We had great hope for this Parkinson’s supplement. A randomized trial found it actually made symptoms worse. Nicotinamide riboside (NR) is a form of vitamin B3 that boosts NAD, a molecule essential for cellular energy production, mitochondrial function and brain cell health. There was considerable excitement that boosting NAD might protect dopamine-producing neurons and slow Parkinson’s disease. Brage Brakedal and colleagues describe in a new paper published in JAMA how this promising supplement performed in a large, randomized, double-blind, placebo-controlled Phase 3 clinical trial. Unfortunately, the results were not what we had hoped. Key points: - The NOPARK trial randomized 410 folks w/ early Parkinson’s disease at 11 centers in Norway to receive nicotinamide riboside (500 mg twice daily) or placebo for 52 weeks. - Parkinson’s symptoms actually worsened more in the supplement group. The total MDS-UPDRS score increased by 2.45 points in the NR group compared to a 0.27-point decrease in the placebo group, a statistically significant 2.72-point difference favoring placebo (P = .02). - Non-motor symptoms also worsened relative to placebo (4.22-point difference, P = .009). There was no significant benefit on dopamine transporter brain imaging, and the trial failed to demonstrate that NR slowed Parkinson’s progression. My take: This is a disappointing and important study. We had great hope for nicotinamide riboside because earlier studies suggested it could boost brain NAD, improve mitochondrial function and potentially protect vulnerable dopamine neurons. The biological rationale was compelling. However, when investigators conducted a rigorous year-long randomized trial, not only did the supplement fail to help, but folks taking it actually experienced statistically worse clinical outcomes. The average difference was modest and below the threshold generally considered clinically meaningful, but the direction of the results should get our attention. This is precisely why we need randomized trials and why we should be cautious about recommending supplements based on promising laboratory findings or small preliminary studies. Raising NAD levels is not the same as improving Parkinson’s disease. Here are 5 points that resonated w/ me: 1- A supplement can have a compelling scientific rationale and still fail when tested in folks living w/ Parkinson’s disease. 2- The most concerning finding was not simply the absence of benefit. The supplement group actually did worse on the overall Parkinson’s rating scale and on non-motor symptoms. 3- Earlier small studies suggested biological effects and possible clinical improvements. This larger trial reminds us why early signals should never be confused w/ proof of benefit. 4- These findings do not mean that mitochondrial dysfunction or NAD biology are unimportant in Parkinson’s. They mean that this particular supplement, at this dose and disease stage, did not deliver the hoped-for clinical benefit. Folks taking NR should discuss these findings w/ their health care providers. 5- Negative trials are not wasted trials. They protect patients, challenge our assumptions and help redirect research toward treatments that actually work. We need to follow the science, even when the results disappoint us. The bottom line: Natural does not automatically mean safe or effective. In Parkinson’s disease, hope must be matched by evidence, and this trial is an important reminder that supplements deserve the same scientific scrutiny as prescription medications. jamanetwork.com/journals/jam…

Mini-brains in a dish: why are Parkinson’s and Alzheimer’s researchers are so excited? Brain organoids, sometimes called mini-brains in a dish, are tiny 3D collections of human brain cells grown from stem cells that can reproduce some features of the developing human brain. Chun-Hui Duan and colleagues describe in a new review in Brain how rapidly these models are becoming more sophisticated and why they could change the way we study diseases like Parkinson’s and Alzheimer’s. Key points: - Brain organoids can contain multiple types of neurons and supporting cells and can be engineered to model specific brain regions and even connections between regions. - In Alzheimer’s disease, organoids can reproduce important features including amyloid plaques, tau pathology and neuroinflammation, creating a human platform for studying disease mechanisms and testing therapies. - In Parkinson’s disease, organoids can model dopamine neurons and alpha-synuclein aggregation, potentially helping us understand why certain brain cells become vulnerable while others survive. My take: This is one of those technologies that makes neuroscientists sit up in their chairs. Imagine taking a person’s cells, turning them back into stem cells and then growing a tiny 3D model containing some of the brain cells relevant to their disease. We could potentially watch aspects of Parkinson’s or Alzheimer’s biology unfold in a dish, probe genetics and environmental exposures and test drugs before moving them into expensive human trials. These are NOT miniature thinking brains and they are not replacements for the human brain. They remain immature models and lack many features of an aging brain including complete blood vessels, immune systems and long-range connections. However, they could become an extraordinary bridge between a flat layer of cells, animal models and the complexity of human disease. Here are 5 points that resonated w/ me: 1- Human biology matters. Many promising treatments work in laboratory animals and fail in humans. Organoids give us another way to study disease directly in human cells. 2- Parkinson’s organoids may help us understand alpha-synuclein and why dopamine neurons are selectively vulnerable; one of the biggest unanswered questions in the field. 3- Alzheimer’s organoids can reproduce pieces of the amyloid, tau and inflammatory story in the same 3D system, potentially letting us study how these processes interact. 4- Personalized medicine is perhaps the most exciting possibility. Could we someday grow organoids from an individual person and use them to help identify which therapy is most likely to work? We are not there yet, however this is where the science could take us. 5- Keep the hype in check. A mini-brain is not a brain and a result in a dish is not a cure. The real excitement is that we are building increasingly human relevant models that could help us ask better questions, discard ineffective treatments earlier and hopefully move the right therapies faster toward folks living w/ Parkinson’s and Alzheimer’s disease. academic.oup.com/brain/advan…

The FDA has approved tavapadon (JUVMO), a new once-daily dopamine D1/D5 receptor partial agonist for Parkinson’s disease that can be used as an initial symptomatic therapy or added to levodopa in people experiencing motor fluctuations, with the goal of improving good “ON” time. If you try tavapadon, remember that it is not automatically a replacement for your current Parkinson’s medications and that changes should be made with your treating clinician. Although clinical trials suggest that some of the problems traditionally associated with dopamine agonists may occur less frequently with this more selective drug, as tavapadon moves into real-world use we need to remain vigilant for the full spectrum of dopamine agonist related effects, including sleepiness, hallucinations, orthostatic hypotension, dyskinesia, and impulse-control behaviors (shopping, gambling, hypersexuality, others). New mechanism and once-a-day dosing are exciting, but careful monitoring after approval will tell us how tavapadon performs in the broader Parkinson’s community.

Negative trials matter, particularly in a disease as devastating as ALS, because we need failures to get to successes. DNL343 had a compelling rationale: it is a brain-penetrant small molecule that activates eIF2B and is designed to inhibit the integrated stress response, a cellular pathway involved in protein production and the response to cellular stress that can become persistently dysregulated in ALS; encouraging phase 1 data showed that the drug entered the brain and affected biomarkers of this pathway. But in this rigorous HEALEY ALS Platform Trial, 200 mg daily did not slow ALS progression, with no significant benefit on the primary combined measure of function and survival or on the major secondary outcomes. That is disappointing, but it is not wasted science: it tells us where this particular approach fell short, raises important questions about target engagement and the biological heterogeneity of ALS, and helps us design the next trial better. Thomas Edison is famously credited with reframing his repeated attempts to build the light bulb as, “I have not failed. I've just found 10,000 ways that won't work.” That is how we should view well-designed negative trials. Every carefully measured failure narrows the field, teaches us something, and hopefully moves us one experiment closer to a treatment that works. jamanetwork.com/journals/jam…

What resonates with me most about this paper is that it shifts the genetics conversation in Parkinson’s from simply “Who gets the disease?” to “Who progresses faster, and why?” Schumacher and colleagues report that common loss-of-function variants in MC1R, a gene many people associate primarily with pigmentation, were associated with about 30% faster motor progression in sporadic Parkinson’s, with an even larger effect in an independent replication cohort; importantly, the signal showed dose-response features and was driven particularly by worsening bradykinesia and orofacial function. The accompanying editorial makes several points I think are especially important: genetics that influence Parkinson’s risk may not be the same genetics that determine its trajectory; longitudinal off-medication measurements and independent replication make this study stronger than many traditional candidate-gene reports; and we should resist over-interpreting a single gene until these observations are confirmed in larger, multi-ancestry, genome-wide studies. Perhaps most exciting is where this could lead: combining genetics with the exposome and gene-environment interactions to understand not only why Parkinson’s develops, but why it moves faster in some people than others. That could ultimately help us provide better prognostic information, identify biologically meaningful subtypes, and enrich clinical trials with the people most likely to progress during the study window. jamanetwork.com/journals/jam…