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1.
Lancet Neurol ; 14(8): 804-813, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26139022

RESUMO

BACKGROUND: The biomarker model of Alzheimer's disease postulates a dynamic sequence of amyloidosis, neurodegeneration, and cognitive decline as an individual progresses from preclinical Alzheimer's disease to dementia. Despite supportive evidence from cross-sectional studies, verification with long-term within-individual data is needed. METHODS: For this prospective cohort study, carriers of autosomal dominant Alzheimer's disease mutations (aged ≥21 years) were recruited from across the USA through referrals by physicians or from affected families. People with mutations in PSEN1, PSEN2, or APP were assessed at the University of Pittsburgh Alzheimer's Disease Research Center every 1-2 years, between March 23, 2003, and Aug 1, 2014. We measured global cerebral amyloid ß (Aß) load using (11)C-Pittsburgh Compound-B PET, posterior cortical metabolism with (18)F-fluorodeoxyglucose PET, hippocampal volume (age and sex corrected) with T1-weighted MRI, verbal memory with the ten-item Consortium to Establish a Registry for Alzheimer's Disease Word List Learning Delayed Recall Test, and general cognition with the Mini Mental State Examination. We estimated overall biomarker trajectories across estimated years from symptom onset using linear mixed models, and compared these estimates with cross-sectional data from cognitively normal control individuals (age 65-89 years) who were negative for amyloidosis, hypometabolism, and hippocampal atrophy. In the mutation carriers who had the longest follow-up, we examined the within-individual progression of amyloidosis, metabolism, hippocampal volume, and cognition to identify progressive within-individual changes (a significant change was defined as an increase or decrease of more than two Z scores standardised to controls). FINDINGS: 16 people with mutations in PSEN1, PSEN2, or APP, aged 28-56 years, completed between two and eight assessments (a total of 83 assessments) over 2-11 years. Significant differences in mutation carriers compared with controls (p<0·01) were detected in the following order: increased amyloidosis (7·5 years before expected onset), decreased metabolism (at time of expected onset), decreased hippocampal volume and verbal memory (7·5 years after expected onset), and decreased general cognition (10 years after expected onset). Among the seven participants with longest follow-up (seven or eight assessments spanning 6-11 years), three individuals had active amyloidosis without progressive neurodegeneration or cognitive decline, two amyloid-positive individuals showed progressive neurodegeneration and cognitive decline without further progressive amyloidosis, and two amyloid-positive individuals showed neither active amyloidosis nor progressive neurodegeneration or cognitive decline. INTERPRETATION: Our results support amyloidosis as the earliest component of the biomarker model in autosomal dominant Alzheimer's disease. Our within-individual examination suggests three sequential phases in the development of autosomal dominant Alzheimer's disease-active amyloidosis, a stable amyloid-positive period, and progressive neurodegeneration and cognitive decline-indicating that Aß accumulation is largely complete before progressive neurodegeneration and cognitive decline occur. These findings offer supportive evidence for efforts to target early Aß deposition for secondary prevention in individuals with autosomal dominant Alzheimer's disease. FUNDING: National Institutes of Health and Howard Hughes Medical Institute.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides/metabolismo , Amiloidose/metabolismo , Biomarcadores , Córtex Cerebral , Progressão da Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Compostos de Anilina , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Feminino , Hipocampo/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tiazóis
2.
Neurology ; 83(8): 710-7, 2014 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-25031286

RESUMO

OBJECTIVE: To evaluate alterations in cerebral blood flow (CBF) using arterial spin-labeled MRI in autosomal dominant Alzheimer disease (ADAD) mutation carriers (MCs) in relation to cerebral amyloid and compared with age-matched healthy controls. BACKGROUND: Recent work has identified alterations in CBF in elderly subjects with mild cognitive impairment and Alzheimer dementia using MRI. However, similar studies are lacking in ADAD. Subjects with ADAD are generally free of significant vascular disease and offer the opportunity to measure CBF early in the pathologic process before significant symptom onset when unique markers might be identified. METHODS: Fourteen MCs (presenilin-1 and amyloid beta precursor protein) (Clinical Dementia Rating [CDR] 0 = 9, CDR 0.5 = 4, CDR 1 = 1) and 50 controls underwent 3-tesla pulsed arterial spin-labeled MRI. SPM8 was used to test the effect of MC status at the voxel level on CBF before and after controlling for age and CDR. RESULTS: MCs had decreased perfusion in the caudate and inferior striatum bilaterally even after controlling for age and CDR. In MCs, separate areas of decreased CBF were associated with increasing cerebral amyloid and to decreased performance of attention and executive function. CONCLUSIONS: Early CBF changes were identified in asymptomatic and mildly symptomatic subjects with ADAD, particularly in the anterior striatum. Furthermore, amyloid deposition was associated with decreased CBF in a number of regions including anterior and posterior cortical areas. Both amyloid and decreased CBF were associated with declines primarily in executive cognitive function.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Circulação Cerebrovascular/fisiologia , Disfunção Cognitiva/metabolismo , Adulto , Doença de Alzheimer/patologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/patologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Perfusão , Presenilina-1/metabolismo
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