Glymphatic dysfunction, plasma neurofilament light, and cortical free water mediate cognitive decline in familial frontotemporal lobar degeneration.

Abstract

Background: Familial frontotemporal lobar degeneration (f-FTLD) is the second most common form of young-onset dementia, with diverse clinical presentations, neuropathological substrates and genetic backgrounds. While evidence suggests that glymphatic dysfunction, neuroaxonal injury, and cortical microstructural alterations may jointly contribute to f-FTLD, their interrelationships across genotypes remain unclear.

Objectives: This study aims to investigate the roles of glymphatic dysfunction, cortical free water (cFW), and plasma neurofilament light (NfL) in f-FTLD and examine their relationship with cognitive decline.

Design: A multimodal approach was applied, involving diffusion tensor imaging along the perivascular space (DTI-ALPS) for glymphatic function, plasma NfL measurement, and voxel-wise cortical free water mapping. Analyses comparing FTLD mutation groups and serial mediation analyses were conducted in 322 participants (C9orf72, GRN, MAPT mutation carriers, and matched controls).

Setting: This study was conducted across multiple participating centers using standardized imaging protocols and harmonized multi-site data.

Participants: A total of 322 participants were included: 87 C9orf72 expansion carriers, 56 GRN mutation carriers, 58 MAPT mutation carriers, and 121 healthy controls.

Intervention: No intervention was applied in this observational study. Participants underwent genetic testing, cognitive assessment, and diffusion MRI scans; plasma NfL was available for mutation carriers.

Measurements: Glymphatic function was assessed using DTI-ALPS, plasma NfL levels were measured to reflect neuroaxonal injury, and cortical microstructure was assessed through cortical free water (cFW) mapping.

Results: Significant reductions in DTI-ALPS and elevations in cFW were observed in C9orf72 and GRN mutation carriers, with strong associations to clinical cognitive decline. Plasma NfL levels were highest in GRN mutation carriers and correlated strongly with cognitive severity. Mediation analysis indicated that the pathway linking DTI-ALPS to cognition through NfL explained a substantial portion of the indirect effect, while residual direct effects suggested that additional mechanisms also contribute to cognitive decline.

Conclusions: This study identifies glymphatic dysfunction as a key factor contributing to cognitive decline in f-FTLD, with plasma NfL serving as an important partial mediator and cFW providing additional region-specific information.