Brainstem substructures and cognition in prodromal Alzheimer’s disease

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.

Examining the Role of the Noradrenergic Locus Coeruleus for Predicting Attention and Brain Maintenance in Healthy Old Age, Mild Cognitive Impairment and Alzheimer’s Disease: An MRI Structural Study On the Adni Cohort

“…However, education level did show a positive association with overall brain volume (in the HC and MCI groups) suggesting it might be more closely associated with brain development and expansion rather than later life brain maintenance. Few studies have investigated the relationship between LC volume and attentional performance in older adults [48,55,33]. The present study utilised the Trail Making Test A (TMT-A) as a putative measure of visual attention speed, and found that greater LC volume in MCI and AD patients was associated with faster attention performance.…”

“…First, to examine the relationship between LC integrity and cognitive function measured by the Trail Making Test A (TMT-A), which is a clinical tool sensitive to basic attentional efficiency, visual search and motor processing speed. We anticipated that greater LC integrity would be negatively associated with TMT-A completion time in seconds, according to previous findings [29,48,55] and consistent with Robertson's theory [1,2]. TMT part A has been chosen over the part B since the latter was not completed by all the selected participants included in the ADNI (specifically in the Alzheimer's group), and also because it is considered to evaluate more structured cognitive processes such as cognitive flexibility and divided attention [75,76].…”

“…To this end, we adopted a neuroimaging voxel-based morphometry (VBM) approach utilizing 3T T1-weighted structural MRI scans from 686 subjects [n=395 (HC), n=156 (MCI), and 135 (AD)] provided by Alzheimer Disease Neuroimaging Initiative -ADNI (ADNI2 and ADNI3 phases) [49,50]. Structural volumetric analyses on 3T T1-weighted MRIs with this methodology have been already carried out by several studies showing accurate reliability investigating the Brainstem [51,52,53,54], the LC also in the ADNI [55,56,57,58] and the other neuromodulators' seeds such as the Raphe Nuclei [59,60,61,62], the Ventral Tegmental Area [63,64,65,66] and the Nucleus Basalis of Meynert [67,68,69,70,71,72,73,74]. The main objectives of this study were threefold.…”

Examining the Role of the Noradrenergic Locus Coeruleus for 2 Predicting Attention and Brain Maintenance in Healthy Old Age 3 and Disease: An MRI Structural Study for the Alzheimer’s Disease 4 Neuroimaging Initiative

“…To this end, we adopted a neuroimaging voxel-based morphometry (VBM) approach utilizing 3T T1-weighted structural MRI scans from 686 subjects [n=395 (HC), n=156 (MCI), and 135 (AD)] provided by Alzheimer's Disease Neuroimaging Initiative -ADNI (ADNI2 and ADNI3 phases) [49,50]. Structural volumetric analyses on 3T T1-weighted MRIs with this methodology have been already carried out by several studies showing accurate reliability investigating the integrity of the Brainstem [51,52,53,54], the LC also in the ADNI [55,56,57,58] and the other neuromodulators' seeds such as the Raphe Nuclei [59,60,61,62], the Ventral Tegmental Area (VTA) [63,64,65,66] and the Nucleus Basalis of Meynert (NBM) [67,68,69,70,71,72,73,74]. The main objectives of this study were threefold.…”

“…First (1 st branch of VBM analyses), to examine the relationship between LC integrity and cognitive function measured by the Trail Making Test A (TMT-A), which is a clinical tool sensitive to basic attentional efficiency, visual search and motor processing speed [79,169,170]. We anticipated that greater LC volume would be negatively associated with TMT-A completion time in seconds, according to previous findings [29,48,55] and consistent with Robertson's theory [1,2]. TMT part A has been chosen over the part B since the latter was not completed by all the selected participants included in the ADNI (specifically in the Alzheimer's group), and also because it is considered to evaluate more structured cognitive processes such as cognitive flexibility and divided attention [75,76].…”