Skin-based test could improve diagnosis of debilitating neurodegenerative disease

Researchers at the University Health Network (UHN) and the University of Toronto have developed a skin-based test that can detect signature features of progressive supranuclear palsy (PSP), a rare neurodegenerative disease that affects body movements, including walking, balance and swallowing.

The test, which the researchers describe in a recent issue of JAMA Neurology, could allow for more accurate and faster PSP diagnosis than current methods.

“This assay is important for assigning patients to the correct clinical trials, but it will be even more important in the future as researchers develop targeted, precision treatments for PSP,” says Ivan Martinez-Valbuena, a scientific associate at the Rossy Progressive Supranuclear Palsy Centre at the UHN’s Krembil Brain Institute and U of T’s Tanz Centre for Research in Neurodegenerative Diseases.

“We need diagnostic tools to be developed hand-in-hand with new treatments, so that as these treatments become available, we can identify the patients who would benefit most.”

In neurodegenerative diseases, misfolded proteins – often alpha synuclein or tau proteins – accumulate in brain and nervous system cells, eventually damaging the cells and causing neurodegeneration. While researchers have successfully detected these misfolded proteins in cerebrospinal fluid obtained through a lumbar puncture, the technique is not always accessible and some patients are unable to undergo the procedure.

As a result, patients are typically diagnosed based on their symptoms and clinical presentation, so some patients may be misdiagnosed – particularly for rarer neurodegenerative diseases such as PSP. This could also have a negative impact on research since patients with PSP may be misdiagnosed with Parkinson’s disease and be included in a trial that targets the wrong protein, influencing the results. 

The research that led to the PSP breakthrough has roots in an earlier study. In previous research, Martinez-Valbuena and his colleagues developed a test that could detect misfolded alpha synuclein protein in the skin in patients with Parkinson’s. Researchers have since validated that assay and hope it can be used in clinical trials, although the test is not yet available for clinical diagnoses.

The team wanted to extend that test for use in PSP. Using the same technology as the alpha synuclein assay, the team developed a test that could detect a sequence of misfolded tau specific to PSP.

“Following a meticulous and innovative strategy, Ivan reported for the first time in the literature that disease-associated tau protein can be detected in the skin in living patients with high accuracy,” says Gabor Kovacs, Martinez-Valbuena’s supervisor, a neuropathologist at UHN and a principal investigator at the Tanz Centre who is also a professor of laboratory medicine and pathobiology in U of T’s Temerty Faculty of Medicine. 

Working collaboratively with colleagues in the Rossy PSP Centre, Martinez-Valbuena, Kovacs and a clinical team led by Anthony Lang – who is director of the Rossy Progressive Supranuclear Palsy Centre, the Lily Safra Chair in Movement Disorders at UHN and the Jack Clark Chair for Parkinson's Disease Research at U of T’s Temerty Faculty of Medicine – were able to access patient samples and validate the new test. 

When the researchers examined skin biopsies of patients with PSP as well as people with multiple system atrophy, corticobasal degeneration, Parkinson’s disease and healthy controls, they found misfolded tau in most patients with PSP, but much less frequently in other neurodegenerative diseases.

Importantly, the misfolded tau protein was not detected in patients with Parkinson’s disease or the healthy controls. Overall, the researchers found the assay had 90 per cent sensitivity and 90 per cent specificity. 

“I am so delighted to see this exciting development of a new biomarker for this rare neurodegenerative disease, made possible by the close collaboration of world-leading scientists in Toronto,” says Graham Collingridge, senior investigator at the Lunenfeld-Tanenbaum Research Institute at Sinai Health and director of the Tanz Centre.

Martinez-Valbuena says the test could be incorporated into a panel of blood- and skin-based tests, along with clinical information, to help clinicians make more precise diagnoses and recommend more appropriate clinical trials. 

“It will be important to pair this skin-based assay together with a patient’s clinical symptoms, and this will give us a much better picture of the patient’s diagnosis,” says Martinez-Valbuena. “Once we have precision treatments targeting these misfolded proteins, we will have a better idea of the treatment each patient should receive.”

Researchers are now validating the assay in more patients through a clinical trial at five PSP centres in North America and Europe. The Toronto team will continue to study the assay to ensure it is practical and convenient for use outside of major research centres.