Investigating the role of neuroinflammation and brain clearance in frontotemporal lobar degeneration using 7T MRI and fluid biomarkers: protocol for a cross-sectional study in a tertiary care setting

Abstract

Introduction: Frontotemporal lobar degeneration (FTLD) is the second most common early-onset dementia. Several studies demonstrated that neuroinflammation and iron accumulation occur in FTLD. However, the timing and relevance of these processes and whether these two are merely cause or consequence remains unclear. Elucidating the role is crucial to assess the rationale for using anti-inflammatory therapies in FTLD. Additionally, the process of glymphatic brain clearance has gained attention as a potential contributor in the disease pathophysiology.

Methods and analysis: In this multimodal biomarker study, we use a combination of ultra-high field (7T) MR, blood and cerebrospinal fluid (CSF) biomarkers to investigate the role of neuroinflammation, iron accumulation and brain clearance in FTLD, and to identify biomarkers to differentiate FTLD-TDP from FTLD-tau. We aim to include 25 patients with probable FTLD-tau, 25 with probable FTLD-TDP and 50 healthy individuals with 50% risk to develop FTLD. We will use several MRI techniques, including magnetic resonance spectroscopy, diffusion weighted spectroscopy and quantitative susceptibility mapping. In addition, we will assess the prevalence of perivascular spaces (PVS) and the mobility of CSF to address glymphatic brain clearance. We will compare quantitative MR markers between patients with FTLD-tau and FTLD-TDP, presymptomatic mutation carriers and healthy controls, and correlate these measures with clinical data and biomarkers in blood and CSF.

Ethics and dissemination: We obtained ethical approval from the Medical Ethics Committee Leiden Den Haag Delft (NL78272.058.21). The results will be disseminated through presentations at national and international conferences, open-access peer-reviewed publications, ClinicalTrials.gov and to the public through social media posts and annual newsletters.

Study registration number: NCT06870838; Pre-results.

Keywords: Dementia; Neuroradiology.

Figure 1. Clinical, pathological and genetic spectrum of FTLD. Genetic forms have predictable pathology: GRN mutations and C9orf72 HRE show TDP-43 pathology, whereas MAPT mutations show tau pathology. In contrast, across the clinical spectrum of FTLD, variable underlying pathologies and genetic forms can be found. ALS, amyotrophic lateral sclerosis; bvFTD, behavioural variant FTD; C9orf72, chromosome 9 open reading frame 72; CBS, corticobasal syndrome; FET, FUS, Ewing sarcoma and TATA-binding protein-associated factor 15; FTD, frontotemporal dementia; FTLD, frontotemporal lobar degeneration; FUS, fused in sarcoma; GRN, progranulin; MAPT, microtubule associated protein tau; MND, motor neuron disease; nfvPPA, non-fluent variant primary progressive aphasia; PSP, progressive supranuclear palsy; svPPA, semantic variant primary progressive aphasia; TARDBP, transactive response DNA-binding protein; tau, tubulin associated unit; TBK-1, TANK-binding kinase 1; TDP-43, transactive response DNA-binding protein 43; TUBA4A, tubulin alpha 4A; VCP, vasolin-containing protein. Reprinted with permission from Prinse et al (2025). Copyright 2025, Springer Nature; Permission obtained through the Copyright Clearance Centre, Inc.

Figure 2. Flowchart of the study design. Clinical data and blood collection will be repeated after 1 year of follow-up. BDI, Beck’s depression inventory; CDR, clinical dementia rating; CSF, cerebrospinal fluid; CSF-STREAM, CSF-selective-T2 prepared Readout with Acceleration and Mobility Encoding; DMRS, diffusion weighted spectroscopy; FAB, frontal assessment battery; FTLD, frontotemporal lobar degeneration; LACC, lateral anterior cingulate cortex; MOCA, Montreal Cognitive Assessment; MRS, magnetic resonance spectroscopy; NFL, neurofilament light chain; NPI, neuropsychiatric inventory; PSP-RS, progressive supranuclear palsy rating scale; tau, tubulin associated unit; TDP, transactive response DNA-binding protein; UPDRS, Unified Parkinson’s Disease Rating Scale.