Pathology

Remyelinating capacity in progressive MS

Background
In multiple sclerosis (MS) there are two clinical subtypes at onset; relapsing-remitting (RRMS) and primary progressive MS (PPMS). RRMS is characterized by acute episodes of neurological deficits followed by recovery. Symptoms occur during formation of white matter lesions characterised in the acute phase by loss of oligodendrocytes, inflammation, destruction of myelin and conduction block. Recovery is associated with remyelination (RM), resolution of inflammation and restoration of nerve conduction. In contrast PPMS patients experience steadily progressing disability without relapses or remissions, accompanied by widespread spinal cord lesions. However most RRMS patients undergo transition within 15 years into secondary progressive MS (SPMS) characterised clinically by steadily increasing disability and pathologically by chronic compartmentalised CNS inflammation (1;2) and possibly RM-failure. In any MS subtype spinal cord lesions are more likely to cause permanent disability due to the condensed nerve tracts and possibly poorer RM capacity in this region.
Animal studies indicate that RM depends on oligodendrocyte precursor cells (OPC’s) and a certain extent of microglia mediated inflammation(3). Stimulation of spinal cord RM has been achieved in experimental models in rats and monkeys and has thus become a promising strategy for developing a therapy of MS related disability. In order to target such future therapy, more needs to be known about the natural occurrence and extent of RM and the causes of RM-failure - particularly with regard to progressive spinal cord disease, which is perhaps the most disabling manifestation of MS.

The objectives are to study
a) The occurrence, extent and clinical impact of remyelination in progressive MS as well as differences in RM between brain and spinal cord
b) If remyelination can be related to inflammation and microglia activation
c) If chronically demyelinated axons express factors that are known to inhibit remyelination
d) The occurrence of OPC’s in spinal cord lesions

Methods
Histopathological, immunohistochemical and morphometric techniques will be applied to a unique collection of spinal cord and brain tissue from 30 clinically well-characterised SPMS and PPMS patients. Areas of chronic demyelination and RM will be estimated on digitised images of sections according to established criteria (4). Immunohistochemical staining will be performed against markers of lymphocytes (CD3, CD8, CD20), microglia/macrophages (CD68), complement (C9neo), antibodies (IgG), axonal factors (PSA-NCAM) and OPC’s of increasing maturity (PDGFRa, NG2, CNP’ase and MOG). The density of relevant immunopositive cell types will be estimated in de- and remyelinated areas using unbiased planimetric methods.

Collaborators
This study is performed under the supervision of Henning Laursen, MD, DMSc, Head of Laboratory of Neuropathology, section 6301, Copenhagen University Hospital, Rigshospitalet. A formal collaboration has been established with Hans Lassmann, MD, Professor, Head of the Department of immunopathology, Brain Research Center, Vienna. Nils Koch-Henriksen, MD, DMSc, Director of the Danish Multiple Sclerosis Registry, Copenhagen is supplying clinical information.

Responsible scientist
Stephan Bramow

Project group
Stephan Bramow, MD; Henning Laursen, MD, DMSc; Hans Lassmann, MD, Professor; Nils Koch-Henriksen, MD, DMSc; Per Soelberg Sørensen MD, Professor.

References

(1) Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: Results of an international survey. Neurology 1996 Apr; 46(4): 907-11.
(2) Kutzelnigg A, Lucchinetti CF, Stadelmann C, Bruck W, Rauschka H, Bergmann M, et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 2005 Nov; 128: 2705-12.
(3) Zhao C, Fancy SPJ, Kotter MR, Li WW, Franklin RJM. Mechanisms of CNS remyelination - the key to therapeutic advances. Journal of the Neurological Sciences 2005 Jun 15; 233(1-2): 87-91.
(4) Patrikios P, Stadelmann C, Kutzelnigg A, Rauschka H, Schmidbauer M, Laursen H, et al. Remyelination is extensive in a subset of multiple sclerosis patients. Brain 2006 Aug 18; 129(Pt 12): 3165-72.