The levels of Neurofilament (Nf) proteins increase in cerebrospinal fluid (CSF) and blood when neuroaxonal damage occurs. This project will evaluate next generation Nf assays to determine whether peripheral Nf measures are sufficiently robust and reproducible to inform on the selection of patients in a clinical trial. The ultimate objective is to establish whether Nf measures in blood provide a prognostic biomarker (i.e., an indicator that predicts an outcome of a disease) to select individuals with Familial Frontotemporal Degeneration (f-FTD) mutations at high risk of converting to symptomatic disease. If qualified, this could be a tool to accelerate novel development of disease-modifying therapeutics to prevent or delay the onset of f-FTD symptoms.

FTD encompasses a range of disorders that impact the frontal and temporal lobes of the brain and progresses rapidly, inflicting high levels of neuroaxonal damage, which makes it a well-suited indication in which to validate blood-based Nf assays. Further, recent studies in f-FTD support neurofilament light (NfL) or phosphorylated neurofilament heavy (pNfH)as a prognostic marker of the conversion from asymptomatic to symptomatic status in gene mutation carriers. Understanding the performance of blood-based Nf assays in this context could speed development of therapeutics for FTD and potentially lay groundwork relevant to many other neurological disorders. As ALS patients have significantly high Nf levels, the inclusion in this project will inform on the assays’ ability to detect Nf at the highest levels.

This two-year project includes two stages with three sub aims each. Stage 1 includes the following Aims: Due Diligence; Reference Material and Procurement and Contracting; Stage 2 includes: Blood-based Validation in Normal Healthy Persons and Patients with ALS; Performance in Matched CSF; and Performance in f-FTD. Key project outputs include: identifying the highest performing NfL and pNfH assays; generating assay analytical performance characteristics in ALS and f-FTD patients and healthy persons; and further informing on the relationship between Nf in CSF and blood.