TY - JOUR
T1 - Retrospective Evaluation of Neuropathologic Proxies of the Minimal Atrophy Subtype Compared With Corticolimbic Alzheimer Disease Subtypes
AU - Boon, Baayla D. C.
AU - Labuzan, Sydney A.
AU - Peng, Zhongwei
AU - Matchett, Billie J.
AU - Kouri, Naomi
AU - Hinkle, Kelly M.
AU - Lachner, Christian
AU - Ross, Owen A.
AU - Ertekin-Taner, Nilufer
AU - Carter, Rickey E.
AU - Ferman, Tanis J.
AU - Duara, Ranjan
AU - Dickson, Dennis W.
AU - Graff-Radford, Neill R.
AU - Murray, Melissa E.
N1 - Funding Information: The Article Processing Charge was funded by the authors. Funding Information: We thank the patients and their families for their generous brain donations to help further our knowledge of AD and related dementias. We also thank Monica Castanedes- Casey and Virginia Phillips for performing histological support. We are especially grateful for the programmatic support of Jessica F. Tranovich, Sabrina Rothberg, and Kelsey Caetano-Anolles. The investigators are supported by grants originating from the Alzheimer's Association (AARG-17-533458), National Institute on Aging (R01-AG054449, R01-AG073282, R01-AG075802, U19-AG069701, P30-AG062677, RF1-AG069052), the Florida Department of Health, and the Ed and EthelMoore Alzheimer's Disease Research Program (8AZ06, 20a22) and a generous gift from David and Frances Strawn. B.D.C. Boon is supported by Alzheimer Nederland (#WE.15-2019-13, #WE.03-2021-15, #WE.06-2023-01). Publisher Copyright: © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.
PY - 2023/10/3
Y1 - 2023/10/3
N2 - Background and ObjectivesAlzheimer disease (AD) is neuropathologically classified into 3 corticolimbic subtypes based on the neurofibrillary tangle distribution throughout the hippocampus and association cortices: limbic predominant, typical, and hippocampal sparing. In vivo, a fourth subtype, dubbed "minimal atrophy,"was identified using structural MRI. The objective of this study was to identify a neuropathologic proxy for the neuroimaging-defined minimal atrophy subtype.MethodsWe applied 2 strategies in the Florida Autopsied Multi-Ethnic (FLAME) cohort to evaluate a neuropathologic proxy for the minimal atrophy subtype. In the first strategy, we selected AD cases with a Braak tangle stage IV (Braak IV) because of the relative paucity of neocortical tangle involvement compared with Braak >IV. Braak IV cases were compared with the 3 AD subtypes. In the alternative strategy, typical AD was stratified by brain weight and cases having a relatively high brain weight (>75th percentile) were defined as minimal atrophy.ResultsBraak IV cases (n = 37) differed from AD subtypes (limbic predominant [n = 174], typical [n = 986], and hippocampal sparing [n = 187] AD) in having the least years of education (median 12 years, group-wise p < 0.001) and the highest brain weight (median 1,140 g, p = 0.002). Braak IV cases most resembled the limbic predominant cases owing to their high proportion of APOE ϵ4 carriers (75%, p < 0.001), an amnestic syndrome (100%, p < 0.001), as well as older age of cognitive symptom onset and death (median 79 and 85 years, respectively, p < 0.001). Only 5% of Braak IV cases had amygdala-predominant Lewy bodies (the lowest frequency observed, p = 0.017), whereas 32% had coexisting pathology of Lewy body disease, which was greater than the other subtypes (p = 0.005). Nearly half (47%) of the Braak IV samples had coexisting limbic predominant age-related TAR DNA-binding protein 43 encephalopathy neuropathologic change. Cases with a high brain weight (n = 201) were less likely to have amygdala-predominant Lewy bodies (14%, p = 0.006) and most likely to have Lewy body disease (31%, p = 0.042) compared with those with middle (n = 455) and low (n = 203) brain weight.DiscussionThe frequency of Lewy body disease was increased in both neuropathologic proxies of the minimal atrophy subtype. We hypothesize that Lewy body disease may underlie cognitive decline observed in minimal atrophy cases.
AB - Background and ObjectivesAlzheimer disease (AD) is neuropathologically classified into 3 corticolimbic subtypes based on the neurofibrillary tangle distribution throughout the hippocampus and association cortices: limbic predominant, typical, and hippocampal sparing. In vivo, a fourth subtype, dubbed "minimal atrophy,"was identified using structural MRI. The objective of this study was to identify a neuropathologic proxy for the neuroimaging-defined minimal atrophy subtype.MethodsWe applied 2 strategies in the Florida Autopsied Multi-Ethnic (FLAME) cohort to evaluate a neuropathologic proxy for the minimal atrophy subtype. In the first strategy, we selected AD cases with a Braak tangle stage IV (Braak IV) because of the relative paucity of neocortical tangle involvement compared with Braak >IV. Braak IV cases were compared with the 3 AD subtypes. In the alternative strategy, typical AD was stratified by brain weight and cases having a relatively high brain weight (>75th percentile) were defined as minimal atrophy.ResultsBraak IV cases (n = 37) differed from AD subtypes (limbic predominant [n = 174], typical [n = 986], and hippocampal sparing [n = 187] AD) in having the least years of education (median 12 years, group-wise p < 0.001) and the highest brain weight (median 1,140 g, p = 0.002). Braak IV cases most resembled the limbic predominant cases owing to their high proportion of APOE ϵ4 carriers (75%, p < 0.001), an amnestic syndrome (100%, p < 0.001), as well as older age of cognitive symptom onset and death (median 79 and 85 years, respectively, p < 0.001). Only 5% of Braak IV cases had amygdala-predominant Lewy bodies (the lowest frequency observed, p = 0.017), whereas 32% had coexisting pathology of Lewy body disease, which was greater than the other subtypes (p = 0.005). Nearly half (47%) of the Braak IV samples had coexisting limbic predominant age-related TAR DNA-binding protein 43 encephalopathy neuropathologic change. Cases with a high brain weight (n = 201) were less likely to have amygdala-predominant Lewy bodies (14%, p = 0.006) and most likely to have Lewy body disease (31%, p = 0.042) compared with those with middle (n = 455) and low (n = 203) brain weight.DiscussionThe frequency of Lewy body disease was increased in both neuropathologic proxies of the minimal atrophy subtype. We hypothesize that Lewy body disease may underlie cognitive decline observed in minimal atrophy cases.
UR - http://www.scopus.com/inward/record.url?scp=85173637938&partnerID=8YFLogxK
U2 - https://doi.org/10.1212/WNL.0000000000207685
DO - https://doi.org/10.1212/WNL.0000000000207685
M3 - Article
C2 - 37580158
SN - 0028-3878
VL - 101
SP - E1412-E1423
JO - Neurology
JF - Neurology
IS - 14
ER -