Metabolite changes in normal-appearing gray and white matter are linked with disability in early primary progressive multiple sclerosis

Background: Abnormalities in normal-appearing brain tissues may contribute to disability in primary progressive multiple sclerosis (PPMS), where few lesions are seen on conventional imaging. Objectives: To evaluate the mechanisms underlying disease progression in the early phase of PPMS by measuring metabolite concentrations in normal-appearing white matter (NAWM) and cortical gray matter (CGM) and to assess their relationship with clinical outcomes. Design: Case-control study. Setting: Tertiary referral hospital. Patients: Forty-three consecutive patients within 5 years of onset of PPMS and 44 healthy control subjects. Main Outcome Measures: Concentrations of choline-containing compounds, phosphocreatine, myo-mositol, total N-acetyl-aspartate (tNAA), and glutamate-glutamine were estimated using proton magnetic resonance spectroscopic imaging. Brain parenchymal, white matter and gray matter fractions and proton density and gadolinium-enhancing lesion loads were calculated. The Expanded Disability Status Scale and Multiple Sclerosis Functional Composite scores were recorded. Results: In CGM, concentrations of the tNAA (P < .001) and glutamate-glutamine (P = .005) were lower in patients with PPMS than in controls. In NAWM, myoinositol levels were higher (P = .002) and tNAA levels were lower (P = .005) in patients with PPMS than in controls. The Expanded Disability Status Scale score correlated with the tNAA concentration in CGM (r = -0.44; P = .03) and with myo-inositol (r = 0.41; P = .01) and glutamate-glutamine concentrations (r = 0.41; P = .01) in NAWM. Proton density lesion load correlated negatively with CGM tNAA concentration and positively with NAWM myoinositol concentration. Conclusion: Metabolite changes, which differ in CGM and NAWM, occur in early PPMS and are linked with disability.