Erin Longbrake, MD, PhD

Expert Perspective

Multiple Sclerosis: Biomarkers, Treatment, and Depression Management

Practice Community
New Haven, CT
Hospital and Institute Affiliations
Yale Medical School, Yale MS Center
Number of Patients Seen in a Week
Approximately 30 per week
Practice Niche
Adult patients with Multiple Sclerosis, Neuromyelitis Optica, and autoimmune diseases of the nervous system


What are the clinical roles for molecular biomarkers in diagnosing and monitoring MS disease progression and treatment response?


Biomarkers have been a hot topic in MS for years, and many different things can be meant by the term “biomarker”. Let me break these down into several different types:

Biomarkers to help diagnose the disease

At present, we use a spinal fluid marker called “oligoclonal bands” to assist in making a diagnosis of multiple sclerosis. Oligoclonal bands are not specific to MS – they can also be seen in certain other diseases – but in combination with MRI findings and a patient’s clinical history, this spinal fluid test can be very helpful in making a correct diagnosis. Spinal fluid testing may not be necessary for everyone with MS, but if there is any question about the correct diagnosis, it should be considered.1 MRI scans can also be considered a “biomarker”. MRIs give a window into the brain, allowing us to see part of the damage that’s occurring there. MRIs are widely used in the clinic and are extremely helpful for diagnosing MS.2

Biomarkers to assess for response to a medication

Being able to determine which patients will respond best to which medication is a long term goal for the field of MS. However, we are still a long way away. At present, there are no blood or spinal fluid tests that predict accurately which patients will do best with any given medication. It’s an active area of research, but I don’t foresee any biomarker of this sort making its way into the clinic in the near future. We do use MRI scans as a tool to monitor how patients are doing on a medication. Our goal is to see no evidence of disease activity – e.g. no new “lesions” (or “white spots”) developing on MRI over time. If the MRI continues to get worse during treatment, it’s a sign that the medicine is not working and a different type of treatment should be considered.

Biomarkers to measure whether/how fast the disease is progressing

As with the prior category, this is a hot area for research. One promising biomarker is neurofilament; this can be detected in spinal fluid and blood, and higher levels of neurofilament correlate with worsening neurologic disability. However, this test is mainly used for research, not in clinical practice.

As noted before, MRI also serves as a marker for disease progression. Measurements of brain atrophy or calculating the volumes of certain structures in the brain have been shown to correlate well with disease progression. It is not yet clear whether the molecular biomarker (neurofilament) provides any improved ability to measure MS progression as compared to MRI measures alone.

One caveat to the concept of “biomarkers” in general is the distinction between tests that are useful in measuring something on average, and tests that will give you information about an individual. For example, let’s say that you have come up with a blood biomarker that on average, is significantly higher in MS patients compared to healthy individuals. This may not actually turn out to be a useful test for clinical care. When you consider hundreds or thousands of individuals together, you get the 10,000-foot view, the “big picture” differences between groups. This is what happens with research – we study enough people so that the big picture becomes clear. When you zoom down to the individual level, the picture is usually much less clear. An individual’s test values may bounce up and down due to random chance, biologic variability, time of day, or a thousand other reasons. This makes it harder to develop molecular biomarkers for disease progression that are meaningful for an individual and useful in the clinic.


How have the newer immunomodulatory agents changed the standard of care? (What do we know about optimal combinations or sequencing of treatments?)


The newer immunomodulatory agents have upped the ante for treating MS. In the past, we considered it a job well done if we were able to simply reduce the number of new lesions that were forming in the brain, or if patients had fewer relapses. Now, that isn’t enough. Now, we want to stop the disease in its tracks – we want no relapses, no new disease visible on the MRIs. By treating aggressively when MS is first identified, we hope to effectively put the disease into remission so that patients can live their lives unimpeded by their diagnosis of MS. That being said, much remains to be learned about these agents, and each has its own quirks – things that doctors need to watch out for to make sure that the medication doesn’t cause a new set of problems. Much also remains to be learned about how long one should treat MS with aggressive immunomodulatory medication and about the sequencing of these medications. At present, the data to help answer these questions just don’t exist.


How should depression be managed among people with MS?


Depression is common in MS, as it is with many chronic diseases. It is helpful for patients and families to know this so that they can recognize symptoms in themselves (or their loved ones) and bring it to their doctor’s attention. Physicians should also be watchful for symptoms of depression in patients with MS and be ready to treat it. The management of depression in patients with MS is not significantly different from the management of depression in patients without MS – both anti-depressant medications and counseling or therapy may be warranted. Lifestyle modifications, such as regular aerobic exercise, also serve as “natural” antidepressants and should be encouraged when possible. One specific consideration for MS is that several of the older disease modifying therapies have been associated with worsening depression. For patients with pre-existing mood problems, these would not be the best choices for treatment.


1) Housley WJ, Pitt D, Hafler DA. Biomarkers in multiple sclerosis. Clinical Immunology. 2015;161:51-58. doi: 10.1016/j.clim.2015.06.015

Ceccarelli A, Bakshi R, Neema M. MRI in multiple sclerosis. Current Opinion in Neurology. 2012;25(4):402-409. doi: 10.1097/WCO.0b013e328354f63f