Neuroinflammation in FTLD

NCT06870838 | Active Not Recruiting

• 1 other identifier: P21.090
• Study Type: observational
• Target: 110
• Locations: 1 country
• Sites: 2

Brief Summary

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

Conditions

Corticobasal Syndrome(CBS); Primary Progressive Aphasia(PPA); Progressive Supranuclear Palsy(PSP); Behavioral Variant Frontotemporal Dementia (bvFTD); Frontotemporal Lobar Degeneration (FTLD)

Keywords

Frontotemporal lobar degeneration; Iron accumulation; 7T-MRI; Neurodegeneration; Neuroinflammation; QSM; CSF; Blood; MRS; dMRS

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (4)

• Clinical and neuropsycological evaluation: Clinical dementia rating scale

  At baseline and 1 year follow-up

• Clinical and neuropsycological evaluation: Montreal Cognitive Assessment

  At baseline and 1 year follow-up

• Clinical evaluation: Parkinson's Disease Rating Score

  At baseline and 1 year follow-up

• Clinical evaluation: Neuropsychiatric assessment

  At baseline and 1 year follow-up

Other Outcomes (3)

• 7T MR markers for brain clearance: CSF mobility

  At baseline

• 7T MRI markers for brain clearance: prevalance of perivascular spaces

  At baseline

• Markers for brain clearance: CSF

  At baseline

Study Arms (4)

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: 7T MRI scan; Diagnostic Test: CSF; Diagnostic Test: Blood withdrawal; Diagnostic Test: Neuropsychological assessment; Diagnostic Test: Clinical measures

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: 7T MRI scan; Diagnostic Test: CSF; Diagnostic Test: Blood withdrawal; Diagnostic Test: Neuropsychological assessment; Diagnostic Test: Clinical measures

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: 7T MRI scan; Diagnostic Test: CSF; Diagnostic Test: Blood withdrawal; Diagnostic Test: Neuropsychological assessment; Diagnostic Test: Clinical measures

Healthy controls

Healthy individuals without increased risk to develop FTLD

Diagnostic Test: 7T MRI scan; Diagnostic Test: CSF; Diagnostic Test: Blood withdrawal; Diagnostic Test: Neuropsychological assessment; Diagnostic Test: Clinical measures

Interventions

7T MRI scan DIAGNOSTIC_TEST

MRI-scanning of the brain using a 7T MRI scanner

At-risk individuals; Healthy controls; Patients with probable FTLD-TDP; Patients with probable FTLD-tau

CSF DIAGNOSTIC_TEST

CSF collection via lumbar puncture

At-risk individuals; Healthy controls; Patients with probable FTLD-TDP; Patients with probable FTLD-tau

Blood withdrawal DIAGNOSTIC_TEST

Blood is collected by doing a blood withdrawal

At-risk individuals; Healthy controls; Patients with probable FTLD-TDP; Patients with probable FTLD-tau

Neuropsychological assessment DIAGNOSTIC_TEST

Tests for memory, language, attention, executive functions, praxis, social cognition, visuoconstructive skills

At-risk individuals; Healthy controls; Patients with probable FTLD-TDP; Patients with probable FTLD-tau

Clinical measures DIAGNOSTIC_TEST

Medical history, neurological assessment, neuropsychiatric inventory

At-risk individuals; Healthy controls; Patients with probable FTLD-TDP; Patients with probable FTLD-tau

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Leiden University Medical Center: lead
• Erasmus Medical Center: collaborator

Study Sites (2)

Leiden University Medical Center

Leiden, Netherlands

Location

Erasmus MC

Rotterdam, 3015GE, Netherlands

Location

Related Publications (1)

• 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.

  PMID: 40754329 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

plasma, serum, DNA, CSF

MeSH Terms

Conditions

Corticobasal Degeneration; Aphasia, Primary Progressive; Supranuclear Palsy, Progressive; Frontotemporal Lobar Degeneration; Nerve Degeneration; Neuroinflammatory Diseases

Condition Hierarchy (Ancestors)

Tauopathies; Neurodegenerative Diseases; Nervous System Diseases; Dementia; Brain Diseases; Central Nervous System Diseases; Aphasia; Speech Disorders; Language Disorders; Communication Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Neurocognitive Disorders; Mental Disorders; Basal Ganglia Diseases; Movement Disorders; Ophthalmoplegia; Ocular Motility Disorders; Cranial Nerve Diseases; Paralysis; Eye Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Pathologic Processes; Inflammation

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: February 3, 2025
• First Posted: March 11, 2025
• Study Start: July 25, 2023
• Primary Completion: August 1, 2025
• Study Completion (Estimated): August 1, 2026
• Last Updated: September 11, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

NL (2)