Recognition memory and divergent cognitive profiles in prodromal genetic frontotemporal dementia.

Although executive dysfunction is the characteristic cognitive marker of behavioral variant frontotemporal dementia (bvFTD), episodic memory deficits are relatively common, and may be present even during the prodromal disease phase. In a cohort of mutation carriers with mild behavioral and/or cognitive symptoms consistent with prodromal bvFTD, we aimed to investigate patterns of performance on an abbreviated list learning task, with a particular focus on recognition memory. We further aimed to characterize the cognitive prodromes associated with the three major genetic causes of frontotemporal dementia, as emerging evidence suggests there may be subtle differences in cognitive profiles among carriers of different genetic mutations. Participants included 57 carriers of a pathogenic mutation in microtubule-associated protein tau (MAPT, N = 23), or progranulin (GRN, N = 15), or a or a hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72, N = 19), with mild cognitive and/or behavioral symptoms consistent with prodromal bvFTD. Familial non-carriers were included as controls (N = 143). All participants completed a comprehensive neuropsychological examination, including an abbreviated list learning test assessing episodic memory recall and recognition. MAPT mutation carriers performed worse than non-carriers in terms of list recall, and had difficulty discriminating targets from distractors on the recognition memory task, primarily due to the endorsement of distractors as targets. MAPT mutation carriers also showed nonverbal episodic memory and semantic memory dysfunction (object naming). GRN mutation carriers were variable in performance and overall the most dysexecutive. Slowed psychomotor speed was evident in C9orf72 repeat expansion carriers. Identifying the earliest cognitive indicators of bvFTD is of critical clinical and research importance. List learning may be a sensitive cognitive marker for incipient dementia in MAPT and potentially a subset of GRN carriers. Our results highlight that distinct cognitive profiles may be evident in carriers of the three disease-causing genes during the prodromal disease stage.
Competing Interests: Declaration of competing interest M.S. Barker, Ph.D.: Nothing to disclose. M. Manoochehri, B.A.: Nothing to disclose. S.J. Rizer, M.A.: Nothing to disclose. B.S. Appleby, M.D.: Has received research funding from Centers for Disease Control and prevention, National Institutes of Health, Ionis, & Alector. D. Brushaber, B.S.: Nothing to disclose. S.I. Dev, Ph.D.: Nothing to disclose. K.L. Devick, Ph.D.: Nothing to disclose. B.C. Dickerson, M.D.: Research support from National Institutes of Health, Alzheimer's Drug Discovery Foundation, consulting for Acadia, Arkuda, Axovant, Lilly, Biogen, Merck, Novartis, Wave LifeSciences. Editorial duties with payment for Elsevier (Neuroimage: Clinical and Cortex). Royalties from Oxford University Press and Cambridge University Press. J.A. Fields, Ph.D., L.P.: Receives research funding from the National Institutes of Health. T.M. Foroud, Ph.D.: Nothing to disclose. L.K. Forsberg, Ph.D.: Nothing to disclose. D.R. Galasko, M.D.: Paid consultant for Biogen, vTv Pharmaceuticals, Cognition Theraptutics, Fujirebio and Amprion and received payment as a journal Editor from Springer. N. Ghoshal, M.D., Ph.D.: Has participated or is currently participating in clinical trials of anti-dementia drugs sponsored by the following companies: Bristol Myers Squibb, Lilly/Avid Radiopharmaceuticals, Janssen, Novartis, Pfizer, Wyeth, SNIFF (The Study of Nasal Insulin to Fight Forgetfulness) study, and A4 (The Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease) trial. She receives research support from Tau Consortium and Association for Frontotemporal Dementia and is funded by the National Institutes of Health. N.R. Graff-Radford, MBBCh: Takes part in multicenter studies funded by Biogen, AbbVie, and Lilly. M. Grossman, M.D., Ed.D.: Nothing to disclose. H.W. Heuer, Ph.D.: Nothing to disclose. G-Y. Hsiung, M.D.: Has received research support as a clinical trials site investigator from Anavax, Biogen, Eli Lilly and Roche; and has received research funding from the Canadian Institutes of Health Research, Alzheimer Society of Canada, and National Institutes of Health. J. Kornak, Ph.D.: Has provided expert witness testimony for 1) Teva Pharmaceuticals in Forest Laboratories Inc. et al. v. Teva Pharmaceuticals USA, Inc., Case Nos. 1:14-cv-00121 and 1:14-cv-00686 (D. Del. filed Jan. 31, 2014 and May 30, 2014) regarding the drug Memantine; 2) for Apotex/HEC/Ezra in Novartis AG et al. v. Apotex Inc., No. 1:15-cv-975 (D. Del. filed Oct. 26, 2015, regarding the drug Fingolimod; 3) on behalf of Puma Biotechnology in Hsingching Hsu et al. versus Puma Biotechnology, INC., et al., 2018 regarding the drug Neratinib and 4) on behalf of Hikma Pharmaceuticals in Amarin Pharma, Inc versus Hikma Pharmaceuticals in 2019. He receives research support from the National Institutes of Health. I. Litvan, M.D.: Research is supported by the National Institutes of Health grants: 5P50AG005131-33, 2R01AG038791-06A, U01NS090259, U01NS100610, U01NS80818, R25NS098999, P20GM109025; U19 AG063911-1; 1R21NS114764-01A1; Parkinson Study Group, Michael J Fox Foundation, Parkinson Foundation, Lewy Body Association, Parkinson Foundation, Roche, Abbvie, Biogen, EIP-Pharma and Biohaven Pharmaceuticals. She was member of a Lundbeck Advisory Board and Corticobasal Degeneration Solutions. She receives her salary from the University of California San Diego and as Chief Editor of Frontiers in Neurology. I.R. Mackenzie, M.D.: Scientific advisory board member for Prevail Therapeutics. M.F. Mendez, M.D.: Nothing to disclose. B. Pascual, Ph.D. Nothing to disclose. K.P. Rankin, Ph.D.: Funding from the National Institutes of Health, Quest Diagnostics, the Rainwater Charitable Foundation, and the Marcus Foundation. K. Rascovsky, Ph.D.: Nothing to disclose. A.M. Staffaroni, Ph.D.: Receives research funding from the National Institute on Aging-National Institutes of Health and Larry L. Hillblom Foundation. M.C. Tartaglia, M.D.: Nothing to disclose. S. Weintraub, Ph.D.: Nothing to disclose. B. Wong, Ph.D.: Nothing to disclose. B.F. Boeve, M.D.: Has served as an investigator for clinical trials sponsored by GE Healthcareand Axovant. He receives royalties from the publication of a book entitled Behavioral Neurology Of Dementia (Cambridge Medicine, 2009,2017). He serves on the Scientific Advisory Board of the Tau Consortium. He receives research support from National Institutes of Health, the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program and the Little Family Foundation. A.L. Boxer, M.D., Ph.D.: Receives research support from National Institutes of Health, the Tau Research Consortium, the Association for Frontotemporal Degeneration and the Bluefield Project to Cure Frontotemporal Dementia. He has served as a consultant for AGTC, Alector, Arkuda, Arvinas, Bioage, Ionis, Lundbeck, Passage BIO, Samumed, Ono, Sangamo, Stealth, Transposon, UCBand Wave, and received research support from Avid, Eisai, Biogen and Roche. H. Rosen, M.D.: has received research support from Biogen Pharmaceuticals, has consulting agreements with Wave Neuroscience and Ionis Pharmaceuticals, and receives research support from National Institutes of Health. J. Goldman, M.S., M.Phil.: Receives research support from National Institutes of Health, Huntington's Disease Society of America, New York State Department of Health (RFA #1510130358). E.D. Huey, M.D.: Nothing to disclose. S. Cosentino, Ph.D.: Nothing to disclose.
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