Biomarkers.

Area of Science:

• Neuroscience
• Neurology
• Gerontology

Background:

• Sporadic frontotemporal dementia (FTD) presents with varying onset ages, impacting younger (early-onset FTD, eoFTD) and older (late-onset FTD, loFTD) individuals.
• Mechanisms underlying age-dependent FTD onset and progression remain unclear.
• Investigating differences in neurodegeneration, microglial activation, and vascular factors may elucidate distinct FTD subtypes.

Purpose of the Study:

• To compare neurodegenerative markers, microglial activation, and vascular comorbidities between eoFTD and loFTD.
• To determine the impact of these factors on longitudinal cognitive decline in each FTD subgroup.
• To identify potential FTD-specific mechanisms driving differential vulnerability.

Main Methods:

• Analyzed cerebrospinal fluid (CSF) biomarkers (amyloid-β42, tau, NfL, sTREM-2) and vascular scores (VS) in 52 sporadic FTD patients (28 eoFTD, 24 loFTD).
• Assessed blood-brain barrier permeability using albumin quotient (Qalb).
• Utilized multivariate regression to associate CSF NfL, sTREM-2, VS, and Qalb with cognitive decline (ΔMMSE) over 18 months.

Main Results:

• No significant differences in CSF biomarkers, sTREM-2, Qalb, or VS between eoFTD and loFTD.
• A trend towards higher CSF NfL in loFTD versus eoFTD (p=0.061).
• CSF NfL negatively associated with cognitive decline (ΔMMSE) in the overall cohort (p=0.005), with a stronger effect in eoFTD (p=0.011) but not loFTD.

Conclusions:

• CSF NfL shows a stronger association with cognitive decline in eoFTD compared to loFTD.
• This may indicate greater neurodegeneration susceptibility or a more direct link to cognitive impairment in younger FTD patients.
• FTD-specific mechanisms, rather than vascular factors or blood-brain barrier integrity, may drive cognitive decline, warranting further investigation.