Section 1: Brain Atrophy
What is atrophy and why is it important in multiple sclerosis?
Atrophy is a term for “brain shrinkage” or “brain volume loss” over time. While atrophy happens naturally with age, it tends to occur more quickly in people with multiple sclerosis MS and some other neurological conditions, due to progressive damage to brain cells.
Atrophy is present from the earliest stages of MS, and a higher rate of atrophy (faster brain shrinkage) is linked to greater disability. Some treatments used in MS may also slow atrophy. Measuring atrophy may therefore help us track how MS is progressing, even if a person isn’t having relapses.
MRI and atrophy
MRI is widely used in MS diagnosis and for subsequently tracking the disease, by radiologists (specialist doctors who interpret scans) examining the ‘plaques’ or ‘lesions’ that appear as white spots or 'blobs' on the scan. Changes in the lesions over time give an indication of inflammation that has happened.
Atrophy is too subtle to be detected by looking at the scan in this way. This ‘hidden’ disease activity can however be measured by comparing two MRI scans taken at different time points some months apart and using special computing methods to detect how much brain tissue has been lost.
How much atrophy is OK?
Atrophy is estimated from two MRI scans as change in whole brain volume per year. This change is typically expressed as a percentage of the total volume inside the skull and shown with a minus sign, indicating that brain volume has decreased (e.g., -0.4%).
Sometimes a positive value appears (e.g., 0.3%), which can be caused by real changes in brain volume such as swelling from inflammation, or may simply be due to software inaccuracy.
Research suggests that more than 0.4% loss per year may point to more active disease in people with MS. Results vary a lot between people, however, and different software programs can also give slightly different results, which means that measurements in individual patients must be interpreted with care.
Why is atrophy difficult to measure?
Changes in brain volume are small, so measuring atrophy isn’t straightforward. Atrophy measurements in research projects and clinical trials are mostly made from research MRI scans, which are taken under very controlled conditions, using the same machine for each scan. The images are analysed using special computing software that can be slow to run, isn’t fully automated, or needs very powerful computers.
The brain’s size can also change slightly for reasons unrelated to MS, such as hydration or time of day. Steroids and some other MS treatments may also influence how much the brain shrinks, making it harder to separate these effects from those caused by the disease itself.
Why isn’t atrophy usually measured in the clinic?
Unlike in research MRI, scans in hospitals and clinics are not always taken in exactly the same way on different occasions – the MRI machines and settings used often change, and as a result image quality and contrast between brain tissues vary. In addition, movement during the scan or differences in how a person’s head is positioned may affect the images. All these factors can make the software less reliable and lead to inaccurate measures of atrophy. The computing facilities and expertise needed to process and analyse the images are also not typically available in the hospital environment. Some easier-to-use programs are becoming available; however, it is not always clear how reliable and accurate these are in real-world clinical use.
What is PrecisionMS aiming to do?
The PrecisionMS project aims to make atrophy measurements from routine clinical scans available to people with MS and their doctors. To achieve this, we are testing and refining different computing methods to improve the accuracy of these measurements so they can be used for individual patients.
Brain atrophy and blood tests such as NFL provide complementary information about MS disease activity and neurodegeneration. Being able to measure these ‘precision markers’ reliably in the clinic will help us understand better how the disease is affecting individuals, monitor how well treatments are working, and make more personalized decisions about care.
Section 2: Neurofilament
What is Neurofilament light chain?
Neurofilament light chain (NfL, or ‘neurofilament’) is a protein that is important for the structural integrity of nerve cells (neurons) in the brain, spinal cord and peripheral nerves of the arms and legs. NfL might therefore be thought of as forming part of the skeleton of a neuron.
What causes an increased NfL?
When neurons are injured, neurofilament proteins are released from the damaged cell into the surrounding fluid. Anything that causes damage to neurons, (and even the simple process of ageing), can result in a release of NfL and elevated NfL levels in spinal fluid and blood. An elevated NfL level is therefore entirely non-specific, and must be interpreted carefully in the context of an individual’s known disease state. In addition, factors such as age, body mass index (BMI) and kidney function, can all affect NfL levels and need to be considered.
How is NfL measured?
NfL can be measured in spinal fluid, and more recently, in blood. NfL levels in blood are around 60 times lower than in spinal fluid and require sophisticated techniques to quantify accurately at such low levels.
What might NfL levels tell us about a person’s MS?
In an MS relapse, inflammation and demyelination (loss of the fatty protective layer of myelin that surrounds neurons) can lead to neuronal injury. Damaged neurons release NfL. In this context, NfL levels rise as a result of the relapse, and then fall again when inflammation and demyelination subside, i.e. during remission. Elevated NfL levels in an individual who has a relapsing form of MS may therefore suggest a recent relapse - even if that relapse did not cause any clinical symptoms.
NfL levels slowly increase with age as ‘wear and tear’ over time damages neurons. In MS, NfL levels can also increase over time, over and above those expected for age. In this context, increasing NfL levels may reflect ongoing accrual of neuronal damage and possibly suggest a more severe MS course.
Whilst NfL levels may be elevated at the point of diagnosis or following a recent relapse, we expect NfL levels to fall within a couple of months - during remission. In addition, disease modifying treatments (DMTs) can affect NfL levels, and some may even reduce NfL levels similar to those seen in the general population. Elevated NfL levels despite DMT may suggest that an individual’s MS is not fully controlled by that DMT.
Why is NfL not routinely measured in MS NHS clinics?
Measuring NfL levels in blood requires sophisticated laboratory equipment that is generally only available in research laboratories. Furthermore, calculation of NfL levels requires careful consideration of influencing factors, such as age and BMI, and only recently have normative values (those expected in the general population) been available.
Finally, interpretation of NfL levels is still an emerging field of research, and care needs to be taken so as not to place too much emphasis on a single NfL result when considering clinical decisions.
What is Precision MS aiming to do?
We believe that quantification of NfL can add new information about the biological activity of an individual’s MS. NfL might be helpful in confirming a recent relapse, or even in identifying relapses that do not cause clinical symptoms. NfL levels may also be of value in assessing whether a particular DMT is adequately controlling an individual’s MS.
Increasing research suggests that NfL levels may also have a prognostic relevance in identifying individuals at risk of a more severe disease course. However, whether knowledge of an individual’s NfL levels can guide clinical decisions to ultimately reduce longterm risk of future disability is as yet unknown and ongoing research is required. Precision MS will not only add to this body of research, but also assess the feasibility of measuring NfL within NHS clinics.