Journal article
LRRK2 -associated parkinsonism with and without in vivo evidence of alpha-synuclein aggregates: longitudinal clinical and biomarker characterization
Brain communications, Vol.7(2), fcaf103
03/04/2025
DOI: 10.1093/braincomms/fcaf103
PMCID: PMC11925012
PMID: 40114783
Abstract
Among LRRK2-associated parkinsonism cases with nigral degeneration, over two-thirds demonstrate evidence of pathologic alpha-synuclein, but many do not. Understanding the clinical phenotype and underlying biology in such individuals is critical for therapeutic development. Our objective was to compare clinical and biomarker features, and rate of progression over 4 years follow-up, among LRRK2-associated parkinsonism cases with and without in vivo evidence of alpha-synuclein aggregates. Data were from the Parkinson’s Progression Markers Initiative, a multicenter prospective cohort study. The sample included individuals diagnosed with Parkinson disease with pathogenic variants in LRRK2. Presence of CSF alpha-synuclein aggregation was assessed with seed amplification assay. A range of clinician- and patient- reported outcome assessments were administered. Biomarkers included dopamine transporter scan, CSF amyloid-beta1-42, total tau, phospho-tau181, urine bis(monoacylglycerol)phosphate levels, and serum neurofilament light chain. Linear mixed effects models examined differences in trajectory in CSF negative and positive groups. 148 LRRK2-parkinsonism cases (86% with G2019S variant), 46 negative and 102 positive for CSF alpha-synuclein seed amplification assay were included. At baseline, the negative group were older than the positive group (median [interquartile range] 69.1 [65.2-72.3] vs 61.5 [55.6-66.9] years, p<0.001) and a greater proportion were female (28 (61%) vs 43 (42%), p=0.035). Despite being older, the negative group had similar duration since diagnosis, and similar motor rating scale (16 [11-23] vs 16 [10-22], p=0.480) though lower levodopa equivalents. Only 13 (29%) of the negative group were hyposmic, compared to 75 (77%) of the positive group. The negative group, compared to the positive group, had higher percent-expected putamenal dopamine transporter binding for their age and sex (0.36 [0.29-0.45] vs 0.26 [0.22-0.37], p<0.001). Serum neurofilament light chain was higher in the negative group compared to the positive group (17.10 [13.60-22.10] vs 10.50 [8.43-14.70] pg/mL; age-adjusted p-value=0.013). In terms of longitudinal change, the negative group remained stable in functional rating scale score in contrast to the positive group who had a significant increase (worsening) of 0.729 per year (p=0.037), but no other differences in trajectory were found. Among individuals diagnosed with Parkinson disease with pathogenic variants in the LRRK2 gene, we found clinical and biomarker differences in cases without versus with in vivo evidence of CSF alpha-synuclein aggregates. LRRK2 parkinsonism cases without evidence of alpha-synuclein aggregates as a group exhibit less severe motor manifestations and decline. The underlying biology in LRRK2-parkinsonism cases without evidence of alpha-synuclein aggregates requires further investigation.
Details
- Title: Subtitle
- LRRK2 -associated parkinsonism with and without in vivo evidence of alpha-synuclein aggregates: longitudinal clinical and biomarker characterization
- Creators
- Lana Chahine - University of PittsburghDavid-Erick Lafontant - University of IowaSeung Ho Choi - University of IowaHirotaka Iwaki - National Institute on AgingCornelis Blauwendraat - National Institute on AgingAndrew B Singleton - National Institutes of HealthMichael C Brumm - University of IowaRoy N. Alcalay - Tel Aviv Sourasky Medical CenterKalpana Merchant - Northwestern UniversityKelly Nicole Holohan Nudelman - Indiana University School of MedicineAlain Dagher - Montreal Neurological Institute and HospitalAndrew Vo - McGill UniversityTao Qin - Montreal Neurological Institute and HospitalCharles S Venuto - University of Rochester Medical CenterKarl Kieburtz - University of Rochester Medical CenterKathleen L Poston - Stanford UniversitySusan Bressman - Icahn School of Medicine at Mount SinaiChelsea Caspell-GarciaPaulina Gonzalez-Latapi - Northwestern UniversityBrian Avants - InvicroChristopher Coffey - University of IowaDanna JenningsEduardo Tolosa - Universitat de BarcelonaAndrew Siderowf - University of PennsylvaniaKen Marek - Institute for Neurodegenerative DisordersTatyana Simuni - Northwestern UniversityParkinson’s Progression Markers Initiative
- Resource Type
- Journal article
- Publication Details
- Brain communications, Vol.7(2), fcaf103
- DOI
- 10.1093/braincomms/fcaf103
- PMID
- 40114783
- PMCID
- PMC11925012
- NLM abbreviation
- Brain Commun
- ISSN
- 2632-1297
- eISSN
- 2632-1297
- Publisher
- OXFORD UNIV PRESS
- Grant note
- Michael J. Fox Foundation for Parkinson's ResearchThe 4D PharmaAbbvieAcureXAllerganAmathus TherapeuticsAligning Science Across Parkinson'sAskBioAvid RadiopharmaceuticalsBial PortelaBioArcticBiogenBiohavenBioLegendBlueRock TherapeuticsBristol-Myers SquibbCalico LabsCapsida BiotherapeuticsCelgeneCerevel TherapeuticsCoave TherapeuticsDaCapo BrainscienceDenaliEdmond J. Safra FoundationEli LillyGain TherapeuticsGeneral Electric HealthCareGenentechGlaxoSmithKline (GSK)Golub CapitalHandl TherapeuticsInsitroJazz PharmaceuticalsJohnson & Johnson Innovative MedicineLundbeckMerckMeso Scale DiscoveryMission TherapeuticsNeurocrine BiosciencesNeuron23Neuropore TherapiesPfizerPiramalPrevail TherapeuticsRocheSanofiServierSun Pharma Advanced Research CompanyTakedaTevaUnion Chimique Belge (UCB)Vanqua BioVerilyVoyager TherapeuticsWeston Family FoundationYumanity TherapeuticsIntramural Research Program of the National Institute on Aging (NIA)Center for Alzheimer's and Related Dementias (CARD): AG000534 National Institutes of Health
The Parkinson's Progression Markers Initiative (PPMI)-a public-private partnership-is funded by the Michael J. Fox Foundation for Parkinson's Research and funding partners, including 4D Pharma, Abbvie, AcureX, Allergan, Amathus Therapeutics, Aligning Science Across Parkinson's, AskBio, Avid Radiopharmaceuticals, Bial Portela, BioArctic, Biogen, Biohaven, BioLegend, BlueRock Therapeutics, Bristol-Myers Squibb, Calico Labs, Capsida Biotherapeutics, Celgene, Cerevel Therapeutics, Coave Therapeutics, DaCapo Brainscience, Denali, Edmond J. Safra Foundation, Eli Lilly, Gain Therapeutics, General Electric HealthCare, Genentech, GlaxoSmithKline (GSK), Golub Capital, Handl Therapeutics, Insitro, Jazz Pharmaceuticals, Johnson & Johnson Innovative Medicine, Lundbeck, Merck, Meso Scale Discovery, Mission Therapeutics, Neurocrine Biosciences, Neuron23, Neuropore Therapies, Pfizer, Piramal, Prevail Therapeutics, Roche, Sanofi, Servier, Sun Pharma Advanced Research Company, Takeda, Teva, Union Chimique Belge (UCB), Vanqua Bio, Verily, Voyager Therapeutics, the Weston Family Foundation and Yumanity Therapeutics. This work was supported in part by the Intramural Research Program of the National Institute on Aging (NIA) and the Center for Alzheimer's and Related Dementias (CARD) under award number AG000534. H.I.'s participation in this project was part of a competi- tive contract awarded to DataTecnica LLC by the National Institutes of Health to support open science research.
- Language
- English
- Electronic publication date
- 03/06/2025
- Date published
- 03/04/2025
- Academic Unit
- Biostatistics
- Record Identifier
- 9984799677802771
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