bluuebunny/crossref_metadata_2025 huggingface dataset:
Astrogliosis and the ApoE Genotype
Authors: Overmyer Margit , Helisalmi Seppo , Soininen Hilkka , Laakso Markku , Riekkinen Sr Paavo , Alafuzoff Irina
Published: April 2003

Significantly increased glial fibrillary acidic protein (GFAP) expression was seen in postmortem brain tissue from demented patients with Alzheimer’s disease (AD) (73 cases, 61 females/12 males, mean age 84 ± 9 years) compared to controls (22 cases, 10 females/12 males, mean age 78 ± 9 years). In demented patients, the GFAP expression, counts of AD lesions, senile/neuritic plaques (SP/NP) and neurofibrillary tangles (NFT) were higher in patients carrying the apolipoprotein E (ApoE) ε4 allele compared to those without the ApoE ε4 allele. The astrogliosis correlated significantly with the counts of NFT in demented patients both with and without the ApoE ε4 allele. Furthermore, the astrogliosis correlated significantly with the counts of SP/NP, but this correlation, however, was influenced by the ApoE ε4 allele, being significant only in those cases without the ApoE ε4 allele. Our results demonstrate that not only the extent of AD lesions and GFAP expression, but also the relationship between AD lesions and the GFAP expression is influenced by the ApoE ε4 allele.
Magnetic Resonance Imaging-Based Hippocampal Volumetry in Patients with Dementia of the Alzheimer Type
Authors: Golebiowski Marek , Barcikowska Maria , Pfeffer Anna
Published: April 2003

A volumetric magnetic resonance imaging assessment of the hippocampal region was done in 50 patients with Alzheimer-type dementia and 25 members of a control group. There were no significant volumetric differences between the right and left hippocampi. The volumetric hippocampal measurements were 39.4% smaller in dementia of the Alzheimer type than in controls. In the differentiation between the analyzed groups of patients, the method had a sensitivity of 95% and a specificity of 92%. A correlation of the hippocampal volumes with the severity of the dementia and the patient’s age was found. The results confirmed the importance of hippocampal atrophy in the etiology of dementia. In vivo the quantitative assessment of the hippocampal formation is a valuable tool in the diagnosis of Alzheimer’s disease.
The Cost of Dementia in Denmark: The Odense Study
Authors: Kronborg Andersen Christian , Søgaard Jes , Hansen Elisabeth , Kragh-Sørensen Anne , Hastrup Lene , Andersen Jutta , Andersen Kjeld , Lolk Annette , Nielsen Henry , Kragh-Sørensen Per
Published: April 2003

In a population-based study of dementia, the cost of care for 245 demented elderly and 490 controls matched by age and gender was estimated. Dementia of Alzheimer’s type was diagnosed according to the NINCDS-ADRDA criteria, and vascular dementia and other types of dementia were diagnosed according to the DSM-IIIR criteria. Severity of dementia was determined by the Clinical Dementia Rating scale. The annual cost of medical care, domestic care, home help, nursing home and special equipment for nondemented patients was DKK 22,000 per person while the cost for very mildly, mildly, moderately and severely demented patients was DKK 49,000, DKK 93,000, DKK 138,000 and DKK 206,000, respectively. Except for very mild dementia the cost did not differ between elderly who suffer from Alzheimer’s disease and those with other types of dementia. The net cost of dementia is the difference in cost between those with dementia and the matched controls and amounts on average to DKK 77,000 per person per year. However, priority setting cannot be based on the cost of dementia per se, but only on the cost of a specific dementia intervention compared to its health benefit.
The Concept of Delirium
Authors: Lindesay James
Published: April 2003

The concept of delirium has a long and confusing history. This article outlines the development of ideas relating to core features of the syndrome: disturbance of consciousness, disturbance of cognition, its course and its external causation. The modern concept of delirium, and the diagnostic criteria found in current classifications are based upon a long tradition of clinical observation in younger patients, and their emphasis on positive symptoms and identifiable external causes may not be applicable to our ageing population.
Neurochemistry and Delirium
Authors: Koponen Hannu J.
Published: April 2003

Acute confusional state or delirium is one of the most common organic brain syndromes especially in the elderly. It develops suddenly, within hours or days, and often during a period of hospitalization. In this paper we review the results of our studies on the neurochemistry of delirium.
Activity in the Hypothalamic-Pituitary- Adrenal Axis and Delirium
Authors: Olsson Tommy
Published: April 2003

Glucocorticoid hormones are important for coping with stress but may have deleterious effects on mood and memory during prolonged excessive secretion. A key abnormality related to cortisol excess in delirium seems to be abnormal ‘shut-off’ of the hypothalamic-pituitary-adrenal (HPA) axis tested by the dexamethasone suppression test. In experimental models, the hippocampal formation is of prime importance for normal HPA axis shut-off. In this brain area, a close interaction between neurotransmittors, notably acetylcholine, serotonin and noradrenaline, and glucocorticoid receptors, is present and possibly relevant for the development of delirium in elderly patients with stroke and neurodegenerative brain diseases.
Postoperative Delirium
Authors: van der Mast Rose C.
Published: April 2003

This article reviews the incidence, pathophysiological hypotheses, and etiology of postoperative delirium, especially in the elderly. Preoperative, intraoperative, and postoperative risk factors for delirium following surgery are discussed. Results of various studies on postoperative delirium appear hardly comparable due to methodological and population differences. Therefore, it is difficult to draw any conclusions on postoperative delirium in general. Special attention is paid to delirium after cardiac surgery since this syndrome has been studied most.
Care of the Delirious Patient
Authors: Brännström Benny
Published: April 2003

In spite of the fact that delirium is a common and often severe cognitive disturbance in the elderly, quite few intervention studies are performed. Descriptive studies of variable quality are much more common. For example, in hip fracture patients delirium is a common complication and the cause of nursing problems that cannot be explained by the fracture per se. Nursing and medical interventions have been published separately but only one study, the Piteå Program, has so far been known that combines nursing and medical knowledge. This program has been shown to reduce the incidence of delirium in elderly hip fracture patients.
Educational Interventions in Delirium
Authors: Rockwood Kenneth
Published: April 2003

In the absence of specific therapies, interventions for delirium are largely educational. This paper reviews educational interventions targeted at physicians, nurses, patients and their families. Most studies to date have had methodological deficiencies, and few have been developed in keeping with current principles for adult learning. Early studies focused on increased recognition of delirium, with less consistent measurement of patient centred outcomes. Subsequent studies provide limited evidence to suggest that, as a result of educational interventions, individual symptoms can be prevented, and, when delirium is present, its consequences – including death and prolonged hospital stays – can be diminished. Future studies should incorporate principles of adult learning and have improved methodological rigour. The strength of educational interventions needs to be assessed carefully. Interventions which are time-sensitive, less complex, directed to observable, patient-focused endpoints are more likely to be successful.
Denbufylline in Dementia: A Double-Blind Controlled Study
Authors: Treves T.A. , Korczyn A.D.
Published: April 2003

The xanthine derivative denbufylline has been evaluated in the treatment of cognitive dysfunction in 110 patients with vascular or mixed dementia (VD) and 226 patients with dementia of the Alzheimer type (DAT). After a run-in period of 4 weeks, during which all patients received placebo, the patients were randomly allocated to denbufylline 25, 50 or 100 mg or to placebo given twice daily for 16 weeks. By the end of the study (completed by 68% of the patients), but also at enrollment, the scores obtained on the Mini-Mental State Examination (MMSE) were higher among those who had received denbufylline than among those who had received placebo, but the differences were not statistically significant; a dose effect of denbufylline was not observed and there was no significant difference in the mean scores of the digit substitution subtest (DSST) of the Wechsler memory test. The responses of patients with VD were similar to those of patients with DAT. When patients were compared in terms of those who received denbufylline versus those who received placebo, improvement in the MMSE scores was observed in 46% of the patients who received placebo and 67% among those who received denbufylline (p < 0.05). An inverse relationship was found between the improvement that occurred during the run-in period and that observed by the end of the study, had the patients received denbufylline or placebo. No major adverse event was ascribed to denbufylline. In conclusion, denbufylline was not deemed efficacious in the treatment of DAT or VD, although patients who received denbufylline tended to improve in terms of cognitive scores, but the effects were not statistically significant. MMSE scores were found to be higher among patients who received denbufylline when these latter were combined as a single group, regardless of their diagnosis or dosage regimen. A placebo effect was observed in about half the patients who completed the study.
Psychometric Analysis of the Selective Reminding Procedure in a Sample from the General Elderly Population
Authors: Burkart Martin , Heun Reinhard
Published: April 2003

The selective reminding procedure (SRP) has been proposed for the assessment of distinct aspects of episodic memory, i.e. storage to and retrieval from short-term and long-term memory, item learning and list learning, and as dementia screening tool. In the present study SRP results were analysed in 256 probands from the general elderly population. SRP scores were highly intercorrelated, and principal component analysis yielded only one single factor. The SRP scores were moderately and not differentially correlated with immediate and delayed free recall and recognition and with verbal fluency. All SRP scores discriminated nondemented probands with episodic long-term memory impairment from those without. The MMSE performed significantly better than any SRP score in detecting dementia. The theory-based assumption that the SRP allows assessment of different, independent aspects of memory could not be validated. It is suggested that the SRP is a mixed measure of semantic memory, episodic long-term and short-term memory, and working memory, and that the different SRP scores do not allow to assess different memory functions. Thus, the SRP may neither be recommended for assessment of different subfunctions of memory nor for dementia screening.
Differential Mechanisms of Impairment of Remote Memory in Alzheimer’s and Frontotemporal Dementia
Authors: Thomas-Antérion C. , Jacquin K. , Laurent B.
Published: April 2003

This paper describes retrograde memory performances of 12 Alzheimer’s disease (AD) patients and 12 frontotemporal dementia (FTD) patients. First of all, we observed that FTD and AD patients did not differ for language tests (verbal fluency tests and oral denomination 80), for semantic memory tests, for logical memory test and Benton visual memory test and differed for anterograde verbal memory and frontal tests. Concerning retrograde memory, there was no difference between AD and FTD patients in retrograde memory scores (autobiographical memory interview, Crovitz’s task, French public events interview battery) and both FTD and AD patients exhibited a retrieval deficit in their remote memory. We observed that the mechanisms of remote memory deficit was different in FTD and in AD patients. We observed no classical paradigm of Ribot for FTD patient’s remote informations, and they appeared to have lost of access to memories and executive difficulties. In AD, the results indicated these patients’ ability to learn new information and to search semantic memory failed.
Features of Regional Cerebral Glucose Metabolism Abnormality in Corticobasal Degeneration
Authors: Hirono Nobutsugu , Ishii Kazunari , Sasaki Masahiro , Kitagaki Hajime , Hashimoto Mamoru , Imamura Toru , Tanimukai Satoshi , Hanihara Tokiji , Kazui Hiroaki , Mori Etsuro
Published: April 2003

We studied regional cerebral glucose metabolism in 15 patients with a clinical diagnosis of corticobasal degeneration (CBD), 15 patients with probable Alzheimer’s disease (AD), and 15 healthy controls for 19 brain regions. Asymmetry in regional glucose metabolism was found in the central and frontal cortices in patients with CBD as compared with either the normal controls or the patients with AD. Regional glucose metabolism in CBD patients was significantly lower in the paracentral and superior parietal areas and thalamus than in patients with AD. Relative glucose metabolism in patients with CBD was significantly higher in the posterior cingulate, medial temporal and basal frontal areas, and significantly lower in the paracentral and superior parietal areas than in those with AD. These features of regional glucose metabolic abnormality in CBD may correspond to neurological and cognitive disturbances peculiar to CBD.
Predictors of Cognitive Decline in the Early Stage of Probable Alzheimer’s Disease
Authors: Marra Camillo , Silveri Maria Caterina , Gainotti Guido
Published: April 2003

Several papers have attempted to find neurological and neuropsychological predictors of progression in Alzheimer’s disease (AD) till now. Despite this quite large amount of works, different and not univocal conclusions have been reported in this field. Different study samples, different end-points and differences in statistical methods can explain much of the inconsistency in the results obtained. In our study, AD patients were examined in a very early stage of the disease to avoid any possible risk to examine subjects at different times of evolution. All the patients underwent an extensive neuropsychological test battery twice (baseline and follow-up) spaced out over about 1 year and were divided into two groups of fast decliners (FD) and slow decliners (SD) on the basis of their rate of decay at the MMSE score. Verbal memory tests, mental control abilities and attention-demanding tasks seem to play a pivotal role in distinguishing the two groups of subjects in the early stage of the disease. Moreover, FD patients show a worse performance than SD at the baseline in most of the cognitive domains explored. In conclusion, different subtypes of AD do exist and an important predictor of progression is represented by the severity of the cognitive impairment at the onset.
One Year Follow-Up of Parkinsonism in Dementia with Lewy Bodies
Authors: Ballard C. , O’Brien J. , Swann A. , Neill D. , Lantos P. , Holmes C. , Burn D. , Ince P. , Perry R. , McKeith I.
Published: April 2003

The progression of parkinsonism over 1 year was evaluated in a prospective cohort of patients (n = 338), suffering from dementia with Lewy bodies (DLB), Alzheimer’s disease (AD) or vascular dementia (VaD). Parkinsonism was assessed using the modified Unified Parkinson’s Disease Rating Scale. Significant parkinsonism was significantly commoner in DLB sufferers (71%) than amongst patients with AD (7%) or VaD (10%). DLB patients with established parkinsonism had an annual increase in severity of 9%, but progression was more rapid (49% in 1 year) in patients with early parkinsonism. Parkinsonism was frequent at all severities in DLB patients, but usually only present in other dementias when MMSE <10.
A 26-Week Analysis of a Double-Blind, Placebo-Controlled Trial of the Ginkgo biloba Extract EGb 761® in Dementia
Authors: Le Bars Pierre L. , Kieser Meinhard , Itil Kurt Z.
Published: April 2003

This intent-to-treat (ITT) analysis was performed to provide a realistic image of the efficacy that could be expected after 26 weeks treatment with a 120-mg dose (40 mg t.i.d.) of EGb 761® (EGb). The data were collected during a 52-week, double-blind, placebo-controlled, fixed dose, parallel-group, multicenter study. Patients were mildly to severely impaired and diagnosed with uncomplicated Alzheimer’s disease or multi-infarct dementia according to ICD-10 and DSM-III-R criteria. The primary outcome measures included the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Geriatric Evaluation by Relative’s Rating Instrument (GERRI) and Clinical Global Impression of Change. From 309 patients included in the ITT analysis, 244 patients (76% for placebo and 73% for EGb) actually reached the 26th week visit. In comparison to the baseline values, the placebo group showed a statistically significant worsening in all domains of assessment, while the group receiving EGb was considered slightly improved on the cognitive assessment and the daily living and social behavior. Mean treatment differences favored EGb with 1.3 and 0.12 points, respectively, on the ADAS-Cog (p = 0.04) and the GERRI (p = 0.007). In the group receiving EGb, 26% of the patients achieved at least a 4-point improvement on the ADAS-Cog, compared to 17% with placebo (p = 0.04). On the GERRI, 30% of the EGb group improved and 17% worsened, while the placebo group showed an opposite trend with 37% of patients worsening for 25% improved (p = 0.006). Regarding safety, no differences between EGb and placebo were observed.
Apolipoprotein E and Intronic Polymorphism of Presenilin 1 and Alpha-1-Antichymotrypsin in Alzheimer’s Disease and Vascular Dementia
Authors: Rodriguez Martin T. , Calella A.M. , Silva S. , Munna E. , Modena P. , Chiesa R. , Terrevazzi S. , Ruggieri R.M. , Palermo R. , Piccoli F. , Confalonieri R. , Tiraboschi P. , Fragiacomo C. , Quadri P. , Lucca U. , Forloni G.
Published: April 2003

Apolipoprotein E (ApoE) genotypes, presenilin 1 (PS-1) and α1-antichymotrypsin (ACT) polymorphism and the association of the genotypes were examined in patients with Alzheimer’s disease (AD, n = 121) or vascular dementia (VD, n = 68) in comparison with elderly controls (n = 125). The frequency of the ApoE ε4 allele was significantly increased both in late-onset AD (0.35) and in VD (0.17); the frequency of ApoE ε2 was significantly reduced in AD, but it was similar in VD and controls. The presence of the allele 1 of PS-1 intronic polymorphism was not associated with AD or VD and was not influenced by the ApoE genotypes. Also, the frequency of allele A of the intronic polymorphism of ACT was similar in AD, VD and controls and it was not altered by ApoE or PS-1 genotypes. The results confirm the association between ApoE ε4 and AD and indicate an increase in ApoE ε4 in Vd, too. A potential protective role of ApoE ε2 is also suggested for late-onset AD but not for VD. No association was shown between ACT allele A and PS-1 allele 1 in AD or VD.
Differential Expression of Metallothioneins in Human Prion Diseases
Authors: Kawashima Toshiro , Doh-ura Katsumi , Torisu Miho , Uchida Yoko , Furuta Akiko , Iwaki Toru
Published: April 2003

We herein report an immunohistochemical and a Western blot analysis on metal/free radical chelating proteins, metallothioneins (MTs; MT-I/II and MT-III), in the brains of human prion disease patients with or without prion protein gene mutation and polymorphism. Irrespective of the isoforms of MTs, the immunoreaction was detected in the cytoplasm and processes of the astrocytes in the cerebral cortex and white matter in normal controls and prion disease brains. Although the immunoreactivities for MTs in Creutzfeldt-Jakob disease (CJD) brains varied from case to case, they were generally dependent upon the disease duration. In CJD patients with a relatively long disease course, the immunoreaction for both MT-I/II and MT-III in the astrocytes was significantly reduced, and this finding was not modified by the genotypes of the patients. On the other hand, in patients with Gerstmann-Sträussler-Scheinker syndrome, MT-I/II immunoreactivity in the astrocytes was exclusively reduced, while the immunoreaction for MT-III was relatively well preserved. Especially the astrocytes in the vicinities of the kuru plaques exhibited a weak or no immunoreaction even for MTs but a strong immunoreaction for glial fibrillary acidic protein. A quantitative Western blot analysis also revealed that MT-I/II protein accumulated in CJD brain with a short disease duration, whereas MT-III in CJD brain with a long disease duration was statistically significantly reduced in comparison to the normal brains. These findings suggest that the protein expression of MTs in the astrocytes is thus regulated differentially among human prion diseases and modified locally by such abnormal prion protein depositions as kuru plaques.
First Symptoms – Frontotemporal Dementia versus Alzheimer’s Disease
Authors: Lindau M. , Almkvist O. , Kushi J. , Boone K. , Johansson S.E. , Wahlund L.O. , Cummings J.L. , Miller B.L.
Published: April 2003

Frontotemporal dementia (FTD) is often misdiagnosed as Alzheimer’s disease (AD). We hypothesized that the first symptoms associated with FTD would be different from those seen in AD and that the first symptoms in FTD would reflect loss of function in the frontal region with the greatest degree of degeneration. The objective of the study was to compare the earliest symptoms in patients with FTD and AD, and to delineate the symptoms that were associated with right, left or bilateral frontotemporal degeneration in FTD. The first symptoms in 52 FTD and 101 AD patients were determined in retrospect. Based on functional imaging studies, the FTD patients were divided into those with predominantly bilateral (n = 15), left-sided (n = 19) and right-sided (n = 18) patterns of atrophy. The results showed that disinhibition, social awkwardness, passivity and loss of executive function were more common in FTD, while memory loss was more common in AD. Disinhibition was greatest in the asymmetric right-sided group, language dysfunction was commonest in the asymmetric left-sided group and loss of executive function was most frequent in the bilateral group. In summary, different first symptoms appeared in FTD and AD, which may help distinguish between the diseases. The anatomic site for FTD largely determined the kind of first symptoms.
Clinical Efficacy and Safety of Donepezil on Cognitive and Global Function in Patients with Alzheimer’s Disease
Authors: Homma Akira , Takeda Masatoshi , Imai Yukimichi , Udaka Fukashi , Hasegawa Kazuo , Kameyama Masakuni , Nishimura Tsuyoshi
Published: April 2003

This study evaluated efficacy and safety of donepezil hydrochloride (donepezil) at 5 mg/day in patients with mild to moderately severe Alzheimer’s disease for 24 weeks in a double-blind, placebo-controlled comparative trial. In this study, 268 patients were enrolled and 39 of these (15%) were withdrawn. In the evaluable population of efficacy, Protocol-Compatible (PC) analyzed patients (n = 228), better effects than that of placebo were confirmed using two primary efficacy measures: a cognitive performance test, the Japanese version of the Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-J cog, p = 0.003) and a clinical global assessment, the Japanese version of the Clinical Global Impression of Change (J-CGIC, p = 0.000). The superiority of donepezil was also shown by secondary measures: the Sum of the Boxes of the Clinical Dementia Rating (CDR-SB), the Mental Function Impairment Scale (MENFIS) and the caregiver-rated modified Crichton scale (CMCS). The same results were obtained in the intention-to-treat (ITT) analysis (n = 263). The incidence of drug-related adverse events was 10% (14/136) in the donepezil and 8% (10/131) in the placebo group; no significant difference was seen between the two groups. The main adverse events were gastrointestinal symptoms, and these were almost all mild, and they all disappeared with continued administration or temporary discontinuation of donepezil. These results indicate that the donepezil appears to be effective and well tolerated in patients with mild to moderately severe Alzheimer’s disease.
Age-Dependent Neurobehavioral Plasticity following Forebrain Dopamine Depletions
Authors: Bruno John P. , Sandstrom Michael I. , Arnold H. Moore , Nelson Christopher L.
Published: April 2003

The differential neurobehavioral effects of forebrain dopamine (DA) depletions in neonatal and adult rats are reviewed. In contrast to the severe and long-lasting parkinsonian sensorimotor deficits seen in rats sustaining large DA depletions as adults, rats comparably depleted as neonates are spared from these gross behavioral deficits. While DA released from residual striatal DA terminals remains necessary for the gradual recovery of sensorimotor function in rats lesioned as adults and the sparing from deficits in rats lesioned as neonates, the specific roles of D1- and D2-like receptors differ between the two age groups. Coactivation of striatal D1 and D2 receptors by residual DA is necessary for the expression of sensorimotor behavior in rats depleted of DA as adults (and in intact rats) whereas activation of either D1 or D2 receptors is sufficient for these behaviors in rats depleted of DA as neonates. We discuss the D1/D2 modulation of several important markers for striatal transmission (acetylcholine release from interneurons, induction of c-fos, and the expression of GAD65 mRNA in striatal efferents) as potential mechanisms underlying this striking age-dependent plasticity following forebrain DA depletions.
Effects of NMDA Receptor Antagonists on D1 Dopamine Receptor-Mediated Changes in Striatal Immediate Early Gene Expression: Evidence for Involvement of Pharmacologically Distinct NMDA Receptors?
Authors: Keefe Kristen A. , Ganguly Anindita
Published: April 2003

Dopamine D1 receptor regulation of striatal gene expression is dependent on N-methyl-D-aspartate (NMDA) receptors. To determine whether pharmacologically distinct NMDA receptors are differentially involved, we examined the effects of different NMDA receptor antagonists on D1-induced immediate early gene expression. Systemic administration of the channel blocking antagonists MK-801 and dextrorphan and the competitive antagonist CGS 19755 blocked gene expression induced by the D1 agonist SKF 82958. The NMDA polyamine site antagonist ifenprodil, however, potentiated the effect of SKF 82958. Since ifenprodil is selective for receptors containing the NR2B subunit, the data suggest that subtypes of NMDA receptors may be differentially involved in regulating striatal function.
Lactate Transport by Cortical Synaptosomes from Adult Rat Brain: Characterization of Kinetics and Inhibitor Specificity
Authors: McKenna Mary C. , Tildon J. Tyson , Stevenson Joseph H. , Hopkins Irene B. , Huang Xueli , Couto Renee
Published: April 2003

Since lactate released by glial cells may be a key substrate for energy in neurons, the kinetics for the uptake of L-[U-14C]lactate by cortical synaptic terminals from 7- to 8-week-old rat brain were determined. Lactate uptake was temperature-dependent, and increased by 64.9% at pH 6.2, and decreased by 43.4% at pH 8.2 relative to uptake at pH 7.3. Uptake of monocarboxylic acids was saturable with increasing substrate concentration. Eadie-Hofstee plots of the data gave evidence of two carrier-mediated uptake mechanisms with a high-affinity Km of 0.66 mM and Vmax of 3.66 mM for pyruvate, and a low-affinity system with a Km of 9.9 mM for both lactate and pyruvate and Vmax values of 16.6 and 23.1 nmol/30 s/mg protein for lactate and pyruvate, respectively. Saturable uptake was seen in the presence of 10 mM α-cyano-4-hydroxycinnamate. Lactate transport by synaptic terminals was much more sensitive to inhibition by sulfhydryl reagents than transport in astrocytes. Addition of 0.5 and 2 mM mersalyl decreased the uptake of 1 mM lactate by synaptic terminals by 59.3 and 66.37%, respectively. Pyruvate moderately decreased lactate transport, whereas 3-hydroxybutyrate had little effect. Quercetin, an inhibitor of lactate release, had little effect on the content of 14C lactate in synaptic terminals, supporting the concept that the majority of lactate produced within brain is from glial cells. Oxidation of L-[U-14C]lactate by synaptosomes was saturable, and yielded a Km of 1.23 mM and a Vmax of 116 nmol/h/mg protein. Overall the studies show that synaptic terminals from adult brain have a high capacity for transport and oxidation of lactate, consistent with the proposed role for this compound in metabolic trafficking in brain. Furthermore, the data provide kinetic evidence of two carrier-mediated mechanisms for monocarboxylic acid transport by synaptosomes and demonstrate that uptake of lactate by synaptic terminals is regulated differently than transport by astrocytes. Uptake of lactate by synaptic terminals also has differences from the systems described for neurons.
Functional Energy Metabolism:In vivo 13C-NMR Spectroscopy Evidence for Coupling of Cerebral Glucose Consumption and Gl utamatergic Neuronal Activity
Authors: Sibson Nicola R. , Shen Jun , Mason Graeme F. , Rothman Douglas L. , Behar Kevin L. , Shulman Robert G.
Published: April 2003

The use of in vivo 13C nuclear magnetic resonance spectroscopy (NMR) has established the pathways of functional interaction between neurons and astrocytes in the mammalian brain and enabled quantitation of these fluxes. A mathematical model of glutamate, glutamine and ammonia metabolism in the brain has been developed, under the constraints of carbon and nitrogen mass balance, allowing the direct and quantitative comparison of in vivo 13C- and 15N-NMR data. Using this model and 13C-NMR data, the authors have separated the neurotransmitter cycling and detoxification components of glutamine synthesis by measuring the rate of glutamine synthesis under normal and hyperammonaemic conditions in the rat brain cortex in vivo. In addition, the simultaneous measurement of the rates of oxidative glucose metabolism and glutamate neurotransmitter cycling in the rat brain cortex has shown that over a range of EEG activity (from isoelectric up to near-resting levels) the stoichiometry between glucose metabolism and glutamate cycling is close to 1:1. Under mild anesthesia, cortical glucose oxidation coupled to glutamatergic synaptic activity accounts for over 80% of total glucose oxidation. Previously, changes in cerebral glucose metabolism have been taken to indicate alterations in functional activity. These recent in vivo results demonstrate, however, that those changes are, in fact, quantitatively coupled to the crux of functional activity, neurotransmitter release. These findings bear upon a number of hypotheses concerning the neurophysiological basis of brain functional imaging methods.
Glutathione Restoration as Indicator for Cellular Metabolism of Astroglial Cells
Authors: Dringen Ralf , Hamprecht Bernd
Published: April 2003

The restoration of glutathione in astroglia-rich primary cultures derived from the brains of newborn rats was used to indicate metabolic properties of astroglial cells. At a culture age of 14–21 days these cultures contain an average total glutathione content of 32.8 ± 3.2 nmol/mg protein and a cytosolic volume, estimated with the 3-O-methylglucose method, of 4.1 ± 0.1 µl/mg protein. Therefore, cells of astroglial cultures have a cytosolic glutathione concentration of about 8 mM. In order to investigate glutathione synthesis in astroglial cultures the cellular glutathione content was reduced by starvation in a minimal medium lacking glucose and amino acids. Resynthesis of glutathione depended on the presence of glucose and the three constituent amino acids glutamate, cysteine and glycine. Absence of glucose reduced the amount of net glutathione restoration found after 4 h of incubation by about 50%. Of known substrates of astroglial energy metabolism, mannose could fully and fructose, lactate, pyruvate or sorbitol could partially replace glucose during glutathione restoration. In contrast to these compounds, galactose, 5-thioglucose and 2-deoxyglucose failed to substitute for glucose during glutathione restoration. Astroglial cells are able to use as precursors for the three constituent amino acids of glutathione a variety of amino acids and dipeptides. The results presented demonstrate that glutathione restoration can be used as an indicator for amino acid as well as energy metabolism of astroglial cells.
15N-NMR Spectroscopy Studies of Ammonia Transport and Glutamine Synthesis in the Hyperammonemic Rat Brain
Authors: Shen Jun , Sibson Nicola R. , Cline Gary , Behar Kevin L. , Rothman Douglas L. , Shulman Robert G.
Published: April 2003

Ammonia transport and glutamine synthesis were studied in the hyperammonaemic rat brain in vivo using 15N-NMR spectroscopy at a plasma ammonia level of approximately 0.39 mM raised via an intravenous [15N]-ammonium acetate infusion. The initial slope of the time course of the summed cerebral 15N-labelled metabolites was used to determine the rate of ammonia net transport during hyperammonemia as 0.13 ± 0.02 µmol/min/g (mean ± SD; n = 5). Based on the total accumulation of glutamine and the 1:2 stoichiometric relationship between fluxes of four-carbon skeletons and nitrogen atoms, the rate of de novo glutamine synthesis through anaplerosis and subsequent glutamate dehydrogenase action was calculated to be 0.065 ± 0.01 µmol/min/g. The rate of total glutamine synthesis was estimated to be 0.20 ± 0.06 µmol/min/g (n = 5) by fitting the [5-15N]glutamine time course to a previously described model of glutamate-glutamine cycling between astrocytes and neurones. A large dilution was also observed in [2-15N]glutamine, which supports the glutamate-glutamine cycle as being an important pathway for neuronal glutamate repletion in vivo.
Expression of Kv3.1 and Kv4.2 Genes in Developing Cerebellar Granule Cells
Authors: Shibata Riichi , Wakazono Yoshihiko , Nakahira Kensuke , Trimmer James S. , Ikenaka Kazuhiro
Published: April 2003

The expression of voltage-gated potassium channels plays an important role in the acquisition of membrane excitability in neurons. We examined the expression pattern of genes in developing cerebellar granule neurons in vivo and in vitro. In situ hybridization of Kv3.1 mRNA demonstrated that the gene was expressed at high levels in the external granule layer (EGL) as well as in the internal granule layer (IGL) at all postnatal stages (P) examined (from P3 to P10). In contrast, Kv4.2 mRNA was detected in the premigratory zone (PMZ) of the EGL, but not in the proliferative zone (PLZ), in addition to the IGL. This indicates that Kv4.2 gene expression initiates in the postmitotic migrating neurons. We also examined the expression of the channel genes in microexplant culture systems. Kv3.1 polypeptide was detected in parallel fibers of granule cells at 2 days in vitro, and the expression continued in later stages. The signal of Kv4.2 protein was very low at 2 days in vitro; however, the number of positive cells and the intensity of the signals were increased at 6 days in vitro. These in vitro observations matched those in vivo and our previous electrophysiological studies in which we demonstrated that delayed- rectifier-type current was predominant in the immature granule cells followed by the later appearance of A-type current. The patterns of K+ channel expression suggest that sequential expression of these channel genes primarily determines the membrane excitability.
Quantitative Estimation of RNA Transcripts Suggests Persistence of Pax-6 Expression in the Postembryonic Chick Retina
Authors: Bhat Suraj P. , Rayner Sylvia A. , Huang Cindy M. , Ariyasu Reginald G.
Published: April 2003

Pax-6 is expressed during early embryonic development of the eye. Very little is known about its expression in the functionally mature retina. We have detected Pax-6 transcripts in the ganglion cell- and amacrine cell layers at days 3, 10, 17 and 31 posthatching and in 2- to 3-month-old chick retina by in situ hybridization. These observations were confirmed by a quantitative analysis. Competitive RT-PCR with a homologous internal control revealed a significant reduction (p < 0.001) in the number of Pax-6 transcripts in day 17 retina [(0.39 ± 0.13) × 1010/mg tissue] compared to day 3 retina [(1.65 ± 0.48) × 1010/mg tissue]. Although significantly lower than at day 3, the day 31 retina [(0.7 ± 0.16) × 1010/mg tissue] and retina from 2- to 3-month-old chicks [(0.9 ± 0.28) × 1010/mg tissue] contained an increased number of Pax-6 transcripts in comparison to day 17. On the basis of the amount of RNA, the number of Pax-6 transcripts in the day 3 retina [(0.45 ± 0.14) × 1010/μg RNA] relative to day 17 retina [(0.4 ± 0.08) × 1010/μg RNA] did not change significantly (p = 0.29). However, at day 31 and at 2–3 months of age an increased number of Pax-6 transcripts [(0.65 ± 0.14) × 1010/μg RNA and (0.65 ± 0.2) × 1010/μg RNA, respectively)] were found. In view of the known association of Pax-6 expression with proliferation and emergence of different cell types, these data suggest that cell types in ganglion and inner nuclear cell layers may retain proliferative potential for an extended period in the young adult retina.
Cellular Morphology and Physiology of the Perinatal Rat Cerebral Cortex
Authors: Luhmann Heiko J. , Schubert Dirk , Kötter Rolf , Staiger Jochen F.
Published: April 2003

The cellular morphology and electrophysiology of the rat neocortex between embryonic day (E) 18 and postnatal day (P) 3 was studied in vitro by extracellular biocytin injections and whole-cell recordings, respectively. Most neurons were characterized by a small number of short-range dendrites and a main axon that was directed towards the white matter. Biocytin injections into the marginal zone and the cortical plate labeled far-reaching connections extending up to 2 mm in horizontal direction, indicating the existence of a dense network of long-range intrinsic projections in the neonatal cortex. Action potentials could be elicited as early as E18 and repetitive firing could first be observed at P0. Electrical stimulation of the immature cortex at various positions elicited polyphasic and long-lasting (up to 1 s) excitatory postsynaptic potentials and currents, which were significantly reduced in amplitude by a selective N-methyl-D-aspartate receptor antagonist. Our data indicate that the perinatal cortex manifests the structural and functional conditions for powerful excitatory interactions, which increase the likelihood for the generation of epileptiform activity during this developmental period.
Developmental Seizure Susceptibility of Kv1.1 Potassium Channel Knockout Mice
Authors: Rho Jong M. , Szot Patricia , Tempel Bruce L , Schwartzkroin Philip A.
Published: April 2003

Potassium channels play a critical role in limiting neuronal excitability. Mutations in certain voltage-gated potassium channels have been associated with hyperexcitable phenotypes in both humans and animals. However, only recently have mutations in potassium channel genes (i.e. KCNQ2 and KCNQ3) been discovered in a human epilepsy, benign familial neonatal convulsions. Recently, it has been reported that mice lacking the voltage-gated Shaker-like potassium channel Kv1.1 α-subunit develop recurrent spontaneous seizures early in postnatal development. The clinical relevance of the Kv1.1 knockout mouse has been underscored by a recent report of epilepsy occurring in a family affected by mutations in the KCNA1 locus (the human homologue of Kv1.1) which typically cause episodic ataxia and myokymia. Here we summarize preliminary studies characterizing the developmental changes in seizure susceptibility and neuronal activation in the three genotypes of Kv1.1 mice (–/–, +/–, +/+). Using behavioral and immediate-early gene indicators of regional brain excitability, we have found that a seizure-sensitive predisposition exists in Kv1.1 –/– animals at a very young age (P10), before either spontaneous seizure activity or changes in c-fos mRNA expression can be demonstrated. Kv1.1 +/– mice, although behaviorally indistinguishable from wild types, also have an increased susceptibility to seizures at a similar early age. The Kv1.1 knockout mouse possesses many features desirable in a developmental animal epilepsy model and represents a clinically relevant model of early-onset epilepsies.
Synaptic Responses of Neurons in Heterotopic Gray Matter in an Animal Model of Cortical Dysgenesis
Authors: Smith Bret N. , Dudek F. Edward , Roper Steven N.
Published: April 2003

Neuronal heterotopia is a malformation of cortical development that is closely associated with epilepsy in humans. Despite emerging interest in the structure and function of the heterotopic cortex, little is known about the membrane properties and synaptic connections of these displaced neurons. We used whole-cell patch-clamp and extracellular field potential recordings from heterotopic neurons in slices from young adult rats with experimentally induced cortical dysgenesis to determine if local synaptic connections were present in nodular heterotopia. Complex synaptic responses were observed after electrical stimulation of adjacent white matter. The results suggest that neurons in nodular heterotopic gray matter can form local excitatory and inhibitory synaptic connections and may participate in epileptiform events.
Hippocampal T2 Abnormalities Correlate with Antecedent Events and Help Predict Seizure Intractability
Authors: Jackson G.D. , Kim S.E. , Fitt G.J. , Mitchell A.L. , Syngeniotis A. , Berkovic S.F.
Published: April 2003

Introduction: We performed hippocampal T2 relaxometry as part of a routine magnetic resonance imaging (MRI) examination in 50 normal controls and 127 consecutive patients referred because of suspected seizures. Methods: On the basis of T2 values in controls (100.2 ± 4.2 ms) we defined normal as <110 ms (113 ms (>mean + 3 SD). Results: After detailed investigation, 103 of these 127 patients had epilepsy and 24 did not. In the nonepilepsy group, none had abnormal hippocampal T2 values. Twenty-seven of the 103 patients in the epilepsy group had abnormal values, 7 were borderline and 69 were normal. Only 5 patients with abnormal T2 values did not have temporal lobe epilepsy: 1 had extratemporal lobe epilepsy, 1 had generalized epilepsy and 3 had unclassified epilepsy. Twenty-two of 27 (81%) patients with abnormal hippocampal T2 values had intractable epilepsy [compared with 32 of 69 (46%) patients with normal values; p < 0.05, χ2 test]. Two thirds of patients with abnormal values had a history of a major antecedent event (compared to only 7% of those with normal values, p < 0.05, χ2 test). Conclusion: Abnormal T2 relaxometry is significantly associated with intractable epilepsy as well as with major antecedent events.
Cortical Dysplasia, Genetic Abnormalities and Neurocutaneous Syndromes
Authors: Vinters Harry V. , Park Sung Hye , Johnson Michael W. , Mischel Paul S. , Catania Michael , Kerfoot Christopher
Published: April 2003

Cortical dysplasia (CD) represents a common neuropathologic substrate of pediatric epilepsy, one frequently encountered in surgical resection specimens from infants and children with intractable seizure disorders, including infantile spasms. Severe CD shows similarities to structural features noted in tubers from individuals with tuberous sclerosis (TSC). The latter disorder, one with neurocutaneous and visceral manifestations, results from mutations in one of two recently cloned genes, TSC1 or TSC2, which encode (respectively) the proteins hamartin and tuberin. There is circumstantial evidence that both proteins may influence cell growth and differentiation, specifically that they may represent growth suppressors. Neither protein has a defined role in brain development. We discuss and illustrate neuropathologic features of both CD and TSC, and discuss the patterns and time course of hamartin/tuberin expression in normal brain, CD and TSC. Other recently cloned genes associated with cortical malformations encompassed by the term CD are briefly described.
Prenatal Ethanol Exposure Reduces Spinal Cord Motoneuron Number in the Fetal Rat but Does Not Affect GDNF Target Tissue Protein
Authors: Barrow Heaton Marieta , Kidd Kara , Bradley Douglas , Paiva Michael , Mitchell Jean , Walker Don W.
Published: April 2003

Fetal rats were exposed throughout gestation to one of three diets: an ethanol-containing liquid diet, a liquid diet with the isocaloric substitution of sucrose for ethanol or a laboratory chow control diet. At postnatal day 1 (P1), the spinal cords were taken for analyses of motoneuron number and size. These analyses revealed a significant loss of motoneurons and a reduction of motoneuron size in the ethanol-exposed animals, compared to both sucrose and chow controls. Spinal cord length and ventral horn volume were not altered as a result of ethanol treatment, so the change in motoneuron number cannot be attributed to volumetric changes. The content of the motoneuron survival factor glial cell-line-derived neurotrophic factor (GDNF) was also assessed in the P1 limb motoneuron target tissue. This analysis was undertaken because GDNF is a potent survival factor for developing motoneurons and has been shown to protect this population from ethanol neurotoxicity. Thus, its depletion could contribute to motoneuron loss. These analyses, using the ELISA assay, did not detect reductions in GDNF in the ethanol-exposed animals. Therefore, alterations in other neurotrophic factors or ethanol neurotoxicity by other means appear to be responsible for the motoneuron loss. These results are consistent with earlier studies in the chick embryo, which also found reduced motoneuron numbers as a function of developmental ethanol exposure, and point again to the general lethality of ethanol to the developing nervous system.
Differential Response of Ventral Midbrain and Striatal Progenitor Cells to Lesions of the Nigrostriatal Dopaminergic Projection
Authors: Kay Jeremy N. , Blum Mariann
Published: April 2003

In response to injury, progenitor cells in the adult brain can proliferate and generate new neurons and/or glia, which may then participate in injury-induced compensatory processes. In this study, we explore the ability of young adult mice to generate new cells in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesions, which selectively kill nigrostriatal dopaminergic neurons. Using the thymidine analogue 5-bromo-2′-deoxyuridine (BrdU), we labeled dividing cells 3, 10, and 15 days after MPTP lesion. A robust proliferative response was seen specifically in the substantia nigra (SN) and the dorsal striatum 3 days postlesion; the response persisted 10–14 days. To explore the fate of proliferative cells, we administered BrdU 3 days postlesion and examined the phenotype of BrdU+ cells at various times thereafter, using double immunolabeling. In the striatum, nearly all newly-generated cells rapidly differentiated into GFAP+ astrocytes that participated in the injury-induced glial reaction. In the SN, however, reactive astroglia were not BrdU+. Some midbrain cells co-immunostained for BrdU and Mac-1, a microglial marker. However, most BrdU+ cells in the SN failed to express markers for microglia, astroglia, oligodendroglia, or neurons, suggesting that they may remain as uncommitted progenitors. Thus, progenitors in the vicinity of the degenerating dopaminergic cell bodies respond differently to lesion than progenitors in the vicinity of the degenerating axon terminal. Although the putative midbrain progenitors appear uncommitted 22 days after their birth, it is possible that they may adopt neural or glial fates if allowed to survive longer, or if exposed to exogenous factors.