A 2-Step Cerebrospinal Algorithm for the Selection of Frontotemporal Lobar Degeneration Subtypes

Area of Science:

• Neuroscience
• Biomarker Discovery
• Neurodegenerative Diseases

Background:

• Core Alzheimer disease (AD) cerebrospinal fluid (CSF) biomarkers are vital for in vivo AD detection.
• CSF phosphorylated tau (p-tau) levels correlate with tau pathology in frontotemporal lobar degeneration (FTLD), even with AD copathology.

Purpose of the Study:

• To develop an algorithm using core AD CSF measures to exclude AD pathology.
• To differentiate between FTLD-tau and FTLD transactive response DNA-binding protein of approximately 43kDa (FTLD-TDP).

Main Methods:

• A case-control study involving 1796 patients with neurodegenerative diseases and available CSF.
• Included autopsy-confirmed FTLD and AD cohorts, FTD mutation cohorts, and a living cohort with FTLD-predictive syndromes.
• Analyzed CSF amyloid β1-42 (Aβ1-42), total tau (t-tau), and p-tau using validated assays and algorithms.

Main Results:

• The p-tau/Aβ1-42 ratio demonstrated excellent accuracy (AUC, 0.98) in excluding AD in autopsy cohorts.
• CSF p-tau levels showed good accuracy (AUC, 0.87) in distinguishing FTLD-TDP from FTLD-tau.
• The developed algorithm successfully discriminated FTLD-TDP from FTLD-tau and mixed FTLD cases, validated in an independent cohort (AUC, 0.9).

Conclusions:

• CSF core biomarkers, when accounting for comorbid AD and genetic status, can identify pure FTLD-TDP and FTLD-tau in vivo.
• The algorithm shows high specificity for differentiating FTLD subtypes, aiding in diagnosis and management.