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.
COI: Nothing relevant
Disclaimer. These are the views of the author