Premyelinating Oligodendrocytes in Chronic Lesions of Multiple Sclerosis

Ansi Chang, M.D., Wallace W. Tourtellotte, M.D., Ph.D., Richard Rudick, M.D., and Bruce D. Trapp, Ph.D.

ABSTRACT

Background Multiple sclerosis is an inflammatory disease of the central nervous system that destroys myelin, oligodendrocytes, and axons. Since most of the lesions of multiple sclerosis are not remyelinated, enhancement of remyelination is a possible therapeutic strategy that could perhaps be achieved with the transplantation of oligodendrocyte-producing cells into the lesions. We investigated the frequency distribution and configuration of oligodendrocytes in chronic lesions of multiple sclerosis to determine whether these factors limit remyelination.

Methods Forty-eight chronic lesions obtained at autopsy from 10 patients with multiple sclerosis were examined immunocytochemically for oligodendrocytes and oligodendrocyte progenitor cells. Using confocal microscopy, we examined the three-dimensional relations between axons and the processes of premyelinating oligodendrocytes.

Results Thirty-four of the 48 chronic lesions of multiple sclerosis contained oligodendrocytes with multiple extended processes that associated with demyelinated axons but failed to myelinate them. These axons were dystrophic and contained multiple swellings. In some regions, the densities of premyelinating oligodendrocytes (25 per square millimeter of tissue) were similar to those in the developing rodent brain (23 per square millimeter). In the patients with disease of long duration (more than 20 years), there were fewer lesions with premyelinating oligodendrocytes (P<0.001).

Conclusions Premyelinating oligodendrocytes are present in chronic lesions of multiple sclerosis, so remyelination is not limited by an absence of oligodendrocyte progenitors or their failure to generate oligodendrocytes. Our findings suggest that in the chronic lesions of multiple sclerosis, the axons are not receptive for remyelination. Understanding the cellular interactions between premyelinating oligodendrocytes, axons, and the microenvironment of lesions of multiple sclerosis may lead to effective strategies for enhancing remyelination.

Natural History of Multiple Sclerosis with Childhood Onset

Christel Renoux, M.D., Sandra Vukusic, M.D., Yann Mikaeloff, M.D., Gilles Edan, M.D., Michel Clanet, M.D., Bénédicte Dubois, M.D., Marc Debouverie, M.D., Bruno Brochet, M.D., Christine Lebrun-Frenay, M.D., Jean Pelletier, M.D., Thibault Moreau, M.D., Catherine Lubetzki, M.D., Patrick Vermersch, M.D., Etienne Roullet, M.D., Laurent Magy, M.D., Marc Tardieu, M.D., Samy Suissa, Ph.D., Christian Confavreux, M.D., for the Adult Neurology Departments KIDMUS Study Group

ABSTRACT

Background The course and prognosis of childhood-onset multiple sclerosis have not been well described.

Methods We used data from 13 adult neurology departments affiliated with the European Database for Multiple Sclerosis (EDMUS) network to identify a cohort of 394 patients who had multiple sclerosis with an onset at 16 years of age or younger and a comparison group of 1775 patients who had multiple sclerosis with an onset after 16 years of age. We determined the initial clinical features, the dates of disease onset, and the occurrence of outcomes, including relapse, conversion to secondary progression, and irreversible disability as measured by scores of 4 (limited walking ability but ability to walk more than 500 m without aid or rest), 6 (ability to walk with unilateral support no more than 100 m without rest), and 7 (ability to walk no more than 10 m without rest while using a wall or furniture for support) on the Kurtzke Disability Status Scale (range, 0 to 10; higher scores indicate more severe disability).

Results For patients with childhood-onset multiple sclerosis, the estimated median time from onset to secondary progression was 28 years, and the median age at conversion to secondary progression was 41 years. The median times from onset to disability scores of 4, 6, and 7 were 20.0, 28.9, and 37.0 years, respectively, and the corresponding median ages were 34.6, 42.2, and 50.5 years. In comparison with patients with adult-onset disease, those with childhood-onset disease were more likely to be female than male (female:male ratio, 2.8 vs. 1.8), were more likely to have an exacerbating–remitting initial course (98% vs. 84%), took approximately 10 years longer to reach secondary progression and irreversible disability, and reached these landmarks at an age approximately 10 years younger (P<0.001> comparisons).

Conclusions Patients with childhood-onset multiple sclerosis take longer to reach states of irreversible disability but do so at a younger age than patients with adult-onset multiple sclerosis.

Risk Alleles for Multiple Sclerosis Identified by a Genomewide Study

The International Multiple Sclerosis Genetics Consortium

ABSTRACT

Background Multiple sclerosis has a clinically significant heritable component. We conducted a genomewide association study to identify alleles associated with the risk of multiple sclerosis.

Methods We used DNA microarray technology to identify common DNA sequence variants in 931 family trios (consisting of an affected child and both parents) and tested them for association. For replication, we genotyped another 609 family trios, 2322 case subjects, and 789 control subjects and used genotyping data from two external control data sets. A joint analysis of data from 12,360 subjects was performed to estimate the overall significance and effect size of associations between alleles and the risk of multiple sclerosis.

Results A transmission disequilibrium test of 334,923 single-nucleotide polymorphisms (SNPs) in 931 family trios revealed 49 SNPs having an association with multiple sclerosis (P<1x10^–4); of these SNPs, 38 were selected for the second-stage analysis. A comparison between the 931 case subjects from the family trios and 2431 control subjects identified an additional nonoverlapping 32 SNPs (P<0.001).> P values (<0.01)> for the second-stage analysis. Of these SNPs, two within the interleukin-2 receptor gene (IL2RA) were strongly associated with multiple sclerosis (P=2.96x10^–8), as were a nonsynonymous SNP in the interleukin-7 receptor gene (IL7RA) (P=2.94x10^–7) and multiple SNPs in the HLA-DRA locus (P=8.94x10^–81).

Conclusions Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis.