Alzheimer Disease: Agid Y

Rösler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, Stähelin HB, Hartman R, Gharabawi M. · Sektion Gerontopsychiatric, Psychiatrische Universitätsklinik, Fuchsleinstrasse 15, D 97080 Würzburg, Germany. · BMJ. · Pubmed #10066203 links to  free full text

Abstract: OBJECTIVES: To assess the effects of rivastigmine on the core domains of Alzheimer's disease. DESIGN: Prospective, randomised, multicentre, double blind, placebo controlled, parallel group trial. Patients received either placebo, 1-4 mg/day (lower dose) rivastigmine, or 6-12 mg/day (higher dose) rivastigmine. Doses were increased in one of two fixed dose ranges (1-4 mg/day or 6-12 mg/day) over the first 12 weeks with a subsequent assessment period of 14 weeks. SETTING: 45 centres in Europe and North America. PARTICIPANTS: 725 patients with mild to moderately severe probable Alzheimer's disease diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, and the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association. OUTCOME MEASURES: Cognitive subscale of the Alzheimer's disease assessment scale, rating on the clinician interview based impression of change incorporating caregiver information scale, and the progressive deterioration scale. RESULTS: At the end of the study cognitive function had deteriorated among those in the placebo group. Scores on the Alzheimer's disease assessment scale improved in patients in the higher dose group when compared with patients taking placebo (P<0.05). Significantly more patients in the higher dose group had improved by 4 points or more than had improved in the placebo group (24% (57/242) v 16% (39/238)). Global function as rated by the clinician interview scale had significantly improved among those in the higher dose group compared with those taking placebo (P<0.001), and significantly more patients in the higher dose group showed improvement than did in the placebo group (37% (80/219) v 20% (46/230)). Mean scores on the progressive deterioration scale improved from baseline in patients in the higher dose group but fell in the placebo group. Adverse events were predominantly gastrointestinal, of mild to moderate severity, transient, and occurred mainly during escalation of the dose. 23% (55/242) of those in the higher dose group, 7% (18/242) of those in the lower dose group, and 7% (16/239) of those in the placebo group discontinued treatment because of adverse events. CONCLUSIONS: Rivastigmine is well tolerated and effective. It improves cognition, participation in activities of daily living, and global evaluation ratings in patients with mild to moderately severe Alzheimer's disease. This is the first treatment to show compelling evidence of efficacy in a predominantly European population.

Verpillat P, Bouley S, Campion D, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Antérion C, Agid Y, Brice A, Clerget-Darpoux F. · INSERM U535, Le Kremlin Bicêtre, France, and INSERM U289, Paris, France. · Eur J Hum Genet. · Pubmed #11436129 links to  free full text

Abstract: The low density lipoprotein receptor-related protein gene (LRP) is a good candidate gene for Alzheimer's Disease (AD). Its protein is involved in the physiopathology of AD and has been found in senile plaques; on the other hand, LRP is located in 12q, a region in which genetic linkage to AD was reported. Two common polymorphisms, a tetranucleotide repeat in the 5' untranslated region and a single nucleotide polymorphism at position 766 in exon 3, were found to be associated with AD, but contradictory results were obtained in subsequent association studies. In the absence of clear hypotheses concerning the association of these polymorphisms with AD and their functional role, our objective was to test the association between AD and the two LRP polymorphisms in a large French case-control sample (274 Caucasian AD patients and 290 matched controls) using haplotype analysis. First, the separate study of each polymorphism showed no significant difference in genotype and allele frequencies between AD cases and controls. Second, strong linkage disequilibrium was found between alleles of the two polymorphisms in controls and in cases and the linkage disequilibrium between the 91 bp and C alleles were opposite in cases and in controls. Third, we found that the frequency of the 91-C haplotype was higher in cases than in controls, but the type I error was 0.061, slightly higher than the conventional one of 5%. The haplotype frequencies did not vary significantly as a function of age and APOE epsilon4 status. One interest in this study is the use of the haplotype analysis, which can be used to combine information from several polymorphisms, taking into account their dependence.

Dubus P, Faucheux B, Boissière F, Groppi A, Vital C, Vital A, Agid Y, Hirsch EC, Merlio JP. · Laboratoire d'Histologie-Embryologie, EA 2406 Université de Bordeaux 2, Bordeaux Cedex, 33076, France. · Exp Neurol. · Pubmed #10993689 No free full text.

Abstract: The TrkAII tyrosine kinase receptor differs from the TrkAI isoform by an insertion of six amino acids in the extracellular domain. We used RT-PCR to determine their respective distribution in rat and human brain. Only trkAII transcripts were detected in 12 rat brain regions, while both trkAI and trkAII transcripts were detected in the cerebellum and pituitary gland. In human, both trkAI and trkAII transcripts were detected in the frontal, temporal, and occipital cortex and thalamus, while only trkAI transcripts were detected in the hippocampus and cerebellum. In the caudate and putamen, trkAII transcripts were exclusively detected. Thereafter, we studied the expression of TrkA isoforms in the striatum of five patients with Alzheimer's disease (AD), four patients with non-AD dementia, seven patients with Parkinson's disease, and six paired nondemented elderly control individuals. In controls and non-AD patients, a constant expression of trkAII transcripts was detected within all striatum parts. In AD patients, a heterogeneous decrease in trkAII expression was observed in the caudate, putamen, and ventral striatum, resulting either in a drop of trkAII transcript levels or in a weak coamplification of trkAII and trkAI transcripts. The alteration of TrkAII gene expression paralleled those of choline acetyltransferase. Together with previous data, this suggests that the alteration of trk gene expression could contribute to a decrease in NGF binding sites and its protective effects on cholinergic neurons of AD patients.

Ransmayr G, Faucheux B, Nowakowski C, Kubis N, Federspiel S, Kaufmann W, Henin D, Hauw JJ, Agid Y, Hirsch EC. · Universitätsklinik für Neurologie, Anichstrasse 35, A-6020, Innsbruck, Austria. · Neurosci Lett. · Pubmed #10889341 No free full text.

Abstract: Cholinergic neurons in the basal forebrain and the upper brainstem undergo changes during aging and in dementia of the Alzheimer type, Parkinson's disease and progressive supranuclear palsy. Little is known about the effect of age on neurons in the tegmental pedunculopontine nucleus. Cholinergic neurons revealed by choline acetyltransferase immunohistochemistry were quantified in the brains of 20 subjects who died without neurological disorder between 28 and 101 years of age. A U-shaped relationship between cell counts and age was found, namely, a decrease in counts between 28 and 70, a minimum between 80 and 91 years of age, and, in four subjects aged 98-101 years counts comparable to those of subjects having died between 28 and 65 years. The findings suggest that the loss of cholinergic pedunculopontine nucleus neurons is not linear. In centenarians age-related neuronal decrease in pedunculopontine nucleus neurons may be slower or the stock of pedunculopontine nucleus neurons greater than in subjects dying earlier.

Murer MG, Boissiere F, Yan Q, Hunot S, Villares J, Faucheux B, Agid Y, Hirsch E, Raisman-Vozari R. · INSERM U289, H ôpital de la Pitié Sal pêtrière, Paris, France. · Neuroscience. · Pubmed #10336117 No free full text.

Abstract: Brain-derived neurotrophic factor is a member of the family of neuronal differentiation and survival-promoting molecules called neurotrophins. Neuronal populations known to show responsiveness to the action of brain-derived neurotrophic factor include the cholinergic forebrain, mesencephalic dopaminergic, cortical, hippocampal and striatal neurons. This fact has aroused considerable interest in the possible contribution of an abnormal brain-derived neurotrophic factor function to the aetiology and physiopathology of different neurodegenerative disorders, such as Alzheimer's disease. This report describes the cellular and regional distribution of brain-derived neurotrophic factor in post mortem control human brain and in limited regions of the brain in patients with Alzheimer's disease, as was revealed by immunohistochemistry. Brain-derived neurotrophic factor is widely expressed in the control human brain, both by neurons and glia. In neurons, brain-derived neurotrophic factor was localized in the cell body, dendrites and axons. Among the structures showing the most intense immunohistochemical labeling were the hippocampus, claustrum, amygdala, bed nucleus of the stria terminalis, septum and the nucleus of the solitary tract. In the striatum, immunoreactivity was more intense in striosomes than in the matrix. Many labeled neurons were found in the substantia nigra pars compacta. The large putatively cholinergic neurons in the basal forebrain showed no immunoreactivity. The general pattern of labeling was similar in individuals with Alzheimer's disease. Brain-derived neurotrophic factor-immunoreactive material was found in senile plaques, and some immunoreactive cortical pyramidal neurons showed neurofibrillary tangles, suggesting that brain-derived neurotrophic factor may be involved in the process of neuronal degeneration and/or compensatory mechanisms which occur in this illness.

Hirsch E, Hu LJ, Prigent A, Constantin B, Agid Y, Drabkin H, Roche J. · INSERM U289, Hôpital de la Salpêtrière, 47, Bd. de l'Hôpital, 75651, Paris Cédex 13, France. · Brain Res. · Pubmed #10095013 No free full text.

Abstract: The semaphorins comprise a family of secreted and membrane bound proteins that influence development of the nervous system as well as non-neural organs. H.SemaIV was originally isolated from a homozygously deleted region involving a subset of small cell lung cancers, a neuroendocrine derived neoplasm. To investigate H.SemaIV expression, specific polyclonal antibodies directed against a unique polypeptide (amino acids 758-773) were developed and their specificity confirmed. In cell lines, H.SemaIV staining was observed in cytoplasmic granules. In the normal adult human brain, we noted three general characteristics of H.SemaIV expression. H.SemaIV was strongly present in specific nuclei or in neuronal regions arranged in defined subnuclear structures. It was also present in neurons but not glial cells or ependymocytes. Lastly, H.SemaIV was not present in cell bodies, but rather in fibers and nerve terminals. Interestingly, an altered pattern of staining was detected in brains of three patients with Alzheimer's disease.

Verpillat P, Bouley S, Hannequin D, Belliard S, Puel M, Thomas-Anterion C, Dubois B, Agid Y, Campion D, Clerget-Darpoux F, Brice A. · No affiliation provided · Ann Neurol. · Pubmed #10976654 No free full text.

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