Tau Tangling Speed May Predict Progression in PSP and Other Dementias

Many people who develop balance issues, muscle stiffness, and movement problems as they age initially are diagnosed with Parkinson’s. But some have a rarer neurodegenerative disease called progressive supranuclear palsy (PSP) which affects up to 30,000 Americans. PSP shares many symptoms with Parkinson’s but progresses faster and affects eye movements, leads to cognitive changes early on, and involves an accumulation of tau tangles.

A recent study published in Nature Communications adds more complexity: It turns out there might be different molecular processes in PSP that determine whether the disease will progress fast or slow. 

“When the patient goes to the doctor, it is very difficult to predict the prognosis,” senior study author Dr. Gabor Kovacs, a neuropathologist at the University Health Network and professor at the University of Toronto, told Being Patient. 

The behavior of tau proteins could help divide people with PSP into groups by how fast their disease might progress, and provides more evidence that neurodegenerative diseases, including Alzheimer’s, might have multiple subtypes when scientists look closer.  

Untangling tau in PSP 

Researchers autopsied the brains of 25 people with PSP to map their tau. There are six different tau proteins, called isoforms. Half of them have molecular segments that repeat three times, known as 3R, and the other half with segments that repeat four times, known as 4R.

In Alzheimer’s, there’s a mix of tau tangles made of 3R and 4R tau. In PSP, the situation is unique: All the tau tangles consist solely of 4R tau. When one 4R protein misfolds into a tangle, it interacts with other healthy 4R tau, but not 3R tau, making it misfold through a process called “seeding.”

“We noticed that those patients who have a very short duration of illness have a very rapid seeding of the bad tau molecule,” said Kovacs. Their tau formed bigger, tangled clumps that spread faster, speeding up the neurodegeneration. 

Kovacs and his team also used techniques called proteomics and transcriptomics to see if fast and slow seeders had different levels of proteins and genes activated in their brains. They saw that there were many differences between those who progressed quickly and those who progressed slowly. 

Why measuring tau seeding matters

When someone goes to the hospital with pneumonia, doctors use molecular testing to distinguish between different viral and bacterial infections that might cause the symptoms. Different infectious agents require their own treatments. UCSF neurologist Dr. Julio Rojas, who wasn’t involved in the study, told Being Patient that this idea applies to PSP as well.

“What we are learning is that not every PSP patient is the same,” said Rojas. “They have different trajectories.” 

Developing biomarkers might allow doctors to diagnose PSP faster and more accurately — some 60 percent of patients report being misdiagnosed — and gain more insight into their disease trajectory. Biomarkers like pTau-217 and pTau-181 could help confirm plaques and tangles in Alzheimer’s, but don’t work for PSP where the tau is different. In some studies, the levels decrease within this patient population.

Kovacs and his colleagues are developing a skin biopsy test that could detect the 4R tau that is specific to PSP and can tell researchers and doctors how fast the disease may progress. 

These biomarkers could soon support clinical trials for drugs targeting specific species of tau. 

“We are now conducting a multicenter international study that includes the United States, Canada, and Europe,” said Kovacs. 

In two years, if they show that the test works, it could be rolled out across trials and specialty clinics, he said. The team is also working on a similar test to spot the signs of dementia with Lewy bodies, opening the door for a more thorough assessment of dementia in living patients who often have multiple forms of the disease at once. 

These biomarkers could also help confirm PSP for clinical trials of new medications. While anti-tau drugs are the leading candidates, Kovacs advocates for complementary approaches that also address the factors that might cause the disease in the first place, such as immune system problems or mitochondrial toxins.