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ß-Glucocerebrosidase activity in GBA-linked Parkinson disease: The type of mutation matters.
Huh, Young Eun; Chiang, Ming Sum Ruby; Locascio, Joseph J; Liao, Zhixiang; Liu, Ganqiang; Choudhury, Karbi; Kuras, Yuliya I; Tuncali, Idil; Videnovic, Aleksandar; Hunt, Ann L; Schwarzschild, Michael A; Hung, Albert Y; Herrington, Todd M; Hayes, Michael T; Hyman, Bradley T; Wills, Anne-Marie; Gomperts, Stephen N; Growdon, John H; Sardi, Sergio Pablo; Scherzer, Clemens R.
Afiliación
  • Huh YE; From the APDA Center for Advanced Parkinson Research (Y.E.H., J.J.L., Z.L., G.L., K.C., Y.I.K., I.T., M.T.H., C.R.S.) and Precision Neurology Program (Y.E.H., Z.L., G.L., Y.I.K., C.R.S.), Harvard Medical School, and Department of Neurology (Y.E.H., G.L., C.R.S.), Brigham and Women's Hospital, Boston
  • Chiang MSR; From the APDA Center for Advanced Parkinson Research (Y.E.H., J.J.L., Z.L., G.L., K.C., Y.I.K., I.T., M.T.H., C.R.S.) and Precision Neurology Program (Y.E.H., Z.L., G.L., Y.I.K., C.R.S.), Harvard Medical School, and Department of Neurology (Y.E.H., G.L., C.R.S.), Brigham and Women's Hospital, Boston
  • Locascio JJ; From the APDA Center for Advanced Parkinson Research (Y.E.H., J.J.L., Z.L., G.L., K.C., Y.I.K., I.T., M.T.H., C.R.S.) and Precision Neurology Program (Y.E.H., Z.L., G.L., Y.I.K., C.R.S.), Harvard Medical School, and Department of Neurology (Y.E.H., G.L., C.R.S.), Brigham and Women's Hospital, Boston
  • Liao Z; From the APDA Center for Advanced Parkinson Research (Y.E.H., J.J.L., Z.L., G.L., K.C., Y.I.K., I.T., M.T.H., C.R.S.) and Precision Neurology Program (Y.E.H., Z.L., G.L., Y.I.K., C.R.S.), Harvard Medical School, and Department of Neurology (Y.E.H., G.L., C.R.S.), Brigham and Women's Hospital, Boston
  • Liu G; From the APDA Center for Advanced Parkinson Research (Y.E.H., J.J.L., Z.L., G.L., K.C., Y.I.K., I.T., M.T.H., C.R.S.) and Precision Neurology Program (Y.E.H., Z.L., G.L., Y.I.K., C.R.S.), Harvard Medical School, and Department of Neurology (Y.E.H., G.L., C.R.S.), Brigham and Women's Hospital, Boston
  • Choudhury K; From the APDA Center for Advanced Parkinson Research (Y.E.H., J.J.L., Z.L., G.L., K.C., Y.I.K., I.T., M.T.H., C.R.S.) and Precision Neurology Program (Y.E.H., Z.L., G.L., Y.I.K., C.R.S.), Harvard Medical School, and Department of Neurology (Y.E.H., G.L., C.R.S.), Brigham and Women's Hospital, Boston
  • Kuras YI; From the APDA Center for Advanced Parkinson Research (Y.E.H., J.J.L., Z.L., G.L., K.C., Y.I.K., I.T., M.T.H., C.R.S.) and Precision Neurology Program (Y.E.H., Z.L., G.L., Y.I.K., C.R.S.), Harvard Medical School, and Department of Neurology (Y.E.H., G.L., C.R.S.), Brigham and Women's Hospital, Boston
  • Tuncali I; From the APDA Center for Advanced Parkinson Research (Y.E.H., J.J.L., Z.L., G.L., K.C., Y.I.K., I.T., M.T.H., C.R.S.) and Precision Neurology Program (Y.E.H., Z.L., G.L., Y.I.K., C.R.S.), Harvard Medical School, and Department of Neurology (Y.E.H., G.L., C.R.S.), Brigham and Women's Hospital, Boston
  • Videnovic A; From the APDA Center for Advanced Parkinson Research (Y.E.H., J.J.L., Z.L., G.L., K.C., Y.I.K., I.T., M.T.H., C.R.S.) and Precision Neurology Program (Y.E.H., Z.L., G.L., Y.I.K., C.R.S.), Harvard Medical School, and Department of Neurology (Y.E.H., G.L., C.R.S.), Brigham and Women's Hospital, Boston
  • Hunt AL; From the APDA Center for Advanced Parkinson Research (Y.E.H., J.J.L., Z.L., G.L., K.C., Y.I.K., I.T., M.T.H., C.R.S.) and Precision Neurology Program (Y.E.H., Z.L., G.L., Y.I.K., C.R.S.), Harvard Medical School, and Department of Neurology (Y.E.H., G.L., C.R.S.), Brigham and Women's Hospital, Boston
  • Schwarzschild MA; From the APDA Center for Advanced Parkinson Research (Y.E.H., J.J.L., Z.L., G.L., K.C., Y.I.K., I.T., M.T.H., C.R.S.) and Precision Neurology Program (Y.E.H., Z.L., G.L., Y.I.K., C.R.S.), Harvard Medical School, and Department of Neurology (Y.E.H., G.L., C.R.S.), Brigham and Women's Hospital, Boston
  • Hung AY; From the APDA Center for Advanced Parkinson Research (Y.E.H., J.J.L., Z.L., G.L., K.C., Y.I.K., I.T., M.T.H., C.R.S.) and Precision Neurology Program (Y.E.H., Z.L., G.L., Y.I.K., C.R.S.), Harvard Medical School, and Department of Neurology (Y.E.H., G.L., C.R.S.), Brigham and Women's Hospital, Boston
  • Herrington TM; From the APDA Center for Advanced Parkinson Research (Y.E.H., J.J.L., Z.L., G.L., K.C., Y.I.K., I.T., M.T.H., C.R.S.) and Precision Neurology Program (Y.E.H., Z.L., G.L., Y.I.K., C.R.S.), Harvard Medical School, and Department of Neurology (Y.E.H., G.L., C.R.S.), Brigham and Women's Hospital, Boston
  • Hayes MT; From the APDA Center for Advanced Parkinson Research (Y.E.H., J.J.L., Z.L., G.L., K.C., Y.I.K., I.T., M.T.H., C.R.S.) and Precision Neurology Program (Y.E.H., Z.L., G.L., Y.I.K., C.R.S.), Harvard Medical School, and Department of Neurology (Y.E.H., G.L., C.R.S.), Brigham and Women's Hospital, Boston
  • Hyman BT; From the APDA Center for Advanced Parkinson Research (Y.E.H., J.J.L., Z.L., G.L., K.C., Y.I.K., I.T., M.T.H., C.R.S.) and Precision Neurology Program (Y.E.H., Z.L., G.L., Y.I.K., C.R.S.), Harvard Medical School, and Department of Neurology (Y.E.H., G.L., C.R.S.), Brigham and Women's Hospital, Boston
  • Wills AM; From the APDA Center for Advanced Parkinson Research (Y.E.H., J.J.L., Z.L., G.L., K.C., Y.I.K., I.T., M.T.H., C.R.S.) and Precision Neurology Program (Y.E.H., Z.L., G.L., Y.I.K., C.R.S.), Harvard Medical School, and Department of Neurology (Y.E.H., G.L., C.R.S.), Brigham and Women's Hospital, Boston
  • Gomperts SN; From the APDA Center for Advanced Parkinson Research (Y.E.H., J.J.L., Z.L., G.L., K.C., Y.I.K., I.T., M.T.H., C.R.S.) and Precision Neurology Program (Y.E.H., Z.L., G.L., Y.I.K., C.R.S.), Harvard Medical School, and Department of Neurology (Y.E.H., G.L., C.R.S.), Brigham and Women's Hospital, Boston
  • Growdon JH; From the APDA Center for Advanced Parkinson Research (Y.E.H., J.J.L., Z.L., G.L., K.C., Y.I.K., I.T., M.T.H., C.R.S.) and Precision Neurology Program (Y.E.H., Z.L., G.L., Y.I.K., C.R.S.), Harvard Medical School, and Department of Neurology (Y.E.H., G.L., C.R.S.), Brigham and Women's Hospital, Boston
  • Sardi SP; From the APDA Center for Advanced Parkinson Research (Y.E.H., J.J.L., Z.L., G.L., K.C., Y.I.K., I.T., M.T.H., C.R.S.) and Precision Neurology Program (Y.E.H., Z.L., G.L., Y.I.K., C.R.S.), Harvard Medical School, and Department of Neurology (Y.E.H., G.L., C.R.S.), Brigham and Women's Hospital, Boston
  • Scherzer CR; From the APDA Center for Advanced Parkinson Research (Y.E.H., J.J.L., Z.L., G.L., K.C., Y.I.K., I.T., M.T.H., C.R.S.) and Precision Neurology Program (Y.E.H., Z.L., G.L., Y.I.K., C.R.S.), Harvard Medical School, and Department of Neurology (Y.E.H., G.L., C.R.S.), Brigham and Women's Hospital, Boston
Neurology ; 95(6): e685-e696, 2020 08 11.
Article en En | MEDLINE | ID: mdl-32540937
ABSTRACT

OBJECTIVE:

To test the relationship between clinically relevant types of GBA mutations (none, risk variants, mild mutations, severe mutations) and ß-glucocerebrosidase activity in patients with Parkinson disease (PD) in cross-sectional and longitudinal case-control studies.

METHODS:

A total of 481 participants from the Harvard Biomarkers Study (HBS) and the NIH Parkinson's Disease Biomarkers Program (PDBP) were analyzed, including 47 patients with PD carrying GBA variants (GBA-PD), 247 without a GBA variant (idiopathic PD), and 187 healthy controls. Longitudinal analysis comprised 195 participants with 548 longitudinal measurements over a median follow-up period of 2.0 years (interquartile range, 1-2 years).

RESULTS:

ß-Glucocerebrosidase activity was low in blood of patients with GBA-PD compared to healthy controls and patients with idiopathic PD, respectively, in HBS (p < 0.001) and PDBP (p < 0.05) in multivariate analyses adjusting for age, sex, blood storage time, and batch. Enzyme activity in patients with idiopathic PD was unchanged. Innovative enzymatic quantitative trait locus (xQTL) analysis revealed a negative linear association between residual ß-glucocerebrosidase activity and mutation type with p < 0.0001. For each increment in the severity of mutation type, a reduction of mean ß-glucocerebrosidase activity by 0.85 µmol/L/h (95% confidence interval, -1.17, -0.54) was predicted. In a first longitudinal analysis, increasing mutation severity types were prospectively associated with steeper declines in ß-glucocerebrosidase activity during a median 2 years of follow-up (p = 0.02).

CONCLUSIONS:

Residual activity of the ß-glucocerebrosidase enzyme measured in blood inversely correlates with clinical severity types of GBA mutations in PD. ß-Glucocerebrosidase activity is a quantitative endophenotype that can be monitored noninvasively and targeted therapeutically.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad de Parkinson / Glucosilceramidasa / Mutación Tipo de estudio: Etiology_studies / Observational_studies / Prevalence_studies / Prognostic_studies / Risk_factors_studies Límite: Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Neurology Año: 2020 Tipo del documento: Article
Texto completo
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad de Parkinson / Glucosilceramidasa / Mutación Tipo de estudio: Etiology_studies / Observational_studies / Prevalence_studies / Prognostic_studies / Risk_factors_studies Límite: Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Neurology Año: 2020 Tipo del documento: Article