Regional Hypoperfusion Predicts Decline in Everyday Functioning at Three-Year Follow-Up in Older Adults without Dementia

Abstract

Background: Increasing evidence indicates that cerebrovascular dysfunction may precede cognitive decline in aging and Alzheimer's disease (AD). Reduced cerebral blood flow (CBF) is associated with cognitive impairment in older adults. However, less is known regarding the association between CBF and functional decline, and whether CBF predicts functional decline beyond cerebrovascular and metabolic risk factors.

Objective: To examine the association between regional CBF and functional decline in nondemented older adults.

Method: One hundred sixty-six (N = 166) participants without dementia from the Alzheimer's Disease Neuroimaging Initiative underwent neuropsychological testing and neuroimaging. Pulsed arterial spin labeling magnetic resonance imaging was acquired to quantify resting CBF. Everyday functioning was measured using the Functional Assessment Questionnaire at baseline and annual follow-up visit across three years.

Results: Adjusting for age, education, sex, cognitive status, depression, white matter hyperintensity volume, cerebral metabolism, and reference (precentral) CBF, linear mixed effects models showed that lower resting CBF at baseline in the medial temporal, inferior temporal, and inferior parietal lobe was significantly associated with accelerated decline in everyday functioning. Results were similar after adjusting for conventional AD biomarkers, including cerebrospinal fluid (CSF) amyloid-β (Aβ) and hyperphosphorylated tau (p-tau) and apolipoprotein E (APOE) ɛ4 positivity. Individuals who later converted to dementia had lower resting CBF in the inferior temporal and parietal regions compared to those who did not.

Conclusion: Lower resting CBF in AD vulnerable regions including medial temporal, inferior temporal, and inferior parietal lobes predicted faster rates of decline in everyday functioning. CBF has utility as a biomarker in predicting functional declines in everyday life and conversion to dementia.

Keywords: Activities of daily living; Alzheimer’s disease; aging; biomarkers; cerebrovascular circulation; dementia; magnetic resonance imaging; neuropsychology; perfusion; regional blood flow.

Figure 1.

Fitted plots displaying model predicted Functional Activities Questionnaire (FAQ) values over the 3-year interval, adjusting for age, education, sex, cognitive status (normal cognition versus mild cognitive impairment), depression, white matter hyperintensity volume, cerebral metabolism, and reference (precentral) cerebral blood flow (CBF) for each of the regions of interest. For visual comparison, the graphs display results for low, middle, and high CBF which were determined by a tertile split of the values in the analytic sample. Higher FAQ scores indicate greater functional difficulty. Shaded regions represent the 95% confidence interval for the regression line. Cut-off scores of >6 on FAQ have been shown to best indicate significant functional difficulties [44].