Digital seed amplification assay for TDP-43 aggregate quantification in CSF.

Area of Science:

• Neuroscience
• Biochemistry
• Medical Diagnostics

Background:

• Dementia is often caused by misfolded protein aggregates.
• Distinct dementia subtypes share symptoms, complicating diagnosis without biomarkers.
• Misdiagnosis in clinical trials hinders effective drug development for dementia.

Purpose of the Study:

• To develop a precise method for quantifying TDP-43 seeds in cerebrospinal fluid (CSF).
• To establish a sensitive diagnostic tool for frontotemporal dementia with TDP-43 pathology (FTLD-TDP).

Main Methods:

• Developed a digital Seed Amplification Assay (dSAA).
• dSAA isolates individual protein aggregates in nanoliter compartments for quantification.
• Assayed TDP-43 seeds in CSF samples from FTLD-TDP patients and healthy controls.

Main Results:

• Elevated TDP-43 seed concentrations were detected in FTLD-TDP patients.
• Seed concentrations correlated with disease severity.
• Demonstrated dSAA's potential as a sensitive diagnostic tool.

Conclusions:

• Introduced a novel quantitative, high-sensitivity digital assay for TDP-43 seeds in CSF.
• The assay offers single-aggregate resolution and a low limit of detection (LOD).
• Established a foundation for diagnostic and monitoring tools for FTLD-TDP and other TDP-43 proteinopathies.