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      Alzheimer's disease Translated title: Enfermedad de Alzheimer Translated title: Maladie d'Alzheimer

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          Abstract

          Alzheimer's disease is one of the most devastating brain disorders of elderly humans. It is an undertreated and under-recognized disease that is becoming a major public health problem. The last decade has witnessed a steadily increasing effort directed at discovering the etiology of the disease and developing pharmacological treatment. Recent developments include improved clinical diagnostic guidelines and improved treatment of both cognitive disturbance and behavioral problems. Symptomatic treatment mainly focusing on cholinergic therapy has been clinically evaluated by randomized, double-blind, placebo-controlled, parallel-group studies measuring performance-based tests of cognitive function, activities of daily living, and behavior. Cholinesterase inhibitors, including donepezil, tacrine, rivastigmine, and galantamine are the recommended treatment of cognitive disturbance in patients with Alzheimer's disease. The role of estrogen replacement, anti-inflammatory agents, and antioxidants is controversial and needs further study. Antidepressants, antipsychotics, mood stabilizers, anxiolytics, and hypnotics are used for the treatment of behavioral disturbance. Future directions in the research and treatment of patients with Alzheimer's disease include: applying functional brain imaging techniques in early diagnosis and evaluation of treatment efficacy; development of new classes of medications working on different neurotransmitter systems (cholinergic, glutamatergic, etc), both for the treatment of the cognitive deficit and the treatment of the behavioral disturbances; and developing preventive methods (amyloid p-peptide immunizations and inhibitors of β-secretase and γ-secretase).

          Translated abstract

          La enfermedad de Alzheimer es uno de los trastornos cerebrales más devastadores de los sujetos de edad avanzada. Es una enfermedad subdiagnosticada y subtratada que se está transformando en un problema importante de la salud pública. La última década ha sido testigo de un esfuerzo creciente dirigido al descubrimiento de la etiología de la enfermedad y al desarrollo de tratamientos farmacológicos. Los progresos recientes incluyen un avance en las pautas del diagnóstico clínico y en el tratamiento tanto de los trastornos cognitivos como de las alteraciones de conducta. El tratamiento sintomático, que se focaliza principalmente en la terapia colinérgica, ha sido evaluado clínicamente a través de estudios randomizados, doble-ciego, placebo controlados y de grupos paralelos mediante pruebas basadas en rendimientos que miden la función cognitiva, actividades de la vida diaria y conductas. Los inhibidores de la colinesterasa como el donepezil, la tacrina, la rivastigmina y la galantamina son los tratamientos recomendados para los trastornos cognitivos en los pacientes con Enfermedad de Alzheimer. El papel de la terapia de reemplazo con estrógenos, el empleo de agentes antiinflamatorios o el uso de antioxidantes constituyen tratamientos en que hay controversia y se requiere de mayor investigación a futuro. Para el tratamiento de las alteraciones de conducta se han utilizado antidepresivos, antipsicóticos, estabilizadores del ánimo, ansiolíticos e hipnóticos. A futuro, la investigación y el tratamiento de los pacientes con Enfermedad de Alzheimer incluirá: a) la aplicación de técnicas de imágenes cerebrales funcionales para el diagnóstico precoz y la evaluación de la eficacia del tratamiento, b) el desarrollo de nuevas clases de medicamentos que actúen sobre diversos sistemas de neurotransmisión (colinérgico, glutamatérgico, etc.) tanto para el tratamiento de los déficits cognitivos como para las alteraciones de conducta, y c) el desarrollo de medidas de prevención (inmunizaciones con beta amiloide e inhibidores de la beta o gama secretasa).

          Translated abstract

          La maladie d'Alzheimer se situe parmi les plus destructrices des pathologies cérébrales chez le sujet âgé. Elle est devenue un problème de Santé publique majeur, mais reste insuffisamment diagnostiquée et traitée. La recherche étiologique et thérapeutique a constamment progressé au cours de la décennie passée, aboutissant récemment à la mise au point de recommandations pour le diagnostic clinique et à l'amélioration de la prise en charge thérapeutique des troubles cognitifs et du comportement. Les traitements symptomatiques, reposant essentiellement sur les traitements cholinergiques, ont été évalués dans des études randomisées, en double aveugle, contrôlées contre placebo, en groupes parallèles, évaluant les tests de performance cognitive, les activités quotidiennes et le comportement. Les traitements recommandés pour les troubles cognitifs sont les inhibiteurs de la cholinestérase, parmi lesquels le donezepil, la tacrine, la rivastigmine et la galantamine. Le rôle des traitements estrogéniques substitutifs, des traitements anti-inflammatoires et des antioxydants reste controversé et mérite de plus amples recherches. Les anti-dépresseurs, les antipsychotiques, les médicaments régulateurs de l'humeur, les anxiolytiques et les hypnotiques sont prescrits dans les troubles du comportement. Parmi les objectifs de recherche dans l'avenir, on peut citer: le développement de techniques d'imagerie cérébrale fonctionnelle permettant un diagnostic précoce de la maladie et l'évaluation de l'efficacité des traitements; la mise au point de nouvelles classes thérapeutiques agissant sur différents systèmes de neurotransmetteurs (cholinergique, glutamatergique, etc.) actifs à la fois sur les troubles du comportement et le déficit cognitif; enfin le développement de traitements préventifs (immunisation par β-peptide amyloïde et inhibiteurs de la β-sécrétase et de la γ-sécrétase).

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          Most cited references81

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          Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse.

          Amyloid-beta peptide (Abeta) seems to have a central role in the neuropathology of Alzheimer's disease (AD). Familial forms of the disease have been linked to mutations in the amyloid precursor protein (APP) and the presenilin genes. Disease-linked mutations in these genes result in increased production of the 42-amino-acid form of the peptide (Abeta42), which is the predominant form found in the amyloid plaques of Alzheimer's disease. The PDAPP transgenic mouse, which overexpresses mutant human APP (in which the amino acid at position 717 is phenylalanine instead of the normal valine), progressively develops many of the neuropathological hallmarks of Alzheimer's disease in an age- and brain-region-dependent manner. In the present study, transgenic animals were immunized with Abeta42, either before the onset of AD-type neuropathologies (at 6 weeks of age) or at an older age (11 months), when amyloid-beta deposition and several of the subsequent neuropathological changes were well established. We report that immunization of the young animals essentially prevented the development of beta-amyloid-plaque formation, neuritic dystrophy and astrogliosis. Treatment of the older animals also markedly reduced the extent and progression of these AD-like neuropathologies. Our results raise the possibility that immunization with amyloid-beta may be effective in preventing and treating Alzheimer's disease.
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            Tau is a candidate gene for chromosome 17 frontotemporal dementia.

            Frontotemporal dementia with parkinsonism, chromosome 17 type (FTDP-17), a recently defined disease entity, is clinically characterized by personality changes sometimes associated with psychosis, hyperorality, and diminished speech output, disturbed executive function and nonfluent aphasia, bradykinesia, and rigidity. Neuropathological changes include frontotemporal atrophy often associated with atrophy of the basal ganglia, substantia nigra, and amygdala. Neurofibrillary tangles (NFTs) are seen in some but not all families. Inheritance is autosomal dominant and the gene has been regionally localized to 17q21-22 in a 2- to 4-centimorgan (cM) region flanked by markers D17S800 and D17S791. The gene for tau, the primary component of NFTs, is located in the same region of chromosome 17. Tau was evaluated as a candidate gene. Physical mapping studies place tau within 2 megabases or less of D17S791, but it is probably outside the D17S800-D17S791 FTDP-17 interval. DNA sequence analysis of tau coding regions in affected subjects from two FTDP-17 families revealed nine DNA sequence variants, eight of which were also identified in controls and are thus polymorphisms. A ninth variant (Val279Met) was found in one FTDP-17 family but not in the second FTDP-17 family. Three lines of evidence indicate that the Val279Met change is an FTDP-17 causative mutation. First, the mutation site is highly conserved, and a normal valine is found at this position in all three tau interrepeat sequences and in other microtubule associated protein tau homologues. Second, the mutation co-segregates with the disease in family A. Third, the mutation is not found in normal controls.
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              Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline.

              Alzheimer disease (AD) is characterized neuropathologically by the presence of amyloid beta-peptide (Abeta)-containing plaques and neurofibrillary tangles composed of abnormal tau protein. Considerable controversy exists as to whether the extent of accumulation of Abeta correlates with dementia and whether Abeta alterations precede or follow changes in tau. To determine whether accumulation of Abeta correlates with the earliest signs of cognitive deterioration and to define the relationship between Abeta accumulation and early tau changes. Postmortem cross-sectional study of 79 nursing home residents with Clinical Dementia Rating (CDR) scale scores of 0.0 to 5.0 who died between 1986 and 1997, comparing the levels of Abeta variants in the cortices of the subjects with no (CDR score, 0.0 [n = 16]), questionable (CDR score, 0.5 [n = 11]), mild (CDR score, 1.0 [n = 22]), moderate (CDR score, 2.0 [n = 15]), or severe (CDR score, 4.0 or 5.0 [n = 15]) dementia. Levels of total Abeta peptides with intact or truncated amino termini and ending in either amino acid 40 (A(beta)x-40) or 42 (A(beta)x-42) in 5 neocortical brain regions as well as levels of tau protein undergoing early conformational changes in frontal cortex, as a function of CDR score. The levels of both A(beta)x-40 and A(beta)x-42 were elevated even in cases classified as having questionable dementia (CDR score = 0.5), and increases of both peptides correlated with progression of dementia. Levels of the more fibril-prone A(beta)x-42 peptide were higher than those of A(beta)x-40 in nondemented cases and remained higher throughout progression of disease in all regions examined. Finally, increases in A(beta)x-40 and A(beta)x-42 precede significant tau pathology at least in the frontal cortex, an area chosen for examination because of the absence of neuritic changes in the absence of disease. In this study, levels of total A(beta)x-40 and A(beta)x-42 were elevated early in dementia and levels of both peptides were strongly correlated with cognitive decline. Of particular interest, in the frontal cortex, Abeta was elevated before the occurrence of significant tau pathology. These results support an important role for Abeta in mediating initial pathogenic events in AD dementia and suggest that treatment strategies targeting the formation, accumulation, or cytotoxic effects of Abeta should be pursued.
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                Author and article information

                Contributors
                Department of Psychiatry, Mount Sinai School of Medicine, Mount Sinai Hospital, Mount Sinai Medical Center; New York, NY, USA
                Department of Psychiatry, Mount Sinai School of Medicine, Mount Sinai Hospital, Mount Sinai Medical Center; New York, NY, USA
                Journal
                Dialogues Clin Neurosci
                Dialogues Clin Neurosci
                Dialogues in Clinical Neuroscience
                Les Laboratoires Servier (France )
                1294-8322
                1958-5969
                June 2000
                June 2000
                : 2
                : 2
                : 91-100
                Affiliations
                Department of Psychiatry, Mount Sinai School of Medicine, Mount Sinai Hospital, Mount Sinai Medical Center; New York, NY, USA
                Department of Psychiatry, Mount Sinai School of Medicine, Mount Sinai Hospital, Mount Sinai Medical Center; New York, NY, USA
                Author notes
                Article
                10.1007/s11940-000-0023-0
                3181599
                22034442
                5a06fea5-46a5-4618-90de-836d39ea96b3
                Copyright: © 2000 LLS

                This is an open-access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Categories
                State of the Art

                Neurosciences
                estrogen replacement therapy,antioxidant,etiology,cholinesterase inhibitor,epidemiology,behavioral disturbance,anti-inflammatory agent,alzheimer's disease,apolipoprotein e4

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