Ultrasensitive test detects protein clumps to diagnose rare dementia subtype

Dementia affects over 57 million people worldwide, a number expected to nearly double in the next 20 years. This permanent loss of cognitive abilities affects daily function and can be caused by multiple brain pathologies, including well known ones like Alzheimer's disease (AD). Right now, biomarkers permit diagnosis of AD but not rarer pathologies like frontotemporal lobar degeneration (FTLD) or its subtypes. Investigators from Mass General Brigham developed an ultrasensitive test capable of detecting abnormal clumps of a protein called TDP-43, which defines a specific subtype of FTLD pathology called FTLD-TDP.

Findings, published in Alzheimer's & Dementia: The Journal of the Alzheimer's Association, could help better diagnose dementia patients with the correct pathology, improving research and drug development.

"In this study, we found elevated concentrations of a biomarker that correlates with FTLD-TDP disease severity," said co-senior author David R. Walt, PhD, of the Mass General Brigham Department of Pathology. Walt is also a core faculty member of the Wyss Institute at Harvard University, associate member at the Broad Institute, and a Howard Hughes Medical Institute professor. "This is just a first step, but it's an important one because it gives us something measurable. Our vision is to create a test to diagnose patients, monitor treatment efficacy in clinical trials, and follow patient progression."

The study represents a collaboration between investigators with deep expertise in pathology and neurology.

Much more work is needed to validate this test rigorously, but this study establishes a framework for developing better tools for diagnosing this devastating disease and monitoring molecular pathology among patients with FTLD. Our test is one of several in development across the world which show promise in eventually giving FTD patients an accurate diagnosis, which is necessary for developing an accurate treatment."

Andrew M. Stern, MD, PhD, co-senior author, principal investigator with Mass General Brigham Neuroscience Institute

Neurologists have learned that a patient's constellation of symptoms alone does not always predict what their microscopic molecular brain changes are. Diagnosis often requires a "biomarker" test that can diagnose this underlying dementia-causing molecular pathology. However, there has been no way for doctors to distinguish between different subtypes of FTLD pathology, all of which progressively impair patients' behavior, emotional regulation, verbal expression, and organization.

Current diagnostic tools for FTLD include imaging tests that can help determine if the brain is degenerating but do not differentiate the molecular pathology. To develop a biomarker specific to FTLD-TDP, researchers adapted a strategy they have previously used to detect misfolded alpha-synuclein, which underlies Parkinson disease pathology. This "digital seed amplification assay" (dSAA) separates a patient's cerebrospinal fluid (CSF) into tiny, nano-liter-sized compartments and digitally counts the number of TDP-43 protein "seeds" they contain under a microscope.

The researchers analyzed 30 CSF samples from individuals with FTLD-TDP and 10 from healthy controls. Those with FTLD-TDP had higher concentrations of TDP-43 seeds. Importantly, seed levels correlated with disease severity-the more severe the patient's symptoms, the more seeds the test detected. The findings highlight the dsAA's potential as a diagnostic tool, which can help recruit patients more accurately for clinical trials and track treatment efficacy or disease progression over time.

The study is limited by its small number of participants, lack of ability to confirm diagnoses of FTLD-TPD on autopsy, and lack of comparison to groups with other types of dementia. Larger studies incorporating diverse neurodegenerative pathologies and long-term follow-up, including gold-standard diagnostic autopsy, can help validate the dSAA's specificity for detecting FTLD-TPD and advance potential research and clinical applications.