End-organ damage: MRI grey matter atrophy is brain lost

Is it not time to change the way we think about progressive MS? #MSBlog #MSResearch

Protecting the MS Brain #MS2015

"The post-mortem study below shows that loss of gray matter volume, or atrophy, correlates at post-mortem to loss of neurones. This finding is not new; we have known about it for sometime in MS and in particular other neurodegenerative diseases. This study supports MS being a progressive neurodegenerative disease that is not limited to the white matter, but clearly involves the gray matter to a large extent. The loss of gray matter also explains why cognition is affected so early in MS and why MS given time causes dementia."

"Our current understanding of MS is that the loss of gray matter is driven by focal inflammatory events. However, if inflammation causes too much damage it then primes the surviving neurons to die off over time. This is why if we want to have a major impact on the prognosis of MS we need to switch off inflammation as soon as possible before too  much damage accrues. The corollary is that if we want to have an impact on progressive MS we need additional therapies to add-on to anti-inflammatory therapies; simply switching of inflammation won't do the job at least in the short-term. The latter explains why anti-inflammatory therapies have not worked in progressive MS in short-term studies. I have proposed the therapeutic lag hypothesis to explain why it will take much longer for anti-inflammatory therapies to have an effect in progressive MS."

"A few days ago someone made a comment that we know nothing about progressive MS. I don't agree with them. I think we have a good idea about a large number of the pathological processes underpinning progressive MS and how to target them. What we haven't worked out is how to do trials in progressive MS. This is why the Progressive MS Alliance (PMSA) is trying to do with their new funding call. They are trying to catalyse and new wave of innovation focusing on progressive MS. I still think we need wider adoption of early effective treatment in relapsing MS as a preventive strategy to try and prevent or delay the onset of progressive MS. There are still many MSers with no access to DMTs or with smouldering MS on DMTs. We need to change this. We also need to go beyond NEDA (no evident disease activity), which at present mainly targets focal inflammation, and start focusing on DMTs that reduce end-organ damage; yes. reduce or normalise brain atrophy rates. We have a responsibility to protect the MS brain; we can do this with DMTs and a brain health programme. 'Protecting the MS brain' is my new mantra for 2015 and to achieve this we need a fresh, new, holistic approach."

Epub: Popescu e al. What drives MRI-measured cortical atrophy in multiple sclerosis? Mult Scler. 2015 Jan 12. pii: 1352458514562440.

BACKGROUND: Cortical atrophy, assessed with magnetic resonance imaging (MRI), is an important outcome measure in multiple sclerosis (MS) studies. However, the underlying histopathology of cortical volume measures is unknown.

OBJECTIVE: We investigated the histopathological substrate of MRI-measured cortical volume in MS using combined post-mortem imaging and histopathology.

METHODS: MS brain donors underwent post-mortem whole-brain in-situ MRI imaging. After MRI, tissue blocks were systematically sampled from the superior and inferior frontal gyrus, anterior cingulate gyrus, inferior parietal lobule, and superior temporal gyrus. Histopathological markers included neuronal, axonal, synapse, astrocyte, dendrite, myelin, and oligodendrocyte densities. Matched cortical volumes from the aforementioned anatomical regions were measured on the MRI, and used as outcomes in a nested prediction model.

RESULTS: Forty-five tissue blocks were sampled from 11 MS brain donors. Mean age at death was 68±12 years, post-mortem interval 4±1 hours, and disease duration 35±15 years. MRI-measured regional cortical volumes varied depending on anatomical region. Neuronal density, neuronal size, and axonal density were significant predictors of GM volume.

CONCLUSIONS: In patients with long-standing disease, neuronal and axonal pathology are the predominant pathological substrates of MRI-measured cortical volume in chronic MS.

CoI: multiple

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