Effect Modifiers of TDP-43-Associated Hippocampal Atrophy Rates in Patients with Alzheimer’s Disease Neuropathological Changes

Article type: Research Article

Authors: Buciuc, Marina^a | Wennberg, Alexandra M.^a | Weigand, Stephen D.^c | Murray, Melissa E.^e | Senjem, Matthew L.^b | Spychalla, Anthony J.^b | Boeve, Bradley F.^a | Knopman, David S.^a | Jack Jr, Clifford R.^b | Kantarci, Kejal^b | Parisi, Joseph E.^d | Dickson, Dennis W.^e | Petersen, Ronald C.^a | 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 Health Science Research, Mayo Clinic, Rochester, MN, USA | [d] Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA | [e] Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA

Correspondence: [*] Correspondence to: Keith A. Josephs, MD, MST, MSc, Professor of Neurology and Neuroscience, Mayo Clinic, College of Medicine and Science, 200 First Street S.W., Rochester, MN 55905, USA. Tel.: +1 507 538 1038; Fax: +1 507 538 6012; E-mail: josephs.keith@mayo.edu.

Abstract: Background:Transactive response DNA-binding protein of 43 kDa (TDP-43) is associated with hippocampal atrophy in Alzheimer’s disease (AD), but whether the association is modified by other factors is unknown. Objective:To evaluate whether the associations between TDP-43 and hippocampal volume and atrophy rate are affected by age, gender, apolipoprotein E (APOE) ɛ4, Lewy bodies (LBs), amyloid-β (Aβ), or Braak neurofibrillary tangle (NFT) stage. Methods:In this longitudinal neuroimaging-clinicopathological study of 468 cases with AD neuropathological changes (Aβ-positive) that had completed antemortem head MRI, we investigated how age, gender, APOE ɛ4, presence of LBs, Aβ, TDP-43, and Braak NFT stages are associated with hippocampal volumes and rates of atrophy over time. We included field strength in the models since our cohort included 1.5T and 3T scans. We then determined whether the associations between hippocampal atrophy and TDP-43 are modified by these factors using mixed effects models. Results:Older age, female gender, APOE ɛ4, higher field strength, higher TDP-43, and Braak NFT stages were associated with smaller hippocampi. Rate of atrophy was greater with higher TDP-43 and Braak NFT stage, but lower in older patients. The association of TDP-43 with greater rate of atrophy was enhanced in APOE ɛ4 carriers (p = 0.04). Conclusion:Neurodegenerative effects of TDP-43 seem to be independent of most factors except perhaps APOE in cases with AD neuropathological changes. TDP-43 and tau appear to behave independently of one another.

Keywords: Alzheimer’s disease, apolipoprotein E4, atrophy, dementia, hippocampus, MRI, pathology, TDP-43

DOI: 10.3233/JAD-191040

Journal: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1511-1523, 2020