Neurochemical correlates of functional decline in amyotrophic lateral sclerosis

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6 Scopus citations

Abstract

Objective To determine whether proton magnetic resonance spectroscopy (1 H-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 1 H-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. 1 H-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. 1 H-MRS was a better predictor of study withdrawal due to ALS progression than ALSFRS-R.

Original languageEnglish (US)
Pages (from-to)294-301
Number of pages8
JournalJournal of Neurology, Neurosurgery and Psychiatry
Volume90
Issue number3
DOIs
StatePublished - 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.

Keywords

  • 7 tesla
  • amyotrophic lateral sclerosis
  • biomarker
  • longitudinal
  • motor cortex
  • proton MRS

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