Clinical Progression in Alpha-Synuclein Positive LRRK2-PD and Sporadic Parkinson's Disease: A Longitudinal Analysis

Lucy A. Morse; Seung Ho Choi; Caroline Gochanour; David Erick Lafontant; Lana M. Chahine; Kalpana M. Merchant; Barbara Wendelberger; Tanya Simuni; Kenneth Marek; Tanya Simuni; Andrew Siderowf; Caroline Tanner; Thomas F. Tropea; Tatiana Foroud; Lana Chahine; Brit Mollenhauer; Kalpana Merchant; Douglas Galasko; Christopher Coffey; Kathleen Poston; Roseanne Dobkin; Ethan Brown; Roy Alcalay; Dan Weintraub; Emily Flagg; Kimberly Fabrizio; Susan Bressman; Cornelis Blauwendraat; Paola Casalin; Sonya Dumanis; Raymond James; Karl Kieburtz; Sneha Mantri; Werner Poewe; Michael Schwarzschild; John Seibyl1; David Standaert; Duygu Tosun-Turgut; Sohini Chowdhury; Jamie Eberling; Mark Frasier; Leslie Kirsch; Katie Kopil; Maggie Kuhl; Alyssa O'Grady; Todd Sherer; Tawny Willson; Emily Flagg; Sonja Jonsdottir; Claire Pauly; the Parkinson’s Progression Markers Initiative

doi:10.1002/mdc3.70640

Clinical Progression in Alpha-Synuclein Positive LRRK2-PD and Sporadic Parkinson's Disease: A Longitudinal Analysis

Lucy A. Morse
, Seung Ho Choi
, Caroline Gochanour
, David Erick Lafontant
, Lana M. Chahine
, Kalpana M. Merchant
, Barbara Wendelberger
, Tanya Simuni^*
, Kenneth Marek
, Tanya Simuni^*
, Andrew Siderowf
, Caroline Tanner
, Thomas F. Tropea
, Tatiana Foroud
, Lana Chahine
, Brit Mollenhauer
, Kalpana Merchant
, Douglas Galasko
, Christopher Coffey
, Kathleen Poston

Roseanne Dobkin, Ethan Brown, Roy Alcalay, Dan Weintraub, Emily Flagg, Kimberly Fabrizio, Susan Bressman, Cornelis Blauwendraat, Paola Casalin, Sonya Dumanis, Raymond James, Karl Kieburtz, Sneha Mantri, Werner Poewe, Michael Schwarzschild, John Seibyl1, David Standaert, Duygu Tosun-Turgut, Sohini Chowdhury, Jamie Eberling, Mark Frasier, Leslie Kirsch, Katie Kopil, Maggie Kuhl, Alyssa O'Grady, Todd Sherer, Tawny Willson, Emily Flagg, Sonja Jonsdottir, Claire Pauly, the Parkinson’s Progression Markers Initiative

^*Corresponding author for this work

Transversal Translational Medicine

Research output: Contribution to journal › Article › Research › peer-review

Abstract

Background: LRRK2-Parkinson's disease (LRRK2-PD) is biologically heterogeneous with approximately 30% lacking aggregated alpha synuclein (αSyn) in cerebrospinal fluid by seed amplification assay (SAA). Prior work has suggested slower progression in LRRK2-PD compared to sporadic PD (sPD). Objective: We aimed to assess how LRRK2-PD with αSyn aggregates on SAA (S+ LRRK2-PD) compares to S+ sPD. Methods: Data from the Parkinson's Progression Markers Initiative were used to compare S+ LRRK2-PD and S+ sPD cohorts propensity score-matched on age, disease duration, sex and levodopa equivalent dose (N = 79 per cohort). Baseline clinical and biological features and 4-year longitudinal features were assessed. Results: At baseline, S+ LRRK2-PD participants had lower motor scores and dopaminergic deficit. Among measures showing within group progression, longitudinal trajectories did not differ significantly between groups. Conclusions: Longitudinal clinical progression of S+ LRRK2-PD and sPD in the PPMI study is similar despite differences in baseline features.

Original language	English
Number of pages	9
Journal	Movement Disorders Clinical Practice
Early online date	19 Apr 2026
DOIs	https://doi.org/10.1002/mdc3.70640
Publication status	E-pub ahead of print - 19 Apr 2026

Keywords

LRRK2-PD
alpha-synuclein
sporadic Parkinson's disease

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Morse, L. A., Choi, S. H., Gochanour, C., Lafontant, D. E., Chahine, L. M., Merchant, K. M., Wendelberger, B., Simuni, T., Marek, K., Simuni, T., Siderowf, A., Tanner, C., Tropea, T. F., Foroud, T., Chahine, L., Mollenhauer, B., Merchant, K., Galasko, D., Coffey, C., ... the Parkinson’s Progression Markers Initiative (2026). Clinical Progression in Alpha-Synuclein Positive LRRK2-PD and Sporadic Parkinson's Disease: A Longitudinal Analysis. Movement Disorders Clinical Practice. Advance online publication. https://doi.org/10.1002/mdc3.70640

@article{9a76b6b8b887416d9fe022d154d0e285,

title = "Clinical Progression in Alpha-Synuclein Positive LRRK2-PD and Sporadic Parkinson's Disease: A Longitudinal Analysis",

abstract = "Background: LRRK2-Parkinson's disease (LRRK2-PD) is biologically heterogeneous with approximately 30\% lacking aggregated alpha synuclein (αSyn) in cerebrospinal fluid by seed amplification assay (SAA). Prior work has suggested slower progression in LRRK2-PD compared to sporadic PD (sPD). Objective: We aimed to assess how LRRK2-PD with αSyn aggregates on SAA (S+ LRRK2-PD) compares to S+ sPD. Methods: Data from the Parkinson's Progression Markers Initiative were used to compare S+ LRRK2-PD and S+ sPD cohorts propensity score-matched on age, disease duration, sex and levodopa equivalent dose (N = 79 per cohort). Baseline clinical and biological features and 4-year longitudinal features were assessed. Results: At baseline, S+ LRRK2-PD participants had lower motor scores and dopaminergic deficit. Among measures showing within group progression, longitudinal trajectories did not differ significantly between groups. Conclusions: Longitudinal clinical progression of S+ LRRK2-PD and sPD in the PPMI study is similar despite differences in baseline features.",

keywords = "LRRK2-PD, alpha-synuclein, sporadic Parkinson's disease",

author = "Morse, \{Lucy A.\} and Choi, \{Seung Ho\} and Caroline Gochanour and Lafontant, \{David Erick\} and Chahine, \{Lana M.\} and Merchant, \{Kalpana M.\} and Barbara Wendelberger and Tanya Simuni and Kenneth Marek and Tanya Simuni and Andrew Siderowf and Caroline Tanner and Tropea, \{Thomas F.\} and Tatiana Foroud and Lana Chahine and Brit Mollenhauer and Kalpana Merchant and Douglas Galasko and Christopher Coffey and Kathleen Poston and Roseanne Dobkin and Ethan Brown and Roy Alcalay and Dan Weintraub and Emily Flagg and Kimberly Fabrizio and Susan Bressman and Cornelis Blauwendraat and Paola Casalin and Sonya Dumanis and Raymond James and Karl Kieburtz and Sneha Mantri and Werner Poewe and Michael Schwarzschild and John Seibyl1 and David Standaert and Duygu Tosun-Turgut and Sohini Chowdhury and Jamie Eberling and Mark Frasier and Leslie Kirsch and Katie Kopil and Maggie Kuhl and Alyssa O'Grady and Todd Sherer and Tawny Willson and Emily Flagg and Sonja Jonsdottir and Claire Pauly and \{the Parkinson{\textquoteright}s Progression Markers Initiative\}",

note = "{\textcopyright} 2026 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.",

year = "2026",

month = apr,

day = "19",

doi = "10.1002/mdc3.70640",

language = "English",

journal = "Movement Disorders Clinical Practice",

issn = "2330-1619",

publisher = "John Wiley and Sons Ltd",

}

Morse, LA, Choi, SH, Gochanour, C, Lafontant, DE, Chahine, LM, Merchant, KM, Wendelberger, B, Simuni, T, Marek, K, Simuni, T, Siderowf, A, Tanner, C, Tropea, TF, Foroud, T, Chahine, L, Mollenhauer, B, Merchant, K, Galasko, D, Coffey, C, Poston, K, Dobkin, R, Brown, E, Alcalay, R, Weintraub, D, Flagg, E, Fabrizio, K, Bressman, S, Blauwendraat, C, Casalin, P, Dumanis, S, James, R, Kieburtz, K, Mantri, S, Poewe, W, Schwarzschild, M, Seibyl1, J, Standaert, D, Tosun-Turgut, D, Chowdhury, S, Eberling, J, Frasier, M, Kirsch, L, Kopil, K, Kuhl, M, O'Grady, A, Sherer, T, Willson, T, Flagg, E, Jonsdottir, S , Pauly, C & the Parkinson’s Progression Markers Initiative 2026, 'Clinical Progression in Alpha-Synuclein Positive LRRK2-PD and Sporadic Parkinson's Disease: A Longitudinal Analysis', Movement Disorders Clinical Practice. https://doi.org/10.1002/mdc3.70640

TY - JOUR

T1 - Clinical Progression in Alpha-Synuclein Positive LRRK2-PD and Sporadic Parkinson's Disease

T2 - A Longitudinal Analysis

AU - Morse, Lucy A.

AU - Choi, Seung Ho

AU - Gochanour, Caroline

AU - Lafontant, David Erick

AU - Chahine, Lana M.

AU - Merchant, Kalpana M.

AU - Wendelberger, Barbara

AU - Simuni, Tanya

AU - Marek, Kenneth

AU - Simuni, Tanya

AU - Siderowf, Andrew

AU - Tanner, Caroline

AU - Tropea, Thomas F.

AU - Foroud, Tatiana

AU - Chahine, Lana

AU - Mollenhauer, Brit

AU - Merchant, Kalpana

AU - Galasko, Douglas

AU - Coffey, Christopher

AU - Poston, Kathleen

AU - Dobkin, Roseanne

AU - Brown, Ethan

AU - Alcalay, Roy

AU - Weintraub, Dan

AU - Flagg, Emily

AU - Fabrizio, Kimberly

AU - Bressman, Susan

AU - Blauwendraat, Cornelis

AU - Casalin, Paola

AU - Dumanis, Sonya

AU - James, Raymond

AU - Kieburtz, Karl

AU - Mantri, Sneha

AU - Poewe, Werner

AU - Schwarzschild, Michael

AU - Seibyl1, John

AU - Standaert, David

AU - Tosun-Turgut, Duygu

AU - Chowdhury, Sohini

AU - Eberling, Jamie

AU - Frasier, Mark

AU - Kirsch, Leslie

AU - Kopil, Katie

AU - Kuhl, Maggie

AU - O'Grady, Alyssa

AU - Sherer, Todd

AU - Willson, Tawny

AU - Flagg, Emily

AU - Jonsdottir, Sonja

AU - Pauly, Claire

AU - the Parkinson’s Progression Markers Initiative

PY - 2026/4/19

Y1 - 2026/4/19

N2 - Background: LRRK2-Parkinson's disease (LRRK2-PD) is biologically heterogeneous with approximately 30% lacking aggregated alpha synuclein (αSyn) in cerebrospinal fluid by seed amplification assay (SAA). Prior work has suggested slower progression in LRRK2-PD compared to sporadic PD (sPD). Objective: We aimed to assess how LRRK2-PD with αSyn aggregates on SAA (S+ LRRK2-PD) compares to S+ sPD. Methods: Data from the Parkinson's Progression Markers Initiative were used to compare S+ LRRK2-PD and S+ sPD cohorts propensity score-matched on age, disease duration, sex and levodopa equivalent dose (N = 79 per cohort). Baseline clinical and biological features and 4-year longitudinal features were assessed. Results: At baseline, S+ LRRK2-PD participants had lower motor scores and dopaminergic deficit. Among measures showing within group progression, longitudinal trajectories did not differ significantly between groups. Conclusions: Longitudinal clinical progression of S+ LRRK2-PD and sPD in the PPMI study is similar despite differences in baseline features.

AB - Background: LRRK2-Parkinson's disease (LRRK2-PD) is biologically heterogeneous with approximately 30% lacking aggregated alpha synuclein (αSyn) in cerebrospinal fluid by seed amplification assay (SAA). Prior work has suggested slower progression in LRRK2-PD compared to sporadic PD (sPD). Objective: We aimed to assess how LRRK2-PD with αSyn aggregates on SAA (S+ LRRK2-PD) compares to S+ sPD. Methods: Data from the Parkinson's Progression Markers Initiative were used to compare S+ LRRK2-PD and S+ sPD cohorts propensity score-matched on age, disease duration, sex and levodopa equivalent dose (N = 79 per cohort). Baseline clinical and biological features and 4-year longitudinal features were assessed. Results: At baseline, S+ LRRK2-PD participants had lower motor scores and dopaminergic deficit. Among measures showing within group progression, longitudinal trajectories did not differ significantly between groups. Conclusions: Longitudinal clinical progression of S+ LRRK2-PD and sPD in the PPMI study is similar despite differences in baseline features.

KW - LRRK2-PD

KW - alpha-synuclein

KW - sporadic Parkinson's disease

UR - https://www.scopus.com/pages/publications/105039050293

UR - https://pubmed.ncbi.nlm.nih.gov/42003081/

U2 - 10.1002/mdc3.70640

DO - 10.1002/mdc3.70640

M3 - Article

C2 - 42003081

AN - SCOPUS:105039050293

SN - 2330-1619

JO - Movement Disorders Clinical Practice

JF - Movement Disorders Clinical Practice

ER -

Clinical Progression in Alpha-Synuclein Positive LRRK2-PD and Sporadic Parkinson's Disease: A Longitudinal Analysis

Abstract

Keywords

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