MS - a disease of nerve pathways?

Kolasinski J, Stagg CJ, Chance SA, Deluca GC, Esiri MM, Chang EH, Palace JA, McNab JA, Jenkinson M, Miller KL, Johansen-Berg H. A combined post-mortem magnetic resonance imaging and quantitative histological study of multiple sclerosis pathology. Brain. 2012 Oct;135(Pt 10):2938-51. doi: 10.1093/brain/aws242.

Multiple sclerosis is a chronic inflammatory neurological condition characterized by focal and diffuse neurodegeneration and demyelination throughout the central nervous system. Factors influencing the progression of pathology are poorly understood. One hypothesis is that anatomical connectivity influences the spread of neurodegeneration. This predicts that measures of neurodegeneration will correlate most strongly between interconnected structures. However, such patterns have been difficult to quantify through post-mortem neuropathology or in vivo scanning alone. 

In this study, we used the complementary approaches of whole brain post-mortem magnetic resonance imaging and quantitative histology to assess patterns of multiple sclerosis pathology. Two thalamo-cortical projection systems were considered based on their distinct neuroanatomy and their documented involvement inmultiple sclerosis: lateral geniculate nucleus to primary visual cortex and mediodorsal nucleus of the thalamus to prefrontal cortex. Within the anatomically distinct thalamo-cortical projection systems, magnetic resonance imaging derived cortical thickness was correlated significantly with both a measure of myelination in the connected tract and a measure of connected thalamic nucleus cell density. Such correlations did not exist between these markers of neurodegeneration across different thalamo-cortical systems.

Magnetic resonance imaging lesion analysis depicted clearly demarcated subcortical lesions impinging on the white matter tracts of interest; however, quantitation of the extent of lesion-tract overlap failed to demonstrate any appreciable association with the severity of markers of diffuse pathology within each thalamo-cortical projection system. Diffusion-weighted magnetic resonance imaging metrics in both white matter tracts were correlated significantly with a histologically derived measure of tract myelination. These data demonstrate the relevance of functional anatomical connectivity to the spread of multiple sclerosis pathology in a 'tract-specific' pattern. Furthermore, the persisting relationship between metrics from post-mortem diffusion-weighted magnetic resonance imaging and histological measures from fixed tissue further validates the potential of imaging for future neuropathological studies.

This study by a team in Oxford further underpins the suspicion that ‘inflammatory demyelination’ is only a fraction of what underlies disease progression in MS.  In a combined MRI and histology study using whole brains donated to the UK MS Society’s Tissue Bank the authors detected correlation between various measures of neurodegeneration ‘within connected pathways’ in the brain, however no such association ‘between different areas’ of the brain.  Measures of neurodegeneration included cortical thickness, neuronal cell and nerve fibre counts.  The two pathways included were tracts connecting specific nerve cell populations in the thalamus (a major ‘switchboard’ of information in the brain) and (i) the visual and (ii) the pre-frontal cortex. Demyelinating lesions had virtually no impact on the detected relationships.

What is the significance of these results?
According to this data MS leads to preferential damage of directly connected areas in the brain suggesting MS is a systemic neurodegenerative disease leading to nerve cell and fibre loss irrespective of demyelinating lesions.

What needs to be done next?
We need to better understand the mechanisms underlying neurodegeneration in MS to enable development of new treatments targeting these mechanisms!

This study is open access so you can all read it.

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