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CitationGPTRetr11600

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: an increase in ptau has consistently been found in the csf of ad patients compared with controls with sensitivity and specificity levels of between 80 and 9021 in addition csf levels of ptau231p have been found to correlate with not only nft pathology in neocortex but also the rate of hippocampal atrophy in the brain3536 high csf ptau181p has been associated with a fast progression from mci to ad and with rapid cognitive decline in ad3536 as ptau is not elevated in patients with acute stroke31 or other neurodegenerative diseases such as cjd37 frontotemporal lobe dementia38 and normal pressure hydrocephalus in contrast to ttau which just reflects intensity of axonal injury in these patients the ratio between ptau and ttau is more helpful for identifying ad tau pathology and differentiating ad from these conditions Title of the paper: Clinical Experience with Cerebrospinal Fluid Aβ42, Total and Phosphorylated Tau in the Evaluation of 1,016 Individuals for Suspected Dementia. Abstract of the paper: BACKGROUND Elevated total tau (tTau), 181-phosphorylated phosphorylated tau (pTau), and low amyloid-β42 (Aβ42) in cerebrospinal fluid (CSF) represent a diagnostic biomarker for Alzheimer's disease (AD). OBJECTIVE The goal was to determine the overall accuracy of CSF Aβ42, tTau, pTau, and the Aβ42/total tau index (ATI) in a non-research, clinical setting for the diagnosis of AD. METHODS From medical records in 1,016 patients that had CSF studies for dementia over a 12-year period (2005 to 2017), we calculated the sensitivity and specificity of CSF Aβ42, tTau, and pTau and the ATI in relation to the final clinical diagnosis. RESULTS Compared with non-demented patients and patients with other dementias or mild cognitive impairment (MCI), the sensitivity and specificity of the recommended ATI and pTau cut-offs (ATI < 1.0 and pTau >61 pg/ml) for the diagnosis of AD were 0.88 and 0.72, respectively. Similar results were obtained comparing AD with non-demented patients only (0.88, 0.82) and AD with other types of dementia (0.81, 0.77). A subgroup of patients with presumed normal pressure hydrocephalus (n = 154) were biopsied at the time of shunt placement. Using the pathological manifestations of AD as the standard, the sensitivity was 0.83 while the specificity was 0.72. CONCLUSIONS In a non-research setting, CSF biomarkers for AD showed a high sensitivity in accordance with previous studies, but modest specificity differentiating AD from other types of dementia or MCI. This study of unselected patients provides a valid and realistic assessment of the diagnostic accuracy of these CSF biomarkers in clinical practice.

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CitationGPTRetr11601

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: an increase in ptau has consistently been found in the csf of ad patients compared with controls with sensitivity and specificity levels of between 80 and 9021 in addition csf levels of ptau231p have been found to correlate with not only nft pathology in neocortex but also the rate of hippocampal atrophy in the brain3536 high csf ptau181p has been associated with a fast progression from mci to ad and with rapid cognitive decline in ad3536 as ptau is not elevated in patients with acute stroke31 or other neurodegenerative diseases such as cjd37 frontotemporal lobe dementia38 and normal pressure hydrocephalus in contrast to ttau which just reflects intensity of axonal injury in these patients the ratio between ptau and ttau is more helpful for identifying ad tau pathology and differentiating ad from these conditions Title of the paper: Cerebrospinal fluid levels of tau phosphorylated at threonine 181 in patients with Alzheimer's disease and vascular dementia. Abstract of the paper: In 31 patients with probable Alzheimer's disease (AD), 19 with probable vascular dementia (VaD) and 20 with Possible AD and Possible VaD, cerebrospinal fluid (CSF) tau levels hyperphosphorylated at threonine 181 (Ptau) were measured by ELISA. Thirty-six age-matched subjects were used as controls. The severity of the cognitive decline was assessed at the time of CSF analysis and after a 12-month follow-up. The groups had comparable age, degree of cognitive impairment and disease duration; these parameters were not related to P-tau levels. P-tau discriminated between demented patients and controls, but no significant difference emerged between AD and the other groups. By contrast, higher P-tau values were found to predict, independently of the clinical diagnosis, a more rapid evolution of cognitive decline. Whether these findings are due to a lack of CSF P-tau specificity or to the low reliability of clinical and radiological criteria remains unclear. P-tau may be useful in the evaluation of disease evolution, by predicting the rate of cognitive decline.

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CitationGPTRetr11602

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: an increase in ptau has consistently been found in the csf of ad patients compared with controls with sensitivity and specificity levels of between 80 and 9021 in addition csf levels of ptau231p have been found to correlate with not only nft pathology in neocortex but also the rate of hippocampal atrophy in the brain3536 high csf ptau181p has been associated with a fast progression from mci to ad and with rapid cognitive decline in ad3536 as ptau is not elevated in patients with acute stroke31 or other neurodegenerative diseases such as cjd37 frontotemporal lobe dementia38 and normal pressure hydrocephalus in contrast to ttau which just reflects intensity of axonal injury in these patients the ratio between ptau and ttau is more helpful for identifying ad tau pathology and differentiating ad from these conditions Title of the paper: Normalization of CSF pTau measurement by Aβ40 improves its performance as a biomarker of Alzheimer's disease. Abstract of the paper: BACKGROUND Alzheimer's disease (AD)-related tauopathy can be measured with CSF phosphorylated tau (pTau) and tau PET. We aim to investigate the associations between these measurements and their relative ability to predict subsequent disease progression. METHODS In 219 cognitively unimpaired and 122 impaired Alzheimer's Disease Neuroimaging Initiative participants with concurrent amyloid-β (Aβ) PET (18F-florbetapir or 18F-florbetaben), 18F-flortaucipir (FTP) PET, CSF measurements, structural MRI, and cognition, we examined inter-relationships between these biomarkers and their predictions of subsequent FTP and cognition changes. RESULTS The use of a CSF pTau/Aβ40 ratio eliminated positive associations we observed between CSF pTau alone and CSF Aβ42 in the normal Aβ range likely reflecting individual differences in CSF production rather than pathology. Use of the CSF pTau/Aβ40 ratio also increased expected associations with Aβ PET, FTP PET, hippocampal volume, and cognitive decline compared to pTau alone. In Aβ+ individuals, abnormal CSF pTau/Aβ40 only individuals (26.7%) were 4 times more prevalent (p <  0.001) than abnormal FTP only individuals (6.8%). Furthermore, among individuals on the AD pathway, CSF pTau/Aβ40 mediates the association between Aβ PET and FTP PET accumulation, but FTP PET is more closely linked to subsequent cognitive decline than CSF pTau/Aβ40. CONCLUSIONS Together, these findings suggest that CSF pTau/Aβ40 may be a superior measure of tauopathy compared to CSF pTau alone, and CSF pTau/Aβ40 enables detection of tau accumulation at an earlier stage than FTP among Aβ+ individuals.

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CitationGPTRetr11603

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: an increase in ptau has consistently been found in the csf of ad patients compared with controls with sensitivity and specificity levels of between 80 and 9021 in addition csf levels of ptau231p have been found to correlate with not only nft pathology in neocortex but also the rate of hippocampal atrophy in the brain3536 high csf ptau181p has been associated with a fast progression from mci to ad and with rapid cognitive decline in ad3536 as ptau is not elevated in patients with acute stroke31 or other neurodegenerative diseases such as cjd37 frontotemporal lobe dementia38 and normal pressure hydrocephalus in contrast to ttau which just reflects intensity of axonal injury in these patients the ratio between ptau and ttau is more helpful for identifying ad tau pathology and differentiating ad from these conditions Title of the paper: Cerebrospinal fluid tau and ptau(181) increase with cortical amyloid deposition in cognitively normal individuals: implications for future clinical trials of Alzheimer's disease. Abstract of the paper: Alzheimer's disease (AD) pathology is estimated to develop many years before detectable cognitive decline. Fluid and imaging biomarkers may identify people in early symptomatic and even preclinical stages, possibly when potential treatments can best preserve cognitive function. We previously reported that cerebrospinal fluid (CSF) levels of amyloid-beta(42) (Abeta(42)) serve as an excellent marker for brain amyloid as detected by the amyloid tracer, Pittsburgh compound B (PIB). Using data from 189 cognitively normal participants, we now report a positive linear relationship between CSF tau/ptau(181) (primary constituents of neurofibrillary tangles) with the amount of cortical amyloid. We observe a strong inverse relationship of cortical PIB binding with CSF Abeta(42) but not for plasma Abeta species. Some individuals have low CSF Abeta(42) but no cortical PIB binding. Together, these data suggest that changes in brain Abeta(42) metabolism and amyloid formation are early pathogenic events in AD, and that significant disruptions in CSF tau metabolism likely occur after Abeta(42) initially aggregates and increases as amyloid accumulates. These findings have important implications for preclinical AD diagnosis and treatment.

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CitationGPTRetr11604

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: an increase in ptau has consistently been found in the csf of ad patients compared with controls with sensitivity and specificity levels of between 80 and 9021 in addition csf levels of ptau231p have been found to correlate with not only nft pathology in neocortex but also the rate of hippocampal atrophy in the brain3536 high csf ptau181p has been associated with a fast progression from mci to ad and with rapid cognitive decline in ad3536 as ptau is not elevated in patients with acute stroke31 or other neurodegenerative diseases such as cjd37 frontotemporal lobe dementia38 and normal pressure hydrocephalus in contrast to ttau which just reflects intensity of axonal injury in these patients the ratio between ptau and ttau is more helpful for identifying ad tau pathology and differentiating ad from these conditions Title of the paper: Diagnostic accuracy of cerebrospinal fluid biomarkers measured by chemiluminescent enzyme immunoassay for Alzheimer disease diagnosis. Abstract of the paper: In the last decades, an important role of cerebrospinal fluid (CSF) biomarkers for Alzheimer disease (AD) diagnosis has emerged. The evaluation of the triad consisting of 42 aminoacid-long amyloid-beta peptide (Aβ42), total Tau (tTau) and Tau phosphorylated at threonine 181 (pTau) have been recently integrated into the research diagnostic criteria of AD. For a long time, the enzyme-linked immunosorbent assay (ELISA) has represented the most commonly used method for the measurement of CSF biomarkers levels. This study aimed to assess the diagnostic accuracy of CSF biomarkers, namely Aβ42, tTau and pTau and their ratio, measured by fully automated CLEIA assay (Lumipulse). We included 96 patients clinically diagnosed as AD (48) and non-AD (48). All CSF biomarkers levels were measured on Lumipulse G1200 fully automated platform (Fujirebio Inc. Europe, Gent, Belgium). Aβ42 levels, 42/40 ratio, 42/tTau ratio, 42/PTau ratio were significantly reduced, and tTau and PTau levels were significantly increased in AD patients in comparison with non-AD patients. The receiving operator curve (ROC) analysis showed good diagnostic accuracy of all CSF biomarkers and their ratios for discriminating AD patients from non-AD patients, with 42/40 ratio having the best AUC (0.724, 95%CI 0.619-0.828; p < 0.001). Our findings support the use of CSF biomarkers measured by CLEIA method on a fully automated platform for AD diagnosis.

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CitationGPTRetr11605

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: an increase in ptau has consistently been found in the csf of ad patients compared with controls with sensitivity and specificity levels of between 80 and 9021 in addition csf levels of ptau231p have been found to correlate with not only nft pathology in neocortex but also the rate of hippocampal atrophy in the brain3536 high csf ptau181p has been associated with a fast progression from mci to ad and with rapid cognitive decline in ad3536 as ptau is not elevated in patients with acute stroke31 or other neurodegenerative diseases such as cjd37 frontotemporal lobe dementia38 and normal pressure hydrocephalus in contrast to ttau which just reflects intensity of axonal injury in these patients the ratio between ptau and ttau is more helpful for identifying ad tau pathology and differentiating ad from these conditions Title of the paper: Comparing tau status determined via plasma pTau181, pTau231 and [18F]MK6240 tau-PET. Abstract of the paper: BACKGROUND Tau in Alzheimer's disease (AD) is assessed via cerebrospinal fluid (CSF) and Positron emission tomography (PET). Novel methods to detect phosphorylated tau (pTau) in blood have been recently developed. We aim to investigate agreement of tau status as determined by [18F]MK6240 tau-PET, plasma pTau181 and pTau231. METHODS We assessed cognitively unimpaired young, cognitively unimpaired, mild cognitive impairment and AD individuals with [18F]MK6240, plasma pTau181, pTau 231, [18F]AZD4694 amyloid-PET and MRI. A subset underwent CSF assessment. We conducted ROC curves to obtain cut-off values for plasma pTau epitopes. Individuals were categorized as positive or negative in all biomarkers. We then compared the distribution among concordant and discordant groups in relation to diagnosis, Aβ status, APOEε4 status, [18F]AZD4694 global SUVR, hippocampal volume and CSF pTau181. FINDINGS The threshold for positivity was 15.085 pg/mL for plasma pTau181 and 17.652 pg/mL for plasma pTau231. Most individuals had concordant statuses, however, 18% of plasma181/PET, 26% of plasma231/PET and 25% of the pTau231/pTau181 were discordant. Positivity to at least one biomarker was often accompanied by diagnosis of cognitive impairment, Aβ positivity, APOEε4 carriership, higher levels of [18F]AZD4694 global SUVR, hippocampal atrophy and CSF pTau181. INTERPRETATION Plasma pTau181, pTau231 and [18F]MK6240 seem to reflect different stages of tau progression. Plasma biomarkers can be useful in the context of diagnostic information and clinical trials, to evaluate the disease stage. Moreover, they seem to confidently evaluate tau-PET positivity. FUNDING Moreover, this study was supported by Weston Brain Institute, Canadian Institute of Health Research and Fonds de Recherche du Québec.

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CitationGPTRetr11606

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: an increase in ptau has consistently been found in the csf of ad patients compared with controls with sensitivity and specificity levels of between 80 and 9021 in addition csf levels of ptau231p have been found to correlate with not only nft pathology in neocortex but also the rate of hippocampal atrophy in the brain3536 high csf ptau181p has been associated with a fast progression from mci to ad and with rapid cognitive decline in ad3536 as ptau is not elevated in patients with acute stroke31 or other neurodegenerative diseases such as cjd37 frontotemporal lobe dementia38 and normal pressure hydrocephalus in contrast to ttau which just reflects intensity of axonal injury in these patients the ratio between ptau and ttau is more helpful for identifying ad tau pathology and differentiating ad from these conditions Title of the paper: Reproducibility of Alzheimer's Disease Cerebrospinal Fluid-Biomarker Measurements under Clinical Routine Conditions. Abstract of the paper: Analysis of cerebrospinal fluid (CSF) is one of the key tools for the state-of-the-art differential diagnosis of dementias. Dementia due to Alzheimer's disease (AD) is characterized by elevated CSF levels of total Tau (tTau) and phospho-181-Tau (pTau) and low CSF amyloid-β42 (Aβ42). Discrepancies in the laboratory analysis of human materials are well known and much effort has been put into harmonization procedures. In this study, we measured CSF biomarkers of more than 100 patients obtained under clinical routine conditions in two different clinical laboratories. The CSF biomarker levels obtained from the two different sites were significantly correlated: R2 = 0.7129 (tTau, p < 0.001), 0.7914 (pTau, p < 0.001), 0.5078 (Aβ42, p < 0.001), 0.5739 (Aβ40, p < 0.001), and 0.4308 (Aβ42/40, p < 0.001). However, the diagnostic classifications of the Aβ42, tTau, and pTau levels of identical subjects into normal versus pathological range made by the two different sites showed substantial discrepancies (31.5%, 29.6%, and 25.0% discordant cases, respectively). Applying Aβ42/40, instead of CSF Aβ42 alone, lead to a reduction of the discordant cases to 16.8%. Our findings suggest that CSF Aβ42/40 can outperform Aβ42 as a biomarker for AD neuropathology, not only under well-controlled study conditions but also in real life clinical routine. Thus, we recommend the inclusion of Aβ42/40 as a CSF biomarker in the diagnostic procedure.

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CitationGPTRetr11607

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: an increase in ptau has consistently been found in the csf of ad patients compared with controls with sensitivity and specificity levels of between 80 and 9021 in addition csf levels of ptau231p have been found to correlate with not only nft pathology in neocortex but also the rate of hippocampal atrophy in the brain3536 high csf ptau181p has been associated with a fast progression from mci to ad and with rapid cognitive decline in ad3536 as ptau is not elevated in patients with acute stroke31 or other neurodegenerative diseases such as cjd37 frontotemporal lobe dementia38 and normal pressure hydrocephalus in contrast to ttau which just reflects intensity of axonal injury in these patients the ratio between ptau and ttau is more helpful for identifying ad tau pathology and differentiating ad from these conditions Title of the paper: Cerebrospinal fluid biomarkers and rate of cognitive decline in very mild dementia of the Alzheimer type. Abstract of the paper: BACKGROUND Cerebrospinal fluid (CSF) levels of Abeta peptide 1-42 (Abeta 42), tau, and phosphorylated tau (ptau) are potential biomarkers of Alzheimer disease. OBJECTIVE To determine whether Abeta 42, tau, and ptau predict the rate of cognitive change in individuals with very mild dementia of the Alzheimer type (DAT). DESIGN Retrospective analysis of CSF biomarkers and clinical data. SETTING An academic Alzheimer disease research center. PARTICIPANTS Research volunteers in a longitudinal study of aging and cognition. Participants (n = 49) had a clinical diagnosis of very mild DAT with a Clinical Dementia Rating (CDR) of 0.5 at the time of lumbar puncture. All the participants had at least 1 follow-up assessment (mean [SD] follow-up, 3.5 [1.8] years). MAIN OUTCOME MEASURES Baseline CSF levels of Abeta 42, Abeta 40, tau, and ptau at threonine 181 (ptau181) and the rate of dementia progression as measured using the CDR sum of boxes (CDR-SB) score and psychometric performance. RESULTS The rate of dementia progression was significantly more rapid in individuals with lower baseline CSF Abeta 42 levels, higher tau or ptau181 levels, or high tau: Abeta 42 ratios. For example, the annual change in the CDR-SB score was 1.1 for the lowest 2 tertiles of Abeta 42 values and 0.3 for the highest tertile of Abeta 42 values. CONCLUSIONS In individuals with very mild DAT, lower CSF Abeta 42 levels, high tau or ptau181 levels, or high tau:Abeta 42 ratios quantitatively predict more rapid progression of cognitive deficits and dementia. Biomarkers of CSF may be useful prognostically and to identify individuals who are more likely to progress for participation in therapeutic clinical trials.

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CitationGPTRetr11608

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: an increase in ptau has consistently been found in the csf of ad patients compared with controls with sensitivity and specificity levels of between 80 and 9021 in addition csf levels of ptau231p have been found to correlate with not only nft pathology in neocortex but also the rate of hippocampal atrophy in the brain3536 high csf ptau181p has been associated with a fast progression from mci to ad and with rapid cognitive decline in ad3536 as ptau is not elevated in patients with acute stroke31 or other neurodegenerative diseases such as cjd37 frontotemporal lobe dementia38 and normal pressure hydrocephalus in contrast to ttau which just reflects intensity of axonal injury in these patients the ratio between ptau and ttau is more helpful for identifying ad tau pathology and differentiating ad from these conditions Title of the paper: Characterization of novel CSF Tau and ptau biomarkers for Alzheimer's disease. Abstract of the paper: Cerebral spinal fluid (CSF) Aβ42, tau and p181tau are widely accepted biomarkers of Alzheimer's disease (AD). Numerous studies show that CSF tau and p181tau levels are elevated in mild-to-moderate AD compared to age-matched controls. In addition, these increases might predict preclinical AD in cognitively normal elderly. Despite their importance as biomarkers, the molecular nature of CSF tau and ptau is not known. In the current study, reverse-phase high performance liquid chromatography was used to enrich and concentrate tau prior to western-blot analysis. Multiple N-terminal and mid-domain fragments of tau were detected in pooled CSF with apparent sizes ranging from <20 kDa to ~40 kDa. The pattern of tau fragments in AD and control samples were similar. In contrast, full-length tau and C-terminal-containing fragments were not detected. To quantify levels, five tau ELISAs and three ptau ELISAs were developed to detect different overlapping regions of the protein. The discriminatory potential of each assay was determined using 20 AD and 20 age-matched control CSF samples. Of the tau ELISAs, the two assays specific for tau containing N-terminal sequences, amino acids 9-198 (numbering based on tau 441) and 9-163, exhibited the most significant differences between AD and control samples. In contrast, CSF tau was not detected with an ELISA specific for a more C-terminal region (amino acids 159-335). Significant discrimination was also observed with ptau assays measuring amino acids 159-p181 and 159-p231. Interestingly, the discriminatory potential of p181 was reduced when measured in the context of tau species containing amino acids 9-p181. Taken together, these results demonstrate that tau in CSF occurs as a series of fragments and that discrimination of AD from control is dependent on the subset of tau species measured. These assays provide novel tools to investigate CSF tau and ptau as biomarkers for other neurodegenerative diseases.

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CitationGPTRetr11609

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: an increase in ptau has consistently been found in the csf of ad patients compared with controls with sensitivity and specificity levels of between 80 and 9021 in addition csf levels of ptau231p have been found to correlate with not only nft pathology in neocortex but also the rate of hippocampal atrophy in the brain3536 high csf ptau181p has been associated with a fast progression from mci to ad and with rapid cognitive decline in ad3536 as ptau is not elevated in patients with acute stroke31 or other neurodegenerative diseases such as cjd37 frontotemporal lobe dementia38 and normal pressure hydrocephalus in contrast to ttau which just reflects intensity of axonal injury in these patients the ratio between ptau and ttau is more helpful for identifying ad tau pathology and differentiating ad from these conditions Title of the paper: Clinical significance of fluid biomarkers in Alzheimer's Disease. Abstract of the paper: The number of patients with Alzheimer's Disease (AD) and other types of dementia disorders has drastically increased over the last decades. AD is a complex progressive neurodegenerative disease affecting about 14 million patients in Europe and the United States. The hallmarks of this disease are neurotic plaques consist of the Amyloid-β peptide (Aβ) and neurofibrillary tangles (NFTs) formed of hyperphosphorylated Tau protein (pTau). Currently, four CSF biomarkers: Amyloid beta 42 (Aβ42), Aβ42/40 ratio, Tau protein, and Tau phosphorylated at threonine 181 (pTau181) have been indicated as core neurochemical AD biomarkers. However, the identification of additional fluid biomarkers, useful in the prognosis, risk stratification, and monitoring of drug response is sorely needed to better understand the complex heterogeneity of AD pathology as well as to improve diagnosis of patients with the disease. Several novel biomarkers have been extensively investigated, and their utility must be proved and eventually integrated into guidelines for use in clinical practice. This paper presents the research and development of CSF and blood biomarkers for AD as well as their potential clinical significance. Upper panel: Aβ peptides are released from transmembrane Amyloid Precursor Protein (APP) under physiological conditions (blue arrow). In AD, however, pathologic accumulation of Aβ monomers leads to their accumulation in plaques (red arrow). This is reflected in decreased concentration of Aβ1-42 and decreased Aβ42/40 concentration ratio in the CSF. Lower panel: Phosphorylated Tau molecules maintain axonal structures; hyperphosphorylation of Tau (red arrow) in AD leads to degeneration of axons, and release of pTau molecules, which then accumulate in neurofibrillary tangles. This process is reflected by increased concentrations of Tau and pTau in the CSF.

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CitationGPTRetr11610

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: an increase in ptau has consistently been found in the csf of ad patients compared with controls with sensitivity and specificity levels of between 80 and 9021 in addition csf levels of ptau231p have been found to correlate with not only nft pathology in neocortex but also the rate of hippocampal atrophy in the brain3536 high csf ptau181p has been associated with a fast progression from mci to ad and with rapid cognitive decline in ad3536 as ptau is not elevated in patients with acute stroke31 or other neurodegenerative diseases such as cjd37 frontotemporal lobe dementia38 and normal pressure hydrocephalus in contrast to ttau which just reflects intensity of axonal injury in these patients the ratio between ptau and ttau is more helpful for identifying ad tau pathology and differentiating ad from these conditions Title of the paper: 18F-AV-1451 and CSF T-tau and P-tau as biomarkers in Alzheimer's disease. Abstract of the paper: To elucidate the relationship between cerebrospinal fluid (CSF) total-tau (T-tau) and phosphorylated tau (P-tau) with the tau PET ligand 18F-AV-1451 in Alzheimer's disease (AD), we examined 30 cognitively healthy elderly (15 with preclinical AD), 14 prodromal AD, and 39 AD dementia patients. CSF T-tau and P-tau were highly correlated (R = 0.92, P < 0.001), but they were only moderately associated with retention of 18F-AV-1451, and mainly in demented AD patients. 18F-AV-1451, but not CSF T-tau or P-tau, was strongly associated with atrophy and cognitive impairment. CSF tau was increased in preclinical AD, despite normal 18F-AV-1451 retention. However, not all dementia AD patients exhibited increased CSF tau, even though 18F-AV-1451 retention was always increased at this disease stage. We conclude that CSF T-tau and P-tau mainly behave as biomarkers of "disease state", since they appear to be increased in many cases of AD at all disease stages, already before the emergence of tau aggregates. In contrast, 18F-AV-1451 is a biomarker of "disease stage", since it is increased in clinical stages of the disease, and is associated with brain atrophy and cognitive decline.

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CitationGPTRetr11611

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: an increase in ptau has consistently been found in the csf of ad patients compared with controls with sensitivity and specificity levels of between 80 and 9021 in addition csf levels of ptau231p have been found to correlate with not only nft pathology in neocortex but also the rate of hippocampal atrophy in the brain3536 high csf ptau181p has been associated with a fast progression from mci to ad and with rapid cognitive decline in ad3536 as ptau is not elevated in patients with acute stroke31 or other neurodegenerative diseases such as cjd37 frontotemporal lobe dementia38 and normal pressure hydrocephalus in contrast to ttau which just reflects intensity of axonal injury in these patients the ratio between ptau and ttau is more helpful for identifying ad tau pathology and differentiating ad from these conditions Title of the paper: Longitudinal cerebrospinal fluid tau load increases in mild cognitive impairment. Abstract of the paper: Cross-sectional cerebrospinal fluid (CSF) levels of tau and amyloid (A) beta (beta) are of diagnostic importance for Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, most longitudinal studies of tau fail to demonstrate progression. Because predominantly brain-derived proteins such as tau, have higher ventricle to lumbar ratios, we hypothesized that adjusting for the ventricular enlargement of AD would correct for the dilution of tau, and improve detection of longitudinal change. Abeta which is not exclusively brain derived, shows a ratio <1, and no benefit was expected from adjustment. In a 1 year longitudinal study of eight MCI and ten controls, we examined CSF levels of hyperphosphorylated (P) tau231, Abeta40, and Abeta42. In cross-section, MCI patients showed elevated Ptau231 and Abeta40 levels, and greater ventricular volumes. Longitudinally, only after adjusting for the ventricular volume and only for Ptau231, were increases seen in MCI. Further studies are warranted on mechanisms of tau clearance and on using imaging to interpret CSF studies.

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CitationGPTRetr11612

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: an increase in ptau has consistently been found in the csf of ad patients compared with controls with sensitivity and specificity levels of between 80 and 9021 in addition csf levels of ptau231p have been found to correlate with not only nft pathology in neocortex but also the rate of hippocampal atrophy in the brain3536 high csf ptau181p has been associated with a fast progression from mci to ad and with rapid cognitive decline in ad3536 as ptau is not elevated in patients with acute stroke31 or other neurodegenerative diseases such as cjd37 frontotemporal lobe dementia38 and normal pressure hydrocephalus in contrast to ttau which just reflects intensity of axonal injury in these patients the ratio between ptau and ttau is more helpful for identifying ad tau pathology and differentiating ad from these conditions Title of the paper: Cerebrospinal fluid tau, p-tau 181 and amyloid-β38/40/42 in frontotemporal dementias and primary progressive aphasias. Abstract of the paper: BACKGROUND/AIMS We determined cerebrospinal fluid (CSF) concentrations of amyloid-β (Aβ)(1-38), Aβ(1-40), Aβ(1-42), total tau and phospho-tau (p-tau) in order to study their differential expression in frontotemporal dementia (FTD, n = 25) and primary progressive aphasia (PPA, n = 12) as compared to Alzheimer's dementia (AD, n = 25) and nondemented controls (n = 20). METHODS Commercially available ELISA and electrochemiluminescence methods were applied. RESULTS High CSF p-tau and low ratios of Aβ(1-42)/Aβ(1-40) and Aβ(1-42)/Aβ(1-38), respectively, were specific for AD. CSF Aβ(1-38) was reduced in FTD as compared to each of the other diagnostic groups, including PPA. CSF tau and p-tau levels were elevated in PPA as compared to FTD. CONCLUSION This is the first detailed report on biomarker patterns in PPA, indicating distinct CSF biomarker patterns in FTD and PPA as major subgroups of frontotemporal lobar degeneration. The diagnostic and pathophysiological implications of our results warrant further studies on larger and neuropathologically diagnosed patient populations.

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CitationGPTRetr11613

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: an increase in ptau has consistently been found in the csf of ad patients compared with controls with sensitivity and specificity levels of between 80 and 9021 in addition csf levels of ptau231p have been found to correlate with not only nft pathology in neocortex but also the rate of hippocampal atrophy in the brain3536 high csf ptau181p has been associated with a fast progression from mci to ad and with rapid cognitive decline in ad3536 as ptau is not elevated in patients with acute stroke31 or other neurodegenerative diseases such as cjd37 frontotemporal lobe dementia38 and normal pressure hydrocephalus in contrast to ttau which just reflects intensity of axonal injury in these patients the ratio between ptau and ttau is more helpful for identifying ad tau pathology and differentiating ad from these conditions Title of the paper: An examination of a novel multipanel of CSF biomarkers in the Alzheimer's disease clinical and pathological continuum. Abstract of the paper: INTRODUCTION This study examines the utility of a multipanel of cerebrospinal fluid (CSF) biomarkers complementing Alzheimer's disease (AD) biomarkers in a clinical research sample. We compared biomarkers across groups defined by clinical diagnosis and pTau181 /Aβ42 status (+/-) and explored their value in predicting cognition. METHODS CSF biomarkers amyloid beta (Aβ)42 , pTau181 , tTau, Aβ40 , neurogranin, neurofilament light (NfL), α-synuclein, glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (YKL-40), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), S100 calcium binding protein B (S100B), and interleukin 6 (IL6), were measured with the NeuroToolKit (NTK) for 720 adults ages 40 to 93 years (mean age = 63.9 years, standard deviation [SD] = 9.0; 50 with dementia; 54 with mild cognitive impairment [MCI], 616 unimpaired). RESULTS Neurodegeneration and glial activation biomarkers were elevated in pTau181 /Aβ42 + MCI/dementia participants relative to all pTau181 /Aβ42 - participants. Neurodegeneration biomarkers increased with clinical severity among pTau181 /Aβ42 + participants and predicted worse cognitive performance. Glial activation biomarkers were unrelated to cognitive performance. DISCUSSION The NTK contains promising markers that improve the pathophysiological characterization of AD. Neurodegeneration biomarkers beyond tTau improved statistical prediction of cognition and disease stages.

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CitationGPTRetr11614

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: an increase in ptau has consistently been found in the csf of ad patients compared with controls with sensitivity and specificity levels of between 80 and 9021 in addition csf levels of ptau231p have been found to correlate with not only nft pathology in neocortex but also the rate of hippocampal atrophy in the brain3536 high csf ptau181p has been associated with a fast progression from mci to ad and with rapid cognitive decline in ad3536 as ptau is not elevated in patients with acute stroke31 or other neurodegenerative diseases such as cjd37 frontotemporal lobe dementia38 and normal pressure hydrocephalus in contrast to ttau which just reflects intensity of axonal injury in these patients the ratio between ptau and ttau is more helpful for identifying ad tau pathology and differentiating ad from these conditions Title of the paper: High tau levels in cerebrospinal fluid predict nursing home placement and rapid progression in Alzheimer's disease. Abstract of the paper: BACKGROUND Increased concentrations of cerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated tau, as well as decreased amyloid-β 42 peptide, are biomarkers of Alzheimer's disease (AD) pathology, but few studies have shown an association with AD progression rate. We hypothesized that high CSF tau, as a marker of ongoing neurodegeneration, would predict a more aggressive course of AD, using time to nursing home placement (NHP) as the main outcome. METHODS Our sample inlcuded 234 patients with mild cognitive impairment (MCI) due to AD (n = 134) or mild to moderate AD (n = 100) who underwent lumbar puncture at a memory clinic and were followed for 2-11 years (median 4.9 years). RESULTS Individuals with CSF t-tau in the highest quartile (≥900 ng/L) had a higher ratio of NHP, both in the total cohort and in patients with MCI only (adjusted HR 2.17 [95% CI 1.24-3.80]; HR 2.37 [95% CI 1.10-5.09], respectively), than the lowest quartile. The association between high t-tau levels and future steep deterioration was confirmed in analyses with conversion to moderate dementia (HR 1.66; 95% CI 1.08-2.56), rapid decline in Mini Mental State Examination score (≥4-point drop/12 months), and dying in severe dementia as outcomes. CONCLUSIONS To our knowledge, this is the first study to show that high CSF t-tau levels predict early NHP and conversion to moderate dementia in an AD cohort. Selecting patients with high CSF t-tau, indicating more aggressive neurodegeneration and steeper decline, for AD immunotherapy trials might increase the possibility of showing contrast between active treatment and placebo.

False

CitationGPTRetr11615

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: an increase in ptau has consistently been found in the csf of ad patients compared with controls with sensitivity and specificity levels of between 80 and 9021 in addition csf levels of ptau231p have been found to correlate with not only nft pathology in neocortex but also the rate of hippocampal atrophy in the brain3536 high csf ptau181p has been associated with a fast progression from mci to ad and with rapid cognitive decline in ad3536 as ptau is not elevated in patients with acute stroke31 or other neurodegenerative diseases such as cjd37 frontotemporal lobe dementia38 and normal pressure hydrocephalus in contrast to ttau which just reflects intensity of axonal injury in these patients the ratio between ptau and ttau is more helpful for identifying ad tau pathology and differentiating ad from these conditions Title of the paper: Increased total TAU but not amyloid-beta(42) in cerebrospinal fluid correlates with short-term memory impairment in Alzheimer's disease. Abstract of the paper: Given the need for tools for early and accurate diagnosis, prediction of disease progression, and monitoring efficacy of therapeutic agents for AD, the study of cerebrospinal fluid (CSF) biomarkers has become a rapidly growing field of research. Several studies have reported conflicting data regarding the relationships between CSF biomarkers and dementia severity. In this study, we have focused on the identification of CSF biomarkers and their correlations with the impairment of different cognitive domains measured using the Cognitive Abilities Screening Instrument (CASI). Patients with AD (n=28), non-AD dementia (n=16), other neurological disorders (OND, n=14), and healthy controls (HC, n=21) were enrolled. Our results revealed significantly higher CSF total tau (t-tau) and lower amyloid-beta(42) levels in AD patients compared with those in HC and OND groups. Moreover, our data show that CSF t-tau levels, but not Abeta(42) levels, have an inverse correlation with the score of short-term memory in CASI for patients with AD (Spearman: r=-0.444; p=0.018). This data might indicate that the higher CSF t-tau level is associated with more NFT pathology and more severe impairment of short-term memory in AD patients.

False

CitationGPTRetr11616

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: an increase in ptau has consistently been found in the csf of ad patients compared with controls with sensitivity and specificity levels of between 80 and 9021 in addition csf levels of ptau231p have been found to correlate with not only nft pathology in neocortex but also the rate of hippocampal atrophy in the brain3536 high csf ptau181p has been associated with a fast progression from mci to ad and with rapid cognitive decline in ad3536 as ptau is not elevated in patients with acute stroke31 or other neurodegenerative diseases such as cjd37 frontotemporal lobe dementia38 and normal pressure hydrocephalus in contrast to ttau which just reflects intensity of axonal injury in these patients the ratio between ptau and ttau is more helpful for identifying ad tau pathology and differentiating ad from these conditions Title of the paper: Clinical indications for analysis of Alzheimer's disease CSF biomarkers. Abstract of the paper: The cerebrospinal fluid (CSF) biomarkers β-amyloid1-42 (Aβ1-42), total tau protein (T-tau) and hyperphosphorylated tau (P-tau181P) are well-validated and are increasingly used in clinical practice as an affirmative diagnostic tool for Alzheimer's disease (AD). These biomarkers have also been implemented in the revised diagnostic criteria of AD. The combination of the CSF biomarkers Aβ1-42, T-tau and P-tau181P results in high levels of sensitivity, specificity and diagnostic accuracy for discriminating AD from controls (including psychiatric disorders like depression). These biomarkers can be applied for diagnosing AD in the prodromal phase of the disease (mild cognitive impairment). In case of doubt between vascular dementia (VaD) or mixed AD-VaD pathology in dementia patients, the determination of CSF Aβ1-42, T-tau and P-tau181P levels is of help to confirm or exclude the AD component in the pathophysiology of the dementia syndrome. However, their discriminatory power for the differential diagnosis of dementia is suboptimal. Other CSF biomarkers like Aβ1-40, and those that are reflective of the pathology of non-AD dementias, could improve the accuracy of differential dementia diagnosis. The added differential diagnostic value of the CSF biomarkers Aβ1-42, T-tau and P-tau181P could lie within those cases in which the routine clinical diagnostic work-up is not able to discriminate between AD or non-AD dementias. In summary, the CSF biomarkers Aβ1-42, T-tau and P-tau181P can be used in clinical practice to discriminate AD from healthy aging (including psychiatric disorders like depression), to diagnose AD in its prodromal phase or in atypical forms with prominent non-memory impairment, to identify AD in patients with mixed pathologies and in case of an ambiguous (AD versus non-AD) dementia diagnosis.

False

CitationGPTRetr11617

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: an increase in ptau has consistently been found in the csf of ad patients compared with controls with sensitivity and specificity levels of between 80 and 9021 in addition csf levels of ptau231p have been found to correlate with not only nft pathology in neocortex but also the rate of hippocampal atrophy in the brain3536 high csf ptau181p has been associated with a fast progression from mci to ad and with rapid cognitive decline in ad3536 as ptau is not elevated in patients with acute stroke31 or other neurodegenerative diseases such as cjd37 frontotemporal lobe dementia38 and normal pressure hydrocephalus in contrast to ttau which just reflects intensity of axonal injury in these patients the ratio between ptau and ttau is more helpful for identifying ad tau pathology and differentiating ad from these conditions Title of the paper: CSF biomarker levels in early and late onset Alzheimer's disease. Abstract of the paper: OBJECTIVE To compare CSF levels of beta-amyloid 1-42 (Abeta(1-42)), total tau (tau) and tau phosphorylated at threonine 181 (ptau-181) between AD patients and controls according to age. METHODS 248 AD patients (48% men) and 127 controls (51% men, 22 volunteers and 105 subjective complainers) underwent lumbar puncture. Both patients and controls were divided into a young (<65 years) and old (>or=65 years) group. RESULTS All three biomarkers showed main effects of diagnosis (p<0.001). There was an interaction between diagnosis and age for all three biomarkers (p<0.05), as old controls had lower Abeta(1-42) and higher (p)tau than young controls (Abeta(1-42) 699+/-250 versus 866+/-191pg/ml, tau 408+/-245 versus 243+/-102pg/ml, ptau-181 60+/-28 versus 42+/-15pg/ml), but there was no difference according to age among AD patients (Abeta(1-42) 451+/-178 versus 425+/-146pg/ml, tau 741+/-460 versus 798+/-467pg/ml, ptau-181 91+/-42 versus 91+/-41pg/ml). CONCLUSION We found that the older control group had lower Abeta(1-42) and higher (p)tau compared to the younger control group. This suggests that older individuals may have AD pathology, even in the absence of objective cognitive impairment.

False

CitationGPTRetr11618

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: an increase in ptau has consistently been found in the csf of ad patients compared with controls with sensitivity and specificity levels of between 80 and 9021 in addition csf levels of ptau231p have been found to correlate with not only nft pathology in neocortex but also the rate of hippocampal atrophy in the brain3536 high csf ptau181p has been associated with a fast progression from mci to ad and with rapid cognitive decline in ad3536 as ptau is not elevated in patients with acute stroke31 or other neurodegenerative diseases such as cjd37 frontotemporal lobe dementia38 and normal pressure hydrocephalus in contrast to ttau which just reflects intensity of axonal injury in these patients the ratio between ptau and ttau is more helpful for identifying ad tau pathology and differentiating ad from these conditions Title of the paper: Relationship between CSF biomarkers of Alzheimer's disease and rates of regional cortical thinning in ADNI data. Abstract of the paper: Previously it was reported that Alzheimer's disease (AD) patients have reduced amyloid (Aβ 1-42) and elevated total tau (t-tau) and phosphorylated tau (p-tau 181p) in the cerebro-spinal fluid (CSF), suggesting that these same measures could be used to detect early AD pathology in healthy elderly (CN) and mild cognitive impairment (MCI). In this study, we tested the hypothesis that there would be an association among rates of regional brain atrophy, the CSF biomarkers Aβ 1-42, t-tau, and p-tau 181p and ApoE ε4 status, and that the pattern of this association would be diagnosis specific. Our findings primarily showed that lower CSF Aβ 1-42 and higher tau concentrations were associated with increased rates of regional brain tissue loss and the patterns varied across the clinical groups. Taken together, these findings demonstrate that CSF biomarker concentrations are associated with the characteristic patterns of structural brain changes in CN and MCI that resemble to a large extent the pathology seen in AD. Therefore, the finding of faster progression of brain atrophy in the presence of lower Aβ 1-42 levels and higher p-tau levels supports the hypothesis that CSF Aβ 1-42 and tau are measures of early AD pathology. Moreover, the relationship among CSF biomarkers, ApoE ε4 status, and brain atrophy rates are regionally varying, supporting the view that the genetic predisposition of the brain to amyloid and tau mediated pathology is regional and disease stage specific.

False

CitationGPTRetr11619

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: an increase in ptau has consistently been found in the csf of ad patients compared with controls with sensitivity and specificity levels of between 80 and 9021 in addition csf levels of ptau231p have been found to correlate with not only nft pathology in neocortex but also the rate of hippocampal atrophy in the brain3536 high csf ptau181p has been associated with a fast progression from mci to ad and with rapid cognitive decline in ad3536 as ptau is not elevated in patients with acute stroke31 or other neurodegenerative diseases such as cjd37 frontotemporal lobe dementia38 and normal pressure hydrocephalus in contrast to ttau which just reflects intensity of axonal injury in these patients the ratio between ptau and ttau is more helpful for identifying ad tau pathology and differentiating ad from these conditions Title of the paper: Phosphorylated tau as a candidate biomarker for amyotrophic lateral sclerosis. Abstract of the paper: IMPORTANCE An increasingly varied clinical spectrum of cases with amyotrophic lateral sclerosis (ALS) has been identified, and objective criteria for clinical trial eligibility are necessary. OBJECTIVE To develop a cerebrospinal fluid (CSF) biomarker sensitive and specific for the diagnosis of ALS. DESIGN, SETTING, AND PARTICIPANTS A case-control study including 51 individuals with ALS and 23 individuals with a disorder associated with a 4-repeat tauopathy was conducted at an academic medical center. MAIN OUTCOMES AND MEASURES The CSF level of tau phosphorylated at threonine 181 (ptau) and ratio of ptau to total tau (ttau). RESULTS Using a cross-validation prediction procedure, we found significantly reduced CSF levels of ptau and the ptau:ttau ratio in ALS relative to 4-repeat tauopathy and to controls. In the validation cohort, the receiver operating characteristic area under the curve for the ptau:ttau ratio was 0.916, and the comparison of ALS with 4-repeat tauopathy showed 92.0% sensitivity and 91.7% specificity. Correct classification based on a low CSF ptau:ttau ratio was confirmed in 18 of 21 cases (86%) with autopsy-proved or genetically determined disease. In patients with available measures, ptau:ttau in ALS correlated with clinical measures of disease severity, such as the Mini-Mental State Examination (n = 51) and ALS Functional Rating Scale-Revised (n = 42), and regression analyses related the ptau:ttau ratio to magnetic resonance imaging (n = 10) evidence of disease in the corticospinal tract and white matter projections involving the prefrontal cortex. CONCLUSIONS AND RELEVANCE The CSF ptau:ttau ratio may be a candidate biomarker to provide objective support for the diagnosis of ALS.

False

CitationGPTRetr11620

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: consistent with our and others previous observations we observed significant deficits in learning and memory in controlfed transgenic pdapp animals Title of the paper: Learning and memory in transgenic mice modeling Alzheimer's disease. Abstract of the paper: Recent advances in behavioral analyses of transgenic mouse models of Alzheimer's disease (AD) are discussed, and their impact on our understanding of the molecular basis of cognitive impairment in AD is considered. Studies of the relationship between memory and A Beta in transgenic mice expressing the amyloid precursor protein (APP) and its variants suggest that aging promotes the formation of soluble A Beta assemblies mediating negative effects on memory. A significant component of memory loss in APP transgenic mice is apparently caused by soluble A Beta assemblies, but whether and how much of the dementia within individuals afflicted with AD is caused by these A Beta species is unclear. Future studies in composite transgenic mice developing amyloid plaques, neurofibrillary tangles, and other AD pathology may allow for the determination of the relative contribution of A Beta and non-A Beta components to dementia.

False

CitationGPTRetr11621

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: consistent with our and others previous observations we observed significant deficits in learning and memory in controlfed transgenic pdapp animals Title of the paper: Behavioral disturbances in transgenic mice overexpressing the V717F beta-amyloid precursor protein. Abstract of the paper: PDAPP transgenic mice have been shown to develop age dependently much of the cerebral histopathology associated with Alzheimer's disease. PDAPP mice (3-10 months old) were tested in a battery of memory tasks to determine whether they develop memory-behavioral deficits and whether these deficits occur before or after amyloid deposition. PDAPP mice manifest robust impairments in a radial-maze spatial discrimination task at all ages tested. Mild deficits were observed in a barpress learning task in 3-month-old PDAPP mice. In contrast, PDAPP mice show an age-dependent decrease in spontaneous object-recognition performance that appears to be severe at ages when amyloid deposition is known to occur. Thus, the PDAPP mouse shows severe deficits in the radial maze well before amyloid plaque deposition, whereas object-recognition performance decreases with age and may be associated with amyloid deposition.

False

CitationGPTRetr11622

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: consistent with our and others previous observations we observed significant deficits in learning and memory in controlfed transgenic pdapp animals Title of the paper: Learning and memory deficits in APP transgenic mouse models of amyloid deposition. Abstract of the paper: Several different transgenic APP mice develop learning and memory deficits. In some cases the mice have deficits very early in life, while in other instances the mice exhibit deficits only after they have aged and amyloid deposits have accumulated. In many cases, there is a correlation in individual mice of the same age and genotype between the extent of learning and memory deficits and the amounts of deposited amyloid found in the central nervous system. While superficially this might imply that the deposited material is somehow toxic to cognition, it is likely that deposited amyloid is also an index of the overall rate of amyloid production in each mouse. Rate of production would be expected to modify not only the amounts of deposited amyloid, but also other amyloid pools, including soluble, oligomeric, conjugated (e.g. ADDLs) and intracellular. Thus, the deposited material may be an integrated reflection of total A beta production, in addition to indicating the amounts in fibrillar forms. As such, it is conceivable that other A beta pools may be more directly linked to memory deficits. Thus far, the one manipulation found to mitigate the learning and memory deficits in APP transgenic mice is immunotherapy for A beta, either using active or passive immunization against the peptide. These data together with other findings are leading to a conclusion that the fibrillar A beta deposits are not directly linked to the memory deficits in mice, and that some other A beta pool, more readily diminished by immunotherapy, is more directly linked to the mechanisms leading to poor performance in learning and memory tasks.

False

CitationGPTRetr11623

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: consistent with our and others previous observations we observed significant deficits in learning and memory in controlfed transgenic pdapp animals Title of the paper: Associative and motor learning in 12-month-old transgenic APP+PS1 mice. Abstract of the paper: Doubly transgenic 12-month-old amyloid precursor protein and presenilins 1 (APP+PS1) mice (n=14) and littermate control mice (n=17) were tested on eyeblink classical conditioning-a task impaired in humans with Alzheimer's disease (AD). Mice were also tested on a motor learning task (rotorod) and on sensory tasks (prepulse inhibition [PPI] and acoustic startle). Transgenic mice had impaired motor performance on rotorod. Overall, APP+PS1 mice performed similarly to controls on both 500ms delay and 500ms trace eyeblink conditioning as well as on prepulse inhibition (PPI) and acoustic startle. However, within the transgenic group, cortical amyloid burden correlated significantly with decreased trace eyeblink conditioning. Moreover, cortical amyloid burden and hippocampal microglia activation correlated significantly with decreased PPI. These data suggest that only those transgenic mice with the most severe amyloid pathology exhibited deficits in hippocampus-dependent tasks. Transgenic mouse models of amyloid deposition differ from Alzheimer patients not only by the absence of major neuronal loss, but also by the general absence of severe impairments in eyeblink conditioning, except for mice with the greatest amyloid pathology.

False

CitationGPTRetr11624

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: consistent with our and others previous observations we observed significant deficits in learning and memory in controlfed transgenic pdapp animals Title of the paper: Neuroanatomical abnormalities in behaviorally characterized APP(V717F) transgenic mice. Abstract of the paper: Histological analyses were performed on the brains of APP(V717F) transgenic (Tg)mice previously studied in a battery of behavioral tests. We describe here the regional and age-dependent deposition of amyloid in both heterozygous and homozygous Tg mice. We also report that Tg mice show significant and age-dependent changes in synaptic density measured by synaptophysin immunoreactivity. Surprisingly, a rather marked hippocampal atrophy is observed as early as 3 months of age in Tg mice (20-40%). Statistical analyses revealed that the deficits in object recognition memory are related to the number of amyloid deposits in specific brain regions, whereas deficits in spatial reference and working memory are related to the changes in synaptic density and hippocampal atrophy. Our study suggests that the behavioral deficits observed in Tg mice are only in part related to amyloid deposition, but are also related to neuroanatomical alterations secondary to overexpression of the APP(V717F) transgene and independent of amyloid deposition.

False

CitationGPTRetr11625

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: consistent with our and others previous observations we observed significant deficits in learning and memory in controlfed transgenic pdapp animals Title of the paper: Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Abstract of the paper: We investigated synaptic communication and plasticity in hippocampal slices from mice overexpressing mutated 695-amino-acid human amyloid precursor protein (APP695SWE), which show behavioral and histopathological abnormalities simulating Alzheimer's disease. Although aged APP transgenic mice exhibit normal fast synaptic transmission and short term plasticity, they are severely impaired in in-vitro and in-vivo long-term potentiation (LTP) in both the CA1 and dentate gyrus regions of the hippocampus. The LTP deficit was correlated with impaired performance in a spatial working memory task in aged transgenics. These deficits are accompanied by minimal or no loss of presynaptic or postsynaptic elementary structural elements in the hippocampus, suggesting that impairments in functional synaptic plasticity may underlie some of the cognitive deficits in these mice and, possibly, in Alzheimer's patients.

False

CitationGPTRetr11626

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: consistent with our and others previous observations we observed significant deficits in learning and memory in controlfed transgenic pdapp animals Title of the paper: Long-term prevention of Alzheimer's disease-like behavioral deficits in PDAPP mice carrying a mutation in Asp664. Abstract of the paper: The deficits of Alzheimer's disease (AD) are believed to result, at least in part, from neurotoxicity of beta-amyloid (Abeta), a set of 38-43 amino acid fragments derived from the beta-amyloid precursor protein (APP). In addition, APP generates the APP-C31 and Jcasp toxic fragments intracellularly by cleavage at Asp664. We reported that mutation of Asp664 to Ala in a FAD-human APP transgene prevented AD-like deficits but did not affect Abeta production or deposition in PDAPP mice, arguing that D664A plays a crucial role in the generation of AD-like deficits. Whether D664A simply delays or completely prevents AD-like deficits, however, remained undefined. To address this question, we performed behavioral studies longitudinally on a pretrained mouse cohort at 9 and 13 months (mo) of age. While behavioral deficits were present in PDAPP mice, performance of Tg PDAPP(D664A) mice was not significantly different from non-Tg littermates' across all ages tested. Moreover, aberrant patterns in non-cognitive components of behavior in PDAPP mice were ameliorated in PDAPP(D664A) animals as well. A trend towards poorer retention at 9 mo and poorer learning at 13 mo that did not reach statistical significance was observed in PDAPP(D664A) mice. These results support and extend recent studies showing that cleavage of APP at Asp664 (or protein-protein interactions dependent on Asp664) is a crucial event in the generation of AD-like deficits in PDAPP mice. Our results thus further demonstrate that the D664A mutation either completely precludes, or markedly delays (beyond 13 mo) the appearance of AD-like deficits in this mouse model of AD.

True

CitationGPTRetr11627

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: consistent with our and others previous observations we observed significant deficits in learning and memory in controlfed transgenic pdapp animals Title of the paper: Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Abstract of the paper: Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer beta-amyloid (Abeta) precursor protein containing a Lys670 --> Asn, Met671 --> Leu mutation had normal learning and memory in spatial reference and alternation tasks at 3 months of age but showed impairment by 9 to 10 months of age. A fivefold increase in Abeta(1-40) and a 14-fold increase in Abeta(1-42/43) accompanied the appearance of these behavioral deficits. Numerous Abeta plaques that stained with Congo red dye were present in cortical and limbic structures of mice with elevated amounts of Abeta. The correlative appearance of behavioral, biochemical, and pathological abnormalities reminiscent of Alzheimer's disease in these transgenic mice suggests new opportunities for exploring the pathophysiology and neurobiology of this disease.

False

CitationGPTRetr11628

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: consistent with our and others previous observations we observed significant deficits in learning and memory in controlfed transgenic pdapp animals Title of the paper: An in vitro and in vivo study of early deficits in associative learning in transgenic mice that over-express a mutant form of human APP associated with Alzheimer's disease. Abstract of the paper: Transgenic mice over-expressing a mutated form of the human amyloid precursor protein (APP, 695 isoform) bearing a mutation associated with Alzheimer's disease (V642I, so-called London mutation, hereafter APPLd2) and wild-type controls were studied at age periods (3 and 10 months) prior to the overt development of neuritic amyloid plaques. Both 3- and 10-month-old APPLd2 mice had reflex eyelid responses like those of controls, but only younger mice were able to acquire a classical conditioning of eyelid responses in a trace paradigm. In vitro studies on hippocampal slices showed that 10-month-old APPLd2 mice also presented deficits in paired-pulse facilitation and long-term potentiation, but presented a normal synaptic activation of CA1 pyramidal cells by the stimulation of Schaffer collaterals. It is proposed that definite functional changes may appear well in advance of noticeable structural alterations in this animal model of Alzheimer's disease, and that specific learning tasks could have a relevant diagnostic value.

False

CitationGPTRetr11629

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: consistent with our and others previous observations we observed significant deficits in learning and memory in controlfed transgenic pdapp animals Title of the paper: APPSw transgenic mice develop age-related A beta deposits and neuropil abnormalities, but no neuronal loss in CA1. Abstract of the paper: The recent availability of transgenic mouse models of Alzheimer disease has allowed direct in vivo assessment of the molecular and neuropathological effects of cerebral amyloid deposition. We examined 16-month-old Tg(HuAPP695. K670N-M671L)2576 mice expressing human APP K670N-M671L (APPSw), which have amyloid deposition and behavioral deficits by 11 months of age. Transgene expression is predominantly neuronal, and results in amyloid deposits, comparable to human senile plaques, at terminal zones of transgene positive neurons in cortical and limbic regions. Amyloid deposits were associated with prominent gliosis and neuritic dystrophy, without neuronal loss in CA1, loss of synaptophysin immunoreactivity in the hippocampal dentate gyrus, or loss of messenger RNA for neuronal synaptic, cytoskeletal, or metabolic proteins. We conclude that A beta is not acutely neurotoxic, but can disrupt neuronal processes and provoke an inflammatory response.

False

CitationGPTRetr11630

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: consistent with our and others previous observations we observed significant deficits in learning and memory in controlfed transgenic pdapp animals Title of the paper: Age-related learning deficits in transgenic mice expressing the 751-amino acid isoform of human beta-amyloid precursor protein. Abstract of the paper: The beta-amyloid precursor protein (beta-APP), from which the beta-A4 peptide is derived, is considered to be central to the pathogenesis of Alzheimer disease (AD). Transgenic mice expressing the 751-amino acid isoform of human beta-APP (beta-APP751) have been shown to develop early AD-like histopathology with diffuse deposits of beta-A4 and aberrant tau protein expression in the brain, particularly in the hippocampus, cortex, and amygdala. We now report that beta-APP751 transgenic mice exhibit age-dependent deficits in spatial learning in a water-maze task and in spontaneous alternation in a Y maze. These deficits were mild or absent in 6-month-old transgenic mice but were severe in 12-month-old transgenic mice compared to age-matched wild-type control mice. No other behavioral abnormalities were observed. These mice therefore model the progressive learning and memory impairment that is a cardinal feature of AD. These results provide evidence for a relationship between abnormal expression of beta-APP and cognitive impairments.

False

CitationGPTRetr11631

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: consistent with our and others previous observations we observed significant deficits in learning and memory in controlfed transgenic pdapp animals Title of the paper: Correlation between cognitive deficits and Abeta deposits in transgenic APP+PS1 mice. Abstract of the paper: Doubly transgenic mAPP+mPS1 mice (15-16 months) had impaired cognitive function in a spatial learning and memory task that combined features of a water maze and a radial arm maze. Nontransgenic mice learned a new platform location each day during 4 consecutive acquisition trials, and exhibited memory for this location in a retention trial administered 30 min later. In contrast, transgenic mice were, on average, unable to improve their performance in finding the hidden platform over trials. The cognitive performance of individual mice within the transgenic group were inversely related to the amount of Abeta deposited in the frontal cortex and hippocampus. These findings imply that mAPP+mPS1 transgenic mice develop deficits in cognitive ability as Abeta deposits increase. These data argue that radial arm water maze testing of doubly transgenic mice may be a useful behavioral endpoint in evaluating the functional consequences of potential AD therapies, especially those designed to reduce Abeta load.

False

CitationGPTRetr11632

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: consistent with our and others previous observations we observed significant deficits in learning and memory in controlfed transgenic pdapp animals Title of the paper: Memory deficits correlating with acetylcholinesterase splice shift and amyloid burden in doubly transgenic mice. Abstract of the paper: Current mouse models of Alzheimer's disease show brain pathology that correlates to a degree with memory impairment, but underlying molecular mechanisms remained unknown. Here we report studies with three lines of transgenic mice: animals that doubly express mutated human amyloid precursor protein (APPswe) and human acetylcholinesterase (hAChE); and animals transgenic for only the APPswe or the hAChE. Among these genotypes, variations were observed in expression of mRNA for presenilin-1, which was highest in singly transgenic hAChE mice, and the stress-inducible form of AChE, which was elevated when both transgenes were present. At the age of nine months, both double and single transgenic mice displayed working memory impairment in a radial arm water maze. However, as compared with mice expressing amyloid alone, the double transgenic animals exhibited more numerous plaques and greater amyloid burden in brain (both by histochemistry and by ELISA of amyloid protein). Moreover, the amyloid burden in double transgenics was tightly correlated with memory impairment as measured by total maze errors (r2= 0.78, p = .002). This correlation was markedly stronger than observed in mice with amyloid alone. These new findings support the notion of cholinergic-amyloid interrelationships and highlight the double transgenic mice as a promising alternative for testing Alzheimer's therapies.

False

CitationGPTRetr11633

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: consistent with our and others previous observations we observed significant deficits in learning and memory in controlfed transgenic pdapp animals Title of the paper: Episodic memory deficits are not related to altered glutamatergic synaptic transmission and plasticity in the CA1 hippocampus of the APPswe/PS1δE9-deleted transgenic mice model of ß-amyloidosis. Abstract of the paper: Alzheimer's disease (AD) is characterized by progressive memory impairment and the formation of amyloid plaques in the brain. Dysfunctional excitatory synaptic transmission and synaptic plasticity are generally accepted as primary events in the development of AD, and beta-amyloid is intimately involved. Here we describe age related differences in learning, memory, synaptic transmission and long-term potentiation (LTP) in wild type and APPswe/PS1DeltaE9 mice, which produce increasing amounts of Abeta1-42 with age. The mice have both age related and age-independent deficits in radial arm water maze performance. Blind studies of hippocampal slices from transgenic and wild type mice demonstrate that transgenic mice have impaired transient LTP and that the degree of impairment is not related to age from 3 to 12 months. The deficiencies in transient LTP may be related to the behavioral deficits that did not progress with age. The accumulation of beta-amyloid and the episodic memory deficits, both of which increased with age, were not accompanied by an alteration in synaptic transmission or sustained LTP in the in vitro hippocampal slices.

False

CitationGPTRetr11634

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: consistent with our and others previous observations we observed significant deficits in learning and memory in controlfed transgenic pdapp animals Title of the paper: Behavioral changes in transgenic mice expressing both amyloid precursor protein and presenilin-1 mutations: lack of association with amyloid deposits. Abstract of the paper: Mutations in the amyloid precursor protein (mAPP) and in presenilin 1 (mPS1) have both been linked to increased production of the beta-amyloid peptide (A beta). Doubly transgenic mice produced by mating of a parental line carrying the "Swedish" (K670N/M671L) APP mutation with a FAD4 (M146L) mutant presenilin 1 line developed numerous fibrillar A beta deposits by 6 months of age. Prior work demonstrated that mAPP and doubly transgenic (mAPP/mPS1) mice have deficits in Y-maze alternation behavior as early as 3 months of age. Increased activity was also apparent in the mAPP/mPS1 mice at this time point. These changes in Y-maze performance persisted in mAPP/mPS1 mice at 6 and 9 months of age. The mPS1 singly transgenic mice were not impaired on this task at any age. Six- and nine-month-old mice were also tested for spatial navigation behavior in the Morris water maze. In training trials, no differences in escape latency were detected among the four genotypes. In probe trials, no differences were detected in either the time spent in the trained quadrant or the number of platform crossings among the four groups. Histological staining for A beta amyloid deposits indicates that all doubly transgenic mice have amyloid deposits by 6 months of age (roughly 25 mice examined thus far), yet no 3-month-old mice have been found with deposits. A beta immunostaining confirmed that the 9-month-old mice tested behaviorally also have A beta deposits. Thus, doubly transgenic mice exhibited changes in Y-maze performance prior to the formation of amyloid deposits, which are essentially unchanged as the deposits increase in number and size to 9 months of age. Yet these mice fail to reveal impairments in spatial navigation at 6 or 9 months in spite of the increasing plaque burden. These data indicate that A beta deposits alone are not sufficient to cause robust spatial memory impairment in mice of this mixed background lineage and age.

False

CitationGPTRetr11635

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: consistent with our and others previous observations we observed significant deficits in learning and memory in controlfed transgenic pdapp animals Title of the paper: A specific amyloid-beta protein assembly in the brain impairs memory. Abstract of the paper: Memory function often declines with age, and is believed to deteriorate initially because of changes in synaptic function rather than loss of neurons. Some individuals then go on to develop Alzheimer's disease with neurodegeneration. Here we use Tg2576 mice, which express a human amyloid-beta precursor protein (APP) variant linked to Alzheimer's disease, to investigate the cause of memory decline in the absence of neurodegeneration or amyloid-beta protein amyloidosis. Young Tg2576 mice (< 6 months old) have normal memory and lack neuropathology, middle-aged mice (6-14 months old) develop memory deficits without neuronal loss, and old mice (> 14 months old) form abundant neuritic plaques containing amyloid-beta (refs 3-6). We found that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kDa soluble amyloid-beta assembly, which we term Abeta*56 (Abeta star 56). Abeta*56 purified from the brains of impaired Tg2576 mice disrupts memory when administered to young rats. We propose that Abeta*56 impairs memory independently of plaques or neuronal loss, and may contribute to cognitive deficits associated with Alzheimer's disease.

False

CitationGPTRetr11636

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: consistent with our and others previous observations we observed significant deficits in learning and memory in controlfed transgenic pdapp animals Title of the paper: Normal cognitive behavior in two distinct congenic lines of transgenic mice hyperexpressing mutant APP SWE. Abstract of the paper: Amyloid deposition appears to be an early and crucial event in Alzheimer's disease (AD). To generate animal models of AD, mice expressing full-length amyloid precursor protein (APP), with mutations linked to FAD, have been created. These animals exhibit abnormalities characteristic of AD, including deposits of beta-amyloid (Abeta), neuritic plaques, and glial responses. In studies of cognition in these animals, there have been several reports of memory disturbances well before the appearance of amyloid deposits. We have developed two distinct lines of transgenic mice (C3-3 and E1-2) that express the "Swedish" variant of APP (APP(SWE)) at levels that are approximately three-fold higher than endogenous mouse APP. Both lines have been backcrossed to C57BL/6J mice for 10 generations. Here, we use longitudinal and cross-sectional studies to evaluate the cognitive performance of our animals, where the concentration of Abeta1-42 in brain increases with aging from low levels (2-10 pmol/g) at 6-14 months of age to relatively high levels (60-100 pmol/g) at 24-26 months, when deposits of Abeta were beginning to form. When 12-month-old mice were tested in tasks that assess reference and working memory, transgenic mice from both lines could not be distinguished from nontransgenic littermates. Further study of 24- to 26-month-old transgenic mice (C3-3 line) found no evidence of memory impairment despite the presence of high levels of human Abeta (60-100 pmol/g). Thus, the expression of APP(SWE) at approximately three-fold over endogenous levels, which is sufficient to induce amyloid deposition at advanced ages, does not significantly erode cognitive performance in aged mice.

False

CitationGPTRetr11637

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: consistent with our and others previous observations we observed significant deficits in learning and memory in controlfed transgenic pdapp animals Title of the paper: Specific spatial learning deficits become severe with age in beta -amyloid precursor protein transgenic mice that harbor diffuse beta -amyloid deposits but do not form plaques. Abstract of the paper: Memory impairment progressing to dementia is the main clinical symptom of Alzheimer's disease (AD). AD is characterized histologically by the presence of beta-amyloid (Abeta) plaques and neurofibrillary tangles in specific brain regions. Although Abeta derived from the Abeta precursor protein (beta-APP) is believed to play a central etiological role in AD, it is not clear whether soluble and/or fibrillar forms are responsible for the memory deficit. We have generated and previously described mice expressing human wild-type beta-APP(751) isoform in neurons. These transgenic mice recapitulate early histopathological features of AD and form Abeta deposits but no plaques. Here we describe a specific and progressive learning and memory impairment in these animals. In the Morris water maze, a spatial memory task sensitive to hippocampal damage, one pedigree already showed significant differences in acquisition in 3-month-old mice that increased in severity with age and were expressed clearly in 6-month- and 2-year-old animals. The second transgenic pedigree displayed a milder impairment with a later age of onset. Performance deficits significantly decreased during the 6 days of training in young but not in aged transgenic animals. Both pedigrees of the transgenic mice differed from wild-type mice by less expressed increase of escape latencies after the platform position had been changed in the reversal experiment and by failure to prefer the goal quadrant in probe trials. Both pedigrees performed at wild-type level in a number of other tests (open field exploration and passive and active place avoidance). The results suggest that plaque formation is not a necessary condition for the neuronal beta-APP(751) transgene-induced memory impairment, which may be caused by beta-APP overexpression, isoform misexpression, or elevated soluble Abeta.

False

CitationGPTRetr11638

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: consistent with our and others previous observations we observed significant deficits in learning and memory in controlfed transgenic pdapp animals Title of the paper: Progressive, age-related behavioral impairments in transgenic mice carrying both mutant amyloid precursor protein and presenilin-1 transgenes. Abstract of the paper: This study provides a comprehensive behavioral characterization during aging of transgenic mice bearing both presenilin-1 (PS1) and amyloid precursor protein (APP(670,671)) mutations. Doubly transgenic mice and non-transgenic controls were evaluated at ages wherein beta-amyloid (Abeta) neuropathology in APP+PS1 mice is low (5-7 months) or very extensive (15-17 months). Progressive cognitive impairment was observed in transgenic mice for both water maze acquisition and radial arm water maze working memory. However, transgenicity did not affect Y-maze alternations, circular platform performance, standard water maze retention, or visible platform recognition at either age, nor did transgenicity affect anxiety levels in elevated plus-maze testing. In sensorimotor tasks, transgenic mice showed a progressive increase in open field activity, a progressive impairment in string agility, and an early-onset impairment in balance beam. None of these sensorimotor changes appeared to be contributory to any cognitive impairments observed, however. Non-transgenic mice showed no progressive behavioral change in any measure evaluated. Given the age-related cognitive impairments presently observed in APP+PS1 transgenic mice and their progressive Abeta deposition/neuroinflammation, Abeta neuropathology could be involved in these progressive cognitive impairments. As such, the APP+PS1 transgenic mouse offers unique opportunities to develop therapeutics to treat or prevent Alzheimer's Disease through modulation of Abeta deposition/neuroinflammation.

False

CitationGPTRetr11639

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: consistent with our and others previous observations we observed significant deficits in learning and memory in controlfed transgenic pdapp animals Title of the paper: Selectively reduced expression of synaptic plasticity-related genes in amyloid precursor protein + presenilin-1 transgenic mice. Abstract of the paper: A critical question in Alzheimer's disease (AD) research is the cause of memory loss that leads to dementia. The amyloid precursor protein + presenilin-1 (APP+PS1) transgenic mouse is a model for amyloid deposition, and like AD, the mice develop memory deficits as amyloid deposits accumulate. We profiled gene expression in these transgenic mice by microarray and quantitative RT-PCR (qRT-PCR). At the age when these animals developed cognitive dysfunction, they had reduced mRNA expression of several genes essential for long-term potentiation and memory formation (Arc, Zif268, NR2B, GluR1, Homer-1a, Nur77/TR3). These changes appeared to be related to amyloid deposition, because mRNA expression was unchanged in the regions that did not accumulate amyloid. Transgene expression was similar in both amyloid-containing and amyloid-free regions of the brain. Interestingly, these changes occurred without apparent changes in synaptic structure, because a number of presynaptic marker mRNAs (growth-associated protein-43, synapsin, synaptophysin, synaptopodin, synaptotagmin, syntaxin) remained stable. Additionally, a number of genes related to inflammation were elevated in transgenic mice, primarily in the regions containing amyloid. In AD cortical tissue, the same memory-associated genes were downregulated. However, all synaptic and neuronal transcripts were reduced, implying that the loss of neurons and synapses contributed to these changes. We conclude that reduced expression of selected genes associated with memory consolidation are linked to memory loss in both circumstances. This suggests that the memory loss in APP+PS1 transgenic mice may model the early memory dysfunction in AD before the degeneration of synapses and neurons.

False

CitationGPTRetr11640

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: despite the fact that epo is a critical modulator of erythropoiesis the presence of a diminished oxygen tension is required rather than a low concentration of red blood cells gene transcription of epo is mediated by the transcription enhancer located in the 3flanking region of the epo gene that specifically binds to hypoxiainducible factor 1 hif1 yet hypoxia is not the only condition that can alter the expression of epo and the epor Title of the paper: Production and processing of erythropoietin receptor transcripts in brain. Abstract of the paper: The expression of erythropoietin receptor (EpoR) in brain and neuronal cells, and hypoxia-responsive production of erythropoietin (Epo) in the brain suggests that the function of Epo as a survival or viability factor may extend beyond hematopoietic tissue and erythroid progenitor cells. Epo, produced by astrocytes and neurons, can be induced by hypoxia by severalfold, and in animal models Epo administration is neuroprotective to ischemic challenge. We characterized the human EpoR transcript in brain and neuronal cells to determine its contribution in regulating the Epo response in brain. Screening of a human brain cDNA library and quantitative analysis of EpoR transcripts indicate that the EpoR gene locus is transcriptionally active in brain. In addition to the proximal promoter that is active in hematopoietic cells, a significant proportion of transcripts originates far upstream from the EpoR coding region. Unlike erythroid cells with efficient splicing of EpoR transcripts to its mature form, brain EpoR transcripts are inefficiently or alternately processed with a bias towards the 3' coding region. In human EpoR transgenic mice, anemic stress induces expression of the transgene and endogenous EpoR gene in hematopoietic tissue and brain. In culture of neuronal cells, hypoxia induces EpoR expression and increases sensitivity to Epo. Induction of EpoR expression appears to be a consequence of increased transcription from the upstream region and proximal promoter, and a shift towards increased processing efficiency. These data suggest that in contrast to erythropoiesis where erythroid progenitor cells express high levels of EpoR and are directly responsive to Epo stimulation, the neuroprotective effect of Epo and its receptor may require two molecular events: the induction of Epo production by hypoxia and an increase in EpoR expression in neuronal cells resulting in increased sensitivity to Epo.

False

CitationGPTRetr11641

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: despite the fact that epo is a critical modulator of erythropoiesis the presence of a diminished oxygen tension is required rather than a low concentration of red blood cells gene transcription of epo is mediated by the transcription enhancer located in the 3flanking region of the epo gene that specifically binds to hypoxiainducible factor 1 hif1 yet hypoxia is not the only condition that can alter the expression of epo and the epor Title of the paper: Erythropoietin and the hypoxic brain. Abstract of the paper: Normal tissue function in mammals depends on adequate supply of oxygen through blood vessels. A discrepancy between oxygen supply and consumption (hypoxia) induces a variety of specific adaptation mechanisms at the cellular, local and systemic level. These mechanisms are in part governed by the activation of hypoxia-inducible transcription factors (HIF-1, HIF-2), which in turn modulate expression of hypoxically regulated genes such as those encoding vascular endothelial growth factor (VEGF) and erythropoietin (EPO). EPO is a glycoprotein that is produced mainly by interstitial fibroblasts in the kidneys of the adult and in hepatocytes in the foetus. Released into the circulation, EPO makes its way to the bone marrow, where it regulates red cell production by preventing apoptosis of erythroid progenitor cells. Recently, EPO has emerged as a multifunctional growth factor that plays a significant role in the nervous system. Both EPO and its receptor are expressed throughout the brain in glial cells, neurones and endothelial cells. Hypoxia and ischaemia have been recognised as important driving forces of EPO expression in the brain. EPO has potent neuroprotective properties in vivo and in vitro and appears to act in a dual way by directly protecting neurones from ischaemic damage and by stimulating endothelial cells and thus supporting the angiogenic effect of VEGF in the nervous system. Thus, hypoxia-induced gene products such as VEGF and EPO might be part of a self-regulated physiological protection mechanism to prevent neuronal injury, especially under conditions of chronically reduced blood flow (chronic ischaemia). In this review, I will briefly summarize the recent findings on the molecular mechanisms of hypoxia-regulated EPO expression in general and give an overview of its expression in the central nervous system, its action as a growth factor with non-haematopoietic functions and its potential clinical relevance in various brain pathologies.

False

CitationGPTRetr11642

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: despite the fact that epo is a critical modulator of erythropoiesis the presence of a diminished oxygen tension is required rather than a low concentration of red blood cells gene transcription of epo is mediated by the transcription enhancer located in the 3flanking region of the epo gene that specifically binds to hypoxiainducible factor 1 hif1 yet hypoxia is not the only condition that can alter the expression of epo and the epor Title of the paper: Erythropoietin as a Neuroprotective Molecule: An Overview of Its Therapeutic Potential in Neurodegenerative Diseases. Abstract of the paper: Erythropoietin (EPO) is a cytokine mainly induced in hypoxia conditions. Its major production site is the kidney. EPO primarily acts on the erythroid progenitor cells in the bone marrow. More and more studies are highlighting its secondary functions, with a crucial focus on its role in the central nervous system. Here, EPO may interact with up to four distinct isoforms of its receptor (erythropoietin receptor [EPOR]), activating different signaling cascades with roles in neuroprotection and neurogenesis. Indeed, the EPO/EPOR axis has been widely studied in the neurodegenerative diseases field. Its potential therapeutic effects have been evaluated in multiple disorders, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, spinal cord injury, as well as brain ischemia, hypoxia, and hyperoxia. EPO is showing great promise by counteracting secondary neuroinflammatory processes, reactive oxygen species imbalance, and cell death in these diseases. Multiple studies have been performed both in vitro and in vivo, characterizing the mechanisms through which EPO exerts its neurotrophic action. In some cases, clinical trials involving EPO have been performed, highlighting its therapeutic potential. Together, all these works indicate the potential beneficial effects of EPO.

False

CitationGPTRetr11643

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: despite the fact that epo is a critical modulator of erythropoiesis the presence of a diminished oxygen tension is required rather than a low concentration of red blood cells gene transcription of epo is mediated by the transcription enhancer located in the 3flanking region of the epo gene that specifically binds to hypoxiainducible factor 1 hif1 yet hypoxia is not the only condition that can alter the expression of epo and the epor Title of the paper: Erythropoietin and erythropoietin receptors in human CNS neurons, astrocytes, microglia, and oligodendrocytes grown in culture. Abstract of the paper: Erythropoietin (EPO) is a hematopoietic growth factor that stimulates proliferation and differentiation of erythroid precursor cells and is also known to exert neurotrophic activity in the central nervous system (CNS). However, little is known about expression of EPO and EPO receptor (EPOR) in human CNS tissues. In the present study, we investigated the effects of proinflammatory cytokines on EPO and EPOR expression in highly purified cultures of human neurons, astrocytes, microglia, and oligodendrocytes using reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). EPO mRNA was demonstrated only in human astrocytes, while EPOR expression was found in human neurons, astrocytes, and microglia. Neither EPO nor EPOR expression was found in oligodendrocytes. In human astrocytes, EPO mRNA and secreted EPO protein levels were downregulated after exposure to proinflammatory cytokines (IL-1beta, IL-6, or TNF-alpha). In human neurons, TNF-alpha treatment markedly increased EPOR expression. These results suggest that proinflammatory cytokines regulate expression of EPO and EPOR in human neurons, astrocytes, and microglia and further facilitate interactions among different cell types in the human CNS.

False

CitationGPTRetr11644

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: despite the fact that epo is a critical modulator of erythropoiesis the presence of a diminished oxygen tension is required rather than a low concentration of red blood cells gene transcription of epo is mediated by the transcription enhancer located in the 3flanking region of the epo gene that specifically binds to hypoxiainducible factor 1 hif1 yet hypoxia is not the only condition that can alter the expression of epo and the epor Title of the paper: Erythropoietin (epoetin) as a protective factor for the brain. Abstract of the paper: Erythropoietin (EPO) has been viewed traditionally as a hematopoietic cytokine. Emerging evidence now exists supporting a physiologic role for EPO within the nervous system. EPO is expressed in the developing central nervous system and is capable of regulating the production of neuronal progenitor cells. There are numerous preclinical studies demonstrating a neuroprotective potential for EPO in a variety of disorders of both the central and peripheral nervous systems. A small pilot study in patients with acute ischemic stroke has recently been completed and the results are encouraging. Its mechanism of action is multifactorial but probably related to its ability to act as an antiapoptotic agent. Its widespread use clinically for the treatment of anemias has given us the experience and knowledge of its safety and pharmacokinetics. EPO is thus an ideal compound to study for the potential treatment of a variety of neurologic disorders.

False

CitationGPTRetr11645

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: despite the fact that epo is a critical modulator of erythropoiesis the presence of a diminished oxygen tension is required rather than a low concentration of red blood cells gene transcription of epo is mediated by the transcription enhancer located in the 3flanking region of the epo gene that specifically binds to hypoxiainducible factor 1 hif1 yet hypoxia is not the only condition that can alter the expression of epo and the epor Title of the paper: Erythropoietin: a neuroprotective agent in cerebral hypoxia, neurodegeneration, and epilepsy. Abstract of the paper: Neuronal damage secondary to brain injuries such as cerebral hypoxia, seizures as well as neurodegenerative process, may include pro-inflammatory changes. The activation of a common mechanism related to survival or cell death, mediated by the stabilization and trans-activation of Hypoxia-Inducible Factor 1 (HIF-1), has been observed in these conditions. HIF-1 may induce over expression of P-glycoprotein, the product multidrug-resistance gene (MDR-1), both on blood-brain barrier as well as on the cerebral damaged cells, producing the refractoriness to therapeutic strategies for neuroprotection. However, in these same cells, HIF-1 can also induce the expression of erythropoietin receptor (Epo-R). Irrespective of its known properties on hematopoiesis, it was proposed that erythropoietin can trigger neuroprotective mechanisms mediated by Epo-R activation. Brain hypoxia, epilepsy, neurodegeneration and inflammation, can share the induction of Epo-R and several other growth factor receptors as well as signal transductions pathways after HIF-1 transactivation. Perhaps, the use of the intranasal route for the exogenous administration of Epo, (or other biological compounds) could help neuroprotection as well as to repair the brain areas damaged.

False

CitationGPTRetr11646

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: despite the fact that epo is a critical modulator of erythropoiesis the presence of a diminished oxygen tension is required rather than a low concentration of red blood cells gene transcription of epo is mediated by the transcription enhancer located in the 3flanking region of the epo gene that specifically binds to hypoxiainducible factor 1 hif1 yet hypoxia is not the only condition that can alter the expression of epo and the epor Title of the paper: Non-erythroid functions of erythropoietin. Abstract of the paper: The oxygen-dependent, renal cytokine eythropoietin (Epo) is well known to increase red cell production. Binding of Epo to the Epo receptor (EpoR) represses apoptosis of erythroid progenitor cells, thereby allowing their final maturation. We and others showed that Epo and its receptor are expressed in many other tissues, including brain, spinal cord, retina and testis. The presence of a blood barrier suggests that Epo plays a local role in these organs. Indeed, therapeutically applied or hypoxically induced Epo has been shown to reduce the infarct volume in various stroke animal models, to prevent retinal degeneration, and to ameliorate spinal cord injury. In a study conducted by Ehrenreich and colleagues, stroke patients treated with Epo showed reduced infarct volume, fast neurological recovery and improved clinical outcome. In analogy to its function on erythroid progenitor cells, this neuroprotective effect of Epo might be explained by repression of programmed cell death. Apart from neuroprotection, there is an assumption that Epo present in breast milk has the potential to protect against mother-to-infant transmission of HIV. When using Epo at high doses for longer time periods; however, care has to be taken to control the resulting chronic polycythemia that most probably caused enlarged cerebral infarct volumes in a transgenic mouse model that due to Epo-overexpression reached hematocrit levels of about 0.8. Overall, these data strongly support the notion that Epo will soon find new applications in the clinic.

False

CitationGPTRetr11647

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: despite the fact that epo is a critical modulator of erythropoiesis the presence of a diminished oxygen tension is required rather than a low concentration of red blood cells gene transcription of epo is mediated by the transcription enhancer located in the 3flanking region of the epo gene that specifically binds to hypoxiainducible factor 1 hif1 yet hypoxia is not the only condition that can alter the expression of epo and the epor Title of the paper: Erythropoietin gene expression in human, monkey and murine brain. Abstract of the paper: The haematopoietic growth factor erythropoietin is the primary regulator of mammalian erythropoiesis and is produced by the kidney and the liver in an oxygen-dependent manner. We and others have recently demonstrated erythropoietin gene expression in the rodent brain. In this work, we show that cerebral erythropoietin gene expression is not restricted to rodents but occurs also in the primate brain. Erythropoietin mRNA was detected in biopsies from the human hippocampus, amygdala and temporal cortex and in various brain areas of the monkey Macaca mulatta. Exposure to a low level of oxygen led to elevated erythropoietin mRNA levels in the monkey brain, as did anaemia in the mouse brain. In addition, erythropoietin receptor mRNA was detected in all brain biopsies tested from man, monkey and mouse. Analysis of primary cerebral cells isolated from newborn mice revealed that astrocytes, but not microglia cells, expressed erythropoietin. When incubated at 1% oxygen, astrocytes showed >100-fold time-dependent erythropoietin mRNA accumulation, as measured with the quantitative reverse transcription-polymerase chain reaction. The specificity of hypoxic gene induction in these cells was confirmed by quantitative Northern blot analysis showing hypoxic up-regulation of mRNA encoding the vascular endothelial growth factor, but not of other genes. These findings demonstrate that erythropoietin and its receptor are expressed in the brain of primates as they are in rodents, and that, at least in mice, primary astrocytes are a source of cerebral erythropoietin expression which can be up-regulated by reduced oxygenation.

False

CitationGPTRetr11648

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: despite the fact that epo is a critical modulator of erythropoiesis the presence of a diminished oxygen tension is required rather than a low concentration of red blood cells gene transcription of epo is mediated by the transcription enhancer located in the 3flanking region of the epo gene that specifically binds to hypoxiainducible factor 1 hif1 yet hypoxia is not the only condition that can alter the expression of epo and the epor Title of the paper: Erythropoietin and erythropoietin receptor in the developing human central nervous system. Abstract of the paper: We have previously shown the presence of erythropoietin (Epo) within the spinal fluid of normal preterm and term infants, and the presence of Epo receptor (Epo-R) in the spinal cords of human fetuses. It is not known, however: 1) whether cells within the fetal central nervous system (CNS) express Epo; 2) if so, whether this expression changes with development; 3) which cells within the CNS express Epo-R; 4) whether Epo-R expression within the CNS changes with development; and 5) whether Epo-R within the fetal CNS are functional. Expression of mRNA for Epo and Epo-R was sought by reverse transcription-PCR in mixed primary cultures of fetal spinal cords as well as NT2 and hNT cells, human cell lines of neuronal precursors and mature neurons, respectively. Epo was measured by ELISA in spent media from primary cell culture, and immunohistochemistry was used to identify Epo-R on neurons and glia in cell culture, and in brain sections. Developmental changes in Epo and Epo-R expression were sought in spinal cords and brains from fetuses of 7-24 wk postconception by semiquantitative PCR. To assess Epo-R function, NT2 cells were exposed to conditions which stimulate programmed cell death, and rescue from apoptosis by the addition of recombinant Epo was evaluated by nuclear matrix protein ELISA, cell counts, and by Klenow labeling of DNA fragments. Epo and Epo-R mRNA were expressed in mixed primary cultures of neural tissues and NT2 and hNT cells. Epo was detected by ELISA in media removed from mixed cell cultures, and immunohistochemical staining confirmed the presence of Epo-R on neurons and their supporting cells. Semiquantitative PCR revealed no significant change in expression of either Epo or Epo-R in spinal cords between 7 and 16 wk of gestation, with increased expression of Epo and Epo-R in brains from 8 to 24 wk of gestation. Epo mRNA expression from neurons doubled under conditions of hypoxia. Recombinant Epo decreased apoptotic cell death of neurons under conditions of hypoxia. Protein and mRNA for Epo and its receptor are expressed by human neurons and glial cells in spinal cord and brain during fetal development. These receptors appear to have a neuroprotective effect in conditions of hypoxia.

False

CitationGPTRetr11649

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: despite the fact that epo is a critical modulator of erythropoiesis the presence of a diminished oxygen tension is required rather than a low concentration of red blood cells gene transcription of epo is mediated by the transcription enhancer located in the 3flanking region of the epo gene that specifically binds to hypoxiainducible factor 1 hif1 yet hypoxia is not the only condition that can alter the expression of epo and the epor Title of the paper: General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Abstract of the paper: Transcription of the human erythropoietin (EPO) gene is activated in Hep3B cells exposed to hypoxia. Hypoxia-inducible factor 1 (HIF-1) is a nuclear factor whose DNA binding activity is induced by hypoxia in Hep3B cells, and HIF-1 binds at a site in the EPO gene enhancer that is required for hypoxic activation of transcription. In this paper, we demonstrate that HIF-1 DNA binding activity is also induced by hypoxia in a variety of mammalian cell lines in which the EPO gene is not transcribed. The composition of the HIF-1 DNA binding complex and its isolated DNA binding subunit and the mechanism of HIF-1 activation appear to be similar or identical in EPO-producing and non-EPO-producing cells. Transcription of reporter genes containing the EPO gene enhancer is induced by hypoxia in non-EPO-producing cells and mutations that eliminate HIF-1 binding eliminate inducibility. These results provide evidence that HIF-1 and its recognition sequence are common components of a general mammalian cellular response to hypoxia.

False

CitationGPTRetr11650

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: despite the fact that epo is a critical modulator of erythropoiesis the presence of a diminished oxygen tension is required rather than a low concentration of red blood cells gene transcription of epo is mediated by the transcription enhancer located in the 3flanking region of the epo gene that specifically binds to hypoxiainducible factor 1 hif1 yet hypoxia is not the only condition that can alter the expression of epo and the epor Title of the paper: Erythropoietin and erythropoietin receptor in human ischemic/hypoxic brain. Abstract of the paper: Using immunohistochemistry, expression of erythropoietin (EPO), a hypoxia-inducible neuroprotective factor, and its receptor (EPOR) were investigated in human brain tissue after ischemia/hypoxia. Autopsy brains of neuropathologically normal subjects were compared to those with ischemic infarcts or hypoxic damage. In normal brain, weak EPO/EPOR immunoreactivity was mainly neuronal. In fresh infarcts, EPO immunoreactivity appeared in vascular endothelium, EPOR in microvessels and neuronal fibers. In older infarcts reactive astrocytes exhibited EPO/EPOR immunoreactivity. Acute hypoxic brain damage was associated with vascular EPO expression, older hypoxic damage with EPO/EPOR immunoreactivity in reactive astrocytes. The pronounced up-regulation of EPO/EPOR in human ischemic/hypoxic brains underlines their role as an endogenous neuroprotective system and suggests a novel therapeutic potential in cerebrovascular disease for EPO, a clinically well-characterized and safe compound.

False

CitationGPTRetr11651

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: despite the fact that epo is a critical modulator of erythropoiesis the presence of a diminished oxygen tension is required rather than a low concentration of red blood cells gene transcription of epo is mediated by the transcription enhancer located in the 3flanking region of the epo gene that specifically binds to hypoxiainducible factor 1 hif1 yet hypoxia is not the only condition that can alter the expression of epo and the epor Title of the paper: Functional hypoxia drives neuroplasticity and neurogenesis via brain erythropoietin. Abstract of the paper: Erythropoietin (EPO), named after its role in hematopoiesis, is also expressed in mammalian brain. In clinical settings, recombinant EPO treatment has revealed a remarkable improvement of cognition, but underlying mechanisms have remained obscure. Here, we show with a novel line of reporter mice that cognitive challenge induces local/endogenous hypoxia in hippocampal pyramidal neurons, hence enhancing expression of EPO and EPO receptor (EPOR). High-dose EPO administration, amplifying auto/paracrine EPO/EPOR signaling, prompts the emergence of new CA1 neurons and enhanced dendritic spine densities. Single-cell sequencing reveals rapid increase in newly differentiating neurons. Importantly, improved performance on complex running wheels after EPO is imitated by exposure to mild exogenous/inspiratory hypoxia. All these effects depend on neuronal expression of the Epor gene. This suggests a model of neuroplasticity in form of a fundamental regulatory circle, in which neuronal networks-challenged by cognitive tasks-drift into transient hypoxia, thereby triggering neuronal EPO/EPOR expression.

False

CitationGPTRetr11652

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: despite the fact that epo is a critical modulator of erythropoiesis the presence of a diminished oxygen tension is required rather than a low concentration of red blood cells gene transcription of epo is mediated by the transcription enhancer located in the 3flanking region of the epo gene that specifically binds to hypoxiainducible factor 1 hif1 yet hypoxia is not the only condition that can alter the expression of epo and the epor Title of the paper: Erythropoietin in the brain: can the promise to protect be fulfilled? Abstract of the paper: Erythropoietin (EPO) has emerged as a versatile growth factor that has transcended its traditional role as a mediator of erythroid maturation to one that modulates stem cell development, cellular protection and angiogenesis in the brain. As a possible candidate for nervous system disorders, it becomes crucial to understand the cellular mechanisms that foster cytoprotection rather than cytotoxicity for EPO. EPO offers novel neuronal and vascular protection not only through the maintenance of cellular integrity, but also through the prevention of cellular inflammation. The protective and anti-inflammatory capacities of EPO originate with the Janus tyrosine kinase 2 protein and protein kinase B (Akt). Downstream cellular pathways include FOXO3a, GSK-3beta, Bad, Bcl-xL, NF-kappaB, mitochondrial membrane permeability, APAF-1 and caspases. Further understanding of the cellular pathways that are susceptible to modulation by EPO will be crucial to foster the development of this agent as a robust and efficacious therapy for the brain.

True

CitationGPTRetr11653

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: despite the fact that epo is a critical modulator of erythropoiesis the presence of a diminished oxygen tension is required rather than a low concentration of red blood cells gene transcription of epo is mediated by the transcription enhancer located in the 3flanking region of the epo gene that specifically binds to hypoxiainducible factor 1 hif1 yet hypoxia is not the only condition that can alter the expression of epo and the epor Title of the paper: Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Abstract of the paper: Erythropoietin, a kidney cytokine regulating haematopoiesis (the production of blood cells), is also produced in the brain after oxidative or nitrosative stress. The transcription factor hypoxia-inducible factor-1 (HIF-1) upregulates EPO following hypoxic stimuli. Here we show that preconditioning with EPO protects neurons in models of ischaemic and degenerative damage due to excitotoxins and consequent generation of free radicals, including nitric oxide (NO). Activation of neuronal EPO receptors (EPORs) prevents apoptosis induced by NMDA (N-methyl-d-aspartate) or NO by triggering cross-talk between the signalling pathways of Janus kinase-2 (Jak2) and nuclear factor-kappaB (NF-kappaB). We show that EPOR-mediated activation of Jak2 leads to phosphorylation of the inhibitor of NF-kappaB (IkappaB), subsequent nuclear translocation of the transcription factor NF-kappaB, and NF-kappaB-dependent transcription of neuroprotective genes. Transfection of cerebrocortical neurons with a dominant interfering form of Jak2 or an IkappaBalpha super-repressor blocks EPO-mediated prevention of neuronal apoptosis. Thus neuronal EPORs activate a neuroprotective pathway that is distinct from previously well characterized Jak and NF-kappaB functions. Moreover, this EPO effect may underlie neuroprotection mediated by hypoxic-ischaemic preconditioning.

False

CitationGPTRetr11654

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: despite the fact that epo is a critical modulator of erythropoiesis the presence of a diminished oxygen tension is required rather than a low concentration of red blood cells gene transcription of epo is mediated by the transcription enhancer located in the 3flanking region of the epo gene that specifically binds to hypoxiainducible factor 1 hif1 yet hypoxia is not the only condition that can alter the expression of epo and the epor Title of the paper: Erythropoietin protects cultured cortical neurons, but not astroglia, from hypoxia and AMPA toxicity. Abstract of the paper: In addition to its better-known hemopoietic action, erythropoietin (Epo) has neurotrophic properties and neuroprotective effects in some models of hypoxic-ischemic injury. To define further the cellular mechanisms underlying neuroprotection by Epo, we studied the effects of Epo on hypoxia with glucose deprivation in cultured rat cortical neurons and astroglia and on exposure to excitotoxins in cultured rat cortical neurons. Epo (30 pM) reduced neuronal, but not astroglial, cell death from hypoxia with glucose deprivation, and also attenuated the neurotoxic effect of (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), but not other excitotoxins. Epo appears to protect against cerebral ischemia through a direct effect on neurons that may be mediated in part by AMPA receptors.

False

CitationGPTRetr11655

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: despite the fact that epo is a critical modulator of erythropoiesis the presence of a diminished oxygen tension is required rather than a low concentration of red blood cells gene transcription of epo is mediated by the transcription enhancer located in the 3flanking region of the epo gene that specifically binds to hypoxiainducible factor 1 hif1 yet hypoxia is not the only condition that can alter the expression of epo and the epor Title of the paper: Structure, production and function of erythropoietin: implications for therapeutical use in cardiovascular disease. Abstract of the paper: Erythropoietin (EPO) is a 30,400 daltons glycoprotein, consisting of 165 amino acids produced mainly in the kidney and in the liver and regulating erythrocyitosis. It primarily acts on erythroid precursor cell at colony-forming units-erythroid stage inhibiting the apoptosis. EPO binds on a specific membrane receptor thereby activating at least three specific intracellular signaling pathways, such as phosphatidylinositol 3-kinase/ protein kinase B, Ras-mitogen-activated protein kinase and some members of the signal transducers and activators of transcription family. In addition to kidney and liver, EPO mRNA has been detected in other tissues; accordingly EPO receptor has been identified in several type of cells and recent reports have suggested new roles for EPO in non-haematopoietic tissues with a robust evidence for neuroprotective and cardioprotective activity. In different animal models, in vitro, in isolated perfused heart and in vivo, recombinant human erythropoietin protects heart from ischemia reperfusion injury and reduces myocardial damage. EPO tissue protective activity can be separated from erythropoietic activity. Molecules owing the first property but not the second one have been described. In patients with acute myocardial infarction serum EPO level correlates inversely with infarct size. Acute coronary syndrome, extracorporeal circulation and percutaneous coronary intervention are potential fields of application for tissue protective EPO activity to reduce myocardial damage, increase cardiac function ad improve outcome.

False

CitationGPTRetr11656

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: despite the fact that epo is a critical modulator of erythropoiesis the presence of a diminished oxygen tension is required rather than a low concentration of red blood cells gene transcription of epo is mediated by the transcription enhancer located in the 3flanking region of the epo gene that specifically binds to hypoxiainducible factor 1 hif1 yet hypoxia is not the only condition that can alter the expression of epo and the epor Title of the paper: Neuroprotective effects of EpoL against oxidative stress induced by soluble oligomers of Aβ peptide. Abstract of the paper: Erythropoietin is a glycoproteic hormone that regulates hematopoiesis by acting on its specific receptor (EpoR). The expression of EpoR in the central nervous system (CNS) suggests a role for this hormone in the brain. Recently, we developed a new Epo variant without hematopoietic activity called EpoL, which showed marked neuroprotective effects against oxidative stress in brain ischemia related models. In this study, we have evaluated the neuroprotective effects of EpoL against oxidative stress induced by chronic treatment with Aβ. Our results show that EpoL was neuroprotective against Aβ-induced toxicity by a mechanism that implicates EpoR, reduction in reactive oxygen species, and reduction in astrogliosis. Furthermore, EpoL treatment improved calcium handling and SV2 levels. Interestingly, the neuroprotective effect of EpoL against oxidative stress induced by chronic Aβ treatment was achieved at a concentration 10 times lower than that of Epo. In conclusion, EpoL, a new variant of Epo without hematopoietic activity, is of potential interest for the treatment of diseases related to oxidative stress in the CNS such as Alzheimer disease.

False

CitationGPTRetr11657

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: despite the fact that epo is a critical modulator of erythropoiesis the presence of a diminished oxygen tension is required rather than a low concentration of red blood cells gene transcription of epo is mediated by the transcription enhancer located in the 3flanking region of the epo gene that specifically binds to hypoxiainducible factor 1 hif1 yet hypoxia is not the only condition that can alter the expression of epo and the epor Title of the paper: Hematopoietic factor erythropoietin fosters neuroprotection through novel signal transduction cascades. Abstract of the paper: In addition to promoting the survival, proliferation, and differentiation of immature erythroid cells, erythropoietin and the erythropoietin receptor have recently been shown to modulate cellular signal transduction pathways that extend beyond the erythropoietic function of erythropoietin. In particular, erythropoietin has been linked to the prevention of programmed cell death in neuronal systems. Although this work is intriguing, the underlying molecular mechanisms that serve to mediate neuroprotection by erythropoietin are not well understood. Further analysis illustrates that erythropoietin modulates two distinct components of programmed cell death that involve the degradation of DNA and the externalization of cellular membrane phosphatidylserine residues. Initiation of the cascades that modulate protection by erythropoietin and its receptor may begin with the activation of the Janus tyrosine kinase 2 protein. Subsequent downstream mechanisms appear to lead to the activation of multiple signal transduction pathways that include transcription factor STAT5 (signal transducers and activators of transcription), Bcl-2, protein kinase B, cysteine proteases, mitogen-activated protein kinases, protein-tyrosine phosphatases, and nuclear factor-kappaB. New knowledge of the cellular pathways regulated by erythropoietin in neuronal environments will potentially solidify the development and initiation of therapeutic strategies against nervous system disorders.

False

CitationGPTRetr11658

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: despite the fact that epo is a critical modulator of erythropoiesis the presence of a diminished oxygen tension is required rather than a low concentration of red blood cells gene transcription of epo is mediated by the transcription enhancer located in the 3flanking region of the epo gene that specifically binds to hypoxiainducible factor 1 hif1 yet hypoxia is not the only condition that can alter the expression of epo and the epor Title of the paper: Brain-derived erythropoietin protects from focal cerebral ischemia by dual activation of ERK-1/-2 and Akt pathways. Abstract of the paper: Apart from its hematopoietic function, erythropoietin (Epo) exerts neuroprotective functions in brain hypoxia and ischemia. To examine the mechanisms mediating Epo's neuroprotective activity in vivo, we made use of our transgenic mouse line tg21 that constitutively expresses human Epo in brain without inducing excessive erythrocytosis. We show that human Epo is expressed in tg21 brains and that cortical and striatal neurons carry the Epo receptor. After middle cerebral artery occlusion, human Epo potently protected brains of tg21 mice against ischemic injury, both when severe (90 min) and mild (30 min) ischemia was imposed. Histochemical studies revealed that Epo induced an activation of JAK-2, ERK-1/-2, and Akt pathways in the ischemic brain. This activation was associated with elevated Bcl-XL and decreased NO synthase-1 and -2 levels in neurons. Intracerebroventricular injections of selective inhibitors of ERK-1/-2 (PD98059) or Akt (wortmannin) pathways revealed that both ERK-1/-2 and Akt were required for Epo's neuroprotective function, antagonization of either pathway completely abolishing tissue protection. On the other hand, ERK-1/-2 and Akt blockade did not reverse the neuronal NO synthase-1/-2 inhibition, indicating that Epo down-regulates these NO synthases in an ERK-1/-2 and Akt independent manner. On the basis of our data, the dual activation of ERK-1/-2 and Akt is crucial for Epo's neuroprotective activity.

False

CitationGPTRetr11659

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: despite the fact that epo is a critical modulator of erythropoiesis the presence of a diminished oxygen tension is required rather than a low concentration of red blood cells gene transcription of epo is mediated by the transcription enhancer located in the 3flanking region of the epo gene that specifically binds to hypoxiainducible factor 1 hif1 yet hypoxia is not the only condition that can alter the expression of epo and the epor Title of the paper: Erythropoietin on a tightrope: balancing neuronal and vascular protection between intrinsic and extrinsic pathways. Abstract of the paper: Enthusiasm for erythropoietin (EPO) as a broad cytoprotective agent continues to increase at an almost exponential rate. The premise that EPO was required only for erythropoiesis was eventually shed by recent work demonstrating the existence of EPO and its receptor in other organs and tissues outside of the liver and the kidney, such as the brain and heart. As a result, EPO has been identified as a possible candidate in the formulation of therapeutic strategies for both cardiac and nervous system diseases. EPO has been shown to mediate an array of vital cellular functions that involve progenitor stem cell development, cellular protection, angiogenesis, DNA repair, and cellular longevity. An important requirement to achieve the goal of preventing or even reducing cellular injury by any cytoprotective agent is the ability to uncover the cellular pathways that ultimately drive a cell to its demise. We present for consideration several critical cellular pathways modulated by EPO that involve Janus kinase 2 (Jak2), the serine-threonine kinase Akt, forkhead transcription factors, glycogen synthase kinase-3beta (GSK-3beta), cellular calcium, protein kinase C, caspases, as well as the control of inflammatory microglial activation. As we continue to gain new insight into these pathways, EPO should emerge as a critical agent for the development, maturation, and survival of cells throughout the body.

False

CitationGPTRetr11660

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: yet these lines of investigation are not without limitations since chemical derivatives of epo can become absent of clinical efficacy as well as possibly loose the ability to promote sustainable cytoprotective effects such as neurogenesis and angiogenesis Title of the paper: Erythropoietin--a novel concept for neuroprotection. Abstract of the paper: Neuroprotection as a means to prevent or oppose pathological neuronal loss in central nervous system disease of various pathophysiological origins represents a novel therapeutic approach. This approach is supported by extensive experimental evidence on cell culture and animal studies demonstrating beneficial effects of growth factors on neuronal survival and functional recovery. The clinical use of neuroprotective agents has been hampered by the toxicity of many of the compounds that showed promising therapeutic potential in animal studies. The focus of this review is on a novel neuroprotective approach with erythropoietin, a hematopoietic growth factor that: 1) is expressed in the human central nervous system, 2) is hypoxia-inducible, 3) has demonstrated remarkable neuroprotective potential in cell culture and animal models of disease, 4) has multiple protective effects (antiapoptotic, neurotrophic, antioxidant, angiogenic), and 5) is a clinically extremely well tolerated compound.

False

CitationGPTRetr11661

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: yet these lines of investigation are not without limitations since chemical derivatives of epo can become absent of clinical efficacy as well as possibly loose the ability to promote sustainable cytoprotective effects such as neurogenesis and angiogenesis Title of the paper: Erythropoietin (epoetin) as a protective factor for the brain. Abstract of the paper: Erythropoietin (EPO) has been viewed traditionally as a hematopoietic cytokine. Emerging evidence now exists supporting a physiologic role for EPO within the nervous system. EPO is expressed in the developing central nervous system and is capable of regulating the production of neuronal progenitor cells. There are numerous preclinical studies demonstrating a neuroprotective potential for EPO in a variety of disorders of both the central and peripheral nervous systems. A small pilot study in patients with acute ischemic stroke has recently been completed and the results are encouraging. Its mechanism of action is multifactorial but probably related to its ability to act as an antiapoptotic agent. Its widespread use clinically for the treatment of anemias has given us the experience and knowledge of its safety and pharmacokinetics. EPO is thus an ideal compound to study for the potential treatment of a variety of neurologic disorders.

False

CitationGPTRetr11662

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: yet these lines of investigation are not without limitations since chemical derivatives of epo can become absent of clinical efficacy as well as possibly loose the ability to promote sustainable cytoprotective effects such as neurogenesis and angiogenesis Title of the paper: New avenues of exploration for erythropoietin. Abstract of the paper: Discovery that the hormone erythropoietin (EPO) and its receptor play a significant biological role in tissues outside of the hematopoietic system has fueled significant interest in EPO as a novel cytoprotective agent in both neuronal and vascular systems. Erythropoietin is now considered to have applicability in a variety of disorders that include cerebral ischemia, myocardial infarction, and chronic congestive heart failure. Erythropoietin modulates a broad array of cellular processes that include progenitor stem cell development, cellular integrity, and angiogenesis. As a result, cellular protection by EPO is robust and EPO inhibits the apoptotic mechanisms of injury, including the preservation of cellular membrane asymmetry to prevent inflammation. As the investigation into clinical applications for EPO that maximize efficacy and minimize toxicity progresses, a deeper appreciation for the novel roles that EPO plays in the brain and heart and throughout the entire body should be acquired.

True

CitationGPTRetr11663

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: yet these lines of investigation are not without limitations since chemical derivatives of epo can become absent of clinical efficacy as well as possibly loose the ability to promote sustainable cytoprotective effects such as neurogenesis and angiogenesis Title of the paper: Erythropoietin: elucidating new cellular targets that broaden therapeutic strategies. Abstract of the paper: Given that erythropoietin (EPO) is no longer believed to have exclusive biological activity in the hematopoietic system, EPO is now considered to have applicability in a variety of nervous system disorders that can overlap with vascular disease, metabolic impairments, and immune system function. As a result, EPO may offer efficacy for a broad number of disorders that involve Alzheimer's disease, cardiac insufficiency, stroke, trauma, and diabetic complications. During a number of clinical conditions, EPO is robust and can prevent metabolic compromise, neuronal and vascular degeneration, and inflammatory cell activation. Yet, use of EPO is not without its considerations especially in light of frequent concerns that may compromise clinical care. Recent work has elucidated a number of novel cellular pathways governed by EPO that can open new avenues to avert deleterious effects of this agent and offer previously unrecognized perspectives for therapeutic strategies. Obtaining greater insight into the role of EPO in the nervous system and elucidating its unique cellular pathways may provide greater cellular viability not only in the nervous system but also throughout the body.

False

CitationGPTRetr11664

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: yet these lines of investigation are not without limitations since chemical derivatives of epo can become absent of clinical efficacy as well as possibly loose the ability to promote sustainable cytoprotective effects such as neurogenesis and angiogenesis Title of the paper: Erythropoietin as a Neuroprotective Molecule: An Overview of Its Therapeutic Potential in Neurodegenerative Diseases. Abstract of the paper: Erythropoietin (EPO) is a cytokine mainly induced in hypoxia conditions. Its major production site is the kidney. EPO primarily acts on the erythroid progenitor cells in the bone marrow. More and more studies are highlighting its secondary functions, with a crucial focus on its role in the central nervous system. Here, EPO may interact with up to four distinct isoforms of its receptor (erythropoietin receptor [EPOR]), activating different signaling cascades with roles in neuroprotection and neurogenesis. Indeed, the EPO/EPOR axis has been widely studied in the neurodegenerative diseases field. Its potential therapeutic effects have been evaluated in multiple disorders, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, spinal cord injury, as well as brain ischemia, hypoxia, and hyperoxia. EPO is showing great promise by counteracting secondary neuroinflammatory processes, reactive oxygen species imbalance, and cell death in these diseases. Multiple studies have been performed both in vitro and in vivo, characterizing the mechanisms through which EPO exerts its neurotrophic action. In some cases, clinical trials involving EPO have been performed, highlighting its therapeutic potential. Together, all these works indicate the potential beneficial effects of EPO.

False

CitationGPTRetr11665

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: yet these lines of investigation are not without limitations since chemical derivatives of epo can become absent of clinical efficacy as well as possibly loose the ability to promote sustainable cytoprotective effects such as neurogenesis and angiogenesis Title of the paper: Erythropoietin and derivatives: Potential beneficial effects on the brain. Abstract of the paper: Erythropoietin (Epo), the main erythropoiesis-stimulating factor widely prescribed to overcome anemia, is also known nowadays for its cytoprotective action on non-hematopoietic tissues. In this context, Epo showed not only its ability to cross the blood-brain barrier, but also its expression in the brain of mammals. In clinical trials, recombinant Epo treatment has been shown to stimulate neurogenesis; improve cognition; and activate antiapoptotic, antioxidant, and anti-inflammatory signaling pathways. These mechanisms, proposed to characterize a neuroprotective property, opened new perspectives on the Epo pharmacological potencies. However, many questions arise about a possible physiological role of Epo in the central nervous system (CNS) and the factors or environmental conditions that induce its expression. Although Epo may be considered a strong candidate to be used against neuronal damage, long-term treatments, particularly when high Epo doses are needed, may induce thromboembolic complications associated with increases in hematocrit and blood viscosity. To avoid these adverse effects, different Epo analogs without erythropoietic activity but maintaining neuroprotection ability are currently being investigated. Carbamylated erythropoietin, as well as alternative molecules like Epo fusion proteins and partial peptides of Epo, seems to match this profile. This review will focus on the discussion of experimental evidence reported in recent years linking erythropoietin and CNS function through investigations aimed at finding benefits in the treatment of neurodegenerative diseases. In addition, it will review the proposed mechanisms for novel derivatives which may clarify and, eventually, improve the neuroprotective action of Epo.

False

CitationGPTRetr11666

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: yet these lines of investigation are not without limitations since chemical derivatives of epo can become absent of clinical efficacy as well as possibly loose the ability to promote sustainable cytoprotective effects such as neurogenesis and angiogenesis Title of the paper: Erythropoietin on a tightrope: balancing neuronal and vascular protection between intrinsic and extrinsic pathways. Abstract of the paper: Enthusiasm for erythropoietin (EPO) as a broad cytoprotective agent continues to increase at an almost exponential rate. The premise that EPO was required only for erythropoiesis was eventually shed by recent work demonstrating the existence of EPO and its receptor in other organs and tissues outside of the liver and the kidney, such as the brain and heart. As a result, EPO has been identified as a possible candidate in the formulation of therapeutic strategies for both cardiac and nervous system diseases. EPO has been shown to mediate an array of vital cellular functions that involve progenitor stem cell development, cellular protection, angiogenesis, DNA repair, and cellular longevity. An important requirement to achieve the goal of preventing or even reducing cellular injury by any cytoprotective agent is the ability to uncover the cellular pathways that ultimately drive a cell to its demise. We present for consideration several critical cellular pathways modulated by EPO that involve Janus kinase 2 (Jak2), the serine-threonine kinase Akt, forkhead transcription factors, glycogen synthase kinase-3beta (GSK-3beta), cellular calcium, protein kinase C, caspases, as well as the control of inflammatory microglial activation. As we continue to gain new insight into these pathways, EPO should emerge as a critical agent for the development, maturation, and survival of cells throughout the body.

False

CitationGPTRetr11667

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: yet these lines of investigation are not without limitations since chemical derivatives of epo can become absent of clinical efficacy as well as possibly loose the ability to promote sustainable cytoprotective effects such as neurogenesis and angiogenesis Title of the paper: Hematopoietic factor erythropoietin fosters neuroprotection through novel signal transduction cascades. Abstract of the paper: In addition to promoting the survival, proliferation, and differentiation of immature erythroid cells, erythropoietin and the erythropoietin receptor have recently been shown to modulate cellular signal transduction pathways that extend beyond the erythropoietic function of erythropoietin. In particular, erythropoietin has been linked to the prevention of programmed cell death in neuronal systems. Although this work is intriguing, the underlying molecular mechanisms that serve to mediate neuroprotection by erythropoietin are not well understood. Further analysis illustrates that erythropoietin modulates two distinct components of programmed cell death that involve the degradation of DNA and the externalization of cellular membrane phosphatidylserine residues. Initiation of the cascades that modulate protection by erythropoietin and its receptor may begin with the activation of the Janus tyrosine kinase 2 protein. Subsequent downstream mechanisms appear to lead to the activation of multiple signal transduction pathways that include transcription factor STAT5 (signal transducers and activators of transcription), Bcl-2, protein kinase B, cysteine proteases, mitogen-activated protein kinases, protein-tyrosine phosphatases, and nuclear factor-kappaB. New knowledge of the cellular pathways regulated by erythropoietin in neuronal environments will potentially solidify the development and initiation of therapeutic strategies against nervous system disorders.

False

CitationGPTRetr11668

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: yet these lines of investigation are not without limitations since chemical derivatives of epo can become absent of clinical efficacy as well as possibly loose the ability to promote sustainable cytoprotective effects such as neurogenesis and angiogenesis Title of the paper: Erythropoietin: cytoprotection in vascular and neuronal cells. Abstract of the paper: One of the principal functions of erythropoietin (EPO) is to stimulate the survival, proliferation, and differentiation of immature erythroid cells. Yet, EPO has recently been shown to modulate cellular signal transduction pathways to perform multiple functions other than erythropoiesis. EPO is cytoprotective through the prevention of programmed cell death in both vascular and neuronal systems by modulating two distinct components of programmed cell death that involve the degradation of genomic DNA and the externalization of cellular membrane phosphatidylserine (PS) residues. Cytoprotection by EPO is initiated by the activation of the EPO receptor (EPOR) and subsequent signal transduction pathways that originate with the Janus-tyrosine kinase 2 (Jak2) protein. Further down-stream cellular pathways include the activation of signal transducers and activators of transcription (STATs), Bcl-x(L), phosphoinositide-3-kinase/Akt, mitogen-activated protein kinases, cysteine proteases, protein tyrosine phosphatases, and nuclear factor kappaB. Further understanding of the cellular pathways that modulate EPO cytoprotection in the nervous system will be crucial for the development of therapeutic strategies against neurodegenerative diseases.

False

CitationGPTRetr11669

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: yet these lines of investigation are not without limitations since chemical derivatives of epo can become absent of clinical efficacy as well as possibly loose the ability to promote sustainable cytoprotective effects such as neurogenesis and angiogenesis Title of the paper: Erythropoietin as a novel neuroprotectant. Abstract of the paper: PURPOSE To provide an overview of the current knowledge on neuroprotective properties of Erythropoietin (Epo), mechanisms by which Epo produces neuroprotection, and signaling pathways regulated by Epo in the nervous system. METHODS The Medline database was searched for articles on the neuroprotective properties of Epo. Experimental and clinical studies were systematically reviewed. RESULTS In addition to promoting the survival, proliferation, and differentiation of immature erythroid cells, Epo and the Epo receptor (EpoR) have recently been shown to exist and function in the nervous system. The Epo/EpoR system plays a critical role in neurodevelopment and neuroprotection. Epo ameliorates or prevents neuronal injury by neuroprotective, anti-apoptotic, anti-inflammatory, anti-oxidant, angiogenic, neurogenic and neurotrophic effects in cell culture and animal models of neurological diseases. The clinical effectiveness of recombinant human Epo in ischemic stroke in human patients has also been reported recently. CONCLUSION Recent studies suggest that Epo is a potential novel neurotherapeutic agent and further clinical studies are warranted.

False

CitationGPTRetr11670

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: yet these lines of investigation are not without limitations since chemical derivatives of epo can become absent of clinical efficacy as well as possibly loose the ability to promote sustainable cytoprotective effects such as neurogenesis and angiogenesis Title of the paper: Erythropoietin as neuroprotective and neuroregenerative treatment strategy: comprehensive overview of 12 years of preclinical and clinical research. Abstract of the paper: Erythropoietin (EPO), originally discovered as hematopoietic growth factor, has direct effects on cells of the nervous system that make it a highly attractive candidate drug for neuroprotection/neuroregeneration. Hardly any other compound has led to so much preclinical work in the field of translational neuroscience than EPO. Almost all of the >180 preclinical studies performed by many independent research groups from all over the world in the last 12 years have yielded positive results on EPO as a neuroprotective drug. The fact that EPO was approved for the treatment of anemia >20 years ago and found to be well tolerated and safe, facilitated the first steps of translation from preclinical findings to the clinic. On the other hand, the same fact, naturally associated with loss of patent protection, hindered to develop EPO as a highly promising therapeutic strategy for application in human brain disease. Therefore, only few clinical neuroprotection studies have been concluded, all with essentially positive and stimulating results, but no further development towards the clinic has occurred thus far. This article reviews the preclinical and clinical work on EPO for the indications neuroprotection/neuroregeneration and cognition, and hopefully will stimulate new endeavours promoting development of EPO for the treatment of human brain diseases.

False

CitationGPTRetr11671

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: yet these lines of investigation are not without limitations since chemical derivatives of epo can become absent of clinical efficacy as well as possibly loose the ability to promote sustainable cytoprotective effects such as neurogenesis and angiogenesis Title of the paper: Erythropoietin: a neuroprotective agent in cerebral hypoxia, neurodegeneration, and epilepsy. Abstract of the paper: Neuronal damage secondary to brain injuries such as cerebral hypoxia, seizures as well as neurodegenerative process, may include pro-inflammatory changes. The activation of a common mechanism related to survival or cell death, mediated by the stabilization and trans-activation of Hypoxia-Inducible Factor 1 (HIF-1), has been observed in these conditions. HIF-1 may induce over expression of P-glycoprotein, the product multidrug-resistance gene (MDR-1), both on blood-brain barrier as well as on the cerebral damaged cells, producing the refractoriness to therapeutic strategies for neuroprotection. However, in these same cells, HIF-1 can also induce the expression of erythropoietin receptor (Epo-R). Irrespective of its known properties on hematopoiesis, it was proposed that erythropoietin can trigger neuroprotective mechanisms mediated by Epo-R activation. Brain hypoxia, epilepsy, neurodegeneration and inflammation, can share the induction of Epo-R and several other growth factor receptors as well as signal transductions pathways after HIF-1 transactivation. Perhaps, the use of the intranasal route for the exogenous administration of Epo, (or other biological compounds) could help neuroprotection as well as to repair the brain areas damaged.

False

CitationGPTRetr11672

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: yet these lines of investigation are not without limitations since chemical derivatives of epo can become absent of clinical efficacy as well as possibly loose the ability to promote sustainable cytoprotective effects such as neurogenesis and angiogenesis Title of the paper: Erythropoietin enhances long-term neuroprotection and neurogenesis in neonatal stroke. Abstract of the paper: Neonatal stroke leads to mortality and severe morbidity, but there is no effective treatment currently available. Erythropoietin (EPO) has been shown to promote cytoprotection and neurogenesis and decrease subventricular zone morphologic changes following brain injury. The long-term cellular response to EPO has not been defined, and local changes in cell fate decision may play a role in functional improvement. We performed middle cerebral artery occlusion in P10 rats. EPO treatment (5 U/g i.p.) significantly preserved hemispheric brain volume 6 weeks after injury. Furthermore, EPO increased the percentage of newly generated neurons while decreasing newly generated astrocytes following brain injury, without demonstrating long-term differences in the subventricular zone. These results suggest that EPO may neuroprotect and direct cell fate toward neurogenesis and away from gliogenesis in neonatal stroke.

True

CitationGPTRetr11673

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: yet these lines of investigation are not without limitations since chemical derivatives of epo can become absent of clinical efficacy as well as possibly loose the ability to promote sustainable cytoprotective effects such as neurogenesis and angiogenesis Title of the paper: Erythropoietin 2nd cerebral protection after acute injuries: a double-edged sword? Abstract of the paper: Over the past 15 years, a large body of evidence has revealed that the cytokine erythropoietin exhibits non-erythropoietic functions, especially tissue-protective effects. The discovery of EPO and its receptors in the central nervous system and the evidence that EPO is made locally in response to injury as a protective factor in the brain have raised the possibility that recombinant human EPO (rhEPO) could be administered as a cytoprotective agent after acute brain injuries. This review highlights the potential applications of rhEPO as a neuroprotectant in experimental and clinical settings such as ischemia, traumatic brain injury, and subarachnoid and intracerebral hemorrhage. In preclinical studies, EPO prevented apoptosis, inflammation, and oxidative stress induced by injury and exhibited strong neuroprotective and neurorestorative properties. EPO stimulates vascular repair by facilitating endothelial progenitor cell migration into the brain and neovascularisation, and it promotes neurogenesis. In humans, small clinical trials have shown promising results but large prospective randomized studies failed to demonstrate a benefit of EPO for brain protection and showed unwanted side effects, especially thrombotic complications. Recently, regions have been identified within the EPO molecule that mediate tissue protection, allowing the development of non-erythropoietic EPO variants for neuroprotection conceptually devoid of side effects. The efficacy and the safety profile of these new compounds are still to be demonstrated to obtain, in patients, the benefits observed in experimental studies.

False

CitationGPTRetr11674

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: yet these lines of investigation are not without limitations since chemical derivatives of epo can become absent of clinical efficacy as well as possibly loose the ability to promote sustainable cytoprotective effects such as neurogenesis and angiogenesis Title of the paper: Erythropoietin in the brain: can the promise to protect be fulfilled? Abstract of the paper: Erythropoietin (EPO) has emerged as a versatile growth factor that has transcended its traditional role as a mediator of erythroid maturation to one that modulates stem cell development, cellular protection and angiogenesis in the brain. As a possible candidate for nervous system disorders, it becomes crucial to understand the cellular mechanisms that foster cytoprotection rather than cytotoxicity for EPO. EPO offers novel neuronal and vascular protection not only through the maintenance of cellular integrity, but also through the prevention of cellular inflammation. The protective and anti-inflammatory capacities of EPO originate with the Janus tyrosine kinase 2 protein and protein kinase B (Akt). Downstream cellular pathways include FOXO3a, GSK-3beta, Bad, Bcl-xL, NF-kappaB, mitochondrial membrane permeability, APAF-1 and caspases. Further understanding of the cellular pathways that are susceptible to modulation by EPO will be crucial to foster the development of this agent as a robust and efficacious therapy for the brain.

True

CitationGPTRetr11675

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: yet these lines of investigation are not without limitations since chemical derivatives of epo can become absent of clinical efficacy as well as possibly loose the ability to promote sustainable cytoprotective effects such as neurogenesis and angiogenesis Title of the paper: Raves and risks for erythropoietin. Abstract of the paper: Global use of erythropoietin (EPO) continues to increase as a proven agent for the treatment of anemia. Yet, EPO is no longer believed to have exclusive biological activity in the hematopoietic system and is now considered applicable for a variety of disorders such as diabetes, Alzheimer's disease, and cardiovascular disease. Treatment with EPO is considered to be robust and can prevent metabolic compromise, neuronal and vascular degeneration, and inflammatory cell activation. On the converse side, observations that EPO administration is not without risk have fueled controversy. Here we present recent advances that have elucidated a number of novel cellular pathways governed by EPO to open new therapeutic avenues for this agent and avert its potential deleterious effects.

False

CitationGPTRetr11676

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: yet these lines of investigation are not without limitations since chemical derivatives of epo can become absent of clinical efficacy as well as possibly loose the ability to promote sustainable cytoprotective effects such as neurogenesis and angiogenesis Title of the paper: Erythropoietin and treatment of non-anemic conditions--cardiovascular protection. Abstract of the paper: The well-established physiological function of erythropoietin (EPO) is the induction of erythropoiesis. A growing body of evidence indicates that EPO has tissue-protective effects and prevents tissue damage during ischemia and inflammation. Tissue protection after ischemia and injury has been found in the brain, heart, and kidney. It has been speculated that EPO has anti-apoptotic effects in cardiovascular cells. These novel effects of EPO seem to be independent of its erythropoietic activity. Unclear is the role of the known EPO receptor or whether other signaling pathways are involved; a novel EPO receptor might be involved in tissue protection by this hormone. This review article summarizes present knowledge of cardiovascular and renal protective effects of EPO and discusses possible underlying mechanisms.

False

CitationGPTRetr11677

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: yet these lines of investigation are not without limitations since chemical derivatives of epo can become absent of clinical efficacy as well as possibly loose the ability to promote sustainable cytoprotective effects such as neurogenesis and angiogenesis Title of the paper: Unravelling the potential neuroprotective facets of erythropoietin for the treatment of Alzheimer's disease. Abstract of the paper: During the last three decades, recombinant DNA technology has produced a wide range of hematopoietic and neurotrophic growth factors, including erythropoietin (EPO), which has emerged as a promising protein drug in the treatment of several diseases. Cumulative studies have recently indicated the neuroprotective role of EPO in preclinical models of acute and chronic neurodegenerative disorders, including Alzheimer's disease (AD). AD is one of the most prevalent neurodegenerative illnesses in the elderly, characterized by the accumulation of extracellular amyloid-ß (Aß) plaques and intracellular neurofibrillary tangles (NFTs), which serve as the disease's two hallmarks. Unfortunately, AD lacks a successful treatment strategy due to its multifaceted and complex pathology. Various clinical studies, both in vitro and in vivo, have been conducted to identify the various mechanisms by which erythropoietin exerts its neuroprotective effects. The results of clinical trials in patients with AD are also promising. Herein, it is summarized and reviews all such studies demonstrating erythropoietin's potential therapeutic benefits as a pleiotropic neuroprotective agent in the treatment of Alzheimer's disease.

False

CitationGPTRetr11678

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: yet these lines of investigation are not without limitations since chemical derivatives of epo can become absent of clinical efficacy as well as possibly loose the ability to promote sustainable cytoprotective effects such as neurogenesis and angiogenesis Title of the paper: Derivatives of erythropoietin that are tissue protective but not erythropoietic. Abstract of the paper: Erythropoietin (EPO) is both hematopoietic and tissue protective, putatively through interaction with different receptors. We generated receptor subtype-selective ligands allowing the separation of EPO's bioactivities at the cellular level and in animals. Carbamylated EPO (CEPO) or certain EPO mutants did not bind to the classical EPO receptor (EPOR) and did not show any hematopoietic activity in human cell signaling assays or upon chronic dosing in different animal species. Nevertheless, CEPO and various nonhematopoietic mutants were cytoprotective in vitro and conferred neuroprotection against stroke, spinal cord compression, diabetic neuropathy, and experimental autoimmune encephalomyelitis at a potency and efficacy comparable to EPO.

False

CitationGPTRetr11679

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: yet these lines of investigation are not without limitations since chemical derivatives of epo can become absent of clinical efficacy as well as possibly loose the ability to promote sustainable cytoprotective effects such as neurogenesis and angiogenesis Title of the paper: Erythropoietin promotes hippocampal neurogenesis in in vitro models of neonatal stroke. Abstract of the paper: The hippocampus is often injured in neonatal stroke. We have investigated the effect of erythropoietin (EPO) on oxygen-glucose deprived hippocampal slices and hypoxic progenitor cells. EPO improved survival of the organotypic hippocampal slices with significantly less cell death in the dentate gyrus and an increased number of proliferating cells 4-5 days after insult. Significantly fewer markers of neurogenesis were seen after the insult but when EPO was added to the culture medium, neurogenesis was sustained. When hippocampal progenitor cultures were stimulated into differentiation, more cells chose a neuronal cell fate when treated with EPO. These findings support the hypothesis that EPO not only prevents ischemia induced cell death but promotes neuronal cell fate commitment in in vitro models of neonatal stroke.

False

CitationGPTRetr11680

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: several followup studies have reported a decreased risk of ad associated with increasing dietary or supplementary intake of antioxidants eg vitamins e and c although some negative findings were also reported furthermore studies found that higher adherence to mediterranean diet ie a dietary pattern with higher intake of fish fruits and vegetables rich in antioxidants was associated with a reduced risk of ad independent of vascular pathways Title of the paper: Diet and Alzheimer's disease. Abstract of the paper: Alzheimer's disease (AD) is increasing in prevalence. There are no known preventive or curative measures. There is evidence that oxidative stress, homo-cysteine-related vitamins, fats, and alcohol have a role in the pathogenesis of AD. Some epidemiologic studies suggest that higher dietary intake of antioxidants, vitamins B(6), B(12), and folate, unsaturated fatty acids, and fish are related to a lower risk of AD, but reports are inconsistent. Modest to moderate alcohol intake, particularly wine, may be related to a lower risk of AD. The Mediterranean diet may also be related to lower AD risk. However, randomized clinical trials of supplements of vitamins E, B(12), B(6), and folate have shown no cognitive benefit, and randomized trials for other nutrients or diets in AD are not available. The existing evidence does not support the recommendation of specific supplements, foods, or diets for the prevention of AD.

False

CitationGPTRetr11681

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: several followup studies have reported a decreased risk of ad associated with increasing dietary or supplementary intake of antioxidants eg vitamins e and c although some negative findings were also reported furthermore studies found that higher adherence to mediterranean diet ie a dietary pattern with higher intake of fish fruits and vegetables rich in antioxidants was associated with a reduced risk of ad independent of vascular pathways Title of the paper: Dietary factors and Alzheimer's disease. Abstract of the paper: Alzheimer's disease (AD) is increasing in prevalence, and environmental risk factors have not been identified with certainty. There is evidence that oxidative stress, homocysteine-related vitamins, fats, and alcohol have a role in the pathogenesis of AD. Few large epidemiological studies have explored the associations between nutrients and AD, and there has been only one trial of vitamin E in the prevention of AD. Some studies suggest that high intake of vitamins C, E, B6, and B12, and folate, unsaturated fatty acids, and fish are related to a low risk of AD, but reports are inconsistent. Modest to moderate alcohol intake, particularly wine, may be related to a low risk of AD. Available data do not permit definitive conclusions regarding diet and AD or specific recommendations on diet modification for the prevention of AD.

False

CitationGPTRetr11682

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: several followup studies have reported a decreased risk of ad associated with increasing dietary or supplementary intake of antioxidants eg vitamins e and c although some negative findings were also reported furthermore studies found that higher adherence to mediterranean diet ie a dietary pattern with higher intake of fish fruits and vegetables rich in antioxidants was associated with a reduced risk of ad independent of vascular pathways Title of the paper: Dietary intake of antioxidants and risk of Alzheimer disease. Abstract of the paper: CONTEXT Laboratory findings have suggested that oxidative stress may contribute to the pathogenesis of Alzheimer disease. Therefore, the risk of Alzheimer disease might be reduced by intake of antioxidants that counteract the detrimental effects of oxidative stress. OBJECTIVE To determine whether dietary intake of antioxidants is related to risk of Alzheimer disease. DESIGN AND SETTING The Rotterdam Study, a population-based, prospective cohort study conducted in the Netherlands. PARTICIPANTS A total of 5395 participants who, at baseline (1990-1993), were aged at least 55 years, free of dementia, and noninstitutionalized and had reliable dietary assessment. Participants were reexamined in 1993-1994 and 1997-1999 and were continuously monitored for incident dementia. MAIN OUTCOME MEASURES Incidence of Alzheimer disease, based on Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R) criteria and National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer Disease and Related Disorders Association (NINCDS-ADRDA) criteria, associated with dietary intake of beta carotene, flavonoids, vitamin C, and vitamin E. RESULTS After a mean follow-up of 6 years, 197 participants developed dementia, of whom 146 had Alzheimer disease. When adjustments were made for age, sex, baseline Mini-Mental State Examination score, alcohol intake, education, smoking habits, pack-years of smoking, body mass index, total energy intake, presence of carotid plaques, and use of antioxidative supplements, high intake of vitamin C and vitamin E was associated with lower risk of Alzheimer disease (rate ratios [RRs] per 1-SD increase in intake were 0.82 [95% confidence interval [CI], 0.68-0.99] and 0.82 [95% CI, 0.66-1.00], respectively). Among current smokers, this relationship was most pronounced (RRs, 0.65 [95% CI, 0.37-1.14] and 0.58 [95% CI, 0.30-1.12], respectively) and also was present for intake of beta carotene (RR, 0.49 [95% CI, 0.27-0.92]) and flavonoids (RR, 0.54 [95% CI, 0.31-0.96]). The associations did not vary by education or apolipoprotein E genotype. CONCLUSION High dietary intake of vitamin C and vitamin E may lower the risk of Alzheimer disease.

False

CitationGPTRetr11683

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: several followup studies have reported a decreased risk of ad associated with increasing dietary or supplementary intake of antioxidants eg vitamins e and c although some negative findings were also reported furthermore studies found that higher adherence to mediterranean diet ie a dietary pattern with higher intake of fish fruits and vegetables rich in antioxidants was associated with a reduced risk of ad independent of vascular pathways Title of the paper: Nutrition and the risk of Alzheimer's disease. Abstract of the paper: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that accounts for the major cause of dementia, and the increasing worldwide prevalence of AD is a major public health concern. Increasing epidemiological studies suggest that diet and nutrition might be important modifiable risk factors for AD. Dietary supplementation of antioxidants, B vitamins, polyphenols, and polyunsaturated fatty acids are beneficial to AD, and consumptions of fish, fruits, vegetables, coffee, and light-to-moderate alcohol reduce the risk of AD. However, many of the results from randomized controlled trials are contradictory to that of epidemiological studies. Dietary patterns summarizing an overall diet are gaining momentum in recent years. Adherence to a healthy diet, the Japanese diet, and the Mediterranean diet is associated with a lower risk of AD. This paper will focus on the evidence linking many nutrients, foods, and dietary patterns to AD.

False

CitationGPTRetr11684

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: several followup studies have reported a decreased risk of ad associated with increasing dietary or supplementary intake of antioxidants eg vitamins e and c although some negative findings were also reported furthermore studies found that higher adherence to mediterranean diet ie a dietary pattern with higher intake of fish fruits and vegetables rich in antioxidants was associated with a reduced risk of ad independent of vascular pathways Title of the paper: Dietary antioxidants and dementia in a population-based case-control study among older people in South Germany. Abstract of the paper: Oxidative stress is believed to play a central role in the pathogenesis of Alzheimer's disease (AD), a neurodegenerative disease. Antioxidants may prevent the onset AD as high dietary intake of vitamin C and E were reported to be associated with lower risk of the disease. The objective of this study was to evaluate the serum levels of antioxidants in persons with mild dementia to test whether it is associated with lower levels of antioxidants in a cross-sectional study in the population of the "Activity and Function in the Ederly in Ulm" (ActiFE) study. Main exposure measures were vitamin C, vitamin E, β-carotene, lycopene, and coenzyme Q10 as analyzed by HPLC. Main outcome measures were mild cognitive impairment among 74 mildly demented compared to 158 age- and gender-matched controls. We found that blood vitamin C and β-carotene concentrations were significantly lower in demented than in control persons even after adjusting for school education, intake of dietary supplements, smoking habits, body mass index, and alcohol consumption (3rd versus 1st tertile: OR: 0.29, 95% CI, 0.09-0.96 and 0.13, 95% CI, 0.03-0.55, respectively). No associations were found for vitamin E, lycopene, and coenzyme Q10. Our findings suggest an association of vitamin C and β-carotene with dementia. However this is limited to the cross-sectional character of our study and longitudinal data will give further insight into this association.

False

CitationGPTRetr11685

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: several followup studies have reported a decreased risk of ad associated with increasing dietary or supplementary intake of antioxidants eg vitamins e and c although some negative findings were also reported furthermore studies found that higher adherence to mediterranean diet ie a dietary pattern with higher intake of fish fruits and vegetables rich in antioxidants was associated with a reduced risk of ad independent of vascular pathways Title of the paper: Antioxidant vitamin intake and risk of Alzheimer disease. Abstract of the paper: BACKGROUND The generation of oxygen free radicals is involved in the pathogenesis of Alzheimer disease (AD). OBJECTIVE To determine whether the intake of antioxidant vitamins decreases the risk of AD. METHODS We investigated the relationship between AD and the intake of carotenes, vitamin C, and vitamin E in 980 elderly subjects in the Washington Heights-Inwood Columbia Aging Project who were free of dementia at baseline and were followed for a mean time of 4 years. Semiquantitative food frequency questionnaires were administered between baseline and the first follow-up visit. Cox proportional hazards regression models were conducted with quartiles of each vitamin intake as the exposure of interest and incident AD as the outcome, adjusted for age, level of education, sex, APOE epsilon4 status, ethnicity, and smoking. RESULTS There were 242 incident cases of AD in 4,023 person-years of follow-up (6 per 100 person-years). Intake of carotenes and vitamin C, or vitamin E in supplemental or dietary (nonsupplemental) form or in both forms, was not related to a decreased risk of AD. Trend tests for the association between quartiles of total intake of vitamins C and E also were not significant. CONCLUSION Neither dietary, supplemental, nor total intake of carotenes and vitamins C and E was associated with a decreased risk of AD in this study.

False

CitationGPTRetr11686

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: several followup studies have reported a decreased risk of ad associated with increasing dietary or supplementary intake of antioxidants eg vitamins e and c although some negative findings were also reported furthermore studies found that higher adherence to mediterranean diet ie a dietary pattern with higher intake of fish fruits and vegetables rich in antioxidants was associated with a reduced risk of ad independent of vascular pathways Title of the paper: Dietary antioxidants and long-term risk of dementia. Abstract of the paper: BACKGROUND The Rotterdam Study previously found that higher dietary intakes of vitamins E and C related to lower risk of dementia and Alzheimer disease (AD) over 6 years of follow-up. OBJECTIVE To study consumption of major dietary antioxidants relative to long-term risk of dementia. DESIGN Population-based prospective cohort study. SETTING The Rotterdam Study in the Netherlands. PARTICIPANTS A total of 5395 participants, 55 years and older, who were free of dementia and provided dietary information at study baseline. MAIN OUTCOME MEASURES Incidence of dementia and AD, based on internationally accepted criteria, relative to dietary intake of vitamin E, vitamin C, beta carotene, and flavonoids. RESULTS During a mean follow-up period of 9.6 years, dementia developed in 465 participants, of whom 365 were diagnosed as having AD. In multivariate models adjusted for age, education, apolipoprotein E epsilon4 genotype, total energy intake, alcohol intake, smoking habits, body mass index, and supplement use, higher intake of vitamin E at study baseline was associated with lower long-term risk of dementia (P = .02 for trend). Compared with participants in the lowest tertile of vitamin E intake, those in the highest tertile were 25% less likely to develop dementia (hazard ratio, 0.75; 95% confidence interval, 0.59-0.95 with adjustment for potential confounders). Dietary intake levels of vitamin C, beta carotene, and flavonoids were not associated with dementia risk after multivariate adjustment (P > .99 for trend for vitamin C and beta carotene and P = .60 for trend for flavonoids). Results were similar when risk for AD was specifically assessed. CONCLUSION Higher intake of foods rich in vitamin E may modestly reduce long-term risk of dementia and AD.

False

CitationGPTRetr11687

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: several followup studies have reported a decreased risk of ad associated with increasing dietary or supplementary intake of antioxidants eg vitamins e and c although some negative findings were also reported furthermore studies found that higher adherence to mediterranean diet ie a dietary pattern with higher intake of fish fruits and vegetables rich in antioxidants was associated with a reduced risk of ad independent of vascular pathways Title of the paper: The role of diet in cognitive decline. Abstract of the paper: Recent findings suggest a possible role of diet in age-related cognitive decline, and cognitive impairment of both degenerative (Alzheimer's disease, AD) or vascular origin. In particular, in an older population of Southern Italy with a typical Mediterranean diet, high monounsaturated fatty acids energy intake appeared to be associated with a high protection against cognitive decline. In addition, dietary fat and energy in older people seem to be risk factors, while fish consumption and cereals are found to reduce the prevalence of AD in the European and North American countries. Moreover, foods with large amounts of aluminium-containing additives or aluminium from drinking water may affect the risk of developing AD. Vitamin deficiencies, especially vitamin B6, B12 and folates, and antioxidant deficiencies (vitamins E and C) could also influence the memory capabilities and have an effect on cognitive decline. Dietary anti-oxidants and supplements and specific macronutrients of the diet may act synergistically with other protective factors opening new possibilities of intervention for cognitive decline.

False

CitationGPTRetr11688

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: several followup studies have reported a decreased risk of ad associated with increasing dietary or supplementary intake of antioxidants eg vitamins e and c although some negative findings were also reported furthermore studies found that higher adherence to mediterranean diet ie a dietary pattern with higher intake of fish fruits and vegetables rich in antioxidants was associated with a reduced risk of ad independent of vascular pathways Title of the paper: Reduced risk of Alzheimer's disease with high folate intake: the Baltimore Longitudinal Study of Aging. Abstract of the paper: BACKGROUND Study findings have suggested an association between Alzheimer's disease (AD) risk and several vitamins and have speculated about their use as preventive agents. Here, we examine whether total intake (intake from diet plus supplements) of antioxidant vitamins (E, C, carotenoids) and B vitamins (folate, B(6), and B(12)) is associated with a reduced risk of AD. METHODS Participants were 579 nondemented elderly volunteers from the Baltimore Longitudinal Study of Aging who completed dietary diaries and recorded supplement intake for a 7-day period. Cox regression was used to estimate the relative risk (RR) of AD associated with total vitamin intake categorized into levels above or below the Recommended Dietary Allowance (RDA). RESULTS After a mean follow-up of 9.3 years, AD developed in 57 participants. Higher intake of folate (RR, 0.41; 95% confidence interval [CI], 0.22 to 0.76), vitamin E (RR, 0.56; 95% CI, 0.30 to 1.06), and vitamin B(6) (RR, 0.41; 95% CI, 0.20 to 0.84) were associated individually with a decreased risk of AD after adjusting for age, gender, education, and caloric intake. When these 3 vitamins were analyzed together, only total intake of folate at or above the RDA (RR, 0.45; 95% CI, 0.21 to 0.97) was associated with a significant decreased risk of AD. No association was found between total intake of vitamins C, carotenoids, or vitamin B(12) and risk of AD. CONCLUSIONS These findings suggest that total intake of folate at or above the RDA is associated with a reduced risk of AD. Additional studies are necessary to further investigate whether folate or other(s) unmeasured factor(s) may be responsible for this reduction in risk.

False

CitationGPTRetr11689

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: several followup studies have reported a decreased risk of ad associated with increasing dietary or supplementary intake of antioxidants eg vitamins e and c although some negative findings were also reported furthermore studies found that higher adherence to mediterranean diet ie a dietary pattern with higher intake of fish fruits and vegetables rich in antioxidants was associated with a reduced risk of ad independent of vascular pathways Title of the paper: Dietary intakes of vitamin E, vitamin C, and β-carotene and risk of Alzheimer's disease: a meta-analysis. Abstract of the paper: In view of the vital role of oxidative stress in the pathogenesis of Alzheimer's disease (AD), the potential of antioxidant supplements to prevent AD have gained much interest, while there are conflicting results on this topic in recent years. The purpose of the present study is to comprehensively evaluate the association between dietary intakes, instead of supplements, of the most common three antioxidants (vitamin E, vitamin C, and β-carotene) and the risk of AD on the basis of the meta-analysis studies published up to October 2011 in Medline and Scopus databases. In total, seven articles were included in the meta-analysis. According to the pooled relative risk [(95% CI) 0.76 (0.67-0.84) for vitamin E, 0.83 (0.72-0.94) for vitamin C, and 0.88 (0.73-1.03) for β-carotene], dietary intakes of the three antioxidants can lower the risk of AD, with vitamin E exhibiting the most pronounced protective effects. The findings will be of significance to the prevention and interventional treatment of AD.

False

CitationGPTRetr11690

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: several followup studies have reported a decreased risk of ad associated with increasing dietary or supplementary intake of antioxidants eg vitamins e and c although some negative findings were also reported furthermore studies found that higher adherence to mediterranean diet ie a dietary pattern with higher intake of fish fruits and vegetables rich in antioxidants was associated with a reduced risk of ad independent of vascular pathways Title of the paper: Diet and biomarkers of Alzheimer's disease: a systematic review and meta-analysis. Abstract of the paper: Alzheimer's disease (AD) risk increases with age and lacks efficacious pharmacological options. Summaries of the existing evidence reveal an association between Mediterranean-style diet adherence and reduced AD incidence; however, no review has investigated this relationship with respect to the hallmark AD biomarkers (tau and beta-amyloid) that manifest decades before clinical symptomatology. MEDLINE, PubMed, PsycINFO, Google Scholar, and SCOPUS databases were systematically searched to identify peer-reviewed articles investigating diet and AD biomarkers in the last 2 decades. Two thousand seven hundred twenty-six records were extracted, quality assessed, and double-blind screened by 2 authors. Fifteen studies met the inclusion criteria and 13 studies found a significant relationship. Of these, 4 studies found a high-glycemic load was related to an increase in AD biomarker burden; 6 found adherence to a Mediterranean or "AD-protective" dietary pattern conferred a reduction in AD biomarker burden. Meta-analysis revealed a small but significant effect of diet on AD biomarkers (β = 0.11 [95% CI 0.04-0.17], p = 0.002). This systematic review supports the notion that diet and nutrition display potential for nonpharmacological AD prevention.

False

CitationGPTRetr11691

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: several followup studies have reported a decreased risk of ad associated with increasing dietary or supplementary intake of antioxidants eg vitamins e and c although some negative findings were also reported furthermore studies found that higher adherence to mediterranean diet ie a dietary pattern with higher intake of fish fruits and vegetables rich in antioxidants was associated with a reduced risk of ad independent of vascular pathways Title of the paper: Dietary Patterns and Risk of Dementia: a Systematic Review and Meta-Analysis of Cohort Studies. Abstract of the paper: Dietary patterns and some dietary components have been linked with dementia. We therefore performed a meta-analysis of available studies to determine whether there is an association between diet and risk of dementia. We included eligible articles and estimated risk ratio (RR) with 95 % confidence intervals (95 % CIs). Finally, there were 43 trials that met the inclusion standard. Some food intake was related with decrease of dementia, such as unsaturated fatty acids (RR: 0.84, 95 % CI: [0.74-0.95], P = 0.006), antioxidants (RR: 0.87, 95 % CI: [0.77-0.98], P = 0.026), vitamin B (RR: 0.72, 95 % CI: [0.54-0.96], P = 0.026), and the Mediterranean diet (MeDi) (RR: 0.69, 95 % CI: [0.57-0.84], P < 0.001). Some material intakes were related with increase of dementia, such as aluminum (RR: 2.24, 95 % CI: [1.49-3.37], P < 0.001), smoking (RR: 1.43, 95 % CI: [1.15-1.77], P = 0.001), and low levels of vitamin D (RR: 1.52, 95 % CI: [1.17-1.98], P = 0.002). The effect of some materials needs further investigation, such as fish (RR: 0.79, 95 % CI: [0.59-1.06], P = 0.113), vegetables and fruits (RR: 0.46, 95 % CI: [0.16-1.32], P = 0.149), and alcohol (RR: 0.74, 95 % CI: [0.55- 1.01], P = 0.056). Thus, the MeDi and higher consumption of unsaturated fatty acids, antioxidants, and B vitamins decrease the risk of dementia while smoking and higher consumption of aluminum increase the risk of dementia. Low levels of vitamin D were associated with cognitive decline. The effect of fish, vegetables, fruits, and alcohol needs further investigation. The findings will be of great significance to guide people to prevent dementia.

False

CitationGPTRetr11692

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: several followup studies have reported a decreased risk of ad associated with increasing dietary or supplementary intake of antioxidants eg vitamins e and c although some negative findings were also reported furthermore studies found that higher adherence to mediterranean diet ie a dietary pattern with higher intake of fish fruits and vegetables rich in antioxidants was associated with a reduced risk of ad independent of vascular pathways Title of the paper: Mediterranean diet and risk for Alzheimer's disease. Abstract of the paper: OBJECTIVE Previous research in Alzheimer's disease (AD) has focused on individual dietary components. There is converging evidence that composite dietary patterns such as the Mediterranean diet (MeDi) is related to lower risk for cardiovascular disease, several forms of cancer, and overall mortality. We sought to investigate the association between MeDi and risk for AD. METHODS A total of 2,258 community-based nondemented individuals in New York were prospectively evaluated every 1.5 years. Adherence to the MeDi (zero- to nine-point scale with higher scores indicating higher adherence) was the main predictor in models that were adjusted for cohort, age, sex, ethnicity, education, apolipoprotein E genotype, caloric intake, smoking, medical comorbidity index, and body mass index. RESULTS There were 262 incident AD cases during the course of 4 (+/-3.0; range, 0.2-13.9) years of follow-up. Higher adherence to the MeDi was associated with lower risk for AD (hazard ratio, 0.91; 95% confidence interval, 0.83-0.98; p=0.015). Compared with subjects in the lowest MeDi tertile, subjects in the middle MeDi tertile had a hazard ratio of 0.85 (95% confidence interval, 0.63-1.16) and those at the highest tertile had a hazard ratio of 0.60 (95% confidence interval, 0.42-0.87) for AD (p for trend=0.007). INTERPRETATION We conclude that higher adherence to the MeDi is associated with a reduction in risk for AD.

True

CitationGPTRetr11693

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: several followup studies have reported a decreased risk of ad associated with increasing dietary or supplementary intake of antioxidants eg vitamins e and c although some negative findings were also reported furthermore studies found that higher adherence to mediterranean diet ie a dietary pattern with higher intake of fish fruits and vegetables rich in antioxidants was associated with a reduced risk of ad independent of vascular pathways Title of the paper: Antioxidant vitamin supplement use and risk of dementia or Alzheimer's disease in older adults. Abstract of the paper: OBJECTIVES To examine whether use of vitamins C or E alone or in combination was associated with lower incidence of dementia or Alzheimer's disease (AD). DESIGN Prospective cohort study. SETTING Group Health Cooperative, Seattle, Washington. PARTICIPANTS Two thousand nine hundred sixty-nine participants aged 65 and older without cognitive impairment at baseline in the Adult Changes in Thought study. MEASUREMENTS Participants were followed biennially to identify incident dementia and AD diagnosed according to standard criteria. Participants were considered to be users of vitamins C or E if they self-reported use for at least 1 week during the month before baseline. RESULTS Over a mean follow-up+/-standard deviation of 5.5+/-2.7 years, 405 subjects developed dementia (289 developed AD). The use of vitamin E was not associated with dementia (adjusted hazard ratio (HR)=0.98, 95% confidence interval (CI)=0.77-1.25) or with AD (HR=1.04; 95% CI=0.78-1.39). No association was found between vitamin C alone (dementia: HR=0.90, 95% CI=0.71-1.13; AD: HR=0.95, 95% CI=0.72-1.25) or concurrent use of vitamin C and E (dementia: HR=0.93, 95% CI=0.72-1.20; AD: HR=1.00, 95% CI=0.73-1.35) and either outcome. CONCLUSION In this study, the use of supplemental vitamin E and C, alone or in combination, did not reduce risk of AD or overall dementia over 5.5 years of follow-up.

True

CitationGPTRetr11694

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: several followup studies have reported a decreased risk of ad associated with increasing dietary or supplementary intake of antioxidants eg vitamins e and c although some negative findings were also reported furthermore studies found that higher adherence to mediterranean diet ie a dietary pattern with higher intake of fish fruits and vegetables rich in antioxidants was associated with a reduced risk of ad independent of vascular pathways Title of the paper: MIND diet associated with reduced incidence of Alzheimer's disease. Abstract of the paper: INTRODUCTION In a previous study, higher concordance to the MIND diet, a hybrid Mediterranean-Dietary Approaches to Stop Hypertension diet, was associated with slower cognitive decline. In this study we related these three dietary patterns to incident Alzheimer's disease (AD). METHODS We investigated the diet-AD relations in a prospective study of 923 participants, ages 58 to 98 years, followed on average 4.5 years. Diet was assessed by a semiquantitative food frequency questionnaire. RESULTS In adjusted proportional hazards models, the second (hazards ratio or HR = 0.65, 95% confidence interval or CI 0.44, 0.98) and highest tertiles (HR = 0.47, 95% CI 0.26, 0.76) of MIND diet scores had lower rates of AD versus tertile 1, whereas only the third tertiles of the DASH (HR = 0.61, 95% CI 0.38, 0.97) and Mediterranean (HR = 0.46, 95% CI 0.26, 0.79) diets were associated with lower AD rates. DISCUSSION High adherence to all three diets may reduce AD risk. Moderate adherence to the MIND diet may also decrease AD risk.

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CitationGPTRetr11695

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: several followup studies have reported a decreased risk of ad associated with increasing dietary or supplementary intake of antioxidants eg vitamins e and c although some negative findings were also reported furthermore studies found that higher adherence to mediterranean diet ie a dietary pattern with higher intake of fish fruits and vegetables rich in antioxidants was associated with a reduced risk of ad independent of vascular pathways Title of the paper: Midlife dietary intake of antioxidants and risk of late-life incident dementia: the Honolulu-Asia Aging Study. Abstract of the paper: Antioxidants have been hypothesized to protect against Alzheimer's disease, but studies conducted in late life have been inconsistent. Risk factors measured in midlife may better predict dementia in late life because they are less affected by the disease process. The authors examined the association of midlife dietary intake of antioxidants to late-life dementia and its subtypes. Data were obtained from the Honolulu-Asia Aging Study, a prospective community-based study of Japanese-American men who were aged 45-68 years in 1965-1968, when a 24-hour dietary recall was administered. The analysis included 2,459 men with complete dietary data who were dementia-free at the first assessment in 1991-1993 and were examined up to two times for dementia between 1991 and 1999. The sample included 235 incident cases of dementia (102 cases of Alzheimer's disease, 38 cases of Alzheimer's disease with contributing cerebrovascular disease, and 44 cases of vascular dementia). Relative risks by quartile of intake were calculated using Cox proportional hazards models with age as the time scale, after adjustment for sociodemographic and lifestyle factors, cardiovascular risk factors, other dietary constituents, and apolipoprotein E e4. Intakes of beta-carotene, flavonoids, and vitamins E and C were not associated with the risk of dementia or its subtypes. This analysis suggests that midlife dietary intake of antioxidants does not modify the risk of late-life dementia or its most prevalent subtypes.

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CitationGPTRetr11696

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: several followup studies have reported a decreased risk of ad associated with increasing dietary or supplementary intake of antioxidants eg vitamins e and c although some negative findings were also reported furthermore studies found that higher adherence to mediterranean diet ie a dietary pattern with higher intake of fish fruits and vegetables rich in antioxidants was associated with a reduced risk of ad independent of vascular pathways Title of the paper: Diet, cognition, and Alzheimer's disease: food for thought. Abstract of the paper: INTRODUCTION The prevention of Alzheimer's disease (AD) has become a real challenge due to its rising prevalence and the lack of an effective cure. Diet and nutrients have gained significant interest as potentially modifiable protective factors. PURPOSE The aim of this review is to provide an updated summary of evidence related to the effect of diet and nutritional factors on the risk of AD and cognitive aging, and discuss the potential mechanisms and confounding factors involved. METHODS A search was conducted in Medline and Web of Knowledge for epidemiological and clinical studies in the international literature from January 2000 to February 2013 using combinations of the following keywords: "Alzheimer's disease", "mild cognitive impairment", "cognitive function", "dietary factors", "omega-3", "antioxidants", "B vitamins", "dietary patterns", and "Mediterranean diet". RESULTS AND CONCLUSION Data from observational studies point to a protective role for certain nutrients, such as omega-3 fatty acids, antioxidants or B vitamins, and dietary patterns (Mediterranean diet). However, data from randomized controlled trials do not show a consistent effect. Whether confounding factors such as age, disease stage, other dietary components, cooking processes, and other methodological issues explain the divergent results remains to be established. Moreover, if certain nutrients protect against dementia, it is as yet unknown whether they may have a general effect on brain vascular health or directly interfere with the etiopathogenesis of AD.

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CitationGPTRetr11697

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: several followup studies have reported a decreased risk of ad associated with increasing dietary or supplementary intake of antioxidants eg vitamins e and c although some negative findings were also reported furthermore studies found that higher adherence to mediterranean diet ie a dietary pattern with higher intake of fish fruits and vegetables rich in antioxidants was associated with a reduced risk of ad independent of vascular pathways Title of the paper: Dietary patterns, cognitive decline, and dementia: a systematic review. Abstract of the paper: Nutrition is an important modifiable risk factor that plays a role in the strategy to prevent or delay the onset of dementia. Research on nutritional effects has until now mainly focused on the role of individual nutrients and bioactive components. However, the evidence for combined effects, such as multinutrient approaches, or a healthy dietary pattern, such as the Mediterranean diet, is growing. These approaches incorporate the complexity of the diet and possible interaction and synergy between nutrients. Over the past few years, dietary patterns have increasingly been investigated to better understand the link between diet, cognitive decline, and dementia. In this systematic review we provide an overview of the literature on human studies up to May 2014 that examined the role of dietary patterns (derived both a priori as well as a posteriori) in relation to cognitive decline or dementia. The results suggest that better adherence to a Mediterranean diet is associated with less cognitive decline, dementia, or Alzheimer disease, as shown by 4 of 6 cross-sectional studies, 6 of 12 longitudinal studies, 1 trial, and 3 meta-analyses. Other healthy dietary patterns, derived both a priori (e.g., Healthy Diet Indicator, Healthy Eating Index, and Program National Nutrition Santé guideline score) and a posteriori (e.g., factor analysis, cluster analysis, and reduced rank regression), were shown to be associated with reduced cognitive decline and/or a reduced risk of dementia as shown by all 6 cross-sectional studies and 6 of 8 longitudinal studies. More conclusive evidence is needed to reach more targeted and detailed guidelines to prevent or postpone cognitive decline.

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CitationGPTRetr11698

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: several followup studies have reported a decreased risk of ad associated with increasing dietary or supplementary intake of antioxidants eg vitamins e and c although some negative findings were also reported furthermore studies found that higher adherence to mediterranean diet ie a dietary pattern with higher intake of fish fruits and vegetables rich in antioxidants was associated with a reduced risk of ad independent of vascular pathways Title of the paper: Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. Abstract of the paper: CONTEXT Oxidative processes have been suggested as elements in the development of Alzheimer disease (AD), but whether dietary intake of vitamin E and other antioxidant nutrients prevents its development is unknown. OBJECTIVE To examine whether intake of antioxidant nutrients, vitamin E, vitamin C, and beta carotene is associated with incident AD. DESIGN, SETTING, AND PARTICIPANTS Prospective study, conducted from 1993 to 2000, of individuals selected in a stratified random sample of community-dwelling residents. The 815 residents 65 years and older were free of AD at baseline and were followed up for a mean of 3.9 years. They completed food frequency questionnaires an average of 1.7 years after baseline. MAIN OUTCOME MEASURE Incident AD diagnosed in clinical evaluations with standardized criteria. RESULTS Increasing vitamin E intake from foods was associated with decreased risk of developing AD after adjustment for age, education, sex, race, APOE epsilon 4, and length of follow-up. Relative risks (95% confidence intervals [CIs]) from lowest to highest quintiles of intake were 1.00, 0.71 (0.24-2.07), 0.62 (0.26-1.45), 0.71 (0.27-1.88), and 0.30 (0.10-0.92) (P for trend =.05). The protective association of vitamin E was observed only among persons who were APOE epsilon 4 negative. Adjustment for other dietary factors reduced the protective association. After adjustment for baseline memory score, the risk was 0.36 (95% CI, 0.11-1.17). Intake of vitamin C, beta carotene, and vitamin E from supplements was not significantly associated with risk of AD. CONCLUSION This study suggests that vitamin E from food, but not other antioxidants, may be associated with a reduced risk of AD. Unexpectedly, this association was observed only among individuals without the APOE epsilon 4 allele.

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CitationGPTRetr11699

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: several followup studies have reported a decreased risk of ad associated with increasing dietary or supplementary intake of antioxidants eg vitamins e and c although some negative findings were also reported furthermore studies found that higher adherence to mediterranean diet ie a dietary pattern with higher intake of fish fruits and vegetables rich in antioxidants was associated with a reduced risk of ad independent of vascular pathways Title of the paper: Dietary patterns and risk of dementia: the Three-City cohort study. Abstract of the paper: BACKGROUND Dietary fatty acids and antioxidants may contribute to decrease dementia risk, but epidemiologic data remain controversial. The aim of our study was to analyze the relationship between dietary patterns and risk of dementia or Alzheimer disease (AD), adjusting for sociodemographic and vascular risk factors, and taking into account the ApoE genotype. METHODS A total of 8,085 nondemented participants aged 65 and over were included in the Three-City cohort study in Bordeaux, Dijon, and Montpellier (France) in 1999-2000 and had at least one re-examination over 4 years (rate of follow-up 89.1%). An independent committee of neurologists validated 281 incident cases of dementia (including 183 AD). RESULTS Daily consumption of fruits and vegetables was associated with a decreased risk of all cause dementia (hazard ratio [HR] 0.72, 95% CI 0.53 to 0.97) in fully adjusted models. Weekly consumption of fish was associated with a reduced risk of AD (HR 0.65, 95% CI 0.43 to 0.994) and all cause dementia but only among ApoE epsilon 4 noncarriers (HR 0.60, 95% CI 0.40 to 0.90). Regular use of omega-3 rich oils was associated with a decreased risk of borderline significance for all cause dementia (HR 0.46, 95% CI 0.19 to 1.11). Regular consumption of omega-6 rich oils not compensated by consumption of omega-3 rich oils or fish was associated with an increased risk of dementia (HR 2.12, 95% CI 1.30 to 3.46) among ApoE epsilon 4 noncarriers. CONCLUSION Frequent consumption of fruits and vegetables, fish, and omega-3 rich oils may decrease the risk of dementia and Alzheimer disease, especially among ApoE epsilon 4 noncarriers.

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