Brainstem volumetric integrity in preclinical and prodromal Alzheimer’s disease

Abstract

AbstractBackgroundAutopsy‐based 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 risk. The present study examined whether MRI‐based brainstem sub‐structural volumes differ between cognitively normal (CN) older adults and those with MCI or dementia due to AD, and whether early preclinical brainstem volumes predict future progression to dementia.MethodAlzheimer’s Disease Neuroimaging Initiative participants diagnosed as CN (n=822), MCI (n=543), or AD (n=300) underwent baseline T1‐weighted structural MRI scanning with variable clinical follow‐up (6‐120 months). A subset of participants completed baseline fasting lumbar puncture to quantify levels of amyloid‐beta 1‐42 and phospho‐tau. We employed region‐of‐interest and voxel‐based morphometric methods to assess differences between clinically‐diagnosed and biomarker‐defined groups in volumes of the whole brainstem, midbrain, pons, and locus coeruleus. Longitudinal Cox regression analyses determined value of baseline brainstem sub‐structure volumes in predicting progression to a future clinical diagnosis of AD dementia.ResultCompared with CN individuals, we observed smaller regional volumes in whole brainstem, midbrain, pons, and locus coeruleus regions in patients clinically diagnosed with MCI and AD, and specifically within the midbrain in biomarker‐confirmed cases. Brainstem‐masked voxel‐wise comparisons confirmed volume reduction of a dorsal rostral brainstem region corresponding to the locus coeruleus in MCI and AD relative to CN, as well as in CN who progressed to AD dementia versus those that did not progress to AD dementia. In a preclinical risk analysis, cognitively normal individuals who later progressed to AD dementia exhibited smaller baseline midbrain volumes than individuals who did not develop dementia, and longitudinal analyses indicated smaller midbrain and locus coeruleus volumes conferred greater risk of progression.ConclusionOur study indicated that brainstem MRI changes are detectible in preclinical and prodromal populations. Our findings are consistent with the neuropathological observation that AD‐related pathology occurs early in brainstem nuclei and further suggest the clinical relevance of brainstem sub‐structural volumes for preclinical and prodromal AD populations.