Remyelinating capacity in progressive MS
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
b) If remyelination can be related to inflammation and microglia
c) If chronically demyelinated axons express factors that are known
to inhibit remyelination
d) The occurrence of OPC’s in spinal cord lesions
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.
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.
Stephan Bramow, MD; Henning Laursen, MD, DMSc; Hans Lassmann, MD,
Professor; Nils Koch-Henriksen, MD, DMSc; Per Soelberg Sørensen
(1) Lublin FD, Reingold SC. Defining the clinical course of multiple
sclerosis: Results of an international survey. Neurology 1996 Apr;
(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.