RESUMO
Recent evidence suggests that rare genetic variants within the TREM2 gene are associated with increased risk of Alzheimer's disease. TREM2 mutations are the genetic basis for a condition characterized by polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) and an early-onset dementia syndrome. TREM2 is important in the phagocytosis of apoptotic neuronal cells by microglia in the brain. Loss of function might lead to an impaired clearance and to accumulation of necrotic debris and subsequent neurodegeneration. In this study, we investigated a consanguineous family segregating autosomal recessive behavioral variant FTLD from Antioquia, Colombia. Exome sequencing identified a nonsense mutation in TREM2 (p.Trp198X) segregating with disease. Next, using a cohort of clinically characterized and neuropathologically verified sporadic AD cases and controls, we report replication of the AD risk association at rs75932628 within TREM2 and demonstrate that TREM2 is significantly overexpressed in the brain tissue from AD cases. These data suggest that a mutational burden in TREM2 may serve as a risk factor for neurodegenerative disease in general, and that potentially this class of TREM2 variant carriers with dementia should be considered as having a molecularly distinct form of neurodegenerative disease.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Comportamento/fisiologia , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/psicologia , Glicoproteínas de Membrana/genética , Mutação , Receptores Imunológicos/genética , Estudos de Coortes , Humanos , Glicoproteínas de Membrana/fisiologia , Receptores Imunológicos/fisiologia , Fatores de RiscoRESUMO
OBJECTIVE: To examine how phenotype affects longitudinal decline on the Mini-Mental State Examination (MMSE) in patients with frontotemporal lobar degeneration (FTLD) and Alzheimer disease (AD). BACKGROUND: The MMSE is the most commonly administered assessment for dementia severity; however, the effects of phenotype on longitudinal MMSE performance in FTLD and AD have not been extensively studied. METHODS: Data from 185 patients diagnosed with AD (n=106) and 3 FTLD (n=79) phenotypes [behavioral variant frontotemporal dementia (bvFTD), nonfluent agrammatic variant of primary progressive aphasia (nfaPPA), and semantic variant PPA (svPPA)] were collected for up to 52 months since initial evaluation. RESULTS: Differential rates of decline were noted in that MMSE scores declined more precipitously for AD and svPPA compared with bvFTD and nfaPPA patients (P=0.001). The absolute 4-year MMSE decline given median baseline MMSE for bvFTD [14.67; 95% confidence interval (CI), 14.63-14.71] and nfaPPA (11.02; 95% CI, 10.98-11.06) were lower than svPPA (22.32; 95% CI, 22.29-22.34) or AD (22.24; 95% CI, 22.22-22.26). CONCLUSIONS: These data suggest that within-group AD and FTLD phenotypes present distinct patterns of longitudinal decline on the MMSE. MMSE may not be adequately sensitive to track disease progression in some phenotypes of FTLD.
Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Escalas de Graduação Psiquiátrica Breve , Progressão da Doença , Degeneração Lobar Frontotemporal/diagnóstico , Degeneração Lobar Frontotemporal/psicologia , Idoso , Estudos de Coortes , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Método Simples-CegoRESUMO
BACKGROUND: Early progressive nonfluent aphasia (PNFA) may be difficult to differentiate from semantic dementia (SD) in a nonspecialist setting. There are descriptions of the clinical and neuropsychological profiles of patients with PNFA and SD but few systematic comparisons. METHOD: We compared the performance of groups with SD (n=27) and PNFA (n=16) with comparable ages, education, disease duration, and severity of dementia as measured by the Clinical Dementia Rating Scale on a comprehensive neuropsychological battery. Principal components analysis and intergroup comparisons were used. RESULTS: A 5-factor solution accounted for 78.4% of the total variance with good separation of neuropsychological variables. As expected, both groups were anomic with preserved visuospatial function and mental speed. Patients with SD had lower scores on comprehension-based semantic tests and better performance on verbal working memory and phonological processing tasks. The opposite pattern was found in the PNFA group. CONCLUSIONS: Neuropsychological tests that examine verbal and nonverbal semantic associations, verbal working memory, and phonological processing are the most helpful for distinguishing between PNFA and SD.
Assuntos
Doença de Alzheimer/diagnóstico , Degeneração Lobar Frontotemporal/diagnóstico , Degeneração Lobar Frontotemporal/psicologia , Afasia Primária Progressiva não Fluente/diagnóstico , Afasia Primária Progressiva não Fluente/psicologia , Idoso , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Transtornos Cognitivos/diagnóstico , Compreensão/fisiologia , Degeneração Lobar Frontotemporal/fisiopatologia , Humanos , Memória/fisiologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Afasia Primária Progressiva não Fluente/fisiopatologia , SemânticaRESUMO
Over a 100 years have passed since Pick's description of what is now termed frontotemporal lobar degeneration (FTLD). FTLD is a topic of intense current research interest yet some relevant contributions by non-English speaking authors have received little attention, which makes the history of FTLD research incomplete. In the hopes of filling some of the gaps in the history of FTLD research, the present article introduces fundamental work carried out in Argentina during the first half of the 20th century by Christfried Jakob and Braulio A. Moyano. Jakob's neurophilosophy, as well as his empirical descriptions on dementia and theoretic insights into the role of the frontal lobes are highlighted. Moyano's works on frontotemporal dementia (FTD), specifically concerning language deficits and the concept of focal pathology in Alzheimer disease presenting with progressive aphasia are introduced. These early contributions are examined in the light of the current knowledge on FTLD, highlighting some of the authors' early original contributions, as well as their misconceptions. These authors remain largely unknown despite the fact that their contributions were fundamental in kindling interest in behavioral neurology in Latin America, which continues to this day.
Assuntos
Degeneração Lobar Frontotemporal/história , Neurologia/história , Argentina , Lobo Frontal/patologia , Lobo Frontal/fisiologia , Degeneração Lobar Frontotemporal/patologia , Degeneração Lobar Frontotemporal/psicologia , Alemanha , História do Século XX , Humanos , Vias Neurais , Doença de Pick/história , Doença de Pick/patologiaRESUMO
BACKGROUND/AIMS: Functional assessment is essential in dementia as it provides an invaluable tool for diagnosis and treatment. To date, most scales of activities of daily living (ADL) have focused either on basic or instrumental activities, providing an incomplete profile of the patients' level of dependence on their caregivers. Some scales concentrate too intensely on the way in which physical impairment affects ADL, with a decreasing sensitivity to the detection of demented patients who do not necessarily present with physical impediments. The Activities of Daily Living Questionnaire (ADLQ) assesses functioning in self-care, household care, employment and recreation, shopping and money, travel and communication. The present study sought to determine the usefulness of the Spanish version of the ADLQ (ADLQ-SV) for assessing functional impairment in different types of dementia. METHODS: The ADLQ-SV, the Clinical Dementia Rating (CDR) scale and the Functional Activities Questionnaire (FAQ) were administered to the caregivers of patients (n = 40) with different types of dementia. RESULTS: Strong internal consistency (Cronbach's alpha = 0.88) and concurrent validity (significant correlations with CDR and FAQ, both p < 0.001) were observed. CONCLUSIONS: The authors discuss response trends in the ADLQ-SV and show the utility of the scale in Spanish-speaking populations of patients with dementia.