Progression in the LRRK2-Asssociated Parkinson disease population

Rachel Saunders-Pullman, Anat Mirelman, Roy N. Alcalay, Cuiling Wang, Roberto A. Ortega, Deborah Raymond, Helen Mejia-Santana, Martha Orbe-Reilly, Brooke A. Johannes, Avner Thaler, Laurie Ozelius, Avi Orr-Urtreger, Karen S. Marder, Nir Giladi, Susan B. Bressman

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Abstract

IMPORTANCE Few prospective longitudinal studies have evaluated the progression of Parkinson disease (PD) in patients with the leucine-rich repeat kinase 2 (LRRK2 [OMIM 609007]) mutation. Knowledge about such progression will aid clinical trials. OBJECTIVE To determine whether the longitudinal course of PD in patients with the LRRK2 mutation differs from the longitudinal course of PD in patients without the mutation. DESIGN, SETTING, AND PARTICIPANTS A prospective comprehensive assessment of a large cohort of patients from 3 sites with LRRK2 PD or with nonmutation PD was conducted from July 21, 2009, to September 30, 2016. All patients of Ashkenazi Jewish ancestry with PD were approached at each site; approximately 80% agreed to an initial visit. A total of 545 patients of Ashkenazi Jewish descent with PD who had 1 to 4 study visits were evaluated. A total of 144 patients (26.4%) had the LRRK2 G2019S mutation. Patients with GBA (OMIM 606463) mutations were excluded from the analysis. MAIN OUTCOMES AND MEASURES Linear mixed-effects models for longitudinal motor scores were used to examine the association of LRRK2 mutation status with the rate of change in Unified Parkinson's Disease Rating Scale III scores using disease duration as the time scale, adjusting for sex, site, age, disease duration, cognitive score, and levodopa-equivalent dose at baseline. Mixed-effects models were used to assess change in cognition, as measured by Montreal Cognitive Assessment scores. RESULTS Among the 545 participants, 233 were women, 312 were men, and the mean (SD) age was 68.2 (9.1) years for participants with the LRRK2 mutation and 67.8 (10.7) years for those without it. Seventy-Two of 144 participants with the LRRK2 mutation and 161 of 401 participants with no mutation were women. The estimate (SE) of the rate of change in the Unified Parkinson's Disease Rating Scale III motor score per year among those with the LRRK2 mutation (0.689 [0.192] points per year) was less than among those without the mutation (1.056 [0.187] points per year; difference, -0.367 [0.149] points per year; P = .02). The estimate (SE) of the difference in the rate of change of the Montreal Cognitive Assessment score between those with the LRRK2 mutation (-0.096 [0.090] points per year) and those without the mutation (-0.192 [0.102] points per year) did not reach statistical significance (difference, 0.097 [0.055] points per year; P = .08). CONCLUSIONS AND RELEVANCE Prospective longitudinal follow-up of patients with PD with or without the LRRK2 G2019S mutation supports data from a cross-sectional study and demonstrates a slower decline in motor Unified Parkinson's Disease Rating Scale scores among those with LRRK2 G2019S-associated PD.

Original languageEnglish (US)
Pages (from-to)312-319
Number of pages8
JournalJAMA Neurology
Volume75
Issue number3
DOIs
StatePublished - Mar 1 2018

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Parkinson Disease
Mutation
Population
Genetic Databases
Levodopa
Leucine
Cognition
Longitudinal Studies
Phosphotransferases
Cross-Sectional Studies
Clinical Trials
Prospective Studies

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Saunders-Pullman, R., Mirelman, A., Alcalay, R. N., Wang, C., Ortega, R. A., Raymond, D., ... Bressman, S. B. (2018). Progression in the LRRK2-Asssociated Parkinson disease population. JAMA Neurology, 75(3), 312-319. https://doi.org/10.1001/jamaneurol.2017.4019

Progression in the LRRK2-Asssociated Parkinson disease population. / Saunders-Pullman, Rachel; Mirelman, Anat; Alcalay, Roy N.; Wang, Cuiling; Ortega, Roberto A.; Raymond, Deborah; Mejia-Santana, Helen; Orbe-Reilly, Martha; Johannes, Brooke A.; Thaler, Avner; Ozelius, Laurie; Orr-Urtreger, Avi; Marder, Karen S.; Giladi, Nir; Bressman, Susan B.

In: JAMA Neurology, Vol. 75, No. 3, 01.03.2018, p. 312-319.

Research output: Contribution to journalArticle

Saunders-Pullman, R, Mirelman, A, Alcalay, RN, Wang, C, Ortega, RA, Raymond, D, Mejia-Santana, H, Orbe-Reilly, M, Johannes, BA, Thaler, A, Ozelius, L, Orr-Urtreger, A, Marder, KS, Giladi, N & Bressman, SB 2018, 'Progression in the LRRK2-Asssociated Parkinson disease population', JAMA Neurology, vol. 75, no. 3, pp. 312-319. https://doi.org/10.1001/jamaneurol.2017.4019
Saunders-Pullman R, Mirelman A, Alcalay RN, Wang C, Ortega RA, Raymond D et al. Progression in the LRRK2-Asssociated Parkinson disease population. JAMA Neurology. 2018 Mar 1;75(3):312-319. https://doi.org/10.1001/jamaneurol.2017.4019
Saunders-Pullman, Rachel ; Mirelman, Anat ; Alcalay, Roy N. ; Wang, Cuiling ; Ortega, Roberto A. ; Raymond, Deborah ; Mejia-Santana, Helen ; Orbe-Reilly, Martha ; Johannes, Brooke A. ; Thaler, Avner ; Ozelius, Laurie ; Orr-Urtreger, Avi ; Marder, Karen S. ; Giladi, Nir ; Bressman, Susan B. / Progression in the LRRK2-Asssociated Parkinson disease population. In: JAMA Neurology. 2018 ; Vol. 75, No. 3. pp. 312-319.
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abstract = "IMPORTANCE Few prospective longitudinal studies have evaluated the progression of Parkinson disease (PD) in patients with the leucine-rich repeat kinase 2 (LRRK2 [OMIM 609007]) mutation. Knowledge about such progression will aid clinical trials. OBJECTIVE To determine whether the longitudinal course of PD in patients with the LRRK2 mutation differs from the longitudinal course of PD in patients without the mutation. DESIGN, SETTING, AND PARTICIPANTS A prospective comprehensive assessment of a large cohort of patients from 3 sites with LRRK2 PD or with nonmutation PD was conducted from July 21, 2009, to September 30, 2016. All patients of Ashkenazi Jewish ancestry with PD were approached at each site; approximately 80{\%} agreed to an initial visit. A total of 545 patients of Ashkenazi Jewish descent with PD who had 1 to 4 study visits were evaluated. A total of 144 patients (26.4{\%}) had the LRRK2 G2019S mutation. Patients with GBA (OMIM 606463) mutations were excluded from the analysis. MAIN OUTCOMES AND MEASURES Linear mixed-effects models for longitudinal motor scores were used to examine the association of LRRK2 mutation status with the rate of change in Unified Parkinson's Disease Rating Scale III scores using disease duration as the time scale, adjusting for sex, site, age, disease duration, cognitive score, and levodopa-equivalent dose at baseline. Mixed-effects models were used to assess change in cognition, as measured by Montreal Cognitive Assessment scores. RESULTS Among the 545 participants, 233 were women, 312 were men, and the mean (SD) age was 68.2 (9.1) years for participants with the LRRK2 mutation and 67.8 (10.7) years for those without it. Seventy-Two of 144 participants with the LRRK2 mutation and 161 of 401 participants with no mutation were women. The estimate (SE) of the rate of change in the Unified Parkinson's Disease Rating Scale III motor score per year among those with the LRRK2 mutation (0.689 [0.192] points per year) was less than among those without the mutation (1.056 [0.187] points per year; difference, -0.367 [0.149] points per year; P = .02). The estimate (SE) of the difference in the rate of change of the Montreal Cognitive Assessment score between those with the LRRK2 mutation (-0.096 [0.090] points per year) and those without the mutation (-0.192 [0.102] points per year) did not reach statistical significance (difference, 0.097 [0.055] points per year; P = .08). CONCLUSIONS AND RELEVANCE Prospective longitudinal follow-up of patients with PD with or without the LRRK2 G2019S mutation supports data from a cross-sectional study and demonstrates a slower decline in motor Unified Parkinson's Disease Rating Scale scores among those with LRRK2 G2019S-associated PD.",
author = "Rachel Saunders-Pullman and Anat Mirelman and Alcalay, {Roy N.} and Cuiling Wang and Ortega, {Roberto A.} and Deborah Raymond and Helen Mejia-Santana and Martha Orbe-Reilly and Johannes, {Brooke A.} and Avner Thaler and Laurie Ozelius and Avi Orr-Urtreger and Marder, {Karen S.} and Nir Giladi and Bressman, {Susan B.}",
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T1 - Progression in the LRRK2-Asssociated Parkinson disease population

AU - Saunders-Pullman, Rachel

AU - Mirelman, Anat

AU - Alcalay, Roy N.

AU - Wang, Cuiling

AU - Ortega, Roberto A.

AU - Raymond, Deborah

AU - Mejia-Santana, Helen

AU - Orbe-Reilly, Martha

AU - Johannes, Brooke A.

AU - Thaler, Avner

AU - Ozelius, Laurie

AU - Orr-Urtreger, Avi

AU - Marder, Karen S.

AU - Giladi, Nir

AU - Bressman, Susan B.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - IMPORTANCE Few prospective longitudinal studies have evaluated the progression of Parkinson disease (PD) in patients with the leucine-rich repeat kinase 2 (LRRK2 [OMIM 609007]) mutation. Knowledge about such progression will aid clinical trials. OBJECTIVE To determine whether the longitudinal course of PD in patients with the LRRK2 mutation differs from the longitudinal course of PD in patients without the mutation. DESIGN, SETTING, AND PARTICIPANTS A prospective comprehensive assessment of a large cohort of patients from 3 sites with LRRK2 PD or with nonmutation PD was conducted from July 21, 2009, to September 30, 2016. All patients of Ashkenazi Jewish ancestry with PD were approached at each site; approximately 80% agreed to an initial visit. A total of 545 patients of Ashkenazi Jewish descent with PD who had 1 to 4 study visits were evaluated. A total of 144 patients (26.4%) had the LRRK2 G2019S mutation. Patients with GBA (OMIM 606463) mutations were excluded from the analysis. MAIN OUTCOMES AND MEASURES Linear mixed-effects models for longitudinal motor scores were used to examine the association of LRRK2 mutation status with the rate of change in Unified Parkinson's Disease Rating Scale III scores using disease duration as the time scale, adjusting for sex, site, age, disease duration, cognitive score, and levodopa-equivalent dose at baseline. Mixed-effects models were used to assess change in cognition, as measured by Montreal Cognitive Assessment scores. RESULTS Among the 545 participants, 233 were women, 312 were men, and the mean (SD) age was 68.2 (9.1) years for participants with the LRRK2 mutation and 67.8 (10.7) years for those without it. Seventy-Two of 144 participants with the LRRK2 mutation and 161 of 401 participants with no mutation were women. The estimate (SE) of the rate of change in the Unified Parkinson's Disease Rating Scale III motor score per year among those with the LRRK2 mutation (0.689 [0.192] points per year) was less than among those without the mutation (1.056 [0.187] points per year; difference, -0.367 [0.149] points per year; P = .02). The estimate (SE) of the difference in the rate of change of the Montreal Cognitive Assessment score between those with the LRRK2 mutation (-0.096 [0.090] points per year) and those without the mutation (-0.192 [0.102] points per year) did not reach statistical significance (difference, 0.097 [0.055] points per year; P = .08). CONCLUSIONS AND RELEVANCE Prospective longitudinal follow-up of patients with PD with or without the LRRK2 G2019S mutation supports data from a cross-sectional study and demonstrates a slower decline in motor Unified Parkinson's Disease Rating Scale scores among those with LRRK2 G2019S-associated PD.

AB - IMPORTANCE Few prospective longitudinal studies have evaluated the progression of Parkinson disease (PD) in patients with the leucine-rich repeat kinase 2 (LRRK2 [OMIM 609007]) mutation. Knowledge about such progression will aid clinical trials. OBJECTIVE To determine whether the longitudinal course of PD in patients with the LRRK2 mutation differs from the longitudinal course of PD in patients without the mutation. DESIGN, SETTING, AND PARTICIPANTS A prospective comprehensive assessment of a large cohort of patients from 3 sites with LRRK2 PD or with nonmutation PD was conducted from July 21, 2009, to September 30, 2016. All patients of Ashkenazi Jewish ancestry with PD were approached at each site; approximately 80% agreed to an initial visit. A total of 545 patients of Ashkenazi Jewish descent with PD who had 1 to 4 study visits were evaluated. A total of 144 patients (26.4%) had the LRRK2 G2019S mutation. Patients with GBA (OMIM 606463) mutations were excluded from the analysis. MAIN OUTCOMES AND MEASURES Linear mixed-effects models for longitudinal motor scores were used to examine the association of LRRK2 mutation status with the rate of change in Unified Parkinson's Disease Rating Scale III scores using disease duration as the time scale, adjusting for sex, site, age, disease duration, cognitive score, and levodopa-equivalent dose at baseline. Mixed-effects models were used to assess change in cognition, as measured by Montreal Cognitive Assessment scores. RESULTS Among the 545 participants, 233 were women, 312 were men, and the mean (SD) age was 68.2 (9.1) years for participants with the LRRK2 mutation and 67.8 (10.7) years for those without it. Seventy-Two of 144 participants with the LRRK2 mutation and 161 of 401 participants with no mutation were women. The estimate (SE) of the rate of change in the Unified Parkinson's Disease Rating Scale III motor score per year among those with the LRRK2 mutation (0.689 [0.192] points per year) was less than among those without the mutation (1.056 [0.187] points per year; difference, -0.367 [0.149] points per year; P = .02). The estimate (SE) of the difference in the rate of change of the Montreal Cognitive Assessment score between those with the LRRK2 mutation (-0.096 [0.090] points per year) and those without the mutation (-0.192 [0.102] points per year) did not reach statistical significance (difference, 0.097 [0.055] points per year; P = .08). CONCLUSIONS AND RELEVANCE Prospective longitudinal follow-up of patients with PD with or without the LRRK2 G2019S mutation supports data from a cross-sectional study and demonstrates a slower decline in motor Unified Parkinson's Disease Rating Scale scores among those with LRRK2 G2019S-associated PD.

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