Cognitive function and neurophysiological correlates in relapsing-remitting multiple sclerosis

Impaired cognitive function is a frequent consequence of multiple sclerosis (MS). It negatively affects vocational status, treatment adherence, physical independence, competence in activities of daily life, rehabilitation potential, driving safety and quality of life. All papers in this thesis concern cognitive function in relapsing-remitting MS (RRMS), with emphasis on clinical and neurophysiological predictors, moderating factors and the effect of natalizumab (NZ) treatment. I. The aim of this paper was to identify the strongest clinical predictors for cognitive impairment in RRMS patients. Patients with RRMS (n=72) and healthy control subjects (n=89) underwent comprehensive cognitive testing and clinical assessment. Physical disability (EDSS), fatigue (FSS), somatic and non-somatic components of depression (BDI-S and BDI-NS), disease progression rate (MSSS), and presence of psychotropic medication were included in the analysis. Patients had a mean EDSS of 2.7 and disease duration of 9.3 years. Depression and fatigue estimates were significantly higher in patients than in control subjects (p<0.0001). Cognitive impairment had a prevalence of 30.5% in patients affecting preferentially executive functions, attention and processing speed. EDSS, FSS, BDI-NS and BDI-S were significantly correlated with several cognitive domains and global cognitive function in patients. In regression models, cognitive performance was best predicted by BDINS alone or in combination with EDSS. Exclusion of patients with any psychotropic medication did not influence the main findings. II. The objective of paper II was to explore if cognitive impairment in RRMS is associated with abnormal neural function, and if there is evidence of neural compensatory mechanisms. The study population described in paper I underwent event-related brain potential (ERP) recordings with visual and auditory choice reaction tasks. Patients had increased visual P300 amplitude frontally. Auditory and visual P300 amplitude were normal in other brain areas, and response time (RT) was normal. P300 latency was normal except for an increase in auditory latency occipitally. Cognitive performance correlated positively with visual and auditory parietal P300 amplitude in patients (p<0.0001 and p=0.009, respectively) but not in controls. Global cognitive score had a significantly stronger correlation (negative) with RT in patients than in controls (intergroup difference for visual stimulation p=0.015, and for auditory p=0.050). Notably, these associations were not an epiphenomenon of the cognitive impairment in patients, because parietal P300 amplitude and RT were normal. We concluded that patients with low P300 amplitude and long RT were more often cognitively impaired. III. The aim of paper III was to distinguish different mechanisms for cognitive reserve in RRMS. Thus, we wished to test the cognitive reserve hypothesis in the present study population. This hypothesis predicts that high premorbid intelligence, as may be estimated from years of education and vocabulary knowledge, attenuates the effects of disease burden on cognitive functioning. In this analysis, the normal effects of premorbid intelligence on the test scores need to be accounted for. Thus we compared the strength of the correlation between premorbid intelligence and cognitive performance in patients and controls, respectively. Contrary to the prediction, premorbid intelligence had no stronger effect on cognition in patients than in controls. This finding contrasted against the results in paper II where P300 amplitude and RT did have stronger effect on cognitive function in patients than in controls, i.e. showed features of a reserve against cognitive impairment in patients. The strongest neurophysiological (visual P300 amplitude and RT) and clinical (EDSS and BDINS) predictors of cognitive function were studied in a hierarchical linear regression model. P300 amplitude and RT explained 34% of the variance in global cognitive function (p<0.001). EDSS and BDI-NS added significantly to explained variance, and the final model accounted for 44% (p<0.001) of the variation. In a separate analysis, we found that the effects of P300 and RT on cognitive function were not moderated by premorbid intelligence. IV. The objective of paper IV was to evaluate the cognitive effects of NZ treatment, compared to patients on stable first-line treatment and healthy control subjects. Fifteen MS patients (MS-NZ) underwent cognitive testing when starting NZ treatment and were tested again after one year. They were compared with fifteen MS patients on stable interferon beta therapy (MS-C) and twelve healthy control subjects (HC) who also were tested twice with an interval of one year. The effects of NZ on levels of self-reported depression, fatigue, daytime sleepiness and perceived health were also examined. MS patients (MS-NZ and MS-C) had significantly lower baseline cognitive performance compared to HC (global score, p=0.002). At follow-up, both MS-NZ and MS-C had improved significantly in four and five cognitive domains, respectively, and in global cognitive score (p=0.013 and p<0.001, respectively). HC improved significantly in three cognitive domains but not in global score. A regression analysis showed that participants with lower baseline scores had a significantly greater improvement, compared to those with a better initial performance (p=0.021). There were no significant changes in depression, fatigue, daytime sleepiness or perceived health in MS-NZ or MS-C.