Brain shrinkage

B

Today Dr Filipa Serrazina from Lisbon in Portugal talking about Brain Shrinkage

Brain atrophy in MS: what we know and would like to know in clinical practice

Although multiple sclerosis (MS) is known to be mainly an inflammatory demyelinating disease characterized by many areas of white matter lesions, cortical lesions and brain atrophy (or brain shrinkage) have also emerged as new pathological markers of disease progression. All people tend to lose brain volume as they age – a process known as atrophy. But in people who have MS, this process typically happens much faster. It has been widely accepted that brain atrophy in MS is a sensitive measure of neurodegeneration. Brain tissue loss can now be easily and reproducibly detected and quantified by MRI, which has led to an increasing amount of research correlating brain tissue loss with other MRI markers, such as white matter lesions, and to clinical disabilities (motor or cognitive), in order to assess its clinical relevance. As this information has been widely spread, it has become a frequent topic of discussion among patients and healthcare professionals. However, there are still some limitations on how to manage this information in clinical practice. Patients with MS may have a couple of questions on this topic and there are some answers that we know, but others that we also would like to know.

Why brain volume loss is a concern in MS?

The brain is commonly seen as a mix of grey and white matter. Grey matter consists of the main bodies of nerve cells and is mainly responsible for cognition and processing information. White matter consists of the nerve fibres that extend from the nerve cell bodies and gets its colour from the myelin that surrounds nerve fibres; it is mainly responsible for carrying signals between different parts of the brain and spinal cord.

Brain atrophy, related to both grey matter and white matter, has been reported in people with MS. It can be seen in the earliest stages of MS, progresses faster compared to healthy adults and seems to be a reliable predictor of future physical and cognitive disability in people with MS. In a study carried out overtime, whole brain and cortical atrophy (the atrophy of the outer layer of the brain, composed of folded grey matter), as well as other MRI-related metrics, have been associated with disability progression over a 10-year follow-up (Zivadinov R, et al. Mult Scler. 2016). Also, changes in brain volume have been shown to predict cognitive impairment over 2 years in patients with early MS (Zivadinov R, et al. J Neurol Neurosurg Psychiatry. 2001) and cortical atrophy was the best predictor of poor cognitive functioning. Other reported clinical aspects of CNS atrophy include mood and personality disorders (e.g. euphoria, disinhibition, major depressive disorder) (Benedict RH, et al. J Neurol Sci. 2005). Taken together, this growing body of evidence suggests that brain atrophy is a valid and sensitive measure of disease burden and progression in MS patients.

What do we know about the mechanisms driving brain atrophy in MS?

Brain atrophy in MS occurs as a result of damage that takes place via a number of different complex mechanisms. Inflammation may be an important contributor to global tissue loss specially in early disease stages. Brain volume loss may also be the consequence of more diffuse primary or secondary neurodegenerative processes that occur independently of lesion activity. Additional mechanisms include microglia activation, meningeal inflammation leading to subpial grey matter pathology, astrocyte damage, iron deposition, oxidative stress, diffuse axonal damage in normal appearing white matter, progressive loss of chronically demyelinated axons outside MS lesions and smouldering activity (Andravizou et al. Autoimmun Highlights, 2019).

What does it mean if my brain MRI reports lower brain volume for my age?

Establishing cut-offs able to discriminate between physiological and pathological rates in patients with MS is not an easy task. In a complex disease such as MS, brain volume loss might be due to several mechanisms (discussed above). The respective contribution of each component to brain atrophy may depend on many factors, such as disease stage, presence of comorbidities and other factors unrelated to the disease. In this context, it might be challenging the use of MRI-based assessments on an individual basis to reliably classify patients into normal versus abnormal categories. So, a single cross-sectional measurement of brain volume could not be informative unless it is significantly way off the norm. Moreover, is important to note that the measurement of brain atrophy is considerably influenced by the amount of tissue fluids. So, factors like dehydration and excessive alcohol consumption can influence the brain volume temporarily.

What does it mean if my follow-up brain MRI reports brain volume loss?

Gradual loss of brain volume occurs with ageing in healthy adults, at about 0.1-0.5% per year. Brain atrophy progresses over time and may be more pronounced when ageing is complicated by other risk factors, such as smoking, diabetes and other cardiovascular risk factors. However, in patients with MS, the brain typically atrophies at a much higher rate, at about 0.5–1.35% per year (Giovannoni G, Mult Scler Relat Disord. 2016). Accelerated brain atrophy starts early in the disease, often before the diagnosis of MS, and progresses across the disease. So, a small annual loss of brain tissue volume is likely to be real as reflects the pathophysiology of the disease and it is probably more informative than a cross-sectional evaluation of the brain volume.

Does my disease-modifying therapy help with my brain volume?

Reducing the rate of brain atrophy has only recently been incorporated as a critical endpoint into the clinical trials of new or emerging disease-modifying drugs in MS. The pattern of results emerging from treatment trials to date is that DMT has, at best, only a limited effect on brain atrophy and that this effect is often delayed, possibly related to the mechanisms underlying atrophy. There are several potential reasons why treatments able to significantly reduce clinical and MRI-measured inflammatory MS activity did not show any substantial effect on the development of brain atrophy. These include inadequacy of trial design, the limitations of brain volume measurement strategies and, finally, the limited ability of these therapies to modify the pathological mechanisms leading to tissue loss in MS. Most of the published trials were not originally designed and powered to test the efficacy of treatments on brain atrophy and the short duration of the follow-up periods may also limit sensitivity for detecting any effect of treatments on brain volume changes.

With the information available to date, it is known that DMTs may prevent or slow down brain volume loss through mechanisms that are not fully understood to date. Currently approved treatments for MS may differ in their effects on brain atrophy. Both immunomodulating and immunosuppressive treatments primarily exert an anti-inflammatory action, which is one of the mechanisms contributing to brain volume loss in MS. Promoting a significant reduction of the inflammatory components of MS-related damage should have at least a partial effect on the progressive loss of tissue seen in patients with MS.

I have been stable, and free of inflammatory activity (without new lesions or relapse activity), but my brain volume loss is worsening. Does it matter?

In fact, historically, targets for treatment outcomes in MS have been settled on NEIDA (no evident inflammatory disease activity), which considers the occurrence of relapses and new brain MRI lesions. Then the treatment target was referred to as NEDA (no evident disease activity), which also included the evaluation of disability worsening. Despite it being the most widely adopted treatment target to date in MS services, this approach places emphasis on inflammatory activity in the brain and mostly overlooks ongoing neurodegenerative damage (Giovannoni G, et al. Mult Scler. 2017).

However, it has been suggested that brain atrophy should be included in the definition of NEDA as it might be very helpful in expanding the concept of no evident disease activity. A measure of diffuse brain damage would shift the focus of MS treatments to treat to a target beyond NEIDA, optimize the treatment effect, prevent end-organ damage, and promote brain health.

What can I do to prevent brain atrophy?

People with MS need to be fully aware that, at the moment, unfortunately, there isn’t any treatment available to restore the brain volume already lost. On the other hand, they also need to be aware that brain atrophy may not manifest as clinical symptoms until late, which depends on the capacity to preserve the brain reserve and cognitive reserve. Both are part of the neurological reserve, which means the capacity of the brain to retain function by remodelling itself to compensate for the loss of nerve cells, loss of nerve fibres and atrophy.

Extremely important is to choose an effective DMT as it aims to suppress inflammatory activity and, so, is an important tool to slow down further loss. Another important point for patients with MS is to preserve neurological reserve by adopting a brain-healthy lifestyle. Maximizing lifelong brain health in MS involves a holistic approach that incorporates lifestyle measures such as cardiovascular fitness/regular exercise, avoidance of smoking, limiting the use of alcohol, promote activities that enhance cognitive reserve by being intellectually enriching (such as education, reading, puzzles, hobbies); also, interventions to minimize comorbidities (other diseases present alongside MS, e.g. high blood pressure, diabetes, dyslipidaemia) should be prioritized in MS patients.

Filipa Serrazina

COI: Nothing relevant

Disclaimer. These are the views of the author

About the author

The MS Bloggger

20 comments

  • Thanks for your post.

    What your post should does is highlight how serious MS is – it’s a slow, sometimes fast, death sentence. The neuro who diagnosed me was very flippant “you’ve got MS, it’s an autoimmune disease, and in many cases it’s does causes too many problems”.

    The key takeaways from your post for me are: “All people tend to lose brain volume as they age – a process known as atrophy. But in people who have MS, this process typically happens much faster.”

    “The pattern of results emerging from treatment trials to date is that DMT has, at best, only a limited effect on brain atrophy and that this effect is often delayed, possibly related to the mechanisms underlying atrophy.”

    Researchers should now only be focusing on the mechanisms causing accelerated atrophy and identifying therapies to reduce atrophy to normal rates. The seriousness of this disease has always been underplayed and, to date, all we have are DMTs which reduce relapses but do little to address the real MS.

  • This is what really frustrates me about multiple sclerosis. There have been clinical definitions for elements of the disease, such as Uhthoff’s phenomena and likewise, that have existed for the last 200 years, yet there has been no real progress in terms of effectively curing young people that have the disease.

    Is shameful, actually. A lot of this suggests the neurologists are not entirely sure if these new DMTs actually work. An MRI will not actually show progression, therefore, it’s all based on supposition. I don’t believe that, in the long term, these pharmaceutical biologicals are actually going to cure people of this infernal disease.

  • Thanks for sharing, nice read for pwMS. Is there a correlation between BVL and SCVL?
    I have an spinal form of ppms with only SC lesions and atrophy at the cervical level.
    So this could be do to chronic activated Microglia at the cervical level?
    MRI says lesions are stable only tiny increase of atrophy at the cervical level. Radiologist calls this stable spinal disease. I have to disagree as I went from EDSS 4 to 6.

    Neurologists keep telling me my brain looks fine but they don’t measure anything.
    I know I lost a tiny bit of processing speed over the last years. Could be age and becoming a father as kids take up lots of Brain space! I will be in BTKI trial and my brain tells me I will not process further than EDSS 6, brains are funny that way. Next post SCVL? 😁

    • Thanks for your comment. In fact, similar to brain atrophy, there are also studies that found an association between spinal cord atrophy and disability progression (Bischof A, Papinutto N, Keshavan A, et al. Spinal Cord Atrophy Predicts Progressive Disease in Relapsing Multiple Sclerosis. Ann Neurol. 2022 Feb;91(2):268-281.)

    • Thanks for your comment. In fact, similar to brain atrophy, there are also studies that found an association between spinal cord atrophy and disability progression (Bischof A, Papinutto N, Keshavan A, et al. Spinal Cord Atrophy Predicts Progressive Disease in Relapsing Multiple Sclerosis. Ann Neurol. 2022 Feb;91(2):268-281.)

  • Thanks for this (rather grim) post.

    “Additional mechanisms include microglia activation, meningeal inflammation leading to subpial grey matter pathology, astrocyte damage, iron deposition, oxidative stress, diffuse axonal damage in normal appearing white matter, progressive loss of chronically demyelinated axons outside MS lesions and smouldering activity.”

    To what extent are these additional mechanisms linked? Surely they have to be? Could a brain / spinal cord infected with EBV (or B cells containing EBV) explain these mechanisms?

    Why didn’t all the work on EAE identity these mechanisms and the extent of neuro-degeneration/ atrophy? EAE steered the researchers to focus on relapses / focal inflammation and not the real disease ie the mechanisms causing neurodegeneration / atrophy. You have to ask how helpful EAE has been if the therespies developed from it are having limited affect on neurodegeneration.

    • The work on EAE did identify these mechanisms…the focus on relapses is because that is where the interest (and the money) was laying and the experiments are quick and easy….Do not blame EAE the responsibility lays with the people who use EAE, if you do not ask the questions you are not going to get the right answers

      • We’ll have to agree to differ on this one. EAE was great for PhD students and for grant applications. However, recent research has pretty much proved that EBV is the main cause (possibly driver) of MS and that there is good evidence to show that MS is primarily a neurodegenerative disease (the real MS) and that relapses (focal inflammation) are just a response to the real MS. Someone diagnosed with PPMS (inactive) today has no treatment options. EAE (even the chronic inflammation model/s) has not led to any therapies to treat progression / neuro-degeneration. Even those treated with the most highly effective DMTs are merely delaying the inevitable climb up the EDSS. I can’t say if EAE led to the Sizomus trial or the BTK inhibitor trials, perhaps it did. But for many MSers it’s too little too late.

  • “Maximizing lifelong brain health in MS involves a holistic approach that incorporates lifestyle measures such as cardiovascular fitness/regular exercise, avoidance of smoking, limiting the use of alcohol, promote activities that enhance cognitive reserve by being intellectually enriching (such as education, reading, puzzles, hobbies); also, interventions to minimize comorbidities (other diseases present alongside MS, e.g. high blood pressure, diabetes, dyslipidaemia) should be prioritized in MS patients.”

    Brain Health is being promoted by several MS experts. I have no issue with the concept, but it’s just living a healthy lifestyle (good weight, exercise, stop smoking). Is there any evidence that taking a Brain Health approach reduces the rate of brain atrophy? To me taking a Brain Health approach should be the fourth arrow in the fight against MS. The first to third are (1) effective anti-inflammatories (that also work in the CNS), (2) neuroprotective therapies, and (3) remyelination therapies. I feel let down by the MS research community when I’m told to do puzzles and cut back on alcohol. I expected a bit more from 60 years of well funded research.

  • I think that in this blog was mantioned several time ( Porf G also) that hsct actually normilizes the athrophy rate?

  • Dr Filipa,

    Thank you for your post.

    What hope is there on the horizon to help reduce the rate of brain atrophy for MSers?

    Are there any drug trials I can join which may help eg Sizomus, BTK inhibitors etc? I thought I was doing well on Nataluzamab but your post has worried me ie brain atrophy is still ongoing.

    • Thanks for your comment. As we know so far, the two main points that help in brain atrophy are suppressing inflammatory activity with DMT and preserving neurological reserve by adopting a brain-healthy lifestyle. Clinical trials have specific inclusion criteria that must be evaluated on a case-by-case basis.

  • Whenever I have asked about BVL in the past the reply has been, ‘Nope, something we don’t measure. Different MRI hardware means it is impossible even if we were looking for it.’

    Does anyone know when UK-wide MS neurology will be getting on-board with what seems like a highly worthwhile measurement?

    It is great to talk about it from a research centre of excellence but pretty depressing when away from a very few centres the answer is a version of, ‘Hard luck mate’.

  • Hello Dr. Serrazina –
    Based on the following, I do take 1200 mcg Alpha Lipoic Acid (ALA) Daily. I’m 65, still walking with occasional assistance and seem to be holding “about” steady after 23 years of Betaseron (no DMT now). I’ve essentially survived 4/5 or so of my MS career without “severe disability” (which of course, is relative).

    The “following”: Phase 2/3 trial (NCT01188811). The trial (N=51 non-active SPMS) met its main goal, which was to determine if lipoic acid could significantly prevent the loss of brain volume (brain atrophy) after two years. Over the duration of the trial, patients given a placebo lost, on average, 0.65% of their brain volume per year. That rate was reduced to 0.21% per year with lipoic acid. Participants treated with lipoic acid also tended to have better walking function, though the difference was not statistically significant.

    So while I’m not at all “hoping for anything”, and I know N=51 is not much, I figure, what the heck? It sounds pretty safe and it’s not expensive (easy access). How does this info fit into what you are describing here? Thank you for reading and any comment.

Translate

Categories

Recent Posts

Recent Comments

Archives