Spatial pattern of brain atrophy in Alzheimer’s and LATE neuropathology
Poster No:
295
Submission Type:
Abstract Submission
Authors:
Khalid Saifullah1, Abdur Raquib Ridwan2, David Bennett2, Julie Schneider2, Konstantinos Arfanakis1,2
Institutions:
1Illinois Institute of Technology, Chicago, IL, 2Rush University Medical Center, Chicago, IL
First Author:
Co-Author(s):
Konstantinos Arfanakis
Illinois Institute of Technology|Rush University Medical Center
Chicago, IL|Chicago, IL
Illinois Institute of Technology|Rush University Medical Center
Chicago, IL|Chicago, IL
Introduction:
Alzheimer's disease neuropathologic change (AD-NC)1 and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC)2 are common in older adults and have been associated with brain atrophy, cognitive decline, and dementia3. Furthermore, AD-NC and LATE-NC are often comorbid increasing the odds for dementia4. Since AD-NC and LATE-NC are often comorbid and due to the fact that LATE-NC can only be detected at autopsy, the differential effects of the two pathologies on brain morphometry have not been systematically investigated. In this work, we combined deformation-based morphometry (DBM) on ex-vivo brain MRI and detailed neuropathological evaluation in a large number of community-based older adults (N=912) that came to autopsy to investigate the difference in brain atrophy patterns associated with AD-NC and LATE-NC.
Methods:
Participants and Data
Cerebral hemispheres from 912 older adults participating in four longitudinal, clinical-pathologic cohort studies of aging were included in this work: the Rush Memory and Aging Project (MAP), Religious Orders Study (ROS), Minority Aging Research Study (MARS), and the African American Clinical Core (AA Core) of the Rush Alzheimer's Disease Research Center (Rush ADRC) (Fig.1)5,6. All hemispheres were imaged ex-vivo on 3T clinical MRI scanners approximately 1-month postmortem while immersed in 4% formaldehyde solution. T2-weighted images of all hemispheres were non-linearly registered to a brain hemisphere template using ANTs. The logarithm of the Jacobian determinant (LogJ) of the deformation field was calculated in each voxel, and the resulting maps were smoothed by a Gaussian filter with FWHM=4mm. Following ex-vivo MRI, all hemispheres underwent detailed neuropathologic examination by a board-certified neuropathologist. The pathologies that were assessed were AD-NC, LATE-NC, Lewy bodies, gross infarcts, microscopic infarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy. Participants were divided into four groups: AD-NC-neg LATE-NC-neg (n=453), AD-NC-pos LATE-NC-neg (n=108), AD-NC-neg LATE-NC-pos (n=225), and AD-NC-pos LATE-NC-pos (n=126), where AD-NC-pos was defined as moderate or severe AD-NC according to the NIA-AA criteria1 , and LATE-NC-pos was defined as LATE-NC stages 2 or 3.
Statistical analysis
Voxel-wise linear regression was used to test the association of the deformations observed in the smoothed log Jacobian maps with the four different groups, controlling for all other neuropathologies, demographics (age, sex, years of education), postmortem intervals, and scanner. The analysis was conducted using FSL PALM7. We used 5000 permutations, and statistical significance was set at p<0.05 after family wise error (FWE) correction. Significant clusters were defined using threshold-free cluster enhancement (TFCE).
Cerebral hemispheres from 912 older adults participating in four longitudinal, clinical-pathologic cohort studies of aging were included in this work: the Rush Memory and Aging Project (MAP), Religious Orders Study (ROS), Minority Aging Research Study (MARS), and the African American Clinical Core (AA Core) of the Rush Alzheimer's Disease Research Center (Rush ADRC) (Fig.1)5,6. All hemispheres were imaged ex-vivo on 3T clinical MRI scanners approximately 1-month postmortem while immersed in 4% formaldehyde solution. T2-weighted images of all hemispheres were non-linearly registered to a brain hemisphere template using ANTs. The logarithm of the Jacobian determinant (LogJ) of the deformation field was calculated in each voxel, and the resulting maps were smoothed by a Gaussian filter with FWHM=4mm. Following ex-vivo MRI, all hemispheres underwent detailed neuropathologic examination by a board-certified neuropathologist. The pathologies that were assessed were AD-NC, LATE-NC, Lewy bodies, gross infarcts, microscopic infarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy. Participants were divided into four groups: AD-NC-neg LATE-NC-neg (n=453), AD-NC-pos LATE-NC-neg (n=108), AD-NC-neg LATE-NC-pos (n=225), and AD-NC-pos LATE-NC-pos (n=126), where AD-NC-pos was defined as moderate or severe AD-NC according to the NIA-AA criteria1 , and LATE-NC-pos was defined as LATE-NC stages 2 or 3.
Statistical analysis
Voxel-wise linear regression was used to test the association of the deformations observed in the smoothed log Jacobian maps with the four different groups, controlling for all other neuropathologies, demographics (age, sex, years of education), postmortem intervals, and scanner. The analysis was conducted using FSL PALM7. We used 5000 permutations, and statistical significance was set at p<0.05 after family wise error (FWE) correction. Significant clusters were defined using threshold-free cluster enhancement (TFCE).
Results:
Both the AD-NC-pos LATE-NC-neg group (Fig.2a) as well as the AD-NC-neg LATE-NC-pos group (Fig.2b) were associated with lower tissue volume mainly in medial temporal lobe structures8. The AD-NC-pos LATE-NC-pos group (Fig.2c) showed substantially lower volume in the temporal, frontal, and parietal lobes4,9. Interestingly, the AD-NC-neg LATE-NC-pos group showed lower volume in the anterior portion of the hippocampus than the AD-NC-pos LATE-NC-neg group (Fig.2d)10.
Conclusions:
This is the largest study combining brain morphometry and pathology in community-based older adults to date, and as such it provides strong evidence on the brain atrophy patterns associated with AD-NC and LATE-NC. Both AD-NC and LATE-NC are associated with lower volume mainly in the medial temporal lobes. Furthermore, LATE-NC stages 2 or 3 are associated with more atrophy in the anterior portion of the hippocampus compared to moderate or severe AD-NC. This finding suggests that in the presence of LATE-NC, the volume of the hippocampus cannot serve as a marker of AD-NC.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Lifespan Development:
Aging 2
Keywords:
Aging
Degenerative Disease
Morphometrics
MRI
1|2Indicates the priority used for review
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