Abstract
Neuropathological research suggests the tau pathology of Alzheimer’s disease may originate in brainstem nuclei, yet it remains unknown whether tau-mediated degeneration of brainstem nuclei influences cognitive impairment in prodromal Alzheimer’s disease. The present study examined cognitive domains impacted in prodromal Alzheimer’s disease and brainstem substructure volume in cognitively normal older adults (n = 814) and those with mild cognitive impairment (n = 542). Subsamples of cognitively normal (n = 112) and mild cognitive impairment (n = 202) also had cerebrospinal fluid Alzheimer’s disease biomarker characterization. Region-of-interest and voxel-level analyses related whole brainstem, midbrain, pons, and locus coeruleus volumes to cognition with multiple linear regression models corrected for age, sex, education, apolipoprotein-ε4 carrier status, and MRI magnet strength. Within mild cognitive impairment participants, smaller midbrain and locus coeruleus volumes were significantly related to poorer performance on tests of attention and executive function, and the relationship between locus coeruleus volume and executive abilities remained significant in the mild cognitive impairment subsample with biomarker-confirmed Alzheimer’s disease. A brainstem-masked voxel-wise regression further demonstrated an association between locus coeruleus volume and executive abilities. Brainstem volumes were not significantly related to memory processes. Study findings implicate midbrain and locus coeruleus volume in attention and executive deficits in mild cognitive impairment. Together with prior neuropathological studies, our data suggest a link between Alzheimer’s disease-related degeneration of brainstem nuclei and cognitive deficits in prodromal Alzheimer’s disease.
Highlights
Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database
We recently demonstrated volumetric differences specific to the midbrain and LC in the prodromal phase of AD, mild cognitive impairment (MCI), compared to cognitively normal (CN) individuals, and at an earlier preclinical stage in asymptomatic CN individuals who later received a diagnosis of AD dementia (Dutt et al 2020)
MCI participants who were both amyloid-β (Aβ) and phosphorylated tau positive based on pre-established cutoffs (Hansson et al 2018) comprised the MCI due to AD group (MCIAβ + pTau+, n = 202)
Summary
Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni. loni.usc.edu). Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database The investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. Recent updated Braak staging of Alzheimer’s disease (AD) implicates the brainstem as the first site of tau-related pathology, with the locus coeruleus (LC) the first nucleus to demonstrate signs of pretangles (i.e., precursors to neurofibrillary tangle pathology) (Braak and Del Tredici 2015). The LC is the noradrenergic epicenter of the brain and helps regulate autonomic and neurovascular function and modulate aspects of cognition. Human and animal studies reveal the LCnoradrenergic system modulates attentional shifts, executive function, cognitive control and memory processes (AstonJones and Cohen 2005; Mather 2020; Mather et al 2016; Brain Imaging and Behavior (2021) 15:2572–2582
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