Chahine Lana M, Lafontant David-Erick, Ho Choi Seung, Iwaki Hirotaka, Blauwendraat Cornelis, Singleton Andrew B, Brumm Michael C, Alcalay Roy N, Merchant Kalpana, Nudelman Kelly Nicole Holohan, Dagher Alain, Vo Andrew, Tao Qin, Venuto Charles S, Kieburtz Karl, Poston Kathleen L, Bressman Susan, Gonzalez-Latapi Paulina, Avants Brian, Coffey Christopher, Jennings Danna, Tolosa Eduard, Siderowf Andrew, Marek Ken, Simuni Tanya
Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA, 15213.
Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA, USA.
medRxiv. 2024 Jul 22:2024.07.22.24310806. doi: 10.1101/2024.07.22.24310806.
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 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, total tau, phospho-tau, 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.
Among individuals diagnosed with Parkinson disease with pathogenic variants in the LRRK2 gene, we found clinical and biomarker differences in cases without versus with 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.
在伴有黑质变性的LRRK2相关帕金森综合征病例中，超过三分之二有病理α-突触核蛋白的证据，但也有许多病例没有。了解这些个体的临床表型和潜在生物学特性对于治疗开发至关重要。我们的目的是比较有和没有α-突触核蛋白聚集体证据的LRRK2相关帕金森综合征病例的临床和生物标志物特征以及4年随访期间的疾病进展速度。
数据来自帕金森病进展标志物倡议组织，这是一项多中心前瞻性队列研究。样本包括诊断为帕金森病且LRRK2基因存在致病变异的个体。采用种子扩增试验评估脑脊液α-突触核蛋白聚集体的存在情况。进行了一系列临床医生和患者报告的结局评估。生物标志物包括多巴胺转运体SPECT扫描、脑脊液淀粉样蛋白β、总tau蛋白、磷酸化tau蛋白、尿双（单酰甘油）磷酸水平和血清神经丝轻链。线性混合效应模型检验了脑脊液阴性和阳性组轨迹的差异。
纳入了148例LRRK2帕金森综合征病例（86%携带G2019S变异），其中46例脑脊液α-突触核蛋白种子扩增试验为阴性，102例为阳性。在基线时，阴性组比阳性组年龄更大（中位数[四分位间距]69.1[65.2 - 72.3]岁对61.5[55.6 - 66.9]岁，p<0.001），女性比例更高（28例（61%）对43例（42%），p = 0.035）。尽管年龄较大，但阴性组自诊断以来的病程相似，运动评分量表得分相似（16[11 - 23]对16[10 - 22]，p = 0.480），不过左旋多巴等效剂量较低。阴性组中只有13例（29%）嗅觉减退，而阳性组中有75例（77%）。阴性组壳核多巴胺转运体结合率低于预期年龄和性别的最低值高于阳性组（0.36[0.29 - 0.45]对0.26[0.22 - 0.37]，p<0.001）。阴性组血清神经丝轻链高于阳性组（17.10[13.60 - 22.10]对10.50[8.43 - 14.70]；年龄调整p值 = 0.013）。就纵向变化而言，阴性组功能评分量表得分保持稳定，而阳性组每年显著增加（恶化）0.729（p = 0.037），但未发现其他轨迹差异。
在诊断为帕金森病且LRRK2基因存在致病变异的个体中，我们发现有无脑脊液α-突触核蛋白聚集体证据的病例在临床和生物标志物方面存在差异。没有α-突触核蛋白聚集体证据的LRRK2帕金森综合征病例作为一个群体表现出较轻的运动症状，疾病进展可能有更显著的认知功能障碍。没有α-突触核蛋白聚集体证据的LRRK2帕金森综合征病例的潜在生物学特性需要进一步研究。
