Summary: Researchers analyzing UK Biobank data have identified medical and lifestyle factors that can appear up to a decade before a diagnosis of progressive supranuclear palsy (PSP). This rare neurodegenerative disorder, which affects balance, eye movement and cognition, is frequently misdiagnosed. Tracking more than 500,000 people over roughly 20 years, the team found that depression, delirium, and functional gastrointestinal disorders such as irritable bowel syndrome (IBS) are notable early indicators. The study also observed a strong inverse relationship between prior cancer and later PSP diagnosis.
The findings suggest PSP may begin a long, silent progression in brain circuits that regulate mood and gut function well before the movement and balance problems that typically prompt clinical attention. Early recognition of these warning signs could help clinicians diagnose PSP sooner and identify candidates for early intervention or clinical trials.
Key Facts
- Long premotor phase: Depression was associated with increased risk of PSP up to ten years before clinical diagnosis, indicating early involvement of mood-related brain circuits.
- Cancer inverse association: People with a prior cancer diagnosis were about half as likely to develop PSP, a pattern similar to observations in Parkinson’s and Alzheimer’s disease.
- Gut–brain link: Functional gastrointestinal disorders, including IBS, were tied to higher PSP risk, supporting a connection between gastrointestinal health and neurodegeneration.
- Acute confusion as an early sign: Episodes of delirium during acute illness were identified as warning signs at least five years before PSP diagnosis.
Source: Mass General Brigham
Overview: Using UK Biobank records, researchers at Mass General Brigham examined premorbid factors linked to higher or lower likelihood of receiving a PSP diagnosis. Their goal was to identify early, detectable markers that appear before the classic motor symptoms that lead to diagnosis.
Why this matters
Progressive supranuclear palsy (PSP) is a rare tau-related neurodegenerative disease that impairs balance, vertical eye movements and cognition. Because its early features often resemble Parkinson’s disease, many people with PSP receive incorrect diagnoses for years. There has been limited knowledge about premorbid risk factors, so a large prospective cohort study was needed to search for early clinical clues.
Research question
The investigators asked: Which nonmedical and medical factors identifiable before symptom onset predict later PSP diagnosis? They examined demographics, medical history, medications, lifestyle (including alcohol and smoking), and environmental exposures, using data collected before any participant developed overt PSP symptoms. A key aim was to determine how long before diagnosis these markers become detectable.
Methods
The team conducted a matched nested case–control analysis within the UK Biobank, a prospective cohort of more than 500,000 adults aged 37–73. From records spanning 2007 through August 2025, they identified 240 incident PSP cases and matched each case to ten controls by age and sex. An iterative logistic regression approach tested a wide range of potential risk factors and assessed how far back each factor could be detected to distinguish true early markers from emerging disease symptoms.
Findings
Five prominent premorbid risk factors emerged. Depression and delirium were among the strongest signals: depression could be detected up to ten years before diagnosis, and delirium episodes at least five years prior. Functional gastrointestinal disorders, including IBS, were also associated with higher PSP risk. Heavy alcohol use and higher body mass index showed elevated risk compared with moderate drinking and lower BMI ranges. Remarkably, a history of cancer was associated with a substantially lower risk of PSP—about a 44% reduction in odds—mirroring an inverse relationship reported for other neurodegenerative diseases. No clear associations were found for smoking, diet patterns, air pollution or pesticide exposure in this study.
Implications for patients and clinicians
PSP may evolve silently for many years before the classic signs prompt evaluation. Recognizing that long-standing depression, episodes of acute confusion, and persistent gut symptoms can be early indicators may help clinicians consider PSP earlier in the diagnostic process. Earlier identification could enable timely referrals, improved symptom management and eligibility for clinical trials testing disease-modifying therapies at a stage when intervention may be most effective.
Unexpected observations
Investigators were particularly struck by the inverse association between cancer and PSP. This supports a broader hypothesis that proliferative diseases like cancer and degenerative brain disorders may reflect opposing cellular processes. The long lead time of depression as an early sign also emphasizes the need to study mood changes as part of PSP’s premotor phase.
Authorship and citation
Lead authors include Charlie Weige Zhao and Anne-Marie Wills. Additional contributors are 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. Funded by the Dolce Family Fund for Massachusetts General Hospital.
Key Questions Answered:
A: Early features such as balance problems and stiffness overlap with Parkinson’s. This study highlights premorbid markers—long-term depression and delirium episodes—that can help distinguish PSP risk years before motor symptoms appear.
A: Researchers describe a “seesaw” relationship: cancer involves uncontrolled cell growth, whereas PSP reflects premature neuronal loss. These opposing biological tendencies may underlie the inverse association observed.
A: No immediate cause for alarm. PSP is rare. Depression and IBS are risk markers in a large population study, not determinative diagnoses. The value lies in recognizing combinations of signs that may prompt further evaluation.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The cited journal paper was reviewed in full by the editorial team.
- Additional explanatory context was added by staff to clarify the findings for a general audience.
About this neurology and PSP research news
Author: Brandon Chase
Source: Mass General Brigham
Contact: Brandon Chase – Mass General Brigham
Image: Image 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 with limited knowledge about epidemiological risk factors and premorbid features.
Objective
This study aimed to identify premorbid medical and nonmedical risk factors for PSP diagnosis in a large prospective population cohort.
Methods
A matched nested case–control design was used within the UK Biobank cohort of over 500,000 adults aged 37–73. PSP cases from 2007 through August 2025 (n=240) were matched 1:10 by age and sex to controls without parkinsonism or dementia. Risk factors were derived using an iterative logistic regression strategy to identify robust associations.
Results
In adjusted models, premorbid depression, delirium, and functional gastrointestinal disorders were significantly associated with increased PSP risk. Heavy alcohol use and higher BMI carried additional risk compared with moderate consumption and lower BMI ranges. A cancer diagnosis showed an inverse association with PSP. Depression and delirium remained significant when examined five to ten years before diagnosis.
Conclusions
In this large prospective cohort, PSP showed associations with premorbid lifestyle factors and neuropsychiatric diagnoses years before clinical diagnosis, suggesting a prolonged premotor phase. These results highlight opportunities for earlier diagnosis, further mechanistic research, and potential enrollment of at-risk individuals into early-stage clinical trials. © 2026 International Parkinson and Movement Disorder Society.