HMN 2026: How Subtle health changes may signal progressive supranuclear palsy years in advance

Drawing from UK Biobank data, Mass General Brigham researchers have uncovered specific health factors linked to higher or lower risk of developing progressive supranuclear palsy (PSP), a rare but devastating neurological disease. Weige “Charlie” Zhao, MD, and Anne-Marie Wills, MD, MPH, of the Mass General Brigham Neuroscience Institute, are the lead and senior authors of a paper published in Movement Disorders, titled “Risk Factors for the Diagnosis of Progressive Supranuclear Palsy in the UK Biobank.”

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.

Mass General Brigham researchers set out with a straightforward question: What are the risk factors for developing PSP? They 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.

The researchers 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.

Using UK Biobank data—a large health study that followed more than 500,000 adults in the United Kingdom for close to 20 years—the team found 240 people who were later diagnosed with PSP. Their health habits, medical histories and living environments were compared to those of their healthy counterparts using a careful, step-by-step statistical method that tested many possible risk factors.

The researchers also checked how far back in time each risk factor could be detected to ensure they were finding true early warning signs, rather than symptoms of PSP that had already started.

The investigators 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, say the researchers, 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.

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.

The link between cancer and lower PSP risk really stood out to the 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.

The team was also struck by the fact that depression showed up as a warning sign a full 10 years before PSP diagnosis. That informed them the disease may stealthily affect brain circuits involved in mood long before anyone notices problems with movement or balance.

This pushes the team to look for ways to detect PSP during this hidden early phase, when future treatments could potentially have the biggest impact.

The content is provided for information purposes only.