Spectroscopic axonal damage of the right locus coeruleus relates to selective attention impairment in early stage relapsing-remitting multiple sclerosis

Lower levels of N-acetylaspartate (NAA), a marker of axonal damage, have been found in the normal-appearing white matter (NAWM) of relapsing-remitting multiple sclerosis (RRMS) patients with low physical disability. However, its relation to the clinical status of these patients remains unclear. We explored the association between NAA levels [normalized to creatine (Cr), NAA/Cr] and a cognitive feature that is not measured by the standard scales that address functional disability [e.g. Expanded Disability Scale Score (EDSS)] in early RRMS. Given that a considerable number of RRMS patients present attentional dysfunction early in the disease and assuming a functional-anatomical oriented guide, it was hypothesized that patients with worse attentional performance would show lower NAWM NAA/Cr values in the locus coeruleus nuclei of the pontine ascendant reticular activating system. Proton magnetic resonance spectroscopy (H-1-MRS) examinations with concurrent clinical evaluation were acquired for 19 RRMS patients with a mean evolution time of 24 months (range 10-60) and mild disability (EDSS 0-3.5, median = 1). H-1-MRS was obtained with spectroscopic imaging and measures were taken from the right and left hemipons. Attention was measured by means of the dichotic listening (DL) paradigm to increase the sensitivity of the testing to subtle attentional deficits. A consonant-vowel DL test was measured with and without attentional instructions. For the attentional condition, the test was digitally manipulated to cue automatically to the ear to be attended, thus allowing the obtention of both a linguistic lateralization index (LI) and an index of integrity of attentional shifts (ASI). Attentional impairment was demonstrated in 47.3% of the patients. Pontine NAA/Cr levels accounted for 39% of the ASI variability (beta = 0.65, P < 0.002) but did not relate to the LI. Moreover, when NAA/Cr levels were considered separately as left and right hemipons values in a multivariate stepwise linear regression model, the right NAA/Cr ratio alone explained 43% of the ASI variability (beta = 0.68, P < 0.001). Since the RRMS patients with greater attentional disturbances exhibited the lowest NAA/Cr levels, it is concluded that NAA provides a specific measure of pathological changes that are also relevant for cognitive functions. The use of both H-1-MRS and DL showed the connection between axonal damage at right locus coeruleus and auditive selective attention dysfunction in early-stage RRMS.