Kopal Jakub, Vo Andrew, Tao Qin, Simuni Tanya, Chahine Lana M, Bzdok Danilo, Dagher Alain
Centre for Precision Psychiatry, Division of Mental Health and Addiction, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
medRxiv. 2025 Mar 10:2025.03.09.25323610. doi: 10.1101/2025.03.09.25323610.
gene variants are a major genetic risk factor for both familial and sporadic Parkinson's disease (PD), opening an unattended window on the disease's mechanisms and potential therapies. Investigating the influence of pathogenic variants in gene on brain structure is a crucial step toward enabling early diagnosis and personalized treatment. Yet, despite its significance, the ways in which 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. In this study, we overcome such important limitations by combining explicit modeling of population background variation and pattern matching. Specifically, we leveraged a large cohort of 641 participants (including 364 with a PD diagnosis) to examine MRI-detectable cortical atrophy patterns associated with the pathogenic variants in people with PD and non-manifesting individuals. LRRK2 PD patients exhibited 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 showed no significant cortical atrophy, indicating no structural signs of subclinical PD. We further analyzed the relationship between aggregated alpha-synuclein in cerebrospinal fluid and atrophy. We found that those with evidence of aggregated alpha-synuclein experienced pronounced neurodegeneration and increased cortical thinning, possibly defining another aggressive PD subtype. Our findings highlight avenues for distinguishing PD subtypes, which could lead to more targeted treatment approaches and a more complete understanding of Parkinson's disease progression.
基因变异是家族性和散发性帕金森病（PD）的主要遗传风险因素，为该疾病的发病机制和潜在治疗方法打开了一扇未被关注的窗口。研究基因中致病变异对脑结构的影响是实现早期诊断和个性化治疗的关键一步。然而，尽管其意义重大，但基因型影响脑结构的方式在很大程度上仍未得到探索。该领域的研究受到样本量小和队列组成差异的困扰，这可能掩盖临床亚组之间的真正差异。在本研究中，我们通过结合群体背景变异的显式建模和模式匹配克服了这些重要限制。具体而言，我们利用了一个由641名参与者组成的大型队列（包括364名被诊断为PD的患者），来检查与PD患者和未表现出症状的个体中的致病变异相关的MRI可检测到的皮质萎缩模式。与散发性PD相比，携带LRRK2基因的PD患者皮质变薄程度较轻，颞叶和枕叶区域有明显保留，这表明存在一种独特的神经退行性变模式。未表现出症状的LRRK2基因携带者没有明显的皮质萎缩，表明没有亚临床PD的结构迹象。我们进一步分析了脑脊液中聚集的α-突触核蛋白与萎缩之间的关系。我们发现，有聚集α-突触核蛋白证据的患者经历了明显的神经退行性变和皮质变薄增加，这可能定义了另一种侵袭性PD亚型。我们的研究结果突出了区分PD亚型的途径，这可能会带来更有针对性的治疗方法，并更全面地了解帕金森病的进展。
