Clustering of Motor and Nonmotor Traits in Leucine-Rich Repeat Kinase 2 G2019S Parkinson’s Disease Nonparkinsonian Relatives: A Multicenter Family Study Tiago A. Mestre, MD, MSc , 1,2 * Claustre Pont-Sunyer, MD, 3,4 Farah Kausar, PhD, 5 Naomi P. Visanji, PhD, 1 Taneera Ghate, MSc, 1 Barbara S. Connolly, MD, 1 Carmen Gasca-Salas, MD, PhD, 1,6 Drew S. Kern, MD, 1,7 Jennifer Jain, MD, 1 Elizabeth J. Slow, MD, PhD, 1 Achinoam Faust-Socher, MD, 1 Meike Kasten, MD, 8,9 Pettarusp M. Wadia, MD, 1,10 Cindy Zadikoff, MD, 1 Prakash Kumar, MD, 1 Ronald M. de Bie, MD, PhD, 1,11 Teri Thomsen, MD, 1,12 Anthony E. Lang, MD, 1 Birgitt Sch€ ule, MD, 5 Christine Klein, MD, 8 Eduardo Tolosa, MD, 3 and Connie Marras, MD, PhD 1 1 Movement Disorders Centre, Toronto Western Hospital, and the Edmond J Safra program in Parkinson’s Research, Toronto, Canada 2 Parkinson’s Disease and Movement Disorders Center, Division of Neurology, Department of Medicine, The Ottawa Hospital Research Institute, University of Ottawa Brain and Mind Institute, Ottawa, Canada (current affiliation) 3 Parkinson’s Disease and Movement Disorders Unit, Neurology Service, Hospital Clinic de Barcelona, Universitat de Barcelona, Institut d’Investigacions Biomediques August Pi I Sunyer, Centro de Investigaci on Biom edica en Red sobre Enfermedades Neurodegenerativas, Barcelona, Spain 4 Neurology Unit, Hospital General de Granollers, Universitat Internacional de Catalunya, Granollers, SpainBarcelona 5 Parkinson’s Institute and Clinical Center, Sunnyvale, California, USA 6 Centro Integral en Neurociencias Abarca Cid on, Hospitales de Madrid Hospitales Puerta del Sur, CEU San Pablo University, Madrid, Spain (cur- rent affiliation) 7 Department of Neurology, Movement Disorders Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA (current affiliation) 8 Institute of Neurogenetics, University of L€ ubeck, L€ ubeck, Germany 9 Department of Psychiatry and Psychotherapy, University of L€ ubeck, L€ ubeck, Germany 10 Department of Neurology, Jaslok Hospital and Research Centre, Mumbai, India (current affiliation) 11 Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (current affiliation) 12 Neurology Department, University of Iowa, Iowa City, Iowa, USA (current affiliation) ABSTRACT: Objectives: The objective of this study was to determine phenotypic features that differenti- ate nonparkinsonian first-degree relatives of PD leucine- rich repeat kinase 2 (LRRK2) G2019S multiplex families, regardless of carrier status, from healthy controls because nonparkinsonian individuals in multiplex families seem to share a propensity to present neurological features. Methods: We included nonparkinsonian first-degree relatives of LRRK2 G2019S familial PD cases and unre- lated healthy controls participating in established multi- plex family LRRK2 cohorts. Study participants underwent neurologic assessment including cognitive screening, olfaction testing, and questionnaires for day- time sleepiness, depression, and anxiety. We used a multiple logistic regression model with backward vari- able selection, validated with bootstrap resampling, to establish the best combination of motor and nonmotor features that differentiates nonparkinsonian first-degree relatives of LRRK2 G2019S familial PD cases from unre- lated healthy controls. Results: We included 142 nonparkinsonian family members and 172 unrelated healthy controls. The com- bination of past or current symptoms of anxiety (adjusted odds ratio, 4.16; 95% confidence interval, 2.01-8.63), less daytime sleepiness (adjusted odds ratio [1 unit], 0.90; 95% confidence interval, 0.83-0.97], and worse motor UPDRS score (adjusted odds ratio [1 unit], 1.4; 95% confidence interval, 1.20-1.67) distinguished non- parkinsonian family members, regardless of LRRK2 G2019S mutation status, from unrelated healthy controls. The model accuracy was good (area under the curve 5 79.3%). Conclusions: A set of motor and nonmotor features distinguishes first-degree relatives of LRRK2 G2019S ------------------------------------------------------------------------------------------------------------------------------ *Corresponding author: Dr. Tiago Mestre, Parkinson’s Disease and Movement Disorders Center, The Ottawa Hospital - Civic Campus, 1053 Carling Avenue, Ottawa ON K1Y 4E9, Canada; tmestre@toh.on.ca Relevant conflicts of interests/financial disclosures: Nothing to report. Received: 7 August 2017; Revised: 15 November 2017; Accepted: 16 November 2017 Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.27272 RESEARCH ARTICLE Movement Disorders, Vol. 00, No. 00, 2018 1