@article{7e5bfba67b3a4a4c855444b28f5507a6,
title = "Clinical, pathophysiological and genetic features of motor symptoms in autosomal dominant Alzheimer's disease",
abstract = "Owing to an early and marked deposition of amyloid-β in the basal ganglia, autosomal dominant Alzheimer's disease could distinctly involve motor symptoms. Therefore, we aimed to assess the prevalence and characteristics of motor signs in autosomal dominant Alzheimer's disease. Baseline Unified Parkinson Disease Rating Scale part three scores (UPDRS-III) from 433 participants of the Dominantly Inherited Alzheimer's Network observational study were analysed. Motor symptoms were scrutinized with respect to associations with mutation carrier status, mutation site within PSEN1, basal ganglia amyloid-β as measured by Pittsburgh compound B PET, estimated years to symptom onset and Clinical Dementia Rating Scale-Sum of Boxes. Motor findings in mutation carriers were compared to patients with sporadic Alzheimer's disease using data of the National Alzheimer's Coordination Center. Mutation carriers showed motor findings at a higher frequency (28.4% versus 12.8%; P < 0.001) and severity (mean UPDRS-III scores 2.0 versus 0.4; P < 0.001) compared to non-carriers. Eleven of the 27 UPDRS-III items were statistically more frequently affected in mutation carriers after adjustment for multiple comparisons. Ten of these 11 items were subscale components of bradykinesia. In cognitively asymptomatic mutation carriers, dysdiadochokinesia was more frequent compared to non-carriers (right hand: 3.8% versus 0%; adjusted P = 0.023; left: 4.4% versus 0.6%; adjusted P = 0.031). In this cohort, the positive predictive value for mutation carrier status in cognitively asymptomatic participants (50% a priori risk) of dysdiadochokinesia was 100% for the right and 87.5% for the left side. Mutation carriers with motor findings more frequently were basal ganglia amyloid-β positive (84% versus 63.3%; P = 0.006) and showed more basal ganglia amyloid-β deposition (Pittsburgh compound B-standardized uptake value ratio 2.472 versus 1.928; P = 0.002) than those without. Frequency and severity of motor findings were greater in post-codon 200 PSEN1 mutations (36%; mean UPDRS-III score 3.03) compared to mutations pre-codon 200 PSEN1 (19.3%, P = 0.022; 0.91, P = 0.013). In mutation carriers, motor symptom severity was significantly positively correlated with basal ganglia amyloid-β deposition, Clinical Dementia Rating scores and estimated years to symptom onset. Mutation carriers with a Clinical Dementia Rating global score of 2 exhibited more pronounced motor symptoms than sporadic Alzheimer's disease patients with the same Clinical Dementia Rating global score (mean UPDRS-III scores 20.71 versus 5.96; P < 0.001). With a prevalence of approximately 30% and increasing severity with progression of dementia, motor symptoms are proven as a clinically relevant finding in autosomal dominant Alzheimer's disease, in particular in advanced dementia stages, that correlates with deposition of amyloid-β in the basal ganglia. In a very small per cent of cognitively asymptomatic members of families with autosomal dominant Alzheimer's disease, dysdiadochokinesia may increase the chance of an individual's status as mutation carrier.",
keywords = "Alzheimer's disease, Unified Parkinson Disease Rating Scale, amyloid-β, genetics, motor symptoms",
author = "Jonathan V{\"o}glein and Katrina Paumier and Mathias Jucker and Oliver Preische and Eric McDade and Jason Hassenstab and Benzinger, {Tammie L.} and Noble, {James M.} and Berman, {Sarah B.} and Graff-Radford, {Neill R.} and Bernardino Ghetti and Farlow, {Martin R.} and Jasmeer Chhatwal and Stephen Salloway and Chengjie Xiong and Karch, {Celeste M.} and Nigel Cairns and Hiroshi Mori and Schofield, {Peter R.} and Masters, {Colin L.} and Alison Goate and Virginia Buckles and Nick Fox and Martin Rossor and Patricio Chrem and Ricardo Allegri and Ringman, {John M.} and G{\"u}nter H{\"o}glinger and Harald Steiner and Marianne Dieterich and Christian Haass and Christoph Laske and Morris, {John C.} and Bateman, {Randall J.} and Adrian Danek and Johannes Levin",
note = "Funding Information: This project was supported by The Dominantly Inherited Alzheimer{\textquoteright}s Network (DIAN, UF1 AG032438) funded by the National Institute on Aging (NIA), the German Center for Neurodegenerative Diseases (DZNE), the NIHR Queen Square Dementia Biomedical Research Centre and the MRC Dementias Platform UK (MR/L023784/1 and MR/ 009076/1), and AMED under Grant Number JP17dk0207036 and JP17kk0205009. This work was supported by the Deutsche Forschungsgemeinschaft (DFG) within the framework of the Munich Cluster for Systems Neurology (EXC 1010 SyNergy), the European Research Council under the European Union{\textquoteright}s Seventh Framework Program (FP7/2007–2013)/ERC Grant Agreement No. 321366-Amyloid, the general legacy of Mrs. Ammer, the MetLife award, and the Cure Alzheimer{\textquoteright}s fund. The NACC database is funded by NIA/NIH Grant U01 AG016976. Funding Information: NACC data are contributed by the NIA-funded ADCs: P30 AG019610 (PI Eric Reiman, MD), P30 AG013846 (PI Neil Kowall, MD), P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P50 AG047266 (PI Todd Golde, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P50 AG005134 (PI Bradley Hyman, MD, PhD), P50 AG016574 (PI Ronald Petersen, MD, PhD), P50 AG005138 (PI Mary Sano, PhD), P30 AG008051 (PI Thomas Wisniewski, MD), P30 AG013854 (PI M. Marsel Mesulam, MD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P50 AG047366 (PI Victor Henderson, MD, MS), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P50 AG005131 (PI James Brewer, MD, PhD), P50 AG023501 (PI Bruce Miller, MD), P30 AG035982 (PI Russell Swerdlow, MD), P30 AG028383 (PI Linda Van Eldik, PhD), P30 AG053760 (PI Henry Paulson, MD, PhD), P30 AG010124 (PI John Trojanowski, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005142 (PI Helena Chui, MD), P30 AG012300 (PI Roger Rosenberg, MD), P30 AG049638 (PI Suzanne Craft, PhD), P50 AG005136 (PI Thomas Grabowski, MD), P50 AG033514 (PI Sanjay Asthana, MD, FRCP), P50 AG005681 (PI John Morris, MD), P50 AG047270 (PI Stephen Strittmatter, MD, PhD). G.H was funded by the Deutsche Forschungsgemeinschaft (DFG, HO2402/18–1, Munich Cluster for Systems Neurology SyNergy), the German Federal Ministry of Education and Research (BMBF, 01EK1605A HitTau), the NOMIS foundation (FTLD project). Publisher Copyright: {\textcopyright} 2019 The Author(s).",
year = "2019",
month = may,
day = "1",
doi = "10.1093/brain/awz050",
language = "English",
volume = "142",
pages = "1429--1440",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "5",
}