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 language | English (US) |
|---|---|
| Journal | Annals of Clinical and Translational Neurology |
| DOIs | |
| State | Accepted/In press - 2020 |
ASJC Scopus subject areas
- Neuroscience(all)
- Clinical Neurology
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Longitudinal Measurements of Glucocerebrosidase activity in Parkinson’s patients. / Alcalay, Roy N.; Wolf, Pavlina; Chiang, Ming Sum Ruby; Helesicova, Karolina; Zhang, Xiaokui Kate; Merchant, Kalpana; Hutten, Samantha J.; Scherzer, Clemens; Caspell-Garcia, Chelsea; Blauwendraat, Cornelis; Foroud, Tatiana; Nudelman, Kelly; Gan-Or, Ziv; Simuni, Tanya; Chahine, Lana M.; Levy, Oren; Zheng, Dandi; Li, Gen; Sardi, Sergio Pablo; Marek, Kenneth; Siderowf, Andrew; Seibyl, John; Coffey, Christopher; Tanner, Caroline; Tosun-Turgut, Duygu; Shaw, Leslie M.; Trojanowski, John Q.; Singleton, Andrew; Kieburtz, Karl; Toga, Arthur; Mollenhauer, Brit; Galasko, Douglas; Chahine, Lana M.; Poewe, Werner; Poston, Kathleen; Bressman, Susan; Reimer, Alyssa; Arnedo, Vanessa; Clark, Adrienne; Frasier, Mark; Kopil, Catherine; Chowdhury, Sohini; Sherer, Todd; Casaceli, Cynthia; Dorsey, Ray; Wilson, Renee; Mahes, Sugi; Salerno, Christina; Crawford, Karen; Casalin, Paola; Malferrari, Giulia; Weisz, Mali Gani; Orr-Urtreger, Avi; Montine, Thomas; Baglieri, Chris; Christini, Amanda; Russell, David; Dahodwala, Nabila; Giladi, Nir; Factor, Stewart; Hogarth, Penelope; Standaert, David; Hauser, Robert; Jankovic, Joseph; Saint-Hilaire, Marie; Richard, Irene; Shprecher, David; Fernandez, Hubert; Brockmann, Katrina; Rosenthal, Liana; Barone, Paolo; Espay, Alberto; Rowe, Dominic; Marder, Karen; Santiago, Anthony; Hu, Shu Ching; Isaacson, Stuart; Martinez, Javiar Ruiz; Tolosa, Eduardo; Tai, Yen; Politis, Marios; Smejdir, Debra; Rees, Linda; Williams, Karen; Kausar, Farah; Richardson, Whitney; Willeke, Diana; Peacock, Shawnees; Sommerfeld, Barbara; Freed, Alison; Wakeman, Katrina; Blair, Courtney; Guthrie, Stephanie; Harrell, Leigh; Hunter, Christine; Thomas, Cathi Ann; James, Raymond; Zimmerman, Grace; Brown, Victoria; Mule, Jennifer; Hilt, Ella; Ribb, Kori; Ainscough, Susan; Wethington, Misty; Ranola, Madelaine; Mejia Santana, Helen; Moreno, Juliana; Raymond, Deborah; Speketer, Krista; Carvajal, Lisbeth; Carvalo, Stephanie; Croitoru, Ioana; Garrido, Alicia; Payne, Laura Marie; Viswanth, Veena; Severt, Lawrence; Facheris, Maurizio; Soares, Holly; Mintun, Mark A.; Cedarbaum, Jesse; Taylor, Peggy; Biglan, Kevin; Vandenbroucke, Emily; Haider Sheikh, Zulfiqar; Bingol, Baris; Fischer, Tanya; Sardi, Pablo; Forrat, Remi; Reith, Alastair; Egebjerg, Jan; Hillert, Gabrielle Ahlberg; Saba, Barbara; Min, Chris; Umek, Robert; Mather, Joe; De Santi, Susan; Post, Anke; Boess, Frank; Taylor, Kirsten; Grachev, Igor; Avbersek, Andreja; Muglia, Pierandrea; Merchant, Kaplana; Tauscher, Johannes.
In: Annals of Clinical and Translational Neurology, 2020.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Longitudinal Measurements of Glucocerebrosidase activity in Parkinson’s patients
AU - Alcalay, Roy N.
AU - Wolf, Pavlina
AU - Chiang, Ming Sum Ruby
AU - Helesicova, Karolina
AU - Zhang, Xiaokui Kate
AU - Merchant, Kalpana
AU - Hutten, Samantha J.
AU - Scherzer, Clemens
AU - Caspell-Garcia, Chelsea
AU - Blauwendraat, Cornelis
AU - Foroud, Tatiana
AU - Nudelman, Kelly
AU - Gan-Or, Ziv
AU - Simuni, Tanya
AU - Chahine, Lana M.
AU - Levy, Oren
AU - Zheng, Dandi
AU - Li, Gen
AU - Sardi, Sergio Pablo
AU - Marek, Kenneth
AU - Siderowf, Andrew
AU - Seibyl, John
AU - Coffey, Christopher
AU - Tanner, Caroline
AU - Tosun-Turgut, Duygu
AU - Shaw, Leslie M.
AU - Trojanowski, John Q.
AU - Singleton, Andrew
AU - Kieburtz, Karl
AU - Toga, Arthur
AU - Mollenhauer, Brit
AU - Galasko, Douglas
AU - Chahine, Lana M.
AU - Poewe, Werner
AU - Poston, Kathleen
AU - Bressman, Susan
AU - Reimer, Alyssa
AU - Arnedo, Vanessa
AU - Clark, Adrienne
AU - Frasier, Mark
AU - Kopil, Catherine
AU - Chowdhury, Sohini
AU - Sherer, Todd
AU - Casaceli, Cynthia
AU - Dorsey, Ray
AU - Wilson, Renee
AU - Mahes, Sugi
AU - Salerno, Christina
AU - Crawford, Karen
AU - Casalin, Paola
AU - Malferrari, Giulia
AU - Weisz, Mali Gani
AU - Orr-Urtreger, Avi
AU - Montine, Thomas
AU - Baglieri, Chris
AU - Christini, Amanda
AU - Russell, David
AU - Dahodwala, Nabila
AU - Giladi, Nir
AU - Factor, Stewart
AU - Hogarth, Penelope
AU - Standaert, David
AU - Hauser, Robert
AU - Jankovic, Joseph
AU - Saint-Hilaire, Marie
AU - Richard, Irene
AU - Shprecher, David
AU - Fernandez, Hubert
AU - Brockmann, Katrina
AU - Rosenthal, Liana
AU - Barone, Paolo
AU - Espay, Alberto
AU - Rowe, Dominic
AU - Marder, Karen
AU - Santiago, Anthony
AU - Hu, Shu Ching
AU - Isaacson, Stuart
AU - Martinez, Javiar Ruiz
AU - Tolosa, Eduardo
AU - Tai, Yen
AU - Politis, Marios
AU - Smejdir, Debra
AU - Rees, Linda
AU - Williams, Karen
AU - Kausar, Farah
AU - Richardson, Whitney
AU - Willeke, Diana
AU - Peacock, Shawnees
AU - Sommerfeld, Barbara
AU - Freed, Alison
AU - Wakeman, Katrina
AU - Blair, Courtney
AU - Guthrie, Stephanie
AU - Harrell, Leigh
AU - Hunter, Christine
AU - Thomas, Cathi Ann
AU - James, Raymond
AU - Zimmerman, Grace
AU - Brown, Victoria
AU - Mule, Jennifer
AU - Hilt, Ella
AU - Ribb, Kori
AU - Ainscough, Susan
AU - Wethington, Misty
AU - Ranola, Madelaine
AU - Mejia Santana, Helen
AU - Moreno, Juliana
AU - Raymond, Deborah
AU - Speketer, Krista
AU - Carvajal, Lisbeth
AU - Carvalo, Stephanie
AU - Croitoru, Ioana
AU - Garrido, Alicia
AU - Payne, Laura Marie
AU - Viswanth, Veena
AU - Severt, Lawrence
AU - Facheris, Maurizio
AU - Soares, Holly
AU - Mintun, Mark A.
AU - Cedarbaum, Jesse
AU - Taylor, Peggy
AU - Biglan, Kevin
AU - Vandenbroucke, Emily
AU - Haider Sheikh, Zulfiqar
AU - Bingol, Baris
AU - Fischer, Tanya
AU - Sardi, Pablo
AU - Forrat, Remi
AU - Reith, Alastair
AU - Egebjerg, Jan
AU - Hillert, Gabrielle Ahlberg
AU - Saba, Barbara
AU - Min, Chris
AU - Umek, Robert
AU - Mather, Joe
AU - De Santi, Susan
AU - Post, Anke
AU - Boess, Frank
AU - Taylor, Kirsten
AU - Grachev, Igor
AU - Avbersek, Andreja
AU - Muglia, Pierandrea
AU - Merchant, Kaplana
AU - Tauscher, Johannes
N1 - Funding Information: Funding for this study was primarily provided by the Michael J. Fox Foundation. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. The authors thank all PPMI participants for their contribution to PD research. Funding Information: Data used in the preparation of this article were obtained from the Parkinson’s Progression Markers Initiative (PPMI) database (www.ppmi‐info.org/data). For up‐to‐date information on the study, visit www.ppmi‐info.org” and the industry partners of the study “” PPMI – a public‐private partnership – is funded by the Michael J. Fox Foundation for Parkinson’s Research funding partners Abbvie, Allergan, Avid Radiopharmaceuticals, Biogen, BioLegend, Bristol‐Myers Squibb, Celgene, Denali, GE Healthcare, Genentech, GlaxoSmithKline, Lilly, Lundbeck, Merck, Meso Scale Discovery, Pfizer, Piramal, Prevail, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, Verily, and Voyager Therapeutics.” (Golub Capital) Publisher Copyright: © 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85090126779&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85090126779&partnerID=8YFLogxK
U2 - 10.1002/acn3.51164
DO - 10.1002/acn3.51164
M3 - Article
C2 - 32888397
AN - SCOPUS:85090126779
JO - Annals of Clinical and Translational Neurology
JF - Annals of Clinical and Translational Neurology
SN - 2328-9503
ER -