Department of Neurology, Mount Sinai Beth Israel Medical Center, New York, New York.
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York.
JAMA Neurol. 2018 Mar 1;75(3):312-319. doi: 10.1001/jamaneurol.2017.4019.
Few prospective longitudinal studies have evaluated the progression of Parkinson disease (PD) in patients with the leucine-rich repeat kinase 2 (LRRK2 [OMIM 609007]) mutation. Knowledge about such progression will aid clinical trials.
To determine whether the longitudinal course of PD in patients with the LRRK2 mutation differs from the longitudinal course of PD in patients without the mutation.
DESIGN, SETTING, AND PARTICIPANTS: A prospective comprehensive assessment of a large cohort of patients from 3 sites with LRRK2 PD or with nonmutation PD was conducted from July 21, 2009, to September 30, 2016. All patients of Ashkenazi Jewish ancestry with PD were approached at each site; approximately 80% agreed to an initial visit. A total of 545 patients of Ashkenazi Jewish descent with PD who had 1 to 4 study visits were evaluated. A total of 144 patients (26.4%) had the LRRK2 G2019S mutation. Patients with GBA (OMIM 606463) mutations were excluded from the analysis.
Linear mixed-effects models for longitudinal motor scores were used to examine the association of LRRK2 mutation status with the rate of change in Unified Parkinson's Disease Rating Scale III scores using disease duration as the time scale, adjusting for sex, site, age, disease duration, cognitive score, and levodopa-equivalent dose at baseline. Mixed-effects models were used to assess change in cognition, as measured by Montreal Cognitive Assessment scores.
Among the 545 participants, 233 were women, 312 were men, and the mean (SD) age was 68.2 (9.1) years for participants with the LRRK2 mutation and 67.8 (10.7) years for those without it. Seventy-two of 144 participants with the LRRK2 mutation and 161 of 401 participants with no mutation were women. The estimate (SE) of the rate of change in the Unified Parkinson's Disease Rating Scale III motor score per year among those with the LRRK2 mutation (0.689 [0.192] points per year) was less than among those without the mutation (1.056 [0.187] points per year; difference, -0.367 [0.149] points per year; P = .02). The estimate (SE) of the difference in the rate of change of the Montreal Cognitive Assessment score between those with the LRRK2 mutation (-0.096 [0.090] points per year) and those without the mutation (-0.192 [0.102] points per year) did not reach statistical significance (difference, 0.097 [0.055] points per year; P = .08).
Prospective longitudinal follow-up of patients with PD with or without the LRRK2 G2019S mutation supports data from a cross-sectional study and demonstrates a slower decline in motor Unified Parkinson's Disease Rating Scale scores among those with LRRK2 G2019S-associated PD.
很少有前瞻性纵向研究评估富亮氨酸重复激酶 2 (LRRK2 [OMIM 609007]) 突变患者帕金森病 (PD) 的进展。了解这种进展将有助于临床试验。
确定 LRRK2 突变患者的 PD 纵向病程是否与无突变患者的 PD 纵向病程不同。
设计、地点和参与者：对来自 3 个地点的 LRRK2 PD 或非突变 PD 的大量患者进行了前瞻性综合评估，从 2009 年 7 月 21 日至 2016 年 9 月 30 日进行。每个地点都接近所有具有 PD 的阿什肯纳兹犹太人血统的患者；约 80%的患者同意进行初次就诊。评估了 545 名具有 PD 的阿什肯纳兹犹太人后裔患者，他们进行了 1 到 4 次研究访问。共有 144 名（26.4%）患者携带 LRRK2 G2019S 突变。排除携带 GBA（OMIM 606463）突变的患者进行分析。
使用线性混合效应模型对纵向运动评分进行分析，使用疾病持续时间作为时间尺度，调整性别、地点、年龄、疾病持续时间、认知评分和基线左旋多巴等效剂量，以评估 LRRK2 突变状态与统一帕金森病评定量表 III 评分变化率之间的关系。使用蒙特利尔认知评估量表评估认知变化的混合效应模型。
在 545 名参与者中，233 名女性，312 名男性，携带 LRRK2 突变的参与者平均（SD）年龄为 68.2（9.1）岁，未携带 LRRK2 突变的参与者为 67.8（10.7）岁。144 名携带 LRRK2 突变的参与者中有 72 名是女性，401 名无突变的参与者中有 161 名是女性。携带 LRRK2 突变的患者每年统一帕金森病评定量表 III 运动评分变化的估计值（SE）为 0.689 [0.192]分/年，低于无突变的患者（1.056 [0.187]分/年；差异为 0.367 [0.149]分/年；P =.02）。携带 LRRK2 突变的患者和未携带 LRRK2 突变的患者的蒙特利尔认知评估评分变化率之间的估计值（SE）差异无统计学意义（差异为 0.097 [0.055]分/年；P =.08）。
具有或不具有 LRRK2 G2019S 突变的 PD 患者的前瞻性纵向随访支持横断面研究的数据，并表明携带 LRRK2 G2019S 的 PD 患者的运动性统一帕金森病评定量表评分下降速度较慢。
