Resolving the cognitive clinico-radiological paradox - Microstructural degeneration of fronto-striatal-thalamic loops in early active multiple sclerosis.

BACKGROUND: Associations between cognitive impairment (CI) and both global and regional brain volumes can be weak in early multiple sclerosis (MS), a dilemma known as cognitive clinico-radiological paradox. We hypothesized that white-matter (WM) integrity within fronto-striatal-thalamic networks may be a sensitive marker for impaired performance in speed-dependent tasks, typical for early MS. METHODS: Twenty-seven patients with early active relapsing-remitting MS (RRMS) received comprehensive neuropsychological assessment and underwent structural and diffusion-weighted brain magnetic resonance imaging (MRI). Global and regional brain volumes were obtained using FreeSurfer software. Fractional anisotropy (FA) was computed from diffusion tensor images to assess microstructural alterations within three anatomically predefined fronto-striatal-thalamic loops known to be relevant for speed-dependent attention and executive functions. RESULTS: Overall cognitive performance (Spearman's ρ = .51) and performance in the domains processing speed (ρ = .44) and executive functions (ρ = .41) were correlated with patients' mean FA within the right dorsolateral-prefrontal loop. In addition, overall cognitive performance correlated with mean FA within the right lateral orbitofrontal loop (ρ = .39) - but only before controlling for WM lesion count. In contrast, regional volumes of grey-matter structures within these fronto-striatal-thalamic loops (including the thalamus) were not significantly related to CI. The total brain volume was associated with performance in the domain verbal memory (ρ = .43) only. CONCLUSIONS: Microstructural degeneration within specific fronto-striatal-thalamic WM networks, previously characterized as crucial for task-monitoring, better accounts for speed-dependent CI in patients with early active RRMS than global or regional brain volumes. Our findings may advance our understanding of the neural substrates underlying CI characteristic for early RRMS.

Alemtuzumab Improves Cognitive Processing Speed in Active Multiple Sclerosis-A Longitudinal Observational Study.

BACKGROUND: Several disease-modifying drugs have shown promising effects on cognitive impairment in multiple sclerosis (MS). Alemtuzumab, a humanized monoclonal antibody, is effective in controlling disease activity, however, has not been evaluated for its effects on cognition in detail so far. OBJECTIVE: To explore the influence of alemtuzumab on cognitive impairment in active relapsing-remitting MS (RRMS) as well as possible clinical and neuroimaging predictors of cognitive changes during the first year of therapy. METHODS: Extensive neuropsychological assessment was administered to 21 patients with active RRMS at baseline and again after the second treatment with alemtuzumab (mean time span: 15.05 months). Clinical and routine structural neuroimaging markers were explored for their capacity to predict individual courses of cognitive change. RESULTS: Overall cognitive functioning remained stable or improved during the observational period of alemtuzumab treatment on average. Scores on two neuropsychological tests of processing speed significantly improved and clinically relevant individual gains of processing speed were seen in the majority of patients. Linear regression models showed that clinical and routine neuroimaging measures of disease activity could not fully account for these cognitive changes. CONCLUSION: Results suggest that alemtuzumab treatment in active RRMS stabilizes overall cognitive functioning and furthermore positively affects cognitive processing speed. Changes in processing speed were independent from clinical and structural neuroimaging parameters of disease activity and may thus represent an underrated and independent outcome measure to evaluate treatment effects.