Summary: Researchers utilizing data from the UK Biobank have identified specific health factors that appear up to a decade before a diagnosis of Progressive Supranuclear Palsy (PSP). This rare and often misdiagnosed neurological disease affects balance, vision, and cognition. The study tracked over 500,000 individuals for 20 years, finding that depression, delirium, and irritable bowel syndrome are significant early indicators.
Conversely, the study found a “seesaw” effect between cancer and PSP, where cancer survivors were 50% less likely to develop the brain disease. These findings suggest that PSP begins its silent progression in the brain’s mood and gut-related circuits long before physical symptoms like falls occur.
Key Facts
- A Decade of Silence: Depression was linked to an increased risk of PSP as far back as 10 years before clinical diagnosis, indicating early disruption of mood-regulating brain circuits.
- The “Seesaw” Effect: Individuals with a history of cancer were approximately half as likely to develop PSP, a biological inverse relationship also observed in Alzheimer’s and Parkinson’s.
- Gut-Brain Connection: Irritable bowel syndrome (IBS) and other gut problems were associated with an elevated risk, reinforcing the link between gastrointestinal health and neurodegeneration.
- Acute Confusion: Episodes of delirium (temporary confusion during acute illness) were identified as warning signs at least five years before the onset of overt PSP symptoms.
Source: Mass General
Drawing from UK Biobank data, Mass General Brigham researchers uncovered specific health factors linked to higher or lower risk of developing progressive supranuclear palsy (PSP), a rare but devastating neurological disease.
Q: What challenges or unmet needs make this study important?
Progressive supranuclear palsy, or PSP, is a rare brain disease that causes problems with balance, eye movements and thinking. Civil rights leader Jesse Jackson recently passed away after living with the disease for more than a decade. Most individuals with PSP, like Jackson, are initially misdiagnosed with Parkinson’s disease, and correct diagnosis can be delayed by several years.
Until now, scientists have known very little about what raises a person’s chances of getting PSP, so there was a significant need for a large study that tracked healthy people over time to look for early clues.
Q: What central question(s) were you investigating?
We set out with a straightforward question: What are the risk factors for developing PSP? We looked at factors like where people lived, what medical conditions they had and what medications they took, as well as their drinking/smoking habits and diet. All of this information was collected before anyone in the study had overt symptoms of PSP.
We also wanted to know how early these warning signs could be spotted, which would tell us how long the disease might quietly build before symptoms become noticeable.
Q: What methods or approach did you use?
Using data from the UK Biobank—a large health study that followed more than 500,000 adults in the United Kingdom for close to 20 years—we found 240 people who were later diagnosed with PSP. We compared their health habits, medical histories and living environments to those of their healthy counterparts using a careful, step-by-step statistical method that tested many possible risk factors. We also checked how far back in time each risk factor could be detected to ensure we were finding true early warning signs, rather than symptoms of PSP that had already started.
Q: What did you find?
We found five clear risk factors for PSP. Depression and delirium (temporary confusion due to an acute medical illness such as a urinary tract infection) diagnosed years before PSP stood out the most. Depression was linked to higher risk as far back as 10 years before diagnosis, and delirium at least five years before. Gut problems like irritable bowel syndrome were also associated with elevated risk. Finally, heavy drinking was associated with increased risk compared to moderate drinking, as was being overweight.
One of the most surprising findings was that people who had been diagnosed with cancer were about half as likely to develop PSP, a pattern also seen in Parkinson’s and Alzheimer’s disease. It was also interesting to discover that smoking, diet, air pollution and pesticide exposure did not appear to affect PSP risk.
Q: What are the real-world implications, particularly for patients?
PSP may silently develop for 10 years or more before the well-known symptoms, like falls and trouble with eye movements, show up. If clinicians recognize that depression, confusion episodes and gut issues could be early signs of PSP rather than unrelated problems, they may be able to arrive at the right diagnosis sooner. Identifying people in this early, silent stage of disease could open the door to enrolling them in clinical trials for new treatments at a point when those treatments are most likely to help.
Q: Were you surprised by any of the findings?
The link between cancer and lower PSP risk really stood out to our research team. It fits an emerging idea in science that cancer is a disease of cells growing out of control, while brain diseases like PSP involve cells dying too soon. These two processes may work in opposite directions, almost like two ends of a seesaw.
We were also struck by the fact that depression showed up as a warning sign a full 10 years before PSP diagnosis. That tells us the disease may stealthily affect brain circuits involved in mood long before anyone notices problems with movement or balance. It pushes us to look for ways to detect PSP during this hidden early phase, when future treatments could potentially make the biggest impact.
Authorship: In addition to Zhao and Wills, other study authors include Marian Dale, Alexander Pantelyat, Maria Carmela Tartaglia, Ruth Schneider, David Coughlin, Federico Rodriguez-Porcel, Zbigniew Wszolek, Tao Xie, Lawrence Golbe and James Rowe.
Paper cited: Zhao, W., et al. “Risk Factors for the Diagnosis of Progressive Supranuclear Palsy in the UK Biobank.” Movement Disorders. DOI: 10.1002/mds.70287
Funding: This study was funded by the Dolce Family Fund for Massachusetts General Hospital.
Key Questions Answered:
A: Early symptoms like balance issues and stiffness are very similar. This study helps differentiate them by showing that specific precursors—like long-term depression and delirium episodes—can flag PSP risk years earlier.
A: Scientists call it the “seesaw” effect. Cancer involves cells that won’t stop growing, while PSP involves brain cells that die too soon. These biological processes appear to work in opposite directions, potentially protecting cancer survivors from neurodegeneration.
A: Not necessarily. PSP is extremely rare. These factors are “risk markers” in a massive population study, not guarantees of disease. The goal is to help doctors spot the combination of signs in at-risk patients to start treatments earlier.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this neurology and PSP research news
Author: Brandon Chase
Source: Mass General Brigham
Contact: Brandon Chase – Mass General Brigham
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Risk Factors for the Diagnosis of Progressive Supranuclear Palsy in the UK Biobank” by Charlie Weige Zhao MD, Marian Dale MD, Alexander Pantelyat MD, Maria Carmela Tartaglia MD, Ruth B. Schneider MD, David G. Coughlin MD, MTR, Federico Rodriguez-Porcel MD, Zbigniew Wszolek MD, Tao Xie MD, PhD, Lawrence I. Golbe MD, James B. Rowe MD, PhD, Anne-Marie Wills MD, MPH. Movement Disorders
DOI:10.1002/mds.70287
Abstract
Risk Factors for the Diagnosis of Progressive Supranuclear Palsy in the UK Biobank
Background
Progressive supranuclear palsy (PSP) is a tauopathy for which there is limited understanding of epidemiological risk factors.
Objective
The objective of this study was to identify premorbid nonmedical and medical risk factors for PSP diagnosis in a large prospective population-based cohort.
Methods
We performed a matched nested case–control study using the UK Biobank (UKB) cohort consisting of >500,000 adults aged 37 to 73 years. PSP diagnoses were identified from 2007 to censor date (August 2025) and matched 1:10 by age and sex to control subjects without parkinsonism or dementia diagnoses. We derived risk factors using an iterative logistic regression approach.
Results
There were 240 incident PSP diagnoses in the UKB. In the fully adjusted model, premorbid depression (odds ratio [OR], 3.22; 95% confidence interval [CI], 2.30–4.50; P < 0.001), delirium (OR, 6.76; 95% CI, 4.08–11.19; P < 0.001), and functional gastrointestinal disorders (OR, 1.91; 95% CI, 1.39–2.63; P < 0.001) were associated with increased risk. Heavy alcohol consumption was associated with higher risk compared with moderate consumption (OR, 1.65; 95% CI: 1.21–2.26; P = 0.0017). Body mass index (BMI) and alcohol consumption had nonlinear risk profiles. Cancer diagnosis was inversely associated with PSP (OR, 0.56; 95% CI, 0.40–0.79; P < 0.001). Depression and delirium diagnoses remained significant 5 to 10 years before diagnosis.
Conclusions
In this large prospective cohort, PSP was associated with premorbid lifestyle practices and neuropsychiatric diagnoses years before diagnosis. This suggests a long premotor phase and highlights opportunities for earlier diagnosis and further mechanistic investigation. The inverse association with cancer mirrors the relationship seen in other neurodegenerative conditions and may point toward shared mechanisms. © 2026 International Parkinson and Movement Disorder Society.
