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. 2022 Oct 22;8(1):140.
doi: 10.1038/s41531-022-00404-w.

Longitudinal clinical and biomarker characteristics of non-manifesting LRRK2 G2019S carriers in the PPMI cohort

Tanya Simuni  1 , Kalpana Merchant  2 , Michael C Brumm  3 , Hyunkeun Cho  3 , Chelsea Caspell-Garcia  3 , Christopher S Coffey  3 , Lana M Chahine  4 , Roy N Alcalay  5   6 , Kelly Nudelman  7 , Tatiana Foroud  7 , Brit Mollenhauer  8 , Andrew Siderowf  9 , Caroline Tanner  10 , Hirotaka Iwaki  11 , Todd Sherer  12 , Kenneth Marek  13 ; Parkinson’s Progression Marker Initiative Authors
Collaborators, Affiliations

Longitudinal clinical and biomarker characteristics of non-manifesting LRRK2 G2019S carriers in the PPMI cohort

Tanya Simuni et al. NPJ Parkinsons Dis. .

Abstract

We examined 2-year longitudinal change in clinical features and biomarkers in LRRK2 non-manifesting carriers (NMCs) versus healthy controls (HCs) enrolled in the Parkinson's Progression Markers Initiative (PPMI). We analyzed 2-year longitudinal data from 176 LRRK2 G2019S NMCs and 185 HCs. All participants were assessed annually with comprehensive motor and non-motor scales, dopamine transporter (DAT) imaging, and biofluid biomarkers. The latter included cerebrospinal fluid (CSF) Abeta, total tau and phospho-tau; serum urate and neurofilament light chain (NfL); and urine bis(monoacylglycerol) phosphate (BMP). At baseline, LRRK2 G2019S NMCs had a mean (SD) age of 62 (7.7) years and were 56% female. 13% had DAT deficit (defined as <65% of age/sex-expected lowest putamen SBR) and 11% had hyposmia (defined as ≤15th percentile for age and sex). Only 5 of 176 LRRK2 NMCs developed PD during follow-up. Although NMCs scored significantly worse on numerous clinical scales at baseline than HCs, there was no longitudinal change in any clinical measures over 2 years or in DAT binding. There were no longitudinal differences in CSF and serum biomarkers between NMCs and HCs. Urinary BMP was significantly elevated in NMCs at all time points but did not change longitudinally. Neither baseline biofluid biomarkers nor the presence of DAT deficit correlated with 2-year change in clinical outcomes. We observed no significant 2-year longitudinal change in clinical or biomarker measures in LRRK2 G2019S NMCs in this large, well-characterized cohort even in the participants with baseline DAT deficit. These findings highlight the essential need for further enrichment biomarker discovery in addition to DAT deficit and longer follow-up to enable the selection of NMCs at the highest risk for conversion to enable future prevention clinical trials.

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Conflict of interest statement

Tanya Simuni, MD has served as a consultant for 4D Pharma, Acadia, AcureX, AskBio, Amneal, Blue Rock Therapeutics, Caraway Therapeutics, Critical Path for Parkinson’s Consortium (CPP), Denali, Michael J Fox Foundation, Neuroderm, Sanofi, Sinopia, Sunovion, Roche, Takeda, UCB, Vanqua Bio and Voyager. Dr. Simuni served on the ad board for Acadia, AcureX, AskBio, Amneal, Denali, Sunovion, Roche. Dr. Simuni has served as a member of the scientific advisory board of 4D Pharma, Neuroderm, Sanofi and UCB. Dr. Simuni has received research funding from Amneal, Biogen, Roche, Neuroderm, Sanofi, Prevail and UCB and an investigator for NINDS, MJFF, Parkinson’s Foundation. Michael C. Brumm, MS reports no disclosures. Hyunkeun Ryan Cho, PhD reports no disclosures. Chelsea Caspell-Garcia, MS reports no disclosures. Christopher S. Coffey, PhD receives funding from NINDS, NHLBI, and the Michael J. Fox Foundation. He is also a paid consultant to MJFF. Andrew Siderowf, MD has been a consultant to the following companies in the past year: Biogen, Merck, Denali, Wave Life Sciences and Prilenia Therapeutics. He has received grant funding from the Michael J. Fox Foundation and NINDS. Tatiana Foroud, PhD receives funding from the National Institutes of Health (NIH), The Michael J. Fox Foundation, the US Department of Defense. Kelly Nudelman, PhD receives funding from the National Institutes of Health (NIH), the Michael J. Fox Foundation, the National Collegiate Athletic Association, the United States Department of Defense, the United States Army Medical Research Acquisition Activity, the National Alzheimer’s Coordinating Center, the Indiana State Department of Health, the Lilly Endowment Incorporated, and Biohaven Pharmaceuticals, Inc. Brit Mollenhauer, MD is employed by Parcacelsus Kliniken Germany and the University medical center Goettingen; BM has received independent research grants from TEVA-Pharma, Desitin, Boehringer Ingelheim, GE Healthcare and honoraria for consultancy from Bayer Schering Pharma AG, Roche, AbbVie, TEVA-Pharma, Biogen and for presentations from GlaxoSmithKline, Orion Pharma, TEVA-Pharma and travel costs from TEVA-Pharma. BM is member of the executive steering committee of the Parkinson Progression Marker Initiative and the Systemic Synuclein Sampling Study of the Michael J. Fox Foundation for Parkinson’s Research and has received grants from the BMBF, EU, Parkinson Fonds Deutschland, Deutsche Parkinson Vereinigung, Michael J. Fox Foundation for Parkinson’s Research, Stifterverband für die deutsche Wissenschaft, and has scientific collaborations with Roche, Bristol Myers Squibb, Ely Lilly, Covance and Biogen. Caroline M. Tanner, MD, PhD is an employee of the San Francisco Veterans Affairs Medical Center and the University of California – San Francisco. She receives grants from the Michael J. Fox Foundation, the Parkinson’s Foundation, the Department of Defense, BioElectron, Roche/Genentech, Biogen Idec and the National Institutes of Health, compensation for serving on Data Monitoring Committees from Biotie Therapeutics, Voyager Therapeutics and Intec Pharma and personal fees for consulting from Neurocrine Biosciences, Adamas Therapeutics, Biogen Idec, 23andMe, Alexza, Grey Matter and CNS Ratings. Lana M. Chahine, MD receives research support from the Michael J. Fox Foundation, UPMC Competitive Medical Research Fund, and the University of Pittsburgh, support as site investigator for a study sponsored by Biogen, receives research support from the National Institutes of Health, receives consulting fees from Grey Matter Technologies, receives royalties from Elsevier (for authorship), and receives royalties from Wolters Kluwel (for authorship). Roy Alcalay, MD MS, receives research support from the NIH, DoD, Parkinson’s Foundation, MJFF. He received consultation fees from Avrobio, Caraway, Merck, GSK, Ono Therapeutics, Sanofi and Takeda. Hirotaka Iwaki, MD, PhD is a consultant employed by Data Tecnica International, whose participation in this is part of a consulting agreement between the US National Institutes of Health and said company. Todd Sherer, PhD is employed by The Michael J. Fox Foundation. Kenneth Marek is a consultant for MJFox Foundation, GE Healthcare, Biogen, Prothena, Roche, Neuropore, US Worldmeds, Proclara, Oxford Biomedica, Prevail, UCB, Neuraly, Lysosomal Therapetic, Inc, Neuroderm, Denali, Takeda W81XWH-06-1-0678 Establishing an ‘at risk’ cohort for Parkinson Disease Neuroprevention using olfactory testing and DAT imaging, DOD, Investigator 10/1/06–09/30/19; Parkinson Progression Marker Initiative (PPMI), Michael J. Fox Foundation, Principal Investigator; DAT imaging in LRRK2 family members, the Michael J. Fox Foundation, Principal Investigator 1/15/10–1/14/23. Ownership in Invicro, LLC.

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