Preprint
LRRK2-Associated Parkinsonism With and Without In Vivo Evidence of Alpha-Synuclein Aggregates
medRxiv : the preprint server for health sciences
Cold Spring Harbor Laboratory
07/22/2024
DOI: 10.1101/2024.07.22.24310806
PMCID: PMC11302724
PMID: 39108519
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.BackgroundAmong 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 SPECT scan, CSF amyloid-beta 1-42 , total tau, phospho-tau 181 , urine bis(monoacylglycerol)phosphate levels, and serum neurofilament light chain. Linear mixed effects models examined differences in trajectory in CSF negative and positive groups.MethodsData 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 SPECT scan, CSF amyloid-beta 1-42 , total tau, phospho-tau 181 , 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. Lowest putamen dopamine transporter binding expected for age and sex was greater in the negative vs positive groups (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]; 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.Results148 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. Lowest putamen dopamine transporter binding expected for age and sex was greater in the negative vs positive groups (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]; 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 may have more significant cognitive dysfunction. The underlying biology in LRRK2-parkinsonism cases without evidence of alpha-synuclein aggregates requires further investigation.ConclusionAmong 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 may have more significant cognitive dysfunction. 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
- Creators
- Lana M 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 - Columbia University Irving Medical CenterKalpana Merchant - Northwestern UniversityKelly Nicole Holohan Nudelman - Indiana University School of MedicineAlain Dagher - Montreal Neurological Institute and HospitalAndrew Vo - McGill UniversityQin Tao - 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 SinaiPaulina Gonzalez-Latapi - Northwestern UniversityBrian Avants - Invicro (United States)Christopher Coffey - University of IowaDanna Jennings - Denali Therapeutics (United States)Eduard Tolosa - Consorci Institut D'Investigacions Biomediques August Pi I SunyerAndrew Siderowf - University of PennsylvaniaKen Marek - Institute for Neurodegenerative DisordersTanya Simuni - Northwestern University
- Resource Type
- Preprint
- Publication Details
- medRxiv : the preprint server for health sciences
- DOI
- 10.1101/2024.07.22.24310806
- PMID
- 39108519
- PMCID
- PMC11302724
- Publisher
- Cold Spring Harbor Laboratory
- Language
- English
- Date posted
- 07/22/2024
- Academic Unit
- Biostatistics
- Record Identifier
- 9984696702302771
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