Tau Subtypes of Alzheimer’s Disease Determined in vivo Using Flortaucipir PET Imaging

Article type: Research Article

Authors: Charil, Arnaud^{a; 1} | Shcherbinin, Sergey^{a; *} | Southekal, Sudeepti^e | Devous, Michael D.^e | Mintun, Mark^{a; e} | Murray, Melissa E.^d | Miller, Bradley B.^a | Schwarz, Adam J.^{a; b; c; 1}

Affiliations: [a] Eli Lilly and Company, Indianapolis, IN, USA | [b] Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA | [c] Department of Radiology and Imaging Sciences, Indiana University, Indianapolis, IN, USA | [d] Mayo Clinic, Jacksonville, FL, USA | [e] Avid Radiopharmaceuticals, Philadelphia, PA, USA

Correspondence: [*] Correspondence to: Sergey Shcherbinin, PhD, Eli Lilly and Company, DC 1059, Lilly Corporate Center, 835 S Delaware St, Indianapolis, IN 46285, USA. Tel.: +1 317 220 7465; E-mail: shcherbinin_sergey@lilly.com.

Note: [1] Arnaud Charil is currently an employee of Novartis and Adam J Schwarz is currently an employee of Takeda Pharmaceuticals.

Abstract: At autopsy, individuals with Alzheimer’s disease (AD) exhibit heterogeneity in the distribution of neurofibrillary tangles in neocortical and hippocampal regions. Subtypes of AD, defined using an algorithm based on the relative number of tangle counts in these regions, have been proposed—hippocampal sparing (relative sparing of the hippocampus but high cortical load), limbic predominant (high hippocampal load but lower load in association cortices), and typical (balanced neurofibrillary tangles counts in the hippocampus and association cortices) AD—and shown to be associated with distinct antemortem clinical phenotypes. The ability to distinguish these AD subtypes from the more typical tau signature in vivo could have important implications for clinical research. Flortaucipir positron emission tomography (PET) images acquired from 45 amyloid-positive participants, defined clinically as mild cognitive impairment or AD, aged 50–92 years, 56% female, and estimated to be Braak V-VI based on their PET pattern of tau pathology, were studied. By translating the neuropathologic algorithm to flortaucipir PET scans, patterns of tau pathology consistent with autopsy findings, and with a similar prevalence, were identified in vivo. 6/45 (13%) participants were identified as hippocampal sparing and 6/45 (13%) as limbic predominant AD subtypes. Hippocampal sparing participants were significantly younger than those assigned to the other two subtypes. Worse performance on delayed recall was associated with increased hippocampal tau signal, and worse performance on the trail making test B-A was associated with lower values of the hippocampus to cortex ratio. Prospective studies can further validate the flortaucipir SUVR cut-points and the phenotype of the corresponding AD subtypes.

Keywords: Hippocampal sparing, limbic predominant, subtype, tau

DOI: 10.3233/JAD-190264

Journal: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 1037-1048, 2019