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; PPMI Investigators

doi:10.1002/acn3.51164

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, PPMI Investigators

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

22 Citations (Scopus)

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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
Pages (from-to)	1816-1830
Number of pages	15
Journal	Annals of Clinical and Translational Neurology
Volume	7
Issue number	10
Early online date	5 Sept 2020
DOIs	https://doi.org/10.1002/acn3.51164
Publication status	Published - Oct 2020

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Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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10.1002/acn3.51164Licence: CC BY-NC-ND

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Alcalay, R. N., Wolf, P., Chiang, M. S. R., Helesicova, K., Zhang, X. K., Merchant, K., Hutten, S. J., Scherzer, C., Caspell-Garcia, C., Blauwendraat, C., Foroud, T., Nudelman, K., Gan-Or, Z., Simuni, T., Chahine, L. M., Levy, O., Zheng, D., Li, G., Sardi, S. P., & PPMI Investigators (2020). Longitudinal measurements of glucocerebrosidase activity in Parkinson’s patients. Annals of Clinical and Translational Neurology, 7(10), 1816-1830. https://doi.org/10.1002/acn3.51164

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title = "Longitudinal measurements of glucocerebrosidase activity in Parkinson{\textquoteright}s patients",

abstract = "Objective: Reduction in glucocerebrosidase (GCase; encoded by GBA) enzymatic activity has been linked to Parkinson{\textquoteright}s disease (PD). Here, we correlated GCase activity and PD phenotype in the Parkinson{\textquoteright}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{\textquoteright}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.",

author = "Alcalay, {Roy N.} and Pavlina Wolf and Chiang, {Ming Sum Ruby} and Karolina Helesicova and Zhang, {Xiaokui Kate} and Kalpana Merchant and Hutten, {Samantha J.} and Clemens Scherzer and Chelsea Caspell-Garcia and Cornelis Blauwendraat and Tatiana Foroud and Kelly Nudelman and Ziv Gan-Or and Tanya Simuni and Chahine, {Lana M.} and Oren Levy and Dandi Zheng and Gen Li and Sardi, {Sergio Pablo} and {PPMI Investigators} and Kenneth Marek and Andrew Siderowf and Danna Jennings and Caroline Tanner and Christopher Coffey and Karl Kieburtz and Werner Poewe and Brit Mollenhauer and Douglas Galasko and Todd Sherer and Sohini Chowdhury and Mark Frasier and Vanessa Arnedo and Jamie Eberling and Reimer, {Alyssa N.} and Luba Smolensky and Dave Alonso and Chris Baglieri and Amanda Christini and Susan Bressman and Ray Dorsey and Cynthia Casaceli and Paola Casalin and Giulia Malferrari and Nichole Daegele and Margaret Bockus and Raymond James and Sugi Mahes and Kathleen Poston and Ekemini Riley and John Seibyl and Leslie Shaw and Andrew Singleton and Arthur Toga and Duygu Tosun-Turgut and John Trojanowski and Dan Weintraub and Emily Flagg and Roseanne Dobkin and Ethan Brown and Renee Wilson and Christina Salerno and Liz Uribe and Janel Fedler and Michael Brumm and LaFontant, {David Erick} and Karen Crawford and Weisz, {Mali Gani} and Avi Orr-Urtreger and Thomas Montine and {de Blieck}, Lisa and Whitney Richardson and David Russell and Stewart Factor and Penelope Hogarth and David Standaert and Robert Hauser and Joseph Jankovic and Nabila Dahodwala and Marie Saint-Hilaire and Irene Richard and Klaus Seppi and David Shprecher and Hubert Fernandez and Katrina Brockmann and Isabel Wurster and David Brooks and Yen Tai and Paolo Barone and Stuart Isaacson and Alberto Espay and Dominic Rowe and Christopher Way and Eduardo Tolosa and Shu-Ching Hu and Emile Moukheiber and Jean-Christophe Corvol and Nir Giladi and Martinez, {Javiar Ruiz} and Aasly, {Jan O.} and Leonidas Stefanis and Karen Marder and Julie Festa and Cheryl Riordan and Katrina Wakeman and Alison Freed and Karen Williams and Courtney Blair and Leigh Harrell and Christine Hunter and Krista Specketer and Cathi-Ann Thomas and Nicole Guerrero and Beatrice Heim and Diana Willeke and Victoria Brown and Jennifer Mule and Ella Hilt and Shawnees Peacock and Arita McCoy and Kori Ribb and Susan Ainscough and Lisbeth Pennente and Christina Gruenwald and Madelaine Ranola and Barbara Sommerfeld and Farah Kausar and Alicia Garrido and Deborah Raymond and {Le Toullec}, Benjamin and Anat Mirelman and Ioana Croitoru and Kristiansen, {Anne Grete} and Maria Stamelou and {Mejia Santana}, Helen and Mather, {Robert Joe} and Minhua Yang and Christine Brand and Cindy Zadikoff and Kirsten Taylor and Thomas McAvoy and Baris Bingol and Reith, {Alastair D.} and Peggy Taylor and Hillert, {Gabrielle Ahlberg} and Mark Mintun and Pierandrea Muglia and Robert Umek and Barbara Saba and Lawrence Severt and Karl Schmidt and Matt Troyer and Kevin Biglan and Tanya Fischer and Jeffrey Sevigny and Adam Schwarz and William Marks and Omar Khwaja",

note = "Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2020",

month = oct,

doi = "10.1002/acn3.51164",

language = "English",

volume = "7",

pages = "1816--1830",

journal = "Annals of Clinical and Translational Neurology",

issn = "2328-9503",

publisher = "John Wiley & Sons",

number = "10",

}

Alcalay, RN, Wolf, P, Chiang, MSR, Helesicova, K, Zhang, XK, Merchant, K, Hutten, SJ, Scherzer, C, Caspell-Garcia, C, Blauwendraat, C, Foroud, T, Nudelman, K, Gan-Or, Z, Simuni, T, Chahine, LM, Levy, O, Zheng, D, Li, G, Sardi, SP & PPMI Investigators 2020, 'Longitudinal measurements of glucocerebrosidase activity in Parkinson’s patients', Annals of Clinical and Translational Neurology, vol. 7, no. 10, pp. 1816-1830. https://doi.org/10.1002/acn3.51164

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 - PPMI Investigators

AU - Marek, Kenneth

AU - Siderowf, Andrew

AU - Jennings, Danna

AU - Tanner, Caroline

AU - Coffey, Christopher

AU - Kieburtz, Karl

AU - Poewe, Werner

AU - Mollenhauer, Brit

AU - Galasko, Douglas

AU - Sherer, Todd

AU - Chowdhury, Sohini

AU - Frasier, Mark

AU - Arnedo, Vanessa

AU - Eberling, Jamie

AU - Reimer, Alyssa N.

AU - Smolensky, Luba

AU - Alonso, Dave

AU - Baglieri, Chris

AU - Christini, Amanda

AU - Bressman, Susan

AU - Dorsey, Ray

AU - Casaceli, Cynthia

AU - Casalin, Paola

AU - Malferrari, Giulia

AU - Daegele, Nichole

AU - Bockus, Margaret

AU - James, Raymond

AU - Mahes, Sugi

AU - Poston, Kathleen

AU - Riley, Ekemini

AU - Seibyl, John

AU - Shaw, Leslie

AU - Singleton, Andrew

AU - Toga, Arthur

AU - Tosun-Turgut, Duygu

AU - Trojanowski, John

AU - Weintraub, Dan

AU - Flagg, Emily

AU - Dobkin, Roseanne

AU - Brown, Ethan

AU - Wilson, Renee

AU - Salerno, Christina

AU - Uribe, Liz

AU - Fedler, Janel

AU - Brumm, Michael

AU - LaFontant, David Erick

AU - Crawford, Karen

AU - Weisz, Mali Gani

AU - Orr-Urtreger, Avi

AU - Montine, Thomas

AU - de Blieck, Lisa

AU - Richardson, Whitney

AU - Russell, David

AU - Factor, Stewart

AU - Hogarth, Penelope

AU - Standaert, David

AU - Hauser, Robert

AU - Jankovic, Joseph

AU - Dahodwala, Nabila

AU - Saint-Hilaire, Marie

AU - Richard, Irene

AU - Seppi, Klaus

AU - Shprecher, David

AU - Fernandez, Hubert

AU - Brockmann, Katrina

AU - Wurster, Isabel

AU - Brooks, David

AU - Tai, Yen

AU - Barone, Paolo

AU - Isaacson, Stuart

AU - Espay, Alberto

AU - Rowe, Dominic

AU - Way, Christopher

AU - Tolosa, Eduardo

AU - Hu, Shu-Ching

AU - Moukheiber, Emile

AU - Corvol, Jean-Christophe

AU - Giladi, Nir

AU - Martinez, Javiar Ruiz

AU - Aasly, Jan O.

AU - Stefanis, Leonidas

AU - Marder, Karen

AU - Festa, Julie

AU - Riordan, Cheryl

AU - Wakeman, Katrina

AU - Freed, Alison

AU - Williams, Karen

AU - Blair, Courtney

AU - Harrell, Leigh

AU - Hunter, Christine

AU - Specketer, Krista

AU - Thomas, Cathi-Ann

AU - Guerrero, Nicole

AU - Heim, Beatrice

AU - Willeke, Diana

AU - Brown, Victoria

AU - Mule, Jennifer

AU - Hilt, Ella

AU - Peacock, Shawnees

AU - McCoy, Arita

AU - Ribb, Kori

AU - Ainscough, Susan

AU - Pennente, Lisbeth

AU - Gruenwald, Christina

AU - Ranola, Madelaine

AU - Sommerfeld, Barbara

AU - Kausar, Farah

AU - Garrido, Alicia

AU - Raymond, Deborah

AU - Le Toullec, Benjamin

AU - Mirelman, Anat

AU - Croitoru, Ioana

AU - Kristiansen, Anne Grete

AU - Stamelou, Maria

AU - Mejia Santana, Helen

AU - Mather, Robert Joe

AU - Yang, Minhua

AU - Brand, Christine

AU - Zadikoff, Cindy

AU - Taylor, Kirsten

AU - McAvoy, Thomas

AU - Bingol, Baris

AU - Reith, Alastair D.

AU - Taylor, Peggy

AU - Hillert, Gabrielle Ahlberg

AU - Mintun, Mark

AU - Muglia, Pierandrea

AU - Umek, Robert

AU - Saba, Barbara

AU - Severt, Lawrence

AU - Schmidt, Karl

AU - Troyer, Matt

AU - Biglan, Kevin

AU - Fischer, Tanya

AU - Sevigny, Jeffrey

AU - Schwarz, Adam

AU - Marks, William

AU - Khwaja, Omar

N1 - Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2020/10

Y1 - 2020/10

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

U2 - 10.1002/acn3.51164

DO - 10.1002/acn3.51164

M3 - Article

C2 - 32888397

AN - SCOPUS:85090126779

SN - 2328-9503

VL - 7

SP - 1816

EP - 1830

JO - Annals of Clinical and Translational Neurology

JF - Annals of Clinical and Translational Neurology

IS - 10

ER -

Longitudinal measurements of glucocerebrosidase activity in Parkinson’s patients

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