Prof Michael Okun: My Take
From autonomic failure to Parkinson’s and beyond: tracking the early warning signs of synuclein related disease. Phenoconversion means the transition from one clinical condition to another over time, in this case from pure autonomic failure to disorders like Parkinson’s disease, dementia with Lewy bodies or multiple system atrophy. Virameteekul and colleagues describe in a new paper in JAMA Neurology how frequently and under what conditions folks w/ pure autonomic failure develop central α-synucleinopathies. Key points: - Approximately 30% of individuals w/ pure autonomic failure developed a central α-synucleinopathy over follow-up, w/ an annual conversion rate of about 5%. - Multiple system atrophy tended to emerge earlier, while Parkinson’s disease and dementia with Lewy bodies showed a more gradual and sustained risk over time. - Clinical features such as REM sleep behavior disorder, subtle motor signs and hyposmia (smell loss) were among the most consistent predictors of conversion. My take: This study reinforces something many of us have suspected for years: the autonomic nervous system may be one of the earliest windows into neurodegeneration. The ability to identify who is at highest risk and when conversion may occur could reshape how we think about early diagnosis and intervention. Here are 5 points that resonated w/ me: 1- Autonomic symptoms may represent an early stage of Parkinson’s biology rather than a separate condition. 2- A 5% annual conversion rate is meaningful and highlights the need for close longitudinal follow-up. 3- Timing matters as different diseases emerge on different trajectories. 4- Simple clinical features like smell loss and dream enactment may help stratify risk today. 5- The future will likely combine clinical signs w/ biomarkers to identify the right folks for early intervention and disease modifying trials. https://cutt.ly/DtXwCc8u #michaelokun #fixelinstitute #parkinson
Stem cells and Parkinson’s: hope, hype, and hard truths. Stem cells are special cells that can develop into many different cell types, including dopamine producing brain cells. Stamper, Bulstrode and Barker describe in a new paper in the Journal of Parkinson’s Disease how stem cell therapies for Parkinson’s disease have evolved, and where science meets misconception. Key points: - Dopamine cell therapy aims to replace lost dopamine-producing neurons, however it is not a cure because it does not stop the underlying disease process. - Early and current clinical trials show modest and variable benefits, w/ ongoing challenges in cell survival, delivery and integration into brain circuits. - Safety signals so far are encouraging, however long term risks, optimal patient selection and dosing strategies remain to be fully defined. My take: This is a thoughtful and grounded review. I had the honor of interviewing Roger Barker for our book the Parkinson's Plan. Stem cell therapy for Parkinson’s disease is real science, not science fiction, however it is also not ready to meet the expectations that frequently circulate online. Progress is steady, and the field is learning from each step forward and each misstep. Here are 5 points that resonated w/ me: 1- Stem cell therapies are designed to repair dopamine systems, not to cure Parkinson’s disease. 2- Results so far show signals of benefit, however they are inconsistent and not yet transformative. 3- Safety appears reassuring in early trials, however long term follow up is essential before broad adoption. 4- Not every patient will be an ideal candidate, and timing of therapy will likely matter. 5- The future may depend on improving delivery, survival of transplanted cells and integrating therapies w/ precision medicine approaches. https://journals.sagepub.com/doi/full/10.1177/1877718X261434672 #parkinson #stemcells #michaelokun #fixelinstitute
Parkinson’s Prognosis: What really happens over time? A new population-based meta-analysis reveals the trajectory. Prognosis means the expected course and outcomes of a disease over time. Macleod and colleagues describe in a new paper in Movement Disorders how Parkinson’s disease unfolds using pooled data from six European population-based cohorts followed for up to 12 years. Key Points: - Parkinson’s outcomes such as postural instability and loss of independence occurred earlier and more frequently than previously reported w/ ~70% affected by 10 years. - Dementia developed in about half of individuals by 10 years, and over half had died by 12 years, highlighting a more aggressive natural history in real-world populations. - Older age, worse motor severity, and early cognitive changes were the strongest predictors of worse outcomes across all domains. My take: This study is important because it moves us away from overly optimistic clinic-based data and toward what truly happens across entire populations. It reinforces that Parkinson’s is not just a movement disorder, it is a whole-brain and whole-body condition that evolves over time. These findings should push us to identify risk earlier, personalize care plans, and intervene more aggressively where possible. Here are 5 points that resonated w/ me: 1- Prognosis in Parkinson’s disease may be worse than many of us were taught, especially when we look at real-world populations. 2- Age at diagnosis remains one of the most powerful predictors of how the disease will unfold. 3- Cognitive symptoms early in the disease are not subtle, they are signals that should shape care planning. 4- Genetics such as GBA and APOE variants are beginning to inform risk and may guide future personalized therapies. 5- The future of Parkinson’s care will depend on combining clinical features, biology and timing to better predict and change outcomes. https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.70303 #michaelokun #fixelinstitute #parkinson
Not so fast: Are we moving too quickly to dismiss amyloid therapies in Alzheimer’s disease? Spoiler alert: this recent Cochrane paper over-reached on its conclusions. Amyloid refers to a protein that builds up in the brain in Alzheimer’s disease and is thought to play a role in its progression. Nonino and colleagues describe in a new paper in the Cochrane Database of Systematic Reviews, an analysis of amyloid-beta-targeting monoclonal antibodies for early Alzheimer’s disease. Key Points: - Across 17 trials and over 20,000 participants, pooled antibody therapies showed little to no difference in cognition and only small effects on function at 18 months. - These therapies were associated w/ increased rates of ARIA, including brain swelling and microbleeds. - The authors conclude that removing amyloid from the brain does not appear to lead to clinically meaningful benefit. My take: Not so fast. I delayed writing about this paper until asking several colleagues to weigh in on the conclusions drawn. This is an important topic and the authors over-reached on their conclusions. The analysis pools multiple antibodies w/ very different biology, including agents that do not effectively clear amyloid. When you combine these together, you risk diluting signal and drawing mechanistic conclusions. Here are 5 points that resonated w/ me: 1- Class level pooling of biologically different antibodies may bias results toward no effect. 2- Not all amyloid therapies are the same, and whether your therapy engages the target matters. 3- The conclusion of the authors over-reaches. 4- We need to be thinking about the right drug, in the appropriately selected population. Disease stage will matter; earlier is likely better. 5- We should be careful not to prematurely redirect the field away from amyloid. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD016297/full #michaelokun #fixelinstitute #alzheimers
Pickleball tremor: when movement quiets the shake. What is task-specific tremor? Task-specific tremor refers to shaking that appears only during a particular action or context, rather than all the time. Jankovic describes in a new paper in Movement Disorders Clinical Practice a fascinating observation of pickleball tremor in a person w/ Parkinson’s. He compares it to shopping bag tremor. Ganguly and colleagues responded to the observation w/ important insights on what this may mean biologically. Key Points: - Tremor can emerge when holding a pickleball paddle, yet disappear the moment the ball is struck, highlighting strong context dependence of motor symptoms. - This phenomenon resembles load-related tremors such as shopping bag tremor, where sustained weight holding triggers rhythmic shaking. - Tremor may be shaped by dynamic brain networks, where task demands and mechanical load influence how tremor is expressed. The person shaping the observation had Parkinson’s disease. My take: This is a beautiful reminder that tremor is frequently not static. It can be dynamic, context driven and deeply tied to how the brain interacts w/ the body during real world tasks. The idea that hitting the ball can turn off tremor should make all of us think differently about therapy, exercise and how we evaluate tremors. Here are 5 points that resonated w/ me: 1- Tremor is not just about disease severity, it is about context and what the body is doing in that moment. 2- Mechanical load matters and the weight of an object may amplify or dampen tremor. 3- Brain circuits may switch states depending on task demands and sensory feedback. 4- Exercise like pickleball can be both enjoyable and therapeutic even in the presence of visible tremor. 5- Studying real world activities using wearables and EMG may unlock more personalized strategies for managing tremor. https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mdc3.70618 https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mdc3.70619 #michaelokun #fixelinstitute #parkinson #pickelball
Why does the room spin when you roll over in bed? Have you heard of BPPV. Kristin Walter and colleagues describe in a new person w/ disease page in JAMA what benign paroxysmal positional vertigo is, why it happens and how we can treat it effectively. Key Points: - BPPV occurs when tiny calcium crystals in the inner ear become dislodged and move into the semicircular canals, triggering false signals of movement. - Episodes are brief, typically less than one minute, and are frequently triggered by head movements like lying down or turning in bed. - The Epley maneuver maneuver is highly effective, resolving symptoms in most folks, frequently after just one or a few treatments. My take: This is one of the most common and most treatable causes of dizziness we see. The key is recognizing it early and getting the right maneuver. Many folks suffer longer than needed because the diagnosis is missed or delayed. Don't forget about the recent randomized trial in JAMAN that showed Semont plus superior to Epley. https://jamanetwork.com/journals/jamaneurology/fullarticle/2806601 Here are 5 points that resonated w/ me from person w/ disease page: 1- BPPV is mechanical, not dangerous, and it comes from displaced crystals in the inner ear. 2- Simple bedside testing by health care providers can confirm the diagnosis quickly. 3- The Epley (or Semont-plus) maneuvers can fix the problem by moving crystals back where they belong. 4- Fall risk increases in untreated BPPV, especially in older adults, so early treatment matters. 5- If symptoms persist, referral to vestibular experts such as neurologists, otolaryngologists or physical therapists can make a big difference. https://cutt.ly/gtJ9DDZI #michaelokun #fixelinstitute #vertigo #dizziness
Who are today's Dystonia Think Tank experts? Live on Zoom. Register at: https://fixel.ufhealth.org/dystonia-think-tank-2/ #michaelokun #fixelinstitute #dystonia
The Dystonia Think Tank is underway, join us live on Zoom (open to everyone: clinicians, researchers, industry, and people living with dystonia). Check your ego at the door. Let’s create real change and impact for DYT-1 dystonia and beyond. The experts are around the table and challenging dogma and creating a roadmap for the future. We will be here all day! Register: https://fixel.ufhealth.org/dystonia-think-tank-2/ Thanks to TylersHope for making this happen. michaelokun #dystonia #fixelinstitute
Sometimes I sit back in my office, put my feet up, and dive into the growing stack of new books on Parkinson’s disease. It reminds me how much we are learning together, and how far the field has come. I am deeply grateful for the sharing of ideas, the open dialogue, and the generosity of these authors, and many others who continue to teach and inspire me every day. #michaelokun #parkinson #fixelinstitute
New data on adaptive DBS just dropped: A smarter way to treat Parkinson’s disease? Adaptive means the system can adjust stimulation in real time based on brain signals rather than by delivering constant stimulation. The investigators describe in a new abstract presented this week at the American Academy of Neurology Annual Meeting how adaptive deep brain stimulation is being applied to Parkinson’s disease and how it may improve symptom control. Key points: - Adaptive DBS used real time brain signals to adjust stimulation dynamically rather than continuously. There were 68 folks enrolled. - This approach showed improved control of motor symptoms including fluctuations and dyskinesia. - The system reduced unnecessary stimulation, suggesting potential for fewer side effects and improved efficiency. They reported 98% opted for an adaptive approach. My take: This is important data for the field as we move toward precision neuromodulation. DBS has been life changing for many folks, however it has largely been delivered in an open loop fashion. Moving to adaptive systems means we can listen to the brain and responding in real time. Here are 5 points that resonated w/ me from the AAN abstract: 1- DBS may be shifting from constant stimulation to responsive and personalized therapy. 2- Brain signals such as beta activity may serve as useful biomarkers to guide treatment. 3- Reducing excess stimulation could lower side effects and extend device longevity. 4- Adaptive systems may better handle fluctuations that occur throughout the day. 5- The future of Parkinson’s care may include fully closed loop systems that will integrate brain signals, symptoms and behavior and do it in real time. https://www.aan.com/MSA/Public/Events/AbstractDetails/55517 #michaelokun #fixelinstitute #parkinson
Lecanemab and long term Alzheimer’s: are we finally bending the curve? Low baseline tau seems to be important. Amyloid refers to sticky protein clumps in the brain that are believed to contribute to Alzheimer's disease. Christopher van Dyck and colleagues describe in an abstract from this years American Academy of Neurology meeting the most recent findings from the Clarity AD open label extension study examining up to 48 months of treatment w/ lecanemab in early Alzheimer’s disease. Key points: - Lecanemab treatment showed continued slowing of cognitive and functional decline through 48 months compared to matched controls. - Treatment differences increased over time suggesting a possible cumulative or durable disease modifying effect. - A meaningful proportion of participants showed no decline or even improvement especially in those w/ low baseline tau. My take: This is important as longitudinal signals in Alzheimer’s disease matter. The idea that treatment effects may grow over time is provocative and raises the possibility that early and sustained intervention could meaningfully alter trajectory. At the same time we must remain cautious as these are open label extension data, and longer term real world validation will also matter. Here are 5 points that resonated w/ me: 1- Early treatment may be key to maximizing benefit in Alzheimer’s disease. 2- Slowing decline over years rather than months is what folks and families care about most. 3- The subgroup w/ low tau may represent a window where intervention is most effective. 4- Safety signals appear stable over time which is reassuring for ongoing use. 5- The future may include combining amyloid therapies w/ other approaches to further shift the disease course. https://index.mirasmart.com/AAN2026/PDFfiles/AAN2026-004068.html #michaelokun #fixelinstitute #alzheimer
Semaglutide and Alzheimer’s: are we seeing signals in the brain biology? Semaglutide is a GLP-1 analog, which means it mimics a hormone involved in metabolism and may also influence inflammation and brain cell health. Dylan Belmont-Rausch and colleagues describe new data presented at the AAN Annual Meeting in Chicago this week exploring how semaglutide may impact Alzheimer’s disease biology using biofluid biomarkers and multiomics immune profiling over a 12 week period. Key points: - Semaglutide reduced key CSF biomarkers linked to Alzheimer’s pathology including p-tau181, t-tau and neurogranin after 12 weeks. - There were no significant differences in overall gene expression changes between treatment and placebo groups in blood and CSF. - Immune profiling suggested a shift toward less inflammatory states, including reduced NK cell signaling and altered CD8+ T cell activity. My take: This is an intriguing early signal study. There are possible biological effects in fluid markers and immune pathways over a short time window. The lack of broad gene expression changes should remind us that mechanisms may be subtle and targeted. The real question will be whether these biomarker shifts translate into clinical benefit over longer periods. Here are 5 points that resonated w/ me: 1- Early Alzheimer’s may be influenced by metabolic and immune pathways, not just amyloid and tau. 2- Biomarker changes in CSF may offer a readout of whether a therapy is hitting its biological target. 3- Immune system shifts toward less inflammation may be an important pathway for slowing disease progression. 4- Small sample sizes and short duration mean we should be cautious in interpreting these findings. 5- The future may include combining metabolic therapies like semaglutide w/ other disease modifying strategies for a more complete approach. https://sciencehub.novonordisk.com/congresses/aan2026/belmont-rausch.html #michaelokun #fixelinstitute #alzheimer