Cognition in Multiple sclerosis with special emphasis on MRI findings and cerebrosterol

Sammanfattning: Multiple sclerosis (MS) is a progressive inflammatory and degenerative disease of the central nervous system (CNS). This thesis focuses on cognition in MS, with special emphasis on long-term magnetic resonance imaging (MRI) findings and cerebrosterol plasma levels. In study I, the effects of MS on a variety of cognitive aspects were evaluated longitudinally over an eight-year follow-up period in 31 patients who had been diagnosed as having relapsing-remitting MS, secondary progressive MS (SP-MS) or primary progressive MS. A selective pattern of decline was found at baseline in the whole group, with marked decline in information-processing speed (IPS). These deficits in IPS at baseline predicted further cognitive decline over the follow-up period. A differential pattern of cognitive decline over time was noticed in the subgroups, with the most pronounced decline in the SP-MS group; in these patients, the deterioration in visual IPS was clearly more marked than that in auditory IPS. A high disability score (on the expanded disability status scale; EDSS) during follow-up was associated with cognitive decline. These findings indicate that tests measuring IPS are especially strong predictors of cognitive decline over longer periods in patients with MS. In Study II, 25 patients with MS and 25 matched control participants were tested with a picture-naming test (Boston Naming Test; BNT) and a letter-word fluency test (using the letters FAS). In the BNT, the MS patients used less distinct descriptions and substitutions and had significantly more off-target substitutions than the control group. The MS patients were significantly less effective in using strategies for retrieval in the word fluency FAS test than the control participants. These results suggest that language function becomes impaired in MS, with semantically nonspecific naming responses and less effective use of strategies for retrieval in word fluency. In Study III, 22 MS patients were given tasks investigating IPS, covering the following aspects: cognitive (symbol digit modalities test; SDMT), sensory (visual and auditory reaction time tests), motor (finger-tapping speed test) and auditory interhemispheric transfer (verbal dichotic listening test; VDL). These parameters were related to the area of the corpus callosum in the brain (CCA), measured with MRI at baseline and at follow-up nine years later. The relative brain volume (RBV) and the T2 lesion load were taken into account. The results showed that the CCA, but not the RBV or the T2 lesion load, was associated with the SDMT score, and that the higher the annual rate of change in the CCA, the poorer the performance in the left ear VDL, with a subsequently more pronounced advantage in the right ear VDL. These results indicate that corpus callosum is related to a clearly cognitive component, rather than a sensory-motor component. Study IV analyzed the relationships between cognitively demanding information processing (measured with the SDMT), clinical status (EDSS), plasma cerebrosterol 24OHC levels, and MRI-normalized measurement of RBV, grey and white matter volumes, and ventricular cerebrospinal fluid volume in a cross-sectional sample of 21 MS patients. The results showed that slow IPS in SDMT was related to neurodegeneration, particularly loss of grey matter volume, and high cerebrosterol plasma concentrations, reflecting membrane turnover in the CNS. Poor EDSS was associated with high plasma cerebrosterol levels, which is hypothetically a biomarker of MS progression. Conclusions: Deterioration in IPS seems to be a central aspect of cognitive decline in MS. Slow IPS occurs already at an early phase in the disease and predicts long term cognitive decline. The MS patients have less effective strategies for lexical substitution and retrieval than healthy persons. The poor lexical processing in the MS patients could putatively be due to slow IPS, especially in the markedly speed demanding word fluency test. CCA in contrast to RBV and the T2 lesion load, appears to be exclusively related to a cognitively demanding IPS task but not to sensory-motor speed tasks, which suggests that CC is especially important for cognitive speed processes. Slow IPS seems to be primarily associated with low grey matter volume and high plasma concentration level of cerebrosterol while disability appears to be related to high plasma level of cerebrosterol. Since there were no interaction between cerebrosterol and the neurodegenerative predictors, it is putative that the cytotoxic properties of the cerebrosterol independently could cause neuronal cell death and thereby affect IPS independently of neurodegeneration.