Increased glutamate and deep brain atrophy can predict the severity of multiple sclerosis

In multiple sclerosis (MS), deep grey matter (DGM) atrophy has been recognised as a crucial component of the disease that presents early and it has been associated with disability. Although the precise mechanism underlying grey matter atrophy is unknown, several hypotheses have been postulated. Our previous research pointed to correlations of hypothalamic metabolic alterations with clinical outcomes of MS, therefore we decided to further test the relationship of these alterations with DGM atrophy.

We used ¹H-Magnetic Resonance spectroscopy (¹H-MRS) of the hypothalamus to test its metabolites in 26 patients with RRMS and 22 healthy age-matched controls. DGM atrophy was evaluated by simple planimetry of third ventricular width on the hypothalamic level (3VW) in T1 weighted MRI pictures. Metabolite ratios of N-acetyl aspartate (NAA), choline (Cho), glutamate and glutamine (Glx), myo-inositol (mIns) and creatine (Cr) were correlated with Multiple Sclerosis Severity Scale (MSSS) and 3VW.

Metabolite concentrations were compared between patients and controls using multiple regression models allowing for age, 3VW and metabolites. It revealed that the only relevant predictors of MSSS were 3VW and Glx/NAA. At a significance level of P<0.05, a unit increase of 3VW was associated with a 0.35 increase of MSSS, for a typical value of Glx/NAA; P value 0.0039. A unit increase of Glx/NAA was associated with a 0.93 increase of MSSS, for a typical value of atrophy; P value 0.090. There were significant linear correlations between Glx/Cr and MSSS, Glx/NAA and MSSS, and between mIns/NAA and 3VW.

The results suggest that both NAA and Glx are associated with neurodegeneration of hypothalamic DGM and severe disease course. Glx related ¹H-MRS parameters seem to be superior to other metabolites in determining disease burden, independently of otherwise powerful 3VW planimetry. Significantly increased mIns/NAA in MS patients compared to controls point to gliosis, which parallels the atrophy of hypothalamic DGM.