Abstract
The cholinergic neurons of the basal forebrain (BF) provide virtually all of the brain's cortical and amygdalar cholinergic input. They are particularly vulnerable to neuropathology in early Alzheimer's disease (AD) and may trigger the emergence of neuropathology in their cortico-amygdalar projection system through cholinergic denervation and trans-synaptic spreading of misfolded proteins. We examined whether longitudinal degeneration within the BF can explain longitudinal cortico-amygdalar degeneration in older human adults with abnormal cerebrospinal fluid biomarkers of AD neuropathology. We focused on two BF subregions, which are known to innervate cortico-amygdalar regions via two distinct macroscopic cholinergic projections. To further assess whether structural degeneration of these regions in AD reflects cholinergic denervation, we used the [18F] FEOBV radiotracer, which binds to cortico-amygdalar cholinergic terminals. We found that the two BF subregions explain spatially distinct patterns of cortico-amygdalar degeneration, which closely reflect their cholinergic projections, and overlap with [18F] FEOBV indices of cholinergic denervation.
Highlights
The emergence of Alzheimer’s disease (AD) neuropathologies, such as misfolded b-amyloid (Ab) and Tau proteins, progresses in stages across anatomically and functionally connected regions of the brain, with certain brain regions affected before others (Braak and Braak, 1991; Braak and Del Tredici, 2015; Raj et al, 2012, 2015; Seeley et al, 2009)
In order to ensure our sample was at a stage of AD characterized by longitudinal degeneration in amygdalar, allocortical, and neocortical areas (Grothe et al, 2013; Schmitz and Spreng, 2016), we further filtered individuals according to their neuropsychological status
Individuals presenting mild cognitive impairment (MCI) neuropsychological status but normal cerebrospinal fluid (CSF) Ab levels were excluded from all forthcoming analyses, as their cognitive symptoms are likely to be caused by non-AD pathology, for example, vascular dementia and hippocampal sclerosis
Summary
The emergence of Alzheimer’s disease (AD) neuropathologies, such as misfolded b-amyloid (Ab) and Tau proteins, progresses in stages across anatomically and functionally connected regions of the brain, with certain brain regions affected before others (Braak and Braak, 1991; Braak and Del Tredici, 2015; Raj et al, 2012, 2015; Seeley et al, 2009). Vulnerable neurons typically have large axonal projections that extend relatively long distances, from one region of the brain to another. As a result, they require high metabolic expenditure to maintain trophic support—transporting materials over long distances and maintaining enormous cytoskeletal surface areas. They require high metabolic expenditure to maintain trophic support—transporting materials over long distances and maintaining enormous cytoskeletal surface areas These morphological properties increase vulnerability to oxidative stress and neuroinflammation, perturbed energy homeostasis, and accumulation of misfolded proteins (Lewis et al, 2010; Mattson and Magnus, 2006; Wang et al, 2010)
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