M. Stoecklin

Contribution of cortical and white matter lesions to cognitive impairment in multiple sclerosis

Background: Cortical lesions (CLs) have been reported to be a better predictor for cognitive impairment than white matter (WM) lesions in relapsing–remitting multiple sclerosis (RRMS). Objectives: The objectives of this article are to investigate the contribution of CLs and WM lesions to cognitive impairment in 91 patients with MS and clinically isolated syndrome, and to test potential associations of CLs and WM lesions with fatigue and depression. Methods: Lesions were scored and segmented on 3D double inversion recovery sequences, according to their location (cortical, WM). Normalised grey matter volume was also determined. Cognitive performance was assessed with the SDMT and PASAT-3, fatigue with the FSMC and depression with the German version of the CES-D. Results: CL volume did not correlate with fatigue or depression, but correlated significantly with both neuropsychological outcome measures: PASAT-3 (r = −0.275, p = 0.009) and SDMT (r = −0.377, p < 0.001). Multiple regression analyses with age, WM lesions, CLs and GM volume as independent variables, however, did not reveal CL volume as a significant predictor of neuropsychological outcomes, whereas WM lesion volume significantly predicted SDMT and by trend PASAT performance. Conclusions: These findings suggest a role of WM lesions in the development of cognitive deficits, especially information-processing speed, which may be higher than previously assumed. Abbreviations: CES-D: Center for Epidemiologic Studies Depression scale (ADS-L: Allgemeine Depressions Skala-L, German version of CES-D), CIS: clinically isolated syndrome, CL: cortical lesion, DIR: double inversion recovery, EDSS: Expanded Disability Status Scale, FSMC: fatigue scale for motor and cognitive functions, GM: grey matter, MRI: magnetic resonance imaging, MS: multiple sclerosis, PASAT-3: paced auditory serial addition test 3s, PPMS: primary progressive multiple sclerosis, RRMS: relapsing–remitting multiple sclerosis, SDMT: symbol digit modalities test, SPM: statistical parametric mapping, SPMS: secondary progressive multiple sclerosis, WM: white matter

Reduced response to reward in smokers and cannabis users.

Background: Cannabis is one of the most commonly used illicit drugs. Reduced neural and behavioral reactions to reward have been demonstrated in other forms of addiction, as expressed by reduced mood reactivity and lack of striatal activation to rewards, but this effect has not yet been investigated in cannabis users. Methods: We hypothesized that cannabis users and tobacco smokers would evidence lower positive mood ratings in rewarded conditions than control participants and that this reduction would be greater in cannabis users than in smokers. We examined the influence of reward on mood and performance in a group of regular cannabis users, a group of tobacco smokers and a group of nonsmokers while they performed a spatial recognition task with delayed response that incorporated 3 levels of difficulty. Correct responses were either not reinforced or reinforced with money. We measured the accuracy of reactions, reaction times and mood ratings throughout the trials. Results: Cannabis users rated their mood as significantly worse than the smokers and nonsmokers during the easiest level of the rewarded condition. A significant positive correlation between mood ratings and monetary reward was found in the nonsmokers but not in the cannabis users and smokers. The groups did not differ with regard to task performance. Conclusions: Our results suggest that regular cannabis use affects certain aspects of motivation and that both tobacco smoking and cannabis use lead to similar motivational changes. However, the use of cannabis seems to affect motivation in a stronger way than does tobacco smoking alone.

The FSMC (Fatigue scale for motor and cognitive functions) : a new instrument to assess MS-related fatigue

The adaptive immune system is critically involved in development and maintenance of tissue damage in the CNS. We recently demonstrated that primary oligodendrocyte damage by overexpression of Proteolipidprotein (PLP) induces a low grade inflammation causing demyelination and axonopathy. Absence of lymphocytes by RAG1deficiency significantly ameliorated the phenotype. By chimerizing PLPtg/RAG1-/mice with either CD4(=CD8+) or CD8(=CD4+) deficient bone marrow, we could identify CD8+T-lymphocytes as the pathogenic cell subset. In the present study we investigated the impact of regulatory mechanisms involved in modulation of autoimmune responses in this mouse model of inherited demyelination. We focussed on the role of the coinhibitory receptor PD1 which is expressed on activated T-and B-lymphocytes and associated with immune homeostasis and autoimmunity. Of specific interest in this context is the finding that a human PD1 polymorphism is associated with progressive forms of multiple sclerosis. We therefore challenged the question how the conjunction of a genetically-mediated CNS pathology (PLP-myelinopathy) with a mutation affecting T-cell homeostasis (PD1 deficiency) affects tissue destruction and adaptive immune reactivity. In order to delineate the relevance of a combined pathology, we generated bone marrow chimeras of PLPtg mice which received either wild type or PD1 deficient bone marrow. Supplementary, we crossbred PLPtg mice with PD1 deficient mice. The CNS of adult mice with double pathology exhibited significantly increased numbers of CD4+ and CD8+T lymphocytes. While mice with PD1 deficiency alone showed no detectable CNS pathology, demyelination and axonopathy of PLPtg mutants was substantially aggravated in PLPtgPD1-/mice when compared to PLPtg mutants with a wild type immune system. In contrast to PLPtg or PD1-/mutants alone, brains of PLPtgPD1-/double mutants showed an increase of IFN-g producing cells indicating a more aggressive lymphocyte phenotype. Furthermore, CDR3 spectratype analysis of CNS lymphocytes exhibited substantial clonal expansions of PLPtgPD1-/double mutants. Our study identifies PD1 as a crucial regulator of T lymphocyte tissue homeostasis and indicates that a primary glial damage combined with alterations in this regulatory pathway can lead to overt neuroinflammatory reactions of high pathogenic impact. Thus, our findings may have substantial relevance for some forms of multiple sclerosis and other leukodystrophies.