Multiple System Atrophy Awareness Month and MSA Biomarkers

Multiple System Atrophy (MSA) Awareness Month is observed annually in the month of March by the patient and clinician communities. One key area of current research in MSA is biomarker research. Because MSA is a rare disease and can often have overlap in symptoms with other neurological diseases like Parkinson disease, specific biomarkers are of prime importance for diagnosis and early treatment.

To learn more about the current state of research in MSA biomarkers, NeurologyLive® reached out to Wolfgang Singer, MD, a professor of neurology at Mayo Clinic. Singer gave his insight on several types of biomarkers with potential for diagnosing and assessing progression of MSA and emphasized the importance of further research in this field.

NeurologyLive: Given the ongoing diagnostic challenges in early MSA, what are the most promising biomarkers currently under investigation that could improve diagnostic confidence?

Wolfgang Singer, MD: There's actually quite a bit of activity in this field, and there's quite a few exciting biomarkers that have been described in recent years and are still being validated further. I would say probably the most exciting one that has emerged is α-synuclein seed aggregation assays, where we can basically detect the pathologic biosignature in spinal fluid, and more recently, even in skin. We can not only detect patients with MSA in similar conditions, but actually differentiate MSA not only from normal controls, but also from patients with Parkinson disease and dementia with Lewy bodies.

There's other markers that are certainly of interest. One that's easy to obtain is neurofilament light chain. We have shown that neurofilament light chain is very high in the spinal fluid of patients with MSA—which is not specific—there's many other conditions that have high levels of neurofilament light chain. These are typically rapidly progressive or acute injuries to the central nervous system. But in a context where we want to differentiate patients with MSA from Parkinson disease or dementia with Lewy bodies, this marker has been shown to be excellent in differentiating those groups.

These are the fluid markers that are probably the most discussed and most interesting at the moment. But there's other markers that have been shown to be exciting. Those include detection of phosphorylated α-synuclein in skin nerve fibers specifically. This can be detected, again, in patients with MSA, but also patients with Parkinson disease and dementia with Lewy bodies. Up until recently, that was a marker to detect any form of synucleinopathy, but the recent advances suggest that the type of deposition of phosphorylated α-synuclein by fiber type in the skin can actually differentiate MSA from Parkinson disease and dementia with Lewy bodies, as well. There's been some concern about how well this marker is holding up in the real world, in real world clinics compared to control trials, but I think the jury is still out in terms of how useful this marker is going to be going forward.

Then there's yet another set of biomarkers that have been developed in recent years. Those include imaging markers. There's markers on PET scan, and very active field markers on MRI, and specifically quantitative MRI, both structural MRI and diffusion MRI, where there's quite useful markers that have been developed to differentiate MSA from other synucleinopathies.

That doesn't cover disease progression markers, this is only diagnostic markers, but this is really the the area where the field has really emerged in recent years.

How do you view the role of α-synuclein–based assays, such as RT-QuIC, in differentiating MSA from Parkinson disease and other synucleinopathies?

These are the seed aggregation assays that I just mentioned. Those are arguably the most exciting biomarkers that have recently been developed as they really reproduce in the vial in the lab, what we believe is going on in vivo, and therefore using that bio signal and finding the abnormal aggregation of alpha synuclein in the vial that actually is expected to be seen on the pathologic specimen is a very exciting technique, and has been shown to be a very sensitive and specific way of confirming or ruling out the diagnosis. There is some concern about the signal and how sensitive the signal can be detected in MSA compared to Parkinson disease in some assays. There's not just one seed aggregation assay, there's many. They're called under the umbrella “seed aggregation assays”, but there's RT-QuIC, there is PMCA, there's different assay times ranging from less than a day to a couple of weeks of runtime, and depending on what assay you use and the specific assay characteristics, the MSA signal can be very good or can be rather poor. So it depends on what assay you use in order to really pick up the signal of MSA compared to Parkinson disease. Most of these assays are very robust when it comes to Parkinson disease and dementia with Lewy bodies, but the MSA signal seems to differ from assay to assay, and depending on the assay characteristics.

Can you discuss the potential utility of fluid biomarkers—whether CSF or blood-based—in identifying disease progression or stratifying patients in clinical trials?

I think the jury is still out on how helpful seed aggregation assays can be, at least at the present time, in terms of monitoring disease progression. We know it seems to be a very good marker for detecting the signal for making a diagnosis, but not necessarily for monitoring and tracking disease progression. That is true for spinal fluid, but that's particularly true for blood-based assays, where we really are in the infant stages at this moment, and we don't really have a reliable plasma assay even for diagnostic purposes yet.

Advanced imaging continues to evolve—are there specific MRI or PET markers that you believe are nearing clinical applicability for MSA?

Yes, there has been a lot of development of MRI markers with specific regions of interest, regions that we know are pathologically involved in the disease progression of MSA, namely the cerebellum, the basal ganglia regions, and those have been shown to not only be a potentially good diagnostic marker, but also a marker of disease progression. Individual regions have been shown to be helpful in that regard, in tracking disease progression, particularly the cerebellum. But there's also been indices developed—different types, including AI-based indices—that can track disease progression quite nicely.

Is there anything else you want to add?

I think it’s an exciting field, biomarker development for MSA. MSA is a rare disease and is not always on the radar right away when a neurologist sees a patient and having a marker that's easily accessible and easily testable I think will open the path towards an earlier diagnosis. Even if MSA is just suspected, it could be run and ruled out or ruled in, and I think that will hopefully get patients earlier to a diagnosis, earlier into trials, and I think this will really help advance the field going forward.

This transcript has been edited for clarity.