Neurochemical correlates of functional decline in amyotrophic lateral sclerosis

Ian Cheong; Dinesh K. Deelchand; Lynn E. Eberly; Małgorzata Marjańska; Georgios Manousakis; Gaurav Guliani; David Walk; Gülin Öz

doi:10.1136/jnnp-2018-318795

Neurochemical correlates of functional decline in amyotrophic lateral sclerosis

Ian Cheong, Dinesh K. Deelchand, Lynn E. Eberly, Małgorzata Marjańska, Georgios Manousakis, Gaurav Guliani, David Walk, Gülin Öz

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

16 Scopus citations

Abstract

OBJECTIVE: To determine whether proton magnetic resonance spectroscopy ( 1H-MRS) can detect neurochemical changes in amyotrophic lateral sclerosis (ALS) associated with heterogeneous functional decline.

METHODS: Nineteen participants with early-stage ALS and 18 age-matched and sex ratio-matched controls underwent ultra-high field 1H-MRS scans of the upper limb motor cortex and pons, ALS Functional Rating Scale-Revised (ALSFRS-R total, upper limb and bulbar) and upper motor neuron burden assessments in a longitudinal observational study design with follow-up assessments at 6 and 12 months. Slopes of neurochemical levels over time were compared between patient subgroups classified by the rate of upper limb or bulbar functional decline. 1H-MRS and clinical ratings at baseline were assessed for ability to predict study withdrawal due to disease progression.

RESULTS: Motor cortex total N-acetylaspartate to myo-inositol ratio (tNAA:mIns) significantly declined in patients who worsened in upper limb function over the follow-up period (n=9, p=0.002). Pons glutamate + glutamine significantly increased in patients who worsened in bulbar function (n=6, p<0.0001). Neurochemical levels did not change in patients with stable function (n=5-6) or in healthy controls (n=14-16) over time. Motor cortex tNAA:mIns and ALSFRS-R at baseline were significantly lower in patients who withdrew from follow-up due to disease progression (n=6) compared with patients who completed the 12-month scan (n=10) (p<0.001 for tNAA:mIns; p<0.01 for ALSFRS-R), with a substantially larger overlap in ALSFRS-R between groups.

CONCLUSION: Neurochemical changes in motor areas of the brain are associated with functional decline in corresponding body regions. 1H-MRS was a better predictor of study withdrawal due to ALS progression than ALSFRS-R.

Original language	English (US)
Pages (from-to)	294-301
Number of pages	8
Journal	Journal of Neurology, Neurosurgery and Psychiatry
Volume	90
Issue number	3
DOIs	https://doi.org/10.1136/jnnp-2018-318795
State	Published - Mar 1 2019

Bibliographical note

Funding Information:
Competing interests Ic, DKD, Lee, MM, GM and GG report no disclosures. DW consults for acceleron pharma and receives research support from the aLs association, acceleron pharma, pharnext and FLeX pharma. GO received research support from Takeda pharmaceuticals and NeuroVia.

Funding Information:
This work was supported by the Bob Allison Ataxia Research Center, the Curt O'Hagan ALS-PLS and ALS-Lou Gehrig Disease funds of the University of Minnesota Foundation, and the National Institute of Neurological Disorders and Stroke (NINDS) (grant R01 NS080816). 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). This study was also supported by the National Center for Advancing Translational Sciences (NCATS) award (UL1TR000114). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding Information:
Funding This work was supported by the Bob allison ataxia Research center, the curt O’hagan aLs-pLs and aLs-Lou Gehrig Disease funds of the University of Minnesota Foundation, and the National Institute of Neurological Disorders and stroke (NINDs) (grant R01 Ns080816). 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). This study was also supported by the National center for advancing Translational sciences (NcaTs) award (UL1TR000114). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of health.

Publisher Copyright:
© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Keywords

7 tesla
amyotrophic lateral sclerosis
biomarker
longitudinal
motor cortex
proton MRS
Motor Cortex/metabolism
Prognosis
Humans
Middle Aged
Male
Aspartic Acid/analogs & derivatives
Motor Neurons/metabolism
Case-Control Studies
Disease Progression
Pons/metabolism
Glutamic Acid/metabolism
Proton Magnetic Resonance Spectroscopy
Adult
Female
Upper Extremity
Aged
Amyotrophic Lateral Sclerosis/diagnosis
Longitudinal Studies

Center for Magnetic Resonance Research (CMRR) tags

ANDI
SMCT

PubMed: MeSH publication types

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.1136/jnnp-2018-318795

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467050

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title = "Neurochemical correlates of functional decline in amyotrophic lateral sclerosis",

abstract = "OBJECTIVE: To determine whether proton magnetic resonance spectroscopy ( 1H-MRS) can detect neurochemical changes in amyotrophic lateral sclerosis (ALS) associated with heterogeneous functional decline. METHODS: Nineteen participants with early-stage ALS and 18 age-matched and sex ratio-matched controls underwent ultra-high field 1H-MRS scans of the upper limb motor cortex and pons, ALS Functional Rating Scale-Revised (ALSFRS-R total, upper limb and bulbar) and upper motor neuron burden assessments in a longitudinal observational study design with follow-up assessments at 6 and 12 months. Slopes of neurochemical levels over time were compared between patient subgroups classified by the rate of upper limb or bulbar functional decline. 1H-MRS and clinical ratings at baseline were assessed for ability to predict study withdrawal due to disease progression. RESULTS: Motor cortex total N-acetylaspartate to myo-inositol ratio (tNAA:mIns) significantly declined in patients who worsened in upper limb function over the follow-up period (n=9, p=0.002). Pons glutamate + glutamine significantly increased in patients who worsened in bulbar function (n=6, p<0.0001). Neurochemical levels did not change in patients with stable function (n=5-6) or in healthy controls (n=14-16) over time. Motor cortex tNAA:mIns and ALSFRS-R at baseline were significantly lower in patients who withdrew from follow-up due to disease progression (n=6) compared with patients who completed the 12-month scan (n=10) (p<0.001 for tNAA:mIns; p<0.01 for ALSFRS-R), with a substantially larger overlap in ALSFRS-R between groups. CONCLUSION: Neurochemical changes in motor areas of the brain are associated with functional decline in corresponding body regions. 1H-MRS was a better predictor of study withdrawal due to ALS progression than ALSFRS-R. ",

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author = "Ian Cheong and Deelchand, {Dinesh K.} and Eberly, {Lynn E.} and Ma{\l}gorzata Marja{\'n}ska and Georgios Manousakis and Gaurav Guliani and David Walk and G{\"u}lin {\"O}z",

note = "Funding Information: Competing interests Ic, DKD, Lee, MM, GM and GG report no disclosures. DW consults for acceleron pharma and receives research support from the aLs association, acceleron pharma, pharnext and FLeX pharma. GO received research support from Takeda pharmaceuticals and NeuroVia. Funding Information: This work was supported by the Bob Allison Ataxia Research Center, the Curt O'Hagan ALS-PLS and ALS-Lou Gehrig Disease funds of the University of Minnesota Foundation, and the National Institute of Neurological Disorders and Stroke (NINDS) (grant R01 NS080816). 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). This study was also supported by the National Center for Advancing Translational Sciences (NCATS) award (UL1TR000114). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: Funding This work was supported by the Bob allison ataxia Research center, the curt O{\textquoteright}hagan aLs-pLs and aLs-Lou Gehrig Disease funds of the University of Minnesota Foundation, and the National Institute of Neurological Disorders and stroke (NINDs) (grant R01 Ns080816). 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). This study was also supported by the National center for advancing Translational sciences (NcaTs) award (UL1TR000114). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of health. Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.",

year = "2019",

month = mar,

day = "1",

doi = "10.1136/jnnp-2018-318795",

language = "English (US)",

volume = "90",

pages = "294--301",

journal = "Journal of Neurology, Neurosurgery and Psychiatry",

issn = "0022-3050",

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TY - JOUR

T1 - Neurochemical correlates of functional decline in amyotrophic lateral sclerosis

AU - Cheong, Ian

AU - Deelchand, Dinesh K.

AU - Eberly, Lynn E.

AU - Marjańska, Małgorzata

AU - Manousakis, Georgios

AU - Guliani, Gaurav

AU - Walk, David

AU - Öz, Gülin

N1 - Funding Information: Competing interests Ic, DKD, Lee, MM, GM and GG report no disclosures. DW consults for acceleron pharma and receives research support from the aLs association, acceleron pharma, pharnext and FLeX pharma. GO received research support from Takeda pharmaceuticals and NeuroVia. Funding Information: This work was supported by the Bob Allison Ataxia Research Center, the Curt O'Hagan ALS-PLS and ALS-Lou Gehrig Disease funds of the University of Minnesota Foundation, and the National Institute of Neurological Disorders and Stroke (NINDS) (grant R01 NS080816). 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). This study was also supported by the National Center for Advancing Translational Sciences (NCATS) award (UL1TR000114). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: Funding This work was supported by the Bob allison ataxia Research center, the curt O’hagan aLs-pLs and aLs-Lou Gehrig Disease funds of the University of Minnesota Foundation, and the National Institute of Neurological Disorders and stroke (NINDs) (grant R01 Ns080816). 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). This study was also supported by the National center for advancing Translational sciences (NcaTs) award (UL1TR000114). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of health. Publisher Copyright: © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2019/3/1

Y1 - 2019/3/1

N2 - OBJECTIVE: To determine whether proton magnetic resonance spectroscopy ( 1H-MRS) can detect neurochemical changes in amyotrophic lateral sclerosis (ALS) associated with heterogeneous functional decline. METHODS: Nineteen participants with early-stage ALS and 18 age-matched and sex ratio-matched controls underwent ultra-high field 1H-MRS scans of the upper limb motor cortex and pons, ALS Functional Rating Scale-Revised (ALSFRS-R total, upper limb and bulbar) and upper motor neuron burden assessments in a longitudinal observational study design with follow-up assessments at 6 and 12 months. Slopes of neurochemical levels over time were compared between patient subgroups classified by the rate of upper limb or bulbar functional decline. 1H-MRS and clinical ratings at baseline were assessed for ability to predict study withdrawal due to disease progression. RESULTS: Motor cortex total N-acetylaspartate to myo-inositol ratio (tNAA:mIns) significantly declined in patients who worsened in upper limb function over the follow-up period (n=9, p=0.002). Pons glutamate + glutamine significantly increased in patients who worsened in bulbar function (n=6, p<0.0001). Neurochemical levels did not change in patients with stable function (n=5-6) or in healthy controls (n=14-16) over time. Motor cortex tNAA:mIns and ALSFRS-R at baseline were significantly lower in patients who withdrew from follow-up due to disease progression (n=6) compared with patients who completed the 12-month scan (n=10) (p<0.001 for tNAA:mIns; p<0.01 for ALSFRS-R), with a substantially larger overlap in ALSFRS-R between groups. CONCLUSION: Neurochemical changes in motor areas of the brain are associated with functional decline in corresponding body regions. 1H-MRS was a better predictor of study withdrawal due to ALS progression than ALSFRS-R.

AB - OBJECTIVE: To determine whether proton magnetic resonance spectroscopy ( 1H-MRS) can detect neurochemical changes in amyotrophic lateral sclerosis (ALS) associated with heterogeneous functional decline. METHODS: Nineteen participants with early-stage ALS and 18 age-matched and sex ratio-matched controls underwent ultra-high field 1H-MRS scans of the upper limb motor cortex and pons, ALS Functional Rating Scale-Revised (ALSFRS-R total, upper limb and bulbar) and upper motor neuron burden assessments in a longitudinal observational study design with follow-up assessments at 6 and 12 months. Slopes of neurochemical levels over time were compared between patient subgroups classified by the rate of upper limb or bulbar functional decline. 1H-MRS and clinical ratings at baseline were assessed for ability to predict study withdrawal due to disease progression. RESULTS: Motor cortex total N-acetylaspartate to myo-inositol ratio (tNAA:mIns) significantly declined in patients who worsened in upper limb function over the follow-up period (n=9, p=0.002). Pons glutamate + glutamine significantly increased in patients who worsened in bulbar function (n=6, p<0.0001). Neurochemical levels did not change in patients with stable function (n=5-6) or in healthy controls (n=14-16) over time. Motor cortex tNAA:mIns and ALSFRS-R at baseline were significantly lower in patients who withdrew from follow-up due to disease progression (n=6) compared with patients who completed the 12-month scan (n=10) (p<0.001 for tNAA:mIns; p<0.01 for ALSFRS-R), with a substantially larger overlap in ALSFRS-R between groups. CONCLUSION: Neurochemical changes in motor areas of the brain are associated with functional decline in corresponding body regions. 1H-MRS was a better predictor of study withdrawal due to ALS progression than ALSFRS-R.

KW - 7 tesla

KW - amyotrophic lateral sclerosis

KW - biomarker

KW - longitudinal

KW - motor cortex

KW - proton MRS

KW - Motor Cortex/metabolism

KW - Prognosis

KW - Humans

KW - Middle Aged

KW - Male

KW - Aspartic Acid/analogs & derivatives

KW - Motor Neurons/metabolism

KW - Case-Control Studies

KW - Disease Progression

KW - Pons/metabolism

KW - Glutamic Acid/metabolism

KW - Proton Magnetic Resonance Spectroscopy

KW - Adult

KW - Female

KW - Upper Extremity

KW - Aged

KW - Amyotrophic Lateral Sclerosis/diagnosis

KW - Longitudinal Studies

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JO - Journal of Neurology, Neurosurgery and Psychiatry

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ER -

Neurochemical correlates of functional decline in amyotrophic lateral sclerosis

Abstract

Bibliographical note

Keywords

Center for Magnetic Resonance Research (CMRR) tags

PubMed: MeSH publication types

UN SDGs

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