Carriers of LRRK2 pathogenic variants show a milder, anatomically distinct brain signature of Parkinson's disease.
Carriers of LRRK2 pathogenic variants show a milder, anatomically distinct brain signature of Parkinson's disease.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Oslo, NO · Author affiliation
Centre for Precision Psychiatry, Division of Mental Health and Addiction, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.Location evidence
Montréal, CA · Author affiliation
Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, QC, Canada.Location evidence
Chicago, US · Author affiliation
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.Location evidence
Pittsburgh, US · Author affiliation
Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.Location evidence
Québec, CA · Author affiliation
Mila - Quebec Artificial Intelligence Institute, Montréal, QC, Canada. danilo.bzdok@mcgill.ca.Location evidence
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Original abstract
BACKGROUND: Pathogenic LRRK2 gene variants are a major genetic risk factor for both familial and sporadic Parkinson's dissease (PD), opening an unattended window into disease mechanisms and potential therapies. Investigating the influence of pathogenic variants in LRRK2 gene on brain structure is a crucial step toward enabling early diagnosis and personalized treatment. Yet, despite its significance, the ways in which LRRK2 genotype affects brain structure remain largely unexplored. Work in this domain is plagued by small sample sizes and differences in cohort composition, which can obscure genuine distinctions among clinical subgroups. METHODS: In this study, we overcome such important limitations by combining explicit modeling of population background variation and pattern matching. Specifically, we leverage a cohort of 603 participants (including 370 with a PD diagnosis) to examine MRI-detectable cortical atrophy patterns associated with the LRRK2 pathogenic variants in people with PD and carriers without Parkinson's symptoms. RESULTS: LRRK2 PD patients exhibit milder cortical thinning compared to sporadic PD, with notable preservation in temporal and occipital regions, suggesting a distinct pattern of neurodegeneration. Non-manifesting LRRK2 carriers show no significant cortical atrophy, indicating no structural signs of subclinical PD. We further analyze the relationship between aggregated alpha-synuclein in cerebrospinal fluid and atrophy. We find that those with evidence of aggregated alpha-synuclein experienced pronounced neurodegeneration and increased cortical thinning, possibly defining another aggressive PD subtype. CONCLUSIONS: Our findings highlight genetic avenues for distinguishing PD subtypes, which could lead to more targeted treatment approaches and a more complete understanding of Parkinson's disease progression.