RealTalk MS – Episode 433: "Our Most Important Conversations of 2025"

Host: Jon Strum
Guests: Dr. John Corboy, Dr. Mikael Simons, Dr. John DeLuca, Dr. Steven Krieger
Date: December 15, 2025

Episode Overview

In this special year-end episode, Jon Strum revisits four of the most impactful conversations from 2025, chosen based on listener feedback. The topics, which deeply resonated with the MS community, include the challenges of aging with MS and discontinuing disease-modifying therapies, advances in myelin repair research, the science and treatment of MS-related fatigue, and the evolving understanding of MS progression and its clinical implications.

1. Aging and MS: When to Discontinue Therapy

Guest: Dr. John Corboy (Principal Investigator, Disco MS Trial)
Key Segment: [02:12–10:51]

Key Discussion Points & Insights

• Nearly half of people living with MS in the U.S. are aged 55 or older; aging in MS is a growing and critical focus (02:24).
• MS is no longer a "young person's disease"—people live longer and are diagnosed at later ages.
• Advances in therapy and healthcare (e.g., infection management, ICU care) have contributed to greater longevity among MS patients (03:22).
• Pathological changes in MS as people age:
  • Fewer inflammatory relapses; instead, slow progression of disability becomes more prominent (04:18).
  • Aging and MS both contribute to brain volume loss, with aging becoming more significant over time.
  • Disease-modifying therapies (DMTs) are most effective in youth; their benefits diminish with age as progression becomes more prominent (05:50).
• Differentiating between age-related changes and MS progression is complex and requires careful clinical attention (06:26).
• The central question of the Disco MS trial: Should older adults (60+) discontinue DMTs if benefits wane and risks/costs persist?
  • There is no “one-size-fits-all” answer—decisions must be individualized, considering risks, benefits, and patient/family preferences (07:56).
  • Family members, especially spouses, have significant sway in decision-making (09:05).
• The average age of MS diagnosis is rising (now about 41 years); "late onset" (>50) and "very late onset" (>60) MS are increasingly recognized (09:50).

Notable Quotes

• "Almost half of people are 55 and older. That number is only increasing as we get better at therapies and at diagnosing." – Dr. Corboy [02:24]
• "There's no one-size-fits-all... Everyone views risk differently." – Dr. Corboy [08:13]
• "Late onset MS accounts for about 8% of people, and very late onset just under 1%." – Dr. Corboy [10:09]

2. Myelin Repair: Hope for Remyelination

Guest: Dr. Mikael Simons (Barancik Prize Winner, Myelin Biology Researcher)
Key Segment: [12:45–19:17]

Key Discussion Points & Insights

• Dr. Simons' foundational research: discovery of biological processes governing myelin sheath creation, maintenance, and repair (12:45).
• MS damages the myelin sheath, causing the characteristic neurological symptoms; remyelination is a natural repair process that eventually fails in MS.
• His lab has uncovered mechanisms for why repair fails and how it might be restarted.
  • Reparative inflammation initially aids remyelination, but chronic inflammation suppresses repair (13:58).
  • Specific pathways, like cholesterol metabolism and certain immune cells, are critical; disruption can halt repair (14:53).
  • Chronic inflammation is sustained by factors such as tissue-resident memory CD8+ T cells and interferon pathways.
• Research shows potential for restarting remyelination by targeting chronic inflammation with small molecules (e.g., interferon-gamma pathway modulators) (15:42).
• Exciting advances: For the first time, treatments are being trialed that specifically impact the progressive phase of MS (e.g., BTK inhibitors), offering new hope for slowing progression (17:05).
• Open questions remain about MS onset's true environmental triggers, with ongoing investigations beyond the known Epstein-Barr virus connection (17:49).
• Winning the Barancik Prize motivates Dr. Simons to pursue translating basic science to patient benefit.

Notable Quotes

• "To understand how myelin repair works, it's important to look at the immune system... It's a complex multicellular problem." – Dr. Simons [13:58]
• "When we have a chronic inflammation in the brain, it sustains itself. It doesn't resolve. That's what happens when this disease progresses." – Dr. Simons [15:42]
• "I think there's something big missing in the environment that needs to be discovered. If we know what it is, we could possibly design preventive therapies." – Dr. Simons [17:49]
• "This prize has... provided me motivation to go along this path: take research from the lab to the benefit of the patients." – Dr. Simons [18:40]

3. Fatigue in MS: Science, Measurement & Solutions

Guest: Dr. John DeLuca (Kessler Foundation, Fatigue Researcher)
Key Segment: [20:34–26:08]

Key Discussion Points & Insights

• Fatigue affects up to 80% of people with MS and is a leading cause of workforce withdrawal (19:19).
• Measurement remains a challenge—no reliable, uncontaminated assessment tools exist; subjective measures are influenced by other factors (e.g., sleep, deconditioning) (20:34).
• Defining, measuring, and thus treating fatigue is an ongoing challenge in MS research (21:19).
• DeLuca's team distinguishes "state fatigue" (in the moment) from "trait fatigue" (long-term perception):
  • State fatigue correlates with observable brain changes (particularly in basal ganglia and thalamus), while trait fatigue does not (21:51).
  • The brain's reward network intertwines with fatigue; rewarding experiences (and therapies focused on reward) can alleviate fatigue (22:40).
• Non-pharmacological therapies, especially cognitive-behavioral therapy and exercise, are currently most effective (23:12).
• For exercise, benefits appear linked to changes in the thalamus; crucially, the activity must be personally rewarding for the patient (23:51).
• Dr. DeLuca prescribes personalized, rewarding activities for reducing fatigue, starting small and building up with honesty and support (25:05).

Notable Quotes

• "We do not have a good answer of how we measure fatigue... It's a real problem." – Dr. DeLuca [20:34]
• "If you can reward people, does reward actually reduce fatigue? And the data on that is actually yes." – Dr. DeLuca [22:40]
• "The best plan is to be honest with yourself about what makes you happy and stick with it. Start slow. Work with a professional." – Dr. DeLuca [25:05]

4. MS Progression & Rethinking Disease Categories

Guest: Dr. Steven Krieger (Mount Sinai, MS Disease Classification Expert)
Key Segment: [28:19–41:55]

Key Discussion Points & Insights

• The prevailing MS categories (relapsing-remitting, secondary progressive, primary progressive) rarely fit patients’ lived experiences neatly (28:32).
  • The transition between types is gradual and often diagnosed only in retrospect (29:35).
  • If categories can’t be diagnosed in the moment, do they serve real-world clinical practice?
• Dr. Krieger’s CMSC panel explored whether MS is truly “one disease,” challenging the utility and clarity of current categories (30:11).
  • Patients crave clarity about their individual progress, not abstract labels.
• Most of the professional audience agreed with the “one disease” model ("77% said, yes, MS is one disease") (33:27).
  • This perspective supports personalized care over rigid framework.
  • It recognizes progression can occur independently of relapses and that disease experience is highly individualized (33:50).
• Embracing MS as “one disease” ensures doctors focus on each patient’s evolving symptoms, not just MRIs or checklists (35:20).
  • There is a need for more listening and broader, nuanced evaluation of patient experiences (36:10).
  • New technology (e.g., wearables, MRI advances) and holistic approaches (supporting mental, physical and brain health) facilitate this personalized care (38:21).
• The MS research landscape is "remarkable" and expanding rapidly with new mechanisms in clinical trials—BTK inhibitors, CAR T cell therapy, and more, broadening therapeutic possibilities (40:04).

Notable Quotes

• "Categories are a way of organizing things, but rarely do justice to an individual person's experience, especially with something as diverse and personal as multiple sclerosis." – Dr. Krieger [28:32]
• "If there's no moment that someone transitions from one category to another, are there really categories at all?" – Dr. Krieger [29:51]
• "Categories are not people. Getting away from categories and thinking about people and their individual experience is necessary to personalize care." – Dr. Krieger [38:21]

Memorable Moments & Quotes

• Dr. Corboy: "No one-size-fits-all, especially not in how people understand risk and make decisions about therapy discontinuation." [08:13]
• Dr. Simons: "Chronic inflammation in the brain... sustains itself. If we can dissolve it, we may improve repair." [15:42]
• Dr. DeLuca: "Be honest: what makes you happy, what gets you moving—that's your best path to beating fatigue." [25:05]
• Dr. Krieger: "Personalized care means moving beyond labels, paying attention to the actual person in front of you." [38:21]

Timestamps for Sections

• Aging and MS/Discontinuing Therapy: [02:12–10:51]
• Remyelination/Myelin Repair: [12:45–19:17]
• MS-Related Fatigue: [20:34–26:08]
• Progression and MS Categories: [28:19–41:55]

Takeaways

• MS care must adapt to demographic shifts, longer lifespans, and the shifting efficacy of long-term therapies.
• Groundbreaking research in both myelin repair and the treatment of progressive MS offers new hope on the horizon.
• MS-related fatigue is complex—notoriously hard to measure and treat, but promising strategies now focus on personalized, rewarding interventions.
• The rigid categories of MS are being challenged by clinicians and researchers. Unified, personalized disease models may yield better patient care, more nuanced conversations, and improved outcomes.

This episode is essential listening for anyone touched by MS—patients, families, and clinicians alike—offering hope, clarity, and practical guidance for living with and managing the disease in 2025 and beyond.