The Relationship Between Brain MR Spectroscopy and Disability in Multiple Sclerosis: 20‐Year Data from the U.S. Glatiramer Acetate Extension Study

Abstract

BACKGROUND AND PURPOSEConventional MRI techniques do not necessarily provide information about multiple sclerosis (MS) disease pathology or progression. Nonconventional MRI techniques, including proton magnetic resonance spectroscopy (1H‐MRS), are increasingly used to improve the qualitative and quantitative specificity of MR images. This study explores potential correlations between MRI measures of disease and disability progression as measured by the Expanded Disability Status Scale (EDSS), Functional Systems (FS), and ambulation index scores in a unique cohort of MS patients treated with glatiramer acetate that has been closely monitored for over 20 years.METHODSThis was a multicenter, open‐label, cross‐sectional MRI substudy among participants in the GA‐9004 open‐label extension of the 36‐month, double‐blind GA‐9001 study, timed to coincide with the prospectively planned 20‐year clinical exam.RESULTSOf 64 patients who participated in the MRI substudy, results are presented for the 39 patients (61%) who had a 1H‐MRS assessment at 20 years of treatment. Both total N‐acetylaspartate relative to total creatinine (tNAA/tCr) concentration ratio and T1 lesion volume were found to be robustly associated with disability levels with different statistical approaches. Gray matter (GM) volume was found to be a more consistent parameter than white matter (WM) volume for disability allocation. The elastic net algorithm showed a trade‐off between WM and GM volumes for disability estimation when different disability definitions were used.CONCLUSIONSAmong patients with MS receiving long‐term glatiramer acetate therapy, consistent effects on disability levels indicated by EDSS and pyramidal FS score thresholds were found for tNAA/tCr concentration ratio and T1 lesion volume.

Calibrated imaging reveals altered grey matter metabolism related to white matter microstructure and symptom severity in multiple sclerosis

“…Increased burden on grey matter, coupled with decreased transport of metabolic substrate [see Paling et al, ], probably results in decreases in basal levels of neurometabolism [for work on mitochondrial inhibition and neuroimaging see Kannurpati, ; Sanganahalli et al, ]. For example, negative relationships have been observed between basal NAA:creatine ratios and RD in MS white matter [Hannoun et al, ; see also Kahn et al, ]. Our results showing positive relationships between evoked CMRO 2 and RD/symptom combined with the prospect of MS‐related decreases in basal neurometabolism suggest energy failure as a plausible explanation.…”

“…Foregoing the unlikely scenario of increased basal oxygen metabolism for more WMMS damaged and more symptomatic MS patients [cf. Ge et al, ; Hannoun et al, ; Kahn et al, ], conclusions related to either absolute or relative increases in oxygen metabolism suggest a similar interpretation: stimulation induced oxygen metabolism increased as of function of the extent of WMMS damage and symptomology. Of note is that our MS cohort was predominantly earlier stage MS patients—90% of patients had relapsing‐remitting diagnoses and were on average over 2 years removed from their last exacerbation; all were ambulatory with intact cognitive status (TICS > 21).…”

“…Previous work using cfMRI has established that reduced baselines of BOLD and CBF demonstrate greater evoked changes in CMRO 2 relative to higher baselines [Pasley et al, ; see also Hyder et al, ; Restom et al, ; Shulman et al, ]. Negative relationships between whole‐brain resting CMRO 2 and neurological disability [Ge et al, ; see also Kindred et al, ], and basal NAA:creatine ratios and RD [Hannoun et al, ; see also Kahn et al, ] have also been observed in MS. These baseline associations demonstrate that decreased basal metabolism is associated with increased WMMS damage and more severe MS symptomology.…”

“…Neurometabolism is also intimately linked to changes in BOLD signal [see Kim and Ogawa, ]. Neuroimaging research has produced extensive evidence of altered neurometabolism across MS subtypes [e.g., Cader et al, ; Ge et al, ; Hannoun et al, ; Kahn et al, ; Kindred et al, ; Sijens et al, ; Sun et al, ; see Stromillo et al, for preclinical MS]. Postmortem studies in advanced MS have also traced neurometabolic deficits to the level of the mitochondria and electron transport chain complexes in lesioned and nonlesioned neural tissue [Dutta et al, ; see also Singhal et al, ].…”

CD133-Positive Membrane Particles in Cerebrospinal Fluid of Patients with Inflammatory and Degenerative Neurological Diseases

“…A relation between the inflammation and CD133 expression was noted in solid cancers (Karbanová et al, 2014; Rappa et al, 2015). Altogether, CD133 may serve as a surrogate marker for monitoring disease activity – similar to radiological findings – after initiation of immunomodulatory therapy (Harris and Sadiq, 2014; Khan et al, 2016; Uher et al, 2016; Zivadinov et al, 2016). …”