Longitudinal Measurements of Glucocerebrosidase activity in Parkinson’s patients

Roy N. Alcalay, Pavlina Wolf, Ming Sum Ruby Chiang, Karolina Helesicova, Xiaokui Kate Zhang, Kalpana Merchant, Samantha J. Hutten, Clemens Scherzer, Chelsea Caspell-Garcia, Cornelis Blauwendraat, Tatiana Foroud, Kelly Nudelman, Ziv Gan-Or, Tanya Simuni, Lana M. Chahine, Oren Levy, Dandi Zheng, Gen Li, Sergio Pablo Sardi, Kenneth MarekAndrew Siderowf, John Seibyl, Christopher Coffey, Caroline Tanner, Duygu Tosun-Turgut, Leslie M. Shaw, John Q. Trojanowski, Andrew Singleton, Karl Kieburtz, Arthur Toga, Brit Mollenhauer, Douglas Galasko, Lana M. Chahine, Werner Poewe, Kathleen Poston, Susan Bressman, Alyssa Reimer, Vanessa Arnedo, Adrienne Clark, Mark Frasier, Catherine Kopil, Sohini Chowdhury, Todd Sherer, Cynthia Casaceli, Ray Dorsey, Renee Wilson, Sugi Mahes, Christina Salerno, Karen Crawford, Paola Casalin, Giulia Malferrari, Mali Gani Weisz, Avi Orr-Urtreger, Thomas Montine, Chris Baglieri, Amanda Christini, David Russell, Nabila Dahodwala, Nir Giladi, Stewart Factor, Penelope Hogarth, David Standaert, Robert Hauser, Joseph Jankovic, Marie Saint-Hilaire, Irene Richard, David Shprecher, Hubert Fernandez, Katrina Brockmann, Liana Rosenthal, Paolo Barone, Alberto Espay, Dominic Rowe, Karen Marder, Anthony Santiago, Shu Ching Hu, Stuart Isaacson, Javiar Ruiz Martinez, Eduardo Tolosa, Yen Tai, Marios Politis, Debra Smejdir, Linda Rees, Karen Williams, Farah Kausar, Whitney Richardson, Diana Willeke, Shawnees Peacock, Barbara Sommerfeld, Alison Freed, Katrina Wakeman, Courtney Blair, Stephanie Guthrie, Leigh Harrell, Christine Hunter, Cathi Ann Thomas, Raymond James, Grace Zimmerman, Victoria Brown, Jennifer Mule, Ella Hilt, Kori Ribb, Susan Ainscough, Misty Wethington, Madelaine Ranola, Helen Mejia Santana, Juliana Moreno, Deborah Raymond, Krista Speketer, Lisbeth Carvajal, Stephanie Carvalo, Ioana Croitoru, Alicia Garrido, Laura Marie Payne, Veena Viswanth, Lawrence Severt, Maurizio Facheris, Holly Soares, Mark A. Mintun, Jesse Cedarbaum, Peggy Taylor, Kevin Biglan, Emily Vandenbroucke, Zulfiqar Haider Sheikh, Baris Bingol, Tanya Fischer, Pablo Sardi, Remi Forrat, Alastair Reith, Jan Egebjerg, Gabrielle Ahlberg Hillert, Barbara Saba, Chris Min, Robert Umek, Joe Mather, Susan De Santi, Anke Post, Frank Boess, Kirsten Taylor, Igor Grachev, Andreja Avbersek, Pierandrea Muglia, Kaplana Merchant, Johannes Tauscher

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: Reduction in glucocerebrosidase (GCase; encoded by GBA) 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 for GBA variants 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 a GBA variant. GBA status was strongly associated with GCase activity. Among noncarriers, GCase activity was similar between PD and controls. Among GBA p.E326K carriers (PD, n = 20; controls, n = 5), activity was significantly lower in PD carriers than control carriers (9.53 µmol/L/h vs. 11.68 µmol/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 with GBA genotype, 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.

Original languageEnglish (US)
JournalAnnals of Clinical and Translational Neurology
DOIs
StateAccepted/In press - 2020

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology

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