Abstract
Introduction While degeneration of the basal forebrain cholinergic system (BFCS) substantially contributes to cognitive impairment in Alzheimer's disease (AD), little is known about how the presence and severity of beta amyloid plaques (abeta) and the neurofibrillary tau tangles leverage these relationships at early stages of pathological changes. The goal of this study was to examine the relationships between early changes in BFCS sub-structural volumes and initial signs of cognitive alterations. Further we explored whether abeta and tau burden influence these associations in clinically normal elderly adults. Methods All imaging and cognitive data were obtained from 77 cognitively normal Alzheimer's disease Neuroimaging Initiative (ADNI) subjects (age 77 ± 8). We utilized recently developed cytoarchitectonic maps of BFCS sub-structures to enable sensitive BFCS voxel-based morphometry (VBM) to capture sub-BFCS volume measures. Global abeta and entorhinal tau burden were calculated from the associated regional uptake values that were normalized by reference regions. Cognitive performance was assessed by both objective testing (with standard instruments) and subjective self-reports of everyday functioning (with the ECog). Analyses included these cognitive variables as individual outcomes in multiple linear regression models with BFCS sub-structures as predictors. All models were covaried for age and sex. Results Different BFCS sub-structures were associated with different cognitive measures. The nucleus basalis of Meynert (Ch4) predicted changes in ECog domain of memory whereas the composite structure (Ch1-3) of medial septal nucleus (Ch1), the vertical nucleus of the diagonal band of Broca (Ch2), and the horizontal limb of the diagonal band (Ch3) predicted both ECog memory and ECog visuospatial skills. The associations remained statistically significant after adjusting for global abeta, entorhinal tau burden, and Mini-Mental State Examination (MMSE) as covariates. The negative coefficient of the regression analysis for Ch1-3 indicated that increase in Ch1-3 volume was correlated with decrease in all cognitive measures. A backward elimination regression analysis indicated that the best model for predicting changes in Everyday visuospatial skills included tau, age, and Ch1-3 volume. We did not detect an interactive effect between tau or abeta and Ch1-3 for predicting visuospatial skills. Conclusions Early BFCS changes in cognitively normal elderly adults are associated with alterations in specific subjective cognitive domains. Our results may also support previous studies that found evidence of enlargement in basal forebrain septal nuclei in healthy elderly subjects prior to AD. Measures of sub-BFCS volumes may serve as an early and sensitive MRI-based biomarker for AD. This research was funded by: R01 AG066159 to JD and NP
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