Friday, 30 September 2016

Location, location, location: MS pathology preferentially affects the edges of the brain

The Paper

Objective To assess the association between proximity to the inner (ventricular and aqueductal) and outer (pial) surfaces of the brain and the distribution of normal appearing white matter (NAWM) and grey matter (GM) abnormalities, and white matter (WM) lesions, in multiple sclerosis (MS).

Methods 67 people with relapse-onset MS and 30 healthy controls were included in the study. Volumetric T1 images and high-resolution (1 mm3) magnetisation transfer ratio (MTR) images were acquired and segmented into 12 bands between the inner and outer surfaces of the brain. The first and last bands were discarded to limit partial volume effects with cerebrospinal fluid. MTR values were computed for all bands in supratentorial NAWM, cerebellar NAWM and brainstem NA tissue, and deep and cortical GM. Band WM lesion volumes were also measured.

Results Proximity to the ventricular surfaces was associated with progressively lower MTR values in the MS group but not in controls in supratentorial and cerebellar NAWM, brainstem NA and in deep and cortical GM. The density of WM lesions was associated with proximity to the ventricles only in the supratentorial compartment, and no link was found with distance from the pial surfaces.

Conclusions In MS, MTR abnormalities in NAWM and GM are related to distance from the inner and outer surfaces of the brain, and this suggests that there is a common factor underlying their spatial distribution. A similar pattern was not found for WM lesions, raising the possibility that different factors promote their formation.

The Interpretation

In Multiple Sclerosis (MS), there are two broad kinds of damage done to the brain. There are focal lesions – inflammatory scars - which accumulate over time and are associated with relapses, and there is a diffuse neurodegenerative process which is more associated with the progression of disability. Lesions in MS affect both the grey matter – where nerve cell bodies reside – and the white matter, which consists of nerve cell projections (axons) to distant brain regions.

Interestingly, lesions in MS are more likely to appear in some parts of the brain than others. Post-mortem studies have demonstrated that white matter lesions have a predilection for the outer and inner surfaces of the brain. This predilection for particular sites is important because, amongst other reasons, it sheds light on the processes that initiate and perpetuate MS. For instance, it has been proposed that as MS lesions are most likely to occur in places close to cerebrospinal fluid (CSF) – the fluid that bathes and encases the brain – there may be a ‘toxic’ factor of some description that is involved in triggering and/or perpetuating MS.

It is therefore important that we understand exactly where in the brain is most vulnerable to developing lesions and non-lesional pathology in MS. This nice new paper from Declan Chard and pals uses a funky imaging method to find out the spatial distribution of grey and white matter pathology in people with MS.
The authors used Magnetisation Transfer Ratio (MTR) – a variant of MRI which can show subtle disturbances of brain tissue integrity quite well. MTR is used frequently in studies of MS because it is particularly good at detecting non-lesional pathology. We don’t know exactly what features of brain tissue affect MTR, but we do know that demyelination and axonal loss – which are both common in MS – do affect the MTR image.

This study recruited 30 healthy controls and 67 people with MS, of whom 41 had relapsing-remitting (RRMS) disease, and 26 had secondary progressive MS (SPMS). The authors used MTR to image these participants’ brains. They then took the images and divided each one into 12 bands based on the distance from the edge of the brain.

In normal-appearing white matter of both the cerebellum and the cerebral cortex, MTR values were reduced in MS, with the bands nearest the ventricles – the inside of the brain – most affected. This was also the case for the deep grey matter. The amount of lesioned white matter was also highest nearest the ventricles, and showed a clear relationship with distance from the ventricles. In addition there was a small, if slightly less convincing, reduction in MTR in MS related to distance from the outside edge of the brain (the pia).

These findings are cool but need to be interpreted with a bit of caution. For one, as mentioned, we do not fully understand what MTR imaging is actually measuring, and so some of the imaging abnormalities noted in this paper may not reflect pathological changes that are relevant to MS. Another problem is that some people with MS have slightly smaller brains than control subjects due to atrophy (i.e. degenerative changes) over time – this means that each ‘band’ on their brain images is smaller, and so there is more space for random variability to affect their results. Furthermore, MTR is bad at detecting grey matter lesions, and so it is tricky to say whether the grey matter abnormalities they describe are due to lesions, effects around lesions, or unrelated to lesions altogether. This is important because, as I’ve said, the processes driving lesions and the processes driving neurodegeneration are not the same – if we are trying to use studies like this to discover more about these processes then it is important to be able to distinguish lesional from non-lesional areas. A final gripe is that the control participants weren’t that well matched – the people with MS were mainly women, while the controls were split 50:50 between men and women.

But putting these concerns to one side, this paper does definitely add to our understanding of ‘selective vulnerability’ in MS – it shows that distance from the ventricles – the CSF-filled spaces which abut the inner face of the brain – and to some extent from the pia, is a key determinant of MS grey matter and white matter pathology. We will obviously need further work to determine exactly what MTR is measuring, whether these gradients in MS pathology hold up in bigger studies and to clarify what these gradients actually tell us about the disease processes in MS. Further work will also need to clarify the relationship between MS pathology and proximity to the pia, as this was not entirely clear from this study in my opinion.

In short, this work adds to previous imaging and post-mortem studies by showing that MS pathology selectively affects regions nearest the outer and inner surfaces of the brain.

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