The Amyloid Hypothesis for Alzheimer's disease and Aducanumab

Dr. Zohaib Siddiqi talks with Dr. Catarina Bernardes about a case involving a 35-year-old woman presenting with personality changes and gait impairment.  Show citation:  Bernardes C, Lemos JM, Santo GC. Clinical Reasoning: A 35-Year-Old Woman With Personality Change and Gait Impairment. Neurology. 2025;104(2):e210252. doi:10.1212/WNL.0000000000210252  Show transcript:  Dr. Zohaib Siddiqi: Hi, everyone. My name is Zohaib Siddiqi and I'm a fifth-year neurology resident and a part of the Neurology® Resident and Fellow Section Editorial Board. I just finished interviewing Catarina Bernardes about her article, Clinical Reasoning: A 35-year-old Woman with Personality Change and Gait Impairment. Catarina, can you tell us the main points of the article? Dr. Catarina Bernardes: So in this article, we discussed the case of a 35-year-old woman who presented with a three-year history of walking difficulties. On examination, she had signs of a frontal temporal dysfunction, a dorsal lateral myelopathy, optic atrophy, and pes cavus. Her brain and spinal cord MRI was completely normal, but her son's brain MRI was being studied for spastic paraparesis showed signs of hypomyelination involving the subcortical U fibers. Given the suggestive inheritance pattern, we considered an X-linked leukoencephalopathy and central nervous system hypomyelination points to Pelizaeus-Merzbacher disease. Important learning points. When differentiating leukoencephalopathies, remember that hypomyelinating disorders often have less pronounced hypointensity on T2 and hypointensity on T1, and in demyelinating disorders, there is very prominent hyperintensity on T2 and hypointensity on T1. Also, Pelizaeus-Merzbacher is a hypomyelinating disorder affecting the subcortical U fibers, while X-linked adrenoleukodystrophy presents a demyelinating pattern sparing the subcortical U fibers and involving mainly the parietooccipital regions. Dr. Zohaib Siddiqi: Thanks so much for that summary, Catarina. A lot of learning points there. For those of you who want to learn more about the case, you can listen to the full-length podcast available now on all streaming platforms and find the article titled, Clinical Reasoning: A 35-year-old Woman with Personality Change and Gait Impairment on the Neurology® Resident Fellow Website. Thanks so much for joining today, and see you next time. 

In part four of this seven-part series on FND, Dr. Jon Stone and Dr. Gabriela Gilmour discuss the diagnostic explanation.  Show citation:  Stone J. Functional neurological disorders: the neurological assessment as treatment. Pract Neurol. 2016;16(1):7-17. doi:10.1136/practneurol-2015-001241  Gilmour GS, Lidstone SC. Moving Beyond Movement: Diagnosing Functional Movement Disorder. Semin Neurol. 2023;43(1):106-122. doi:10.1055/s-0043-1763505  Podcast transcript:  Dr. Gabriela Gilmour: This is Gabriela Gilmour with the Neurology Minute. Jon Stone and I are back to continue with part four, of seven, of our series on functional neurological disorder. Today we will focus on the diagnostic explanation. So many patients have never heard of FND before receiving this diagnosis. Can you share how you explain the diagnosis to your patients? Dr. Jon Stone: So I'm aware that many neurologists do find this difficult. And I have to say, having thought about it for 20 years or so now, I think the answer is, don't be weird. Do what you normally do with any condition, when you explain it to patients. I think what goes wrong is that people see FND as something weird and other, and they start to do weird things like telling people that their scans are normal, or telling them what they don't have before they've started to tell them what they do. If you go with the normal rules of explanation, first of all, starting by giving it a name that you prefer, so you've got FND, or try and be specific if you can. You've got functional seizures, functional movement disorder. Give it a name to start with. Don't sort of spend a long time beating around the bush before you do that. Talk a bit about why you've made the diagnosis, because that's what you normally do. So if someone's got a weak leg, show them their Hoover's sign. I think actually showing people their physical signs is probably one of the most powerful things you can do, brings the diagnosis away from the scanner and into the clinic room. And also, they can see in front of them the potential for improvement. So it feeds forward into treatment. Yes, you might need to explain why they don't have some other conditions that they're worried about, but you can leave discussions about why it's happened for later. I think what tends to go wrong is people jump into that too early. So the bottom line, just do what you normally do and things generally go a lot more smoothly. Dr. Gabriela Gilmour: And when you're providing the diagnostic explanation, it can be really helpful to link the patient's experience and their symptoms to the diagnosis. And so, I wonder how you integrate that piece into your diagnostic explanation, or how you tailor your explanation to an individual patient. Dr. Jon Stone: Yeah, I think tailoring is really important here. And this is where obviously if you've done your assessment, so helpful to ask the patient is, "Well, what do you think's wrong? What things were you worried about? " Some people say, "Look, I'm really worried I've got MS." Or some people say, "I haven't got FND. I've read about that. " Or sometimes people are wondering if they've got FND. So, you've got to try and tailor it to what the person is expecting and particularly previous experiences. If they're telling you how angry they were about doctors A, B, and C, then obviously you want to use that and try not to end up with the same outcome. Why would there be a problem with this diagnosis? It's because they haven't heard about it, because they've got misconceptions about it. Do they feel that this diagnosis would be saying it's all in their mind or something like that? You might need to be explicit about that. But I think this links into how, it's not just about the diagnostic label, it's about a formulation, which is something we don't think about much in neurology. So there's a label for what's wrong, but in FND, a formulation, why have you got FND, in your particular case, is what we're sort of moving on to there based on the story that you've heard. Dr. Gabriela Gilmour: Yeah. And I think in my experience and in working with trainees, really just practicing, saying it, is so important and saying it in a way that feels honest and correct to you as a clinician. Dr. Jon Stone: Yeah, absolutely. Dr. Gabriela Gilmour: So we will be back for more Neurology Minute episodes to continue our discussion on FND. Next, we're going to be talking about treatment. Thanks for listening.

In part three of this seven-part series on FND, Dr. Jon Stone and Dr. Gabriela Gilmour discuss causes of functional neurologic disorder.  Show citation:  Hallett M, Aybek S, Dworetzky BA, McWhirter L, Staab JP, Stone J. Functional neurological disorder: new subtypes and shared mechanisms. Lancet Neurol. 2022;21(6):537-550. doi:10.1016/S1474-4422(21)00422-1 Show transcript:  Dr. Gabriela Gilmour: This is Gabriela Gilmour with the Neurology Minute. Jon Stone and I are back to continue with part three of our seven-part series on functional neurological disorder. Today, we will focus on the causes of FND. So Jon, there have been many advances in our understanding of the mechanism of FND in the last 10, 15 years. And so what do we know about this now? Dr. Jon Stone: I think the key message I want to get across here is that whereas previously we had a very psychiatric, purely psychiatric view of FND, it used to be called conversion disorder, what we've got now is a multi-perspective view of the mechanisms, which mean that we can understand FND at a kind of neural level or brain circuit level, but we can also still retain the importance of psychological factors, traumatic events. And I think it's also important to separate out, as you've done here with a question, what's the mechanism? How is the symptom happening versus why is it happening? Which often people don't do. So for this question, how is it happening? How is it that somebody, for example, gets a weak leg? Well, at a very simple level, their brain is disconnecting from their leg and that's what dissociation is. And you can explain that to patients at sort of brain circuit level. We've learned that there are disruptions probably in the circuits in our brain that relate to that sense of agency, the parts of our brain that tell us that our bodies belong to us. And people are particularly interested in an area called the temporary parietal junction. And at a higher broader level, people are particularly interested in the idea that FND is a disorder that you would expect to happen based on our understanding of the brain as a predictive organ. So if the brain spends its time predicting things, maybe in FND what's gone wrong is this is very strong prediction that the leg is weak or that there's a tremor or that a seizure's about to happen that overrides sensory input telling our brain otherwise. Dr. Gabriela Gilmour: And I guess to follow into that, you mentioned what is going on. So now can you talk a little bit about why somebody might develop FND or the etiology of FND? Dr. Jon Stone:  I think this helps clinically as well as neurologists, because we can talk about mechanism as we would, for example, with MS as inflammation, but why is there inflammation? So okay, the brain's gone wrong, but why has it gone wrong? And there we need a much more complex view of multiple range of risk factors, predisposing, precipitating, and perpetuating that we know are associated with FND, but vary a lot from person to person. So no one person's the same. If you've had traumatic experiences in the past, that will make you more prone to dissociation. If you've had other functional disorders, if you have almost certainly some forms of genetics make people predisposed. And then as we said in the last episode, having another neurological condition, so having migraine aura, a physical injury, an infective illness, these are powerful reasons to trigger neurological symptoms. And it's not so much why they happen. It's more why do they get there and get stuck? We all probably have transient functional symptoms actually, but why they get stuck in people with FND for various reasons to do with the way their brains work or their past experiences, or sometimes what happens to them in medical systems. So developing a very open idea about why someone might have FND really helps you, I think, explain that back to patients and produce individual sort of formulations of the problem. Dr. Gabriela Gilmour: Yeah. And I often say to my patients, "I don't know exactly why you, why today have this." And that's true in medicine in general. We actually often don't know why anybody develops any medical condition with a few exceptions, but we know about risk factors really. Dr. Jon Stone: Absolutely. It's one of the reasons I hate the term medically unexplained. Actually, I think FND is perhaps more explained in some ways than some of the other conditions like multiple sclerosis and ALS that we actually deal with where we really don't know why they happen. Dr. Gabriela Gilmour: Well, we will be back for more Neurology Minute episodes to continue our discussion on FND. Thanks for listening. 

In part two of this two-part series on this year's World Stroke Congress, Dr. Andy Southerland and Dr. Seemant Chaturvedi discuss the ATLAS meta-analysis.  Learn more on the World Stroke Congress website.  Show transcript:  Dr. Andy Southerland: Hello everyone and welcome to this week's Neurology Minute. For this series, I've been speaking again with my friend and colleague, Seemant Chaturvedi, who is the director of the stroke program at the University of Maryland. And as always, Seemant is sharing hot off the presses results of presentations from this year's World Stroke Congress that was held in Barcelona, Spain in October. And for this Neurology Minute, he is going to be sharing with us the presentation of the ATLAS meta-analysis, a systematic review which looked at pulled data from multiple clinical trials and patients presenting with large vessel occlusions and large ischemic cores, looking at folks randomized between endovascular therapy and best medical management. So Seemant, what were the results of the ATLAS meta-analysis? Dr. Seemant Chaturvedi: So this was a meta-analysis of six clinical trials, which looked at patients with large core infarcts, and they evaluated the results in patients who were treated with endovascular therapy or medical therapy, and it included over 1,800 patients. The primary outcome was the shift analysis on the 90-day modified Rankin Scale, and this was favorable for a thrombectomy with an adjusted odds ratio of 1.63. In terms of the specific outcomes for modified Rankin of zero to two, this was seen in 20% with thrombectomy, 7.5% with medical therapy, for modified Rankin of zero to three, 37% with thrombectomy, and 20% with medical therapy. One important observation was that the mortality was lower with thrombectomy, 31% compared to 37%. Also, two other points worth mentioning, the cerebral hemorrhage rate was increased with thrombectomy compared to medical therapy 5.5 to 2.7%, and then we frequently wondered how big of an infarct will no longer benefit from thrombectomy. And so here, Dr. Sarraj presented the results and showed that there seemed to be some benefit up to 149 mLs and no benefit in 150 mLs or above. And so I think this gives us a lot of useful information in terms of material we can bring back to our emergency rooms for discussion with our interventional teams about who to treat, who not to treat, and about what are the realistic expectations. And so we look forward to the full publication. Dr. Andy Southerland: Well, thank you, Seemant, and it's nice to see that this full pooled analysis of these randomized clinical trials not only supports the finding of most of the individual trials, but also enhances it through increased sample size and data across trials. So as you point out, we'll look forward to the peer reviewed publication, but glad to be presented with these new data. And once again, thank you for joining us for this week's Neurology Minute, sharing your observations from the World Stroke Congress in Barcelona, Spain in October. Seek out the full podcast where we discuss these studies and more. 

In part two of this series, Dr. Jeff Ratliff and Dr. Dara Albert discuss what advice they have for people who care for patients with FND.  Show citation:  Miller R, Lidstone S, Perez DL, Albert DVF. Education Research: Targeting Self-Described Knowledge Gaps to Improve Functional Neurologic Disorder Education Among Clinicians. Neurol Educ. 2025;4(3):e200239. Published 2025 Sep 5. doi:10.1212/NE9.0000000000200239  Show transcript:  Dr. Jeff Ratliff: Hi, this is Jeff Ratliff with Neurology Minute. I'm back with Dara Albert for the second neurology minute episode following our podcast episode about her paper published in Neurology® Education titled Education Research Targeting Self-Described Knowledge Gaps to Improve Functional Neurologic Disorder Education among Clinicians. Dara, what advice do you have for people who take care of patients with FND now that you've learned about the types of knowledge gaps and misunderstandings that exist in the healthcare community about FND? Dr. Dara Albert: I think it's really important that folks recognize that FND is a real disorder, that patients are really suffering with symptoms. It's not fake, it's not feigned, it's not malingering, and that these symptoms are very real and distressing to the patients who experience them. And so that's really important for folks taking care of these patients to first and foremost to recognize. And then it's really important that we recognize that there's been an explosion in our understanding. There's been a wealth of new knowledge that has been generated about this diagnosis over the last 10 to 20 years. And so it's really important for folks that are less knowledgeable about this topic to read up and learn what we've been learning about FND and be able to approach these patients in a whole different way. Dr. Jeff Ratliff: Dara, thank you. Check out the full podcast discussion that we had about this topic to hear more details and read the paper. It's in the September, 2025 issue of Neurology® Education. This has been the Neurology Minute Daily Briefing. Thanks for listening. 

Drs. Dan Ackerman, Valérie Biousse, and Nancy J. Newman discuss the clinical presentations, diagnostic challenges, and the importance of accurate diagnosis in managing CRAO and BRAO.  Show citation: Bénard-Séguin É, Nahab F, Pendley AM, et al. Eye stroke protocol in in the emergency department. J Stroke Cerebrovasc Dis. 2024;33(9):107895. doi:10.1016/j.jstrokecerebrovasdis.2024.107895 

In part one of this two-part series on this year's World Stroke Congress, Dr. Andy Southerland and Dr. Seemant Chaturvedi discuss the TRIDENT trial.  Learn more on the World Stroke Congress website. 

In part two of this seven-part series on FND, Dr. Jon Stone and Dr. Gabriela Gilmour discuss pitfalls in the diagnostic process.  Show citation:  Finkelstein SA, Popkirov S. Functional Neurological Disorder: Diagnostic Pitfalls and Differential Diagnostic Considerations. Neurol Clin. 2023;41(4):665-679. doi:10.1016/j.ncl.2023.04.001   

In part one of this seven-part series on FND, Dr. Jon Stone and Dr. Gabriela Gilmour discuss the process of diagnosing FND.  Show citation:  Aybek S, Perez DL. Diagnosis and management of functional neurological disorder. BMJ. 2022;376:o64. Published 2022 Jan 24. doi:10.1136/bmj.o64 

In the final episode of our five-part series on primary progressive aphasia (PPA), Dr. Rogan Magee discusses bedside testing for PPA.  Show citations:  Show citations:  Grossman M, Seeley WW, Boxer AL, et al. Frontotemporal lobar degeneration. Nat Rev Dis Primers. 2023;9(1):40. Published 2023 Aug 10. doi:10.1038/s41572-023-00447-0  Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology. 2011;76(11):1006-1014. doi:10.1212/WNL.0b013e31821103e6 Santos-Santos MA, Rabinovici GD, Iaccarino L, et al. Rates of Amyloid Imaging Positivity in Patients With Primary Progressive Aphasia. JAMA Neurol. 2018;75(3):342-352. doi:10.1001/jamaneurol.2017.4309 Mandelli ML, Lorca-Puls DL, Lukic S, et al. Network anatomy in logopenic variant of primary progressive aphasia. Hum Brain Mapp. 2023;44(11):4390-4406. doi:10.1002/hbm.26388  Putcha D, Erkkinen M, Daffner KR. Functional Neurocircuitry of Cognition and Cognitive Syndromes. In: Silbersweig DA, Safar LT, Daffner KR. eds. Neuropsychiatry and behavioral neurology: principles and practice. McGraw Hill; 2021. Accessed November 6, 2025. https://neurology.mhmedical.com/content.aspx?bookid=3007&sectionid=253215676  Montembeault M, Brambati SM, Gorno-Tempini ML, Migliaccio R. Clinical, Anatomical, and Pathological Features in the Three Variants of Primary Progressive Aphasia: A Review. Front Neurol. 2018;9:692. Published 2018 Aug 21. doi:10.3389/fneur.2018.00692 Clark DG. Frontotemporal Dementia. Continuum (Minneap Minn). 2024;30(6):1642-1672. doi:10.1212/CON.0000000000001506