Fatigue in Multiple Sclerosis: Assessing Pontine Involvement Using Proton MR Spectroscopic Imaging

Abstract

Background/ObjectiveThe underlying mechanism of fatigue in multiple sclerosis (MS) remains poorly understood. Our study investigates the involvement of the ascending reticular activating system (ARAS), originating in the pontine brainstem, in MS patients with symptoms of fatigue.MethodsFemale relapsing-remitting MS patients (n = 17) and controls (n = 15) underwent a magnetic resonance spectroscopic imaging protocol at 1.5T. Fatigue was assessed in every subject using the Fatigue Severity Scale (FSS). Using an FSS cut-off of 36, patients were categorized into a low (n = 9, 22 ± 10) or high (n = 10, 52 ± 6) fatigue group. The brain metabolites N-acetylaspartate (NAA) and total creatine (tCr) were measured from sixteen 5x5x10 mm3 spectroscopic imaging voxels in the rostral pons.ResultsMS patients with high fatigue had lower NAA/tCr concentration in the tegmental pons compared to control subjects. By using NAA and Cr values in the cerebellum for comparison, these NAA/tCr changes in the pons were driven by higher tCr concentration, and that these changes were focused in the WM regions.Discussion/ConclusionSince there were no changes in NAA concentration, the increase in tCr may be suggestive of gliosis, or an imbalanced equilibrium of the creatine and phosphocreatine ratio in the pons of relapsing-remitting MS patients with fatigue.

Current Methods of Magnetic Resonance for Noninvasive Assessment of Molecular Aspects of Pathoetiology in Multiple Sclerosis

“…In particular, the reduction in tNAA in the frontal cingulate gyrus has been found to correlate with global memory functions in a group of early MS patients [ 60 , 69 ]. Lower tNAA in the tegmental pons of patients with RRMS has been associated with higher fatigue [ 70 ]. An inverse correlation of tNAA to disability has been observed in chronic lesions of RRMS, SPMS, and PPMS patients [ 25 ] and in the hypothalamus of patients in early MS stages [ 24 ].…”

“…With respect to its brain distribution, mIns is predominantly localized in astrocytes (~6 mM [ 84 ]), and not in neuronal cells (less than 0.5 mM [ 84 ]) [ 70 , 78 , 84 ], suggesting that mIns can be stored and regulated in glial cells before their utilization in the PIP cycle [ 84 ]. During glial proliferation, mIns levels have been shown to rise, making mIns a useful glial marker [ 25 , 79 , 84 ].…”

“…Furthermore, the glutamate level has been found to be elevated, whereas the glutamine concentration persists unchanged in the MS brain [ 51 , 90 ]. Elevated Glx, as measured by MRS, has been reported in various CNS structures: in NAWM and in active (but not in chronic) WM lesions of RRMS [ 70 , 111 ], SPMS, and PPMS patients [ 77 ], and in NAWM and the thalamus in CDMS patients [ 51 ]. Therefore, glutamate has been proposed as a predictive marker for WM pathology [ 51 , 70 ].…”

“…Elevated Glx, as measured by MRS, has been reported in various CNS structures: in NAWM and in active (but not in chronic) WM lesions of RRMS [ 70 , 111 ], SPMS, and PPMS patients [ 77 ], and in NAWM and the thalamus in CDMS patients [ 51 ]. Therefore, glutamate has been proposed as a predictive marker for WM pathology [ 51 , 70 ]. The findings in GM are contradictory: Glx is elevated in cortical GM and hypothalamus in RRMS and SPMS [ 52 , 70 ], is unchanged in the thalamus, hippocampus, and cortical GM in RRMS, SPMS, and PPMS [ 56 ], or declines in cortical GM [ 1 ] and in the hippocampus, thalamus, cingulate, and parietal cortices in RRMS [ 111 ].…”

“…Therefore, glutamate has been proposed as a predictive marker for WM pathology [ 51 , 70 ]. The findings in GM are contradictory: Glx is elevated in cortical GM and hypothalamus in RRMS and SPMS [ 52 , 70 ], is unchanged in the thalamus, hippocampus, and cortical GM in RRMS, SPMS, and PPMS [ 56 ], or declines in cortical GM [ 1 ] and in the hippocampus, thalamus, cingulate, and parietal cortices in RRMS [ 111 ]. Altered Glx metabolism in the hypothalamus has previously been shown, in RRMS and SPMS, to correlate with disease severity [ 52 , 58 ] and in the early MS state suggesting a positive correlation to disability in MS patients [ 24 ].…”