帕金森病家族史和多基因风险评分与纵向预后的关联
Association of Family History and Polygenic Risk Score With Longitudinal Prognosis in Parkinson Disease.
作者信息
Park Mincheol, Lee Young-Gun
机构信息
From the Department of Neurology (M.P.), Gwangmyeong Hospital, Chung-Ang University College of Medicine; and Department of Neurology (Y.L.), Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea.
出版信息
Neurol Genet. 2023 Dec 8;10(1):e200115. doi: 10.1212/NXG.0000000000200115. eCollection 2024 Feb.
BACKGROUND AND OBJECTIVES
Evidence suggests that either family history or polygenic risk score (PRS) is associated with developing Parkinson disease (PD). However, little is known about the longitudinal prognosis of PD according to family history and higher PRS.
METHODS
From the Parkinson's Progression Markers Initiative database, 395 patients with PD who followed up for more than 2 years were grouped into those with family history within first-degree, second-degree, and third-degree relatives (N = 127 [32.2%]) vs those without (N = 268 [67.8%]). The PRS of 386 patients was computed using whole-genome sequencing data. Longitudinal assessment of motor, cognition, and imaging based on dopaminergic degeneration was conducted during the regular follow-up period. Effects of family history, PRS, or both on longitudinal changes of cognition, motor severity, and nigrostriatal degeneration were tested using a linear mixed model. The risk of freezing of gait (FOG) according to family history was assessed using the Kaplan-Meier analysis and Cox regression models.
RESULTS
During a median follow-up of 9.1 years, PD with positive family history showed a slower decline of caudate dopamine transporter uptake (β estimate of family history × time = 0.02, 95% CI = 0.002-0.036, = 0.027). Family history of PD and higher PRS were independently associated with a slower decline of Montreal Cognitive Assessment (β estimate of family history × time = 0.12, 95% CI = 0.02-0.22, = 0.017; β estimate of PRS × time = 0.09, 95% CI = 0.03-0.16, = 0.006). In those 364 patients without FOG at baseline, PD with positive family history had a lower risk of FOG (hazard ratio of family history = 0.57, 95% CI = 0.38-0.84, = 0.005).
DISCUSSION
Having a family history of PD predicts slower progression of cognitive decline and caudate dopaminergic degeneration, and less FOG compared with those without a family history independent of PRS. Taken together, information on family history could be used as a proxy for the clinical heterogeneity of PD.
TRIAL REGISTRATION INFORMATION
The study was registered at clinicaltrials.gov (NCT01141023), and the enrollment began June 1, 2010.
背景与目的
有证据表明，家族病史或多基因风险评分（PRS）与帕金森病（PD）的发生有关。然而，关于根据家族病史和较高的PRS对PD进行纵向预后的了解却很少。
方法
从帕金森病进展标志物倡议数据库中，将395例随访超过2年的PD患者分为有一级、二级和三级亲属家族病史的患者（N = 127 [32.2%]）和无家族病史的患者（N = 268 [67.8%]）。使用全基因组测序数据计算386例患者的PRS。在定期随访期间，基于多巴胺能变性对运动、认知和影像学进行纵向评估。使用线性混合模型测试家族病史、PRS或两者对认知、运动严重程度和黑质纹状体变性纵向变化的影响。使用Kaplan-Meier分析和Cox回归模型评估根据家族病史发生冻结步态（FOG）的风险。
结果
在中位随访9.1年期间，有阳性家族病史的PD患者尾状核多巴胺转运体摄取下降较慢（家族病史×时间的β估计值 = 0.02，95%CI = 0.002 - 0.036，P = 0.027）。PD家族病史和较高的PRS与蒙特利尔认知评估下降较慢独立相关（家族病史×时间的β估计值 = 0.12，95%CI = 0.02 - 0.22，P = 0.017；PRS×时间的β估计值 = 0.09，95%CI = 0.03 - 0.16，P = 0.006）。在基线时无FOG的364例患者中，有阳性家族病史的PD患者发生FOG的风险较低（家族病史的风险比 = 0.57，95%CI = 0.38 - 0.84，P = 0.005）。
讨论
与无家族病史的患者相比，有PD家族病史预示着认知衰退和尾状核多巴胺能变性进展较慢，且FOG较少，与PRS无关。综上所述，家族病史信息可作为PD临床异质性的替代指标。
试验注册信息
该研究在clinicaltrials.gov注册（NCT01141023），入组于2010年6月1日开始。
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