In Depth: Neurodegenerative Disorders

Cracking the Code of Neurodegenerative Disorders

A neurologist takes insights from bedside to bench and back again for ALS and diabetic neuropathy.

Eva Feldman, MD, PhD, is the James W. Albers Distinguished University Professor of Neurology at the University of Michigan. Her studies on amyotrophic lateral sclerosis (ALS) and the neurological complications of diabetes have yielded important insights into the processes involved in these disorders, along with innovative diagnostic tools and therapeutic approaches. 

What motivated you to study ALS?
When I was quite young, I saw a woman in my clinic who was my age. At the time, I had three young children, as did this woman, and I realized after I’d spoken to her for just a few minutes that she had Lou Gehrig’s disease, or ALS. I thought, oh my God—here she is, and we’re trying to entertain her toddler as I’m going to tell her she has ALS. It’s interesting how your career in many ways can be moved by one patient. I had specialized as a neuromuscular neurologist, but I don’t think I realized at the time that I would devote a good part of my career to ALS. 

It’s been gratifying to see how the field has grown in the last three decades. But what motivated me was a patient, and what continues my motivation is clinical practice. Every week, after I diagnose three or four new patients, I come back to my office and I say, “We just have to do more.”

What approaches have you taken, and what has resulted from this work?
I’ve approached ALS in multiple ways. When I was younger, I wanted to develop one specific therapy. I took the idea of insulin-like growth factor 1 from the preclinical work to the clinic to a Food and Drug Administration (FDA) Phase 1, 2 and 3 multicenter trial. I remember the day I got the results of the trial—I was shaking, I was so excited. It had been 15 years in the making. And I opened the results and here was the progression of the control group, and the progression of the patients who had been on the drug, and they were completely superimposable. I remember feeling really discouraged. 

I took a two-pronged approach at that point. One is that I’ve done a lot of work in stem cell therapy. We’ve done a Phase 1 and Phase 2 FDA-approved trial looking at intraspinal stem cell transplantation in patients with ALS. In March 2020, I went to Washington, D.C., to present to the FDA the results of our Phase 2 trial to propose a Phase 2/3 trial. The hearing went well, but COVID hit two days later. The biotech company that was supporting our work went bankrupt, sold it to another company and another company, and at this point no one is interested in making the investment. We were one of the victims of COVID; there are many similar stories. That foray into stem cell therapy now is on hold. 

However, what has robustly continued over the past decade is our work on the environment. [This started when] I thought, why have I diagnosed six husband and wife teams if it’s supposed to be one or two cases per 100,000 people? I had in one square block four people who knew each other since kindergarten, and they all got ALS. I had three people whose boats were lined up on the same dock, and all three got ALS. It kept hitting me that there must be an environmental component. 

We’ve been able to show in very large cohorts that patients with ALS have a significant increase in legacy pesticides in their blood and persistent organic pollutants. We’ve combined these pollutants into an environmental risk score, and that’s been transformative. We’ve also developed the first polygenic risk score for ALS, of greater than 200 genes, that can predict ALS risk. So now we have been able to assemble a polygenic risk score, an environmental risk score, and look at occupations and hobbies, and collectively, what that’s enabling us to do is come forward with a program to strongly advocate for ALS prevention.

What other areas are you excited about? 
I’ve also done a lot with diabetic neuropathy, the peripheral nervous system complications of diabetes. When I started out, the idea that if you had prediabetes you could get nervous system complications was unheard of. In fact, I got asked to leave the stage giving a talk very early on in my career when I was saying that prediabetes could give you peripheral neuropathy. Now that’s in the textbooks. 

What also became clear to me in my clinical practice—because I’ve been practicing for a long time, and I see a lot of people with diabetic neuropathy—is I noticed that these individuals seemed to be having cognitive decline sooner than they should. It made me think that neuropathy is probably a neurodegenerative disease. It may be the first biomarker of neurodegeneration, so early neuropathy may portend early cognitive impairment. So, we went after that in our research program, and we’ve been successful in that realm, both in animal models and in patients. 

What advice do you give to early-career scientists? 
It requires persistence. If science always goes someone’s way, you better question the science they’re doing. My R01 got rejected six times before it got accepted. You can’t take things personally, like if a trial fails. When one door closes you can find five that will open. 

You have to believe in what you’re doing. That mission I have for understanding neurologic diseases is part of my core values. If your core value is to understand a scientific question or a disease or make an impact, then regardless of how many times you’re knocked off the horse, you need to get back on the horse. 

Interview conducted by science writer Anne Frances Johnson.

This article was originally published in the November 2024 issue of The Physiologist Magazine. Copyright © 2024 by the American Physiological Society. Send questions or comments to tphysmag@physiology.org.