New Directions in MS Research: New Therapeutic Approaches

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A biomarker is a finding on an imaging study or from an analysis of blood or other substances or tissues from a patient’s body that can help clinicians assess the patient’s health. Biomarkers are used to make diagnoses, assess any changes in the status of a condition, and evaluate how an individual is responding to a treatment, among other purposes. Two biomarkers – one involving MRI studies and the other involving a blood test – have emerged in recent years as having considerable potential value in guiding the management of MS.

The first is called the central vein sign, or CVS. This term refers to the identification of a central vein in brain lesions on MRI. A recent multi-center study examined how useful the finding of a central vein sign on high-powered 3 Tesla (3T) MRI was in distinguishing MS from other conditions. The study involved 606 subjects, including 236 with relapsingremitting MS, 142 with various types of cerebral small-vessel disease, 117 with clinically isolated syndromes (CIS) suggestive of MS, 25 with systemic lupus erythematosus, 29 with migraine, 20 with diabetes, and 37 with other conditions.

Clinicians examined the images of 4,447 lesions without knowing the associated diagnosis. The median proportion of lesions with a positive CVS identified was 50% among patients with CIS or RRMS, and was 0% among patients who did not have MS. The researchers also found that the ability to identify RRMS or CIS was greater with the use of specific imaging techniques and when the individual had at least three lesions with a central vein evident on imaging.104

Another, smaller study found that the CVS can help improve the diagnosis of MS in people who have some signs of MS but who also have atypical findings, or “red flags,” that cast doubt on whether they actually have MS or some other condition. The prospective study was conducted at three centers in Europe, and included 17 people. Eight had clinical signs that were “red flags”; another eight had laboratory findings that raised concerns about the correct diagnosis; and one had imaging findings that created uncertainty.

Each patient underwent a single-standardized 3T MRI protocol, with two independent raters evaluating the images obtained to look for a CVS. Meanwhile, expert clinicians who did not know the results of the CVS assessment conducted a thorough evaluation of the patients and then made a diagnosis. Twelve of the 17 participants were diagnosed with MS, while the remaining five received alternative diagnoses. More than half of the lesions in those diagnosed with MS had the CVS, while less than 50% of the lesions in those who received other diagnoses had the sign. The investigators said this finding was “preliminary evidence that the CVS detected on 3T FLAIR images can accurately predict MS diagnosis in patients suspected to have MS, but with atypical clinical, laboratory, and imaging features.” 105

The CVS also has shown promise in the diagnosis of MS in children and adolescents. Investigators analyzed 232 lesions found on the imaging of 26 individuals with pediatriconset multiple sclerosis (POMS). All of the participants had at least one lesion containing a central vein, while 21 of the 26 patients had two lesions with CVS, and 17 (65%) had three or more lesions with a central vein. The researchers said that their findings suggest “a high potential of the CVS to improve POMS diagnosis.” 105

Other investigators are focusing on how blood levels of a protein called neurofilament light chain (NfL) can predict brain atrophy and response to treatment in MS. NfL is a “scaffolding protein” that helps give form to neurons. When axons, or nerve fibers, are damaged, NfL is released and can be found in the cerebrospinal fluid (CSF) and peripheral blood. However, since obtaining CSF requires a lumbar puncture procedure, investigators have focused on understanding the significance of NfL levels, which are more easily obtained from blood samples.

One study involving 85 people with relapsing forms of MS, 42 with progressive MS, and 20 with CIS, examined how serum NfL levels correlated with MRI measures of brain atrophy and disability progression. The researchers found the baseline serum NfL predicted brain-volume change, atrophied lesion volume as measured by T2 MRI imaging, and absolute change in lesion volume as measured by T1 MRI. After five years of follow-up, participants who had baseline serum NfL of 30 pg/ml or more had significantly higher atrophied lesion volume on T2 MRI imaging as well as a higher percentage of brain-volume change, compared to study participants with serum NfL levels of less than 30 pg/ml.106

Another study drew on data from Phase III trials of two DMTs to analyze the impact of serum NfL in secondary-progressive MS (SPMS) versus primary-progressive MS (PPMS). The retrospective analysis involved 1,452 people with SPMS and 378 with PPMS. Baseline serum NfL levels were categorized as low (<30 pg/ml), medium (30 pg/ml to 60/pg/ml), or high (>60 pg/ml). Researchers found that baseline serum NfL levels were higher in people with SPMS than in those with PPMS. In both forms of progressive MS, serum NfL levels were higher in those with gadolinium-enhancing lesions on MRI at baseline relative to those without such lesions. Similarly, in both PPMS and SPMS, high serum NfL at baseline was associated with a greater percentage of brain-volume loss at Month 12 and Month 24. The researchers concluded, “In both SPMS and PPMS patients, NfL may serve as a prognostic marker of brain atrophy.” 107

Serum NfL levels may also be useful in measuring response to therapy, according to researchers who drew on data from the Swiss MS Cohort Study. These investigators examined baseline and annual follow-up NfL levels on more than 230 patients who were taking disease-modifying therapies (DMTs). They found that serum NfL levels increased with age, with worsening disability as measured by the Expanded Disability Status Scale (EDSS) score, and by history of relapse in the past 120 days. Conversely, blood levels of NfL decreased with time on DMT at a rate of 3.2 percent per year, with the rate of decrease varying among different DMTs. The investigators concluded that by following the change in serum NfL levels over time, this provides another means of monitoring how a patient is responding to treatment.108

Previous: Genetics