Skin-based test may allow better diagnosis of rare but debilitating neurodegenerative disease

Researchers at the University of Toronto have developed a skin-based test that can detect signature features of progressive supranuclear palsy (PSP), pointing toward the potential for a minimally invasive diagnostic test.

Such a test, which the researchers describe in a recent issue of JAMA Neurology, could allow for PSP diagnosis with greater specificity, and earlier 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 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 protein — often alpha synuclein or tau protein — accumulates in brain and nervous system cells, eventually damaging the cells and causing neurodegeneration.

Researchers have successfully detected these misfolded proteins in cerebrospinal fluid obtained through a lumbar puncture. However, this technique is not always accessible, and some patients are unable to undergo the procedure.

Patients are typically diagnosed based on their symptoms and clinical presentation, but this means that some patients may be misdiagnosed, especially for rarer diseases such as PSP.

For example, some patients with PSP could currently be diagnosed with Parkinson’s disease and included in a trial that targets the alpha synuclein protein — which could influence the results of the trial.

In previous research, Martinez-Valbuena and his colleagues developed a test that could detect misfolded alpha synuclein protein in the skin — specifically the nerves found in the skin — of people with Parkinson’s disease.

Researchers have validated that assay, and they hope it can be used in clinical trials, but the test is not yet available for clinical diagnoses.

The team wanted to extend that test for use in PSP, which is caused by misfolded tau protein and has no treatment, although some symptoms can be managed with treatments for other diseases such as Parkinson’s.

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 and a principal investigator at the Tanz Centre, who is also a professor of laboratory medicine and pathobiology at U of T’s Temerty Faculty of Medicine and a neuropathologist at University Health Network.

Working collaboratively with colleagues in the Rossy PSP Centre at, Martinez-Valbuena, Kovacs and the clinical team led by Anthony Lang were able access patient samples and validate the new test.

When the researchers examined skin biopsies of patients with PSP as well as 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, this misfolded tau was not detected in patients with Parkinson’s disease or the healthy controls. Overall, they 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, director of the Tanz Centre.

Martinez-Valbuena says the test could be incorporated into a panel of blood- and skin-based tests, together 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 many more patients through a clinical trial at five PSP centres in North America and Europe, and the Toronto team will continue to study the assay to ensure it is practical and convenient for use outside of major research centres.