Neurochemical abnormalities in patients with type 1 Gaucher disease on standard of care therapy

Reena V. Kartha; James Joers; Marcia R. Terluk; Abigail Travis; Kyle Rudser; Paul J. Tuite; Neal J. Weinreb; Jeanine R. Jarnes; James C. Cloyd; Gülin Öz

doi:10.1002/jimd.12182

Neurochemical abnormalities in patients with type 1 Gaucher disease on standard of care therapy

Reena V. Kartha, James Joers, Marcia R. Terluk, Abigail Travis, Kyle Rudser, Paul J. Tuite, Neal J. Weinreb, Jeanine R. Jarnes, James C. Cloyd, Gülin Öz

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

4 Scopus citations

Abstract

Type 1 Gaucher disease (GD1), a glycosphingolipid storage disorder caused by deficient activity of lysosomal glucocerebrosidase, is classically considered non-neuronopathic. However, current evidence challenges this view. Multiple studies show that mutations in GBA1 gene and decreased glucocerebrosidase activity are associated with increased risk for Parkinson disease. We tested the hypothesis that subjects with GD1 will show neurochemical abnormalities consistent with cerebral involvement. We performed Magnetic Resonance Spectroscopy at 7 T to quantify neurochemical profiles in participants with GD1 (n = 12) who are on stable therapy. Age and gender matched healthy participants served as controls (n = 13). Neurochemical profiles were obtained from parietal white matter (PWM), posterior cingulate cortex (PCC), and putamen. Further, in the GD1 group, the neurochemical profiles were compared between individuals with and without a single L444P allele. We observed significantly lower levels of key neuronal markers, N-acetylaspartate, γ-aminobutyric acid, glutamate and glutamate-to-glutamine ratio in PCC of participants with GD1 compared to healthy controls (P <.015). Glutamate concentration was also lower in the putamen in GD1 (P =.01). Glucose + taurine concentration was significantly higher in PWM (P =.04). Interestingly, individuals without L444P had significantly lower aspartate and N-acetylaspartylglutamate in PCC (both P <.001), although this group was 7 years younger than those with an L444P allele. This study demonstrates neurochemical abnormalities in individuals with GD1, for which clinical and prognostic significance remains to be determined. Further studies in a larger cohort are required to confirm an association of neurochemical levels with mutation status and glucocerebrosidase structure and function. Synopsis: Ultrahigh field magnetic resonance spectroscopy reveals abnormalities in neurochemical profiles in patients with GD1 compared to matched healthy controls.

Original language	English (US)
Pages (from-to)	564-573
Number of pages	10
Journal	Journal of Inherited Metabolic Disease
Volume	43
Issue number	3
DOIs	https://doi.org/10.1002/jimd.12182
State	Published - May 1 2020

Bibliographical note

Funding Information:
We thank all the participants in the study and the National Gaucher Foundation for promoting our study. Authors also acknowledge Renee Dahring, MSN, RN, CNP, CCHP for assistance with the neurological examination, Sarah Hilbert for regulatory support and Evelyn Redtree for logistical help with the study. We thank Vanderbilt Minerals, LLC (Norwalk, CT) for the gift of Darvan, a chemical dispersant used in the production of the barium titanate dielectric pads used in this study. Financial support was provided by the Lysosomal Disease Network (protocol no. 6722) and Pfizer Inc. The Lysosomal Disease Network (U54NS065768) is a part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), and National Center for Advancing Translational Sciences (NCATS). This consortium is funded through a collaboration between NCATS, NINDS, and NIDDK. The Center for Magnetic Resonance Research is supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) grant P41 EB015894 and the Institutional Center Cores for Advanced Neuroimaging award P30 NS076408. Research reported in this publication was also supported by the NCATS of the National Institutes of Health Award Number UL1TR000114. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Infrastructure support for clinical research was provided by the University of Minnesota Office of the Vice President for Research.

Funding Information:
RVK has received grants from NIH, Pfizer Inc. related to this work and Sanofi‐Genzyme outside of this work. JJ declares no conflict of interest. MRT declares no conflict of interest. AT declares no conflict of interest. KR has received grants from NIH. PJT has received grants from NIH, Parkinson Study Group, Northwestern University, Biogen Inc., and Bristol‐Myers Squibb. NJW has received grants from Sanofi‐Genzyme and Takeda‐Shire, personal fees from Sanofi‐Genzyme, Takeda‐Shire and Pfizer Inc, and non‐financial support from Sanofi‐Genzyme. JRJ declares no conflict of interest. JCC has received grants from NIH, Pfizer Inc. related to this work and Sanofi‐Genzyme outside of this work. GÖ has received grants from NIH and Pfizer Inc. related to this work and grants from Takeda, NeuroVia, Inc. and National Ataxia Foundation outside this work.

Funding Information:
We thank all the participants in the study and the National Gaucher Foundation for promoting our study. Authors also acknowledge Renee Dahring, MSN, RN, CNP, CCHP for assistance with the neurological examination, Sarah Hilbert for regulatory support and Evelyn Redtree for logistical help with the study. We thank Vanderbilt Minerals, LLC (Norwalk, CT) for the gift of Darvan, a chemical dispersant used in the production of the barium titanate dielectric pads used in this study. Financial support was provided by the Lysosomal Disease Network (protocol no. 6722) and Pfizer Inc. The Lysosomal Disease Network (U54NS065768) is a part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), and National Center for Advancing Translational Sciences (NCATS). This consortium is funded through a collaboration between NCATS, NINDS, and NIDDK. The Center for Magnetic Resonance Research is supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) grant P41 EB015894 and the Institutional Center Cores for Advanced Neuroimaging award P30 NS076408. Research reported in this publication was also supported by the NCATS of the National Institutes of Health Award Number UL1TR000114. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Infrastructure support for clinical research was provided by the University of Minnesota Office of the Vice President for Research.

Publisher Copyright:
© 2019 SSIEM

Keywords

GABA
GBA1 mutation
Gaucher disease
brain
glutamate
magnetic resonance spectroscopy (MRS)

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@article{3845f11355784306b522af7ee7039340,

title = "Neurochemical abnormalities in patients with type 1 Gaucher disease on standard of care therapy",

abstract = "Type 1 Gaucher disease (GD1), a glycosphingolipid storage disorder caused by deficient activity of lysosomal glucocerebrosidase, is classically considered non-neuronopathic. However, current evidence challenges this view. Multiple studies show that mutations in GBA1 gene and decreased glucocerebrosidase activity are associated with increased risk for Parkinson disease. We tested the hypothesis that subjects with GD1 will show neurochemical abnormalities consistent with cerebral involvement. We performed Magnetic Resonance Spectroscopy at 7 T to quantify neurochemical profiles in participants with GD1 (n = 12) who are on stable therapy. Age and gender matched healthy participants served as controls (n = 13). Neurochemical profiles were obtained from parietal white matter (PWM), posterior cingulate cortex (PCC), and putamen. Further, in the GD1 group, the neurochemical profiles were compared between individuals with and without a single L444P allele. We observed significantly lower levels of key neuronal markers, N-acetylaspartate, γ-aminobutyric acid, glutamate and glutamate-to-glutamine ratio in PCC of participants with GD1 compared to healthy controls (P <.015). Glutamate concentration was also lower in the putamen in GD1 (P =.01). Glucose + taurine concentration was significantly higher in PWM (P =.04). Interestingly, individuals without L444P had significantly lower aspartate and N-acetylaspartylglutamate in PCC (both P <.001), although this group was 7 years younger than those with an L444P allele. This study demonstrates neurochemical abnormalities in individuals with GD1, for which clinical and prognostic significance remains to be determined. Further studies in a larger cohort are required to confirm an association of neurochemical levels with mutation status and glucocerebrosidase structure and function. Synopsis: Ultrahigh field magnetic resonance spectroscopy reveals abnormalities in neurochemical profiles in patients with GD1 compared to matched healthy controls.",

keywords = "GABA, GBA1 mutation, Gaucher disease, brain, glutamate, magnetic resonance spectroscopy (MRS)",

author = "Kartha, {Reena V.} and James Joers and Terluk, {Marcia R.} and Abigail Travis and Kyle Rudser and Tuite, {Paul J.} and Weinreb, {Neal J.} and Jarnes, {Jeanine R.} and Cloyd, {James C.} and G{\"u}lin {\"O}z",

note = "Funding Information: We thank all the participants in the study and the National Gaucher Foundation for promoting our study. Authors also acknowledge Renee Dahring, MSN, RN, CNP, CCHP for assistance with the neurological examination, Sarah Hilbert for regulatory support and Evelyn Redtree for logistical help with the study. We thank Vanderbilt Minerals, LLC (Norwalk, CT) for the gift of Darvan, a chemical dispersant used in the production of the barium titanate dielectric pads used in this study. Financial support was provided by the Lysosomal Disease Network (protocol no. 6722) and Pfizer Inc. The Lysosomal Disease Network (U54NS065768) is a part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), and National Center for Advancing Translational Sciences (NCATS). This consortium is funded through a collaboration between NCATS, NINDS, and NIDDK. The Center for Magnetic Resonance Research is supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) grant P41 EB015894 and the Institutional Center Cores for Advanced Neuroimaging award P30 NS076408. Research reported in this publication was also supported by the NCATS of the National Institutes of Health Award Number UL1TR000114. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Infrastructure support for clinical research was provided by the University of Minnesota Office of the Vice President for Research. Funding Information: RVK has received grants from NIH, Pfizer Inc. related to this work and Sanofi‐Genzyme outside of this work. JJ declares no conflict of interest. MRT declares no conflict of interest. AT declares no conflict of interest. KR has received grants from NIH. PJT has received grants from NIH, Parkinson Study Group, Northwestern University, Biogen Inc., and Bristol‐Myers Squibb. NJW has received grants from Sanofi‐Genzyme and Takeda‐Shire, personal fees from Sanofi‐Genzyme, Takeda‐Shire and Pfizer Inc, and non‐financial support from Sanofi‐Genzyme. JRJ declares no conflict of interest. JCC has received grants from NIH, Pfizer Inc. related to this work and Sanofi‐Genzyme outside of this work. G{\"O} has received grants from NIH and Pfizer Inc. related to this work and grants from Takeda, NeuroVia, Inc. and National Ataxia Foundation outside this work. Funding Information: We thank all the participants in the study and the National Gaucher Foundation for promoting our study. Authors also acknowledge Renee Dahring, MSN, RN, CNP, CCHP for assistance with the neurological examination, Sarah Hilbert for regulatory support and Evelyn Redtree for logistical help with the study. We thank Vanderbilt Minerals, LLC (Norwalk, CT) for the gift of Darvan, a chemical dispersant used in the production of the barium titanate dielectric pads used in this study. Financial support was provided by the Lysosomal Disease Network (protocol no. 6722) and Pfizer Inc. The Lysosomal Disease Network (U54NS065768) is a part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), and National Center for Advancing Translational Sciences (NCATS). This consortium is funded through a collaboration between NCATS, NINDS, and NIDDK. The Center for Magnetic Resonance Research is supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) grant P41 EB015894 and the Institutional Center Cores for Advanced Neuroimaging award P30 NS076408. Research reported in this publication was also supported by the NCATS of the National Institutes of Health Award Number UL1TR000114. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Infrastructure support for clinical research was provided by the University of Minnesota Office of the Vice President for Research. Publisher Copyright: {\textcopyright} 2019 SSIEM",

year = "2020",

month = may,

day = "1",

doi = "10.1002/jimd.12182",

language = "English (US)",

volume = "43",

pages = "564--573",

journal = "Journal of Inherited Metabolic Disease",

issn = "0141-8955",

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TY - JOUR

T1 - Neurochemical abnormalities in patients with type 1 Gaucher disease on standard of care therapy

AU - Kartha, Reena V.

AU - Joers, James

AU - Terluk, Marcia R.

AU - Travis, Abigail

AU - Rudser, Kyle

AU - Tuite, Paul J.

AU - Weinreb, Neal J.

AU - Jarnes, Jeanine R.

AU - Cloyd, James C.

AU - Öz, Gülin

N1 - Funding Information: We thank all the participants in the study and the National Gaucher Foundation for promoting our study. Authors also acknowledge Renee Dahring, MSN, RN, CNP, CCHP for assistance with the neurological examination, Sarah Hilbert for regulatory support and Evelyn Redtree for logistical help with the study. We thank Vanderbilt Minerals, LLC (Norwalk, CT) for the gift of Darvan, a chemical dispersant used in the production of the barium titanate dielectric pads used in this study. Financial support was provided by the Lysosomal Disease Network (protocol no. 6722) and Pfizer Inc. The Lysosomal Disease Network (U54NS065768) is a part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), and National Center for Advancing Translational Sciences (NCATS). This consortium is funded through a collaboration between NCATS, NINDS, and NIDDK. The Center for Magnetic Resonance Research is supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) grant P41 EB015894 and the Institutional Center Cores for Advanced Neuroimaging award P30 NS076408. Research reported in this publication was also supported by the NCATS of the National Institutes of Health Award Number UL1TR000114. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Infrastructure support for clinical research was provided by the University of Minnesota Office of the Vice President for Research. Funding Information: RVK has received grants from NIH, Pfizer Inc. related to this work and Sanofi‐Genzyme outside of this work. JJ declares no conflict of interest. MRT declares no conflict of interest. AT declares no conflict of interest. KR has received grants from NIH. PJT has received grants from NIH, Parkinson Study Group, Northwestern University, Biogen Inc., and Bristol‐Myers Squibb. NJW has received grants from Sanofi‐Genzyme and Takeda‐Shire, personal fees from Sanofi‐Genzyme, Takeda‐Shire and Pfizer Inc, and non‐financial support from Sanofi‐Genzyme. JRJ declares no conflict of interest. JCC has received grants from NIH, Pfizer Inc. related to this work and Sanofi‐Genzyme outside of this work. GÖ has received grants from NIH and Pfizer Inc. related to this work and grants from Takeda, NeuroVia, Inc. and National Ataxia Foundation outside this work. Funding Information: We thank all the participants in the study and the National Gaucher Foundation for promoting our study. Authors also acknowledge Renee Dahring, MSN, RN, CNP, CCHP for assistance with the neurological examination, Sarah Hilbert for regulatory support and Evelyn Redtree for logistical help with the study. We thank Vanderbilt Minerals, LLC (Norwalk, CT) for the gift of Darvan, a chemical dispersant used in the production of the barium titanate dielectric pads used in this study. Financial support was provided by the Lysosomal Disease Network (protocol no. 6722) and Pfizer Inc. The Lysosomal Disease Network (U54NS065768) is a part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), and National Center for Advancing Translational Sciences (NCATS). This consortium is funded through a collaboration between NCATS, NINDS, and NIDDK. The Center for Magnetic Resonance Research is supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) grant P41 EB015894 and the Institutional Center Cores for Advanced Neuroimaging award P30 NS076408. Research reported in this publication was also supported by the NCATS of the National Institutes of Health Award Number UL1TR000114. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Infrastructure support for clinical research was provided by the University of Minnesota Office of the Vice President for Research. Publisher Copyright: © 2019 SSIEM

PY - 2020/5/1

Y1 - 2020/5/1

N2 - Type 1 Gaucher disease (GD1), a glycosphingolipid storage disorder caused by deficient activity of lysosomal glucocerebrosidase, is classically considered non-neuronopathic. However, current evidence challenges this view. Multiple studies show that mutations in GBA1 gene and decreased glucocerebrosidase activity are associated with increased risk for Parkinson disease. We tested the hypothesis that subjects with GD1 will show neurochemical abnormalities consistent with cerebral involvement. We performed Magnetic Resonance Spectroscopy at 7 T to quantify neurochemical profiles in participants with GD1 (n = 12) who are on stable therapy. Age and gender matched healthy participants served as controls (n = 13). Neurochemical profiles were obtained from parietal white matter (PWM), posterior cingulate cortex (PCC), and putamen. Further, in the GD1 group, the neurochemical profiles were compared between individuals with and without a single L444P allele. We observed significantly lower levels of key neuronal markers, N-acetylaspartate, γ-aminobutyric acid, glutamate and glutamate-to-glutamine ratio in PCC of participants with GD1 compared to healthy controls (P <.015). Glutamate concentration was also lower in the putamen in GD1 (P =.01). Glucose + taurine concentration was significantly higher in PWM (P =.04). Interestingly, individuals without L444P had significantly lower aspartate and N-acetylaspartylglutamate in PCC (both P <.001), although this group was 7 years younger than those with an L444P allele. This study demonstrates neurochemical abnormalities in individuals with GD1, for which clinical and prognostic significance remains to be determined. Further studies in a larger cohort are required to confirm an association of neurochemical levels with mutation status and glucocerebrosidase structure and function. Synopsis: Ultrahigh field magnetic resonance spectroscopy reveals abnormalities in neurochemical profiles in patients with GD1 compared to matched healthy controls.

AB - Type 1 Gaucher disease (GD1), a glycosphingolipid storage disorder caused by deficient activity of lysosomal glucocerebrosidase, is classically considered non-neuronopathic. However, current evidence challenges this view. Multiple studies show that mutations in GBA1 gene and decreased glucocerebrosidase activity are associated with increased risk for Parkinson disease. We tested the hypothesis that subjects with GD1 will show neurochemical abnormalities consistent with cerebral involvement. We performed Magnetic Resonance Spectroscopy at 7 T to quantify neurochemical profiles in participants with GD1 (n = 12) who are on stable therapy. Age and gender matched healthy participants served as controls (n = 13). Neurochemical profiles were obtained from parietal white matter (PWM), posterior cingulate cortex (PCC), and putamen. Further, in the GD1 group, the neurochemical profiles were compared between individuals with and without a single L444P allele. We observed significantly lower levels of key neuronal markers, N-acetylaspartate, γ-aminobutyric acid, glutamate and glutamate-to-glutamine ratio in PCC of participants with GD1 compared to healthy controls (P <.015). Glutamate concentration was also lower in the putamen in GD1 (P =.01). Glucose + taurine concentration was significantly higher in PWM (P =.04). Interestingly, individuals without L444P had significantly lower aspartate and N-acetylaspartylglutamate in PCC (both P <.001), although this group was 7 years younger than those with an L444P allele. This study demonstrates neurochemical abnormalities in individuals with GD1, for which clinical and prognostic significance remains to be determined. Further studies in a larger cohort are required to confirm an association of neurochemical levels with mutation status and glucocerebrosidase structure and function. Synopsis: Ultrahigh field magnetic resonance spectroscopy reveals abnormalities in neurochemical profiles in patients with GD1 compared to matched healthy controls.

KW - GABA

KW - GBA1 mutation

KW - Gaucher disease

KW - brain

KW - glutamate

KW - magnetic resonance spectroscopy (MRS)

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Neurochemical abnormalities in patients with type 1 Gaucher disease on standard of care therapy

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