With the emergence of new disease-modifying therapies that target the specific proteins responsible for neurodegenerative diseases like Alzheimer disease and Parkinson disease (PD), the timing and accuracy of diagnosis are increasingly important. Published in Nature Medicine, a new study led by Drs. Anthony Lang and Ivan Martinez-Valbuena at UHN’s Krembil Brain Institute (KBI), introduces a diagnostic approach that combines multiple biomarkers—biological molecules, often proteins, that can signal disease—to better distinguish between PD and similar neurodegenerative conditions called parkisonian syndromes. This approach could support earlier and more accurate diagnosis, and better care for patients as a result.

The challenge in getting it right 

Current diagnostic methods often misclassify other parkinsonian syndromes, including progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), as PD because of overlapping symptoms. This challenge is especially pronounced in early disease stages, when distinguishing clinical features are not yet present. 

However, despite their similarities, these conditions are driven by different underlying proteins—and identifying which is key to improving diagnosis.

“Misdiagnosis means patients miss the opportunity to use disease-modifying therapies during the critical window in early disease stages when these treatments may have the greatest impact,” says Dr. Martinez-Valbuena, the first author of this study.

A new approach: combining multiple biomarkers

To address this issue, the KBI team developed a diagnostic protocol that integrates three biomarkers associated with parkinsonian syndromes: 4-repeat tau (4R-tau), neurofilament light chain (NfL), and α-synuclein. Each biomarker provides distinct information. α-synuclein identifies the abnormal protein build up seen in diseases like PD and MSA. 4R-tau signals the abnormal protein build up seen in PSP. NfL reflects the extent of damage to nerve cells. The new protocol uses a blood sample to measure NfL, and a single skin biopsy is to perform tests called seeding amplification assays (SAAs) to identify 4R-tau and α-synuclein. Although evaluation of α-synuclein is currently marketed diagnosis of PD, these diagnostic methods do not use SAAs.

The researchers first tested their approach in a sample of 166 participants—40 with PD, 77 with PSP, 29 with MSA, and 20 healthy controls. They then validated their findings in an independent cohort of 63 participants—35 with PD, 17 with PSP, nine with MSA, and two healthy controls. Participants in both groups varied in age and duration since disease onset.

Individually, each biomarker test showed high sensitivity and specificity. Skin tests detected α-synuclein in approximately 85% and 90% of people with PD and MSA, respectively, and 4R-tau in about 88% of people with PSP. Blood levels of NfL were lowest in healthy individuals and highest in people with MSA. The multimodal approach significantly outperformed the diagnostic accuracy—herein defined as the ability to correctly distinguish between MSA, PSP, and PD—of any single biomarker test on its own; receiving a performance score (AUC) of 0.96 for PD, 0.90 for MSA and 0.97 for PSP. AUC describes how well a model, the diagnostic protocol in this case, matches the data it is trying to explain. A perfect model has an AUC of 1.

Importantly, α-synuclein was found in about 23% of patients with PSP. This indicated that diagnostic testing that is limited to this protein, as some companies currently offer, is insufficient as it could misdiagnose PSP as PD.

Notably, the researchers also found that, in addition to better differentiating between PSP and other parkinsonian syndromes, combining biomarkers also enabled doctors to separate patients according to PSP severity. 

To further validate the method, the KBI team compared the results from their diagnostic protocol with findings from brain tissue analysis in a subset of 11 participants. The diagnosis made using the integrated protocol consistently matched brain tissue findings, providing strong real-world validation of the approach. Importantly, in 1 case clinically diagnosed as having PSP—where the individual’s skin SAA tested negative both 4R tau and α-synuclein—brain tissue analysis later revealed a diagnosis of Alzheimer disease. This alternative diagnosis validated the negative skin SAA results. 

A promising (and less invasive) path forward

While researchers emphasize that further testing is required—particularly in patients in earlier disease stages—the findings represent a promising advancement in the diagnosis of parkinsonian syndromes.

“Combining assessment of 4R-tau, NfL, and α-synuclein was a logical step,” says Dr. Lang, the study’s senior author. “These biomarkers complement each other—where one shows limitations, the others provide additional diagnostic value.”

“We are encouraged by the potential of this protocol to address gaps in the clinical evaluation of complex or unclear parkinsonian syndromes,” adds Dr. Martinez-Valbuena.

In addition to performance, the KBI team’s new diagnostic approach is also advantageous because it is less invasive than other approaches. The integrated approach uses a blood sample and one skin biopsy. This contrasts currently marketed testing for α-synuclein, which requires a cerebrospinal fluid sample obtained through a lumbar puncture or multiple skin biopsies. By simplifying sample collection and reducing reliance on specialized equipment and procedures, the integrated diagnostic protocol may make diagnostic testing more widely accessible.

For patients with PD, MSA, and PSP, earlier and more precise diagnosis could enable better disease management and, eventually, an improved quality of life. As new therapies continue to emerge, tools like this may help ensure patients receive the right care at the right time.

The first author of this study, Dr. Ivan Martinez-Valbuena, is a Scientific Associate at UHN’s Krembil Brain Institute.

The senior author of this study, Dr. Anthony E. Lang, is a Senior Scientist at UHN’s Krembil Brain Institute and a Professor at the University of Toronto's Temerty Faculty of Medicine and Institute of Medical Science. He is also the Lily Safra Chair in Movement Disorders, the Director of the Edmond J. Safra Program in Parkinson's Disease, Director of the Rossy PSP Centre, and the Jack Clark Chair for Parkinson’s Disease Research.

This work was supported by the Rossy Family Foundation, the Edmond J. Safra Philanthropic Foundation, the Maybank Foundation, the Blidner Family Foundation, Ajay Virmani, Jen Cerny, the Michael J. Fox Foundation for Parkinson’s Research., the Rainwater Charitable Foundation, the Bay Tree Foundation/Mohammad Al Zaibak Fellowships in Parkinson’s Disease, The Paul and Susan Hansen Foundation, the University Medical Center Goettingen-UMG Clinician Scientist Program, the Mohammad and Najla Al Zaibak Family Parkinson’s Disease Research Fund, the Fonds de Recherche du Québec Santé, and UHN Foundation.

Drs. Martinez-Valbuena, Kovacs, and Lang share a pending patent for movement disorders diagnostic assays, and Dr. Kovacs has a patent for the 5G4 synuclein antibody. 

Dr. Martinez-Valbuena received consulting fees from Ferrer and research funding from the Michael J. Fox Foundation for Parkinson’s Research outside of this work. 

Dr. Lang served as an advisor for AbbVie, Amylyx, Aprinoia, Biogen, BioAdvance, Biohaven, BioVie, BlueRock Therapeutics, Bristol Myers Squibb, Denali, EG427, Ferrer, Janssen, Lilly, Northera, Pharma 2B, Sun Pharma, UCB and Ventyx Bio. He also received honoraria from Sun Pharma and AbbVie and grants from Brain Canada, the Canadian Institutes of Health Research, the Michael J. Fox Foundation for Parkinson’s Research, the Parkinson Foundation, Parkinson Canada, and the Weston Foundation. Dr. Lang also serves as an expert witness in litigation related to paraquat and PD, and has received publishing royalties from Elsevier, Saunders, Wiley-Blackwell, Johns Hopkins Press, and Cambridge University Press.

For a full list of competing interests, see the publication.

Martinez-Valbuena I, Emamikhah M, Olszewska DA, Weber SK, Schnell S, Fereshtehnejad SM, Reyes NGD, Sousa M, Di Luca DG, Ta J, Anastassiadis C, Li J, Sasitharan J, Bhakta P, Visanji NP, Fox SH, Mollenhauer B, Tartaglia MC, Kovacs GG, Lang AE. Dermal α-Synuclein and 4R-Tau SAAs Combined with Serum NfL: Enhancing Diagnostic Precision in Neurodegenerative Parkinsonism. Nat Med. 2026 May 19. doi: 10.1038/s41591-026-04398-3