Regional glucose metabolism and instrumental activities of daily living across the Alzheimer's disease spectrum

Abstract

Background: Impairment in instrumental activities of daily living (IADL) begins as individuals with amnestic mild cognitive impairment (MCI) transition to Alzheimer‟s disease (AD) dementia. IADL impairment in AD dementia has been associated with inferior parietal, inferior temporal, and superior occipital hypometabolism using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Objective: The objective of this study was to investigate the relationship between regional cerebral FDG metabolism and IADL cross-sectionally and longitudinally in clinically normal (CN) elderly, MCI, and mild AD dementia subjects. Methods: Four hundred and two subjects (104 CN, 203 MCI, 95 AD dementia) participating in the Alzheimer‟s Disease Neuroimaging Initiative at academic centers across North America underwent clinical assessments every 6 to 12 months for up to 3 years and FDG-PET at their baseline visits. The subjective informant-based Functional Activities Questionnaire (FAQ) was used to assess IADL. Data reduction analyses were first conducted to reduce 35 FDG regions to 6 regions that significantly associated with total FAQ score after adjusting for multiple tests. These 6 FDG regions were then entered into a general linear model with backward elimination (p<0.05) assessing their cross-sectional relation to baseline FAQ and a mixed random and fixed coefficient linear longitudinal regression model assessing their relation to FAQ over time. Analyses included the following covariates: diagnosis, demographics, Apolipoprotein E4 (ApoE4) carrier status, memory and executive function, and behavioral factors. Results: The cross-sectional analysis showed that middle frontal (p=0.003) and orbitofrontal hypometabolism (p=0.009) were significantly associated with greater IADL impairment. Additionally, the interaction of diagnosis with posterior cingulate (p<0.0001) and with parahippocampal hypometabolism (p=0.0008) showed a steeper decline in IADL performance as FDG metabolism decreased for the AD dementia group relative to the MCI group, and the MCI group relative to the CN group. The longitudinal analysis showed that baseline middle frontal (p=0.0005) and posterior cingulate hypometabolism (p=0.004) were significantly associated with greater rate of increase in IADL impairment over time. Conclusions: These results suggest that frontal and medial parietal synaptic dysfunction relates to functional decline at baseline and over time across the AD spectrum independent of demographics, APOE4 carrier status, memory and executive function performance, and behavioral factors.