Associations of hippocampal cholinergic receptor binding and subcortical cerebrovascular disease with whole brain volume in cognitive aging and AD

Abstract

AbstractBackgroundAlzheimer’s Disease (AD) is associated with compromise to the cholinergic system. Using PET ligand imaging, our group has reported reduced nicotinic cholinergic receptors (nAchR) in the hippocampus in AD relative to cognitively unimpaired older adults. Studies have increasingly identified that chronic ischemic cerebrovascular disease (CVD) serves as a risk factor for neurodegeneration, and also directly correlates with B‐amyloid and tau accumulation (Flaherty et al., 2020; Wei et al., 2019). We sought to determine the unique contributions of cholinergic dysfunction and CVD to brain health in cognitive aging. We therefore tested differential contributions of T1 white matter hypointensities and hippocampal nAchR binding in predicting whole brain volume among individuals with varying levels of cognitive impairment.Method84 individuals (clinical Alzheimer’s Disease (AD), n=27; Mild Cognitive Impairment (MCI), n=25; and Cognitively Unimpaired (CU), n=32) completed MRI and 2‐18F‐fluoro‐3(2(S)azetidinylmethoxy) pyridine (2FA) ‐PET imaging sessions. Total Brain Volume, excluding cerebellum, brain stem, and ventricles, was calculated using FreeSurfer. SPM was used to generate nAchR binding estimates using anatomical ROI of bilateral hippocampus.ResultWhen covarying for diagnostic group, age, and use of cholinesterase inhibitors, hierarchical linear regressions identified a significant association between hippocampal nAchR binding and total brain volume (B(SE)=.013(.003); p<.001), while the association between white matter hypointensities and total brain volume was not significant (B(SE)=‐.99(.84); p=.24). Stratified by group, the same pattern emerged in a combined sample of clinical AD and MCI (nAchR binding B(SE)=.013(.005); p<.01, hypointensities B(SE)=‐.18(.91); p=.84). In CU, however, white matter hypointensities were negatively associated with total brain volume (B(SE)=‐10.60(3.53); p<.01), while the relationship between hippocampal nAchR binding and total brain volume was not significant (B(SE)=.006(.005); p=.26).ConclusionWhite matter hypointensities are associated with a measure of brain health among CU; such vascular risk factors may be important to track in preventative treatment. Hippocampal cholinergic function, relative to hypointensities, may be more closely aligned with brain health among those with cognitive decline. Longitudinal study of vascular and cholinergic systems and their interactions are warranted; corroboration of these findings in longitudinal studies may elucidate different treatment targets across stages of AD.