Longitudinal Measurements of Glucocerebrosidase activity in Parkinson's patients

被引：28

作者：

Alcalay, Roy N. ^{[1
]}

Wolf, Pavlina ^{[2
]}

Chiang, Ming Sum Ruby ^{[3
]}

Helesicova, Karolina ^{[2
]}

Zhang, Xiaokui Kate ^{[2
]}

Merchant, Kalpana ^{[4
]}

Hutten, Samantha J. ^{[5
]}

Scherzer, Clemens ^{[6
,7
,8
]}

Caspell-Garcia, Chelsea ^{[9
]}

Blauwendraat, Cornelis ^{[10
]}

Foroud, Tatiana ^{[11
]}

Nudelman, Kelly ^{[11
]}

Gan-Or, Ziv ^{[12
,13
,14
]}

Simuni, Tanya ^{[4
]}

Chahine, Lana M. ^{[15
]}

Levy, Oren ^{[1
]}

Zheng, Dandi ^{[16
]}

Li, Gen ^{[16
]}

Sardi, Sergio Pablo ^{[3
]}

机构：

[1] Columbia Univ, Dept Neurol, Irving Med Ctr New York, New York, NY USA

[2] Sanofi, Translat Sci, Framingham, MA USA

[3] Sanofi, Rare & Neurol Dis Therapeut Area, Framingham, MA USA

[4] Northwestern Univ, Feinberg Sch Med, Dept Neurol, Chicago, IL 60611 USA

[5] Michael J Fox Fdn Parkinsons Res, New York, NY USA

[6] Harvard Med Sch, Adv Ctr Parkinsons Dis Res, Brigham & Womens Hosp, Boston, MA 02115 USA

[7] Harvard Med Sch, Brigham & Womens Hosp, Precis Neurol Program, Boston, MA 02115 USA

[8] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA

[9] Univ Iowa, Coll Publ Hlth, Dept Biostat, Iowa City, IA USA

[10] NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA

[11] Indiana Univ Sch Med, Med & Mol Genet, Indianapolis, IN 46202 USA

[12] McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ, Canada

[13] McGill Univ, Montreal Neurol Inst & Hosp, Montreal, PQ, Canada

[14] McGill Univ, Dept Human Genet, Montreal, PQ, Canada

[15] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA

[16] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, Irving Med Ctr New York, New York, NY USA

来源：

ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY | 2020年 / 7卷 / 10期

关键词：

LYSOSOMAL STORAGE DISORDERS; DISEASE; MUTATIONS; PERFORMANCE; DEMENTIA;

D O I：

10.1002/acn3.51164

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Objective: Reduction in glucocerebrosidase (GCase; encoded byGBA) enzymatic activity has been linked to Parkinson's disease (PD). Here, we correlated GCase activity and PD phenotype in the Parkinson's Progression Markers Initiative (PPMI) cohort. Methods: We measured GCase activity in dried blood spots from 1559 samples of participants in the inception PPMI cohort, collected in four annual visits (from baseline visit to Year-3). Participants (PD,n = 392; controls,n = 175) were fully sequenced forGBAvariants by means of genome-wide genotyping arrays, whole-exome sequencing, whole-genome sequencing, Sanger sequencing, and RNA-sequencing. Results: Fifty-two PD participants (13.4%) and 13 (7.4%) controls carried aGBAvariant.GBAstatus was strongly associated with GCase activity. Among noncarriers, GCase activity was similar between PD and controls. AmongGBAp.E326K carriers (PD,n = 20; controls,n = 5), activity was significantly lower in PD carriers than control carriers (9.53 mu mol/L/h vs. 11.68 mu mol/L/h,P = 0.035). Glucocerebrosidase activity was moderately (r = 0.45) associated with white blood cell (WBC) count. Next, we divided the noncarriers with PD to tertiles based on WBC count-corrected enzymatic activity. Members of the lower tertile had higher MDS-Unified Parkinson's Disease Rating Scale motor score in the "off" medication examination at year-III exam. Longitudinal analyses demonstrated slight reduction of activity in samples collected earlier on in the study, likely because of longer storage time. Interpretation: GCase activity is associated withGBAgenotype, WBC count, and among p.E326K variant carriers, with PD status. Reduced activity may also be associated with worse phenotype but longer follow up is required to confirm this observation.

引用

页码：1816 / 1830

页数：15

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