This Is MS Multiple Sclerosis Community: Knowledge & Support

We are trying to find markers of prognosis (a prediction of disease progression) early on because this will help decide who will most likely benefit from new treatments. MRI lesion volume has some effect on the long term course but is a relatively weak predictor. We are now investigating other measures that show a more extensive abnormality than just the visible lesions. There are intrinsic abnormalities in the normal appearing white matter and grey matter that show up with measures including magnetisation transfer ratio (MTR) - specific types of MRI scans allowing more precise detection of damage, and MR spectroscopy. There is also loss of tissue in both the white and grey matter.

Damage in the Grey Matter in Multiple Sclerosis (MS)
March 2005, we look at Professor Margaret Esiri's study of grey matter in MS.

The brain can be divided into grey and white matter. Grey matter is the area where nerve cells communicate with each other. White matter acts as the wiring between different areas of the brain. Traditionally MS researchers focused on damage in the white matter because damage in this area appeared to explain all the characteristic relapsing remitting character of the earlier stages of disease. However, white matter damage cannot explain disability progression in a simple way. It alone also does not easily explain memory problems in MS, which can be found in roughly half of the patients.

Damage in the grey matter in MS provides an alternative explanation for these symptoms. We are interested in investigating changes in the grey matter in MS. Although damage in the grey matter was recognised many years ago, these changes were not widely appreciated. Recent studies have re-examined the grey matter and suggest that we may have underestimated the importance of damage in this area.

A study conducted at our department focused on nerve cells and their junctions in one grey matter area. This work demonstrated that there was a loss of nerve cells and their junctions within damaged grey matter in MS. These observations that nerve cells and their junctions are damaged in MS could help us to explain psychological findings such as memory problems. Our findings could be relevant for new treatments for MS that protect nerve cells and their junctions.

EFFECT OF INTERFERON BETA-1A ON GREY MATTER ATROPHY PROGRESSION IN RELAPSING-REMITTING MULTIPLE SCLEROSIS

R Zivadinov1, L Locatelli2, B Srinivasaraghavan1, M Ukmar2, A Bratina2, C Maggiore2, A Bosco2, A Grop2, R Pozzi-Mucelli2, M Catalan2 and M Zorzon

University of Buffalo, Neurology, Buffalo, New York, USA; University of Trieste, Neurology, Trieste, Italy

Keywords: brain atrophy; grey matter atrophy; interferon
beta-1a; longitudinal; MRI; trial

Background: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system (CNS) that involves most prominently the white matter (WM) of the brain. It has been demonstrated that substantial gray matter (GM) damage in the brain occurs from the earliest stages of the disease. Two recently concluded clinical trials showed that Avonex® (IFN beta-1a; Biogen, Inc., Cambridge, MA) slows down the rate of brain atrophy progression in the second and third year of the trial. However, more detailed information on the effect of this disease-modifying treatment (DMT) on the topography of CNS atrophy has not been provided yet.

Objectives: To determine whether Avonex® slows down progression of brain atrophy by reducing predominantly GM or WM damage, or both.

Methods: Thirty-one patients with MS have been included in the study and followed for 3 years. The inclusion criteria were: relapsing-remitting (RR) MS, Expanded Disability Status Scale (EDSS) 0–5.5 and one exacerbation in the 12 months prior to study entry. At study entry, the therapy with Avonex® has been offeredto all patients. Fourteen patients started treatment with Avonex®, whereas 17 decided to delay the start of DMT and served as study controls. Both groups had quantitative cranial MRI scans at study entry and after three years, and standardized clinical assessments every 6 months. Brain parenchymal fraction (BPF), grey matter fraction (GMF) and white matter fraction (WMF) percent changes were calculated using SPM99 software program.

Results: Three patients in the control arm have been excluded from the study, because they started DMT before the study conclusion. Baseline demographic, clinical, and MRI measures were well matched between the two study arms. None of the patients on Avonex® developed neutralizing antibodies during the study. Mean percent change in BPF ( -1.2% vs. -2.2%, p = 0.003) and GMF (+3.6% vs. -4.2%, p < 0.0001) favored the Avonex® treatment arm. Both treatment groups developed similar amounts of WM atrophy over 3 years (p = NS).

Conclusions: The results of this preliminary study indicate that Avonex® may slow down brain atrophy progression preventing predominantly the development of GM atrophy.

Disclosures: R Zivadinov has nothing to disclose.

Funding: No funding reported.

Robin, Ian, Harry, Reed

An increase in lesion load (LL), a decrease of brain volume (BV) and a reduction of N-acetylaspartate (NAA) are all thought to reflect disease progression in MS.

The reason that Prineas and Barrett's autopsy work has caused such a stir in MS circles is because it is the first time that someone has actually been able to scientifically look at a lethal lesion so quickly after the patient died. They were able to see something very different to what the researches have thought for years..

I'm afraid it was MS: We have a full copy of the paper, which was sent by Dr. Prineas when my husband, also a pathologist, showed much interest.

Recent studies of axon-glia and glia-glia communication have emphasized interactivity and interdependence between central nervous system (CNS) components. Concurrently, data from imaging, biochemical, and morphological studies have changed the view of multiple sclerosis (MS) from a neuroinflammatory condition with primary demyelination to one in which cumulative axonal damage drives progression. We therefore studied axonal damage in the context of inflammation and glial responses, from the pre-clinical to onset stage of murine experimental autoimmune encephalomyelitis (EAE), an established MS model. We report three major findings: (1) the first evidence of axonal injury before significant T-cell entry into the parenchyma, (3) coincidence of the earliest manifestation of axonal damage and astrocytic responses, and (3) an association between accumulation of axonal and astrocytic changes and specific forms of MS. These data demonstrate the relationship between the initiation of axonal injury and early inflammation. Significantly, we show that, in common with a growing number of neurodegenerative conditions, the pathology of murine EAE is characterized by early active contribution from astrocytes. This marks a change in the understanding of the role of astrocytes in MS pathogenesis and has important implications for the development of neuroprotective strategies.

CONCLUSIONS: In patients with multiple sclerosis at the earliest clinical stage, the severity of NAWM damage does not predict new lesion formation in the short term, suggesting that the "diffuse" component of tissue damage is, at least partially, independent of the "discrete," predominantly inflammatory aspects of the disease since its clinical onset.

CONCLUSIONS: Axonal-neuronal damage in the brain of patients with PPMS seems to occur, at least partially, independently of the burden of magnetic resonance imaging-visible lesions.

Interestingly, after Campath-1H the immune cells do seem to encourage nerve cells to grow. Now we have to find out how!

-Alasdair Coles