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Clustering of motor and nonmotor traits in leucine-rich repeat kinase 2 G2019S Parkinson's disease nonparkinsonian relatives: A multicenter family study.
Mov Disord 2018; 33(6):960-965MD

Abstract

OBJECTIVES

The objective of this study was to determine phenotypic features that differentiate 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 unrelated healthy controls participating in established multiplex family LRRK2 cohorts. Study participants underwent neurologic assessment including cognitive screening, olfaction testing, and questionnaires for daytime sleepiness, depression, and anxiety. We used a multiple logistic regression model with backward variable 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 unrelated healthy controls.

RESULTS

We included 142 nonparkinsonian family members and 172 unrelated healthy controls. The combination 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 nonparkinsonian family members, regardless of LRRK2 G2019S mutation status, from unrelated healthy controls. The model accuracy was good (area under the curve = 79.3%).

CONCLUSIONS

A set of motor and nonmotor features distinguishes first-degree relatives of LRRK2 G2019S probands, regardless of mutation status, from unrelated healthy controls. Environmental or non-LRRK2 genetic factors in LRRK2-associated PD may influence penetrance of the LRRK2 G2019S mutation. The relationship of these features to actual PD risk requires longitudinal observation of LRRK2 familial PD cohorts. © 2018 International Parkinson and Movement Disorder Society.

Authors+Show Affiliations

Movement Disorders Centre, Toronto Western Hospital, and the Edmond J Safra program in Parkinson's Research, Toronto, Canada. 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).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 Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Barcelona, Spain. Neurology Unit, Hospital General de Granollers, Universitat Internacional de Catalunya, Granollers, Spain, Barcelona.Parkinson's Institute and Clinical Center, Sunnyvale, California, USA.Movement Disorders Centre, Toronto Western Hospital, and the Edmond J Safra program in Parkinson's Research, Toronto, Canada.Movement Disorders Centre, Toronto Western Hospital, and the Edmond J Safra program in Parkinson's Research, Toronto, Canada.Movement Disorders Centre, Toronto Western Hospital, and the Edmond J Safra program in Parkinson's Research, Toronto, Canada.Movement Disorders Centre, Toronto Western Hospital, and the Edmond J Safra program in Parkinson's Research, Toronto, Canada. Centro Integral en Neurociencias Abarca Cidón, Hospitales de Madrid Hospitales Puerta del Sur, CEU San Pablo University, Madrid, Spain (current affiliation).Movement Disorders Centre, Toronto Western Hospital, and the Edmond J Safra program in Parkinson's Research, Toronto, Canada. Department of Neurology, Movement Disorders Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA (current affiliation).Movement Disorders Centre, Toronto Western Hospital, and the Edmond J Safra program in Parkinson's Research, Toronto, Canada.Movement Disorders Centre, Toronto Western Hospital, and the Edmond J Safra program in Parkinson's Research, Toronto, Canada.Movement Disorders Centre, Toronto Western Hospital, and the Edmond J Safra program in Parkinson's Research, Toronto, Canada.Institute of Neurogenetics, University of Lübeck, Lübeck, Germany. Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany.Movement Disorders Centre, Toronto Western Hospital, and the Edmond J Safra program in Parkinson's Research, Toronto, Canada. Department of Neurology, Jaslok Hospital and Research Centre, Mumbai, India (current affiliation).Movement Disorders Centre, Toronto Western Hospital, and the Edmond J Safra program in Parkinson's Research, Toronto, Canada.Movement Disorders Centre, Toronto Western Hospital, and the Edmond J Safra program in Parkinson's Research, Toronto, Canada.Movement Disorders Centre, Toronto Western Hospital, and the Edmond J Safra program in Parkinson's Research, Toronto, Canada. Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (current affiliation).Movement Disorders Centre, Toronto Western Hospital, and the Edmond J Safra program in Parkinson's Research, Toronto, Canada. Neurology Department, University of Iowa, Iowa City, Iowa, USA (current affiliation).Movement Disorders Centre, Toronto Western Hospital, and the Edmond J Safra program in Parkinson's Research, Toronto, Canada.Parkinson's Institute and Clinical Center, Sunnyvale, California, USA.Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.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 Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Barcelona, Spain.Movement Disorders Centre, Toronto Western Hospital, and the Edmond J Safra program in Parkinson's Research, Toronto, Canada.

Pub Type(s)

Journal Article
Multicenter Study

Language

eng

PubMed ID

29665080

Citation

Mestre, Tiago A., et al. "Clustering of Motor and Nonmotor Traits in Leucine-rich Repeat Kinase 2 G2019S Parkinson's Disease Nonparkinsonian Relatives: a Multicenter Family Study." Movement Disorders : Official Journal of the Movement Disorder Society, vol. 33, no. 6, 2018, pp. 960-965.
Mestre TA, Pont-Sunyer C, Kausar F, et al. Clustering of motor and nonmotor traits in leucine-rich repeat kinase 2 G2019S Parkinson's disease nonparkinsonian relatives: A multicenter family study. Mov Disord. 2018;33(6):960-965.
Mestre, T. A., Pont-Sunyer, C., Kausar, F., Visanji, N. P., Ghate, T., Connolly, B. S., ... Marras, C. (2018). Clustering of motor and nonmotor traits in leucine-rich repeat kinase 2 G2019S Parkinson's disease nonparkinsonian relatives: A multicenter family study. Movement Disorders : Official Journal of the Movement Disorder Society, 33(6), pp. 960-965. doi:10.1002/mds.27272.
Mestre TA, et al. Clustering of Motor and Nonmotor Traits in Leucine-rich Repeat Kinase 2 G2019S Parkinson's Disease Nonparkinsonian Relatives: a Multicenter Family Study. Mov Disord. 2018;33(6):960-965. PubMed PMID: 29665080.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Clustering of motor and nonmotor traits in leucine-rich repeat kinase 2 G2019S Parkinson's disease nonparkinsonian relatives: A multicenter family study. AU - Mestre,Tiago A, AU - Pont-Sunyer,Claustre, AU - Kausar,Farah, AU - Visanji,Naomi P, AU - Ghate,Taneera, AU - Connolly,Barbara S, AU - Gasca-Salas,Carmen, AU - Kern,Drew S, AU - Jain,Jennifer, AU - Slow,Elizabeth J, AU - Faust-Socher,Achinoam, AU - Kasten,Meike, AU - Wadia,Pettarusp M, AU - Zadikoff,Cindy, AU - Kumar,Prakash, AU - de Bie,Ronald M, AU - Thomsen,Teri, AU - Lang,Anthony E, AU - Schüle,Birgitt, AU - Klein,Christine, AU - Tolosa,Eduardo, AU - Marras,Connie, Y1 - 2018/04/17/ PY - 2017/08/07/received PY - 2017/11/15/revised PY - 2017/11/16/accepted PY - 2018/4/18/pubmed PY - 2019/9/4/medline PY - 2018/4/18/entrez KW - G2019S KW - LRRK2 KW - Parkinson's disease KW - anxiety KW - daytime sleepiness KW - motor UPDRS SP - 960 EP - 965 JF - Movement disorders : official journal of the Movement Disorder Society JO - Mov. Disord. VL - 33 IS - 6 N2 - OBJECTIVES: The objective of this study was to determine phenotypic features that differentiate 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 unrelated healthy controls participating in established multiplex family LRRK2 cohorts. Study participants underwent neurologic assessment including cognitive screening, olfaction testing, and questionnaires for daytime sleepiness, depression, and anxiety. We used a multiple logistic regression model with backward variable 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 unrelated healthy controls. RESULTS: We included 142 nonparkinsonian family members and 172 unrelated healthy controls. The combination 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 nonparkinsonian family members, regardless of LRRK2 G2019S mutation status, from unrelated healthy controls. The model accuracy was good (area under the curve = 79.3%). CONCLUSIONS: A set of motor and nonmotor features distinguishes first-degree relatives of LRRK2 G2019S probands, regardless of mutation status, from unrelated healthy controls. Environmental or non-LRRK2 genetic factors in LRRK2-associated PD may influence penetrance of the LRRK2 G2019S mutation. The relationship of these features to actual PD risk requires longitudinal observation of LRRK2 familial PD cohorts. © 2018 International Parkinson and Movement Disorder Society. SN - 1531-8257 UR - https://www.unboundmedicine.com/medline/citation/29665080/Clustering_of_motor_and_nonmotor_traits_in_leucine_rich_repeat_kinase_2_G2019S_Parkinson's_disease_nonparkinsonian_relatives:_A_multicenter_family_study_ L2 - https://doi.org/10.1002/mds.27272 DB - PRIME DP - Unbound Medicine ER -