RESUMO
Psychosis in Alzheimer Disease (AD) represents a distinct clinicopathologic variant associated with increased cognitive and functional morbidity and an accelerated disease course. To date, extant treatments offer modest benefits with significant risks. The development of new pharmacologic treatments for psychosis in AD would be facilitated by validated preclinical models with which to test candidate interventions. The current review provides a brief summary of the process of validating animal models of human disease together with a critical analysis of the challenges posed in attempting to apply those standards to AD-related behavioral models. An overview of phenotypic analogues of human cognitive and behavioral impairments, with an emphasis on those relevant to psychosis, in AD-related mouse models is provided, followed by an update on recent progress in efforts to translate findings in the pathophysiology of psychotic AD into novel models. Finally, some future directions are suggested to expand the catalogue of psychosis-relevant phenotypes that may provide a sturdier framework for model development and targets for preclinical treatment outcomes.
Assuntos
Doença de Alzheimer , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Transtornos Psicóticos , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Transtornos Psicóticos/etiologia , Transtornos Psicóticos/genética , Transtornos Psicóticos/metabolismo , Transtornos Psicóticos/fisiopatologiaRESUMO
Psychosis occurs in approximately half of patients with Alzheimer disease (AD with psychosis, AD+P). AD+P patients have more rapid cognitive decline, greater behavioral symptoms, and higher mortality than do AD patients without psychosis. Studies in three independent cohorts have shown that psychosis in AD aggregates in families, with estimated heritability of 29.5 - 60.8%. These findings have motivated studies to investigate and uncover the genes responsible for the development of psychosis, with the ultimate goal of identifying potential biologic mechanisms that may serve as leads to specific therapies. Linkage analyses have implicated loci on chromosomes 2, 6, 7, 8, 15, and 21 with AD+P. Association studies of APOE do not support it as a risk gene for psychosis in AD. No other candidate genes, such as neurodegenerative and monoamine genes, show conclusive evidence of association with AD+P. However, a recent genome-side association study has produced some promising leads, including among them genes that have been associated with schizophrenia. This review summarizes the current knowledge of the genetic basis of AD+P.
RESUMO
IMPORTANCE: Late-onset Alzheimer disease (LOAD), defined as onset of symptoms after age 65 years, is the most common form of dementia. Few reports investigate incidence rates in large family-based studies in which the participants were selected for family history of LOAD. OBJECTIVE: To determine the incidence rates of dementia and LOAD in unaffected members in the National Institute on Aging Genetics Initiative for Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease (NIA-LOAD/NCRAD) and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) family studies. DESIGN, SETTING, AND PARTICIPANTS: Families with 2 or more affected siblings who had a clinical or pathological diagnosis of LOAD were recruited as a part of the NIA-LOAD/NCRAD Family Study. A cohort of Caribbean Hispanics with familial LOAD was recruited in a different study at the Taub Institute for Research on Alzheimer's Disease and the Aging Brain in New York and from clinics in the Dominican Republic as part of the EFIGA study. MAIN OUTCOMES AND MEASURES: Age-specific incidence rates of LOAD were estimated in the unaffected family members in the NIA-LOAD/NCRAD and EFIGA data sets. We restricted analyses to families with follow-up and complete phenotype information, including 396 NIA-LOAD/NCRAD and 242 EFIGA families. Among the 943 at-risk family members in the NIA-LOAD/NCRAD families, 126 (13.4%) developed dementia, of whom 109 (86.5%) met criteria for LOAD. Among 683 at-risk family members in the EFIGA families, 174 (25.5%) developed dementia during the study period, of whom 145 (83.3%) had LOAD. RESULTS: The annual incidence rates of dementia and LOAD in the NIA-LOAD/NCRAD families per person-year were 0.03 and 0.03, respectively, in participants aged 65 to 74 years; 0.07 and 0.06, respectively, in those aged 75 to 84 years; and 0.08 and 0.07, respectively, in those 85 years or older. Incidence rates in the EFIGA families were slightly higher, at 0.03 and 0.02, 0.06 and 0.05, 0.10 and 0.08, and 0.10 and 0.07, respectively, in the same age groups. Contrasting these results with the population-based estimates, the incidence was increased by 3-fold for NIA-LOAD/NCRAD families (standardized incidence ratio, 3.44) and 2-fold among the EFIGA compared with the NIA-LOAD/NCRAD families (1.71). CONCLUSIONS AND RELEVANCE: The incidence rates for familial dementia and LOAD in the NIA-LOAD/NCRAD and EFIGA families are significantly higher than population-based estimates. The incidence rates in all groups increase with age. The higher incidence of LOAD can be explained by segregation of Alzheimer disease-related genes in these families or shared environmental risks.
Assuntos
Doença de Alzheimer/epidemiologia , Fatores Etários , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Apolipoproteína E4/genética , República Dominicana/epidemiologia , Feminino , Seguimentos , Predisposição Genética para Doença , Humanos , Incidência , Masculino , National Institute on Aging (U.S.) , New York/epidemiologia , Estados Unidos/epidemiologiaRESUMO
The authors prospectively examined elderly patients diagnosed with major depression with psychotic features (MD-P) and patients diagnosed with dementia of the Alzheimer Type (DAT) for neuroleptic-induced parkinsonism (NIP) during perphenazine treatment. Baseline parkinsonian symptoms did not differ between groups. With treatment, mean NIP score doubled in DAT patients but remained unchanged in the MD-P group. The difference between groups was highly significant and remained so after the effects of age, perphenazine dose, and duration of perphenazine treatment were controlled. Although the mechanisms underlying these differences in NIP development remain to be determined, clinical guidelines for neuroleptic dosages in elderly patients need to account for variability in neuroleptic tolerance between diagnostic groups.
RESUMO
To test the hypothesis that primary degenerative dementia of the Alzheimer type (PDD-AT) may increase the likelihood of expression of a lifetime vulnerability to the development of depression, the authors compared the premorbid rates of major depression in psychiatric inpatients with dementia, with or without a concurrent syndrome of depression. A premorbid history of major depression was four times more common in patients with the depressive syndrome of PDD-AT than in PDD-AT patients without depression. The authors discuss the significance of these findings for pathophysiologic models and estimates of comorbidity of depression in PDD-AT.
RESUMO
The authors distinguish demographic and clinical characteristics of elderly suicide attempters admitted to an inpatient psychiatric unit within 4 weeks of a suicide attempt. Of 560 patients admitted, 28 (5%) were recent attempters, 32 (6%) had a past history of suicide attempt, and 500 (89%) were nonattempters. Of the 28 recent attempters, 21 (75%) were diagnosed with a mood disorder, 4 (14%) with an organic mental disorder, and 3 (11%) with other mental disorders. Among the nonattempters, the distribution among the three diagnostic categories was 188 (38%), 251 (50%), and 61 (12%), respectively. Of 166 patients with a diagnosis of major depression, 18 (11%) were recent attempters, 14 (8%) were past attempters, and 134 (71%) were nonattempters. Recent attempts were significantly associated with alcohol abuse. This study confirms earlier reports of high rates of major depression in elderly attempters.