Multiparametric in vivo analyses of the brain and spine identify structural and metabolic biomarkers in men with adrenomyeloneuropathy

Isaac M. Adanyeguh; Xiaofang Lou; Eavan McGovern; Marie Pierre Luton; Magali Barbier; Elise Yazbeck; Romain Valabregue; Dinesh Deelchand; Pierre Gilles Henry; Fanny Mochel

doi:10.1016/j.nicl.2021.102566

Multiparametric in vivo analyses of the brain and spine identify structural and metabolic biomarkers in men with adrenomyeloneuropathy

Isaac M. Adanyeguh, Xiaofang Lou, Eavan McGovern, Marie Pierre Luton, Magali Barbier, Elise Yazbeck, Romain Valabregue, Dinesh Deelchand, Pierre Gilles Henry, Fanny Mochel

Center for Magnetic Resonance Research

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

4 Scopus citations

Abstract

OBJECTIVE: Progressive myelopathy causes severe handicap in men with adrenomyeloneuropathy (AMN), an X-linked disorder due to ABCD1 pathogenic variants. At present, treatments are symptomatic but disease-modifying therapies are under evaluation. Given the small effect size of clinical scales in AMN, biomarkers with higher effect size are needed. Here we used high-resolution magnetic resonance techniques to identify non-invasive in vivo biomarkers of the brain and spine with high effect sizes.

METHODS: We performed a multiparametric imaging and spectroscopy study in 23 male patients with AMN (age: 44 ± 11) and 23 male controls (age: 43 ± 11) of similar age and body-mass index. We combined (i) macrostructural analyses of the spine, using cross-sectional area (CSA) and magnetization transfer ratio (MTR), (ii) microstructural analyses of the spine and the brain, using diffusion tensor and the newly developed fixel-based analysis, and (iii) advanced metabolic analyses of the spine using metabolite cycling coupled to a semi-LASER sequences.

RESULTS: Macrostructural alterations (decrease in CSA and MTR) were observed in patients at all spinal cord levels studied (C1-T2 for CSA and C1-C5 for MTR) (p < 0.001). Microstructural alterations were observed in the spine and brain on diffusion tensor and fixel-based metrics though the latter showed higher effect sizes. Metabolic alterations were observed in patients as a decreased total N-acetylaspartate/myo-inositol ratio (p < 0.001). Overall, MTR showed the highest effect size.

CONCLUSION: This cross-sectional study supports the use of multiparametric techniques that elucidate the structural, microstructural and metabolic alterations in AMN. These outcome measures should be tested longitudinally and in clinical trials.

Original language	English (US)
Article number	102566
Journal	NeuroImage: Clinical
Volume	29
DOIs	https://doi.org/10.1016/j.nicl.2021.102566
State	Published - Jan 2021

Bibliographical note

Funding Information:
We are very grateful to the patients and volunteers who participated in this study. CMRR is supported by NIH grants P41EB027061 and P30NS076408. This study was sponsored and funded by Minoryx Therapeutics. This study was financially supported by the “Investissements d'avenir” program ANR-10-IAIHU-06 (IHU-A-ICM). No disclosure: Adanyeguh, Lou, McGovern, Luton, Barbier, Yazbeck, Valabregue, and Deelchand. Dr Henry received research support from Minoryx Therapeutics, Friedreich's Ataxia Research Alliance (FARA), and NIH. Dr Mochel received research support by grants from INSERM, the French Agency for Research, Carnot Institutes, ASL Foundation, Ultragenyx Pharmaceutical and Minoryx Therapeutics.

Funding Information:
This study was sponsored and funded by Minoryx Therapeutics. This study was financially supported by the “Investissements d’avenir” program ANR-10-IAIHU-06 (IHU-A-ICM).

Funding Information:
Dr Henry received research support from Minoryx Therapeutics, Friedreich’s Ataxia Research Alliance (FARA), and NIH.

Funding Information:
Dr Mochel received research support by grants from INSERM, the French Agency for Research, Carnot Institutes, ASL Foundation, Ultragenyx Pharmaceutical and Minoryx Therapeutics.

Funding Information:
We are very grateful to the patients and volunteers who participated in this study. CMRR is supported by NIH grants P41EB027061 and P30NS076408.

Publisher Copyright:
© 2021

Keywords

Adrenomyeloneuropathy
Fixel-based analysis
Imaging biomarkers
Metabolite cycling
Spinal cord imaging
Spinal cord toolbox
Cross-Sectional Studies
Humans
Middle Aged
Male
Adrenoleukodystrophy/diagnostic imaging
Brain/diagnostic imaging
Magnetic Resonance Imaging
Spinal Cord
Biomarkers
Adult

PubMed: MeSH publication types

Research Support, Non-U.S. Gov't
Journal Article
Research Support, N.I.H., Extramural

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10.1016/j.nicl.2021.102566

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@article{b96c752c9d1d43429e25407bdbd31add,

title = "Multiparametric in vivo analyses of the brain and spine identify structural and metabolic biomarkers in men with adrenomyeloneuropathy",

abstract = "OBJECTIVE: Progressive myelopathy causes severe handicap in men with adrenomyeloneuropathy (AMN), an X-linked disorder due to ABCD1 pathogenic variants. At present, treatments are symptomatic but disease-modifying therapies are under evaluation. Given the small effect size of clinical scales in AMN, biomarkers with higher effect size are needed. Here we used high-resolution magnetic resonance techniques to identify non-invasive in vivo biomarkers of the brain and spine with high effect sizes.METHODS: We performed a multiparametric imaging and spectroscopy study in 23 male patients with AMN (age: 44 ± 11) and 23 male controls (age: 43 ± 11) of similar age and body-mass index. We combined (i) macrostructural analyses of the spine, using cross-sectional area (CSA) and magnetization transfer ratio (MTR), (ii) microstructural analyses of the spine and the brain, using diffusion tensor and the newly developed fixel-based analysis, and (iii) advanced metabolic analyses of the spine using metabolite cycling coupled to a semi-LASER sequences.RESULTS: Macrostructural alterations (decrease in CSA and MTR) were observed in patients at all spinal cord levels studied (C1-T2 for CSA and C1-C5 for MTR) (p < 0.001). Microstructural alterations were observed in the spine and brain on diffusion tensor and fixel-based metrics though the latter showed higher effect sizes. Metabolic alterations were observed in patients as a decreased total N-acetylaspartate/myo-inositol ratio (p < 0.001). Overall, MTR showed the highest effect size.CONCLUSION: This cross-sectional study supports the use of multiparametric techniques that elucidate the structural, microstructural and metabolic alterations in AMN. These outcome measures should be tested longitudinally and in clinical trials.",

keywords = "Adrenomyeloneuropathy, Fixel-based analysis, Imaging biomarkers, Metabolite cycling, Spinal cord imaging, Spinal cord toolbox, Cross-Sectional Studies, Humans, Middle Aged, Male, Adrenoleukodystrophy/diagnostic imaging, Brain/diagnostic imaging, Magnetic Resonance Imaging, Spinal Cord, Biomarkers, Adult",

author = "Adanyeguh, {Isaac M.} and Xiaofang Lou and Eavan McGovern and Luton, {Marie Pierre} and Magali Barbier and Elise Yazbeck and Romain Valabregue and Dinesh Deelchand and Henry, {Pierre Gilles} and Fanny Mochel",

note = "Funding Information: We are very grateful to the patients and volunteers who participated in this study. CMRR is supported by NIH grants P41EB027061 and P30NS076408. This study was sponsored and funded by Minoryx Therapeutics. This study was financially supported by the “Investissements d'avenir” program ANR-10-IAIHU-06 (IHU-A-ICM). No disclosure: Adanyeguh, Lou, McGovern, Luton, Barbier, Yazbeck, Valabregue, and Deelchand. Dr Henry received research support from Minoryx Therapeutics, Friedreich's Ataxia Research Alliance (FARA), and NIH. Dr Mochel received research support by grants from INSERM, the French Agency for Research, Carnot Institutes, ASL Foundation, Ultragenyx Pharmaceutical and Minoryx Therapeutics. Funding Information: This study was sponsored and funded by Minoryx Therapeutics. This study was financially supported by the “Investissements d{\textquoteright}avenir” program ANR-10-IAIHU-06 (IHU-A-ICM). Funding Information: Dr Henry received research support from Minoryx Therapeutics, Friedreich{\textquoteright}s Ataxia Research Alliance (FARA), and NIH. Funding Information: Dr Mochel received research support by grants from INSERM, the French Agency for Research, Carnot Institutes, ASL Foundation, Ultragenyx Pharmaceutical and Minoryx Therapeutics. Funding Information: We are very grateful to the patients and volunteers who participated in this study. CMRR is supported by NIH grants P41EB027061 and P30NS076408. Publisher Copyright: {\textcopyright} 2021",

year = "2021",

month = jan,

doi = "10.1016/j.nicl.2021.102566",

language = "English (US)",

volume = "29",

journal = "NeuroImage: Clinical",

issn = "2213-1582",

publisher = "Elsevier BV",

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TY - JOUR

T1 - Multiparametric in vivo analyses of the brain and spine identify structural and metabolic biomarkers in men with adrenomyeloneuropathy

AU - Adanyeguh, Isaac M.

AU - Lou, Xiaofang

AU - McGovern, Eavan

AU - Luton, Marie Pierre

AU - Barbier, Magali

AU - Yazbeck, Elise

AU - Valabregue, Romain

AU - Deelchand, Dinesh

AU - Henry, Pierre Gilles

AU - Mochel, Fanny

N1 - Funding Information: We are very grateful to the patients and volunteers who participated in this study. CMRR is supported by NIH grants P41EB027061 and P30NS076408. This study was sponsored and funded by Minoryx Therapeutics. This study was financially supported by the “Investissements d'avenir” program ANR-10-IAIHU-06 (IHU-A-ICM). No disclosure: Adanyeguh, Lou, McGovern, Luton, Barbier, Yazbeck, Valabregue, and Deelchand. Dr Henry received research support from Minoryx Therapeutics, Friedreich's Ataxia Research Alliance (FARA), and NIH. Dr Mochel received research support by grants from INSERM, the French Agency for Research, Carnot Institutes, ASL Foundation, Ultragenyx Pharmaceutical and Minoryx Therapeutics. Funding Information: This study was sponsored and funded by Minoryx Therapeutics. This study was financially supported by the “Investissements d’avenir” program ANR-10-IAIHU-06 (IHU-A-ICM). Funding Information: Dr Henry received research support from Minoryx Therapeutics, Friedreich’s Ataxia Research Alliance (FARA), and NIH. Funding Information: Dr Mochel received research support by grants from INSERM, the French Agency for Research, Carnot Institutes, ASL Foundation, Ultragenyx Pharmaceutical and Minoryx Therapeutics. Funding Information: We are very grateful to the patients and volunteers who participated in this study. CMRR is supported by NIH grants P41EB027061 and P30NS076408. Publisher Copyright: © 2021

PY - 2021/1

Y1 - 2021/1

N2 - OBJECTIVE: Progressive myelopathy causes severe handicap in men with adrenomyeloneuropathy (AMN), an X-linked disorder due to ABCD1 pathogenic variants. At present, treatments are symptomatic but disease-modifying therapies are under evaluation. Given the small effect size of clinical scales in AMN, biomarkers with higher effect size are needed. Here we used high-resolution magnetic resonance techniques to identify non-invasive in vivo biomarkers of the brain and spine with high effect sizes.METHODS: We performed a multiparametric imaging and spectroscopy study in 23 male patients with AMN (age: 44 ± 11) and 23 male controls (age: 43 ± 11) of similar age and body-mass index. We combined (i) macrostructural analyses of the spine, using cross-sectional area (CSA) and magnetization transfer ratio (MTR), (ii) microstructural analyses of the spine and the brain, using diffusion tensor and the newly developed fixel-based analysis, and (iii) advanced metabolic analyses of the spine using metabolite cycling coupled to a semi-LASER sequences.RESULTS: Macrostructural alterations (decrease in CSA and MTR) were observed in patients at all spinal cord levels studied (C1-T2 for CSA and C1-C5 for MTR) (p < 0.001). Microstructural alterations were observed in the spine and brain on diffusion tensor and fixel-based metrics though the latter showed higher effect sizes. Metabolic alterations were observed in patients as a decreased total N-acetylaspartate/myo-inositol ratio (p < 0.001). Overall, MTR showed the highest effect size.CONCLUSION: This cross-sectional study supports the use of multiparametric techniques that elucidate the structural, microstructural and metabolic alterations in AMN. These outcome measures should be tested longitudinally and in clinical trials.

AB - OBJECTIVE: Progressive myelopathy causes severe handicap in men with adrenomyeloneuropathy (AMN), an X-linked disorder due to ABCD1 pathogenic variants. At present, treatments are symptomatic but disease-modifying therapies are under evaluation. Given the small effect size of clinical scales in AMN, biomarkers with higher effect size are needed. Here we used high-resolution magnetic resonance techniques to identify non-invasive in vivo biomarkers of the brain and spine with high effect sizes.METHODS: We performed a multiparametric imaging and spectroscopy study in 23 male patients with AMN (age: 44 ± 11) and 23 male controls (age: 43 ± 11) of similar age and body-mass index. We combined (i) macrostructural analyses of the spine, using cross-sectional area (CSA) and magnetization transfer ratio (MTR), (ii) microstructural analyses of the spine and the brain, using diffusion tensor and the newly developed fixel-based analysis, and (iii) advanced metabolic analyses of the spine using metabolite cycling coupled to a semi-LASER sequences.RESULTS: Macrostructural alterations (decrease in CSA and MTR) were observed in patients at all spinal cord levels studied (C1-T2 for CSA and C1-C5 for MTR) (p < 0.001). Microstructural alterations were observed in the spine and brain on diffusion tensor and fixel-based metrics though the latter showed higher effect sizes. Metabolic alterations were observed in patients as a decreased total N-acetylaspartate/myo-inositol ratio (p < 0.001). Overall, MTR showed the highest effect size.CONCLUSION: This cross-sectional study supports the use of multiparametric techniques that elucidate the structural, microstructural and metabolic alterations in AMN. These outcome measures should be tested longitudinally and in clinical trials.

KW - Adrenomyeloneuropathy

KW - Fixel-based analysis

KW - Imaging biomarkers

KW - Metabolite cycling

KW - Spinal cord imaging

KW - Spinal cord toolbox

KW - Cross-Sectional Studies

KW - Humans

KW - Middle Aged

KW - Male

KW - Adrenoleukodystrophy/diagnostic imaging

KW - Brain/diagnostic imaging

KW - Magnetic Resonance Imaging

KW - Spinal Cord

KW - Biomarkers

KW - Adult

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DO - 10.1016/j.nicl.2021.102566

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C2 - 33516063

AN - SCOPUS:85099864171

SN - 2213-1582

VL - 29

JO - NeuroImage: Clinical

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Multiparametric in vivo analyses of the brain and spine identify structural and metabolic biomarkers in men with adrenomyeloneuropathy

Abstract

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Keywords

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