Investigating the Role of Neuroinflammation and Brain Clearance in Frontotemporal Lobar Degeneration using 7T MRI and Biofluid Markers: Protocol for an observational cross-sectional cohort study

Introduction

Frontotemporal lobar degeneration (FTLD) is the second most common early-onset dementia. Several studies demonstrated that neuroinflammation and iron accumulation occurs 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) MRI, 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 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.

Trial registration number

This study is registered on ClinicalTrials.gov ( NCT06870838 ).

Strengths and Limitations of this study

• The first study using 7T MR in the full spectrum of both presymptomatic and symptomatic genetic and sporadic FTLD.

• This study will provide valuable insights in the role of neuroinflammation, iron accumulation, and brain clearance and their role in the disease process of FTLD.

• Multimodal approach using MR and biofluid biomarkers, clinical, neurological, neuropsychological, and neuropsychiatric evaluation.

• No evaluation of the progression of MR and CSF biomarkers due to the cross-sectional design, however, we do perform clinical follow-up.

• The rarity of some specific mutations could result in too small subgroups for sub analyses for each type of mutation separately, but we hope to undermine this issue with the multicenter data inclusion and acquisition.