Disconnection of cognitively important processing regions by injury to the interconnecting white matter provides a potential mechanism for cognitive dysfunction in multiple sclerosis. The contribution of tract-specific white matter injury to dysfunction in different cognitive domains in patients with multiple sclerosis has not previously been studied. We apply tract-based spatial statistics (TBSS) to diffusion tensor imaging (DTI) in a cohort of multiple sclerosis patients to identify loci where reduced white matter tract fractional anisotropy (FA) predicts impaired performance in cognitive testing. Thirty-seven multiple sclerosis patients in remission (median age 43.5 years; Expanded Disability Status Scale range 1.5–6.5; 35 relapsing remitting, two secondary-progressive) underwent 3 T MRI including high-resolution DTI. Multiple sclerosis patients underwent formal testing of performance in multiple cognitive domains. Normalized cognitive scores were used for voxel-wise statistical analysis using TBSS, while treating age as a covariate of no interest. Permutation-based inference on cluster size (t> 2, P<0.05 corrected) was used to correct for multiple comparisons. Statistical mapping revealed differential patterns of FA reduction for tests of sustained attention, working memory and processing speed, visual working memory and verbal learning and recall. FA was not associated with frontal lobe function or visuospatial perception. Cognitively relevant tract localizations only partially overlapped with areas of high FLAIR lesion probability, confirming the contribution of normal-appearing white matter abnormality to cognitive dysfunction. Of note, tract localizations showing significant associations with cognitive impairment were found to interconnect cortical regions thought to be involved in processing in these cognitive domains, or involve possible compensatory processing pathways. This suggests that TBSS reveals functionally relevant tract injury underlying cognitive dysfunction in patients with multiple sclerosis.

The neuropeptide substance P (SP) exhibits cytokine-like properties and exerts different effects in autoimmune inflammation. Various immune cells express SP and its neurokinin-1 receptor (NK1R) isoforms. A role for SP has been demonstrated in a number of autoimmune conditions, including multiple sclerosis (MS). In this work, we studied the role of SP and NK1R in human immune cells with a focus on their relationship with IL-12/IL-23 family cytokines and the associated IFN-γ/IL-17. AIMS: (1) To determine the role of SP mediated effects on induction of various inflammatory cytokines in peripheral blood mononuclear cells (PBMC); (2) to investigate the expression of SP and its receptor in T cells and the effects of stimulation with IL-12 and IL-23. Quantitative real-time PCR, flow cytometry, ELISA, promoter studies on PBMC and primary T cells from healthy volunteers, and Jurkat cell line. Treatment with SP significantly increased the expression of IL-12/IL-23 subunit p40, IL-23 p19 and IL-12 p35 mRNA in human PBMC. Expression of NK1R and SP in T cells was upregulated by IL-23 but a trend was observed with IL-12. The IL-23 effect likely involves IL-17 production that additionally mediates IL-23 effects. Mutual interactions exist with SP enhancing the cytokines IL-23 and IL-12, and SP and NK1R expression being differentially but potentially synergistically regulated by these cytokines. These findings suggest a proinflammatory role for SP in autoimmune inflammation. We propose a model whereby immunocyte derived SP stimulates Th1 and Th17 autoreactive cells migrating to the central nervous system (CNS), enhances their crossing the blood brain barrier and perpetuates inflammation in the CNS by being released from damaged nerves and activating both resident glia and infiltrating immune cells. SP may be a therapeutic target in MS.

Ehlers—Danlos syndrome (EDS) has various neurological manifestations. Here we present an association of EDS with multiple sclerosis (MS). Four MS patients from a total of 1892 followed up at our MS outpatient clinics had EDS. This frequency suggests 10—11 times increased prevalence of EDS in MS patients compared with the general population (P = 0.02). Suggested implications include a possible causal relationship on a connective tissue level with a higher susceptibility to MS in EDS. Diagnostic and management considerations are important in coexisting MS and EDS. Our patients had relatively florid lesions on brain MRIs and typical course and features of MS. Multiple Sclerosis 2008; 14 : 567—570. http://msj.sagepub.com

It has been suggested that multiple sclerosis (MS) patients with positive anticardiolipin antibodies (ACLA) have some atypical features, including absent oligoclonal bands (OCB) in the cerebrospinal fluid (CSF). Our aim was to compare the frequencies of ACLA and related laboratory and clinical features in OCB negative (OCB−) and positive (OCB+) MS patients. We compared 41 OCB− patients attending a MS Clinic in a tertiary referral center, with 206 OCB+ patients. ACLA, anti-b2-glycoprotein and other autoantibodies, lupus anticoagulant and coagulation markers were measured. We found a higher frequency of ACLA in OCB− patients, 18/41 versus 33/206 in OCB+ patients (P < 0.0001). OCB− patients had more progressive MS than OCB+ subjects. There were no differences in age, sex, Expanded Disability Status Scale (EDSS) score, antiphospholipid syndrome symptoms between the groups. ACLA+ MS patients were more frequently in the OCB− group. Although this may suggest that they represent a special subgroup of MS, no other clinical or laboratory findings distinguish the groups. Although OCB− MS patients may be thought to be less active immunologically, this study shows they have more frequently ACLA than OCB+ patients. OCB− MS patients in our cohort do not appear to have a more benign form of MS, as has previously been suggested.