Neuroinflammation in FTLD

Neuroinflammation in Frontotemporal Lobar Degeneration - a Multimodal Biomarker Study

The goal of this observational study is to investigate the role of neuroinflammation in frontotemporal lobar degeneration (FTLD). The main aims of this study are:

1. To elucidate the role and timing of neuroinflammation in FTLD by using a combination of clinical measures, 7T MRI, and CSF biomarkers;
2. To differentiate FTLD-TDP and FTLD-tau during life using biomarkers for neuroinflammation;
3. To identify biomarkers to predict and monitor disease progression in FTLD;

Secondary aim:

1. To explore the role of brain clearance in the disease process of FTLD.

Participants will undergo 7T MRI scans, blood and CSF collection, clinical, neurological, and neuropsychological evaluation.

Study Overview

• Status: Active, not recruiting
• Conditions: Behavioral Variant Frontotemporal Dementia (bvFTD); Frontotemporal Lobar Degeneration (FTLD); Primary Progressive Aphasia(PPA); Progressive Supranuclear Palsy(PSP); Corticobasal Syndrome(CBS)
• Intervention / Treatment: Diagnostic test: Blood withdrawal; Diagnostic test: 7T MRI scan; Diagnostic test: CSF; Diagnostic test: Neuropsychological assessment; Diagnostic test: Clinical measures

Detailed Description

At baseline, the study will involve the following procedures: clinical assessment including neurological and neuropsychological investigation, blood sampling, and a voluntarily lumbar puncture on the first day at the Erasmus MC University Medical Center, (EMC) and two sessions of 7T MRI scanning on the second day at the Leiden University Medical Center (LUMC). After one year, clinical assessment and blood analyses will be repeated in the EMC to assess disease progression. The aim is to include 25 patients with probable or definite FTLD-tau, 25 patients with probable or definite FTLD-TDP, 50 healthy individuals with 50% risk to carry a mutation in MAPT or GRN, or the C9orf72 HRE. If necessary for age matching, 10 additional healthy subjects without increased risk of FTLD will be included.

• Study Type: Observational
• Enrollment (Estimated): 110

Contacts and Locations

Study Locations

• Netherlands
  • Leiden, Netherlands
    • Leiden University Medical Center
  • Rotterdam, Netherlands, 3015GE
    • Erasmus MC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Patients with probable FTLD-tau (n =25) are defined as a clinical diagnosis of PSP, CBS, or nfvPPA, or any clinical FTLD spectrum diagnosis with a proven MAPT mutation. In patients with CBS or nfvPPA, CSF analyses and genetic screening will be used to rule out underlying AD pathology or having a pathogenetic variant causing FTLD-TDP pathology. Patients with probable FTLD-TDP (n=25) are indicated by either a clinical diagnosis of svPPA, FTLD-ALS or any clinical FTLD spectrum diagnosis with a proven GRN mutation or C9orf72 HRE.

At-risk individuals (n=50) will be recruited through our ongoing FTD-RisC project. These individuals have no clinical signs of an FTLD phenotype, but have a first degree relative with genetic FTLD. These subjects have 50% risk to carry one of the genetic variants. Through anonymous genetic screening, this group will be divided into presymptomatic mutation carriers and healthy individuals. If necessary for age-matching, 10 healthy controls will be included.

Description

Inclusion Criteria:

• Ability to undergo MRI scanning
• For probable FTLD-tau: a clinical diagnosis of PSP, CBS or nfvPPA, or any clinical FTLD spectrum diagnosis with a proven MAPT mutation
• For probable FTLD-TDP: a clinical diagnosis of svPPA or any clinical FTLD spectrum diagnosis with a proven GRN mutation or C9orf72 repeat expansion
• For presymptomatic mutation carriers: a MAPT mutation, GRN mutation or a C9orf72 mutation without clinical sign of a FTLD spectrum phenotype (CDR 0) For control subjects: no known neurological or psychiatric disorder
• For controls: no known neurological or psychiatric disorder

Exclusion Criteria:

• Other neurological or psychiatric disorder that may affect cognitive functions, such as a brain tumour, multiple sclerosis or drug or alcohol abuse or use of psycho-active medications
• CSF profile (β-amyloid, p-tau, t-tau) suggestive of AD pathology
• Clinical dementia Rating Scale (CDR) score >1
• Contra-indication to undergo MRI
• Contra-indication to undergo lumbar puncture

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients with probable FTLD-tau; clinical diagnosis of PSP, CBS, or nfvPPA, or any clinical FTLD spectrum diagnosis with a proven MAPT mutation	Diagnostic test: Blood withdrawal; Blood is collected by doing a blood withdrawal; Diagnostic test: 7T MRI scan; MRI-scanning of the brain using a 7T MRI scanner; Diagnostic test: CSF; CSF collection via lumbar puncture; Diagnostic test: Neuropsychological assessment; Tests for memory, language, attention, executive functions, praxis, social cognition, visuoconstructive skills; Diagnostic test: Clinical measures; Medical history, neurological assessment, neuropsychiatric inventory
Patients with probable FTLD-TDP; a clinical diagnosis of svPPA, FTLD-ALS or any clinical FTLD spectrum diagnosis with a proven GRN mutation or C9orf72 HRE	Diagnostic test: Blood withdrawal; Blood is collected by doing a blood withdrawal; Diagnostic test: 7T MRI scan; MRI-scanning of the brain using a 7T MRI scanner; Diagnostic test: CSF; CSF collection via lumbar puncture; Diagnostic test: Neuropsychological assessment; Tests for memory, language, attention, executive functions, praxis, social cognition, visuoconstructive skills; Diagnostic test: Clinical measures; Medical history, neurological assessment, neuropsychiatric inventory
At-risk individuals; Healthy individuals with a first degree relative with a MAPT or GRN mutation or C9orf72 HRE. These subjects therefore all have a 50% risk to carry one of these genetic variants and develop FTLD later in life.	Diagnostic test: Blood withdrawal; Blood is collected by doing a blood withdrawal; Diagnostic test: 7T MRI scan; MRI-scanning of the brain using a 7T MRI scanner; Diagnostic test: CSF; CSF collection via lumbar puncture; Diagnostic test: Neuropsychological assessment; Tests for memory, language, attention, executive functions, praxis, social cognition, visuoconstructive skills; Diagnostic test: Clinical measures; Medical history, neurological assessment, neuropsychiatric inventory
Healthy controls; Healthy individuals without increased risk to develop FTLD	Diagnostic test: Blood withdrawal; Blood is collected by doing a blood withdrawal; Diagnostic test: 7T MRI scan; MRI-scanning of the brain using a 7T MRI scanner; Diagnostic test: CSF; CSF collection via lumbar puncture; Diagnostic test: Neuropsychological assessment; Tests for memory, language, attention, executive functions, praxis, social cognition, visuoconstructive skills; Diagnostic test: Clinical measures; Medical history, neurological assessment, neuropsychiatric inventory

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MR Spectroscopy in the lateral anterior cingulate cortex	MR Spectroscopy data analysis in a single volume of interest in the lateral anterior cingulate cortex to assess changes in metabolites related to neurodegeneration and neuroinflammation. The analysis in LCModel will give us metabolite concentrations for total N-acetyl-aspertate (tNAA), glutamate (Glu), myo-inositol (mI), and total choline compound (tCho).	At baseline
Diffusion weighted MR spectroscopy in the lateral anterior cingulate cortex	Diffusion weighted MR Spectroscopy data analysis in a single volume of interest in the lateral anterior cingulate cortex to assess changes in the apparent diffusion coefficients of specific metabolites related to neurodegeneration and neuroinflammation. The analysis done in LCModel will give us metabolite apparent diffusion coefficients for total N-acetyl-aspertate (tNAA), glutamate (Glu), myo-inositol (mI), and total choline compound (tCho).	At baseline
Quantitative susceptibility mapping for iron localization and quantification	Cross-sectional MR analysis to determine iron accumulation in the brain. The analysis will be performed with the SEPIA toolbox to obtain quantitative susceptibility values in various brain regions.	At baseline
Neurodegeneration biomarkers in blood	Biomarkers for neurodegeneration (neurofilament light chain (NFL), total tau) in blood.	At baseline
Neurodegeneration biomarkers in CSF	Biomarkers for neurodegeneration (neurofilament light chain (NFL), total tau) in CSF.	At baseline
Neuroinflammation biomarkers in CSF	Biomarkers for neuroinflammation (YKL-40, TREM-1, TREM-2, IL-1, IL-6, TNF-α, GFAP, CHIT1) in CSF.	At baseline
Iron accumulation biomarkers in blood	Biomarkers for iron accumulation ( ferritin, and iron) in blood.	At baseline
Iron acccumulation biomarkers in CSF	Biomarkers for iron accumulation (transferritin, ferritin, and iron) in CSF.	At baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical and neuropsycological evaluation: Clinical dementia rating scale	Cognitive and neuropsychological assessments for clinical dementia rating scale (CDR) to assess the cognitive functioning of the participant. The CDR is a combination score including multiple neuropsychological functioning on multiple domains (memory, language, attention, executive function, praxis, social cognition, and visuoconstructive skills) and clinical evaluation. A score of 0 means not impaired or no symptoms, a score of 0.5 means prodromal, and a score of 1 and higher (up to 3) reflects a symptomatic individual.	At baseline and 1 year follow-up
Clinical and neuropsycological evaluation: Montreal Cognitive Assessment	Cognitive and neuropsychological assessments for Montreal Cognitive Assessment (MoCA) to assess the cognitive functioning of the participant. A total score of 30 can be obtained. A higher score reflects a better performance. The cut-off point for a normal score is 26. A score lower than 26 reflects impairments or one or more cognitive domains.	At baseline and 1 year follow-up
Clinical evaluation: Parkinson's Disease Rating Score	Neurological examination for Unified Parkinson's Disease rating score (UPDRS). The score will be between 0 and 260, with a lower score indicating no symptoms and a total score of 260 indicating all symptoms.	At baseline and 1 year follow-up
Clinical evaluation: Neuropsychiatric assessment	Neuropsychiatric examination with the neuropsychiatric inventory (NPI) to assess psychiatric symptoms. The NPI has a total score range of [0, 144], with a higher score indicating more neuropsychiatric symptoms. A NPI score higher than 0 indicates the presence of one or more symptoms, a score of 4 or higher indicates moderate symptoms.	At baseline and 1 year follow-up

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
7T MR markers for brain clearance: CSF mobility	Assessment of the CSF mobility in the perivascular spaces throughout the brain using a T2-weighted scan and diffusion weighted scans.	At baseline
7T MRI markers for brain clearance: prevalance of perivascular spaces	In this analysis, the visible perivascular spaces on a T2-weighted scan (0.6 x 0.6 x 0.6 mm) will be counted and their volume will be calculated to assess changes in the different groups.	At baseline
Markers for brain clearance: CSF	Levels of total tau and AQP4	At baseline

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Collaborators: Erasmus Medical Center

Publications and helpful links

General Publications

• Prinse FAM, van der Weerd L, van Swieten JC, Ronen I, Seelaar H, Hirschler L, Najac C, Dopper EGP. 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. BMJ Open. 2025 Aug 3;15(8):e102668. doi: 10.1136/bmjopen-2025-102668.

Study record dates

Study Major Dates

• Study Start (Actual): July 25, 2023
• Primary Completion (Actual): August 1, 2025
• Study Completion (Estimated): August 1, 2026

Study Registration Dates

• First Submitted: February 3, 2025
• First Submitted That Met QC Criteria: March 10, 2025
• First Posted (Actual): March 11, 2025

Study Record Updates

• Last Update Posted (Estimated): September 11, 2025
• Last Update Submitted That Met QC Criteria: September 4, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Neuroinflammation; Neurodegeneration; Blood; MRS; Iron accumulation; QSM; 7T-MRI; CSF; Frontotemporal lobar degeneration; dMRS
• Additional Relevant MeSH Terms: Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Pathologic Processes; Metabolic Diseases; Neurobehavioral Manifestations; Neurocognitive Disorders; Inflammation; Eye Diseases; Dementia; Tauopathies; Neurodegenerative Diseases; Movement Disorders; Basal Ganglia Diseases; Cranial Nerve Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Communication Disorders; Ophthalmoplegia; Ocular Motility Disorders; Paralysis; Language Disorders; Aphasia; Speech Disorders; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Neuroinflammatory Diseases; Corticobasal Degeneration; Aphasia, Primary Progressive; Frontotemporal Lobar Degeneration; Supranuclear Palsy, Progressive; Nerve Degeneration
• Other Study ID Numbers: P21.090

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No