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1.
Brain ; 122 ( Pt 4): 741-56, 1999 Apr.
Article de Anglais | MEDLINE | ID: mdl-10219785

RÉSUMÉ

We investigated three separate families (designated D, F and G) with frontotemporal dementia that have the same molecular mutation in exon 10 of the tau gene (P301L). The families share many clinical characteristics, including behavioural aberrations, defective executive functions, language deficits, relatively preserved constructional abilities and frontotemporal atrophy on imaging studies. However, Family D has an earlier mean age of onset and shorter duration of disease than Families F and G (49.0 and 5.1 years versus 61-64 and 7.3-8.0 years, respectively). Two members of Families D and F had neuropathological studies demonstrating lobar atrophy, but the brain from Family D had prominent and diffuse circular, intraneuronal, neurofibrillary tangles not seen in Family F. The brain from Family F had ballooned neurons typical of Pick's disease type B not found in Family D. A second autopsy from Family D showed neurofibrillary tangles in the brainstem with a distribution similar to that found in progressive supranuclear palsy. These three families demonstrate that a missense mutation in the exon 10 microtubule-binding domain of the tau protein gene can produce severe behavioural abnormalities with frontotemporal lobar atrophy and microscopic tau pathology. However, the findings in these families also emphasize that additional unidentified environmental and/or genetic factors must be producing important phenotypic variability on the background of an identical mutation. Apolipoprotein E genotype does not appear to be such a factor influencing age of onset in this disease.


Sujet(s)
Démence/génétique , Lobe frontal/anatomopathologie , Mutation ponctuelle , Lobe temporal/anatomopathologie , Protéines tau/génétique , Âge de début , Apolipoprotéines E/génétique , Atrophie , Analyse de mutations d'ADN , Démence/diagnostic , Démence/anatomopathologie , Exons , Santé de la famille , Femelle , Génotype , Hippocampe/anatomopathologie , Humains , Imagerie par résonance magnétique , Mâle , Questionnaire sur l'état mental de Kahn , Microscopie électronique , Adulte d'âge moyen , Enchevêtrements neurofibrillaires/anatomopathologie , Enchevêtrements neurofibrillaires/ultrastructure , Neurones/anatomopathologie , Neurones/ultrastructure , Tests neuropsychologiques , Pedigree , Phénotype
2.
Ann Neurol ; 40(6): 932-6, 1996 Dec.
Article de Anglais | MEDLINE | ID: mdl-9007102

RÉSUMÉ

Mutations in three different genes on chromosomes 1, 14, and 21 cause autosomal dominant forms of familial Alzheimer's disease (FAD). Most result in an early-onset phenotype. However, several kindreds of Volga German ancestry have the same chromosome 1 gene mutation and demonstrate a relatively older mean age of onset and include individuals with late age of onset. In these families, the mean age of onset is 54.9 +/- 8.4 years (range, 40-75 years), mean age at death is 65.9 +/- 10.2 years (range, 43-88 years), and mean disease duration is 11.3 +/- 4.6 years (range, 5-23 years). This contrasts with a group of 7 families with chromosome 14 mutations in which the mean age of onset is 44.8 +/- 4.8 years (range, 30-55 years), mean age at death is 52.6 +/- 5.7 years (range, 39-65 years), and mean disease duration is 7.6 +/- 3.2 years (range, 2-17 years). (All means are significantly different in the 2 groups of families, p < 0.005.) In the chromosome 1 families, 7 persons (16%) had an age of onset at or older than 65 years and 22 (54%) survived to age 65 or older versus none in the chromosome 14 families. An example of probable nonpenetrance of disease at age 89 was also found in a chromosome 1 kindred. It is concluded that, unlike the chromosome 14 gene, mutations in the chromosome 1 FAD gene may result in individuals with a late age of onset overlapping with the more common sporadic form of the disease occurring in the general population. In light of the great variability in age of onset in persons with identical mutations, study of the genetic and environmental factors contributing to delayed onset of disease in chromosomal 1 FAD kindreds will be an important area for further investigation. Apolipoprotein E genotype may be one such factor that plays a partial role in this variability.


Sujet(s)
Maladie d'Alzheimer/génétique , Chromosomes humains de la paire 1 , Adulte , Facteurs âges , Sujet âgé , Maladie d'Alzheimer/ethnologie , Apolipoprotéines E/génétique , Chromosomes humains de la paire 14 , Chromosomes humains de la paire 21 , Ethnies , Femelle , Humains , Mâle , Adulte d'âge moyen , Mutation
3.
Ann Neurol ; 36(3): 368-78, 1994 Sep.
Article de Anglais | MEDLINE | ID: mdl-8080245

RÉSUMÉ

We report the clinical and neuropathological features of chromosome 14-linked familial Alzheimer's disease (14qFAD) in affected members of the L family. Some clinical information on all 16 known affected individuals and detailed neuropathological findings in 6 family members were available for review. Common features of the phenotype of 14qFAD in the L family included onset of dementia before the age of 50, early progressive aphasia, early-appearing myoclonus and generalized seizures, paratonia, cortical atrophy, numerous and extensive senile plaques and neurofibrillary tangles, and prominent amyloid angiopathy. Descriptions of phenotypic features were available for six additional recently defined 14q-linked FAD kindreds: the findings in four of them (FAD4, FAD2, A, B) indicated a relatively consistently shared 14qFAD phenotype, conforming closely with the specific clinical and neuropathological characteristics noted in the L family. Comparisons also suggested several ostensible phenotypic variants in 14qFAD: (1) In two 14q-linked kindreds (SNW/FAD3, FAD1), affected individuals in some instances were noted to survive to age 70 or beyond and the mean age at onset (> 49 years) in these two kindreds was somewhat higher than in their five 14qFAD counterparts (< 48 years in each); (2) in the SNW/FAD3 kindred, seizures and myoclonus were absent in all 10 subjects examined; and (3) cerebellar amyloid plaques were variably present within and among several 14qFAD kindreds. Comparisons with phenotypic features recently detailed in three kindreds (TOR3, F19, ROM) with codon 717 amyloid precursor protein gene mutations (i.e., APP717 FAD) suggested several distinctions: Prominent progressive aphasia, myoclonus, seizures, and paratonia were all apparently less prevalent in APP717 FAD, with language function predominantly spared over the initial disease course. The extent of homogeneity and heterogeneity in the clinical and neuropathological phenotype of 14q-linked FAD and its possible meaningful distinctions from the phenotypes of APP717 FAD await further determination.


Sujet(s)
Maladie d'Alzheimer/génétique , Chromosomes humains de la paire 14 , Liaison génétique , Adulte , Maladie d'Alzheimer/anatomopathologie , Maladie d'Alzheimer/physiopathologie , Encéphale/anatomopathologie , Femelle , Humains , Mâle , Adulte d'âge moyen , Pedigree , Phénotype , Études rétrospectives
4.
Alzheimer Dis Assoc Disord ; 7(2): 88-97, 1993.
Article de Anglais | MEDLINE | ID: mdl-8347332

RÉSUMÉ

Recent reports suggest that cultivated nonneuronal cells from individuals with Alzheimer disease (AD) and other specific hereditary neurodegenerative disorders show hypersensitivity to DNA-damaging agents such as x-rays and radiomimetic chemicals. The hypothesis proposed is that a number of chronic neurologic degenerations, including AD, may be the result of accumulation of damaged DNA, resulting from a defect in DNA repair. We investigated this hypothesis by evaluating cells from individuals from pedigrees of familial Alzheimer disease (FAD) for hypersensitivity to x-irradiation. Sensitivity was assayed by viability measured by trypan blue dye exclusion and micronucleus formation. We tested B-lymphoblastoid cell lines from nine patients and nine unaffected family members from pedigrees with FAD, three unrelated controls, three ataxia telangiectasia (AT) patients, and three Down syndrome individuals. The AT cell lines showed the expected reduced viability and increased micronucleus formation after x-ray treatment. The FAD and control lines showed marked heterogeneity with both assays. There was no significant differences between the FAD patients and controls. The wide variability in the response of cell lines from controls and patients indicates the need for more sensitive assays for detection of radiation sensitivity in cells from various neurologic disorders.


Sujet(s)
Maladie d'Alzheimer/génétique , Survie cellulaire/effets des radiations , Altération de l'ADN/génétique , Sujet âgé , Maladie d'Alzheimer/anatomopathologie , Lignée de cellules transformées , Survie cellulaire/génétique , Relation dose-effet des rayonnements , Humains , Tests de micronucleus , Phénotype
5.
Neurology ; 40(9): 1364-9, 1990 Sep.
Article de Anglais | MEDLINE | ID: mdl-2392219

RÉSUMÉ

To examine the validity of criteria-based (clinical) diagnosis of Alzheimer's disease (AD), 4 physicians experienced in the evaluation of dementia patients applied 3 sets of diagnostic criteria to each of 62 patients based on standardized medical record information. Diagnostic outcome was validated by neuropathologic examination (completed previously) for all (43) demented patients and 4 nondemented patients and by follow-up in the remainder (15) with no dementia. Raters were blind to the composition of the study group as well as to the clinical and pathologic diagnoses. We evaluated 3 diagnostic criteria sets for AD: the American Psychiatric Association diagnostic criteria from the Diagnostic and Statistical Manual (DSM-III), the NINCDS-ADRDA Work Group criteria for the diagnosis of Alzheimer's disease (NINCDS), and the Eisdorfer and Cohen research diagnostic criteria for primary neuronal degeneration (ECRDC). ECRDC had the highest specificity (0.88) but also the greatest odds of false-negative diagnosis (LRneg = 0.61, sensitivity = 0.46). NINCDS had the best sensitivity (0.92, specificity = 0.65), and DSM-III showed intermediate values (sensitivity = 0.76, specificity = 0.80). We conclude that the investigator or clinician who wishes to ensure that patients classified as AD are more likely to be AD should choose DSM-III, whereas the investigator who wishes to include the greatest number of AD cases, seldom assigning a diagnosis of no AD to a true case, should choose NINCDS.


Sujet(s)
Maladie d'Alzheimer/diagnostic , Sujet âgé , Sujet âgé de 80 ans ou plus , Maladie d'Alzheimer/anatomopathologie , Autopsie , Études d'évaluation comme sujet , Femelle , Humains , Mâle , Valeur prédictive des tests
6.
Am J Psychiatry ; 147(2): 168-72, 1990 Feb.
Article de Anglais | MEDLINE | ID: mdl-2301654

RÉSUMÉ

To assess prospectively the accuracy of standard antemortem clinical diagnostic criteria for Alzheimer's disease, post-mortem examinations were performed on 25 patients who had met DSM-III criteria for primary degenerative dementia and National Institute of Neurological and Communicative Disorders and Stroke criteria for probable Alzheimer's disease. Seventeen patients (68%) met neuropathological criteria for Alzheimer's disease. Two presenile-onset patients had diffuse neocortical senile plaques of insufficient number for definite Alzheimer's disease. Six patients had non-Alzheimer's disease diagnoses. Five of these six had presenile-onset dementia. These results suggest caution in the antemortem diagnosis of Alzheimer's disease in presenile-onset dementia.


Sujet(s)
Maladie d'Alzheimer/diagnostic , Encéphale/anatomopathologie , Sujet âgé , Sujet âgé de 80 ans ou plus , Maladie d'Alzheimer/anatomopathologie , Démence/diagnostic , Diagnostic différentiel , Hippocampe/anatomopathologie , Humains , Adulte d'âge moyen , Neurofibrilles/anatomopathologie
7.
Neurology ; 40(2): 257-60, 1990 Feb.
Article de Anglais | MEDLINE | ID: mdl-2300244

RÉSUMÉ

To determine interrater reliability of dementia diagnosis, 4 physicians experienced in the evaluation of dementia patients applied 3 sets of diagnostic criteria to each of 62 patients, based on a standardized set of medical record information. All patients had undergone similar examinations and follow-up to establish the initial clinical diagnosis (76% had autopsy). Raters were blind to the diagnosis and to follow-up information after the initial evaluation period. This paper presents interrater agreement (kappa values) for a diagnosis of Alzheimer's disease using the American Psychiatric Association diagnostic criteria from the Diagnostic and Statistical Manual (DSM-III), the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) criteria for the clinical diagnosis of Alzheimer's disease, and the Eisdorfer and Cohen Research Diagnostic Criteria (ECRDC) for primary neuronal degeneration. The NINCDS showed somewhat higher average interrater reliability (kappa = 0.64) than the DSM-III (kappa = 0.55) and considerably higher interrater reliability than the ECRDC (kappa = 0.37). One rater displayed conspicuously lower levels of interrater reliability than the other 3, especially in DSM-III and ECRDC. This study indicates that interrater reliability of DSM-III and NINCDS criteria are comparable. Documentation of interrater reliability and, if necessary, training to improve reliability is an important consideration in research where different observers are diagnosing dementing illnesses.


Sujet(s)
Maladie d'Alzheimer/diagnostic , Sujet âgé , Sujet âgé de 80 ans ou plus , Maladie d'Alzheimer/épidémiologie , Cognition , Femelle , Humains , Mâle , Mémoire , Tests neuropsychologiques , Biais de l'observateur
8.
Alzheimer Dis Assoc Disord ; 4(4): 217-25, 1990.
Article de Anglais | MEDLINE | ID: mdl-2264979

RÉSUMÉ

Twenty-eight patients with the clinical diagnosis of probable Alzheimer disease (AD) were followed longitudinally until death. The presence of myoclonus, seizures, and paratonia was monitored as part of this process. At autopsy, 22 of the patients met pathologic criteria for AD and 6 had other degenerative neurologic diseases. Myoclonus was present in 55% of the AD patients and none of the non-AD patients. Seizures were present in 64% of the AD patients, and only 17% of the non-AD patients. Paratonia was found frequently in all patient groups. In most patients, symptoms developed late in the course of their illness. The incidence of myoclonus, seizures, and paratonia in our patients was higher than in most previous studies. The reasons for this finding are discussed.


Sujet(s)
Maladie d'Alzheimer/diagnostic , Dystonie/diagnostic , Myoclonie/diagnostic , Crises épileptiques/diagnostic , Adulte , Facteurs âges , Sujet âgé , Maladie d'Alzheimer/complications , Dystonie/complications , Dystonie/épidémiologie , Études de suivi , Humains , Mâle , Adulte d'âge moyen , Contraction musculaire , Tonus musculaire , Myoclonie/complications , Myoclonie/épidémiologie , Prévalence , Crises épileptiques/complications , Crises épileptiques/épidémiologie
9.
Arch Gen Psychiatry ; 46(6): 535-40, 1989 Jun.
Article de Anglais | MEDLINE | ID: mdl-2525015

RÉSUMÉ

To assess central nervous system cholinergic neuroendocrine regulation in Alzheimer's disease (AD), we measured plasma arginine vasopressin, beta-endorphin, and epinephrine responses to a cholinergic challenge elicited by intravenous administration of the acetylcholinesterase inhibitor physostigmine (0.0125 mg/kg) in male patients with AD (n = 12) and compared their responses with those of age-matched normal control subjects (n = 12). Physostigmine promptly increased plasma arginine vasopressin (tenfold), beta-endorphin (twofold to threefold) and epinephrine (threefold) levels in elderly control subjects. In contrast, patients with AD showed attenuated responses to physostigmine. When controls and patients with AD who experienced nausea (n = 2 and n = 6, respectively) were excluded, the arginine vasopressin, beta-endorphin, and epinephrine responses of patients with AD were significantly less than those of control subjects. These data suggest that the central nervous system cholinergic deterioration of AD results in decreased responsiveness of neuroendocrine systems that are regulated by central cholinergic mechanisms.


Sujet(s)
Maladie d'Alzheimer/sang , Arginine vasopressine/sang , Épinéphrine/sang , Physostigmine/pharmacologie , bêta-Endorphine/sang , Sujet âgé , Maladie d'Alzheimer/physiopathologie , Pression sanguine/effets des médicaments et des substances chimiques , Encéphale/effets des médicaments et des substances chimiques , Encéphale/physiopathologie , Humains , Perfusions veineuses , Mâle , Système nerveux parasympathique/effets des médicaments et des substances chimiques , Système nerveux parasympathique/physiopathologie , Physostigmine/administration et posologie
10.
Mol Endocrinol ; 3(4): 605-10, 1989 Apr.
Article de Anglais | MEDLINE | ID: mdl-2471071

RÉSUMÉ

The hypothalamic peptide hormone TRH is also found in other tissues, including the thyroid. While TRH may be regulated by T3 in the hypothalamus, other regulators of TRH have not been identified and the regulation of TRH in nonhypothalamic tissues is unknown. We recently demonstrated the biosynthesis of TRH in the CA77 neoplastic thyroidal C cell line. We studied the regulation of TRH by dexamethasone in this cell line because glucocorticoids have been postulated to inhibit TSH secretion by decreasing TRH in the hypothalamus. Furthermore, TRH in the thyroid inhibits thyroid hormone release. Thus by regulating thyroidal TRH, glucocorticoids could also directly affect thyroid hormone secretion. Treatment of CA77 cells for 4 days with dexamethasone produced dose-dependent increases in both TRH mRNA and cellular and secreted TRH. Increases in TRH mRNA and peptide levels could be seen with 10(-9) M dexamethasone. A 4.8-fold increase in TRH mRNA and a 4-fold increase in secreted peptide were seen with 10(-7) M dexamethasone. Dexamethasone treatment did not increase beta-actin mRNA levels or cell growth. These results suggest that glucocorticoids may be physiological regulators of TRH in normal C cells. In addition to their inhibitory effects on TSH, glucocorticoids may decrease thyroid hormone levels by increasing thyroidal TRH. Since the glucocorticoid effects on C cell TRH are the converse of what is expected for hypothalamic TRH, glucocorticoid effects in these two tissues may be mediated by different regulators.


Sujet(s)
Dexaméthasone/pharmacologie , Hormone de libération de la thyréostimuline/biosynthèse , Actines/génétique , Animaux , Technique de Northern , Calcitonine/analyse , Régulation de l'expression des gènes , ARN/analyse , ARN/isolement et purification , ARN messager/analyse , Rats , Cellules cancéreuses en culture/effets des médicaments et des substances chimiques , Cellules cancéreuses en culture/métabolisme
11.
Psychoneuroendocrinology ; 14(4): 311-20, 1989.
Article de Anglais | MEDLINE | ID: mdl-2510210

RÉSUMÉ

Changes in blood pressure (BP), plasma norepinephrine (NE), serum prolactin (PRL), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) associated with infusions of two thyrotropin-releasing hormone (TRH) doses (0.1 mg, 0.5 mg) were examined in 10 men with early-onset Alzheimer's disease (AD) and nine normal matched controls. During the first 5 min after TRH infusion, significant increases from baseline in systolic BP (p less than 0.001), diastolic BP (p less than 0.001), and plasma NE (p less than 0.006) occurred in the study subjects. The magnitude of the BP and NE responses did not differ significantly as a function of TRH dose (p greater than 0.3). Diastolic pressor responses to TRH were substantially blunted in AD subjects relative to controls, after both the 0.1-mg (p less than 0.003) and 0.5-mg (p less than 0.02) doses. There were trends toward attenuated responses in the AD subjects for systolic BP (p less than 0.09) and plasma NE (p less than 0.07). Significant increments in serum PRL, LH, and FSH (all p less than 0.001) also occurred after TRH, but the magnitude of the hormone responses did not differ significantly between the AD and the normal subjects (p greater than 0.18). These results suggest the possibility that TRH-evoked activation of the sympathetic nervous system (SNS), as reflected by pressor and plasma NE responses, may be attenuated in men with early-onset AD.


Sujet(s)
Maladie d'Alzheimer/physiopathologie , Pression sanguine/effets des médicaments et des substances chimiques , Norépinéphrine/sang , Hypophyse/physiologie , Hormone de libération de la thyréostimuline/administration et posologie , Sujet âgé , Maladie d'Alzheimer/métabolisme , Hormone folliculostimulante/sang , Humains , Perfusions veineuses , Hormone lutéinisante/sang , Mâle , Adulte d'âge moyen , Hypophyse/métabolisme , Hypophyse/physiopathologie , Prolactine/sang , Valeurs de référence , Système nerveux sympathique/métabolisme , Système nerveux sympathique/physiologie , Système nerveux sympathique/physiopathologie , Hormone de libération de la thyréostimuline/pharmacologie
12.
Prog Clin Biol Res ; 317: 229-34, 1989.
Article de Anglais | MEDLINE | ID: mdl-2602419

RÉSUMÉ

We report the clinical and neuropathological manifestations of Alzheimer's disease (AD) in nine kindreds of German ancestry all originating from the same two adjacent villages on the West bank of the Volga River. There have been 89 known demented persons (53 male, 36 female). Mean age of onset is 57.6 +/- 8.4 years with a range of 40 to 84. Mean age at death is 66.5 +/- 7.6 years with a range of 50 to 80. Mean disease duration is 10.3 +/- 4.8 years with a range of 3 to 23. Detailed medical records were available on 50 individuals. Of these, 24% had a seizure, 72% language disturbance, 36% rigidity, 16% tremor and 12% myoclonus. There were 15 autopsies on demented persons from 6 of the kindreds. One brain suggested Creutzfeldt-Jakob disease (CJD) in a woman with the typical clinical course. The remaining 14 brains showed typical neuropathological characteristics of AD including neuritic amyloid plaques, neurofibrillary tangles, amyloid angiopathy and granulovacuolar change. Amyloid plaques were also seen in the cerebellum in all but one brain in which this region was available for review. Autopsy material from five brains in four families has been stained with antibody directed against the amyloid peptide; in all cases, the neuritic plaques stained positively. Many of the families share common surnames. It is likely that these Volga German kindreds carry the same genetic mutation leading to Alzheimer's disease; and thus, they are a valuable resource for genetic investigations of AD. Thus far, the disease in these kindreds does not show close linkage to either the D21S1 or beta amyloid gene loci on chromosome 21.


Sujet(s)
Maladie d'Alzheimer/génétique , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Maladie d'Alzheimer/ethnologie , Maladie d'Alzheimer/anatomopathologie , Femelle , Allemagne , Humains , Mâle , Adulte d'âge moyen
13.
Ann Neurol ; 25(1): 12-25, 1989 Jan.
Article de Anglais | MEDLINE | ID: mdl-2913924

RÉSUMÉ

We report the clinical and neuropathological characteristics occurring in 180 demented individuals from 24 kindreds with familial Alzheimer's disease (FAD). Each family had at least two affected generations, and at least one autopsy or brain biopsy was compatible with the diagnosis of AD. Forty-nine neuropathological specimens or reports were reviewed. Mean age of onset for the total group was 54.7 years +/- 11.5, with a large range of 30 to 84 years. Mean age at death was 63.5 years +/- 12.2, with a range of 46 to 85. Mean duration of disease was 8.8 years +/- 4.4, with a range of 1 to 23 years. Six findings suggested phenotypic heterogeneity in FAD. (1) Five families represented an early age of onset group with mean onset at 42 years (range 30 to 51 years) and mean disease duration of 6.7 years. (2) Eight families represented a late onset group with mean onset at 68 years (range 59 to 78 years) and a mean duration of 8.5 years. (3) Seven families were of Volga German ancestry, all originating from the same two villages in Russia. Mean age of onset was 55.9 years (range 40 to 72 years), with a mean disease duration of 10 years. This group probably represents the genetic founder effect of an autosomal dominant gene for AD. (4) One family had the unusual characteristics of neurofibrillary tangles and granulovacuolar change but no amyloid plaques, a mean disease duration of more than 11 years, and a "schizophrenia-like" onset. (5) One family with late onset also had clinical and pathological evidence for anterior horn cell disease. (6) Two autopsies in 1 family both showed remarkable rarefaction of myelin and expansion of perivascular spaces in centrum semiovale (état criblé), with marked leptomeningeal and cortical amyloid angiopathy, distinct from the other FAD brains. It remains to be determined whether the clinical and pathological differences between these families represent genetic heterogeneity at the biochemical or molecular level.


Sujet(s)
Maladie d'Alzheimer/génétique , Adulte , Sujet âgé , Maladie d'Alzheimer/anatomopathologie , Encéphale/anatomopathologie , Femelle , Humains , Mâle , Adulte d'âge moyen , Neurofibrilles/anatomopathologie , Pedigree , Phénotype
14.
Science ; 241(4872): 1507-10, 1988 Sep 16.
Article de Anglais | MEDLINE | ID: mdl-3420406

RÉSUMÉ

Alzheimer's disease is the most common form of dementia among the elderly population. Although the etiology is unknown, inheritance plays a role in the pathogenesis of the disease. Recent work indicates that an autosomal dominant gene for Alzheimer's disease is located on chromosome 21 at band q21. In the present study of a group of autopsy-documented kindreds, no evidence for linkage was found between familial Alzheimer's disease (FAD) and chromosome 21q21 markers (D21S1/D21S72 and the amyloid beta gene). Linkage to the D21S1/D21S72 locus was excluded at recombination fractions (theta) up to 0.17. Linkage to the amyloid gene was excluded at theta = 0.10. Apparent recombinants were noted in two families for the amyloid gene and in five families for the D21S1/D21S72 locus. These data indicate that FAD is genetically heterogeneous.


Sujet(s)
Maladie d'Alzheimer/génétique , Chromosomes humains de la paire 21 , Cartographie chromosomique , Liaison génétique , Humains
15.
Psychoneuroendocrinology ; 13(3): 245-54, 1988.
Article de Anglais | MEDLINE | ID: mdl-3136487

RÉSUMÉ

TSH responses to two TRH doses (0.1 mg, 0.5 mg) were determined in 10 men with Alzheimer's disease (AD) and in nine healthy matched controls. Maximum change in TSH (delta TSH) and TSH responses over time, analyzed independently for each TRH dose, did not reveal any significant differences between the AD and the normal subjects. Blunted delta TSH responses were an uncommon finding in both groups. Analyses examining the influence of TRH dose on TSH responses revealed significant group differences. In normal subjects, delta TSH responses following the 0.5 mg TRH dose were significantly greater than delta TSH responses following the 0.1 mg TRH dose (p less than 0.01). However, in the AD group, the effects of TRH dose on delta TSH were largely attributable to the exaggerated and outlying TSH responses of one AD subject. For the remaining nine AD subjects, delta TSH responses following the 0.1 mg and 0.5 mg TRH doses were not significantly different (p greater than 0.1). In the analysis of TSH responses over time, the difference between the 0.1 mg and the 0.5 mg TRH-induced TSH responses was significantly smaller in the AD group at several timepoints after infusion compared to the normal subjects.


Sujet(s)
Maladie d'Alzheimer/sang , Hormone de libération de la thyréostimuline , Thyréostimuline/sang , Sujet âgé , Maladie d'Alzheimer/psychologie , Relation dose-effet des médicaments , Humains , Mâle , Questionnaire sur l'état mental de Kahn
16.
Ann Neurol ; 23(1): 25-31, 1988 Jan.
Article de Anglais | MEDLINE | ID: mdl-3345066

RÉSUMÉ

Five families are described in which autopsy-confirmed presenile Alzheimer's disease (AD) has occurred in men and women over multiple generations consistent with autosomal dominant inheritance. All 5 families are descendants of a group of immigrants known as the Volga Germans who came to the United States between 1870 and 1920. Their ancestors moved from Germany to the southern Volga region of Russia in the 1760s. All 5 American families are descendants of persons originally living in two small adjacent Volga German villages and share several surnames known to have been present in the census records of those villages. Although a single affected common ancestor cannot be identified, it is likely that the AD in these families represents an autosomal dominant gene inherited from one ancestor (the founder effect). This information is of importance in the genetic study of AD in these families because it greatly increases the probability of genetic homogeneity. There are more than 300,000 American descendants of the Volga Germans, and the prevalence of AD has never been studied in this population.


Sujet(s)
Maladie d'Alzheimer/génétique , Adulte , Sujet âgé , Maladie d'Alzheimer/ethnologie , Maladie d'Alzheimer/physiopathologie , Femelle , Allemagne/ethnologie , Humains , Nourrisson , Mâle , Adulte d'âge moyen , Pedigree , Russie (avant 1917) , Facteurs temps , États-Unis
17.
Biol Psychiatry ; 22(10): 1264-70, 1987 Oct.
Article de Anglais | MEDLINE | ID: mdl-3663778

RÉSUMÉ

Laboratory tests used for the differential diagnosis of Cushing's syndrome have infrequently been employed in investigations of psychiatric patients who demonstrate hypothalamic-pituitary-adrenal (HPA) overactivity, and these laboratory procedures have not previously been applied for the specific purpose of further evaluating the endocrine function of psychiatric patients with serum cortisol nonsuppression following the standard 1-mg overnight Dexamethasone Suppression Test (DST). Low-dose (4 mg/48 hr) and high-dose (16 mg/48 hr) DSTs were administered to 10 psychiatric patients who exhibited cortisol nonsuppression after the overnight DST. Patients all had normal suppression to both the low-dose and high-dose tests. HPA overactivity in these patients was thus not sufficient to meet laboratory criteria for the diagnosis of Cushing's syndrome. Study results suggest that psychiatric patients with abnormal cortisol suppression following the 1-mg overnight DST are likely to have normal responses when assessed by standard laboratory protocols used for the diagnosis of Cushing's syndrome.


Sujet(s)
Syndrome de Cushing/diagnostic , Trouble dépressif/diagnostic , Dexaméthasone , Hydrocortisone/sang , Hypercorticisme/diagnostic , Adulte , Sujet âgé , Syndrome de Cushing/psychologie , Trouble dépressif/sang , Dexaméthasone/administration et posologie , Diagnostic différentiel , Femelle , Humains , Axe hypothalamohypophysaire/physiopathologie , Mâle , Adulte d'âge moyen
18.
J Clin Psychiatry ; 48(5): 207-8, 1987 May.
Article de Anglais | MEDLINE | ID: mdl-2883174

RÉSUMÉ

Two agitated patients with Alzheimer's disease who either failed to respond or worsened with conventional low-dose neuroleptic and other pharmacologic treatment are described. Both patients demonstrated sustained improvement with very low-dose neuroleptics, one with haloperidol 0.125 mg and the other with thioridazine 5 mg. Clinical, pharmacokinetic, and pharmacodynamic factors that may have accounted for this response are discussed.


Sujet(s)
Maladie d'Alzheimer/traitement médicamenteux , Halopéridol/administration et posologie , Agitation psychomotrice/traitement médicamenteux , Thioridazine/administration et posologie , Sujet âgé , Sujet âgé de 80 ans ou plus , Maladie d'Alzheimer/complications , Maladie d'Alzheimer/psychologie , Neuroleptiques/administration et posologie , Neuroleptiques/effets indésirables , Humains , Mâle , Adulte d'âge moyen , Agitation psychomotrice/complications , Agitation psychomotrice/psychologie
19.
J Clin Psychiatry ; 48 Suppl: 16-8, 1987 May.
Article de Anglais | MEDLINE | ID: mdl-2883175

RÉSUMÉ

Introduced in the 1950s, antipsychotic agents have been found to improve symptomatology and function in young and middle-aged psychotic schizophrenics. Three decades of research, however, have not made clear these agents' usefulness in demented elderly patients. A review of placebo-controlled studies suggests a definite but limited role for antipsychotic medication in behaviorally disturbed elderly dementia patients with agitated behavior. Studies also suggest that cognitive function needs careful monitoring when these drugs are prescribed to treat behavioral symptoms of dementia.


Sujet(s)
Neuroleptiques/usage thérapeutique , Démence/traitement médicamenteux , Sujet âgé , Maladie d'Alzheimer/traitement médicamenteux , Maladie d'Alzheimer/psychologie , Neuroleptiques/effets indésirables , Essais cliniques comme sujet , Troubles de la cognition/induit chimiquement , Démence/psychologie , Femelle , Humains , Mâle , Récidive , Thioridazine/effets indésirables , Thioridazine/usage thérapeutique
20.
J Neurogenet ; 4(2-3): 97-108, 1987 Apr.
Article de Anglais | MEDLINE | ID: mdl-2885403

RÉSUMÉ

In order to identify the genetic locus responsible for familial dementia of the Alzheimer type (DAT), we are studying 10 families in which DAT appears to be inherited as an autosomal dominant trait. Genotypes for a TaqI restriction fragment length polymorphism (RFLP) at the apolipoprotein CII locus were determined for the following groups: affected and unaffected DAT family members, DAT subjects with no family history of the disease, and normal control subjects. The control group included 103 individuals from our study and 123 from the study of Wallis et al. (Hum. Genet., 68 (1984) 286). The frequency of the TaqI fast (F) allele in the affected familial DAT subjects (0.64 +/- 0.08) differed significantly from that for the control group (0.39 +/- 0.02) (Z = 2.87, P less than 0.005). In contrast, the F-allele frequency for the unaffected family members was 0.31 +/- 0.09, which was similar to that of the combined control group (Z = 0.78, P greater than 0.40). Subsequently, genotypes were determined for two other polymorphisms at the Apo CII locus: a BanI RFLP and a BglI RFLP. For these two polymorphisms, the allele frequencies for the familial DAT subjects differed from the unaffected control groups but the differences were smaller and not statistically significant. These data suggest a previously unrecognized association between the Apo CII TaqI F-allele and familial DAT.


Sujet(s)
Allèles , Maladie d'Alzheimer/génétique , Apolipoprotéines C/génétique , Sujet âgé , Sujet âgé de 80 ans ou plus , Apolipoprotéine C-III , Femelle , Humains , Mâle , Adulte d'âge moyen , Pedigree , Polymorphisme de restriction
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