Cognitive Correlates of Basal Forebrain Atrophy and Associated Cortical Hypometabolism in Mild Cognitive Impairment

Abstract

Degeneration of basal forebrain (BF) cholinergic nuclei is associated with cognitive decline, and this effect is believed to be mediated by neuronal dysfunction in the denervated cortical areas. MRI-based measurements of BF atrophy are increasingly being used as in vivo surrogate markers for cholinergic degeneration, but the functional implications of reductions in BF volume are not well understood. We used high-resolution MRI, fluorodeoxyglucose-positron emission tomography (PET), and neuropsychological test data of 132 subjects with mild cognitive impairment (MCI) and 177 cognitively normal controls to determine associations between BF atrophy, cortical hypometabolism, and cognitive deficits. BF atrophy in MCI correlated with both impaired memory function and attentional control deficits, whereas hippocampus volume was more specifically associated with memory deficits. BF atrophy was also associated with widespread cortical hypometabolism, and path analytic models indicated that hypometabolism in domain-specific cortical networks mediated the association between BF volume and cognitive dysfunction. The presence of cortical amyloid pathology, as assessed using AV45-PET, did not significantly interact with the observed associations. These data underline the potential of multimodal imaging markers to study structure-function-cognition relationships in the living human brain and provide important in vivo evidence for an involvement of the human BF in cortical activity and cognitive function.

Keywords: AV45-PET; Alzheimer's disease; FDG-PET; MRI; cholinergic degeneration; nucleus basalis Meynert; substantia innominata.

Figure 1.

Overview of main image processing and analysis steps. Structural MRIs of each subject were segmented and high-dimensionally registered to a population-specific reference template. BF and hippocampus volumes were extracted from warped and modulated GM maps using ROI masks in the template space. FDG-PET scans were coregistered to skull-stripped versions of the corresponding MRIs, corrected for PVEs, and high-dimensionally warped to the reference template using the deformation fields derived from registration of the MRI scans. BF and hippocampus volumes were tested for correlations with neuropsychological test performance, and regressed on preprocessed FDG-PET scans to reveal patterns of cerebral hypometabolism associated with BF and hippocampus atrophy, respectively. Finally, associations between BF-related hypometabolism and neuropsychological test performance were assessed using additional voxel-wise regression models. See text for details. BF: basal forebrain; DARTEL: Diffeomorphic Anatomical Registration using Exponentiated Lie algebra; GM_mask: gray matter mask; GM_{prob, conv}: gray matter probability map convolved by point spread function; Hippo: hippocampus; PET_PVC: partial volume-corrected PET image; PET_WM: estimated (virtual) PET image reflecting white matter activity; PET_CSF: estimated (virtual) PET image reflecting cerebrospinal fluid activity; PSF: point spread function.

Figure 2.

Associations of BF and hippocampus volume with episodic memory and attentional control deficits in MCI. Normalized BF (left) and hippocampus (right) volumes of MCI subjects are plotted on the x-axis against the number of correctly recalled wordlist items at 30-min DR (DR-30, top panel) and the time taken to complete the TMT part B (TMT-B, bottom panel) on the y-axis. BF volumes correlate with both performance on the DR-30 episodic memory test and the TMT-B indexing attentional control. Hippocampus volumes show significant correlation with DR-30 performance, but not with TMT-B performance.

Figure 3.

Hypometabolism associated with BF and hippocampus atrophy in MCI. The figure depicts regional effects of voxel-wise regressions of normalized BF (top, effects in red) and hippocampus volumes (bottom, effects in blue) on preprocessed FDG-PET scans, scaled to pons uptake values, in the MCI group. Analyses were corrected for age, gender, education, and MMSE scores, and results were thresholded at a corrected statistical threshold of P(FDR) < 0.05. Effects are depicted on cortical surface renderings as well as sagittal sections running from left (L) to right (R) through the brain. Lower BF volumes are associated with reduced metabolism in widespread cortical networks spanning limbic, paralimbic, and heteromodal association areas of the frontal, temporal, and parietal lobes. Lower hippocampus volumes are associated with reduced metabolism in the medial temporal lobe and the posterior cingulate/retrosplenial cortex.

Figure 4.

Hypometabolism associated with BF atrophy and domain-specific cognitive deficits in MCI. Hypometabolic areas related to BF atrophy in MCI (red) were tested for their association with DR-30 (top, effects in green) and TMT-B performance (bottom, effects in yellow) using voxel-wise regressions of the respective test scores on preprocessed FDG-PET scans, scaled to pons uptake values. Analyses were corrected for age, gender, education, MMSE scores, and TMT-B or DR-30 performance, respectively. Search space was limited to hypometabolic areas related to BF atrophy (red) and results were thresholded at a corrected statistical threshold of P(FDR) < 0.05. Effects are depicted on cortical surface renderings as well as sagittal sections running from left (L) to right (R) through the brain. DR-30 performance (numbers of correctly recalled wordlist items at 30-min DR) was positively associated with metabolism mainly in the hippocampus and the posterior cingulate/retrosplenial cortex. The time taken to complete the TMT-B was negatively associated with metabolism in a distinct network covering wide parts of the frontal, temporal, and parietal association areas while sparing the medial temporal lobe. DR-30: 30-min delayed recall; TMT-B: Trail Making Test part B.