The World Parkinson Congress (WPC) is a global, multi-day gathering of researchers, clinicians, care partners, advocates, and people living with PD that takes place every three years. This year, the 7th WPC took place from May 24–27, 2026, in Phoenix, Arizona. I was excited to see Stanford neurologists presenting at WPC. Stanford’s movement disorders chief, Dr. Kathleen Poston, gave a talk titled “The Future of Biologically Defining and Staging PD, DLB and Related Disorders: What Do We Still Have to Learn to Transition to Clinic?” The talk was about moving promising research tools into everyday patient care.
For years, Parkinson’s has been diagnosed by watching for symptoms like tremor, slowness, stiffness. But researchers now have biological tests that can detect the disease at a deeper level, by looking for the proteins and brain changes behind it. Dr. Poston’s talk asked a practical question: these tools are exciting, but are they ready for the doctor’s office yet? Her answer, in short, is that they’re getting there — and she walked through what still needs to happen.
Key takeaways from the presentation include:
The new biological tests are promising, but not quite ready for everyday clinical use. Researchers have developed a way to define Parkinson’s based on its biology rather than just its symptoms — a framework called NSD (neuronal alpha-synuclein disease). It’s a step forward, but the system clinicians would use to “stage” the disease (to describe how far it has progressed) still needs work. The parts based on movement symptoms hold up well; the parts based on non-motor symptoms and thinking changes don’t yet, and need more refinement before clinicians can rely on them.
The leading biological test works well in people who already have symptoms — but it has blind spots. The seed amplification assay, or SAA, detects the misfolded protein (alpha-synuclein) that drives Parkinson’s. In a large review combining more than 1,300 people across 14 studies, the test was very accurate. But it works better in some situations than others: it’s nearly perfect when the disease has spread widely in the brain (to the cortex), but much less reliable when the protein is limited to the brainstem (an early or restricted form). Additionally, most of the people studied from the brain donation programs didn’t actually have a Parkinson’s diagnosis during life, so more evidence is needed in everyday patients.
Some people have classic Parkinson’s symptoms but test negative on the SAA — and we want to figure out why. About a third of people who carry the LRRK2 gene mutation linked to Parkinson’s test negative on the SAA. Research from the PPMI study (a major long-term Parkinson’s research project) shows these people tend to keep their sense of smell better and follow a somewhat different disease course. In about 15% of cases, doctors eventually decided and changed a person’s clinical diagnosis to be an atypical parkinsonisms such as multiple system atrophy or progressive supranuclear palsy. Figuring out what’s really going on in this group is an important open question.
A brand-new challenge: people who test positive but feel completely fine. As these tests become more available, doctors will increasingly meet people who carry the biological markers of Parkinson’s but have no symptoms at all. What does that mean for these people? One large study (the Swedish BioFINDER cohort) followed more than 1,300 healthy older adults and among those with the relevant PD markers, only about 24% had a diagnosis of Parkinson’s disease or dementia with Lewy bodies within roughly five years. That’s meaningful, but it also means most did not get a diagnosis of PD or dementia with Lewy bodies — so we need much more information before doctors can responsibly counsel a healthy person about what a positive test means for them.
Less invasive tests are the next big goal. Right now, the most validated version of this testing requires a spinal tap (lumbar puncture), which most patients understandably want to avoid — and which can’t be offered everywhere in the world. Skin-based tests are showing real promise. Blood-based tests would be ideal, but so far they’ve given inconsistent results and need more work.
The full picture will require looking at more than one disease process. Parkinson’s often occurs with other brain changes, including the amyloid and tau proteins associated with Alzheimer’s. People who have both tend to decline faster. Dr. Poston compared today’s biological tests to an early smartphone — genuinely useful, but still basic. To reach the next level, the field needs reliable tests for other processes too, like inflammation and the brain’s energy and waste-clearing systems.
Resources
PPMI (Parkinson’s Progression Markers Initiative)
Keep reading for detailed notes,
Elizabeth
The Future of Biologically Defining and Staging PD, DLB and Related Disorders: What Do We Still Have to Learn to Transition to Clinic?
Speaker: Kathleen Poston, MD, MS, Professor of Neurology and Neurological Sciences, Movement Disorder Specialist, Stanford University
Host: World Parkinson’s Congress
Event Date: May 25, 2026
Summary by: Elizabeth Wong, Stanford Parkinson’s Community Outreach
The NSD (neuronal alpha-synuclein disease) framework offers a new way to define and stage Parkinson’s based on its underlying biology rather than outward symptoms alone. A key question is whether these tools are ready to move from research settings into everyday clinical care.
The speaker compared the current frameworks to the original 2007 smartphone: functional and valuable, but basic, and impossible to fully imagine the future of. Just as smartphones were released and then improved year after year, these biological frameworks can be put to use and refined as more data comes in, rather than held back until they’re perfect.
First Hurdle: The Data So Far Comes From Too Narrow a Group
The information used to build the NDS framework initially came from a fairly limited group of people — most notably the PPMI cohort, which is excellent but a very specific population.
[Editor’s note: PPMI (Parkinson’s Progression Markers Initiative) is a longitudinal study recruiting volunteers with and without Parkinson’s to identify causes and biomarkers of the disease. Learn more at ppmi-info.org.]
The encouraging news is that many other research groups are now expanding this work. New data is coming from dementia with Lewy bodies (DLB) communities in both Europe and the U.S., from a major biomarker program newly funded by the Lewy Body Dementia Association, and from numerous studies funded by the Michael J. Fox Foundation.
These projects are designed to learn how the biological markers behave in a much broader range of people — and to tackle the puzzle of individuals who have classic Parkinson’s symptoms but test negative on the biological markers. Many of these studies are also collecting additional data such as brain imaging, amyloid and tau measurements, and in some cases brain tissue donated after death.
Second Hurdle: Understanding People With Classic Symptoms Who Test Negative
This is one of the questions that has been most pressing since research papers on the topic were published. Several manuscripts addressing it have now come out of PPMI, with more on the way.
[Editor’s Note: Here is one of the papers on the topic, LRRK2-associated parkinsonism with and without in vivo evidence of alpha-synuclein aggregates: longitudinal clinical and biomarker characterization, Brain Communications, Volume 7, Issue 2, 2025, fcaf103, https://doi.org/10.1093/braincomms/fcaf103]
The “LRRK2 puzzle”: about 5–6% of all people diagnosed with Parkinson’s carry a variant in the LRRK2 gene. Of those, roughly one-third test negative on the SAA — which works out to about 2% of all Parkinson’s patients. Researchers asked whether these LRRK2-positive but SAA-negative individuals look different from LRRK2-positive people who do test positive. The answer: there were some differences, but not dramatic ones. Notably, there were unexpected differences between men and women, the SAA-negative group tended to keep their sense of smell better, and there were differences in age and in how the disease progressed over time.
A deeper look at PPMI participants who tested negative showed that, in general, these individuals were a bit older and more likely to have a normal sense of smell. There was a graph that plots how abnormal the dopamine brain scan (DAT scan) looks against the degree of smell loss. In the graph, most of the SAA-negative people clustered in the “normal smell” zone. Unexpectedly, this group also showed a tendency toward loss of certain brain volume on MRI scans, and they tended to develop slightly more trouble with gait and balance over time — a subtle difference in how their condition looked clinically.
Importantly, in about 15% of these SAA-negative individuals, the treating doctor eventually revised the diagnosis to a different condition — most commonly multiple system atrophy or progressive supranuclear palsy. This reclassification happened before anyone knew the person’s biological test result, so it wasn’t influenced by the SAA. The remaining roughly 85% were not reclassified and still need more time and study to understand. The larger point: having a biological test is genuinely useful here, because it shines a light on the people who don’t fit the classic mold and lets researchers study their biology more carefully than ever before.
The deepest question is what’s actually happening in the brains of these individuals — do they have Lewy bodies (the protein clumps associated with Parkinson’s), or some other form of disease entirely? Answering that requires comparing tests done during life against brain tissue examined after death. The PPMI cohort is well-suited to this because participants are followed for years and many agree to donate their brains. So far, about 25–30 people have both an SAA result from during life and a final autopsy. In the cases that lined up as expected, people who tested positive during life were found to have Lewy bodies, and people who tested negative were found not to have them. One person whose diagnosis had been changed to multiple system atrophy was confirmed to have that condition at autopsy. And two LRRK2 carriers from the SAA-negative group showed no evidence of Lewy bodies at all. But this is only a handful of cases — a lot more would be needed before drawing confident conclusions.
What the Autopsy Data Reveals
A meta-analysis and systematic review went beyond PPMI, examining every study comparing SAA results during life against autopsy findings — over 1,300 people across about 14 papers. The test’s specificity (its ability to correctly rule out the disease) was very high. Its sensitivity (its ability to correctly catch the disease) was in the 80s, but varied dramatically depending on where the protein had spread: close to 100% when Lewy bodies had reached the brain’s outer layer (the cortex), but much lower when they were confined to the brainstem.
A crucial caveat: most of these 1,300 people did not have a diagnosis of Parkinson’s, DLB, or REM sleep behavior disorder during life. They came largely from brain banks tied to rapidly progressive dementia programs — places that happen to have both spinal fluid collected before death and a final autopsy. Only about 300 of the 1,300 had any clinical symptoms during life. This points to something important: a large number of people who carry other diagnoses turn out to have Lewy bodies in their brains too. Those individuals might well benefit from treatments aimed at the Parkinson’s protein (alpha-synuclien)— so understanding this hidden group could eventually help treat a much broader population than just classic Parkinson’s patients.
Third Hurdle: People Who Test Positive but Have Vague or No Symptoms
This is one of the more challenging questions, and one that needs answering before these tests reach everyday practice — because once they do, these patients will walk through the clinic door needing answers. Imagine someone whose only sign is a loss of smell, or a family history of Parkinson’s, or a REM sleep behavior disorder, who then tests positive.
The PPMI data offers some early clues. Among people who test positive, the dopamine changes on brain scans generally don’t appear until smell loss becomes fairly pronounced (below roughly the 10th percentile) — meaning most still have normal dopamine scans before that point. And among people who had both a REM sleep behavior disorder and reduced smell, cognitive test scores were lower than those of exceptionally healthy “ultra-control” volunteers — but still within the normal range. In other words, they’d test perfectly normal in a standard clinical setting; the subtle differences only showed up against an unusually pristine comparison group. This isn’t yet enough to act on clinically. The NAPS cohort (the North American Prodromal Synucleinopathy consortium, a multi-site study following people with REM sleep behavior disorder) is an important source of upcoming data.
A further question: what about people who test positive but are completely symptom-free? These individuals are starting to turn up in studies of healthy aging. The most revealing data comes from the Swedish BioFINDER study, in which more than 1,300 healthy older adults with no neurological symptoms agreed to a spinal tap. They were sorted into four groups based on their biomarkers: those with no Lewy body or Alzheimer’s markers; those with Parkinson’s-type (alpha-synuclein) markers only; those with Alzheimer’s markers only; and those with both. Following these people over time, those carrying the disease-related markers were more likely to show declines on cognitive testing. Among those who were positive for the Parkinson’s protein, about 24% had their diagnosis change to Parkinson’s disease or dementia with Lewy bodies within roughly five years.
Inspired by that work, a similar look at a smaller Stanford cohort — about 250 healthy older adults, of whom only about 20 tested positive — already showed very subtle abnormalities in cognitive and motor testing even in that small group. The key missing piece is timing — knowing how long it takes to progress. This is a strong argument for prioritizing healthy aging cohorts so the field can map out how these biomarkers change over the years.
Fourth Hurdle: Getting to Easier, More Available Tests
The current SAA testing is well-validated enough to use in people who already have symptoms — but not yet validated enough to roll out broadly around the world. The biggest barrier is access. The Swedish study participants underwent spinal taps, but most patients are not willing to do a spinal tap, and spinal-fluid testing can’t realistically be offered everywhere. The field needs tests that use easier samples. Skin-based tests are looking genuinely promising. Blood-based tests have been more hit-or-miss — some exciting early results have proven hard to reproduce — so more work is needed there. A reliable blood test is hopefully a matter of “when, not if.”
The biological definition isn’t only about detecting the alpha-synuclein protein. Showing evidence of dopamine-system damage or other neurodegeneration is essential for understanding how someone moves from “positive test, no symptoms” toward mild, moderate, and severe disease. A great deal of imaging work is underway in both PET and MRI, including new ways to measure dopamine-system signals in spinal fluid and blood, and a new method for quantifying dopamine imaging that can track change over time. First-in-human Phase 1 studies of a scan that images the Parkinson’s protein directly are expected in 2026, though no peer-reviewed results have been published yet. This kind of imaging will likely end up being more of a research tool than a routine clinical one.
Fifth Hurdle: Staging Isn’t Ready for the Clinic Yet
The NSD framework includes a staging system:
Stage 1 is a clinically normal person who tests positive on the biomarkers;
Stage 2 adds minimal signs or symptoms;
Stage 3 adds slight-to-mild symptoms,
and so on.
This clinical staging is ready for research use only, not for the clinic. When the “anchors” used to define the stages were examined, the motor (movement) anchors held up very well. However, the non-motor and cognitive anchors did not, and need to be revised with more data. The recommendation: keep the current staging in the research setting until better versions exist.
Sixth Hurdle: Bringing in the Rest of the Biology
Parkinson’s doesn’t happen in isolation, and until the field can fold in other biological processes, it won’t see the whole picture. Returning to the technology analogy: without incorporating multiple biomarkers, the field will only ever reach the equivalent of “2010 iPhone” capability.
One clear example is the overlap with Alzheimer’s-related proteins. Data shows that people who have Lewy body pathology plus amyloid and tau decline faster than those with Lewy body pathology alone. Amyloid can be measured several ways — PET scans (highly accurate but harder to do), spinal fluid, the broad biomarker panels used in the Swedish study, or blood — though blood-based amyloid measures still need to be validated specifically in people with Parkinson’s.
The field cannot advance beyond that “early-smartphone stage” without validated, reproducible biomarkers for processes like inflammation, mitochondrial (cellular energy) dysfunction, lysosomal (cellular waste-clearing) dysfunction, and other forms of neurodegeneration. Some early data exists, but not enough that is reproducible and broadly available. A vast amount of work remains here — and while it doesn’t all have to be done before the tools enter the clinic, it is a very high priority.
Closing Perspective
The closing argument was for “parallelism” — a both/and approach. Biological definitions can be used where they make sense (in research and in certain clinical contexts), while well-validated traditional clinical measures continue to be used elsewhere. The traditional, symptom-based way of diagnosing Parkinson’s still belongs in the clinic, while the biological definitions are used in certain research settings. What matters is matching the tool to the context.
Question and Answer Section
Q: Does the tremor-dominant versus non-tremor-dominant way of describing Parkinson’s still hold up within the new biological framework?
A: This is an active and important area of research. One major goal is to understand how the traditional ways of grouping patients — by whether tremor or balance and walking problems dominate, for example — line up with the new biological framework. The current staging system isn’t yet able to connect those two pictures clearly. Building that bridge is part of the work that still needs to happen before biological staging can be used fully in the clinic.