Journal Article

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

Ronen, Itamar, Najac, Chloé, Dopper, Elise G P, van Swieten, John C, Hirschler, Lydiane, van der Weerd, Louise, Seelaar, Harro, Prinse, Fieke A M

2025

Overview

IntroductionFrontotemporal 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 analysisIn 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 disseminationWe 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 numberNCT06870838; Pre-results.

• Publisher: British Medical Journal Publishing Group,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Aged / Alzheimer's disease / Amyotrophic lateral sclerosis / Aphasia / Biomarkers / Biomarkers - blood / Biomarkers - cerebrospinal fluid / Brain / Brain - diagnostic imaging / Brain - metabolism / Cross-Sectional Studies / Dementia / Ewings sarcoma / Female / Frontotemporal Lobar Degeneration - cerebrospinal fluid / Frontotemporal Lobar Degeneration - diagnostic imaging / Frontotemporal Lobar Degeneration - metabolism / Humans / Iron / Iron - metabolism / Kinases / Magnetic resonance imaging / Magnetic Resonance Imaging - methods / Male / Metabolites / Middle Aged / Mortality / Motor neurone disease / Multicenter Studies as Topic / Mutation / Neuroinflammatory Diseases - diagnostic imaging / Neurology / Neuroradiology / Observational Studies as Topic / Pathology / Proteins / Protocol / Semantics / Spectrum analysis / Tertiary Care Centers