and relatively normal functional abilities. One set of criteria for a clinical characterization of MCI specifies the following characteristics: (1) memory complaint (as reported by patient, informant, or physician), (2) normal activities of daily living (ADLs), (3) normal global cognitive function, (4) abnormal memory for age (defined as scoring more than 1.5 standard deviations below the mean for a given age), and (5) absence of indicators of dementia (as defined by DSM-IV guidelines). Petersen et al., Srch. Neurol. 56: 303-308 (1999); Petersen, “Mild cognitive impairment: Aging to Alzheimer's Disease.” Oxford University Press, N.Y. (2003).
Diagnosis of MCI usually entails an objective assessment of cognitive impairment, which can be garnered through the use of well-established neuropsychological tests, including the Mini Mental State Examination (MMSE), the Cambridge Neuropsychological Test Automated Battery (CANTAB) and individual tests such as Rey Auditory Verbal Learning Test (AVLT), Logical Memory Subtest of the revised Wechsler Memory Scale (WMS-R) and the New York University (NYU) Paragraph Recall Test. See Folstein et al., J Psychiatric Res 12: 189-98 (1975); Robbins et al., Dementia 5: 266-81 (1994); Kluger et al., J Geriatr Psychiatry Neurol 12:168-79 (1999).
“Non-human animal model” refers to a non-human mammal or other animal or organism useful for research.
“Non-parametric test” refers to a statistical test that does not rely on parametric assumptions such as normality. A non-parametric test is used in place of a parametric test when some assumptions about the underlying population are uncertain. In the present invention, a non-parametric test is used when the test or control population is sampled from a non-Gaussian distribution or when a gene's expressed gene product is too high or too low in abundance to be accurately determined.
One of skill in the art would appreciate that non-parametric tests rank the outcome variable from low to high and then analyze the ranks. Preferably, the non-parametric test used for comparing populations in accordance with this invention is selected from the group consisting of a Mann-Whitney U test, a Wilcoxon rank-sum test, a Wilcoxon matched pairs signed-rank test, a Mann-Whitney-Wilcoxon test, a Kruskal-Wallis analysis of variance by ranks, a Friedman two way analysis of variance and a Kolmogorov-Smirnov test. Preferably, the non-parametric test used for assessing the linear association (i.e. correlation) between variables is the Spearman rank correlation coefficient.
“Overexpressed”, “overexpression” or “increase” in expression refers to an abundance of an expressed gene product that is higher than the abundance of that same product under other conditions or in other cells or tissues. Overexpression or increased expression may be effected, for example, by one or more structural changes to the gene's encoding nucleic acid or encoded polypeptide sequence (e.g., primary nucleotide or amino acid changes or post-transcriptional modifications such as phosphorylation), altered gene regulation (e.g., in the promoters, regulators, repressors or chromatin structure of the gene), a chemical modification, an altered association with itself or another cellular component, an altered subcellular localization, a modification which causes higher levels of activity through association with other molecules in the cell (e.g., attachment of a targeting domain) and the like.
“Parametric test” refers to a statistical test that requires a parametric assumption, such as normality, i.e., the assumption that the data are sampled from a Gaussian distribution. Preferably, the parametric test, used when comparing levels of expression across populations, in accordance with this invention, is an analysis of variance (ANOVA). Preferably, the parametric test used for assessing the linear association (i.e. correlation) between variables is the Pearson correlation coefficient.
“P value” is the probability associated with an obtained statistic, such as an F-ratio or at statistic (see “ANOVA”, infra). If the p value is less than the significance level, preferably 0.05, then the result constitutes evidence against the null hypothesis, which states that there is no difference among a set of true population means.
“Plurality” refers to two or more.
“Significant” refers to a confidence level for a measurement being real as opposed to being due to chance, for example, as the result of a random sampling error. In accordance with this invention, significant means a confidence or significance level of at least 95%, wherein p<0.05. More preferably, a significance level of 99%, wherein p<0.01.
“Treatment” refers to the use of a compound to beneficially alter cognitive function in the treated mammal. A treatment, as used herein, is administered by providing a mammal with a compound by any appropriate means and in any appropriate formulation and dosing regime.
“Underexpressed”, “underexpression” or “decrease” in expression refers to an abundance of an expressed gene product that is lower than the abundance of the same product under other conditions or in other cells or tissues. Such underexpression or decreased expression may be effected, for example, by one or more structural changes to the gene's encoding nucleic acid or polypeptide sequence (e.g., primary nucleotide or amino acid changes or post-transcriptional modifications such as phosphorylation), altered gene regulation (e.g., in the promoters, regulators, repressors or chromatin structure of the gene), an altered structure (which causes reduced levels of activity), an altered association with itself or another cellular component, an altered subcellular localization, a modification which causes reduced levels of activity through association with other molecules in the cell (e.g., binding proteins which inhibit activity or sequestration) and the like.
“Young” or “Y” refers to one or more adolescent or adult mammals in or near the first third of their average lifespan, at or after the age of sexual maturity and when the hippocampus is fully mature. For example, a young human would be twenty-five years of age or less. A young rat would be ten months of age or less, and preferably at least four months of age.
Description of Various Claims of the Invention
This invention provides methods of identifying a gene or a plurality of genes associated with cognitive impairment in a mammal.
The method comprises providing three populations of mammals—AI, AU and Y—as defined above. Preferably, the mammals used in identifying the genes of this invention are rats and most preferably outbred rat strains.
CA1, CA3 and DG hippocampal tissue is prepared from each member of the three populations using conventional techniques. The abundance of the expressed gene products in each member of these populations is then determined using standard techniques. These techniques include microarray analysis, macroarray analysis, in situ hybridization histochemistry, fluorescent in situ hybridization (FISH), immunocytochemistry (ICC), enzyme linked immunosorbent assay (ELISA), immunoprecipitation, quantitative polymerase chain reaction (PCR), serial analysis of gene expression (SAGE) analysis, radioimmunoassay (RIA) and blot analysis. More preferably, microarray analysis is used.
Genes or a plurality of genes are then selected based on a significant change—decrease or increase—in the gene's expressed gene product (e.g., RNAs, proteins, polypeptides and peptides) in the AI population relative to the combined AU and Y populations or in the AU population relative to the combined AI and Y populations.
The significance of the change in the abundance of the expressed gene product is assessed using conventional statistical tests, including parametric and non-parametric tests. Preferably, the parametric test, ANOVA is used. Among the preferred non-parametric tests useful in this invention are a Mann-Whitney U test, a Wilcoxon rank-sum test, a Wilcoxon matched pairs signed-rank test, a Mann-Whitney-Wilcoxon test, a Kruskal-Wallis analysis of variance by ranks, a Friedman two way analysis of variance, and a Kolmogorov-Smirnov test.
The preferred selected genes or plurality of genes whose expressed gene products have increased abundances in CA1, CA3 or DG tissue are displayed in Tables 1, 3, 6, 7, 25, 27, 30, and 31; 9, 11, 14, 15, 33, 35, 38 and 39; or 17, 19, 22, 23, 41, 43, 46 and 47, respectively. Tables 1, 3, 9, 11, 17, 19, 25, 27, 33, 35, 41 and 43 depict the genes whose expressed gene products are increased in the AI populations relative to the combined AU and Y populations. Tables 6, 7, 14, 15, 22, 23, 30, 31, 38, 39, 46 and 47 depict the genes whose expressed gene products are increased in the AU population relative to the combined AI and Y populations.
The preferred selected genes or plurality of genes whose expressed gene products have decreased abundances in CA1, CA3 or DG tissue are displayed in Tables 2, 4, 5, 8, 26, 28, 29 and 32; 10, 12, 13, 16, 34, 36, 37 and 40; or 18, 20, 21, 24, 42, 44, 45 and 48, respectively. Tables 5, 8, 13, 16, 21, 24, 29, 32, 37, 40, 45 and 48 depict the genes whose expressed gene products are decreased in the AI population relative to the combined AU and Y populations. Tables —————— depict the genes whose expressed gene products are decreased in the AU population relative to the combined AI and Y populations.
In some elements of this invention, the change in the abundance—increase or decrease—of the expressed gene product(s) of the selected gene or plurality of genes is also correlated with the level of cognitive impairment in each member of the AU and AI populations. The increased or decreased abundances of the expressed gene products of the selected genes or plurality of genes positively or negatively, respectively, correlate with the learning index or cognitive impairment of the animals when poorer learners have higher or lower abundances, respectively. Thus, some of the genes in the above Tables, which depict the genes whose expressed gene products are increased in the AI population relative to the combined AU and Y populations or in the AU population relative to the combined AI and Y populations, will positively and negatively correlate, respectively, with cognitive impairment. See, e.g., Tables 1, 6, 9, 14, 17, 22, 25, 30, 33, 38, 41 and 46. Other genes whose expressed gene products are decreased in the AI population relative to the combined AU and Y populations or in the AU population relative to the combined AI and Y populations, will negatively or positively, correlate, respectively, with cognitive impairment. See, e.g., Tables 2, 5, 10, 13, 18, 21, 26, 29, 34, 37, 42 and 45.
A gene or a plurality of genes whose abundances of expressed gene product(s) have a significant positive or negative correlation with the learning index or level of cognitive impairment is then selected. The significance of the correlation is assessed using standard methods, including but not limited to parametric and non-parametric statistical tests. Preferably, the parametric Pearson correlation coefficient or the non-parametric Spearman ranked coefficient is used.
The preferred selected genes or plurality of genes, whose expressed gene products have increased abundances in CA1, CA3 or DG tissue and whose abundances positively or negatively, respectively correlate with the learning scores or cognitive impairment of the AI and AU outbred rat populations, are displayed in Tables 1, 6, 25 and 30; 9, 14, 33, 38; and 17, 22, 41 and 46, respectively.
The preferred selected genes or plurality of genes whose expressed gene products have decreased abundances in CA1, CA3 and DG tissue and whose abundances negatively or positively, respectively correlate with the learning scores or cognitive impairment of the AI and AU outbred rat populations are displayed in Tables 2, 5, 26 and 29; 10, 13, 34 and 37; and 18, 21, 42 and 45, respectively.
The Tables referred to above list the rat genes identified in the preferred claims of this invention by GENBANK® or “UniGene” accession numbers. GENBANK® is the National Institute of Health's genetic sequence database and provides an annotated collection of all publicly available DNA sequences (Nucleic Acids Research 33 (Database Issue):D34-D36 (2005)). GENBANK® is part of the International Nucleotide Sequence Database Collaboration, which comprises the DNA DataBank of Japan (DDBJ), the European Molecular Biology Laboratory (EMBL), and GENBANK® at the National Center for Biotechnology Information (NCBI). The actual rat nucleotide sequence of the accession numbers listed herein may be found by searching the GENBANK® database on the “Entrez Nucleotide” portal of the NCBI website. Each UniGene entry comprises a set of transcript sequences that appear to come from the same transcription locus (gene or expressed pseudogene), together with information on protein similarities, gene expression, cDNA clone reagents, and genomic location, and is also accessible on the NCBI website.
Non-rat mammalian homologues, including human homologues, of the selected genes may be determined in a variety of ways. For example, one method is to access the “HomoloGene” portal of the NCBI website. and enter the GENBANK® or UniGene accession number to obtain a listing of all HomoloGene listings showing the homologues in every identified species in which the gene is conserved, including humans. The link on the desired species will produce the Entrez gene listing, which will have a reference ID for the human sequence of the gene. Alternatively, the human homologue may be identified by directly accessing the above-listed Entrez Gene website and entering the rat GENBANK® accession number. A map viewer of the homologous chromosomes is then accessible via the gene link. The map viewer identifies the human homologues and a click on the gene symbol will access several databases, including the Entrez Gene Sequence viewer (sv), which provides genomic, protein and mRNA sequences; HomoloGene (hm), see above; and Consensus CDS (CODS), another gene identification database that contains several links to protein and sequences.
The genes, identified and selected, by the above methods, and those specific individual genes listed in the Tables above, and their homologues are useful in identifying compounds useful in the treatment of cognitive impairment, and preferably cognitive impairment in aging in accordance with this invention.
One method to identify a compound useful in treating cognitive impairment in mammals, particularly humans, in accordance with this invention, comprises the steps of determining the abundance of an expressed gene product in a mammalian cell of the mammalian cell's homologue(s) of a gene or a plurality of genes identified as described above or listed in Tables 1-48 in the presence or absence of a candidate compound.
The mammalian cells can be any species of cell, e.g., human cells, mouse cells, rat cells, non-human primate cells. The cells can be from any known or established mammalian cell line, such as those available from the American Type Culture Collection (ATCC; Mannassas, Va.), for example, CHO cells, HEK293 cells or COS7 cells. The cells can be in primary cell culture or from a transformed cell line. The cells may naturally express the gene product (i.e., the gene may be wholly endogenous to the cell or multicellular organism) or the cell may be a recombinant cell or transgenic organism comprising one or more recombinantly expressed gene products.
Preferably, the cells are of human origin and more preferably are selected from the group consisting of neuronal cells and glial cells, including but not limited to, oligodendrocytes, astrocytes, microglia, pyramidal cells, granule cells, motoneurons, and Purkinje cells. Methods for culturing neuronal cells are well known see, e.g., Brewer et al., J. Neuroscience Res. 35:567 (1993) [hippocampal neurons]; Walsh et al., Neuroscience 69:915-29 (1995) [suprachiasmatic neurons]; Zoran et al., Dev Biol. 179:212-22 (1996) [motoneuronal cultures]. Preferably, the neuronal cell is a hippocampal cell or line derived from the hippocampus or a hippocampal region. More preferably, the cell is selected from a CA1, CA3 or DG hippocampal cell.
A number of different screening protocols can be utilized to identify compounds that change the abundance of an expressed gene product of a mammalian cell's homologue(s) of a gene or a plurality of genes identified as described above or individually listed in the above Tables in the mammalian cells. In general terms, the methods include culturing the cells in the presence of individual members of a plurality of candidate compounds to identify a compound that significantly changes—increases or decreases—in the appropriate direction, as defined herein, the abundance of an expressed gene product of a mammalian cell's homologue(s) of a gene or a plurality of genes identified as described above or individually listed in the Tables 1-48.
For example, a compound that decreases the abundance or attenuates the function of an expressed gene product of a gene identified in the methods of this invention or listed in Tables 1, 3, 9, 11, 17, 19, 25, 27, 33, 35, 41 and 43 that was increased in the AI population as compared to the combined AU and Y populations would be useful in treating cognitive impairment. Similarly, a compound that increases the abundance or enhances the function of an expressed gene product of a gene identified in the methods of this invention or listed in Tables 2, 4, 10, 12, 18, 20, 26, 28, 34, 36, 42 and 44 that was decreased in the AI population as compared to the combined AU and Y population would be useful in treating cognitive impairment.
In contrast, a compound that decreases the abundance or attenuates the function of expressed gene products of at least one gene identified in the methods of this invention or listed in Tables 5, 8, 13, 16, 21, 24, 29, 32, 37, 40, 45 and 48 that was decreased in the AU populations as compared to the combined AI and Y populations would be useful in treating cognitive impairment. Similarly, a compound that increases the abundance or enhances the function of one or more expressed gene products of at least one gene identified in the methods of this invention or listed in Tables 6, 7, 14, 15, 22, 23, 30, 31, 38, 39, 46 and 47 that was increased in the AU population as compared to the combined AI and Y populations would be useful in treating cognitive impairment.
One or more compounds from among the candidate compounds are then selected based on the compound's ability to significantly change, in the appropriate direction, as defined herein, the abundance or function of the expressed gene product of a selected gene or plurality of genes in the cell treated with the compound. Preferably, one gene whose decreased abundance of expressed gene product significantly correlates (negatively) with the level of cognitive impairment is the GABA-A α5 receptor gene (corresponding to GENBANK® accession number NM—017295), as shown in Example 10 and Table 10 (CA3 AI ANOVA negative correlation) and its homologues. Preferably, compounds that can significantly increase the abundance or enhance the function of GABA-A α5 protein produced by the gene would be useful for treating cognitive impairment are (1) the GABA-A a5 receptor agonist QH-ii-066 (1-methyl-7-acetyleno-5-phenyl-1,3-dihydro-benzo[e]-1,4-diazepin-2-one), see, Platt et al., Contribution of α1GABAA and α5GABAA Receptor Subtypes to the Discriminative Stimulus Effects of Ethanol in Squirrel Monkeys, J. Pharmacol. Exp. Ther. 313: 658-667 (2005); (2) 6,6 dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one, corresponding to compound number 44 in Chambers et al., Identification of a Novel, Selective GABAA α5 Receptor Inverse Agonist Which Enhances Cognition, J. Med. Chem. 46:2227-2240 (2003); and (3) 8-ethylthio-3-methyl-5-(1-oxidopyridin-2-yl)-3,4-dihydronaphthalen-1(2H)-one, corresponding to compound number 19 in Szekeres et al., 3,4-Dihydronaphthalen-1(2H)-ones: novel ligands for the benzodiazepine site of alpha5-containing GABAA receptors. Bioorg. Med. Chem. Lett. 14:2871-2875 (2004).
Another method of identifying compounds useful in treating cognitive impairment assays the candidate compounds in mammals, preferably aged mammals, and more preferably aged mammals with cognitive impairment. In this element, the abundance or function of the expressed gene product of the mammal's homologue of a gene or plurality of genes selected in accordance with this invention or individually listed in the above Tables, is measured in hippocampal tissue, preferably CA1, CA3 or DG tissue of the mammal, to whom the candidate compound has been administered. Those compounds that cause a significant change—increase or decrease—in the appropriate direction, as defined herein, in that abundance or function in mammals treated with the compound are selected.
Compounds are selected that significantly change—increase or decrease—in the appropriate direction, as defined herein, the abundance or function of the expressed gene product of the mammal's homologue of a gene or plurality of genes selected in the method described above or individually listed in the above Tables in an aged mammal with cognitive impairment who has been treated with the compound, relative to a member of the group consisting of an aged mammal without cognitive impairment, a young mammal, an aged cognitively impaired mammal in the absence of the compound, and two or more of them. Preferably, the selected compound does not alter that abundance or function in a young mammal and/or an aged cognitively unimpaired mammal to whom the candidate compound is administered. Also preferably, the selected compound does not significantly alter the cognitive status of a young mammal and/or an aged cognitively unimpaired mammal to whom the candidate compound is administered.
The methods of this invention for identifying compounds useful in the treatment of cognitive impairment, and preferably that due to aging, also include assays based on the cognitive status of a mammal in the presence and absence of the candidate compound.
The cognitive status of a mammal, preferably an aged mammal and most preferably an aged cognitively impaired mammal, and more preferably a rat, is determined in the presence and absence of a candidate compound. The cognitive status of the mammal may be assessed using various functions. Preferably, the functions are hippocampal-dependent functions. More preferably, the functions are spatial memory acquisition, long-term spatial memory, and spatial memory retrieval.
It is preferable that the candidate compound be one that is believed to increase or decrease, in the appropriate direction, as defined herein, the abundance or function of an expressed gene product of the mammal's homologue of a gene or plurality of genes selected in the methods described above or listed in the Tables.
This belief may be based on actual experimental data using other elements of this invention or may be based on information in the scientific literature. A compound that beneficially alters the cognitive status of the treated animal is then selected as being useful in the treatment of cognitive impairment. Preferably, the selected compound beneficially alters the cognitive status in the treated mammal relative to a member of the group consisting of an aged mammal without cognitive impairment, a young mammal, an aged cognitively impaired mammal to whom the compound is not administered and two or more of them. Preferably, the compound does not significantly alter the cognitive status of young mammals or aged unimpaired mammals of the same species who are treated with the compound.
Candidate compounds for use in the methods of the invention include a wide variety of general types of well-known and available compounds including, but not limited to, small organic molecules (e.g., MW<1000, preferably <500); polypeptides; carbohydrates such as oligosaccharides and polysaccharides; polynucleotides; antibodies, lipids or phospholipids; fatty acids; steroids; amino acid analogs, and peptidomimetics. Candidate compounds can be obtained from libraries, such as natural product libraries and combinatorial libraries. A number of different libraries and collections containing large numbers of natural and synthetic compounds are commercially available and one of ordinary skill in the art would be familiar with methods for preparing and obtaining such libraries. Methods of automating assays are also known that permit screening of several thousands of compounds in a short period.
Compounds identified in accordance with the methods of this invention are useful in the treatment of cognitive impairment in mammals, preferably human, and preferably in methods of treating cognitive impairment in aged mammals, preferably humans. The particular compound from among the compounds selected by the methods of this invention to be used can be determined by those skilled in the art, and will depend, for example, on factors such as the severity of the cognitive impairment; the time period over which treatment of the cognitive impairment is desired; whether the compound is administered in a clinical setting or by the individual; or whether an individual suffers from age-related cognitive impairment.
Compounds, selected in accordance with this invention for use in treating cognitive impairment, and particularly that due to aging, or for use in the screening methods of this invention, can be formulated in pharmaceutical compositions in such a manner to ensure proper distribution in vivo. For example, the blood-brain barrier excludes many highly hydrophilic compounds. To ensure that the selected compounds the blood-brain barrier, they can be formulated, for example, in liposomes, or chemically derivatized. A wide variety of carriers can be used to facilitate targeted drug delivery across the blood-brain barrier to brain tissues, preferably the hippocampus, including but not limited to the use of liposomes, nanoparticles, microparticles, microspheres, encapsulated microbubbles or similar structures which envelope biologically or pharmaceutically active agents, carrier molecules including polymers, and protein including hydrophile proteins.
Administration of a selected compound, or candidate compound(s) to be screened can be in a single dose, or in multiple doses. An effective amount of a compound can be determined by those skilled in the art, and can depend on the chemical and biological properties of the compound and the method of contacting the subject. Typically between 0.1 and 1000 mg/kg is administered daily, for one or more days.
Administration of the compound can be carried out using one of a variety of methods known to those of skill in the art. For example, a compound can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitonealy, intravenously, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorbtion, e.g., through a skin duct). A compound can also appropriately be introduced by rechargeable or biodegradable polymeric devices, which provide for the slow release or controlled delivery of drugs.
Appropriate methods of administering a compound to a mammal will also depend, for example, on the age of the mammal, whether the mammal is active or inactive at the time of administering, whether the mammal is cognitively impaired at the time of administering, and the chemical and biological properties of the compound (e.g. solubility, digestibility, bioavailability, stability and toxicity). Preferably, a compound is administered orally, e.g., to a mammal by ingestion, where the compound is dissolved in food and provided to the mammal at mealtime.
Pharmaceutical compositions for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art in dosages suitable for oral administration that enable the compositions to be formulated as, e.g., tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like. Other appropriate routes of administration and doses of the compound can be determined by those skilled in the art.
It will be understood that the efficacy and safety of a compound in laboratory mammals can be evaluated before administering the compound to humans. For example, the compound can be tested for its maximal efficacy and any potential side-effects using several different non-human mammals, across a range of doses, in a range of formulations, and at various times of day, such as before or after sleeping, before or after eating, and the like. Preferably, the compound selected by the methods of the invention will cause few or no deleterious or unwanted side effects in any of the test populations. More preferably, the compound will cause few or no deleterious side effects in the mammal whose cognitive status is beneficially altered by the administration of the compound. Most preferably, the compound will cause few or no deleterious side effects in an aged cognitively impaired mammal to which the compound is administered.
Illustrative methods of this invention are described in the following Examples. Methods and materials similar or equivalent to those described can also be used in the practice of the present invention and will be apparent to those of skill in the art. The materials, methods, and examples are thus illustrative only and not intended to be limiting.
EXAMPLES
We performed the following examples using rats of an outbred strain behaviorally characterized as described in more detail below into one of three groups: Y, AU and AI.
Behavioral Characterization of Rats
We performed behavioral tests on 9 young (4-6 months) and 18 aged (25-27 months) pathogen-free male outbred Long-Evans rats with the Morris Water Maze (MWM) protocol. An additional 10 aged rats were tested in the MWM, followed by training and testing in the Radial Arm Maze to assess test-retest reliability for individual differences in cognitive function across the two tasks.
Morris Water Maze Apparatus
In the MWM assay, rats learn and remember the location of an escape platform guided by a configuration of spatial cues surrounding the maze. See, Morris, Learning and Motivation 12:239-260 (1981). The cognitive basis of performance is tested in probe trials using measures of the animal's spatial bias in searching for the location of the escape platform. Aged rats in the study population have no difficulty swimming to a visible platform, but an age-dependent cognitive impairment can be detected when the platform is camouflaged, requiring the use of spatial information.
When reassessed using the MWM in a new spatial environment several weeks after the original characterization, the AI animals are consistently impaired, whereas the AU animals again perform proficiently. Colombo et al., Proc. Natl. Acad. Sci. USA, 94:14195-99 (1997). The difference in cognitive ability in the MWM assessment for AI and AU rats is reliable even over an interval of 3 months. See, Gallagher and Burwell, Neurobiol. Aging 10:691-708 (1989). Further, AI and AU characterization in the MWM differentiates the performance of the same aged subjects in other behavioral tasks that require the same cognitive function, such as the Barnes circular maze, and the radial arm maze (RAM). This naturally occurring impairment in an aged population of rodents indicates that cognitive aging is not inevitable or strictly linked to chronological age, and, importantly, it affords the opportunity to compare the trajectory of changes in the brain that lead to decline or preserved memory.
The MWM apparatus consists of a large, circular pool (diameter 1.83 m; height, 0.58 m) filled with water (27° C.) that has been made opaque through the addition of non-toxic pigment or some other substance. In the typical “hidden platform” version of the task, rats are trained to find a camouflaged white escape platform (height, 34.5 cm) that is positioned in the center of one quadrant of the maze just 1.0 cm below the water surface. This platform can be retracted to the bottom of the tank or raised to its normal position from outside the maze during behavioral testing. The location of this platform remained constant from trial to trial. Because there were no local cues that marked the position of the platform, the rat's ability to locate it efficiently from any starting position at the perimeter of the pool depended on using information surrounding the maze. The maze was surrounded by black curtains with white patterns affixed to provide a configuration of spatial cues.
A second platform (height 37.5 cm) with its surface painted black was elevated 2 cm above the water surface during cue training, the version of the task used to control for factors unrelated to cognition. The behavior of a rat in the pool was recorded by a camera suspended 2.5 m above the center of the pool, connected to a video tracking system (HVS Image Advanced Tracker VP200) and a PC computer running HVS software developed by Richard Baker of HVS Image, Hampton, UK.
Morris Water Maze Procedure
We optimized the MWM protocol for sensitivity to the effects of aging on cognition and for measures of reliable individual differences within the aged population of outbred Long-Evans rats (Gallagher et al., Behav. Neurosci. 107:618-626 (1993)).
Rats received three trials per day for 8 consecutive days, using a 60 second inter-trial interval. On each training trial, the rat was released in the maze from one of four equally spaced starting positions around the perimeter of the pool. The starting position varied from trial to trial, thus preventing the use of a response strategy (e.g. always turning left from the start location to locate the escape platform). If a rat did not locate the escape platform within 90 sec on any trial, the experimenter guided the rat to the platform, where it remained for 30 sec. Every sixth trial consisted of a probe trial to assess the development of spatial bias in the maze. During these trials, the rat swam with the platform retracted to the bottom of the pool for 30 sec, at which time the platform was raised to its normal position for completion of an escape trial. At the completion of the protocol using the hidden platform, rats were assessed for cue learning using the visible platform. The location of this platform varied from trial to trial in a single session of 6 training trials.
We used the proximity of the animal's position with respect to the goal for analysis of training trial and probe trial performance. The proximity measure was obtained by sampling the position of the animal in the maze (10×/sec) to provide a record of distance from the escape platform in 1 sec averages. For both probe trials and training trials, a correction procedure was implemented so that trial performance was relatively unbiased by differences in distance to the goal from the various start locations at the perimeter of the pool. In making this correction the average swimming speed was calculated for each trial (path length/latency). Then, the amount of time required to swim to the goal at that speed from the start location used in the trial was removed from the record prior to computing trial performance, i.e. cumulative distance on training trials and average distance from the goal on probe trials. Thus, scores obtained using the proximity measure are designed to reflect search error, representing deviations from an optimal search, i.e. direct path to the goal and search in the immediate vicinity of that location during probe trials.
Morris Water Maze Analysis
Computer records of video-tracking were compiled to provide data on each rat's performance in the maze. Measures on training trials and probe trials were analyzed by ANOVA.
Morris Water Maze Data Results
The performance during training with the hidden, camouflaged platform differed between the groups of young and aged rats [F(1,23)=12.69, p<0.002]. No difference between the groups occurred for the cue training trials with a visible platform. Latencies to escape during cue training averaged 9.36 seconds for young and 10.60 seconds for the aged rats.
The average proximity measure on interpolated probe trials was used to calculate a spatial learning index for each individual subject as described in detail in Gallagher et al., Behav. Neurosci. 107:618-626 (1993). When a rat rapidly learned to search for the platform close to its position, its spatial learning index is low. Overall, aged rats differed from young [F(1,23)=15.18, p<0.001]. Aged rats were classified as either AU or AI relative to the learning index profile of the young study population. Aged rats that fall within the normative range of young rats (index scores<241) were designated AU. The remaining aged subjects that have index scores outside the range of young performance were designated AI.
Radial Arm Maze Apparatus
Each arm (7×75 cm) of the elevated eight arm radial arm maze (RAM) projected from each facet of an octagonal center platform (30 cm diameter, 51.5 cm height). Clear side walls on the arms were 10 cm high and were angled at 65° to form a trough. A food well (4 cm diameter, 2 cm deep) was located at the distal end of each arm. Blocks constructed of Plexiglas (30 cm H×12 cm W) could be positioned to block entry to any arm. Numerous extra maze cues were provided in the room surrounding the apparatus and overhead fixtures provided lighting.
Radial Arm Maze Procedures
Rats were first habituated to the maze for an 8 min session on four consecutive days. In each of these sessions food rewards were scattered on the RAM, initially on the center platform and arms and then progressively confined to the arms. After this habituation phase, a standard training protocol was used in which a food pellet was located at the end of each arm. Rats received one trial each day for 18 days; each daily trial terminated when all eight food pellets had been obtained or when either 16 choices were made or 15 min had elapsed. An error consisted of returning to an arm (all four paws on the arm) from which food had already been obtained.
After completion of this phase, the memory demand of the task was increased by imposing a delay during the trial. At the beginning of each trial three arms were blocked. The identity and configuration of the blocked arms was varied across trials. Rats were allowed to obtain food on the five arms to which access was permitted at the beginning of the trial. The rat was then removed from the maze for 60 seconds, during which time the barriers on the maze were removed, thus allowing access to all eight arms. Rats were then placed back onto the center platform and allowed to obtain the remaining food rewards.
Radial Arm Maze Analysis
A memory error occurred during test trials using a 60 second delay when a rat returned to one of the five arms that were already visited prior to the delay. Each rat's performance was averaged across four consecutive test trials. Parametric statistics (unpaired t-tests) were used to compare performance between young and aged groups. Correlational analysis (Pearson's r) was used to examine the relationship between performance of aged rats (N=10) in the MWM (learning index scores) and RAM (memory errors).
Radial Arm Maze Results
The performance of young adult rats in the delay version of the RAM varies as a function of the delay interval, ranging from 60 seconds to eight hours (Chappell et al. Neuropharmacology 37: 481-488, (1998)). Aged rats previously characterized in the MWM, committed more memory errors after a 60 second delay relative to young rats (p<0.025). On average young rats committed 0.17 errors, whereas aged rats committed an average of 1.52 errors. The ten aged rats, however, exhibited a wide range of performance on the RAM. A significant relationship was found between the initial MWM characterization and memory performance in the RAM (r value=0.82).
Gene Expression Analysis
We then analyzed the gene expression profiles in the CA1, CA3 or DG hippocampal regions. We determined the abundance of a plurality of expressed gene products in CA1, CA3 or DG hippocampal tissue from each mammal of the three populations—AI, AU and Y. We selected those genes, the abundance of whose expressed gene products was significantly increased or decreased in the AI population as compared to the combined Y and AU populations or significantly increased or decreased in the AU population as compared to the combined Y and AI populations. These genes may relate specifically to age-related cognitive impairment.
We selected from the above genes those whose increased or decreased abundance of expressed gene product(s) showed a significant correlation with the level of cognitive impairment in the AU and AI populations.
These analyses are described below.
Preparation of RNA from Behaviorally Characterized Rats
Twenty-four outbred Long-Evans rats, behaviorally characterized as described above, were killed by live decapitation to obtain fresh brain tissue. The brain was removed, the hippocampus dissected and the CA1, CA3 or DG hippocampal region was microdissected from 500 micron sections taken through the transverse axis of the entire hippocampal formation (both left and right hippocampi) of 24 characterized rats. There were 8 animals in each group (AI, AU and Y) and the CA1, CA3 or DG region of each animal was processed independently.
Total RNA was isolated using Trizol reagent (Invitrogen, Carlsbad, Calif.) according to the standard protocol (homogenization in Trizol reagent followed by chloroform extraction and isopropanol precipitation). Total RNA was further purified using the RNeasy mini kit (Qiagen, Valencia, Calif.). cRNA probes were then generated from the RNA samples at The Johns Hopkins Microarray Core Facility, generally according to Affymetrix specifications as detailed herein.
Briefly, 5 micrograms of total RNA were used to synthesize first strand cDNA using oligonucleotide probes with 24 oligo-dT plus T7 promoter as primer (Proligo LLC, Boulder, Calif.), and the SuperScript Choice System (Invitrogen). Following the double stranded cDNA synthesis, the product was purified by phenol-chloroform extraction, and biotinilated anti-sense cRNA was generated through in vitro transcription using the BioArray RNA High Yield Transcript Labeling kit (ENZO Life Sciences Inc., Farmingdale, N.Y.). 15 ug of the biotinilated cRNA was fragmented at 94° C. for 35 min (100 mM Trix-acetate, pH 8.2, 500 mM KOAc, 150 mM MgOAC). Hug of total fragmented cRNA was hybridized to the RAT genome 230-2 Affymetrix GeneChip array for 16 hours at 45° C. with constant rotation (60 rpm). The cRNA prepared from the CA1, CA3 or DG regions for each animal were hybridized to an individual microarray.
Affymetrix Fluidics Station 450 was then used to wash and stain the chips, removing the non-hybridized target and incubating with a streptavidin-phycoerythrin conjugate to stain the biotinilated cRNA. The staining was then amplified using goat immunoglobulin-G (IgG) as blocking reagent and biotinilated anti-streptavidin antibody (goat), followed by a second staining step with a streptavidin-phycoerythrin conjugate.
For quality control of the total RNA from the samples, the Agilent Bioanalyzer, Lab on a Chip technology, was used to confirm that all the samples had optimal rRNA ratios (1:2, for 18S and 28S, respectively) and clean run patterns.
For quality control of the hybridization, chip image, and comparison between chips, the following parameters were considered: Scaling factor: related to the overall intensity of the chip, to confirm the similar signal intensity and staining through out the samples; Background: estimation of unspecific or cross-hybridization; Percentage of present calls (for “MAS5” analysis only, see infra, Data Analysis of Microarray): percentage of transcripts that are considered significantly hybridized to the chip (present) by the algorithm; Glyseraldehyde-3-phosphate dehydrogenase (GAPDH) (3′/5′): representation of the RNA integrity by measuring the ratio of 3′ to 5′ regions for the housekeeping gene GAPDH, its presence in the chip and a ratio close to 1 advocates for a good integrity of the target (sample); Spikes (BioB/BioC) to confirm the detection level and sensitivity after hybridization.
Data Analysis of Microarray
Fluorescence was detected using the Affymetrix G3000 GeneArray Scanner and image analysis of each GeneChip was done through the GeneChip Operating System 1.1.1 (GCOS) software from Affymetrix, using the standard default settings. All of the GeneChip arrays use short oligonucleotides to probe for genes in an RNA sample.
For comparison between different chips, global scaling was used, scaling all probe sets to a user defined target intensity (TGT) of 150. Two different methods were used to estimate the relative expression of genes in different RNA samples. Examples 1-24 processed and summarized the probe set data by “MAS5” analysis. Examples 25-48 processed and summarized the probe set data by “gcRMA” analysis.
The first method, the MAS5 statistical method, produces absolute and comparison analysis results for GeneChip expression arrays. Mas5 employs a statistical algorithm that performs a background adjustment by making regional adjustments or “calls”. This process makes expression level calls as to whether a particular probe set is present or absent. (See, Affymetric statistical algorithm description document, available on the Affymetrix website.)
In Examples 1-24, the total number of present calls and scaling factors were similar across all chips (normalization was scaled by a constant). Further analysis for presence/absence and statistical difference was performed on a region by region basis in the following manner. Probe sets were determined to be present in a region if it had a present call in four of eight animals in a single group, as per the standard MAS5 default settings using Affymetrix software.
The second method used to process and summarize the probe set data was “gcRMA” analysis. This statistical method employs background adjustment by estimating a global signal over the entire probe set and making a whole array adjustment, using quantile normalization. GcRMA is an open-source method that is based on robust averaging techniques and sequence-dependent affinity corrections. The robust averaging employed in gcRMA confers a strong immunity to outliers. See, Wu et al. A Model Based Background Adjustement for Oligonucleotide Expression Arrays. Journal of American Statistical Association. 99:909-917 (2004).
In Examples 25-48, gcRMA analysis was used to perform background and normalization processing, which coupled all the genes together, as did the MAS5 analysis in Examples 1-24. Further analysis for statistical difference included performing a background subtraction. Mismatched sequences (11 for each probe set) were ignored and only the perfect match sequences were considered. There was no elimination of genes based on present/absent calls. See, Quin et al., Evaluation of methods for oligonucleotide array data via quantitative real-time PCR. BMC Bioinformatics, 7:23 (2006).
For Examples 25-48, probe sets were annotated using the most recent Affymetrix annotation of April 2006 and all probe sets representing a specific gene were identified. For Examples 1-24, probe sets were annotated using the Affymetrix annotations of Jun. 20, 2005.
The probe set signal values were then analyzed in the following Examples by various statistical methods to identify those genes or plurality of genes expressed gene products that significantly changed in abundance—increase or decrease—and to identify those genes whose increased or decreased expression product(s) abundance correlated to cognitive impairment.
Example 1
An ANOVA was conducted on the probe set signal values for all present probe sets by combining two groups of animals and comparing them to the third group. An “AI ANOVA” was performed, where Aged Unimpaired were combined with Young and compared to Aged Impaired. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Pearson's correlations comparing probe set signal values to learning indices were then calculated for the aged animals (excluding young) across all present probe sets. Again, correlations representing a p-value of less than 0.05 were considered significantly changed.
Microarray Results
Table 1 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 1





CA1 - AI ANOVA POSITIVE CORRELATION

















GENBANK ® ID



BI295776



AA963364



AY190520



NM_001002016



NM_001005534



NM_001008374



NM_001008862



NM_001012177



NM_001013112



NM_012543



NM_012577



NM_012650



NM_012918



NM_013001



NM_013157



NM_017068



NM_017223



NM_017347



NM_019212



NM_019289



NM_019305



NM_019359



NM_019362



NM_021657



NM_022244



NM_022261



NM_022617



NM_023981



NM_024138



NM_030863



NM_031037



NM_031147



NM_031818



NM_053418



NM_053485



NM_053525



NM_053536



NM_053669



NM_053774



NM_053896



NM_053910



NM_057103



NM_080887



NM_130413



NM_133621



NM_134390



NM_145674



NM_172038



NM_173325



NM_175582



NM_198738



NM_198759



NM_207602



NM_212528



XM_214769



XM_214968



XM_215095



XM_216004



XM_221231



XM_224538



XM_230616



XM_235566



XM_237000



XM_243637



XM_340967



XM_343773



XM_344524



XM_345140



XM_575962



UniGene ID



Rn.110441



Rn.11453










The genes in this set show abundance of expressed gene product(s) in the Aged Impaired population that are significantly increased, as determined by ANOVA, compared to those abundances in Young and Aged Unimpaired populations combined. In addition, the abundance of expressed gene product(s) in the aged animals positively correlate with learning index of the animals, such that poorer learners have higher abundances of expressed gene products of the selected genes. Therefore, compounds useful in treating cognitive impairment selected using these genes should decrease the abundance or attenuate the function of the expressed gene products of these genes.
Example 2
An ANOVA was conducted on the probe set signal values for all present probe sets by combining two groups of animals and comparing them to the third group. An “AI ANOVA” was performed, where Aged Unimpaired were combined with Young and compared to Aged Impaired. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Pearson's correlations comparing probe set signal values to learning indices were then calculated for the aged animals (excluding young) across all present probe sets. Again, correlations representing a p-value of less than 0.05 were considered significantly changed.
Microarray Results
Table 2 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 2





CA1 - AI ANOVA NEGATIVE CORRELATION

















GENBANK ® ID



BG381750



NM_001004210



NM_001004279



NM_001004442



NM_001011955



NM_001012035



NM_001013178



NM_001024765



NM_012919



NM_013083



NM_013086



NM_017322



NM_020078



NM_022395



NM_022867



NM_022934



NM_024000



NM_030861



NM_031699



NM_031707



NM_031730



NM_031821



NM_053328



NM_053402



NM_053434



NM_053686



NM_053748



NM_053883



NM_133563



NM_134383



NM_134408



NM_138838



NM_139091



NM_153472



NM_172332



NM_173133



NM_199091



XM_214043



XM_214245



XM_214428



XM_214836



XM_215812



XM_215883



XM_216102



XM_216884



XM_217464



XM_217893



XM_218502



XM_218506



XM_220281



XM_220629



XM_221635



XM_222773



XM_223693



XM_226779



XM_232995



XM_235878



XM_236914



XM_341663



XM_342044



XM_342920



XM_343059



XM_343154



XM_343581



UniGene ID



Rn.101929










The genes in this set show abundance of expressed gene product(s) in the Aged Impaired population that are significantly decreased, as determined by ANOVA, compared to those abundances in Young and Aged Unimpaired populations combined. In addition, the abundance of expressed gene product(s) in the aged animals negatively correlate with learning index of the animals, such that poorer learners have lower abundances of expressed gene products of the selected genes. Therefore, compounds useful in treating cognitive impairment selected using these genes should increase the abundance or enhance the function of the expressed gene products of these genes.
Example 3
An ANOVA was conducted on the probe set signal values for all present probe sets by combining two groups of animals and comparing them to the third group. An “AI ANOVA” was performed, where Aged Unimpaired were combined with Young and compared to Aged Impaired. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Microarray Results
Table 3 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 3





CA1 - AI ANOVA INCREASE

















GENBANK ® ID



AJ249701



NM_017154



AW528959



AF452647



NM_001002835



NM_001004209



NM_001005539



NM_001005565



NM_001007654



NM_001007682



NM_001007749



NM_001009651



NM_001011890



NM_001011934



NM_001011946



NM_001011974



NM_001011993



NM_001012069



NM_001012097



NM_001012141



NM_001012154



NM_001012351



NM_001013086



NM_001013118



NM_001013121



NM_001013179



NM_001013238



NM_001015004



NM_012488



NM_012512



NM_012523



NM_012562



NM_012654



NM_012671



NM_012703



NM_012749



NM_012771



NM_012823



NM_012838



NM_012884



NM_012899



NM_012984



NM_013015



NM_013055



NM_013091



NM_013096



NM_013107



NM_013198



NM_017009



NM_017109



NM_017169



NM_017181



NM_017209



NM_017320



NM_017351



NM_017356



NM_019238



NM_019278



NM_019335



NM_019363



NM_019620



NM_021576



NM_021690



NM_022390



NM_022500



NM_022502



NM_022512



NM_022526



NM_022531



NM_022864



NM_022948



NM_024155



NM_024387



NM_030992



NM_031153



NM_031357



NM_031509



NM_031552



NM_031640



NM_031714



NM_031797



NM_031798



NM_053021



NM_053314



NM_053323



NM_053424



NM_053455



NM_053492



NM_053502



NM_053516



NM_053538



NM_053612



NM_053639



NM_053818



NM_054001



NM_057107



NM_057120



NM_057123



NM_057185



NM_057197



NM_080890



NM_130409



NM_130428



NM_133298



NM_133392



NM_133393



NM_133548



NM_133605



NM_134334



NM_134349



NM_134407



NM_134410



NM_138508



NM_138521



NM_138539



NM_138826



NM_139060



NM_139110



NM_139185



NM_139192



NM_139256



NM_145775



NM_153315



NM_153621



NM_173095



NM_173118



NM_173123



NM_173141



NM_175578



NM_175756



NM_176077



NM_178095



NM_182821



NM_199404



NM_207591



NM_212466



XM_213329



XM_213574



XM_213610



XM_214250



XM_214298



XM_214403



XM_214518



XM_215037



XM_215578



XM_215935



XM_216367



XM_216565



XM_216665



XM_216882



XM_217252



XM_217470



XM_219447



XM_220264



XM_221369



XM_221387



XM_223080



XM_223087



XM_223190



XM_223781



XM_223785



XM_224337



XM_225885



XM_227701



XM_228073



XM_229225



XM_230296



XM_231120



XM_231287



XM_232531



XM_232671



XM_234483



XM_237049



XM_341081



XM_341509



XM_342291



XM_342331



XM_342794



XM_343057



XM_343126



XM_343159



XM_343259



XM_343310



XM_343640



XM_343650



XM_573983



XM_576401



XM_579460



XM_579675



UniGene ID



Rn.116787



Rn.129174



Rn.24948










The genes in this set show abundance of expressed gene product(s) in the Aged Impaired population that are significantly increased, as determined by ANOVA, compared to those abundances in Young and Aged Unimpaired populations combined. Therefore, compounds useful in treating cognitive impairment selected using these genes should decrease the abundance or attenuate the function of the expressed gene products of these genes.
Example 4
An ANOVA was conducted on the probe set signal values for all present probe sets by combining two groups of animals and comparing them to the third group. An “AI ANOVA” was performed, where Aged Unimpaired were combined with Young and compared to Aged Impaired. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Microarray Results
Table 4 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 4





CA1 - AI ANOVA DECREASE

















GENBANK ® ID



AI231320



BF284573



BF392810



NM_001002289



NM_001004133



NM_001004284



NM_001009605



NM_001009953



NM_001011901



NM_001011964



NM_001011998



NM_001012011



NM_001012078



NM_001012144



NM_001012179



NM_001012214



NM_001012473



NM_001013036



NM_001013096



NM_001013244



NM_001013910



NM_001014793



NM_012527



NM_012550



NM_012561



NM_012573



NM_012576



NM_012769



NM_012911



NM_012985



NM_013102



NM_017041



NM_017074



NM_017204



NM_017242



NM_017318



NM_017336



NM_019169



NM_019211



NM_020306



NM_021597



NM_021697



NM_021850



NM_022252



NM_022254



NM_022289



NM_022548



NM_031036



NM_031318



NM_031325



NM_031514



NM_031560



NM_031740



NM_031745



NM_031753



NM_031777



NM_032085



NM_053375



NM_053401



NM_053410



NM_053441



NM_053483



NM_053772



NM_053849



NM_053868



NM_053933



NM_057196



NM_057200



NM_080411



NM_080582



NM_080902



NM_133406



NM_133425



NM_133429



NM_138837



NM_138849



NM_138866



NM_138887



NM_144758



NM_172034



NM_173145



NM_181380



NM_184051



NM_198726



NM_212520



U57097



X53232



XM_213426



XM_213679



XM_213906



XM_213954



XM_214454



XM_214668



XM_215566



XM_216158



XM_216656



XM_217115



XM_218828



XM_219128



XM_221496



XM_221888



XM_221962



XM_222251



XM_222661



XM_222726



XM_224707



XM_224929



XM_225220



XM_226888



XM_230449



XM_232220



XM_236932



XM_239171



XM_239260



XM_341157



XM_341239



XM_341391



XM_341712



XM_341745



XM_342107



XM_342344



XM_342600



XM_342808



XM_343046



XM_343175



XM_343761



XM_344594



XM_345861



XM_345981



UniGene ID



Rn.122667



Rn.15446



Rn.48866










The genes in this set show abundance of expressed gene product(s) in the Aged Impaired population that are significantly decreased, as determined by ANOVA, compared to those abundances in Young and Aged Unimpaired populations combined. Therefore, compounds useful in treating cognitive impairment selected using these genes should increase the abundance or enhance the function of the expressed gene products of these genes.
Example 5
An ANOVA was conducted on the probe set signal values for all present probe sets by combining two groups of animals and comparing them to the third group. An “AU ANOVA” was performed, where Aged Impaired were combined with Young and compared to Aged Unimpaired. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Pearson's correlations comparing probe set signal values to learning indices were then calculated for the aged animals (excluding young) across all present probe sets. Again, correlations representing a p-value of less than 0.05 were considered significantly changed.
Microarray Results
Table 5 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 5





CA1 - AU ANOVA POSITIVE CORRELATION

















GENBANK ® ID



AI145040



NM_001007629



NM_001012028



NM_012546



NM_019152



NM_022177



NM_022286



NM_022858



NM_022946



NM_080692



NM_138515



NM_139260



NM_172041



XM_213564



XM_214003



XM_222245



XM_233462



XM_341100



XM_341558



XM_342548



XM_343468



XM_343764



XM_346061



UniGene ID



Rn.36521










The genes in this set show abundance of expressed gene product(s) in the Aged Unimpaired population that are significantly decreased, as determined by ANOVA, compared to those abundances in Young and Aged Impaired populations combined. In addition, the abundance of expressed gene product(s) in the aged animals positively correlate with learning index of the animals, such that poorer learners have higher abundances of expressed gene products of the selected genes. Therefore, compounds useful in treating cognitive impairment selected using these genes should decrease the abundance or attenuate the function of the expressed gene products of these genes.
Example 6
An ANOVA was conducted on the probe set signal values for all present probe sets by combining two groups of animals and comparing them to the third group. An “AU ANOVA” was performed, where Aged Impaired were combined with Young and compared to Aged Unimpaired. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Pearson's correlations comparing probe set signal values to learning indices were then calculated for the aged animals (excluding young) across all present probe sets. Again, correlations representing a p-value of less than 0.05 were considered significantly changed.
Microarray Results
Table 6 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 6





CA1 - AU ANOVA NEGATIVE CORRELATION


GENBANK ® ID

















NM_001002830



NM_001012034



NM_001012036



NM_012806



NM_017126



NM_019249



NM_019361



NM_021754



NM_031058



NM_031315



NM_032083



NM_053578



NM_080584



NM_175604



NM_182844



NM_199397



NM_199463



XM_214033



XM_215528



XM_218041



XM_218963



XM_221213



XM_225253



XM_226334



XM_228197



XM_237115



XM_341694



XM_342580



XM_343228










The genes in this set show abundance of expressed gene product(s) in the Aged Unimpaired population that are significantly increased, as determined by ANOVA, compared to those abundances in Young and Aged Impaired populations combined. In addition, the abundance of expressed gene product(s) in the aged animals negatively correlate with learning index of the animals, such that poorer learners have lower abundances of expressed gene products of the selected genes. Therefore, compounds useful in treating cognitive impairment selected using these genes should increase the abundance or enhance the function of the expressed gene products of these genes.
Example 7
An ANOVA was conducted on the probe set signal values for all present probe sets by combining two groups of animals and comparing them to the third group. An “AU ANOVA” was performed, where Aged Impaired were combined with Young and compared to Aged Unimpaired. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Microarray Results
Table 7 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 7





CA1 - AU ANOVA INCREASE


GENBANK ® ID

















NM_001004256



NM_001007797



NM_001008317



NM_001008509



NM_001008515



NM_001008556



NM_001008876



NM_001009619



NM_001011953



NM_001011979



NM_001012105



NM_001012131



NM_001013110



NM_001013151



NM_001013201



NM_001013210



NM_001013213



NM_001015003



NM_001015015



NM_012935



NM_012992



NM_013088



NM_013150



NM_016994



NM_017000



NM_017031



NM_017137



NM_017271



NM_017303



NM_017306



NM_017313



NM_019251



NM_019257



NM_020092



NM_021266



NM_022215



NM_022270



NM_022545



NM_022921



NM_024125



NM_031087



NM_031623



NM_031694



NM_032065



NM_053662



NM_053842



NM_053876



NM_053901



NM_057101



NM_130740



NM_131911



NM_133411



NM_134326



NM_134395



NM_138536



NM_139253



NM_145084



NM_145092



NM_153303



NM_153475



NM_175762



NM_175764



NM_199117



NM_199118



NM_212496



NM_213565



U77829



XM_213883



XM_214163



XM_215283



XM_215733



XM_215947



XM_216225



XM_216968



XM_217388



XM_218648



XM_218816



XM_219885



XM_221307



XM_221656



XM_221787



XM_227674



XM_232413



XM_236263



XM_236911



XM_237828



XM_341742



XM_341803



XM_342154



XM_342459



XM_342579



XM_342591



XM_343619



XM_344606



XM_345421



XM_573903



XM_575860



XM_576437










The genes in this set show abundance of expressed gene product(s) in the Aged Unimpaired population that are significantly increased, as determined by ANOVA, compared to those abundances in Young and Aged Impaired populations combined. Therefore, compounds useful in treating cognitive impairment selected using these genes should increase the abundance or enhance the function of the expressed gene products of these genes.
Example 8
An ANOVA was conducted on the probe set signal values for all present probe sets by combining two groups of animals and comparing them to the third group. An “AU ANOVA” was performed, where Aged Impaired were combined with Young and compared to Aged Unimpaired. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Microarray Results
Table 8 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 8





CA1 - AU ANOVA DECREASE

















GENBANK ® ID



AI236198



NM_001004446



NM_001007150



NM_001008279



NM_001013071



NM_001013122



NM_012545



NM_012648



NM_012762



NM_012784



NM_012808



NM_013197



NM_017061



NM_019159



NM_021671



NM_021703



NM_022250



NM_022609



NM_022676



NM_022853



NM_023972



NM_030988



NM_031018



NM_031654



NM_052983



NM_053428



NM_053788



NM_053797



NM_053811



NM_053859



NM_053893



NM_053996



NM_080394



NM_080580



NM_130430



NM_131906



NM_133313



NM_133400



NM_138854



NM_207592



XM_214963



XM_220884



XM_220982



XM_221273



XM_223768



XM_232640



XM_234901



XM_340775



XM_340999



XM_342134



XM_342863



XM_343559



XM_574284



UniGene ID



Rn.95299










The genes in this set show abundance of expressed gene product(s) in the Aged Unimpaired population that are significantly decreased, as determined by ANOVA, compared to those abundances in Young and Aged Impaired populations combined. Therefore, compounds useful in treating cognitive impairment selected using these genes should decrease the abundance or attenuate the function of the expressed gene products of these genes.
Example 9
An ANOVA was conducted on the probe set signal values for all present probe sets by combining two groups of animals and comparing them to the third group. An “AI ANOVA” was performed, where Aged Unimpaired were combined with Young and compared to Aged Impaired. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Pearson's correlations comparing probe set signal values to learning indices were then calculated for the aged animals (excluding young) across all present probe sets. Again, correlations representing a p-value of less than 0.05 were considered significantly changed.
Microarray Results
Table 9 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 9





CA3 - AI ANOVA POSITIVE CORRELATION

















GENBANK ® ID



BF420467



AF452731



AY190520



NM_001001511



NM_001007146



NM_001007617



NM_001007797



NM_001008289



NM_001008331



NM_001008880



NM_001008893



NM_001009474



NM_001011890



NM_001011893



NM_001011915



NM_001011946



NM_001011991



NM_001012025



NM_001012072



NM_001012075



NM_001012097



NM_001012106



NM_001012123



NM_001012162



NM_001012203



NM_001012215



NM_001013112



NM_001013121



NM_001013130



NM_001013192



NM_001013218



NM_001017386



NM_012502



NM_012519



NM_012577



NM_012618



NM_012671



NM_012720



NM_012778



NM_012781



NM_012804



NM_012809



NM_012825



NM_012925



NM_012999



NM_013005



NM_013045



NM_013060



NM_013096



NM_013137



NM_013199



NM_017012



NM_017015



NM_017026



NM_017031



NM_017041



NM_017068



NM_017073



NM_017175



NM_017181



NM_017197



NM_017206



NM_017214



NM_017223



NM_017239



NM_017248



NM_017261



NM_017274



NM_017307



NM_017329



NM_017333



NM_017354



NM_017357



NM_019161



NM_019185



NM_019249



NM_019256



NM_019288



NM_019312



NM_019341



NM_019358



NM_020098



NM_021595



NM_021682



NM_021769



NM_021868



NM_022178



NM_022207



NM_022285



NM_022861



NM_024161



NM_024364



NM_030832



NM_031006



NM_031022



NM_031034



NM_031049



NM_031092



NM_031093



NM_031140



NM_031357



NM_031521



NM_031576



NM_031587



NM_031613



NM_031755



NM_031798



NM_031841



NM_032062



NM_032066



NM_032617



NM_052807



NM_053314



NM_053328



NM_053416



NM_053467



NM_053492



NM_053536



NM_053615



NM_053639



NM_053643



NM_053681



NM_053741



NM_053766



NM_053799



NM_053814



NM_053824



NM_053936



NM_057137



NM_057138



NM_057148



NM_057197



NM_057200



NM_130403



NM_133560



NM_133602



NM_133605



NM_134351



NM_138832



NM_138905



NM_138914



NM_139038



NM_139103



NM_145081



NM_145094



NM_147136



NM_147210



NM_152847



NM_153470



NM_172030



NM_172033



NM_173120



NM_175578



NM_175582



NM_175595



NM_175838



NM_177928



NM_178095



NM_199119



NM_199253



NM_212529



NM_213629



XM_213779



XM_213824



XM_213849



XM_213920



XM_214172



XM_214187



XM_214539



XM_214740



XM_214968



XM_215095



XM_215184



XM_215264



XM_215733



XM_215739



XM_216340



XM_216688



XM_216755



XM_217062



XM_217279



XM_217409



XM_217570



XM_218162



XM_218226



XM_218292



XM_218816



XM_219262



XM_219998



XM_220420



XM_220805



XM_220986



XM_222745



XM_222780



XM_223583



XM_225008



XM_225014



XM_225404



XM_225628



XM_226237



XM_226779



XM_227203



XM_228073



XM_229225



XM_229988



XM_230288



XM_231121



XM_231193



XM_231287



XM_231714



XM_232172



XM_232671



XM_232809



XM_235326



XM_237042



XM_237232



XM_237381



XM_238057



XM_238103



XM_238213



XM_240330



XM_241375



XM_242032



XM_242057



XM_340739



XM_340825



XM_340879



XM_340911



XM_341052



XM_341172



XM_341352



XM_341538



XM_341940



XM_342141



XM_342405



XM_342591



XM_342626



XM_342648



XM_342662



XM_342928



XM_343131



XM_343174



XM_343358



XM_343380



XM_343570



XM_343919



XM_343971



XM_344403



XM_345446



XM_573298



XM_574593



XM_576343



XM_579200



XM_579675



UniGene ID



Rn.22102










The genes in this set show abundance of expressed gene product(s) in the Aged Impaired population that are significantly increased, as determined by ANOVA, compared to those abundances in Young and Aged Unimpaired populations combined. In addition, the abundance of expressed gene product(s) in the aged animals positively correlate with learning index of the animals, such that poorer learners have higher abundances of expressed gene products of the selected genes. Therefore, compounds useful in treating cognitive impairment selected using these genes should decrease the abundance or attenuate the function of the expressed gene products of these genes.
Example 10
An ANOVA was conducted on the probe set signal values for all present probe sets by combining two groups of animals and comparing them to the third group. An “AI ANOVA” was performed, where Aged Unimpaired were combined with Young and compared to Aged Impaired. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Pearson's correlations comparing probe set signal values to learning indices were then calculated for the aged animals (excluding young) across all present probe sets. Again, correlations representing a p-value of less than 0.05 were considered significantly changed.
Microarray Results
Table 10 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 10





CA3 - AI ANOVA NEGATIVE CORRELATION

















GENBANK ® ID



BG379941



BM389079



AI228348



AY325138



NM_001004133



NM_001004210



NM_001004235



NM_001004442



NM_001005564



NM_001005884



NM_001006972



NM_001007150



NM_001007656



NM_001009605



NM_001009679



NM_001011901



NM_001011923



NM_001011955



NM_001011978



NM_001011996



NM_001012012



NM_001012035



NM_001012103



NM_001012144



NM_001012170



NM_001013087



NM_001013170



NM_001014785



NM_012600



NM_012664



NM_012670



NM_012784



NM_012869



NM_013067



NM_013083



NM_013090



NM_013174



NM_013192



NM_013219



NM_017010



NM_017011



NM_017051



NM_017135



NM_017294



NM_017295



NM_019133



NM_019166



NM_019226



NM_019368



NM_021688



NM_021842



NM_021850



NM_022188



NM_022249



NM_022264



NM_022399



NM_022511



NM_022688



NM_022860



NM_022867



NM_022934



NM_023957



NM_023979



NM_024139



NM_024403



NM_030830



NM_030841



NM_030869



NM_031030



NM_031070



NM_031104



NM_031119



NM_031134



NM_031569



NM_031641



NM_031642



NM_031662



NM_031693



NM_031715



NM_031763



NM_031840



NM_033349



NM_053291



NM_053301



NM_053316



NM_053404



NM_053490



NM_053556



NM_053585



NM_053607



NM_053660



NM_053682



NM_053693



NM_053795



NM_053801



NM_053849



NM_053876



NM_053883



NM_053928



NM_053961



NM_057098



NM_057099



NM_057190



NM_130779



NM_133394



NM_133562



NM_133609



NM_134346



NM_138548



NM_138866



NM_138899



NM_138910



NM_138911



NM_139325



NM_145098



NM_145677



NM_153730



NM_172008



NM_172039



NM_172062



NM_172074



NM_173133



NM_173154



NM_173309



NM_181377



NM_181379



NM_198726



NM_199086



NM_199091



NM_199373



NM_212490



XM_213234



XM_213469



XM_213906



XM_214072



XM_214153



XM_214307



XM_214554



XM_214859



XM_215069



XM_215124



XM_215751



XM_215826



XM_215883



XM_215931



XM_216013



XM_216180



XM_216212



XM_216766



XM_216910



XM_217147



XM_217464



XM_217893



XM_218084



XM_218186



XM_218717



XM_220178



XM_220219



XM_220428



XM_220604



XM_220698



XM_221023



XM_221034



XM_221043



XM_221202



XM_221962



XM_222107



XM_223580



XM_223693



XM_223921



XM_223981



XM_224733



XM_226888



XM_227499



XM_230523



XM_230531



XM_231176



XM_231925



XM_232735



XM_233544



XM_235500



XM_238177



XM_238346



XM_239171



XM_239504



XM_340906



XM_340916



XM_341090



XM_341157



XM_341314



XM_341669



XM_341763



XM_342107



XM_342295



XM_342588



XM_342823



XM_342924



XM_342930



XM_343910



XM_344048



XM_347168



XM_574001



XM_576494



XM_577170



UniGene ID



Rn.102180



Rn.21816



Rn.24317










The genes in this set show abundance of expressed gene product(s) in the Aged Impaired population that are significantly decreased, as determined by ANOVA, compared to those abundances in Young and Aged Unimpaired populations combined. In addition, the abundance of expressed gene product(s) in the aged animals negatively correlate with learning index of the animals, such that poorer learners have lower abundances of expressed gene products of the selected genes. Therefore, compounds useful in treating cognitive impairment selected using these genes should increase the abundance or enhance the function of the expressed gene products of these genes.
Example 11
An ANOVA was conducted on the probe set signal values for all present probe sets by combining two groups of animals and comparing them to the third group. An “AI ANOVA” was performed, where Aged Unimpaired were combined with Young and compared to Aged Impaired. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Microarray Results
Table 11 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 11





CA3 - AI ANOVA INCREASE

















GENBANK ® ID



BI295776



AI178069



AF022087



AF155825



AF187100



M17422



NM_001005539



NM_001005761



NM_001007002



NM_001007005



NM_001007145



NM_001007607



NM_001007628



NM_001007636



NM_001007641



NM_001007744



NM_001008306



NM_001008316



NM_001008356



NM_001008509



NM_001008767



NM_001009623



NM_001011910



NM_001011954



NM_001011959



NM_001011981



NM_001012040



NM_001012163



NM_001012181



NM_001012193



NM_001012217



NM_001012459



NM_001012464



NM_001013058



NM_001013086



NM_001013148



NM_001013173



NM_001013179



NM_001013195



NM_001013200



NM_001014843



NM_001024278



NM_012507



NM_012532



NM_012543



NM_012654



NM_012655



NM_012714



NM_012747



NM_012749



NM_012776



NM_012788



NM_012844



NM_012908



NM_012913



NM_012948



NM_012984



NM_013015



NM_013016



NM_013044



NM_013088



NM_013107



NM_013132



NM_013176



NM_013198



NM_017009



NM_017024



NM_017030



NM_017060



NM_017062



NM_017075



NM_017109



NM_017125



NM_017148



NM_017192



NM_017200



NM_017347



NM_017365



NM_019140



NM_019146



NM_019152



NM_019156



NM_019168



NM_019252



NM_019269



NM_019311



NM_019318



NM_019359



NM_020073



NM_020084



NM_021663



NM_021672



NM_021681



NM_021694



NM_021746



NM_021853



NM_022184



NM_022198



NM_022226



NM_022236



NM_022250



NM_022270



NM_022272



NM_022390



NM_022500



NM_022592



NM_022629



NM_022799



NM_024148



NM_024154



NM_024155



NM_024373



NM_024404



NM_030872



NM_031035



NM_031052



NM_031091



NM_031144



NM_031235



NM_031509



NM_031556



NM_031599



NM_031620



NM_031648



NM_031771



NM_031772



NM_031797



NM_031818



NM_031837



NM_031970



NM_032083



NM_053021



NM_053323



NM_053349



NM_053418



NM_053534



NM_053538



NM_053576



NM_053749



NM_053763



NM_053794



NM_053901



NM_053917



NM_053926



NM_053985



NM_053986



NM_053994



NM_054001



NM_057139



NM_057187



NM_058210



NM_058211



NM_130420



NM_131911



NM_133298



NM_133300



NM_133303



NM_133307



NM_133318



NM_133383



NM_133398



NM_133418



NM_133534



NM_133571



NM_133615



NM_134334



NM_134349



NM_134372



NM_134411



NM_138506



NM_138521



NM_139115



NM_145092



NM_145678



NM_145777



NM_147206



NM_147207



NM_152790



NM_153298



NM_172029



NM_172334



NM_173118



NM_173153



NM_173328



NM_175764



NM_181363



NM_181388



NM_181639



NM_182737



NM_199093



NM_199270



NM_199390



NM_199401



NM_203335



NM_207609



NM_212508



NM_212523



NM_213628



XM_213270



XM_213329



XM_213421



XM_213484



XM_213684



XM_213688



XM_214035



XM_214403



XM_214480



XM_214967



XM_214979



XM_215080



XM_215361



XM_215576



XM_215607



XM_215889



XM_215924



XM_216004



XM_216188



XM_216386



XM_216565



XM_217197



XM_217239



XM_217651



XM_218195



XM_218337



XM_218523



XM_218617



XM_218939



XM_218977



XM_219785



XM_219885



XM_219948



XM_220357



XM_221497



XM_223190



XM_223535



XM_223781



XM_223786



XM_224337



XM_224944



XM_225147



XM_225160



XM_227217



XM_227444



XM_228164



XM_230284



XM_231620



XM_231749



XM_232194



XM_232343



XM_232354



XM_232364



XM_232732



XM_233141



XM_233403



XM_235057



XM_235558



XM_235566



XM_236020



XM_236227



XM_237371



XM_237415



XM_237754



XM_237907



XM_240311



XM_242062



XM_242644



XM_341494



XM_341495



XM_341548



XM_341578



XM_341584



XM_341605



XM_341957



XM_342007



XM_342291



XM_342317



XM_342545



XM_342653



XM_343055



XM_343117



XM_343205



XM_343259



XM_343274



XM_343332



XM_343395



XM_343468



XM_343552



XM_343773



XM_343975



XM_343986



XM_344112



XM_344409



XM_344785



XM_345825



XM_346854



XM_573810



XM_574618



XM_575585



XM_576312



XM_576519



UniGene ID



Rn.110441



Rn.129720










The genes in this set show abundance of expressed gene product(s) in the Aged Impaired population that are significantly increased, as determined by ANOVA, compared to those abundances in Young and Aged Unimpaired populations combined. Therefore, compounds useful in treating cognitive impairment selected using these genes should decrease the abundance or attenuate the function of the expressed gene products of these genes.
Example 12
An ANOVA was conducted on the probe set signal values for all present probe sets by combining two groups of animals and comparing them to the third group. An “AI ANOVA” was performed, where Aged Unimpaired were combined with Young and compared to Aged Impaired. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Microarray Results
Table 12 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 12





CA3 - AI ANOVA DECREASE

















GENBANK ® ID



BI294968



BF284573



AW142828



L13193



BG663483



AF452727



AY316590



NM_001000716



NM_001004072



NM_001004078



NM_001004132



NM_001004233



NM_001005547



NM_001005554



NM_001005905



NM_001005908



NM_001006970



NM_001006997



NM_001007020



NM_001007608



NM_001007626



NM_001007714



NM_001007728



NM_001007742



NM_001008301



NM_001008323



NM_001008338



NM_001008339



NM_001008520



NM_001008558



NM_001008562



NM_001008766



NM_001008888



NM_001009180



NM_001009258



NM_001009424



NM_001009666



NM_001009677



NM_001009688



NM_001009967



NM_001010965



NM_001011969



NM_001011998



NM_001012060



NM_001012066



NM_001012078



NM_001012119



NM_001012187



NM_001012191



NM_001012468



NM_001012473



NM_001013034



NM_001013059



NM_001013153



NM_001013156



NM_001013178



NM_001013189



NM_001013207



NM_001013235



NM_001014792



NM_001014793



NM_001015003



NM_001017374



NM_001024765



NM_012500



NM_012517



NM_012526



NM_012583



NM_012598



NM_012647



NM_012663



NM_012734



NM_012736



NM_012757



NM_012839



NM_012892



NM_012923



NM_012932



NM_012952



NM_012953



NM_012956



NM_012960



NM_012963



NM_012985



NM_013002



NM_013011



NM_013019



NM_013038



NM_013048



NM_013081



NM_013102



NM_013111



NM_013127



NM_013134



NM_013177



NM_013214



NM_013223



NM_017025



NM_017029



NM_017039



NM_017040



NM_017042



NM_017102



NM_017107



NM_017136



NM_017195



NM_017232



NM_017243



NM_017246



NM_017268



NM_017270



NM_017282



NM_017318



NM_017340



NM_017343



NM_017359



NM_017364



NM_019124



NM_019131



NM_019169



NM_019196



NM_019264



NM_019277



NM_019302



NM_019304



NM_019356



NM_021655



NM_021697



NM_021758



NM_021852



NM_022008



NM_022209



NM_022262



NM_022387



NM_022498



NM_022542



NM_022585



NM_022609



NM_022674



NM_022700



NM_022865



NM_022869



NM_022939



NM_023093



NM_023950



NM_023971



NM_023975



NM_024125



NM_024152



NM_024156



NM_024378



NM_024484



NM_024486



NM_030835



NM_030856



NM_031064



NM_031138



NM_031146



NM_031151



NM_031152



NM_031237



NM_031606



NM_031639



NM_031643



NM_031655



NM_031718



NM_031720



NM_031735



NM_031742



NM_031745



NM_031757



NM_031783



NM_031785



NM_031802



NM_031811



NM_031824



NM_031987



NM_032057



NM_032614



NM_033021



NM_053346



NM_053357



NM_053409



NM_053414



NM_053420



NM_053428



NM_053439



NM_053441



NM_053484



NM_053502



NM_053518



NM_053527



NM_053581



NM_053590



NM_053605



NM_053613



NM_053622



NM_053623



NM_053638



NM_053726



NM_053747



NM_053748



NM_053752



NM_053758



NM_053764



NM_053772



NM_053812



NM_053842



NM_053856



NM_053868



NM_053888



NM_053893



NM_053912



NM_053927



NM_053948



NM_053974



NM_053979



NM_053996



NM_054002



NM_054003



NM_057107



NM_057141



NM_057196



NM_057210



NM_080777



NM_080780



NM_080886



NM_080887



NM_080902



NM_130423



NM_130746



NM_130749



NM_130894



NM_131904



NM_133313



NM_133320



NM_133402



NM_133415



NM_133427



NM_133566



NM_133589



NM_134331



NM_134383



NM_134404



NM_138519



NM_138833



NM_138839



NM_138856



NM_138883



NM_139097



NM_139098



NM_139106



NM_139254



NM_145184



NM_147211



NM_152935



NM_153297



NM_153630



NM_153735



NM_171990



NM_171994



NM_172072



NM_173102



NM_173146



NM_173290



NM_177425



NM_177929



NM_178091



NM_181090



NM_181626



NM_182668



NM_182814



NM_182819



NM_183052



NM_183332



NM_184050



NM_184051



NM_198132



NM_198732



NM_198758



NM_198760



NM_198765



NM_198787



NM_198788



NM_199385



NM_199395



NM_199405



NM_199410



NM_199500



NM_207617



NM_212494



NM_212519



NM_212520



XM_213362



XM_213426



XM_213487



XM_213564



XM_213571



XM_213679



XM_213765



XM_213782



XM_213840



XM_214003



XM_214108



XM_214147



XM_214241



XM_214475



XM_214485



XM_214491



XM_214583



XM_214646



XM_214701



XM_214969



XM_215251



XM_215286



XM_215416



XM_215549



XM_215570



XM_215612



XM_216158



XM_216265



XM_216378



XM_216641



XM_216893



XM_217105



XM_217209



XM_217560



XM_217592



XM_217868



XM_218620



XM_218660



XM_219377



XM_219525



XM_219939



XM_220230



XM_220281



XM_220717



XM_220754



XM_221212



XM_221888



XM_221910



XM_222669



XM_222717



XM_223729



XM_224271



XM_225078



XM_226561



XM_227301



XM_228345



XM_230495



XM_231271



XM_231803



XM_232220



XM_232739



XM_232901



XM_233485



XM_233529



XM_234483



XM_234555



XM_235185



XM_235878



XM_236698



XM_237808



XM_238280



XM_238770



XM_239761



XM_340775



XM_340872



XM_340889



XM_340921



XM_340999



XM_341288



XM_341374



XM_341448



XM_341700



XM_341822



XM_341930



XM_342149



XM_342174



XM_342217



XM_342300



XM_342306



XM_342312



XM_342493



XM_342534



XM_342553



XM_342582



XM_342600



XM_342612



XM_342679



XM_342812



XM_342894



XM_342920



XM_343154



XM_343389



XM_343459



XM_343557



XM_343761



XM_343776



XM_344231



XM_344434



XM_344594



XM_573052



XM_573063



XM_573256



XM_574916



XM_578542



XM_579413



UniGene ID



Rn.128732



Rn.15446



Rn.23342



Rn.25029



Rn.92383










The genes in this set show abundance of expressed gene product(s) in the Aged Impaired population that are significantly decreased, as determined by ANOVA, compared to those abundances in Young and Aged Unimpaired populations combined. Therefore, compounds useful in treating cognitive impairment selected using these genes should increase the abundance or enhance the function of the expressed gene products of these genes.
Example 13
An ANOVA was conducted on the probe set signal values for all present probe sets by combining two groups of animals and comparing them to the third group. An “AU ANOVA” was performed, where Aged Impaired were combined with Young and compared to Aged Unimpaired. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Pearson's correlations comparing probe set signal values to learning indices were then calculated for the aged animals (excluding young) across all present probe sets. Again, correlations representing a p-value of less than 0.05 were considered significantly changed.
Microarray Results
Table 13 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 13





CA3 - AU ANOVA POSITIVE CORRELATION

















GENBANK ® ID



BF419095



BF420440



NM_001005889



NM_001009665



NM_001009825



NM_001011974



NM_001012038



NM_001012061



NM_001012150



NM_001012183



NM_001012504



NM_001013128



NM_012504



NM_012518



NM_012527



NM_012574



NM_012633



NM_012836



NM_012920



NM_013029



NM_013065



NM_013066



NM_013126



NM_013135



NM_017065



NM_017066



NM_017211



NM_017213



NM_017242



NM_017262



NM_017290



NM_017304



NM_017327



NM_019128



NM_019204



NM_019275



NM_019351



NM_019375



NM_020075



NM_020088



NM_021597



NM_021678



NM_021767



NM_021835



NM_021847



NM_022254



NM_022380



NM_022690



NM_022703



NM_022850



NM_022946



NM_023020



NM_023983



NM_024366



NM_024397



NM_030871



NM_031028



NM_031036



NM_031081



NM_031515



NM_031535



NM_031608



NM_031665



NM_031743



NM_032613



NM_053311



NM_053369



NM_053424



NM_053457



NM_053475



NM_053508



NM_053589



NM_053859



NM_053878



NM_053891



NM_053910



NM_057116



NM_080482



NM_080583



NM_080904



NM_131907



NM_133395



NM_133579



NM_134413



NM_138502



NM_138509



NM_138896



NM_139060



NM_139189



NM_139217



NM_144756



NM_148891



NM_153309



NM_153317



NM_173152



NM_181550



XM_213626



XM_213746



XM_213969



XM_214253



XM_215403



XM_215467



XM_215578



XM_215919



XM_215990



XM_217021



XM_218828



XM_220232



XM_221426



XM_223205



XM_223837



XM_224474



XM_227623



XM_228644



XM_233798



XM_234901



XM_235179



XM_236268



XM_236362



XM_237241



XM_238072



XM_238336



XM_241981



XM_340747



XM_341081



XM_341104



XM_341201



XM_341341



XM_341857



XM_341961



XM_342521



XM_342535



XM_342682



XM_342684



XM_342808



XM_343059



XM_343109



XM_343157



XM_343427



XM_343483



XM_343513



XM_343582



XM_343630



XM_343736



XM_343764



XM_573205



XM_573259



XM_573634



XM_576311



XM_579869



UniGene ID



Rn.122667



Rn.78244










The genes in this set show abundance of expressed gene product(s) in the Aged Unimpaired population that are significantly decreased, as determined by ANOVA, compared to those abundances in Young and Aged Impaired populations combined. In addition, the abundance of expressed gene product(s) in the aged animals positively correlate with learning index of the animals, such that poorer learners have higher abundances of expressed gene products of the selected genes. Therefore, compounds useful in treating cognitive impairment selected using these genes should decrease the abundance or attenuate the function of the expressed gene products of these genes.
Example 14
An ANOVA was conducted on the probe set signal values for all present probe sets by combining two groups of animals and comparing them to the third group. An “AU ANOVA” was performed, where Aged Impaired were combined with Young and compared to Aged Unimpaired. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Pearson's correlations comparing probe set signal values to learning indices were then calculated for the aged animals (excluding young) across all present probe sets. Again, correlations representing a p-value of less than 0.05 were considered significantly changed.
Microarray Results
Table 14 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 14





CA3 - AU ANOVA NEGATIVE CORRELATION


GENBANK ® ID

















NM_001003978



NM_001004075



NM_001006991



NM_001011905



NM_001011992



NM_001012160



NM_001013206



NM_001013224



NM_001013234



NM_001013873



NM_012645



NM_013154



NM_019364



NM_020308



NM_022210



NM_022394



NM_022541



NM_024374



NM_024385



NM_031062



NM_031345



NM_031596



NM_031978



NM_032079



NM_053295



NM_053442



NM_053539



NM_053642



NM_053713



NM_053714



NM_053787



NM_130413



NM_134326



NM_134456



NM_145778



NM_145785



NM_171995



NM_173117



NM_175579



NM_182816



XM_213658



XM_213993



XM_214730



XM_214890



XM_215637



XM_215908



XM_216380



XM_216661



XM_217050



XM_219297



XM_221050



XM_224588



XM_231052



XM_232168



XM_232860



XM_233767



XM_235051



XM_236210



XM_237828



XM_243652



XM_340911



XM_341750



XM_342032



XM_342044



XM_342396



XM_342578



XM_345160



XM_578548










The genes in this set show abundance of expressed gene product(s) in the Aged Unimpaired population that are significantly increased, as determined by ANOVA, compared to those abundances in Young and Aged Impaired populations combined. In addition, the abundance of expressed gene product(s) in the aged animals negatively correlate with learning index of the animals, such that poorer learners have lower abundances of expressed gene products of the selected genes. Therefore, compounds useful in treating cognitive impairment selected using these genes should increase the abundance or enhance the function of the expressed gene products of these genes.
Example 15
An ANOVA was conducted on the probe set signal values for all present probe sets by combining two groups of animals and comparing them to the third group. An “AU ANOVA” was performed, where Aged Impaired were combined with Young and compared to Aged Unimpaired. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Microarray Results
Table 15 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 15





CA3 - AU ANOVA INCREASE

















GENBANK ® ID



BF287008



AF442812



AY597251



NM_001002854



NM_001004199



NM_001004443



NM_001005557



NM_001006602



NM_001006976



NM_001007686



NM_001007734



NM_001008309



NM_001008515



NM_001008521



NM_001009349



NM_001009369



NM_001009632



NM_001009641



NM_001009645



NM_001009973



NM_001011896



NM_001011948



NM_001012021



NM_001012133



NM_001013033



NM_001013082



NM_001013213



NM_001013223



NM_001013233



NM_012512



NM_012550



NM_012562



NM_012656



NM_012731



NM_012857



NM_012870



NM_012887



NM_012895



NM_012904



NM_012935



NM_012939



NM_012940



NM_012988



NM_013001



NM_013022



NM_013055



NM_017116



NM_017264



NM_019238



NM_021763



NM_021846



NM_021863



NM_021997



NM_022197



NM_022219



NM_022282



NM_022515



NM_022599



NM_022626



NM_022941



NM_022949



NM_024144



NM_024150



NM_024377



NM_024388



NM_031078



NM_031083



NM_031094



NM_031122



NM_031622



NM_031640



NM_031721



NM_031728



NM_031751



NM_032612



NM_033096



NM_052809



NM_053455



NM_053541



NM_053580



NM_053584



NM_053698



NM_053774



NM_053826



NM_053832



NM_053884



NM_053946



NM_053998



NM_130409



NM_133314



NM_133387



NM_133548



NM_133552



NM_134389



NM_138508



NM_138846



NM_138847



NM_138907



NM_139083



NM_139094



NM_145783



NM_148890



NM_172324



NM_173323



NM_175756



NM_175762



NM_177933



NM_181432



NM_181628



NM_182844



NM_183331



NM_183402



NM_199111



NM_201988



U31866



XM_213324



XM_213346



XM_213418



XM_213823



XM_214958



XM_215037



XM_215469



XM_215528



XM_215812



XM_215858



XM_216316



XM_216757



XM_218041



XM_218759



XM_220606



XM_220736



XM_221077



XM_222152



XM_223508



XM_223684



XM_224971



XM_225039



XM_225644



XM_226769



XM_228197



XM_228305



XM_232202



XM_232466



XM_232608



XM_233138



XM_233341



XM_233611



XM_233820



XM_233944



XM_234328



XM_234441



XM_238163



XM_242005



XM_242556



XM_340943



XM_341066



XM_341251



XM_341346



XM_341444



XM_341644



XM_341688



XM_342002



XM_342154



XM_342470



XM_343126



XM_343318



XM_345114



XM_574371



XM_579460



XM_579522



UniGene ID



Rn.14733










The genes in this set show abundance of expressed gene product(s) in the Aged Unimpaired population that are significantly increased, as determined by ANOVA, compared to those abundances in Young and Aged Impaired populations combined. Therefore, compounds useful in treating cognitive impairment selected using these genes should increase the abundance or enhance the function of the expressed gene products of these genes.
Example 16
An ANOVA was conducted on the probe set signal values for all present probe sets by combining two groups of animals and comparing them to the third group. An “AU ANOVA” was performed, where Aged Impaired were combined with Young and compared to Aged Unimpaired. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Microarray Results
Table 16 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 16





CA3 - AU ANOVA DECREASE

















GENBANK ® ID



AI171809



BI395698



NM_001004083



NM_001006971



NM_001007616



NM_001008519



NM_001008694



NM_001009681



NM_001011930



NM_001011938



NM_001011939



NM_001012004



NM_001012175



NM_001012189



NM_001012345



NM_001013045



NM_001013094



NM_001013096



NM_001013138



NM_001013186



NM_012506



NM_012508



NM_012545



NM_012569



NM_012581



NM_012673



NM_012686



NM_012756



NM_012798



NM_012820



NM_012830



NM_012841



NM_012918



NM_013116



NM_013181



NM_013189



NM_016990



NM_017093



NM_017094



NM_017131



NM_017204



NM_017253



NM_017254



NM_017259



NM_017298



NM_017312



NM_019159



NM_019208



NM_019295



NM_019306



NM_019343



NM_020094



NM_021748



NM_021775



NM_021859



NM_022193



NM_022206



NM_022217



NM_022252



NM_022267



NM_022382



NM_022384



NM_022589



NM_022606



NM_022666



NM_022668



NM_022675



NM_022855



NM_022864



NM_022945



NM_023988



NM_024000



NM_024146



NM_024394



NM_030858



NM_030862



NM_031008



NM_031315



NM_031353



NM_031568



NM_031657



NM_031667



NM_031821



NM_031831



NM_053335



NM_053440



NM_053464



NM_053503



NM_053553



NM_053675



NM_053721



NM_053724



NM_053777



NM_053788



NM_053811



NM_053864



NM_053894



NM_053895



NM_053903



NM_053924



NM_053931



NM_053997



NM_057118



NM_057125



NM_057140



NM_057152



NM_057201



NM_080885



NM_133406



NM_133419



NM_133535



NM_133567



NM_133582



NM_134366



NM_134376



NM_134398



NM_134455



NM_134458



NM_134461



NM_139329



NM_139330



NM_139333



NM_145089



NM_145090



NM_145680



NM_147209



NM_148889



NM_173105



NM_175708



NM_175754



NM_175760



NM_175761



NM_175869



NM_177481



NM_178106



NM_181478



NM_181822



NM_182842



NM_199372



NM_199397



NM_212458



XM_213574



XM_213777



XM_213842



XM_213925



XM_213954



XM_213963



XM_214751



XM_214780



XM_214888



XM_215182



XM_215371



XM_215655



XM_215963



XM_215984



XM_216152



XM_216228



XM_216349



XM_216398



XM_216725



XM_216965



XM_217078



XM_217283



XM_217381



XM_217388



XM_218615



XM_220055



XM_220062



XM_220224



XM_220315



XM_222103



XM_222177



XM_222245



XM_222773



XM_224713



XM_225468



XM_227282



XM_227409



XM_227428



XM_228753



XM_230814



XM_230899



XM_232351



XM_233737



XM_233839



XM_235064



XM_235156



XM_235496



XM_235662



XM_236009



XM_236735



XM_238398



XM_340886



XM_341091



XM_341248



XM_341500



XM_341807



XM_343114



XM_343175



XM_343339



XM_343839



XM_345861



XM_573915



XM_575018



XM_575080



XM_579523



XM_579696



UniGene ID



Rn.129749



Rn.116507










The genes in this set show abundance of expressed gene product(s) in the Aged Unimpaired population that are significantly decreased, as determined by ANOVA, compared to those abundances in Young and Aged Impaired populations combined. Therefore, compounds useful in treating cognitive impairment selected using these genes should decrease the abundance or attenuate the function of the expressed gene products of these genes.
Example 17
An ANOVA was conducted on the probe set signal values for all present probe sets by combining two groups of animals and comparing them to the third group. An “AI ANOVA” was performed, where Aged Unimpaired were combined with Young and compared to Aged Impaired. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Pearson's correlations comparing probe set signal values to learning indices were then calculated for the aged animals (excluding young) across all present probe sets. Again, correlations representing a p-value of less than 0.05 were considered significantly changed.
Microarray Results
Table 17 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 17





DG - AI ANOVA POSITIVE CORRELATION


GENBANK ® ID

















NM_001001516



NM_001004080



NM_001004081



NM_001004199



NM_001004209



NM_001004225



NM_001004247



NM_001004273



NM_001004275



NM_001005539



NM_001006987



NM_001006998



NM_001007684



NM_001007691



NM_001008312



NM_001008324



NM_001008374



NM_001009618



NM_001009677



NM_001009708



NM_001011890



NM_001011910



NM_001011946



NM_001011999



NM_001012137



NM_001012149



NM_001012235



NM_001013105



NM_001013167



NM_001013175



NM_001013206



NM_001013213



NM_001013874



NM_001017385



NM_012543



NM_012577



NM_012628



NM_012686



NM_012701



NM_012749



NM_012777



NM_012781



NM_012788



NM_012820



NM_012893



NM_013000



NM_013015



NM_013107



NM_013135



NM_017051



NM_017052



NM_017068



NM_017075



NM_017109



NM_017142



NM_017181



NM_017232



NM_017288



NM_019124



NM_019131



NM_019159



NM_019204



NM_019257



NM_019359



NM_020308



NM_021766



NM_021869



NM_022400



NM_022499



NM_022500



NM_022502



NM_022523



NM_022539



NM_022592



NM_022595



NM_022596



NM_022617



NM_022637



NM_022853



NM_024359



NM_024400



NM_030859



NM_031035



NM_031049



NM_031057



NM_031101



NM_031105



NM_031120



NM_031357



NM_031514



NM_031576



NM_031587



NM_031599



NM_031632



NM_031654



NM_031725



NM_031798



NM_032612



NM_053295



NM_053418



NM_053588



NM_053598



NM_053612



NM_053670



NM_053698



NM_053777



NM_053870



NM_053945



NM_057114



NM_080888



NM_130416



NM_130420



NM_130894



NM_133551



NM_133557



NM_134367



NM_134370



NM_138508



NM_138900



NM_138917



NM_139107



NM_139186



NM_147210



NM_153469



NM_172063



NM_172068



NM_173111



NM_175578



NM_175582



NM_199119



NM_207591



NM_207602



XM_214172



XM_214383



XM_214518



XM_214588



XM_214968



XM_215069



XM_215371



XM_215754



XM_215939



XM_216641



XM_216740



XM_216872



XM_218425



XM_219374



XM_220264



XM_220699



XM_221387



XM_223190



XM_224944



XM_225726



XM_227066



XM_228114



XM_230637



XM_232323



XM_240330



XM_341249



XM_341785



XM_341957



XM_342092



XM_342318



XM_342757



XM_342887



XM_343119



XM_343318



XM_343773



XM_345674



XM_346244



XM_346854



XM_573772



XM_574670



XM_579675










The genes in this set show abundance of expressed gene product(s) in the Aged Impaired population that are significantly increased, as determined by ANOVA, compared to those abundances in Young and Aged Unimpaired populations combined. In addition, the abundance of expressed gene product(s) in the aged animals positively correlate with learning index of the animals, such that poorer learners have higher abundances of expressed gene products of the selected genes. Therefore, compounds useful in treating cognitive impairment selected using these genes should decrease the abundance or attenuate the function of the expressed gene products of these genes.
Example 18
An ANOVA was conducted on the probe set signal values for all present probe sets by combining two groups of animals and comparing them to the third group. An “AI ANOVA” was performed, where Aged Unimpaired were combined with Young and compared to Aged Impaired. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Pearson's correlations comparing probe set signal values to learning indices were then calculated for the aged animals (excluding young) across all present probe sets. Again, correlations representing a p-value of less than 0.05 were considered significantly changed.
Microarray Results
Table 18 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 18





DG - AI ANOVA NEGATIVE CORRELATION

















GENBANK ® ID



AI043800



NM_001001512



NM_001004208



NM_001004446



NM_001008353



NM_001008520



NM_001011923



NM_001012025



NM_001012072



NM_001013873



NM_001015021



NM_012590



NM_012609



NM_012727



NM_012769



NM_012874



NM_012959



NM_012994



NM_013083



NM_013131



NM_017290



NM_019128



NM_019347



NM_020089



NM_021758



NM_021842



NM_022281



NM_022289



NM_022297



NM_022387



NM_022506



NM_022541



NM_022546



NM_022599



NM_022934



NM_022938



NM_023977



NM_024373



NM_024375



NM_031016



NM_031123



NM_031510



NM_031613



NM_031685



NM_031694



NM_031730



NM_053321



NM_053328



NM_053349



NM_053358



NM_053360



NM_053625



NM_053669



NM_053787



NM_053883



NM_080899



NM_080902



NM_131907



NM_138506



NM_138850



NM_138911



NM_138914



NM_139192



NM_139259



NM_144758



NM_145184



NM_153317



NM_172034



NM_172062



NM_173117



NM_173119



NM_173137



NM_176857



NM_181626



NM_199106



NM_201560



XM_213762



XM_213963



XM_213969



XM_215883



XM_215890



XM_218226



XM_218515



XM_219879



XM_220708



XM_220992



XM_222103



XM_222717



XM_222773



XM_224733



XM_225895



XM_231148



XM_232413



XM_234011



XM_234470



XM_236210



XM_236614



XM_241375



XM_341089



XM_341091



XM_341106



XM_341310



XM_342044



XM_342325



XM_342612



XM_342643



XM_343263



XM_343442



XM_344785



XM_345981



XM_574916



XM_576437



UniGene ID



Rn.18726










The genes in this set show abundance of expressed gene product(s) in the Aged Impaired population that are significantly decreased, as determined by ANOVA, compared to those abundances in Young and Aged Unimpaired populations combined. In addition, the abundance of expressed gene product(s) in the aged animals negatively correlate with learning index of the animals, such that poorer learners have lower abundances of expressed gene products of the selected genes. Therefore, compounds useful in treating cognitive impairment selected using these genes should increase the abundance or enhance the function of the expressed gene products of these genes.
Example 19
An ANOVA was conducted on the probe set signal values for all present probe sets by combining two groups of animals and comparing them to the third group. An “AI ANOVA” was performed, where Aged Unimpaired were combined with Young and compared to Aged Impaired. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Microarray Results
Table 19 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 19





DG - AI ANOVA INCREASE

















GENBANK ® ID



BI303253



BF567886



BE112341



AW142720



AI231999



BF398752



AF030087



AY190520



NM_001002016



NM_001004076



NM_001004099



NM_001004218



NM_001005907



NM_001006989



NM_001007557



NM_001007625



NM_001007654



NM_001007712



NM_001007729



NM_001007749



NM_001008287



NM_001008725



NM_001008767



NM_001008768



NM_001009474



NM_001009502



NM_001009662



NM_001009669



NM_001009719



NM_001011985



NM_001012004



NM_001012088



NM_001012147



NM_001012162



NM_001013044



NM_001013112



NM_001013121



NM_001013179



NM_001013194



NM_001013210



NM_001013233



NM_001013249



NM_012512



NM_012546



NM_012562



NM_012581



NM_012637



NM_012663



NM_012762



NM_012844



NM_012862



NM_012913



NM_012925



NM_012939



NM_012971



NM_012974



NM_012985



NM_012992



NM_012993



NM_013044



NM_013070



NM_013122



NM_013137



NM_013146



NM_013156



NM_013194



NM_017060



NM_017116



NM_017125



NM_017132



NM_017175



NM_017192



NM_017200



NM_017280



NM_017307



NM_017320



NM_017351



NM_019156



NM_019232



NM_019249



NM_019253



NM_019289



NM_019312



NM_019363



NM_019904



NM_019906



NM_020073



NM_020074



NM_020075



NM_020088



NM_020099



NM_021690



NM_021769



NM_021909



NM_022210



NM_022226



NM_022270



NM_022382



NM_022390



NM_022526



NM_022530



NM_022531



NM_022601



NM_022638



NM_022692



NM_023967



NM_024155



NM_024353



NM_024358



NM_024369



NM_030826



NM_030831



NM_030863



NM_031013



NM_031099



NM_031114



NM_031140



NM_031328



NM_031509



NM_031511



NM_031525



NM_031544



NM_031593



NM_031677



NM_031683



NM_031778



NM_031789



NM_031797



NM_031818



NM_032067



NM_032416



NM_052983



NM_053314



NM_053356



NM_053404



NM_053411



NM_053455



NM_053485



NM_053516



NM_053560



NM_053583



NM_053584



NM_053592



NM_053618



NM_053714



NM_053783



NM_053886



NM_053896



NM_053927



NM_053936



NM_053999



NM_05710



NM_057197



NM_080480



NM_080584



NM_080691



NM_080698



NM_130409



NM_133296



NM_133298



NM_133305



NM_133605



NM_134449



NM_138542



NM_138855



NM_139110



NM_139216



NM_139327



NM_153297



NM_153628



NM_172029



NM_172033



NM_172325



NM_173118



NM_173123



NM_175756



NM_177426



NM_181365



NM_183328



NM_198134



NM_198786



NM_199093



NM_199115



NM_199118



NM_199378



NM_199388



NM_207598



NM_212463



NM_212501



XM_213972



XM_213995



XM_214441



XM_214656



XM_214927



XM_215095



XM_215222



XM_215285



XM_215576



XM_215733



XM_215840



XM_215935



XM_215942



XM_215994



XM_216410



XM_217061



XM_217152



XM_217154



XM_217271



XM_217283



XM_217297



XM_217367



XM_217690



XM_218292



XM_218816



XM_220567



XM_220736



XM_220810



XM_220982



XM_222476



XM_223524



XM_223583



XM_223690



XM_223781



XM_224969



XM_225014



XM_225259



XM_226016



XM_226211



XM_228073



XM_231620



XM_233138



XM_233345



XM_235518



XM_236380



XM_236675



XM_237371



XM_237825



XM_242644



XM_243637



XM_341107



XM_341227



XM_341352



XM_341574



XM_341578



XM_341653



XM_341657



XM_341664



XM_341790



XM_341948



XM_342007



XM_342048



XM_342409



XM_342542



XM_342591



XM_342759



XM_343006



XM_343065



XM_343126



XM_343166



XM_343174



XM_343198



XM_343332



XM_343564



XM_343570



XM_343845



XM_346594



XM_574170



XM_574618



XM_575585



UniGene ID



Rn.105382



Rn.108166



Rn.114169



Rn.128732



Rn.24825



Rn.48866










The genes in this set show abundance of expressed gene product(s) in the Aged Impaired population that are significantly increased, as determined by ANOVA, compared to those abundances in Young and Aged Unimpaired populations combined. Therefore, compounds useful in treating cognitive impairment selected using these genes should decrease the abundance or attenuate the function of the expressed gene products of these genes.
Example 20
An ANOVA was conducted on the probe set signal values for all present probe sets by combining two groups of animals and comparing them to the third group. An “AI ANOVA” was performed, where Aged Unimpaired were combined with Young and compared to Aged Impaired. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Microarray Results
Table 20 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 20





DG - AI ANOVA DECREASE

















GENBANK ® ID



BG381750



BM391206



BG374818



AI406842



BM388719



BE103926



NM_001001508



NM_001002819



NM_001003978



NM_001004082



NM_001004133



NM_001005765



NM_001006970



NM_001007680



NM_001007742



NM_001008299



NM_001008317



NM_001009679



NM_001009704



NM_001012017



NM_001012131



NM_001012150



NM_001012197



NM_001012214



NM_001013035



NM_001013092



NM_001013128



NM_001014187



NM_012585



NM_012916



NM_012934



NM_013002



NM_013060



NM_013066



NM_013111



NM_013192



NM_017011



NM_017093



NM_017105



NM_017155



NM_017171



NM_017215



NM_017303



NM_017311



NM_017318



NM_017328



NM_017357



NM_017359



NM_019356



NM_021597



NM_021849



NM_022188



NM_022254



NM_022262



NM_022264



NM_022532



NM_022548



NM_022615



NM_022668



NM_022678



NM_022688



NM_022962



NM_024484



NM_030842



NM_030846



NM_030871



NM_031005



NM_031054



NM_031325



NM_031563



NM_031573



NM_031596



NM_031727



NM_031777



NM_031977



NM_052801



NM_053492



NM_053589



NM_053642



NM_053729



NM_053779



NM_053801



NM_053834



NM_053851



NM_053891



NM_053931



NM_057208



NM_080482



NM_080776



NM_080781



NM_130749



NM_133425



NM_133562



NM_133568



NM_133596



NM_134376



NM_134395



NM_134398



NM_138849



NM_138922



NM_139091



NM_145676



NM_145783



NM_153318



NM_172008



NM_173133



NM_173337



NM_183331



NM_198787



NM_207590



XM_213610



XM_213765



XM_214155



XM_214690



XM_214856



XM_215134



XM_215573



XM_215896



XM_216047



XM_216227



XM_217063



XM_217115



XM_217147



XM_217464



XM_218660



XM_219576



XM_220992



XM_221888



XM_221910



XM_221962



XM_222946



XM_223729



XM_224335



XM_224588



XM_224707



XM_224713



XM_225138



XM_225468



XM_226888



XM_232197



XM_232760



XM_235705



XM_237288



XM_239171



XM_340739



XM_340856



XM_340999



XM_341112



XM_341337



XM_341683



XM_341688



XM_341803



XM_342134



XM_342763



XM_342854



XM_342920



XM_343358



XM_343395



XM_343469



XM_343910



XM_344063



XM_344594



XM_344744



NM_134383



NM_053410



XM_579362



UniGene ID



Rn.101929



Rn.11688



Rn.39092



Rn.6994



Rn.8562



Rn.98343










The genes in this set show abundance of expressed gene product(s) in the Aged Impaired population that are significantly decreased, as determined by ANOVA, compared to those abundances in Young and Aged Unimpaired populations combined. Therefore, compounds useful in treating cognitive impairment selected using these genes should increase the abundance or enhance the function of the expressed gene products of these genes.
Example 21
An ANOVA was conducted on the probe set signal values for all present probe sets by combining two groups of animals and comparing them to the third group. An “AU ANOVA” was performed, where Aged Impaired were combined with Young and compared to Aged Unimpaired. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Pearson's correlations comparing probe set signal values to learning indices were then calculated for the aged animals (excluding young) across all present probe sets. Again, correlations representing a p-value of less than 0.05 were considered significantly changed.
Microarray Results
Table 21 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 21





DG - AU ANOVA POSITIVE CORRELATION


GENBANK ® ID

















AF022087



NM_001001514



NM_001005534



NM_001005547



NM_001008301



NM_001009825



NM_001010953



NM_001011895



NM_001011920



NM_001011941



NM_001011990



NM_012634



NM_017346



NM_019379



NM_022675



NM_022936



NM_031034



NM_031575



NM_031631



NM_031735



NM_052981



NM_053440



NM_053639



NM_053804



NM_053842



NM_053871



NM_053965



NM_057141



NM_080478



NM_130406



NM_133313



NM_152935



NM_183402



NM_184049



NM_198785



NM_199380



X76489



XM_213421



XM_213484



XM_213782



XM_213824



XM_214035



XM_214420



XM_216349



XM_216661



XM_220574



XM_220754



XM_227749



XM_232531



XM_232809



XM_233341



XM_236181



XM_236992



XM_340970



XM_341550



XM_341666



XM_341796



XM_342300



XM_342592



XM_342686



XM_343513










The genes in this set show abundance of expressed gene product(s) in the Aged Unimpaired population that are significantly decreased, as determined by ANOVA, compared to those abundances in Young and Aged Impaired populations combined. In addition, the abundance of expressed gene product(s) in the aged animals positively correlate with learning index of the animals, such that poorer learners have higher abundances of expressed gene products of the selected genes. Therefore, compounds useful in treating cognitive impairment selected using these genes should decrease the abundance or attenuate the function of the expressed gene products of these genes.
Example 22
An ANOVA was conducted on the probe set signal values for all present probe sets by combining two groups of animals and comparing them to the third group. An “AU ANOVA” was performed, where Aged Impaired were combined with Young and compared to Aged Unimpaired. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Pearson's correlations comparing probe set signal values to learning indices were then calculated for the aged animals (excluding young) across all present probe sets. Again, correlations representing a p-value of less than 0.05 were considered significantly changed.
Microarray Results
Table 22 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 22





DG - AU ANOVA NEGATIVE CORRELATION


GENBANK ® ID

















NM_001004075



NM_001004200



NM_001005529



NM_001007146



NM_001008511



NM_001008885



NM_001011959



NM_001012034



NM_001012140



NM_001013065



NM_001013165



NM_001013198



NM_001017382



NM_012630



NM_012775



NM_012806



NM_012953



NM_012955



NM_012991



NM_013031



NM_013094



NM_013159



NM_013189



NM_017158



NM_017319



NM_019123



NM_019149



NM_019168



NM_019349



NM_021688



NM_021774



NM_022946



NM_024394



NM_030872



NM_031036



NM_031131



NM_031354



NM_031569



NM_053499



NM_053733



NM_053961



NM_054006



NM_133411



NM_134326



NM_134373



NM_172039



NM_172317



NM_175604



NM_175764



NM_182737



NM_198750



NM_199111



NM_199400



NM_199463



NM_212496



XM_213749



XM_214344



XM_215286



XM_215813



XM_216025



XM_216548



XM_216784



XM_217359



XM_218459



XM_218523



XM_219349



XM_222242



XM_223938



XM_224256



XM_224947



XM_225168



XM_225717



XM_227090



XM_230303



XM_230616



XM_232735



XM_233141



XM_235185



XM_235662



XM_239329



XM_242005



XM_340742



XM_341312



XM_341842



XM_342392



XM_342828



XM_343175



XM_343278



XM_343535



XM_343559



XM_347168



XM_573428



XM_576252



XM_579545










The genes in this set show abundance of expressed gene product(s) in the Aged Unimpaired population that are significantly increased, as determined by ANOVA, compared to those abundances in Young and Aged Impaired populations combined. In addition, the abundance of expressed gene product(s) in the aged animals negatively correlate with learning index of the animals, such that poorer learners have lower abundances of expressed gene products of the selected genes. Therefore, compounds useful in treating cognitive impairment selected using these genes should increase the abundance or enhance the function of the expressed gene products of these genes.
Example 23
An ANOVA was conducted on the probe set signal values for all present probe sets by combining two groups of animals and comparing them to the third group. An “AU ANOVA” was performed, where Aged Impaired were combined with Young and compared to Aged Unimpaired. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Microarray Results
Table 23 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 23





DG - AU ANOVA INCREASE


GENBANK ® ID

















AF452647



NM_001004230



NM_001004279



NM_001004449



NM_001005565



NM_001007011



NM_001007613



NM_001007637



NM_001007739



NM_001008309



NM_001008316



NM_001008339



NM_001008515



NM_001008521



NM_001009619



NM_001009653



NM_001010965



NM_001011942



NM_001011979



NM_001012159



NM_001012174



NM_001013036



NM_001013163



NM_012576



NM_012583



NM_012774



NM_012858



NM_012935



NM_013220



NM_016994



NM_017138



NM_017263



NM_017294



NM_019170



NM_019251



NM_019302



NM_019374



NM_019623



NM_021262



NM_021264



NM_022236



NM_022269



NM_022398



NM_022515



NM_022694



NM_022709



NM_022961



NM_024125



NM_024139



NM_030844



NM_030858



NM_031028



NM_031138



NM_031518



NM_031597



NM_031822



NM_053402



NM_053421



NM_053502



NM_053613



NM_053621



NM_053826



NM_053876



NM_053901



NM_057152



NM_057196



NM_057204



NM_130740



NM_133405



NM_134356



NM_134411



NM_134432



NM_134457



NM_138889



NM_139253



NM_153316



NM_173837



NM_175598



NM_178101



NM_198751



NM_212525



NM_213567



XM_213240



XM_213336



XM_213992



XM_214720



XM_214895



XM_215184



XM_215372



XM_215424



XM_215566



XM_215602



XM_215949



XM_216112



XM_216191



XM_216515



XM_217326



XM_217825



XM_217837



XM_219045



XM_220506



XM_220606



XM_221030



XM_221635



XM_222251



XM_222832



XM_225866



XM_226237



XM_226722



XM_230846



XM_230856



XM_231552



XM_232855



XM_233377



XM_233535



XM_233679



XM_234017



XM_234441



XM_237291



XM_238063



XM_240417



XM_340918



XM_341239



XM_341857



XM_341950



XM_342141



XM_342312



XM_342398



XM_342579



XM_342662



XM_343446



XM_574233



XM_577170










The genes in this set show abundance of expressed gene product(s) in the Aged Unimpaired population that are significantly increased, as determined by ANOVA, compared to those abundances in Young and Aged Impaired populations combined. Therefore, compounds useful in treating cognitive impairment selected using these genes should increase the abundance or enhance the function of the expressed gene products of these genes.
Example 24
An ANOVA was conducted on the probe set signal values for all present probe sets by combining two groups of animals and comparing them to the third group. An “AU ANOVA” was performed, where Aged Impaired were combined with Young and compared to Aged Unimpaired. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Microarray Results
Table 24 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 24





DG - AU ANOVA DECREASE

















GENBANK ® ID



BF564995



BM389079



AI171599



NM_001000510



NM_001001515



NM_001001799



NM_001004132



NM_001005381



NM_001005876



NM_001005879



NM_001006968



NM_001006994



NM_001007667



NM_001008331



NM_001009652



NM_001011891



NM_001012053



NM_001012083



NM_001012175



NM_001013090



NM_001013153



NM_012568



NM_012740



NM_012798



NM_012809



NM_012829



NM_017063



NM_017066



NM_017197



NM_017201



NM_017305



NM_017321



NM_019185



NM_021671



NM_021751



NM_021770



NM_022217



NM_022282



NM_022589



NM_022690



NM_022863



NM_022928



NM_023991



NM_024000



NM_024146



NM_024159



NM_030861



NM_030994



NM_031022



NM_031043



NM_031235



NM_031351



NM_031356



NM_031520



NM_031594



NM_031646



NM_032062



NM_032072



NM_032616



NM_053448



NM_053542



NM_053868



NM_057201



NM_080886



NM_080887



NM_080895



NM_131906



NM_131914



NM_134468



NM_138840



NM_138858



NM_138891



NM_139254



NM_145089



NM_145785



NM_152790



NM_171994



NM_172157



NM_173120



NM_177481



NM_177927



NM_178095



NM_178847



NM_181388



NM_182674



NM_198764



NM_199097



XM_213270



XM_213591



XM_213779



XM_213954



XM_214238



XM_214709



XM_214751



XM_215286



XM_215403



XM_215574



XM_216102



XM_216400



XM_217078



XM_217732



XM_218502



XM_220805



XM_222111



XM_222152



XM_225983



XM_226789



XM_227025



XM_230967



XM_232640



XM_234483



XM_235156



XM_235179



XM_235940



XM_238151



XM_238213



XM_340775



XM_340802



XM_341058



XM_341104



XM_341497



XM_341558



XM_341584



XM_342477



XM_342588



XM_342682



XM_342863



XM_343273



XM_343415



XM_347236



XM_573983



XM_579546



NM_022250



UniGene ID



Rn.17829



Rn.21816



Rn.22355










The genes in this set show abundance of expressed gene product(s) in the Aged Unimpaired population that are significantly decreased, as determined by ANOVA, compared to those abundances in Young and Aged Impaired populations combined. Therefore, compounds useful in treating cognitive impairment selected using these genes should decrease the abundance or attenuate the function of the expressed gene products of these genes.
Example 25
An ANOVA was conducted on the probe set signal values for all probe sets by combining two groups of animals and comparing them to the third group. An “AI ANOVA” was performed, where Aged Unimpaired were combined with Young and compared to Aged Impaired. All probe sets were considered in the statistical analysis based on the gcRMA method of data extraction from the perfect match sequences for each probe. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Pearson's correlations comparing probe set signal values to learning indices were then calculated for the aged animals (excluding young) across all present probe sets. Again, correlations representing a p-value of less than 0.05 were considered significantly changed.
Microarray Results
Table 25 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 25





CA1 - AI ANOVA POSITIVE CORRELATION


GENBANK ® ID

















AA800031



AI101331



AI639001



BG377379



BG662522



NM_001004209



NM_001005762



NM_001005898



NM_001007651



NM_001008322



NM_001008324



NM_001009600



NM_001011946



NM_001012079



NM_001012111



NM_001012126



NM_001012177



NM_001012223



NM_001013082



NM_001017386



NM_001017450



NM_001024371



NM_001024925



NM_001025419



NM_001029901



NM_001033852



NM_001034933



NM_012543



NM_012562



NM_012577



NM_012671



NM_012686



NM_012777



NM_012884



NM_013015



NM_013060



NM_013091



NM_013107



NM_013173



NM_013191



NM_013198



NM_013219



NM_017068



NM_017223



NM_017267



NM_017356



NM_019318



NM_019362



NM_021775



NM_022198



NM_022226



NM_022502



NM_022617



NM_023978



NM_024163



NM_030863



NM_030992



NM_031014



NM_031034



NM_031147



NM_031521



NM_031552



NM_031812



NM_032066



NM_033443



NM_053021



NM_053407



NM_053445



NM_053467



NM_053485



NM_053538



NM_053777



NM_053783



NM_053910



NM_054001



NM_057204



NM_080907



NM_133534



NM_134390



NM_138502



NM_138914



NM_145674



NM_152790



NM_173101



NM_175578



NM_175582



NM_181639



NM_207602



NM_207617



NM_212528



XM_213329



XM_214968



XM_215037



XM_215095



XM_216837



XM_219262



XM_222242



XM_224337



XM_225631



XM_227870



XM_228072



XM_232608



XM_238362



XM_341081



XM_341851



XM_341936



XM_341940



XM_342291



XM_342297



XM_342317



XM_342521



XM_343274



XM_343468



XM_343773



XM_343776



XM_344421



XM_573100










The genes in this set show abundance of expressed gene product(s) in the Aged Impaired population that are significantly increased, as determined by ANOVA, compared to those abundances in Young and Aged Unimpaired populations combined. In addition, the abundance of expressed gene product(s) in the aged animals positively correlate with learning index of the animals, such that poorer learners have higher abundances of expressed gene products of the selected genes. Therefore, compounds useful in treating cognitive impairment selected using these genes should decrease the abundance or attenuate the function of the expressed gene products of these genes.
Example 26
An ANOVA was conducted on the probe set signal values for all probe sets by combining two groups of animals and comparing them to the third group. An “AI ANOVA” was performed, where Aged Unimpaired were combined with Young and compared to Aged Impaired. All probe sets were considered in the statistical analysis based on the gcRMA method of data extraction from the perfect match sequences for each probe. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Pearson's correlations comparing probe set signal values to learning indices were then calculated for the aged animals (excluding young) across all present probe sets. Again, correlations representing a p-value of less than 0.05 were considered significantly changed.
Microarray Results
Table 26 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 26





CA1 - AI ANOVA NEGATIVE CORRELATION


GENBANK ® ID

















AI227598



AW529408



BF397258



NM_001005381



NM_001008354



NM_001008557



NM_001010946



NM_001012012



NM_001012021



NM_001012187



NM_001012195



NM_001013198



NM_001017376



NM_001025271



NM_001025711



NM_001025738



NM_001033701



NM_012736



NM_013083



NM_013113



NM_017030



NM_017059



NM_019128



NM_019142



NM_019194



NM_021840



NM_022229



NM_022289



NM_022300



NM_022615



NM_031069



NM_031315



NM_031707



NM_031821



NM_053316



NM_053410



NM_053434



NM_053633



NM_053698



NM_053713



NM_053849



NM_053883



NM_080402



NM_133580



NM_138838



NM_138911



NM_139060



NM_139091



NM_172034



NM_199394



NM_199463



NM_213627



XM_213658



XM_214245



XM_214369



XM_214697



XM_215826



XM_216102



XM_216679



XM_216762



XM_216884



XM_217115



XM_217210



XM_218506



XM_219500



XM_219525



XM_221333



XM_221635



XM_223693



XM_224389



XM_224929



XM_225039



XM_232936



XM_234385



XM_235179



XM_235552



XM_235878



XM_236953



XM_242556



XM_243390



XM_340809



XM_341663



XM_342107



XM_342179



XM_342763



XM_342930



XM_343046



XM_343326



XM_343574



XM_343761



XM_344130



XM_345861



XM_345981



XM_573165



XM_575396



XM_577023










The genes in this set show abundance of expressed gene product(s) in the Aged Impaired population that are significantly decreased, as determined by ANOVA, compared to those abundances in Young and Aged Unimpaired populations combined. In addition, the abundance of expressed gene product(s) in the aged animals negatively correlate with learning index of the animals, such that poorer learners have lower abundances of expressed gene products of the selected genes. Therefore, compounds useful in treating cognitive impairment selected using these genes should increase the abundance or enhance the function of the expressed gene products of these genes.
Example 27
An ANOVA was conducted on the probe set signal values for all probe sets by combining two groups of animals and comparing them to the third group. An “AI ANOVA” was performed, where Aged Unimpaired were combined with Young and compared to Aged Impaired. All probe sets were considered in the statistical analysis based on the gcRMA method of data extraction from the perfect match sequences for each probe. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Microarray Results
Table 27 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 27





CA1 - AI ANOVA INCREASE


GENBANK ® ID

















AI012566



AI170346



AI179982



AI410079



AI717047



BF396482



BF417285



BG672075



BG673602



BM392140



L26525



NM_001001511



NM_001001513



NM_001001800



NM_001004072



NM_001004081



NM_001004226



NM_001004250



NM_001004273



NM_001005534



NM_001005539



NM_001005565



NM_001006989



NM_001007000



NM_001007617



NM_001007624



NM_001007625



NM_001007629



NM_001007654



NM_001007665



NM_001007677



NM_001007682



NM_001008344



NM_001008365



NM_001008374



NM_001008829



NM_001008835



NM_001009474



NM_001009623



NM_001011893



NM_001011903



NM_001011917



NM_001011920



NM_001011925



NM_001011959



NM_001011981



NM_001011989



NM_001011991



NM_001011993



NM_001012051



NM_001012057



NM_001012065



NM_001012222



NM_001012744



NM_001013081



NM_001013086



NM_001013087



NM_001013121



NM_001013137



NM_001013174



NM_001013179



NM_001013190



NM_001013240



NM_001017383



NM_001024247



NM_001024261



NM_001025056



NM_001025282



NM_001025289



NM_001025423



NM_001025648



NM_001025721



NM_001025722



NM_001031641



NM_001031644



NM_001033968



NM_001034004



NM_001034090



NM_001034164



NM_012488



NM_012497



NM_012512



NM_012512



NM_012531



NM_012595



NM_012645



NM_012671



NM_012703



NM_012747



NM_012749



NM_012771



NM_012815



NM_012819



NM_012823



NM_012837



NM_012838



NM_012925



NM_012939



NM_013001



NM_013044



NM_013055



NM_013069



NM_013137



NM_013157



NM_016986



NM_017008



NM_017009



NM_017014



NM_017113



NM_017125



NM_017132



NM_017154



NM_017160



NM_017169



NM_017177



NM_017181



NM_017193



NM_017196



NM_017257



NM_017264



NM_017274



NM_017288



NM_017320



NM_017333



NM_017348



NM_017351



NM_017356



NM_017359



NM_019238



NM_019289



NM_019290



NM_019346



NM_019358



NM_019359



NM_020082



NM_021576



NM_021690



NM_021989



NM_022266



NM_022285



NM_022381



NM_022390



NM_022392



NM_022500



NM_022510



NM_022512



NM_022525



NM_022526



NM_022597



NM_022602



NM_022668



NM_022697



NM_022703



NM_022856



NM_024155



NM_024160



NM_024366



NM_024396



NM_030826



NM_030859



NM_030872



NM_030987



NM_031057



NM_031090



NM_031140



NM_031357



NM_031509



NM_031614



NM_031624



NM_031648



NM_031660



NM_031668



NM_031672



NM_031685



NM_031698



NM_031756



NM_031789



NM_031818



NM_031827



NM_031841



NM_031973



NM_040669



NM_053323



NM_053442



NM_053455



NM_053516



NM_053536



NM_053553



NM_053554



NM_053560



NM_053597



NM_053612



NM_053684



NM_053773



NM_053794



NM_053838



NM_053959



NM_053979



NM_053985



NM_054006



NM_057114



NM_057137



NM_057197



NM_080887



NM_080890



NM_130403



NM_130416



NM_130419



NM_130428



NM_130739



NM_133297



NM_133298



NM_133392



NM_133405



NM_133418



NM_133605



NM_133618



NM_133621



NM_134334



NM_134349



NM_134389



NM_134410



NM_134432



NM_138508



NM_138521



NM_138826



NM_138828



NM_138900



NM_138905



NM_138917



NM_139103



NM_139110



NM_139189



NM_139216



NM_139327



NM_145081



NM_145775



NM_147210



NM_153621



NM_153628



NM_172033



NM_172038



NM_172222



NM_172335



NM_173095



NM_173118



NM_173123



NM_173147



NM_175756



NM_175838



NM_176077



NM_178095



NM_181363



NM_181381



NM_181628



NM_183330



NM_184046



NM_198738



NM_199087



NM_199092



NM_199118



NM_199399



NM_199404



NM_207591



NM_207599



NM_207609



NM_212495



NM_212525



NM_212538



XM_213335



XM_213408



XM_213540



XM_213650



XM_213777



XM_213824



XM_213879



XM_214250



XM_214316



XM_214478



XM_214480



XM_214518



XM_214583



XM_214769



XM_214838



XM_215524



XM_215607



XM_215733



XM_215897



XM_216565



XM_216688



XM_216704



XM_216740



XM_216962



XM_217239



XM_217335



XM_217372



XM_218617



XM_218816



XM_218977



XM_219948



XM_220095



XM_220357



XM_220541



XM_221100



XM_223012



XM_223785



XM_224535



XM_224538



XM_225014



XM_225147



XM_225160



XM_225628



XM_225644



XM_225711



XM_226165



XM_228701



XM_230036



XM_230291



XM_231287



XM_231620



XM_231749



XM_235497



XM_235558



XM_235710



XM_237381



XM_237790



XM_238019



XM_238380



XM_238770



XM_243637



XM_341389



XM_341509



XM_341796



XM_341882



XM_341957



XM_342002



XM_342300



XM_342528



XM_342600



XM_342686



XM_343034



XM_343259



XM_343268



XM_343306



XM_343396



XM_343427



XM_344524



XM_345535



XM_345584



XM_345825



XM_345849



XM_345870



XM_347163



XM_575585



XM_576343



XM_576401



XM_576459










The genes in this set show abundance of expressed gene product(s) in the Aged Impaired population that are significantly increased, as determined by ANOVA, compared to those abundances in Young and Aged Unimpaired populations combined. Therefore, compounds useful in treating cognitive impairment selected using these genes should decrease the abundance or attenuate the function of the expressed gene products of these genes.
Example 28
An ANOVA was conducted on the probe set signal values for all probe sets by combining two groups of animals and comparing them to the third group. An “AI ANOVA” was performed, where Aged Unimpaired were combined with Young and compared to Aged Impaired. All probe sets were considered in the statistical analysis based on the gcRMA method of data extraction from the perfect match sequences for each probe. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Microarray Results
Table 28 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 28





CA1 - AI ANOVA DECREASE


GENBANK ® ID

















AF073379



AI029288



AI229643



AI599699



AW528891



BE118251



BF404393



BF410962



NM_001002289



NM_001002851



NM_001003957



NM_001004198



NM_001004210



NM_001004277



NM_001004279



NM_001004442



NM_001005536



NM_001005872



NM_001007728



NM_001008320



NM_001008353



NM_001009268



NM_001009605



NM_001011901



NM_001011966



NM_001012043



NM_001012143



NM_001012144



NM_001012211



NM_001012475



NM_001013066



NM_001013096



NM_001013099



NM_001013128



NM_001013133



NM_001013178



NM_001013244



NM_001014792



NM_001015011



NM_001024318



NM_001024766



NM_001024790



NM_001024794



NM_001025136



NM_001025402



NM_001025414



NM_001025650



NM_001025667



NM_001025705



NM_001033655



NM_001033699



NM_001033974



NM_001033984



NM_001034014



NM_001034068



NM_001034131



NM_012568



NM_012573



NM_012576



NM_012596



NM_012651



NM_012653



NM_012688



NM_012701



NM_012727



NM_012780



NM_012835



NM_012934



NM_012991



NM_013036



NM_013100



NM_013102



NM_013111



NM_013126



NM_013161



NM_013179



NM_013189



NM_013199



NM_017041



NM_017073



NM_017238



NM_017303



NM_017352



NM_019163



NM_019218



NM_019282



NM_019288



NM_019347



NM_019348



NM_020306



NM_021266



NM_021653



NM_021763



NM_021843



NM_022249



NM_022254



NM_022688



NM_022847



NM_022850



NM_022867



NM_022962



NM_023971



NM_023989



NM_024362



NM_024401



NM_031056



NM_031123



NM_031130



NM_031318



NM_031720



NM_031730



NM_031753



NM_031777



NM_031828



NM_033485



NM_053349



NM_053441



NM_053487



NM_053503



NM_053530



NM_053616



NM_053693



NM_053703



NM_053718



NM_053740



NM_053775



NM_053781



NM_053786



NM_053876



NM_053888



NM_053895



NM_054008



NM_057212



NM_130748



NM_133318



NM_133411



NM_133548



NM_133591



NM_133596



NM_134383



NM_134388



NM_138837



NM_138907



NM_138922



NM_144758



NM_147135



NM_147142



NM_153317



NM_173145



NM_177419



NM_181370



NM_181380



NM_182668



NM_182844



NM_198749



NM_198760



NM_198761



NM_198770



NM_199373



U48828



XM_213440



XM_213842



XM_213954



XM_214093



XM_214312



XM_214621



XM_214673



XM_214696



XM_214823



XM_214883



XM_215376



XM_215451



XM_215883



XM_215892



XM_215984



XM_216047



XM_216161



XM_216225



XM_216318



XM_217560



XM_217570



XM_217601



XM_218138



XM_218187



XM_218200



XM_218347



XM_218845



XM_219372



XM_219905



XM_221050



XM_221212



XM_221231



XM_221380



XM_221426



XM_221641



XM_221724



XM_221888



XM_221962



XM_222103



XM_222184



XM_222476



XM_222770



XM_223643



XM_223729



XM_225138



XM_225138



XM_225168



XM_225169



XM_225220



XM_226349



XM_226436



XM_226843



XM_226874



XM_227104



XM_227444



XM_227811



XM_230449



XM_230877



XM_231798



XM_231803



XM_232197



XM_232220



XM_232599



XM_233141



XM_233499



XM_233792



XM_234219



XM_234263



XM_234299



XM_234345



XM_234345



XM_234470



XM_234481



XM_234514



XM_234540



XM_234546



XM_235768



XM_239074



XM_239260



XM_341111



XM_341391



XM_341590



XM_341642



XM_341653



XM_341709



XM_342151



XM_342217



XM_342481



XM_342552



XM_342692



XM_342734



XM_342775



XM_342804



XM_342808



XM_343045



XM_343148



XM_343548



XM_344594



XM_345418



XM_345789



XM_574979



XM_575397










The genes in this set show abundance of expressed gene product(s) in the Aged Impaired population that are significantly decreased, as determined by ANOVA, compared to those abundances in Young and Aged Unimpaired populations combined. Therefore, compounds useful in treating cognitive impairment selected using these genes should increase the abundance or enhance the function of the expressed gene products of these genes.
Example 29
An ANOVA was conducted on the probe set signal values for all probe sets by combining two groups of animals and comparing them to the third group. An “AU ANOVA” was performed, where Aged Impaired were combined with Young and compared to Aged Unimpaired. All probe sets were considered in the statistical analysis based on the gcRMA method of data extraction from the perfect match sequences for each probe. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Pearson's correlations comparing probe set signal values to learning indices were then calculated for the aged animals (excluding young) across all present probe sets. Again, correlations representing a p-value of less than 0.05 were considered significantly changed.
Microarray Results
Table 29 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 29





AU ANOVA POSITIVE CORRELATION


GENBANK ® ID

















AA955871



BF288303



BF410275



NM_001002016



NM_001025403



NM_001025744



NM_001035233



NM_012623



NM_012660



NM_012869



NM_013159



NM_013176



NM_013197



NM_017007



NM_017103



NM_017294



NM_017306



NM_017347



NM_017354



NM_019183



NM_019239



NM_019309



NM_019351



NM_019354



NM_031097



NM_033359



NM_053383



NM_053644



NM_053669



NM_053721



NM_053811



NM_053824



NM_053930



NM_053972



NM_057208



NM_080577



NM_080786



NM_130406



NM_131906



NM_138848



NM_153469



NM_172041



NM_172224



NM_173325



XM_213564



XM_214400



XM_216018



XM_216784



XM_218336



XM_220775



XM_223057



XM_223227



XM_224618



XM_230288



XM_230616



XM_230765



XM_234508



XM_239329



XM_341972



XM_342003



XM_342723



XM_343303



XM_343764



XM_573915



XM_575671










The genes in this set show abundance of expressed gene product(s) in the Aged Unimpaired population that are significantly decreased, as determined by ANOVA, compared to those abundances in Young and Aged Impaired populations combined. In addition, the abundance of expressed gene product(s) in the aged animals positively correlate with learning index of the animals, such that poorer learners have higher abundances of expressed gene products of the selected genes. Therefore, compounds useful in treating cognitive impairment selected using these genes should decrease the abundance or attenuate the function of the expressed gene products of these genes.
Example 30
An ANOVA was conducted on the probe set signal values for all probe sets by combining two groups of animals and comparing them to the third group. An “AU ANOVA” was performed, where Aged Impaired were combined with Young and compared to Aged Unimpaired. All probe sets were considered in the statistical analysis based on the gcRMA method of data extraction from the perfect match sequences for each probe. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Pearson's correlations comparing probe set signal values to learning indices were then calculated for the aged animals (excluding young) across all present probe sets. Again, correlations representing a p-value of less than 0.05 were considered significantly changed.
Microarray Results
Table 30 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 30





CA1 - AU ANOVA NEGATIVE CORRELATION


GENBANK ® ID

















BG378690



NM_001002830



NM_001004075



NM_001008382



NM_001008524



NM_001011936



NM_001013204



NM_001013212



NM_001033674



NM_001034129



NM_017089



NM_017271



NM_019161



NM_019364



NM_021262



NM_022921



NM_024002



NM_024131



NM_031041



NM_031082



NM_031122



NM_031133



NM_031139



NM_031642



NM_031645



NM_032058



NM_053389



NM_053499



NM_053500



NM_053578



NM_057207



NM_134395



NM_134408



NM_134417



NM_138536



NM_138856



NM_145677



NM_152861



NM_172243



XM_213725



XM_215082



XM_215616



XM_216295



XM_216400



XM_216712



XM_216841



XM_223674



XM_225726



XM_228197



XM_233467



XM_236745



XM_237179



XM_239510



XM_340856



XM_342131



XM_342268



XM_343318



XM_343413



XM_343513










The genes in this set show abundance of expressed gene product(s) in the Aged Unimpaired population that are significantly increased, as determined by ANOVA, compared to those abundances in Young and Aged Impaired populations combined. In addition, the abundance of expressed gene product(s) in the aged animals negatively correlate with learning index of the animals, such that poorer learners have lower abundances of expressed gene products of the selected genes. Therefore, compounds useful in treating cognitive impairment selected using these genes should increase the abundance or enhance the function of the expressed gene products of these genes.
Example 31
An ANOVA was conducted on the probe set signal values for all probe sets by combining two groups of animals and comparing them to the third group. An “AU ANOVA” was performed, where Aged Impaired were combined with Young and compared to Aged Unimpaired. All probe sets were considered in the statistical analysis based on the gcRMA method of data extraction from the perfect match sequences for each probe. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Microarray Results
Table 31 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 31





CA1 - AU ANOVA INCREASE


GENBANK ® ID

















AA859127



AA998007



AI137495



BF287008



BI294974



BM384139



BM388245



BM390128



NM_001004090



NM_001004238



NM_001004255



NM_001004443



NM_001005528



NM_001006969



NM_001007557



NM_001007609



NM_001007654



NM_001008339



NM_001008364



NM_001008515



NM_001009604



NM_001009973



NM_001009974



NM_001010961



NM_001011922



NM_001011950



NM_001011953



NM_001012003



NM_001012030



NM_001012039



NM_001012096



NM_001012105



NM_001012131



NM_001012181



NM_001012459



NM_001013151



NM_001013152



NM_001013154



NM_001013165



NM_001013165



NM_001013184



NM_001024964



NM_001025035



NM_001025137



NM_001025709



NM_001025725



NM_001030024



NM_001033866



NM_001034110



NM_012592



NM_012720



NM_012805



NM_012806



NM_012848



NM_012895



NM_012913



NM_012924



NM_012935



NM_012992



NM_013057



NM_013088



NM_013150



NM_013151



NM_016994



NM_017212



NM_017290



NM_017318



NM_019251



NM_019361



NM_021584



NM_021846



NM_022205



NM_022252



NM_022499



NM_022529



NM_022545



NM_024125



NM_024153



NM_031058



NM_031112



NM_031148



NM_031517



NM_031623



NM_031740



NM_031763



NM_053482



NM_053662



NM_053707



NM_053926



NM_057107



NM_057108



NM_057143



NM_057196



NM_080906



NM_080910



NM_130740



NM_131911



NM_131914



NM_133303



NM_134326



NM_138530



NM_138835



NM_138873



NM_145084



NM_145670



NM_145673



NM_145788



NM_147205



NM_153475



NM_172325



NM_175764



NM_182821



NM_182955



NM_201415



NM_212496



NM_213628



XM_213370



XM_213560



XM_213898



XM_213906



XM_214153



XM_214163



XM_214927



XM_215423



XM_215564



XM_215947



XM_215949



XM_216202



XM_216403



XM_216407



XM_216643



XM_216757



XM_216893



XM_217086



XM_218162



XM_218502



XM_218648



XM_219879



XM_219925



XM_220398



XM_221120



XM_221307



XM_223327



XM_223580



XM_223597



XM_224863



XM_225439



XM_226076



XM_226329



XM_230845



XM_233535



XM_233883



XM_234238



XM_234377



XM_234394



XM_235296



XM_236948



XM_237093



XM_238731



XM_340798



XM_341508



XM_341578



XM_342154



XM_342580



XM_342662



XM_342810



XM_342819



XM_343050



XM_344976



XM_574504



XM_575968



XM_578542










The genes in this set show abundance of expressed gene product(s) in the Aged Unimpaired population that are significantly increased, as determined by ANOVA, compared to those abundances in Young and Aged Impaired populations combined. Therefore, compounds useful in treating cognitive impairment selected using these genes should increase the abundance or enhance the function of the expressed gene products of these genes.
Example 32
An ANOVA was conducted on the probe set signal values for all probe sets by combining two groups of animals and comparing them to the third group. An “AU ANOVA” was performed, where Aged Impaired were combined with Young and compared to Aged Unimpaired. All probe sets were considered in the statistical analysis based on the gcRMA method of data extraction from the perfect match sequences for each probe. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Microarray Results
Table 32 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 32





CA1 - AU ANOVA DECREASE


GENBANK ® ID

















AA945615



AI764408



BE103926



BF403383



BF567766



BI287800



NM_001002815



NM_001004132



NM_001007607



NM_001007616



NM_001007629



NM_001007725



NM_001007758



NM_001008369



NM_001008823



NM_001009258



NM_001009405



NM_001011894



NM_001011995



NM_001012101



NM_001012191



NM_001012737



NM_001013044



NM_001013108



NM_001013161



NM_001013224



NM_001013432



NM_001013910



NM_001015004



NM_001017381



NM_001024756



NM_001024781



NM_001024795



NM_001024823



NM_001025032



NM_001025032



NM_001025416



NM_001025693



NM_001031656



NM_001031845



NM_001033757



NM_001033882



NM_001033951



NM_001034020



NM_001034133



NM_001034163



NM_001034849



NM_012504



NM_012555



NM_012572



NM_012598



NM_012654



NM_012774



NM_012853



NM_012863



NM_012877



NM_012950



NM_012983



NM_013002



NM_013127



NM_013160



NM_017049



NM_017134



NM_017139



NM_017239



NM_017256



NM_017316



NM_019140



NM_019156



NM_020074



NM_021659



NM_021859



NM_022202



NM_022382



NM_022396



NM_022600



NM_022609



NM_022676



NM_022690



NM_022853



NM_022946



NM_023972



NM_024147



NM_024355



NM_024356



NM_024383



NM_030862



NM_031008



NM_031037



NM_031046



NM_031073



NM_031132



NM_031332



NM_031353



NM_031356



NM_031511



NM_031528



NM_031569



NM_031571



NM_031575



NM_031617



NM_031738



NM_031771



NM_031967



NM_032062



NM_032613



NM_033097



NM_033376



NM_053306



NM_053310



NM_053360



NM_053428



NM_053559



NM_053594



NM_053599



NM_053601



NM_053643



NM_053655



NM_053686



NM_053764



NM_053788



NM_053801



NM_053842



NM_053846



NM_053859



NM_053870



NM_053960



NM_053994



NM_057213



NM_080394



NM_080580



NM_080885



NM_130829



NM_131913



NM_133397



NM_133410



NM_133511



NM_133566



NM_134331



NM_134377



NM_134461



NM_139104



NM_139263



NM_144740



NM_171992



NM_172039



NM_173115



NM_173146



NM_173312



NM_173837



NM_181092



NM_181638



NM_182673



NM_182824



NM_182842



NM_198758



NM_199111



NM_203338



NM_207592



X55812



XM_213318



XM_213993



XM_214630



XM_214669



XM_214720



XM_214775



XM_214916



XM_215469



XM_215742



XM_215887



XM_215939



XM_216189



XM_216745



XM_217021



XM_217124



XM_217188



XM_217279



XM_217388



XM_218412



XM_218851



XM_219529



XM_219801



XM_220224



XM_220602



XM_220884



XM_220982



XM_221672



XM_221977



XM_222223



XM_222896



XM_224261



XM_224952



XM_225259



XM_225625



XM_226213



XM_230296



XM_232488



XM_232640



XM_233231



XM_234205



XM_235426



XM_235500



XM_235640



XM_239504



XM_240330



XM_241981



XM_242982



XM_340775



XM_340911



XM_340967



XM_340999



XM_341790



XM_341998



XM_342032



XM_342134



XM_342389



XM_342409



XM_342632



XM_342905



XM_343058



XM_343247



XM_343394



XM_343459



XM_343483



XM_343582



XM_344434



XM_346464



XM_576183










The genes in this set show abundance of expressed gene product(s) in the Aged Unimpaired population that are significantly decreased, as determined by ANOVA, compared to those abundances in Young and Aged Impaired populations combined. Therefore, compounds useful in treating cognitive impairment selected using these genes should decrease the abundance or attenuate the function of the expressed gene products of these genes.
Example 33
An ANOVA was conducted on the probe set signal values for all probe sets by combining two groups of animals and comparing them to the third group. An “AI ANOVA” was performed, where Aged Unimpaired were combined with Young and compared to Aged Impaired. All probe sets were considered in the statistical analysis based on the gcRMA method of data extraction from the perfect match sequences for each probe. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Pearson's correlations comparing probe set signal values to learning indices were then calculated for the aged animals (excluding young) across all present probe sets. Again, correlations representing a p-value of less than 0.05 were considered significantly changed.
Microarray Results
Table 33 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 33





CA3 - AI ANOVA POSITIVE CORRELATION


GENBANK ® ID

















AA800192



AA892549



AA956317



AI103026



AI556426



BF398122



BI282114



BM391371



NM_001001511



NM_001002016



NM_001004080



NM_001004255



NM_001005765



NM_001007145



NM_001007677



NM_001007797



NM_001008316



NM_001008331



NM_001008374



NM_001008725



NM_001008767



NM_001008880



NM_001009474



NM_001010961



NM_001011893



NM_001011929



NM_001011946



NM_001011954



NM_001011991



NM_001012025



NM_001012040



NM_001012075



NM_001012097



NM_001012111



NM_001012137



NM_001012138



NM_001012150



NM_001012203



NM_001012215



NM_001012235



NM_001013110



NM_001013121



NM_001013130



NM_001013200



NM_001013246



NM_001015009



NM_001017386



NM_001017503



NM_001024238



NM_001024771



NM_001025125



NM_001025289



NM_001031647



NM_001033696



NM_001033701



NM_001033852



NM_001034090



NM_012507



NM_012514



NM_012543



NM_012569



NM_012577



NM_012618



NM_012655



NM_012671



NM_012720



NM_012720



NM_012747



NM_012749



NM_012777



NM_012778



NM_012804



NM_012816



NM_012825



NM_012894



NM_012920



NM_012925



NM_012963



NM_012983



NM_013005



NM_013044



NM_013045



NM_013058



NM_013060



NM_013065



NM_013096



NM_013137



NM_013176



NM_013198



NM_017006



NM_017031



NM_017037



NM_017041



NM_017068



NM_017073



NM_017092



NM_017148



NM_017166



NM_017197



NM_017206



NM_017223



NM_017251



NM_017261



NM_017307



NM_017333



NM_017354



NM_017357



NM_019161



NM_019168



NM_019175



NM_019204



NM_019257



NM_019321



NM_019359



NM_021595



NM_021682



NM_021762



NM_021868



NM_022207



NM_022238



NM_022276



NM_022285



NM_022390



NM_022799



NM_022861



NM_023978



NM_024398



NM_030832



NM_030868



NM_030872



NM_031031



NM_031033



NM_031034



NM_031035



NM_031049



NM_031087



NM_031091



NM_031092



NM_031093



NM_031140



NM_031144



NM_031521



NM_031552



NM_031665



NM_031841



NM_032990



NM_052807



NM_053021



NM_053323



NM_053328



NM_053369



NM_053424



NM_053467



NM_053475



NM_053502



NM_053576



NM_053598



NM_053612



NM_053681



NM_053735



NM_053757



NM_053766



NM_053799



NM_053824



NM_053926



NM_053936



NM_053985



NM_053994



NM_054001



NM_057114



NM_057148



NM_057197



NM_057200



NM_057208



NM_080691



NM_130403



NM_133317



NM_133398



NM_133548



NM_133560



NM_133602



NM_133605



NM_138905



NM_138914



NM_139038



NM_139103



NM_139330



NM_145092



NM_145670



NM_147210



NM_152790



NM_152847



NM_153308



NM_153311



NM_172033



NM_172068



NM_173152



NM_175578



NM_175582



NM_175838



NM_176857



NM_178095



NM_181388



NM_199119



XM_213329



XM_213408



XM_213421



XM_213746



XM_213779



XM_213849



XM_213920



XM_213966



XM_214029



XM_214371



XM_214518



XM_214583



XM_214968



XM_215080



XM_215095



XM_215184



XM_215367



XM_215469



XM_215733



XM_215872



XM_216386



XM_216688



XM_216704



XM_216759



XM_216965



XM_217192



XM_217367



XM_217372



XM_217409



XM_218162



XM_218816



XM_219998



XM_220207



XM_221100



XM_221497



XM_221562



XM_222024



XM_222617



XM_222661



XM_222745



XM_222780



XM_223227



XM_223583



XM_224256



XM_224337



XM_224732



XM_224852



XM_225008



XM_225014



XM_225160



XM_225404



XM_225512



XM_226165



XM_227203



XM_227409



XM_227581



XM_230036



XM_230592



XM_231287



XM_231620



XM_232354



XM_232671



XM_232732



XM_233761



XM_234328



XM_234345



XM_234377



XM_234468



XM_235064



XM_235657



XM_236362



XM_237042



XM_237241



XM_237381



XM_238019



XM_238057



XM_238103



XM_238213



XM_238362



XM_238649



XM_240978



XM_241375



XM_241671



XM_340810



XM_340879



XM_340997



XM_341052



XM_341172



XM_341215



XM_341288



XM_341538



XM_341605



XM_341633



XM_341882



XM_341911



XM_342100



XM_342102



XM_342291



XM_342297



XM_342317



XM_342521



XM_342535



XM_342626



XM_342662



XM_342928



XM_343055



XM_343092



XM_343157



XM_343268



XM_343274



XM_343281



XM_343427



XM_343570



XM_343630



XM_343764



XM_343773



XM_343856



XM_343971



XM_344046



XM_344785



XM_345446



XM_345584



XM_345825



XM_347166



XM_347223



XM_573100



XM_575396



XM_576311



XM_576343



XM_576401










The genes in this set show abundance of expressed gene product(s) in the Aged Impaired population that are significantly increased, as determined by ANOVA, compared to those abundances in Young and Aged Unimpaired populations combined. In addition, the abundance of expressed gene product(s) in the aged animals positively correlate with learning index of the animals, such that poorer learners have higher abundances of expressed gene products of the selected genes. Therefore, compounds useful in treating cognitive impairment selected using these genes should decrease the abundance or attenuate the function of the expressed gene products of these genes.
Example 34
An ANOVA was conducted on the probe set signal values for all probe sets by combining two groups of animals and comparing them to the third group. An “AI ANOVA” was performed, where Aged Unimpaired were combined with Young and compared to Aged Impaired. All probe sets were considered in the statistical analysis based on the gcRMA method of data extraction from the perfect match sequences for each probe. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Pearson's correlations comparing probe set signal values to learning indices were then calculated for the aged animals (excluding young) across all present probe sets. Again, correlations representing a p-value of less than 0.05 were considered significantly changed.
Microarray Results
Table 34 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 34





CA3 - AI ANOVA NEGATIVE CORRELATION


GENBANK ® ID

















BF282715



BM391206



NM_001001718



NM_001002818



NM_001003653



NM_001004075



NM_001004217



NM_001004222



NM_001005543



NM_001006602



NM_001006984



NM_001006994



NM_001007656



NM_001007707



NM_001008304



NM_001008511



NM_001008553



NM_001008557



NM_001009422



NM_001009666



NM_001009677



NM_001010946



NM_001011923



NM_001011934



NM_001011957



NM_001011996



NM_001012012



NM_001012098



NM_001012101



NM_001012125



NM_001012192



NM_001013133



NM_001013201



NM_001013906



NM_001014785



NM_001024250



NM_001024756



NM_001029898



NM_001031649



NM_001033069



NM_012500



NM_012600



NM_012739



NM_013083



NM_013090



NM_013111



NM_013113



NM_013130



NM_013174



NM_017126



NM_017135



NM_017352



NM_021688



NM_021699



NM_022186



NM_022188



NM_022264



NM_022272



NM_022511



NM_022599



NM_022688



NM_022860



NM_022938



NM_022941



NM_022948



NM_022961



NM_023104



NM_024366



NM_024381



NM_024390



NM_030830



NM_030841



NM_031006



NM_031030



NM_031062



NM_031070



NM_031344



NM_031520



NM_031569



NM_031583



NM_031742



NM_031749



NM_031851



NM_032079



NM_033349



NM_053334



NM_053388



NM_053528



NM_053575



NM_053613



NM_053621



NM_053622



NM_053792



NM_053810



NM_053849



NM_053883



NM_053950



NM_053990



NM_053997



NM_054008



NM_133394



NM_133425



NM_133562



NM_133596



NM_133596



NM_138833



NM_138866



NM_138893



NM_139254



NM_139337



NM_145098



NM_147141



NM_152861



NM_172062



NM_173094



NM_173115



NM_178091



NM_182844



NM_184051



NM_198726



NM_198756



NM_198783



NM_199098



NM_199500



NM_206881



NM_212496



NM_212544



XM_213426



XM_213626



XM_213672



XM_214331



XM_214400



XM_214475



XM_214485



XM_214491



XM_214550



XM_214895



XM_215069



XM_215082



XM_215134



XM_215826



XM_215883



XM_215931



XM_216112



XM_217385



XM_217908



XM_218851



XM_219796



XM_220219



XM_221270



XM_221304



XM_221627



XM_221833



XM_221910



XM_222717



XM_223327



XM_223693



XM_223921



XM_225039



XM_225072



XM_226843



XM_227414



XM_227428



XM_232735



XM_232745



XM_232901



XM_233544



XM_234219



XM_235295



XM_235878



XM_236614



XM_240178



XM_340884



XM_340889



XM_341015



XM_341249



XM_341314



XM_341326



XM_341520



XM_341663



XM_341955



XM_341969



XM_342107



XM_342295



XM_342692



XM_343140



XM_343413



XM_343429



XM_343614



XM_344009



XM_344168



XM_344426



XM_345668



XM_345848



XM_346887










The genes in this set show abundance of expressed gene product(s) in the Aged Impaired population that are significantly decreased, as determined by ANOVA, compared to those abundances in Young and Aged Unimpaired populations combined. In addition, the abundance of expressed gene product(s) in the aged animals negatively correlate with learning index of the animals, such that poorer learners have lower abundances of expressed gene products of the selected genes. Therefore, compounds useful in treating cognitive impairment selected using these genes should increase the abundance or enhance the function of the expressed gene products of these genes.
Example 35
An ANOVA was conducted on the probe set signal values for all probe sets by combining two groups of animals and comparing them to the third group. An “AI ANOVA” was performed, where Aged Unimpaired were combined with Young and compared to Aged Impaired. All probe sets were considered in the statistical analysis based on the gcRMA method of data extraction from the perfect match sequences for each probe. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Microarray Results
Table 35 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 35





CA3 - AI ANOVA INCREASE


GENBANK ® ID

















AI029288



AI235284



AW535280



BE118404



BF288606



BI273920



BI274299



BM390128



NM_001001800



NM_001004068



NM_001004214



NM_001004239



NM_001005539



NM_001006963



NM_001007641



NM_001007712



NM_001007734



NM_001007739



NM_001007803



NM_001008312



NM_001008509



NM_001008861



NM_001008893



NM_001009239



NM_001009641



NM_001009660



NM_001009668



NM_001009683



NM_001011890



NM_001011910



NM_001011920



NM_001011970



NM_001011974



NM_001011989



NM_001012039



NM_001012057



NM_001012061



NM_001012067



NM_001012123



NM_001012162



NM_001012181



NM_001012201



NM_001012208



NM_001012217



NM_001012275



NM_001013087



NM_001013120



NM_001013179



NM_001013210



NM_001013213



NM_001013250



NM_001015026



NM_001024903



NM_001024925



NM_001025418



NM_001025423



NM_001025739



NM_001025744



NM_001031641



NM_001033683



NM_001033964



NM_001034004



NM_001034110



NM_001034157



NM_001034933



NM_001034999



NM_012519



NM_012532



NM_012555



NM_012573



NM_012703



NM_012713



NM_012717



NM_012722



NM_012775



NM_012788



NM_012806



NM_012842



NM_012884



NM_013015



NM_013016



NM_013029



NM_013047



NM_013070



NM_013086



NM_013088



NM_013091



NM_013107



NM_013132



NM_013164



NM_013191



NM_013194



NM_016989



NM_017009



NM_017013



NM_017015



NM_017024



NM_017052



NM_017060



NM_017062



NM_017109



NM_017125



NM_017137



NM_017181



NM_017193



NM_017196



NM_017200



NM_017212



NM_017234



NM_017259



NM_017274



NM_017289



NM_017320



NM_017347



NM_017351



NM_019160



NM_019242



NM_019249



NM_019269



NM_019358



NM_020082



NM_021264



NM_021695



NM_021989



NM_022178



NM_022281



NM_022401



NM_022500



NM_022502



NM_022516



NM_022592



NM_022617



NM_022677



NM_022699



NM_022800



NM_022853



NM_022856



NM_023025



NM_024001



NM_024155



NM_024372



NM_024396



NM_030871



NM_030989



NM_031005



NM_031018



NM_031027



NM_031099



NM_031107



NM_031132



NM_031321



NM_031357



NM_031509



NM_031576



NM_031620



NM_031648



NM_031672



NM_031677



NM_031694



NM_031797



NM_031806



NM_031818



NM_031827



NM_031970



NM_032067



NM_032462



NM_032619



NM_033097



NM_033230



NM_033443



NM_052981



NM_053434



NM_053442



NM_053493



NM_053506



NM_053516



NM_053550



NM_053553



NM_053560



NM_053599



NM_053633



NM_053639



NM_053796



NM_053840



NM_053893



NM_053895



NM_058211



NM_078622



NM_080584



NM_080688



NM_131911



NM_133298



NM_133303



NM_133307



NM_133511



NM_133534



NM_133545



NM_133598



NM_133611



NM_134334



NM_134349



NM_134390



NM_134408



NM_134453



NM_138520



NM_138828



NM_138832



NM_139043



NM_139105



NM_139110



NM_139216



NM_139255



NM_147136



NM_147206



NM_147207



NM_171992



NM_172030



NM_173116



NM_173118



NM_175595



NM_175843



NM_176075



NM_177419



NM_181475



NM_182821



NM_182843



NM_198743



NM_198787



NM_199093



NM_199118



NM_199388



NM_199499



NM_203366



NM_206950



NM_207609



NM_212523



NM_213563



NM_214457



XM_213688



XM_214035



XM_214480



XM_214958



XM_215076



XM_215177



XM_215466



XM_215576



XM_215607



XM_215757



XM_215935



XM_215949



XM_216004



XM_216407



XM_216565



XM_216717



XM_216872



XM_216910



XM_216968



XM_217062



XM_217188



XM_217254



XM_217263



XM_217441



XM_217570



XM_218293



XM_218336



XM_218382



XM_218617



XM_219296



XM_219539



XM_219785



XM_220175



XM_220333



XM_220805



XM_220918



XM_220986



XM_221307



XM_221387



XM_222911



XM_223781



XM_224474



XM_224535



XM_224561



XM_225020



XM_225147



XM_225628



XM_226510



XM_226874



XM_226987



XM_227066



XM_227870



XM_228044



XM_228073



XM_231566



XM_231620



XM_231650



XM_231763



XM_232809



XM_232865



XM_233603



XM_234281



XM_235480



XM_235552



XM_235558



XM_235609



XM_235710



XM_236009



XM_236020



XM_236196



XM_236560



XM_237371



XM_237415



XM_238205



XM_240311



XM_242032



XM_242644



XM_242982



XM_243637



XM_341111



XM_341133



XM_341877



XM_341940



XM_341957



XM_342002



XM_342052



XM_342218



XM_342286



XM_342397



XM_342800



XM_343259



XM_343303



XM_343396



XM_343412



XM_343479



XM_344524



XM_345535



XM_574504



XM_575585



XM_576238



XM_576459










The genes in this set show abundance of expressed gene product(s) in the Aged Impaired population that are significantly increased, as determined by ANOVA, compared to those abundances in Young and Aged Unimpaired populations combined. Therefore, compounds useful in treating cognitive impairment selected using these genes should decrease the abundance or attenuate the function of the expressed gene products of these genes.
Example 36
An ANOVA was conducted on the probe set signal values for all probe sets by combining two groups of animals and comparing them to the third group. An “AI ANOVA” was performed, where Aged Unimpaired were combined with Young and compared to Aged Impaired. All probe sets were considered in the statistical analysis based on the gcRMA method of data extraction from the perfect match sequences for each probe. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Microarray Results
Table 36 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 36





CA3 - AI ANOVA DECREASE


GENBANK ® ID

















AA943681



AI228348



AW524426



AW524733



BE103926



BF282660



BF407666



BG379941



BG380494



BI287800



NM_001002253



NM_001002828



NM_001003978



NM_001004078



NM_001004132



NM_001004133



NM_001004210



NM_001004227



NM_001004235



NM_001004250



NM_001004277



NM_001004279



NM_001004442



NM_001005884



NM_001005885



NM_001005905



NM_001005908



NM_001006970



NM_001006981



NM_001006997



NM_001007014



NM_001007149



NM_001007643



NM_001007720



NM_001007742



NM_001008299



NM_001008317



NM_001008382



NM_001008766



NM_001008888



NM_001009180



NM_001009258



NM_001009424



NM_001009536



NM_001009619



NM_001009640



NM_001009661



NM_001009719



NM_001009831



NM_001009967



NM_001010963



NM_001010965



NM_001011901



NM_001011906



NM_001011924



NM_001011932



NM_001011950



NM_001011951



NM_001011955



NM_001011966



NM_001011998



NM_001012017



NM_001012035



NM_001012038



NM_001012060



NM_001012068



NM_001012103



NM_001012119



NM_001012129



NM_001012144



NM_001012152



NM_001012187



NM_001012191



NM_001012195



NM_001012197



NM_001012473



NM_001012738



NM_001013058



NM_001013076



NM_001013170



NM_001013183



NM_001013189



NM_001013198



NM_001013218



NM_001013235



NM_001013426



NM_001013434



NM_001014793



NM_001017377



NM_001024261



NM_001024360



NM_001024754



NM_001025032



NM_001025114



NM_001025271



NM_001025411



NM_001025686



NM_001025696



NM_001025705



NM_001025738



NM_001029900



NM_001029910



NM_001030023



NM_001030029



NM_001030030



NM_001030037



NM_001031645



NM_001031659



NM_001033079



NM_001033674



NM_001033675



NM_001033679



NM_001033684



NM_001033702



NM_001033708



NM_001033715



NM_001033899



NM_001033974



NM_001034014



NM_001034083



NM_001034104



NM_001034112



NM_001034925



NM_001034937



NM_001034994



NM_001035001



NM_001035221



NM_012508



NM_012513



NM_012526



NM_012598



NM_012647



NM_012664



NM_012670



NM_012736



NM_012757



NM_012828



NM_012839



NM_012856



NM_012887



NM_012905



NM_012932



NM_012934



NM_012956



NM_012985



NM_013002



NM_013018



NM_013055



NM_013067



NM_013079



NM_013131



NM_013134



NM_013177



NM_013179



NM_013189



NM_013192



NM_013214



NM_013219



NM_013223



NM_017011



NM_017025



NM_017042



NM_017063



NM_017107



NM_017136



NM_017175



NM_017243



NM_017268



NM_017278



NM_017295



NM_017313



NM_017318



NM_017322



NM_017332



NM_017344



NM_017346



NM_017352



NM_017359



NM_019124



NM_019140



NM_019169



NM_019182



NM_019194



NM_019196



NM_019218



NM_019226



NM_019234



NM_019264



NM_019277



NM_019304



NM_019348



NM_019376



NM_019377



NM_021697



NM_021739



NM_021757



NM_021758



NM_021765



NM_021850



NM_022008



NM_022209



NM_022278



NM_022289



NM_022300



NM_022301



NM_022383



NM_022387



NM_022521



NM_022585



NM_022609



NM_022674



NM_022685



NM_022850



NM_022863



NM_022869



NM_022934



NM_022962



NM_023957



NM_023960



NM_023974



NM_023975



NM_023977



NM_023979



NM_024137



NM_024139



NM_024156



NM_024161



NM_024351



NM_024362



NM_024374



NM_024403



NM_024486



NM_030835



NM_031090



NM_031138



NM_031146



NM_031152



NM_031153



NM_031235



NM_031237



NM_031325



NM_031330



NM_031334



NM_031358



NM_031360



NM_031579



NM_031603



NM_031639



NM_031662



NM_031675



NM_031676



NM_031693



NM_031718



NM_031719



NM_031728



NM_031745



NM_031757



NM_031783



NM_031785



NM_031786



NM_031802



NM_031813



NM_031824



NM_031828



NM_031969



NM_031977



NM_031978



NM_031987



NM_032057



NM_032083



NM_032614



NM_052809



NM_053291



NM_053301



NM_053316



NM_053319



NM_053337



NM_053339



NM_053346



NM_053349



NM_053351



NM_053357



NM_053404



NM_053410



NM_053420



NM_053428



NM_053441



NM_053458



NM_053490



NM_053522



NM_053556



NM_053558



NM_053588



NM_053594



NM_053605



NM_053607



NM_053623



NM_053655



NM_053682



NM_053690



NM_053693



NM_053698



NM_053707



NM_053747



NM_053748



NM_053750



NM_053764



NM_053772



NM_053775



NM_053795



NM_053801



NM_053825



NM_053868



NM_053876



NM_053888



NM_053909



NM_053928



NM_053933



NM_053947



NM_053948



NM_053979



NM_054009



NM_057098



NM_057099



NM_057108



NM_057196



NM_080402



NM_080411



NM_080481



NM_080582



NM_080781



NM_080887



NM_080902



NM_130429



NM_130746



NM_130779



NM_131904



NM_133313



NM_133427



NM_133528



NM_133539



NM_133566



NM_134383



NM_134456



NM_138519



NM_138856



NM_138865



NM_138890



NM_138910



NM_138911



NM_139097



NM_139325



NM_144758



NM_145184



NM_145772



NM_145788



NM_147211



NM_153297



NM_153630



NM_171990



NM_172039



NM_172074



NM_172243



NM_172332



NM_173133



NM_173137



NM_173154



NM_173290



NM_173308



NM_175595



NM_177425



NM_177929



NM_181083



NM_181473



NM_181626



NM_182814



NM_182819



NM_183052



NM_183332



NM_184050



NM_198749



NM_198757



NM_198788



NM_199094



NM_199104



NM_199385



NM_199393



NM_199410



NM_201421



NM_207617



NM_212494



NM_212519



NM_212549



NM_213559



X53232



XM_213362



XM_213382



XM_213782



XM_213898



XM_214021



XM_214053



XM_214241



XM_214296



XM_214420



XM_214446



XM_214505



XM_214625



XM_214701



XM_214833



XM_214954



XM_215044



XM_215113



XM_215118



XM_215178



XM_215286



XM_215416



XM_215424



XM_215481



XM_215549



XM_215570



XM_215612



XM_215706



XM_215717



XM_215751



XM_215758



XM_215769



XM_215771



XM_216013



XM_216212



XM_216378



XM_216393



XM_216398



XM_216563



XM_216643



XM_216661



XM_217019



XM_217124



XM_217464



XM_217560



XM_217587



XM_217592



XM_218196



XM_218790



XM_219525



XM_219685



XM_219693



XM_219801



XM_219939



XM_220047



XM_220155



XM_220167



XM_220178



XM_220269



XM_220281



XM_220428



XM_220506



XM_220534



XM_220541



XM_220753



XM_220992



XM_221050



XM_221212



XM_221276



XM_221888



XM_221941



XM_221946



XM_221962



XM_222177



XM_222214



XM_222478



XM_222670



XM_222946



XM_223485



XM_223580



XM_223981



XM_224271



XM_224332



XM_224417



XM_224478



XM_225078



XM_225138



XM_225923



XM_226014



XM_226238



XM_226422



XM_227811



XM_229106



XM_230523



XM_230531



XM_230861



XM_231148



XM_231251



XM_232252



XM_232343



XM_233231



XM_233467



XM_233609



XM_233944



XM_234011



XM_234272



XM_234483



XM_235185



XM_235224



XM_235496



XM_235497



XM_236476



XM_236745



XM_236941



XM_237291



XM_237327



XM_237787



XM_237957



XM_238334



XM_238346



XM_340874



XM_340986



XM_340987



XM_340999



XM_341071



XM_341337



XM_341354



XM_341558



XM_341653



XM_341661



XM_341669



XM_341686



XM_341700



XM_341709



XM_341803



XM_341947



XM_342048



XM_342101



XM_342149



XM_342174



XM_342180



XM_342217



XM_342223



XM_342340



XM_342442



XM_342489



XM_342534



XM_342551



XM_342581



XM_342600



XM_342632



XM_342657



XM_342829



XM_342851



XM_342857



XM_342924



XM_343018



XM_343154



XM_343175



XM_343175



XM_343459



XM_343469



XM_343557



XM_343579



XM_344130



XM_344450



XM_344706



XM_344971



XM_345150



XM_345266



XM_345938



XM_573165



XM_573256



XM_574503



XM_574916



XM_574979



XM_574991



XM_576252



XM_578542










The genes in this set show abundance of expressed gene product(s) in the Aged Impaired population that are significantly decreased, as determined by ANOVA, compared to those abundances in Young and Aged Unimpaired populations combined. Therefore, compounds useful in treating cognitive impairment selected using these genes should increase the abundance or enhance the function of the expressed gene products of these genes.
Example 37
An ANOVA was conducted on the probe set signal values for all probe sets by combining two groups of animals and comparing them to the third group. An “AU ANOVA” was performed, where Aged Impaired were combined with Young and compared to Aged Unimpaired. All probe sets were considered in the statistical analysis based on the gcRMA method of data extraction from the perfect match sequences for each probe. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Pearson's correlations comparing probe set signal values to learning indices were then calculated for the aged animals (excluding young) across all present probe sets. Again, correlations representing a p-value of less than 0.05 were considered significantly changed.
Microarray Results
Table 37 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 37





CA3 - AU ANOVA POSITIVE CORRELATION


GENBANK ® ID

















AW525560



BF562800



M59859



NM_001002277



NM_001003401



NM_001004082



NM_001004220



NM_001005761



NM_001005889



NM_001006957



NM_001007616



NM_001008335



NM_001008368



NM_001008879



NM_001009692



NM_001009825



NM_001011915



NM_001012064



NM_001012157



NM_001012183



NM_001012504



NM_001017960



NM_001024371



NM_001024790



NM_001024906



NM_001029897



NM_001033961



NM_001034020



NM_001034131



NM_001034924



NM_012504



NM_012518



NM_012673



NM_012734



NM_012809



NM_012836



NM_012877



NM_012886



NM_013038



NM_013066



NM_013126



NM_013135



NM_013181



NM_017155



NM_017190



NM_017211



NM_017242



NM_017288



NM_017290



NM_017294



NM_017304



NM_017327



NM_019128



NM_019148



NM_019288



NM_019375



NM_020075



NM_020088



NM_021597



NM_021659



NM_021748



NM_021767



NM_021775



NM_022206



NM_022254



NM_022533



NM_022589



NM_022668



NM_022690



NM_022703



NM_022946



NM_023020



NM_024397



NM_030862



NM_030990



NM_031036



NM_031037



NM_031066



NM_031117



NM_031150



NM_031515



NM_031608



NM_031613



NM_031690



NM_031707



NM_031715



NM_031730



NM_031743



NM_032617



NM_053311



NM_053335



NM_053358



NM_053391



NM_053457



NM_053589



NM_053664



NM_053777



NM_053818



NM_053859



NM_053878



NM_053910



NM_053980



NM_054003



NM_057139



NM_057140



NM_057201



NM_080482



NM_080904



NM_133395



NM_133405



NM_133567



NM_133568



NM_134413



NM_138502



NM_138896



NM_138907



NM_139060



NM_144756



NM_145091



NM_145094



NM_148891



NM_153317



NM_172023



NM_173120



NM_175708



NM_175761



NM_181087



NM_181634



NM_184049



NM_199372



XM_213824



XM_214031



XM_214172



XM_214253



XM_214740



XM_214775



XM_215182



XM_215919



XM_216739



XM_217021



XM_217059



XM_217279



XM_217432



XM_218226



XM_218704



XM_220420



XM_220423



XM_221672



XM_222245



XM_224538



XM_224713



XM_226076



XM_227510



XM_231121



XM_232345



XM_232351



XM_232946



XM_232987



XM_233767



XM_233798



XM_234901



XM_234908



XM_235179



XM_235639



XM_236268



XM_237790



XM_238072



XM_238336



XM_239329



XM_240330



XM_241981



XM_340912



XM_341081



XM_341201



XM_341341



XM_341352



XM_341548



XM_341789



XM_341857



XM_341961



XM_342279



XM_342405



XM_342612



XM_342682



XM_342684



XM_343114



XM_343175



XM_343358



XM_343468



XM_343483



XM_343513



XM_343588



XM_344661



XM_344862



XM_345867










The genes in this set show abundance of expressed gene product(s) in the Aged Unimpaired population that are significantly decreased, as determined by ANOVA, compared to those abundances in Young and Aged Impaired populations combined. In addition, the abundance of expressed gene product(s) in the aged animals positively correlate with learning index of the animals, such that poorer learners have higher abundances of expressed gene products of the selected genes. Therefore, compounds useful in treating cognitive impairment selected using these genes should decrease the abundance or attenuate the function of the expressed gene products of these genes.
Example 38
An ANOVA was conducted on the probe set signal values for all probe sets by combining two groups of animals and comparing them to the third group. An “AU ANOVA” was performed, where Aged Impaired were combined with Young and compared to Aged Unimpaired. All probe sets were considered in the statistical analysis based on the gcRMA method of data extraction from the perfect match sequences for each probe. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Pearson's correlations comparing probe set signal values to learning indices were then calculated for the aged animals (excluding young) across all present probe sets. Again, correlations representing a p-value of less than 0.05 were considered significantly changed.
Microarray Results
Table 38 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 38





CA3 - AU ANOVA NEGATIVE CORRELATION


GENBANK ® ID

















AA956668



AI716912



NM_001002807



NM_001005561



NM_001008773



NM_001008826



NM_001009651



NM_001011983



NM_001014044



NM_001017376



NM_001024274



NM_001025407



NM_012517



NM_012548



NM_013001



NM_013218



NM_017171



NM_019318



NM_019384



NM_020308



NM_022282



NM_022626



NM_022681



NM_022686



NM_031642



NM_031686



NM_031807



NM_031985



NM_033021



NM_053539



NM_053635



NM_053642



NM_053787



NM_053890



NM_080899



NM_133304



NM_134457



NM_138710



NM_138839



NM_138874



NM_138887



NM_139192



NM_181638



NM_199084



XM_213658



XM_214191



XM_214509



XM_214906



XM_215303



XM_215540



XM_215858



XM_215947



XM_216380



XM_218759



XM_219297



XM_222184



XM_224232



XM_228305



XM_228644



XM_230634



XM_230846



XM_232247



XM_232253



XM_233970



XM_234017



XM_234238



XM_236380



XM_238163



XM_342432



XM_343910



XM_344606



XM_345418



XM_347168



XM_573259










The genes in this set show abundance of expressed gene product(s) in the Aged Unimpaired population that are significantly increased, as determined by ANOVA, compared to those abundances in Young and Aged Impaired populations combined. In addition, the abundance of expressed gene product(s) in the aged animals negatively correlate with learning index of the animals, such that poorer learners have lower abundances of expressed gene products of the selected genes. Therefore, compounds useful in treating cognitive impairment selected using these genes should increase the abundance or enhance the function of the expressed gene products of these genes.
Example 39
An ANOVA was conducted on the probe set signal values for all probe sets by combining two groups of animals and comparing them to the third group. An “AU ANOVA” was performed, where Aged Impaired were combined with Young and compared to Aged Unimpaired. All probe sets were considered in the statistical analysis based on the gcRMA method of data extraction from the perfect match sequences for each probe. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Microarray Results
Table 39 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 39





CA3 - AU ANOVA INCREASE


GENBANK ® ID

















AI071000



BI285065



NM_001004253



NM_001004273



NM_001005557



NM_001005907



NM_001007666



NM_001007704



NM_001007755



NM_001008293



NM_001008344



NM_001008521



NM_001011894



NM_001011941



NM_001012016



NM_001012021



NM_001012049



NM_001012087



NM_001012128



NM_001012160



NM_001012169



NM_001012174



NM_001012459



NM_001013077



NM_001013137



NM_001013148



NM_001013178



NM_001013193



NM_001013873



NM_001014790



NM_001015027



NM_001017381



NM_001024247



NM_001024275



NM_001025027



NM_001025123



NM_001025693



NM_001025708



NM_001025716



NM_001029909



NM_001031655



NM_001031660



NM_001033699



NM_001033705



NM_001034111



NM_001034164



NM_001034199



NM_012636



NM_012645



NM_012731



NM_012801



NM_012935



NM_012945



NM_012988



NM_013006



NM_013040



NM_013057



NM_016993



NM_017067



NM_017103



NM_017172



NM_017303



NM_017305



NM_019163



NM_019340



NM_019363



NM_022197



NM_022506



NM_022715



NM_022921



NM_024002



NM_024373



NM_024388



NM_024405



NM_024489



NM_030987



NM_030992



NM_031021



NM_031023



NM_031082



NM_031083



NM_031098



NM_031114



NM_031322



NM_031597



NM_031599



NM_031640



NM_031656



NM_031699



NM_031721



NM_031771



NM_031779



NM_031789



NM_031793



NM_031798



NM_053453



NM_053541



NM_053584



NM_053604



NM_053713



NM_053714



NM_053826



NM_053842



NM_053887



NM_053946



NM_053965



NM_053998



NM_057107



NM_057147



NM_130400



NM_130409



NM_130413



NM_133392



NM_133571



NM_133593



NM_133620



NM_134326



NM_134364



NM_134389



NM_138873



NM_138888



NM_139332



NM_139336



NM_145789



NM_172157



NM_173123



NM_181363



NM_181432



NM_182816



NM_182953



NM_183331



NM_199111



NM_199268



NM_199403



NM_201988



NM_207602



XM_213338



XM_213370



XM_213418



XM_213679



XM_214043



XM_214362



XM_214621



XM_216225



XM_216517



XM_216725



XM_217146



XM_217191



XM_217209



XM_217210



XM_217284



XM_219531



XM_220095



XM_220335



XM_220612



XM_220813



XM_221034



XM_221231



XM_221263



XM_221333



XM_222155



XM_222773



XM_223117



XM_223161



XM_223390



XM_223418



XM_223643



XM_223820



XM_224588



XM_224627



XM_224733



XM_225559



XM_225644



XM_225688



XM_225864



XM_226237



XM_226769



XM_226976



XM_227475



XM_227657



XM_231524



XM_232330



XM_232466



XM_232578



XM_233485



XM_233535



XM_233815



XM_234205



XM_234540



XM_234921



XM_234942



XM_235248



XM_236275



XM_236292



XM_236914



XM_237458



XM_237808



XM_238039



XM_238166



XM_341173



XM_341208



XM_341280



XM_341295



XM_341312



XM_341380



XM_341508



XM_341578



XM_341590



XM_341639



XM_341688



XM_342044



XM_342271



XM_342528



XM_342605



XM_342641



XM_342837



XM_343002



XM_343088



XM_343318



XM_343326



XM_343548



XM_343559



XM_344002



XM_345652



XM_347163



XM_575968



XM_576312










The genes in this set show abundance of expressed gene product(s) in the Aged Unimpaired population that are significantly increased, as determined by ANOVA, compared to those abundances in Young and Aged Impaired populations combined. Therefore, compounds useful in treating cognitive impairment selected using these genes should increase the abundance or enhance the function of the expressed gene products of these genes.
Example 40
An ANOVA was conducted on the probe set signal values for all probe sets by combining two groups of animals and comparing them to the third group. An “AU ANOVA” was performed, where Aged Impaired were combined with Young and compared to Aged Unimpaired. All probe sets were considered in the statistical analysis based on the gcRMA method of data extraction from the perfect match sequences for each probe. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Microarray Results
Table 40 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 40





CA3 - AU ANOVA DECREASE


GENBANK ® ID

















AW251888



BE111604



BI303536



NM_001004200



NM_001004206



NM_001004233



NM_001004262



NM_001005555



NM_001005560



NM_001005881



NM_001007607



NM_001008364



NM_001008694



NM_001009618



NM_001011925



NM_001011926



NM_001012004



NM_001012065



NM_001012066



NM_001012113



NM_001012175



NM_001013079



NM_001013103



NM_001013231



NM_001024269



NM_001025414



NM_001025649



NM_001025688



NM_001025722



NM_001025770



NM_001031845



NM_001033670



NM_001033681



NM_001033889



NM_001033914



NM_001033968



NM_001034009



NM_001034135



NM_012506



NM_012527



NM_012613



NM_012628



NM_012660



NM_012686



NM_012700



NM_012755



NM_012756



NM_012776



NM_012798



NM_012841



NM_012918



NM_012941



NM_012947



NM_013073



NM_013199



NM_013222



NM_016990



NM_017008



NM_017049



NM_017051



NM_017053



NM_017102



NM_017204



NM_017253



NM_017262



NM_017312



NM_017319



NM_019133



NM_019164



NM_019224



NM_019306



NM_019326



NM_019343



NM_019378



NM_019621



NM_021681



NM_021739



NM_021760



NM_021835



NM_021847



NM_021859



NM_022185



NM_022262



NM_022267



NM_022382



NM_022386



NM_022507



NM_022675



NM_022693



NM_022864



NM_022953



NM_023101



NM_023972



NM_024000



NM_024146



NM_024163



NM_030846



NM_031008



NM_031056



NM_031081



NM_031097



NM_031147



NM_031331



NM_031342



NM_031518



NM_031522



NM_031595



NM_031614



NM_031646



NM_031654



NM_031667



NM_031692



NM_031765



NM_031776



NM_031777



NM_031820



NM_031831



NM_031975



NM_032062



NM_032616



NM_033359



NM_053310



NM_053409



NM_053435



NM_053440



NM_053486



NM_053573



NM_053620



NM_053684



NM_053788



NM_053837



NM_053846



NM_053894



NM_053955



NM_053972



NM_053973



NM_057116



NM_057136



NM_057152



NM_057207



NM_057209



NM_057213



NM_080583



NM_080896



NM_130420



NM_130428



NM_130755



NM_133406



NM_133414



NM_133582



NM_134336



NM_134376



NM_134400



NM_134404



NM_138921



NM_145090



NM_145781



NM_147209



NM_172075



NM_175754



NM_177481



NM_181092



NM_182668



NM_182842



NM_198749



NM_198758



NM_207599



NM_212458



XM_213437



XM_213777



XM_214313



XM_214316



XM_214673



XM_214720



XM_214751



XM_214899



XM_215371



XM_215451



XM_215467



XM_216835



XM_218432



XM_218615



XM_219529



XM_220232



XM_222103



XM_222662



XM_224389



XM_226439



XM_227282



XM_228114



XM_233737



XM_234514



XM_234909



XM_235156



XM_238177



XM_238280



XM_239780



XM_242062



XM_243390



XM_340886



XM_340911



XM_340967



XM_341088



XM_341091



XM_341157



XM_341896



XM_341963



XM_342244



XM_342477



XM_342653



XM_342808



XM_342823



XM_342854



XM_343581



XM_343613



XM_343839



XM_345870



XM_345909



XM_345970



XM_577103



XM_578287










The genes in this set show abundance of expressed gene product(s) in the Aged Unimpaired population that are significantly decreased, as determined by ANOVA, compared to those abundances in Young and Aged Impaired populations combined. Therefore, compounds useful in treating cognitive impairment selected using these genes should decrease the abundance or attenuate the function of the expressed gene products of these genes.
Example 41
An ANOVA was conducted on the probe set signal values for all probe sets by combining two groups of animals and comparing them to the third group. An “AI ANOVA” was performed, where Aged Unimpaired were combined with Young and compared to Aged Impaired. All probe sets were considered in the statistical analysis based on the gcRMA method of data extraction from the perfect match sequences for each probe. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Pearson's correlations comparing probe set signal values to learning indices were then calculated for the aged animals (excluding young) across all present probe sets. Again, correlations representing a p-value of less than 0.05 were considered significantly changed.
Microarray Results
Table 41 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 41





DG - AI ANOVA POSITIVE CORRELATION


GENBANK ® ID

















AA892549



AF023090



AI317821



AI717047



BG662522



BI298090



BM390128



BM391371



NM_001001513



NM_001002815



NM_001002828



NM_001004080



NM_001004081



NM_001004090



NM_001004199



NM_001004209



NM_001004247



NM_001004254



NM_001004255



NM_001004273



NM_001005383



NM_001005539



NM_001005872



NM_001005898



NM_001005902



NM_001006967



NM_001006968



NM_001006987



NM_001006989



NM_001007146



NM_001007616



NM_001007624



NM_001007625



NM_001007654



NM_001007682



NM_001007691



NM_001007712



NM_001008279



NM_001008319



NM_001008324



NM_001008356



NM_001008374



NM_001008509



NM_001009474



NM_001009536



NM_001009625



NM_001009686



NM_001009690



NM_001009693



NM_001009708



NM_001009973



NM_001011891



NM_001011893



NM_001011903



NM_001011906



NM_001011910



NM_001011920



NM_001011946



NM_001011958



NM_001011970



NM_001011974



NM_001012004



NM_001012030



NM_001012050



NM_001012051



NM_001012067



NM_001012083



NM_001012106



NM_001012120



NM_001012159



NM_001012161



NM_001012171



NM_001012180



NM_001012217



NM_001012235



NM_001013034



NM_001013046



NM_001013070



NM_001013082



NM_001013086



NM_001013087



NM_001013105



NM_001013118



NM_001013121



NM_001013167



NM_001013174



NM_001013206



NM_001013231



NM_001013874



NM_001014772



NM_001015005



NM_001024256



NM_001024261



NM_001024746



NM_001024773



NM_001025123



NM_001025130



NM_001025142



NM_001025152



NM_001025625



NM_001025633



NM_001025664



NM_001025678



NM_001025716



NM_001031641



NM_001031644



NM_001033683



NM_001033696



NM_001033699



NM_001033707



NM_001033715



NM_001033852



NM_001033866



NM_001033868



NM_001033926



NM_001033951



NM_001033968



NM_001033987



NM_001034020



NM_001034068



NM_001034090



NM_001034110



NM_001034998



NM_001034999



NM_001035221



NM_012500



NM_012512



NM_012527



NM_012543



NM_012569



NM_012577



NM_012595



NM_012618



NM_012628



NM_012663



NM_012732



NM_012744



NM_012749



NM_012777



NM_012788



NM_012816



NM_012820



NM_012838



NM_012884



NM_012913



NM_012963



NM_012971



NM_012993



NM_013000



NM_013013



NM_013022



NM_013088



NM_013091



NM_013154



NM_013156



NM_013164



NM_013194



NM_013198



NM_013226



NM_016990



NM_017051



NM_017052



NM_017060



NM_017068



NM_017109



NM_017116



NM_017125



NM_017132



NM_017137



NM_017148



NM_017181



NM_017204



NM_017212



NM_017216



NM_017223



NM_017232



NM_017234



NM_017264



NM_017274



NM_017288



NM_017317



NM_017320



NM_017340



NM_017343



NM_019124



NM_019132



NM_019141



NM_019204



NM_019211



NM_019226



NM_019232



NM_019242



NM_019253



NM_019257



NM_019272



NM_019289



NM_019359



NM_019362



NM_020308



NM_021663



NM_021694



NM_021703



NM_021746



NM_021748



NM_021766



NM_021847



NM_021859



NM_021863



NM_022207



NM_022226



NM_022265



NM_022281



NM_022286



NM_022382



NM_022390



NM_022499



NM_022500



NM_022502



NM_022523



NM_022526



NM_022538



NM_022592



NM_022595



NM_022596



NM_022597



NM_022601



NM_022617



NM_022699



NM_022701



NM_022799



NM_022853



NM_022939



NM_023972



NM_023978



NM_024155



NM_024359



NM_024374



NM_024399



NM_024404



NM_030826



NM_030992



NM_031022



NM_031035



NM_031057



NM_031099



NM_031114



NM_031120



NM_031147



NM_031149



NM_031357



NM_031509



NM_031525



NM_031553



NM_031554



NM_031589



NM_031596



NM_031632



NM_031654



NM_031657



NM_031664



NM_031683



NM_031711



NM_031729



NM_031745



NM_031752



NM_031770



NM_031774



NM_031786



NM_031789



NM_031812



NM_031816



NM_031827



NM_031830



NM_031837



NM_031970



NM_031981



NM_032067



NM_032416



NM_032619



NM_053323



NM_053401



NM_053411



NM_053448



NM_053462



NM_053467



NM_053507



NM_053538



NM_053555



NM_053598



NM_053599



NM_053600



NM_053604



NM_053665



NM_053698



NM_053750



NM_053776



NM_053777



NM_053794



NM_053804



NM_053851



NM_053870



NM_053886



NM_053911



NM_053927



NM_053936



NM_053959



NM_053985



NM_054001



NM_057100



NM_057114



NM_057118



NM_057131



NM_057192



NM_057197



NM_057204



NM_057208



NM_057210



NM_080480



NM_080577



NM_080691



NM_080767



NM_080773



NM_080888



NM_080910



NM_130409



NM_130416



NM_133398



NM_133401



NM_133404



NM_133421



NM_133551



NM_133585



NM_134376



NM_134390



NM_134410



NM_134415



NM_134449



NM_134456



NM_134468



NM_138508



NM_138877



NM_138889



NM_138896



NM_138917



NM_139107



NM_139110



NM_139256



NM_139325



NM_139329



NM_147177



NM_147210



NM_153469



NM_153628



NM_153630



NM_172009



NM_172033



NM_172334



NM_173116



NM_175578



NM_175582



NM_175765



NM_177927



NM_181388



NM_181475



NM_182953



NM_183328



NM_183402



NM_198787



NM_199087



NM_199108



NM_199118



NM_199119



NM_199384



NM_199388



NM_199408



NM_206847



NM_207591



NM_207599



NM_212463



NM_212491



NM_212509



XM_213329



XM_213342



XM_213463



XM_213673



XM_213677



XM_213729



XM_213739



XM_213824



XM_213832



XM_213972



XM_213993



XM_214147



XM_214172



XM_214279



XM_214518



XM_214843



XM_214859



XM_214963



XM_214968



XM_215028



XM_215101



XM_215113



XM_215177



XM_215222



XM_215285



XM_215674



XM_215733



XM_215754



XM_215935



XM_215939



XM_216124



XM_216230



XM_216306



XM_216386



XM_216407



XM_216515



XM_216565



XM_216629



XM_216704



XM_216740



XM_216835



XM_216872



XM_216968



XM_217061



XM_217195



XM_217478



XM_217740



XM_218336



XM_218816



XM_218858



XM_219001



XM_219515



XM_219885



XM_219948



XM_220512



XM_220574



XM_220775



XM_221297



XM_221747



XM_222661



XM_223012



XM_223125



XM_223597



XM_223938



XM_224232



XM_224630



XM_224788



XM_225014



XM_225259



XM_225457



XM_225726



XM_226237



XM_226987



XM_227074



XM_228044



XM_228701



XM_230291



XM_230637



XM_231162



XM_232323



XM_232745



XM_232855



XM_233415



XM_233761



XM_233798



XM_234008



XM_234205



XM_234394



XM_235400



XM_235426



XM_235518



XM_235657



XM_236189



XM_236192



XM_236362



XM_236468



XM_236659



XM_236687



XM_237415



XM_237787



XM_238019



XM_238155



XM_241632



XM_242032



XM_243652



XM_340798



XM_340818



XM_340825



XM_340997



XM_341051



XM_341052



XM_341086



XM_341157



XM_341704



XM_341785



XM_341790



XM_341796



XM_341799



XM_341826



XM_341867



XM_341882



XM_341934



XM_341940



XM_341957



XM_342002



XM_342409



XM_342542



XM_342866



XM_342918



XM_343119



XM_343157



XM_343268



XM_343336



XM_343396



XM_343564



XM_343570



XM_343773



XM_343776



XM_343986



XM_344286



XM_344403



XM_344409



XM_344870



XM_344970



XM_345477



XM_345535



XM_345870



XM_346083



XM_573258



XM_574670



XM_577023










The genes in this set show abundance of expressed gene product(s) in the Aged Impaired population that are significantly increased, as determined by ANOVA, compared to those abundances in Young and Aged Unimpaired populations combined. In addition, the abundance of expressed gene product(s) in the aged animals positively correlate with learning index of the animals, such that poorer learners have higher abundances of expressed gene products of the selected genes. Therefore, compounds useful in treating cognitive impairment selected using these genes should decrease the abundance or attenuate the function of the expressed gene products of these genes.
Example 42
An ANOVA was conducted on the probe set signal values for all probe sets by combining two groups of animals and comparing them to the third group. An “AI ANOVA” was performed, where Aged Unimpaired were combined with Young and compared to Aged Impaired. All probe sets were considered in the statistical analysis based on the gcRMA method of data extraction from the perfect match sequences for each probe. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Pearson's correlations comparing probe set signal values to learning indices were then calculated for the aged animals (excluding young) across all present probe sets. Again, correlations representing a p-value of less than 0.05 were considered significantly changed.
Microarray Results
Table 42 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 42





DG - AI ANOVA NEGATIVE CORRELATION


GENBANK ® ID

















BF557865



BM391206



NM_001004102



NM_001009689



NM_001013071



NM_001024238



NM_013111



NM_024355



NM_031123



NM_031127



NM_053775



NM_134383



NM_173094



NM_212504



XM_218939



XM_219292



XM_219879



XM_221074



XM_223729



XM_224733



XM_230288



XM_231453



XM_234508



XM_343446



XM_344594



XM_345938










The genes in this set show abundance of expressed gene product(s) in the Aged Impaired population that are significantly decreased, as determined by ANOVA, compared to those abundances in Young and Aged Unimpaired populations combined. In addition, the abundance of expressed gene product(s) in the aged animals negatively correlate with learning index of the animals, such that poorer learners have lower abundances of expressed gene products of the selected genes. Therefore, compounds useful in treating cognitive impairment selected using these genes should increase the abundance or enhance the function of the expressed gene products of these genes.
Example 43
An ANOVA was conducted on the probe set signal values for all probe sets by combining two groups of animals and comparing them to the third group. An “AI ANOVA” was performed, where Aged Unimpaired were combined with Young and compared to Aged Impaired. All probe sets were considered in the statistical analysis based on the gcRMA method of data extraction from the perfect match sequences for each probe. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Microarray Results
Table 43 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 43





DG - AI ANOVA INCREASE


GENBANK ® ID

















AI103331



AI235284



AW526364



BI291997



NM_001001511



NM_001001516



NM_001002016



NM_001002802



NM_001002835



NM_001004076



NM_001004099



NM_001004218



NM_001004245



NM_001005528



NM_001005529



NM_001005893



NM_001005907



NM_001006971



NM_001007001



NM_001007557



NM_001007677



NM_001007684



NM_001007749



NM_001007755



NM_001007802



NM_001008315



NM_001008725



NM_001008767



NM_001008768



NM_001008829



NM_001009172



NM_001009502



NM_001009623



NM_001009668



NM_001009669



NM_001009683



NM_001011919



NM_001011985



NM_001012147



NM_001012190



NM_001012464



NM_001013047



NM_001013059



NM_001013072



NM_001013081



NM_001013135



NM_001013179



NM_001013193



NM_001013204



NM_001013207



NM_001013210



NM_001013233



NM_001013246



NM_001015026



NM_001017382



NM_001024268



NM_001024771



NM_001024775



NM_001024782



NM_001025423



NM_001025630



NM_001025721



NM_001030026



NM_001030041



NM_001033653



NM_001033656



NM_001033757



NM_001034004



NM_001034164



NM_012515



NM_012523



NM_012532



NM_012546



NM_012562



NM_012576



NM_012578



NM_012614



NM_012650



NM_012701



NM_012703



NM_012722



NM_012740



NM_012771



NM_012856



NM_012862



NM_012886



NM_012925



NM_012940



NM_012974



NM_013015



NM_013070



NM_013104



NM_013107



NM_013122



NM_013135



NM_013137



NM_013146



NM_017009



NM_017024



NM_017037



NM_017043



NM_017062



NM_017139



NM_017142



NM_017200



NM_017224



NM_017262



NM_017351



NM_019143



NM_019144



NM_019219



NM_019249



NM_019266



NM_019312



NM_019313



NM_019318



NM_019335



NM_019346



NM_019386



NM_019904



NM_019905



NM_020082



NM_020088



NM_021578



NM_021582



NM_021690



NM_021769



NM_021771



NM_021989



NM_022215



NM_022244



NM_022251



NM_022257



NM_022266



NM_022270



NM_022285



NM_022401



NM_022504



NM_022516



NM_022531



NM_022677



NM_022692



NM_022866



NM_024129



NM_024131



NM_024133



NM_024353



NM_024358



NM_024369



NM_024372



NM_024400



NM_030843



NM_030847



NM_030863



NM_030872



NM_030987



NM_031018



NM_031031



NM_031118



NM_031140



NM_031145



NM_031242



NM_031320



NM_031332



NM_031511



NM_031514



NM_031549



NM_031560



NM_031630



NM_031728



NM_031739



NM_031797



NM_031814



NM_031818



NM_052804



NM_053356



NM_053455



NM_053485



NM_053503



NM_053536



NM_053554



NM_053560



NM_053570



NM_053583



NM_053612



NM_053618



NM_053654



NM_053670



NM_053684



NM_053796



NM_053838



NM_053857



NM_053882



NM_053896



NM_053933



NM_053936



NM_053992



NM_057107



NM_057200



NM_057211



NM_080479



NM_080584



NM_080698



NM_080899



NM_131911



NM_133296



NM_133298



NM_133305



NM_133307



NM_133317



NM_133522



NM_133526



NM_133548



NM_133598



NM_133605



NM_133624



NM_134419



NM_138502



NM_138521



NM_138542



NM_139185



NM_139216



NM_139255



NM_144757



NM_145091



NM_147205



NM_147206



NM_172022



NM_172029



NM_173118



NM_173145



NM_175579



NM_175756



NM_181087



NM_181368



NM_181377



NM_183330



NM_184051



NM_198786



NM_199093



NM_199208



NM_199270



NM_206849



NM_207596



NM_207598



NM_207609



NM_212466



NM_212505



NM_212523



NM_212525



NM_212547



XM_213408



XM_213421



XM_213460



XM_213526



XM_213611



XM_214344



XM_214441



XM_214526



XM_214583



XM_214673



XM_214721



XM_214769



XM_214935



XM_214993



XM_215076



XM_215095



XM_215117



XM_215372



XM_215376



XM_215424



XM_215576



XM_215578



XM_216018



XM_216688



XM_218368



XM_218963



XM_218977



XM_219045



XM_219470



XM_219966



XM_220333



XM_220398



XM_220644



XM_220810



XM_220982



XM_221272



XM_221380



XM_221387



XM_221916



XM_222636



XM_223583



XM_223781



XM_224296



XM_224538



XM_224561



XM_225196



XM_225548



XM_225625



XM_225631



XM_225644



XM_225997



XM_226016



XM_226213



XM_227066



XM_228197



XM_230036



XM_230462



XM_230647



XM_231134



XM_231402



XM_232283



XM_232622



XM_233779



XM_235024



XM_235049



XM_235710



XM_236458



XM_236560



XM_237371



XM_237754



XM_237792



XM_238447



XM_240178



XM_240311



XM_242644



XM_242982



XM_243637



XM_243815



XM_340939



XM_341227



XM_341448



XM_341509



XM_341540



XM_341584



XM_341784



XM_341857



XM_341877



XM_341880



XM_342072



XM_342092



XM_342271



XM_342284



XM_342317



XM_342432



XM_342759



XM_342829



XM_342905



XM_342979



XM_343058



XM_343065



XM_343126



XM_343259



XM_343334



XM_343479



XM_343619



XM_344421



XM_344524



XM_345584



XM_345702



XM_345789



XM_345825



XM_573544



XM_573983



XM_574161



XM_574618



XM_575585



XM_576363



XM_576401



XM_580221










The genes in this set show abundance of expressed gene product(s) in the Aged Impaired population that are significantly increased, as determined by ANOVA, compared to those abundances in Young and Aged Unimpaired populations combined. Therefore, compounds useful in treating cognitive impairment selected using these genes should decrease the abundance or attenuate the function of the expressed gene products of these genes.
Example 44
An ANOVA was conducted on the probe set signal values for all probe sets by combining two groups of animals and comparing them to the third group. An “AI ANOVA” was performed, where Aged Unimpaired were combined with Young and compared to Aged Impaired. All probe sets were considered in the statistical analysis based on the gcRMA method of data extraction from the perfect match sequences for each probe. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Microarray Results
Table 44 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 44





DG - AI ANOVA DECREASE


GENBANK ® ID

















NM_001005530



NM_001005885



NM_001006994



NM_001007000



NM_001007607



NM_001008353



NM_001008553



NM_001009719



NM_001010965



NM_001011942



NM_001012144



NM_001013209



NM_001017376



NM_001024964



NM_001025136



NM_001025400



NM_001031645



NM_001033684



NM_012585



NM_012934



NM_013066



NM_017030



NM_017093



NM_017197



NM_017259



NM_017290



NM_017318



NM_017357



NM_019264



NM_020097



NM_021597



NM_021702



NM_021760



NM_022615



NM_022688



NM_024364



NM_031082



NM_031318



NM_031571



NM_031613



NM_053301



NM_053340



NM_053360



NM_053441



NM_053883



NM_080397



NM_133315



NM_133387



NM_133562



NM_144758



NM_172034



NM_173325



NM_199081



XM_214701



XM_215134



XM_215883



XM_216477



XM_217115



XM_219723



XM_220607



XM_221888



XM_221941



XM_221962



XM_222223



XM_222460



XM_222662



XM_224474



XM_224947



XM_226624



XM_233260



XM_233490



XM_233679



XM_234470



XM_236614



XM_237307



XM_239171



XM_340856



XM_340999



XM_341241



XM_341709



XM_341983



XM_342107



XM_343817



XM_343919



XM_347168



XM_575397










The genes in this set show abundance of expressed gene product(s) in the Aged Impaired population that are significantly decreased, as determined by ANOVA, compared to those abundances in Young and Aged Unimpaired populations combined. Therefore, compounds useful in treating cognitive impairment selected using these genes should increase the abundance or enhance the function of the expressed gene products of these genes.
Example 45
An ANOVA was conducted on the probe set signal values for all probe sets by combining two groups of animals and comparing them to the third group. An “AU ANOVA” was performed, where Aged Impaired were combined with Young and compared to Aged Unimpaired. All probe sets were considered in the statistical analysis based on the gcRMA method of data extraction from the perfect match sequences for each probe. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Pearson's correlations comparing probe set signal values to learning indices were then calculated for the aged animals (excluding young) across all present probe sets. Again, correlations representing a p-value of less than 0.05 were considered significantly changed.
Microarray Results
Table 45 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 45





DG - AU ANOVA POSITIVE CORRELATION


GENBANK ® ID

















AI501759



BE329232



NM_001003975



NM_001004253



NM_001004269



NM_001004275



NM_001005381



NM_001005876



NM_001006960



NM_001006963



NM_001006981



NM_001007020



NM_001007620



NM_001007714



NM_001007731



NM_001007744



NM_001008277



NM_001008291



NM_001008298



NM_001008338



NM_001008352



NM_001008508



NM_001008556



NM_001008766



NM_001008839



NM_001008891



NM_001009602



NM_001009619



NM_001009637



NM_001009657



NM_001009825



NM_001011964



NM_001011975



NM_001011983



NM_001012138



NM_001012208



NM_001012504



NM_001013114



NM_001013245



NM_001017385



NM_001017386



NM_001024745



NM_001024756



NM_001024785



NM_001024874



NM_001025409



NM_001025660



NM_001025688



NM_001025695



NM_001025735



NM_001025748



NM_001030023



NM_001031648



NM_001031653



NM_001031659



NM_001033065



NM_001033079



NM_001033670



NM_001033702



NM_001033870



NM_001034009



NM_001034026



NM_001034129



NM_001034834



NM_012615



NM_012809



NM_012836



NM_012991



NM_012998



NM_013053



NM_013192



NM_017029



NM_017040



NM_017075



NM_017190



NM_017201



NM_019133



NM_019271



NM_019352



NM_019379



NM_020099



NM_021262



NM_021697



NM_021770



NM_021835



NM_021869



NM_022198



NM_022282



NM_022296



NM_022498



NM_023971



NM_024147



NM_030989



NM_031028



NM_031125



NM_031137



NM_031139



NM_031152



NM_031515



NM_031521



NM_031528



NM_031600



NM_031641



NM_031646



NM_031768



NM_031783



NM_031979



NM_032066



NM_053291



NM_053404



NM_053440



NM_053457



NM_053508



NM_053561



NM_053620



NM_053770



NM_053779



NM_053811



NM_053818



NM_053842



NM_053850



NM_053874



NM_053928



NM_053965



NM_053999



NM_054004



NM_054006



NM_057132



NM_057141



NM_080478



NM_080887



NM_080895



NM_130406



NM_130826



NM_130894



NM_133310



NM_133569



NM_133582



NM_133594



NM_133615



NM_138528



NM_138840



NM_138899



NM_138900



NM_139109



NM_139186



NM_139194



NM_139254



NM_144754



NM_145085



NM_145878



NM_152935



NM_153297



NM_171994



NM_172157



NM_173115



NM_173290



NM_175595



NM_175603



NM_175838



NM_181081



NM_182671



NM_182820



NM_183332



NM_184049



NM_198771



NM_198789



NM_199372



NM_199380



NM_199500



XM_213382



XM_213437



XM_213569



XM_214155



XM_214238



XM_214420



XM_214570



XM_214625



XM_214817



XM_215659



XM_215701



XM_215847



XM_215985



XM_216041



XM_216169



XM_216198



XM_216367



XM_216400



XM_216524



XM_216801



XM_217124



XM_217592



XM_217806



XM_218720



XM_218949



XM_219693



XM_220884



XM_220982



XM_221100



XM_223227



XM_223837



XM_224169



XM_224429



XM_225468



XM_225711



XM_225983



XM_232315



XM_233231



XM_235552



XM_235640



XM_237999



XM_238205



XM_238280



XM_238380



XM_240330



XM_340750



XM_340775



XM_341058



XM_341120



XM_341653



XM_341666



XM_341714



XM_341856



XM_341878



XM_341961



XM_342004



XM_342286



XM_342300



XM_342489



XM_342521



XM_342532



XM_342632



XM_342872



XM_343006



XM_343034



XM_343117



XM_343175



XM_343459



XM_343513



XM_343922



XM_344113



XM_347236



XM_577103










The genes in this set show abundance of expressed gene product(s) in the Aged Unimpaired population that are significantly decreased, as determined by ANOVA, compared to those abundances in Young and Aged Impaired populations combined. In addition, the abundance of expressed gene product(s) in the aged animals positively correlate with learning index of the animals, such that poorer learners have higher abundances of expressed gene products of the selected genes. Therefore, compounds useful in treating cognitive impairment selected using these genes should decrease the abundance or attenuate the function of the expressed gene products of these genes.
Example 46
An ANOVA was conducted on the probe set signal values for all probe sets by combining two groups of animals and comparing them to the third group. An “AU ANOVA” was performed, where Aged Impaired were combined with Young and compared to Aged Unimpaired. All probe sets were considered in the statistical analysis based on the gcRMA method of data extraction from the perfect match sequences for each probe. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Pearson's correlations comparing probe set signal values to learning indices were then calculated for the aged animals (excluding young) across all present probe sets. Again, correlations representing a p-value of less than 0.05 were considered significantly changed.
Microarray Results
Table 46 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 46





DG - AU ANOVA NEGATIVE CORRELATION


GENBANK ® ID

















BF411876



NM_001008511



NM_001012093



NM_001013090



NM_001024258



NM_001024865



NM_001034994



NM_013159



NM_022202



NM_022236



NM_022518



NM_031635



NM_031698



NM_053416



NM_053621



NM_133593



NM_134326



NM_172039



NM_181362



NM_212498



XM_214253



XM_215942



XM_215947



XM_215990



XM_220222



XM_220813



XM_221043



XM_226666



XM_233808



XM_341215



XM_342580



XM_344785










The genes in this set show abundance of expressed gene product(s) in the Aged Unimpaired population that are significantly increased, as determined by ANOVA, compared to those abundances in Young and Aged Impaired populations combined. In addition, the abundance of expressed gene product(s) in the aged animals negatively correlate with learning index of the animals, such that poorer learners have lower abundances of expressed gene products of the selected genes. Therefore, compounds useful in treating cognitive impairment selected using these genes should increase the abundance or enhance the function of the expressed gene products of these genes.
Example 47
An ANOVA was conducted on the probe set signal values for all probe sets by combining two groups of animals and comparing them to the third group. An “AU ANOVA” was performed, where Aged Impaired were combined with Young and compared to Aged Unimpaired. All probe sets were considered in the statistical analysis based on the gcRMA method of data extraction from the perfect match sequences for each probe. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Microarray Results
Table 47 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 47





DG - AU ANOVA INCREASE


GENBANK ® ID

















NM_001002831



NM_001005888



NM_001007680



NM_001007704



NM_001012092



NM_001012195



NM_001013120



NM_001024767



NM_001025125



NM_001025722



NM_001033701



NM_012853



NM_012935



NM_012959



NM_013126



NM_016994



NM_019170



NM_021688



NM_022269



NM_022525



NM_022684



NM_023095



NM_023977



NM_024378



NM_031569



NM_031610



NM_031742



NM_031751



NM_040669



NM_052807



NM_053355



NM_053442



NM_053644



NM_053826



NM_057196



NM_080897



NM_133302



NM_133558



NM_138922



NM_153740



NM_172327



NM_213562



XM_213921



XM_214730



XM_214906



XM_215742



XM_215949



XM_215984



XM_217246



XM_217293



XM_217837



XM_218293



XM_218432



XM_221037



XM_222155



XM_224720



XM_225168



XM_225253



XM_226315



XM_226976



XM_231143



XM_232253



XM_232735



XM_233421



XM_234238



XM_235986



XM_340785



XM_340879



XM_340935



XM_341590



XM_343146



XM_344785



XM_577078










The genes in this set show abundance of expressed gene product(s) in the Aged Unimpaired population that are significantly increased, as determined by ANOVA, compared to those abundances in Young and Aged Impaired populations combined. Therefore, compounds useful in treating cognitive impairment selected using these genes should increase the abundance or enhance the function of the expressed gene products of these genes.
Example 48
An ANOVA was conducted on the probe set signal values for all probe sets by combining two groups of animals and comparing them to the third group. An “AU ANOVA” was performed, where Aged Impaired were combined with Young and compared to Aged Unimpaired. All probe sets were considered in the statistical analysis based on the gcRMA method of data extraction from the perfect match sequences for each probe. Any probe sets having a p-value less than 0.05 were considered significantly changed and the genes or plurality of genes selected.
Microarray Results
Table 48 shows the genes that were identified as being associated with cognitive impairment in this experiment. The reference sequence transcript ID (GENBANK® number for the exemplar sequence) was used to identify genes considered significantly changed. When this exemplar ID was not available, a UniGene identifier was used in conjunction with the GENBANK® accession number.







TABLE 48





DG - AU ANOVA DECREASE


GENBANK ® ID

















AI454679



AW142720



AW524426



BE098467



BF282715



NM_001001510



NM_001001719



NM_001001799



NM_001004094



NM_001004132



NM_001004238



NM_001004274



NM_001005547



NM_001007637



NM_001007721



NM_001008301



NM_001008368



NM_001008558



NM_001009631



NM_001009641



NM_001009713



NM_001010953



NM_001010961



NM_001011896



NM_001011904



NM_001011956



NM_001011978



NM_001011987



NM_001012113



NM_001012152



NM_001012175



NM_001013103



NM_001013199



NM_001017537



NM_001024747



NM_001024784



NM_001024906



NM_001025421



NM_001025753



NM_001033066



NM_001033693



NM_001034131



NM_001034198



NM_012520



NM_012533



NM_012567



NM_012582



NM_012651



NM_012656



NM_012755



NM_012756



NM_012762



NM_012775



NM_012798



NM_012829



NM_012952



NM_012968



NM_013029



NM_013080



NM_013100



NM_013106



NM_013199



NM_016991



NM_017031



NM_017033



NM_017066



NM_017195



NM_017207



NM_017213



NM_017261



NM_017305



NM_017359



NM_019129



NM_019193



NM_019306



NM_019356



NM_021577



NM_021751



NM_021763



NM_021851



NM_022193



NM_022197



NM_022209



NM_022217



NM_022249



NM_022278



NM_022288



NM_022548



NM_022589



NM_022600



NM_022675



NM_022681



NM_022858



NM_022863



NM_022936



NM_022951



NM_024000



NM_024146



NM_024158



NM_024383



NM_030836



NM_030861



NM_030862



NM_030868



NM_031007



NM_031030



NM_031034



NM_031063



NM_031132



NM_031333



NM_031351



NM_031518



NM_031594



NM_031692



NM_031701



NM_031707



NM_031831



NM_031855



NM_032613



NM_032616



NM_033359



NM_053363



NM_053375



NM_053428



NM_053438



NM_053506



NM_053601



NM_053655



NM_053854



NM_053866



NM_053973



NM_057201



NM_057205



NM_131906



NM_131907



NM_131914



NM_133560



NM_133600



NM_134336



NM_134346



NM_134367



NM_139060



NM_139113



NM_139324



NM_173126



NM_173154



NM_175758



NM_175761



NM_182842



NM_198749



NM_198764



NM_199099



NM_199256



NM_199382



NM_206950



NM_212521



NM_212532



NM_214457



XM_213433



XM_213777



XM_213779



XM_214030



XM_214400



XM_214451



XM_214522



XM_214751



XM_214775



XM_215389



XM_215416



XM_215612



XM_216047



XM_216563



XM_216725



XM_216755



XM_216784



XM_216859



XM_216964



XM_217078



XM_217367



XM_217464



XM_217732



XM_218382



XM_219374



XM_220224



XM_220753



XM_221120



XM_221369



XM_221566



XM_222568



XM_222578



XM_222868



XM_223496



XM_224350



XM_224417



XM_224732



XM_225923



XM_226014



XM_230495



XM_231148



XM_231655



XM_232640



XM_232809



XM_232941



XM_233297



XM_233955



XM_233970



XM_234156



XM_234328



XM_235164



XM_235179



XM_235338



XM_236992



XM_237179



XM_237790



XM_238127



XM_238151



XM_238177



XM_243623



XM_340884



XM_341354



XM_341612



XM_342149



XM_342174



XM_342281



XM_342396



XM_342503



XM_342533



XM_342692



XM_342900



XM_343081



XM_343114



XM_343546



XM_343588



XM_343764



XM_344135



XM_344405



XM_345867



XM_573442



XM_574644










The genes in this set show abundance of expressed gene product(s) in the Aged Unimpaired population that are significantly decreased, as determined by ANOVA, compared to those abundances in Young and Aged Impaired populations combined. Therefore, compounds useful in treating cognitive impairment selected using these genes should decrease the abundance or attenuate the function of the expressed gene products of these genes.
While this invention has been particularly shown and described with references to preferred elements thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

## Claims

1. A method for treating cognitive impairment in a subject in need thereof, the method comprising the step of administering to the subject a GABA-A α5 receptor agonist in an amount sufficient to beneficially alter cognitive function in said subject in an amount sufficient to beneficially alter cognitive function in said subject.

2. The method according to claim 1, wherein the subject is a human subject.

3. The method according to claim 1 or 2, wherein the agonist is selected from the group consisting of 1-methyl-7-acetyleno-5-phenyl-1,3-dihydro-benzo[e]-1,4-diazepin-2-one; 6,6 dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one; and 8-ethylthio-3-methyl-5-(1-oxidopyridin-2-yl)-3,4-dihydronaphthalen-1(2H)-one.