PDF(Pubmed)
Abstract：
UNASSIGNED: 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.
UNASSIGNED: 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-beta1-42, total tau, phospho-tau181, urine bis(monoacylglycerol)phosphate levels, and serum neurofilament light chain. Linear mixed effects models examined differences in trajectory in CSF negative and positive groups.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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-beta1-42, total tau, phospho-tau181, urine bis(monoacylglycerol)phosphate levels, and serum neurofilament light chain. Linear mixed effects models examined differences in trajectory in CSF negative and positive groups.
UNASSIGNED: 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.
UNASSIGNED: 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.
摘要：
■在LRRK2相关帕金森病伴黑质变性的病例中，超过三分之二的证据表明有病理性α-突触核蛋白，但很多人没有。了解此类个体的临床表型和潜在生物学对于治疗发展至关重要。我们的目标是比较临床和生物标志物特征，以及4年随访期间的进展率，在有和没有体内α-突触核蛋白聚集体证据的LRRK2相关帕金森病病例中。
■数据来自帕金森进展标志物倡议，多中心前瞻性队列研究。样品包括诊断患有帕金森病的个体,其在LRRK2中具有致病变体。用种子扩增测定法评估CSFα-突触核蛋白聚集的存在。进行了一系列临床和患者报告的结果评估。生物标志物包括多巴胺转运蛋白SPECT扫描，CSF淀粉样蛋白-β1-42，总tau,磷酸化-tau181,尿双（单酰基甘油）磷酸盐水平，和血清神经丝轻链。线性混合效应模型检查了CSF阴性和阳性组的轨迹差异。
■148例LRRK2-帕金森综合征（86％为G2019S变体），包括46个阴性和102个阳性的CSFα-突触核蛋白种子扩增测定。在基线,阴性组比阳性组年龄大（中位数[四分位距]69.1[65.2-72.3]vs61.5[55.6-66.9]岁，p<0.001)，女性比例更高(28(61%)vs43(42%)，p=0.035)。尽管年纪大了,阴性组自诊断以来的持续时间相似，和类似的运动等级量表(16[11-23]vs16[10-22]，p=0.480），但左旋多巴当量较低。阴性组仅有13例（29%）出现过充血，与阳性组的75（77％）相比。在阴性组与阳性组（0.36[0.29-0.45]vs0.26[0.22-0.37]，年龄和性别预期的最低壳核多巴胺转运体结合更大，p<0.001)。与阳性组相比，阴性组的血清神经丝轻链更高（17.10[13.60-22.10]vs10.50[8.43-14.70]；年龄调整后的p值=0.013）。在纵向变化方面，阴性组的功能评定量表得分保持稳定，而阳性组的功能评定量表得分每年显着增加（恶化）0.729（p=0.037），但是没有发现其他轨迹差异。
■在被诊断为帕金森病的LRRK2基因致病变异的个体中，我们发现,与无CSFα-突触核蛋白聚集体体内证据的病例相比,临床和生物标志物存在差异.没有α-突触核蛋白聚集体证据的LRRK2帕金森病病例作为一组表现出不那么严重的运动表现和下降可能具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-帕金森病病例的潜在生物学需要进一步研究。
■数据来自帕金森进展标志物倡议，多中心前瞻性队列研究。样品包括诊断患有帕金森病的个体,其在LRRK2中具有致病变体。用种子扩增测定法评估CSFα-突触核蛋白聚集的存在。进行了一系列临床和患者报告的结果评估。生物标志物包括多巴胺转运蛋白SPECT扫描，CSF淀粉样蛋白-β1-42，总tau,磷酸化-tau181,尿双（单酰基甘油）磷酸盐水平，和血清神经丝轻链。线性混合效应模型检查了CSF阴性和阳性组的轨迹差异。
■148例LRRK2-帕金森综合征（86％为G2019S变体），包括46个阴性和102个阳性的CSFα-突触核蛋白种子扩增测定。在基线,阴性组比阳性组年龄大（中位数[四分位距]69.1[65.2-72.3]vs61.5[55.6-66.9]岁，p<0.001)，女性比例更高(28(61%)vs43(42%)，p=0.035)。尽管年纪大了,阴性组自诊断以来的持续时间相似，和类似的运动等级量表(16[11-23]vs16[10-22]，p=0.480），但左旋多巴当量较低。阴性组仅有13例（29%）出现过充血，与阳性组的75（77％）相比。在阴性组与阳性组（0.36[0.29-0.45]vs0.26[0.22-0.37]，年龄和性别预期的最低壳核多巴胺转运体结合更大，p<0.001)。与阳性组相比，阴性组的血清神经丝轻链更高（17.10[13.60-22.10]vs10.50[8.43-14.70]；年龄调整后的p值=0.013）。在纵向变化方面，阴性组的功能评定量表得分保持稳定，而阳性组的功能评定量表得分每年显着增加（恶化）0.729（p=0.037），但是没有发现其他轨迹差异。
■在被诊断为帕金森病的LRRK2基因致病变异的个体中，我们发现,与无CSFα-突触核蛋白聚集体体内证据的病例相比,临床和生物标志物存在差异.没有α-突触核蛋白聚集体证据的LRRK2帕金森病病例作为一组表现出不那么严重的运动表现和下降可能具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-帕金森病病例的潜在生物学需要进一步研究。
