Carriers of LRRK2 pathogenic variants show a milder, anatomically distinct brain signature of Parkinson's disease

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.

Fig. 1. Complex interrelations between subgroups in ~ 600 participant population cohort.

a Our participant sample consists of 370 participants with the diagnosis with PD diagnosis and 233 participants without PD diagnosis (inner circular bar plot). Among these, 94 non-PD participants and 77 PD patients carry LRRK2 pathogenic variants indicated by the black edge (middle circular bar plot). Finally, the outer circular bar plot depicts the ratio of asyn SAA positive (red) and asyn SAA negative (blue) participants in each subgroup. b PD patients carrying LRRK2 pathogenic variants represent the oldest subgroup. Raincloud plots display the age of each participant in one of the four subgroups. c Proportion of females among subgroups. Non-manifesting carriers with LRRK2 pathogenic variants display the highest proportion of females. The red dotted line marks an equal ratio of male and female participants. d Different disease duration in PD patients. Disease duration is plotted for PD patients separated by the presence of LRRK2 pathogenic variant. The diversity in key demographic metrics poses a challenge to comparing PD and control subgroups. Abbreviations: HC healthy controls, NMC non-manifesting carrier, PD Parkinson’s disease, sPD sporadic PD.

Fig. 2. Region-specific models accurately estimate cortical thinning in PD.

a The infographic shows the HC and sPD subgroups used to derive the reference model of PD-related brain alterations b Selection of carefully matched groups of participants. Only 104 out of 139 HC and 104 out of 293 sPD participants are carried forward to derive estimates of brain alterations associated with PD. c Propensity scores enable careful participant matching. Participants from both subgroups are matched based on age, sex, and site using a flexible propensity score matching strategy. The histograms display frequencies of propensity scores separately for sPD and HC subgroups. d Linear models incorporating diagnosis, age, sex, and site were used to predict cortical thickness and subcortical volume, with colored brain maps indicating regions where PD was associated with reduced (blue) or increased (red) structural measures. e Effect size of diagnosis across all brain regions. The heatmap shows diagnosis beta coefficients among 68 regions based on the Desikan-Killiany cortical parcellation and 14 regions defined by Harvard-Oxford subcortical atlas. Detected cortical thinning and volume loss aligns with established PD changes, underscoring our analytical protocol.

Fig. 3. Parkinson’s patients with LRRK2 pathogenic variants show a milder form of brain atrophy.

a The infographic highlights the sPD and LRRK2 PD subgroups used to assess the extent of PD-related brain atrophy. b Selection of carefully matched groups of PD patients. Only 19 out of 293 sPD and 19 out of 77 LRRK2 participants were selected based on age, sex, disease duration, and site using propensity score matching. c Transferring the model of PD-related atrophy between cohort subgroups. We apply a PD atrophy model, trained on measures from sPD and HC subgroups, to estimate regional thickness and volume in LRRK2 PD and sPD patients. We then average these estimates to derive region-specific measures. d Model estimates reveal less atrophy in LRRK2 PD patients. The plot illustrates region-wise deviations between measured and estimated morphometry, with positive values indicating preserved structure and negative values reflecting greater degeneration. The p-value denotes a two-sample t-test of prediction differences. e LRRK2 pathogenic variants are associated with less cortical thinning in temporal and occipital regions. Region-wise differences between measured and estimated brain metrics are plotted on cortical and subcortical regions for LRRK2 PD participants. Orange indicates less thinning or volume loss; purple denotes increased atrophy. f Relationship of prediction difference with PD atrophy. The diagnosis-related beta coefficients are plotted against prediction differences for every brain region. g Linking predictions of brain structure to cognitive and genetic measures. The correlations quantify linear association strength across all sPD and LRRK2 PD patients between averaged structural predictions and MDS-UPDRS III, MoCA, and PRS. h Relating regional predictions to cognitive and genetic factors. Correlations with regional predictions are shown for MDS-UPDRS III, MoCA, and PRS. Overall, patients carrying LRRK2 pathogenic variants show less brain atrophy, with preservation especially in the temporal and occipital regions.

Fig. 4. Absence of significant brain structure alterations in LRRK2 non-manifesting carriers.

a We analyze the influence of LRRK2 pathogenic variants in participants without PD diagnosis. b Selection of carefully matched groups of HC and LRRK2 NMC participants. Matched groups of 42 HC and 42 LRRK2 NMC were selected based on age, sex, and site. c Transferring the model of PD-related atrophy. We apply a PD atrophy model, trained on measures from sPD and HC subgroups, to estimate brain morphometry. d Comparable estimates of brain morphometry in controls. Boxen plots display differences between measured and predicted morphometry. The p value denotes a two-sample t-test of prediction differences. Unlike in PD patients, the presence of LRRK2 pathogenic variants alone is not associated with significant structural brain alterations in participants without PD diagnosis.

Fig. 5. Aggregated alpha-synuclein proteins associated with increased brain atrophy.

a We analyze the influence of asyn SAA measured in HC, sPD, and LRRK2 PD participants. b Matched groups of 23 asyn SAA negative and 23 asyn SAA positive participants were selected based on age, sex, disease duration, and site. c Greater atrophy in asyn SAA positive participants. Differences between measured and predicted morphometry reveal more pronounced degeneration in asyn SAA positive compared to negative individuals. d Differences between measured and predicted morphometry for asyn SAA positive participants are shown across the brain. Orange indicates regions with less atrophy than expected; purple shows greater thinning or volume loss. Our findings reveal pronounced cortical thinning specifically linked to asyn SAA positive status, with distinct cortical regions showing increased vulnerability.