Inflammation, Limbic White Matter, and Symptoms After Repetitive Head Impacts in Retired Football Players

Dr. Gregg Day and Drs. Sonia Vallabh and Eric Minikel discuss scientific insights and the future of prion disease treatment, highlighting the importance of early diagnosis, personalized medicine, and hope for affected families.  Learn about the clinical trial.   Learn more about the Prion Alliance.  Show transcript:  Dr. Gregg Day: This is Gregg Day with Neurology Minute. I've just been speaking with Eric Minikel and Sonia Vallabh, a husband and wife team at the heart of the PRiSM trial, a first-in-human study of a prion protein-lowering, divalent, small-interfering RNA for patients with symptomatic prion disease. Eric and Sonia, could you provide us with a brief overview of the PRiSM trial and what this first-in-human study seeks to accomplish? Dr. Eric Minikel: The PRiSM trial is testing a short interfering RNA designed to bind the RNA that encodes the prion protein. That is the protein that causes Prion disease. We are at the heart of what causes this disease. Through doing this, we hope to make prion disease a treatable and preventable condition. We both want to stabilize symptomatic patients and prevent the disease in people who are at genetic risk. This is a personal mission for us. Sonia is a carrier of a prion disease mutation that she inherited from her mother who died of prion disease, and we, along the way, aspire to be a different kind of sponsor. We want to create our own clinical data that are shareable learnings for the entire field. Dr. Gregg Day: This is Gregg Day with Neurology Minute. Thanks for listening.

In the second episode of this series, Dr. Tesha Monteith and Dr. Peter Goadsby discuss the prediction of treatment responses for personalized medicine. Show transcript: Dr. Tesha Monteith:  Hi, this is Tesha Monteith with The Neurology Minute. Today I'm speaking with Peter Goadsby from the Division of Biomedical Sciences at King Abdullah University of Science and Technology about key trends in headache medicine and some of the most impactful research presented at the AAN annual meeting. Can you talk a little bit about prediction of treatment response for personalized medicine? Dr. Peter Goadsby I hope that AI gives us some direction. I haven't seen anything yet, but I don't think we've done enough with it to make it stunning yet. I think that the AI systems ... I'd love to know, for example ... I've been using triptans for 30 years and apart from using sumatriptan first when [inaudible 00:00:51] had a triptan simply because it's the commonest triptan, which is generally what I do, that's a pretty naff rule when you think about it. I'd like to think that AI systems could work out where we should be going in terms of acute therapy, preventive therapy, whether there are particular red flags or amber flags you might say in a person's broad history. I don't think we've got there yet, but I actually think we will get there. I think we'll be surprised and we'll learn things about the biology of the disorder and about the pharmacology of these medicines, which must have subtle differences because we all see people who respond to one and don't respond to another, and you sort of scratch your head, but you're happy that it happens. Dr. Tesha Monteith:  I agree with you, and I think the future is really bright for headache medicine and the potential of AI to move the needle. Peter, thank you again for joining us and sharing your insights. I really appreciate you being on. This is Tesha Monteith. Thank you for listening to The Neurology Minute.

In the second episode of a four-part series on Rett syndrome, Dr. Stacey Clardy discusses the importance of early referrals, particularly during the regression phase.  Show transcript:  Dr. Stacey Clardy:  This is the Neurology Minute. I'm Stacey Clardy from the Salt Lake City VA and the University of Utah. This is the second episode in a four-part series on Rett syndrome. Today, let's discuss when to refer and specifically early referral is absolutely critical in Rett syndrome, particularly during the regression phase. Any child, most often a girl with previously acquired developmental milestones who begins to lose language or lose purposeful hand use or develops stereotyped hand movements should prompt urgent neurologic evaluation. This would be referral to pediatric neurology, of course, and this should not wait for genetic confirmation. Early involvement of pediatric neurology allows for diagnostic clarification, anticipatory guidance, and coordination of care across systems. The genetic testing, typically with MECP2 sequencing and deletion or duplication analysis, this should be pursued early and if initial testing is negative but suspicion remains high, expanding that genetic evaluation is warranted. And beyond neurology, early engagement with developmental services, speech, occupational, and physical therapy should start before even a definitive diagnosis is necessarily established. Rett syndrome is a multi-system disorder. So a care team is going to monitor for common comorbidities. This is not just epilepsy, but also gastrointestinal dysfunction, breathing abnormalities, and orthopedic complications. When delayed referrals occur, it's often due to attribution of regression to more common developmental conditions. Be sure to listen to the other Neurology Minute episodes in this series. We'll be back next time for our third episode, and we'll cover treatment options and ongoing management.

Dr. Margarita Fedorova discusses whether a vaccine ingredient is quietly protecting the brain.  Show citation:  Taquet M, Todd JA, Harrison PJ. Lower risk of dementia with AS01-adjuvanted vaccination against shingles and respiratory syncytial virus infections. NPJ Vaccines. 2025;10(1):130. Published 2025 Jun 25. doi:10.1038/s41541-025-01172-3 Show transcript:  Dr. Margarita Fedorova:  Welcome to Neurology Minute. My name is Margarita Fedorova, and I'm a neurology resident at the Cleveland Clinic. Today we're exploring a study that raises a compelling question. Could a vaccine ingredient be quietly protecting the brain? A recent study by Taquet et al., published in npj Vaccines in 2025, investigated whether vaccination with an AS01-adjuvanted vaccine is associated with a lower risk of dementia. You might know it as the immune-boosting ingredient in Shingrix, the shingles vaccine, and Arexvy, the new RSV vaccine. We already know from prior work that the Shingrix vaccine was associated with a reduced risk of dementia, but the question this paper asks is why. Is it because preventing shingles itself protects the brain, or is there something specific about the adjuvant that's doing the work? To answer this, the researchers used a large US electronic health record database comparing over 35,000 people who received the AS01-adjuvanted RSV vaccine, over 100,000 who received the AS01-adjuvanted shingles vaccine and over 78,000 who received both. Each matched against individuals who got the seasonal flu vaccine instead. The findings were interesting. People who received the RSV vaccine had a 29% lower risk of new dementia diagnosis over the following 18 months. Those who received the shingles vaccine had an 18% increase in time without dementia, and those who received both had a 37% increase in dementia-free time. Here's a key insight. Both vaccines target completely different viruses, but both contain the same adjuvant. The fact that a similar protective signal was seen with both suggests the benefit may not be about which virus is prevented, and it may be about the AS01 itself. Why might an adjuvant protect the brain? AS01 contains two active components, monophosphoryl lipid A, known as MPL, and QS21. Together they activate macrophages and dendritic cells, triggering cascade that includes a production of interferon gamma. In animal models, stimulation of a receptor called toll-like receptor 4, which MPL activates, has been shown to reduce Alzheimer's-like pathology. The authors also point out that the protective effect appears within just a few months of vaccination, which is hard to explain purely by prevented infections and may point instead to a direct immunological mechanism. Very important caveat. This is an observational study, not a randomized trial, so we can't prove causation. There was also uncertainty about which brand of RSV vaccines some patients received, which could affect the strength of the AS01-specific conclusion. And with all of the dementia studies, it's unclear whether the vaccines prevent dementia or delay its onset. Though even a delay would be clinically meaningful given how few tools we have. What does this mean for clinical practice? For now, it doesn't change your vaccination recommendations. Both Shingrix and Arexvy already indicated in appropriate patients for the primary purposes, but it adds an intriguing possible benefit when counseling patients who ask about vaccines. And it opens the door to a genuinely exciting question. If AS01 has neuroprotective properties, could it be studied in a therapeutic target in its own right? That's the Neurology Minute for today. Keep exploring and we'll see you next time. If you want to read more, please find the paper by Maxime Taquet, et al., titled Lower Risk of Dementia with AS01-Adjuvanted Vaccination Against Shingles and Respiratory Syncytial Virus Infections, published in npj Vaccines in June 2025. 

In the final episode of this series, Dr. Justin Abbatemarco and Dr. Ruth Dobson discuss navigating conversations with women and their families about potential ocrelizumab exposure during pregnancy and breastfeeding.  Read more about this abstract on the AAN website.   Show transcript: Dr. Justin Abbatemarco: Hello and welcome back. This is Justin Abbatemarco on our final episode with Ruth Dobson from Queen Mary University of London on our AAN annual meeting abstract humoral vaccine response and one year follow-up of infants potentially exposed to ocrelizumab during pregnancy and breastfeeding. Our previous two episodes, we've talked about this wider world of monoclonal antibodies during pregnancy and then we've talked about the data specifically around ocrelizumab. But Ruth, I think the million-dollar question is how do we approach this in clinical care? How can we talk to women and their families during this really exciting time and how do you employ this, especially within the MS space? Dr. Ruth Dobson: So it's a really exciting time for women in our families, but it can be really hard to talk about. And many of my patients have loads of anxieties about living with a chronic disease, thinking about pregnancy and breastfeeding, worrying about how to balance effective treatment against wanting not to cause any potential harm or risk to their child. A lot of this is actually about informed decision making and having those discussions and having the data to back up those discussions. What this data really helps us to do is have those discussions in a way that is meaningful for women so we can say, "Well, actually where you have received treatment up until the point of conception, we can see that babies are being born with normal B cell levels, that the drug is not causing long term effects to the best of our knowledge in your babies." And similarly, when people are thinking about restarting treatment postpartum, we know specifically in MS that the relapse risk is highest in those postpartum three months. So often people feel quite anxious about that and want to get on top of their disease, but don't want to forego breastfeeding for that. We are now in a situation where women no longer have to choose. We know that the drug doesn't get into breast milk. We can reassure them. Certainly in Europe, we've had a label change around CD20s now being safe for use in breastfeeding. So we can have that discussion and enable people to actually have that pregnancy and breastfeeding experience that they want to have without having to make compromises in the way that maybe people have previously. Dr. Justin Abbatemarco: I love that message because our messaging before was compromising. But now we can really have an informed discussion with patients and their families that MS does not define them and does not define their family planning needs. I love that idea about breastfeeding as well. I think that's a really anxious time. It's a really intimate moment that we as the medical community shouldn't dictate that we should allow that to be a time that the families get to choose on how they want to approach that. And so this data helps so much. Maybe we could just talk about that label change, how we could think about keeping up with our governing bodies and how they talk about these medications, because it's really challenging if a patient checks on the internet and sees something different from our FDA or other European governing bodies. How do you think through that? Dr. Ruth Dobson: Yeah, it's really hard and it creates lots of anxieties for patients. And I think even at the moment, the label washout is different across CD20 drugs. It's different between Europe and America. And that in itself causes anxiety. But in some ways that helps with those discussions to say, these labels, they're not always based in the kind of evidence that we need that's really helped us to recruit women studies to get people taking part in this research. And also in Europe, it shortened the washout period. These studies work in terms of changing that policy. I think that regulators are increasingly recognizing, certainly in Europe, class effects. They're increasingly recognizing the importance of including people considering pregnancy, lactating mothers in studies so that we can actually better answer these questions without having to wait eight, 10 years for these kind of data to come out before we can allow our patients to really partake in informed decision making. Dr. Justin Abbatemarco: And your work, work like it is so important for these conversations. So we'll hopefully have some really great discussions and be able to come back and have better conversations with patients because of it. So Ruth, thanks. Dr. Ruth Dobson: Thank you.  

In the first part of this series, Dr. Tesha Monteith and Dr. Peter Goadsby discuss some major themes that emerged from the AAN Annual Meeting regarding headache medicine. 

Dr. Alex Menze and Dr. Breton Asken discuss the long-term impacts of repetitive head impacts in football players, focusing on inflammation, brain microstructure, and cognitive decline. Show citation:  Emanuel OM, Miner AE, Lee SY, et al. Inflammation, Limbic White Matter Microstructure, and Clinical Symptoms in Retired American Football Players With Repetitive Head Impacts. Neurology. 2026;106(6):e214646. doi:10.1212/WNL.0000000000214646 

In the first episode of a four-part series, Dr. Stacey Clardy discusses the diagnosis and clinical presentation of Rett syndrome.   

In part two of this series, Dr. Justin Abbatemarco and Dr. Ruth Dobson discuss the main findings of this study.   Read more about this abstract on the AAN website.  

In part one of this series, Dr. Justin Abbatemarco and Dr. Ruth Dobson discuss current evidence on monoclonal antibodies in pregnancy and breastfeeding and prior understanding of CD20 therapies.  Read more about this abstract on the AAN website.