Association of Dual LRRK2 G2019S and GBA Variations With Parkinson Disease Progression.
Association of Dual LRRK2 G2019S and GBA Variations With Parkinson Disease Progression.
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双LRRK2 G2019S和GBA变异与帕金森氏病进展的关联。
DOI：
10.1001/jamanetworkopen.2021.5845
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发表时间：
2021-04-01
影响因子：
13.8
通讯作者：
Saunders-Pullman R
中科院分区：
文献类型：
--
作者：
Ortega RA;Wang C;Raymond D;Bryant N;Scherzer CR;Thaler A;Alcalay RN;West AB;Mirelman A;Kuras Y;Marder KS;Giladi N;Ozelius LJ;Bressman SB;Saunders-Pullman R
同时发生的LRRK 2 G2019 S和GBA变异与帕金森病（PD）的临床进展有何关联？在这项队列研究中，结合了来自多项研究的1193名PD参与者的数据，具有双重LRRK 2 G2019 S和GBA变异PD的个体的认知下降速度比仅具有GBA PD的个体慢，这与仅具有LRRK 2 G2019 S PD的个体没有区别，支持了LRRK 2基因在具有两种变异的个体中存在显性关联的观点。LRRK 2 G2019 S和GBA变异在认知下降中也存在新的统计学相互作用。这些发现表明，在PD进展中，LRRK 2和GBA变异不存在会聚的有害关联，如基于先前的细胞研究所预期的。这项队列研究探讨了LRRK 2 G2019 S和GBA变体与帕金森病纵向认知和运动下降的相关性。尽管假设富含亮氨酸重复激酶2（LRRK 2）G2019 S变异和葡萄糖脑苷脂酶（GBA）变异与疾病发病机制存在联合有害关联，但已报道LRRK 2和GBA双重变异帕金森病（PD）的临床表型比单独的GBA变异PD更温和。评估LRRK 2 G2019 S和GBA变异体与PD患者纵向认知和运动功能下降的相关性。这项对LRRK 2 PD、GBA PD、LRRK 2/GBA PD和野生型特发性PD进行连续测量的纵向队列研究使用了来自Mount Sinai Beth Israel、帕金森病生物标志物项目、哈佛生物标志物研究、Ashkenazi Jewish-LRRK 2-Consortium、帕金森进展标志物倡议和SPOT-PD研究的2004年至2019年的汇总年度访视数据。纳入了接受GBA和LRRK 2变异筛查并完成运动或认知评估的患者。数据分析时间为2020年5月至7月。使用线性混合效应模型，以PD持续时间为时间尺度，检查LRRK 2 G2019 S和GBA基因型与蒙特利尔认知评估（莫卡）和运动障碍协会统一帕金森病评定量表第三部分评分下降率的相关性。在1193例PD患者中（平均[SD]年龄：66.6 [9.9]岁; 490例[41.2%]女性），128例（10.7%）GBA PD，155例（13.0%）LRRK 2 PD，21例（1.8%）LRRK 2/GBA PD，889例（74.5%）特发性PD。GBA PD患者的莫卡下降速度快于LRRK 2/GBA PD患者（B [SE]，-0.31 [0.09]分/年; P < .001）、LRRK 2 PD患者（B [SE]，-0.33 [0.09]分/年; P < .001）或特发性PD患者（B [SE]，-0.23 [0.08]分/年; P = .005）。在莫卡下降中存在LRRK 2 G2019 S × GBA相互作用（B [SE]，0.22 [0.11]点/y; P = 0.04），但在排除严重GBA变异后不存在（B [SE]，0.12 [0.11]点/y; P = 0.28）。与特发性PD（B [SE]，0.49 [0.22]分/年; P = 0.03）或LRRK 2 PD（B [SE]，0.77 [0.26]分/年; P = 0.004）患者相比，GBA PD患者的运动进展显著更差。这些发现表明，GBA PD患者的纵向认知功能下降比LRRK 2/GBA PD患者更严重，LRRK 2/GBA PD更接近LRRK 2 PD。这进一步支持了LRRK 2在携带两者的个体中对GBA的显性关联的概念，并提高了LRRK 2 × GBA相互作用的可能性。然而，一个占主导地位的协会或相互作用的生物学基础尚不清楚，显然是相反的基本调查。需要对具有严重GBA变异的更大个体队列进行研究。
What are the associations of concurrent LRRK2 G2019S and GBA variations with clinical progression of Parkinson disease (PD)? In this cohort study combining data for 1193 participants with PD from multiple studies, individuals with dual LRRK2 G2019S and GBA variation PD had a slower rate of cognitive decline than those with GBA PD alone, and this was not different from individuals with LRRK2 G2019S PD alone, supporting the notion that there is a dominant association of the LRRK2 gene in individuals with both variations. There was also a novel statistical interaction between LRRK2 G2019S and GBA variations in cognitive decline. These findings suggest that there was not a convergent deleterious association of LRRK2 and GBA variations in PD progression, as would be expected based on prior cellular studies. This cohort study examines the associations of LRRK2 G2019S and GBA variants with longitudinal cognitive and motor decline in Parkinson disease. Despite a hypothesis that harboring a leucine-rich repeat kinase 2(LRRK2) G2019S variation and a glucocerebrosidase (GBA) variant would have a combined deleterious association with disease pathogenesis, milder clinical phenotypes have been reported in dual LRRK2 and GBA variations Parkinson disease (PD) than in GBA variation PD alone. To evaluate the association of LRRK2 G2019S and GBA variants with longitudinal cognitive and motor decline in PD. This longitudinal cohort study of continuous measures in LRRK2 PD, GBA PD, LRRK2/GBA PD, and wild-type idiopathic PD used pooled annual visit data ranging from 2004 to 2019 from the Mount Sinai Beth Israel, Parkinson Disease Biomarker Program, Harvard Biomarkers Study, Ashkenazi Jewish-LRRK2-Consortium, Parkinson Progression Marker Initiative, and SPOT-PD studies. Patients who were screened for GBA and LRRK2 variations and completed either a motor or cognitive assessment were included. Data were analyzed from May to July 2020. The associations of LRRK2 G2019S and GBA genotypes on the rate of decline in Montreal Cognitive Assessment (MoCA) and Movement Disorders Society-Unified Parkinson Disease Rating Scale–Part III scores were examined using linear mixed effects models with PD duration as the time scale. Among 1193 individuals with PD (mean [SD] age, 66.6 [9.9] years; 490 [41.2%] women), 128 (10.7%) had GBA PD, 155 (13.0%) had LRRK2 PD, 21 (1.8%) had LRRK2/GBA PD, and 889 (74.5%) had idiopathic PD. Patients with GBA PD had faster decline in MoCA than those with LRRK2/GBA PD (B [SE], −0.31 [0.09] points/y; P < .001), LRRK2 PD (B [SE], −0.33 [0.09] points/y; P < .001), or idiopathic PD (B [SE], −0.23 [0.08] points/y; P = .005). There was a LRRK2 G2019S × GBA interaction in MoCA decline (B [SE], 0.22 [0.11] points/y; P = .04), but not after excluding severe GBA variations (B [SE], 0.12 [0.11] points/y; P = .28). Patients with GBA PD had significantly worse motor progression compared with those with idiopathic PD (B [SE], 0.49 [0.22] points/y; P = .03) or LRRK2 PD (B [SE], 0.77 [0.26] points/y; P = .004). These findings suggest that longitudinal cognitive decline in patients with GBA PD was more severe than in those with LRRK2/GBA PD, which more closely resembled LRRK2 PD. This further supports the notion of a dominant association of LRRK2 on GBA in individuals who carry both and raises the possibility of an LRRK2 × GBA interaction. However, the biological basis of a dominant association or interaction is not clear and is apparently contrary to basic investigations. Study of a larger cohort of individuals with severe GBA variation is warranted.
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影响因子：
8.6
作者：
Alcalay, Roy N.;Mirelman, Anat;Saunders-Pullman, Rachel;Tang, Ming-X;Mejia Santana, Helen;Raymond, Deborah;Roos, Ernest;Orbe-Reilly, Martha;Gurevich, Tanya;Bar Shira, Anat;Weisz, Mali Gana;Yasinovsky, Kira;Zalis, Maayan;Thaler, Avner;Deik, Andres;Barrett, Matthew James;Cabassa, Jose;Groves, Mark;Hunt, Ann L.;Lubarr, Naomi;San Luciano, Marta;Miravite, Joan;Palmese, Christina;Sachdev, Rivka;Sarva, Harini;Severt, Lawrence;Shanker, Vicki;Swan, Matthew Carrington;Soto-Valencia, Jeannie;Johannes, Brooke;Ortega, Robert;Fahn, Stanley;Cote, Lucien;Waters, Cheryl;Mazzoni, Pietro;Ford, Blair;Louis, Elan;Levy, Oren;Rosado, Llency;Ruiz, Diana;Dorovski, Tsvyatko;Pauciulo, Michael;Nichols, William;Orr-Urtreger, Avi;Ozelius, Laurie;Clark, Lorraine;Giladi, Nir;Bressman, Susan;Marder, Karen S.
通讯作者：
Marder, Karen S.
影响因子：
8.6
作者：
Omer, Nurit;Giladi, Nir;Thaler, Avner
通讯作者：
Thaler, Avner
影响因子：
14.5
作者：
Blauwendraat, Cornelis;Reed, Xylena;Singleton, Andrew B.
通讯作者：
Singleton, Andrew B.
影响因子：
8.6
作者：
Clark, LN;Nicolai, A;Marder, K
通讯作者：
Marder, K
Ninds帕金森氏病生物标志物计划。
DOI：
10.1002/mds.26438
发表时间：
2016-06
期刊：
Movement disorders : official journal of the Movement Disorder Society
影响因子：
--
作者：
Rosenthal LS;Drake D;Alcalay RN;Babcock D;Bowman FD;Chen-Plotkin A;Dawson TM;Dewey RB Jr;German DC;Huang X;Landin B;McAuliffe M;Petyuk VA;Scherzer CR;Hillaire-Clarke CS;Sieber BA;Sutherland M;Tarn C;West A;Vaillancourt D;Zhang J;Gwinn K;PDBP consortium
通讯作者：
PDBP consortium