M. Ukkonen

Volumes of brain atrophy and plaques correlated with neurological disability in secondary progressive multiple sclerosis

The objectives of the present study was to correlate the segmented magnetic resonance imaging (MRI) volumes of intracranial cerebrospinal fluid (CSF) spaces (expressing the extent of brain atrophy) and cerebral plaques with the neurological disability in secondary progressive multiple sclerosis (MS). Earlier studies have mainly correlated MS plaques and neurological disability measured by expanded disability status scale (EDSS). The data on the association between brain atrophy and EDSS or regional functional scoring scale (RFSS) are very limited. We measured the volumes of intracranial CSF spaces in 28 patients with secondary progressive MS using MRI, and semiautomatic segmentation software. The volumes of T1-weighted hypointense and T2-weighted hyperintense MS plaques were also measured. In multiple regression analysis, increasing volumes of total (P=0.006) and relative (P=0.005) intracranial CSF spaces were significantly associated with worsening neurological disability as expressed by EDSS. No associations were found between these intracranial CSF space volumes and total RFSS scores. The mean volume of T2-weighted plaques showed a tendency to associate with total RFSS score (r=0.40, P=0.03), but no correlations were detected between T1- or T2-weighted plaque volumes and EDSS. The application of a new segmentation technique in quantifying intracranial cerebrospinal fluid spaces allowed an exact and sensitive way of assessing brain atrophy. The associations between brain atrophy and neurological disability expressed by EDSS suggests that the effect of MS therapies should be evaluated by measurement of brain atrophy.

Promoter polymorphism of IL-10 and severity of multiple sclerosis

Functional polymorphisms of the genes for interleukin‐10 (IL‐10; promoter position −1082), chemokine receptor‐5 (CCR5 32 bp deletion), tumor necrous factor‐α (TNFα promoter position −308) and cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4 exon 1 position 49) were investigated for possible influence on susceptibility and outcome of multiple sclerosis (MS). The polymorphisms were typed by polymerase chain reaction based methods or by direct sequencing in MS patients (n = 93–116) and controls (n = 109–400). The studied genes were not associated with MS susceptibility. Patients were classified as suffering from a mild/moderate [Expanded Disability Status Scale (EDSS) 0–5.5] or severe (EDSS 6–8.0) form of MS. The AG genotype of IL‐10 proved to be protective against severe MS in all patients (OR = 0.32, P = 0.010), the effect being increased over the years (10 years; OR = 0.33, P = 0.043, 15 years; OR = 0.21, P = 0.025 or 20 years; OR = 0.14, P = 0.026). Our results suggest that differential production of IL‐10 might be a factor in the severity of MS.

Urodynamic findings in primary progressive multiple sclerosis are associated with increased volumes of plaques and atrophy in the central nervous system

Objective – Voiding dysfunction is more frequent in primary progressive multiple sclerosis (PPMS) than in other subtypes of MS. We investigated whether lower urinary tract disorders are reflected in the extent of changes in brain and spinal cord detected by magnetic resonance imaging (MRI).

A study of interleukin-1 cluster genes in susceptibility to and severity of multiple sclerosis

In this explorative study, interleukin-1 (IL-1) receptor antagonist (IL-1RA; polymorphism of variable number of tandem repeats: VNTR), IL-1alpha (-889), IL-1beta (-511) and IL-1beta (+3953) polymorphisms were studied in relation to susceptibility to and severity of multiple sclerosis (MS), in 93 MS patients and 400 normal controls. No associations were found for any polymorphisms, alone or in combination. However, in our MS cohort, females were found to be IL-1RA allele 2 carriers more frequently than males (33/49 vs. 16/44, p = 0.0028). Using a cohort of 109 controls, IL-1RA allele 2 carriers were more frequently women with MS than control women (33/49 vs. 23/43, odds ratio (OR) = 2.19, 95% confidence interval (CI) 1.02-4.72, p = 0.043, P(C) = ns). The data suggest that the IL-1 cluster genes make no major contribution to MS, but the tentative association between IL-1RA allele 2 and susceptibility of MS in women warrants further studies.

Differential intracellular expression of CCR5 and chemokines in multiple sclerosis subtypes

Chemokines are small chemoattractant cytokines which participate in the migration of immune cells into the CNS and contribute to the T cell-mediated pathogenesis of multiple sclerosis (MS). The expression of chemokines and their receptors in freshly isolated mononuclear cells from peripheral blood (PBMC) was studied in relation to MS subtype, disease duration and progression in a total of 57 patients with MS (22 relapsing remitting, RRMS; 21 secondary progressive, SPMS; 14 primary progressive, PPMS) and 17 healthy controls. The RNA expression of CCR5 in PBMC was analysed by reverse transcription polymerase chain reaction (RT-PCR) using specific oligonucleotide primers. The PBMC levels of CCR5-ligands MIP-1α/β and RANTES, and chemokines MCP-1, IL-8, lymphotactin, IP-10 and I-309 were analysed by ribonuclease protection assay (RPA). Significantly increased intracellular CCR5 RNA expression intensity was detected in PPMS when compared with SPMS (p=0.009), RRMS (p=0.013), and controls (p=0.023). However, the surface expression of CCR5 on CD4(+) cells from PBMC, analysed by flow cytometry, appeared to be similar in all MS subtypes and controls. The CCR5-ligands RANTES and MIP-1b were expressed constitutively in all patients and controls. Interleukin-8 was found in all MS subtypes and controls, but IP-10 was detected only in RRMS and SPMS, and lymphotactin occasionally in other subtypes but PPMS. MCP-1, MIP-1a or I-309 were not expressed in any of the groups studied. A correlation was found between the RNA levels of RANTES and CCR5 in PPMS (r=0.735). Differential profile in the expression of CCR5 and chemokines between PPMS and other MS subtypes may contribute to differences in the pathogenesis of MS and thus can be of importance in the development of new treatments for MS.

Cell surface adhesion molecules and cytokine profiles in primary progressive multiple sclerosis

Objective We evaluated the utility of adhesion molecule (AM) and cytokine/chemokine expressions in blood and cerebrospinal fluid (CSF) as markers of disease activity in primary progressive multiple sclerosis (PPMS). Methods The expressions of AMs and the levels of 17 cytokines in patients with PPMS (n = 25) were compared with those in secondary progressive MS (SPMS) (n = 18) and controls (n =11) and correlated with the volumes of focal and atrophic changes on MRI. Results The expressions of very late activation antigen 4 (VLA-4), lymphocyte function-associated antigen 1 (LFA-1) and intercellular adhesion molecule 1 (ICAM-1) in blood and CSF were higher in PPMS than in controls. Comparison between PPMS and SPMS showed higher levels of ICAM-1 in blood and CSF in PPMS, while the level of the vascular adhesion molecule (VCAM-1) was higher only in blood. There was no difference in the levels of cytokines in serum or CSF between PPMS and SPMS or controls, but evidence suggesting intrathecal synthesis of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) was found in PPMS. The expressions of CSF VLA-4 in PPMS correlated with the total volume of cerebral lesions and the number of diffuse brain lesions in MRI, while the amount of LFA-1 in CSF correlated with the number of spinal T2 lesions. The level of serum MIP-1β correlated with the T2 lesion load and EDSS score in PPMS. Conclusions The upregulated expressions of AMs in blood and CSF and evidence for intrathecal synthesis of MCP-1 and IL-8 in PPMS indicate the importance of inflammatory changes in the pathogenesis of PPMS. Multiple Sclerosis 2007; 13: 701-707. http://msj.sagepub.com

The combination of HLA-DR1 and HLA-DR53 protects against MS

The DRB1/3/4/5 loci from 97 patients with MS and 100 normal control subjects were analyzed. DRB1*15 increased the risk of MS (OR = 4.2, p < 0.0001), whereas DR1 decreased the risk (OR = 0.30, pc = 0.005). In analyses of the DR1 risk in relation to DR51, DR52, and DR53 alleles, DR1 in combination with DR53 was found to have the strongest protective effect against MS in all subjects (OR = 0.05, p < 0.0001) and in DRB1*15-negative subjects (OR = 0.09, pc = 0.026). DR53 may be an important allele or haplotype, acting together with DR1 to protect against MS.

Increased nitric oxide products in CSF in primary progressive MS may reflect brain atrophy

Because nitric oxide (NO) is a putative mediator of oligodendrocyte damage in the primary progressive form of MS (PPMS), the authors analyzed the levels of NO oxidation products in CSF and plasma from 25 patients with PPMS and 15 controls. The levels of nitrite + nitrate (NOx) in CSF were fourfold higher in patients with PPMS than in controls (p < 0.001), whereas the concentrations in plasma were similar. These data suggests involvement of NO in nervous tissue damage in PPMS.

Increased disability and MRI lesions after discontinuation of IFN‐β‐1a in secondary progressive MS

Objective –  To examine neurological and magnetic resonance imaging (MRI) changes following discontinuation of interferon (IFN)‐β‐1a treatment in secondary progressive multiple sclerosis (SPMS).

Cognitive dysfunction in primary progressive multiple sclerosis: a neuropsychological and MRI study

Although cognitive dysfunction is known to occur in multiple sclerosis (MS), only few studies have reported cognitive performance in patients with primary progressive MS (PPMS). To find out the pattern of cognitive performance in PPMS, 28 PPMS patients underwent an extensive battery of neuropsychological tests. The results were compared to those of healthy controls (n = 20) and patients with secondary progressive MS (SPMS, n = 28). Furthermore, the results of neuropsychological tests in PPMS were correlated to magnetic resonance imaging findings. Our study showed that the PPMS patients have deficits in several cognitive domains when compared to age-matched and education-matched controls, but the cognitive impairment in the PPMS and SPMS patients appeared to be similar. Cognitive deficits in PPMS patients correlated with diffuse brain lesion, T1- and T2-lesion load, but no correlations were found with atrophy.