Plasma Proteomic Changes in GRN and C9orf72 Frontotemporal Dementia

Area of Science:

• Neuroscience
• Genetics
• Biomarker Discovery

Background:

• Genetic frontotemporal dementia (FTD) requires reliable biomarkers for therapeutic trial development.
• Identifying blood-based biomarkers is crucial for tracking disease pathophysiology.

Purpose of the Study:

• To identify blood biomarker candidates for genetic FTD using a multiplex panel of CNS proteins.
• To evaluate changes in CNS proteins in carriers of GRN and C9orf72 mutations.

Main Methods:

• Cross-sectional evaluation of 67 FTD mutation carriers (GRN, C9orf72) and 42 non-carriers.
• Measurement of 124 CNS-related proteins in plasma using the NULISA CNS panel.
• Analysis of group-level protein changes using linear and non-linear regression models.

Main Results:

• Neurofilament light (NfL) and neurofilament heavy (NfH) were significantly altered in both GRN- and C9orf72-FTD compared to non-carriers.
• Glial fibrillary acidic protein (GFAp) and vascular cell adhesion protein 1 (VCAM1) were exclusively altered in GRN-FTD, correlating with disease severity.
• Neuronal pentraxin receptor (NPTXR) was selectively reduced in C9orf72-FTD, with other inflammatory mediators also showing nominal changes.

Conclusions:

• Established biomarkers like NfL and NfH confirmed previous findings.
• Novel biomarker candidates, including GFAp, VCAM1, and NPTXR, were identified for genetic FTD.
• Validated biomarkers could expand the range of tools for assessing genetic FTD pathophysiology.