Novel CSF biomarkers for frontotemporal lobar degenerations

Area of Science:

• Neuroscience
• Biomarker Discovery
• Neuropathology

Background:

• Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disease with two main pathological subtypes: FTLD with TDP-43 pathology (FTLD-TDP) and FTLD with tau pathology (FTLD-tau).
• Distinguishing between these subtypes antemortem is crucial for accurate diagnosis and management, but current methods are limited.

Purpose of the Study:

• To identify novel cerebrospinal fluid (CSF) biomarkers for the antemortem differentiation of FTLD-TDP and FTLD-tau.
• To evaluate the diagnostic performance of these biomarkers in autopsy-confirmed and clinically diagnosed cohorts.

Main Methods:

• Collected CSF samples from patients with pathologically confirmed FTLD (autopsy cohort), healthy controls, Alzheimer's disease patients, and clinically diagnosed frontotemporal dementia (FTD) patients.
• Measured levels of 151 analytes, including neuropeptides, cytokines, and growth factors, using a targeted multiplex panel, alongside established Alzheimer's disease CSF biomarkers.

Main Results:

• Multiple CSF analytes, including Fas, specific neuropeptides, and chemokines, showed significant differences between FTLD-TDP and FTLD-tau groups.
• A random forest classification model achieved 86% sensitivity and 78% specificity for FTLD-TDP in the autopsy cohort.
• The classification algorithm showed promise in a living FTD cohort, with semantic dementia patients having the highest predicted FTLD-TDP proportion and behavioral variant FTD patients exhibiting distinct neuropsychological profiles based on predicted pathology.

Conclusions:

• Specific CSF analytes can potentially differentiate between FTLD-TDP and FTLD-tau pathology in living patients.
• These findings suggest a pathway towards developing accessible antemortem diagnostic assays for FTLD subtypes.