RESUMO
CONTEXT: Blood-based analytes may be indicators of pathological processes in Alzheimer disease (AD). OBJECTIVE: To identify plasma proteins associated with AD pathology using a combined proteomic and neuroimaging approach. DESIGN: Discovery-phase proteomics to identify plasma proteins associated with correlates of AD pathology. Confirmation and validation using immunodetection in a replication set and an animal model. SETTING: A multicenter European study (AddNeuroMed) and the Baltimore Longitudinal Study of Aging. PARTICIPANTS: Patients with AD, subjects with mild cognitive impairment, and healthy controls with standardized clinical assessments and structural neuroimaging. MAIN OUTCOME MEASURES: Association of plasma proteins with brain atrophy, disease severity, and rate of clinical progression. Extension studies in humans and transgenic mice tested the association between plasma proteins and brain amyloid. RESULTS: Clusterin/apolipoprotein J was associated with atrophy of the entorhinal cortex, baseline disease severity, and rapid clinical progression in AD. Increased plasma concentration of clusterin was predictive of greater fibrillar amyloid-beta burden in the medial temporal lobe. Subjects with AD had increased clusterin messenger RNA in blood, but there was no effect of single-nucleotide polymorphisms in the gene encoding clusterin with gene or protein expression. APP/PS1 transgenic mice showed increased plasma clusterin, age-dependent increase in brain clusterin, as well as amyloid and clusterin colocalization in plaques. CONCLUSIONS: These results demonstrate an important role of clusterin in the pathogenesis of AD and suggest that alterations in amyloid chaperone proteins may be a biologically relevant peripheral signature of AD.
Assuntos
Doença de Alzheimer/sangue , Clusterina/sangue , Idoso , Envelhecimento/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/genética , Animais , Atrofia/patologia , Encéfalo/patologia , Clusterina/genética , Transtornos Cognitivos/sangue , Transtornos Cognitivos/genética , Transtornos Cognitivos/patologia , Modelos Animais de Doenças , Progressão da Doença , Córtex Entorrinal/patologia , Feminino , Expressão Gênica , Genótipo , Humanos , Estudos Longitudinais , Masculino , Camundongos , Camundongos Transgênicos , Chaperonas Moleculares/sangue , Polimorfismo de Nucleotídeo Único/genética , Proteômica/métodos , Índice de Gravidade de DoençaRESUMO
A cross-sectional survey was administered to family members of patients who died at 1 of the 5 Catholic institutions comprising Mercy Health Partners, a health care system in Ohio, to determine their opinions about patient and family participation in decisions about end-of-life care. Among 165 respondents, 118 (86%) of 138 agreed that the family was encouraged to join in decisions and 133 (91%) of 146 that their family member's health care choices were followed. Most agreed that nurses answered their questions (93%, 141/151) and that the doctor communicated well with family members (83%, 128/155). Seventy percent (107/152) indicated that their family member had at least 1 advance directive. There were no differences in whether health care choices were followed when patients with formal advance directives (92%, 92/100) were compared with patients without formal advance directives (88%, 35/40). A unique survey instrument can be used to measure family perceptions and opinions of participation in decisions about end-of-life care.
