Brainstem Volumetric Integrity in Preclinical and Prodromal Alzheimer’s Disease

Article type: Research Article

Authors: Dutt, Shubir^{a; b} | Li, Yanrong^c | Mather, Mara^{a; b} | Nation, Daniel A.^{c; d; *} | for the Alzheimer’s Disease Neuroimaging Initiative¹

Affiliations: [a] Department of Psychology, University of Southern California, Los Angeles, CA, USA | [b] Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA | [c] Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA | [d] Department of Psychological Science, University of California, Irvine, Irvine, CA, USA

Correspondence: [*] Correspondence to: Daniel A. Nation, PhD, Associate Professor, Department of Psychological Science, University of California Irvine, 4544 Social and Behavioral Sciences Gateway, Irvine, CA 92697-7085, USA. Tel.: +1 949 824 9339; E-mail: dnation@uci.edu.

Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (https://adni.loni.usc.edu). As such, 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.

Abstract: Background:Neuropathological studies have suggested the tau pathology observed in Alzheimer’s disease (AD) originates in brainstem nuclei, but no studies to date have quantified brainstem volumes in clinical populations with biomarker-confirmed mild cognitive impairment (MCI) or dementia due to AD or determined the value of brainstem volumetrics in predicting dementia. Objective:The present study examined whether MRI-based brainstem volumes differ among cognitively normal older adults and those with MCI or dementia due to AD and whether preclinical brainstem volumes predict future progression to dementia. Methods:Alzheimer’s Disease Neuroimaging Initiative participants (N = 1,629) underwent baseline MRI scanning with variable clinical follow-up (6–120 months). Region of interest and voxel-based morphometric methods assessed brainstem volume differences among cognitively normal (n = 814), MCI (n = 542), and AD (n = 273) participants, as well as subsets of cerebrospinal fluid biomarker-confirmed MCI (n = 203) and AD (n = 160) participants. Results:MCI and AD cases showed smaller midbrain volumes relative to cognitively normal participants when normalizing to whole brainstem volume, and showed smaller midbrain, locus coeruleus, pons, and whole brainstem volumes when normalizing to total intracranial volume. Cognitively normal individuals who later progressed to AD dementia diagnosis exhibited smaller baseline midbrain volumes than individuals who did not develop dementia, and voxel-wise analyses revealed specific volumetric reduction of the locus coeruleus. Conclusion:Findings are consistent with neuropathological observations of early AD-related pathology in brainstem nuclei and further suggest the clinical relevance of brainstem substructural volumes in preclinical and prodromal AD.

Keywords: Alzheimer’s disease, biomarkers, brainstem, cognitive aging, locus coeruleus, magnetic resonance imaging, mild cognitive impairment, neuroimaging

DOI: 10.3233/JAD-200187

Journal: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1579-1594, 2020