TDP-43 Is Associated with Subiculum and Cornu Ammonis 1 Hippocampal Subfield Atrophy in Primary Age-Related Tauopathy

Article type: Research Article

Authors: Youssef, Hossam^a | Gatto, Rodolfo G.^a | Pham, Nha Trang Thu^b | Petersen, Ronald C.^a | Machulda, Mary M.^c | Reichard, R. Ross ^d | Dickson, Dennis W.^e | Jack, Clifford R.^b | Whitwell, Jennifer L.^b | Josephs, Keith A.^{a; *}

Affiliations: [a] Department of Neurology, Mayo Clinic, Rochester, MN, USA | [b] Department of Radiology, Mayo Clinic, Rochester, MN, USA | [c] Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN, USA | [d] Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA | [e] Department of Neuroscience (Neuropathology), Mayo Clinic, Jacksonville, FL, USA

Correspondence: [*] Correspondence to: Keith A. Josephs, MD, MST, MSc, Professor of Neurology and Neuroscience, Ani Professor of Alzheimer’s Disease Research, Behavioral Neurology and Movement Disorders, Department of Neurology, Mayo Clinic, College of Medicine, and Science, 200 First ST S.W., Rochester, MN 55902, USA. Tel.: +1 507 266 4106; E-mail: [email protected].

Abstract: Background: TAR DNA binding protein 43 (TDP-43) has been shown to be associated with whole hippocampal atrophy in primary age-related tauopathy (PART). It is currently unknown which subregions of the hippocampus are contributing to TDP-43 associated whole hippocampal atrophy in PART. Objective: To identify which specific hippocampal subfield regions are contributing to TDP-43-associated whole hippocampal atrophy in PART. Methods:A total of 115 autopsied cases from the Mayo Clinic Alzheimer Disease Research Center, Neurodegenerative Research Group, and the Mayo Clinic Study of Aging were analyzed. All cases underwent antemortem brain volumetric MRI, neuropathological assessment of the distribution of Aβ (Thal phase), and neurofibrillary tangle (Braak stage) to diagnose PART, as well as assessment of TDP-43 presence/absence in the amygdala, hippocampus and beyond. Hippocampal subfield segmentation was performed using FreeSurfer version 7.4.1. Statistical analyses using logistic regression were performed to assess for associations between TDP-43 and hippocampal subfield volumes, accounting for potential confounders. Results: TDP-43 positive patients (n = 37, 32%), of which 15/15 were type-α, had significantly smaller whole hippocampal volumes, and smaller volumes of the body and tail of the hippocampus compared to TDP-43 negative patients. Subfield analyses revealed an association between TDP-43 and the molecular layer of hippocampal body and the body of cornu ammonis 1 (CA1), subiculum, and presubiculum regions. There was no association between TDP-43 stage and subfield volumes. Conclusions: Whole hippocampal volume loss linked to TDP-43 in PART is mainly due to volume loss occurring in the molecular layer, CA1, subiculum and presubiculum of the hippocampal body.

Keywords: Alzheimer’s disease, Cornu Ammonis 1, LATE-NC, primary age-related tauopathy, TAR DNA binding Protein 43, type-alpha

DOI: 10.3233/JAD-240136

Journal: Journal of Alzheimer's Disease, vol. 99, no. 3, pp. 1023-1032, 2024