Corticobasal Syndrome(CBS), Primary Progressive Aphasia(PPA), Progressive Supranuclear Palsy(PSP), Behavioral Variant Frontotemporal Dementia (bvFTD), Frontotemporal Lobar Degeneration (FTLD)
Conditions
Keywords
Frontotemporal lobar degeneration, Iron accumulation, 7T-MRI, Neurodegeneration, Neuroinflammation, QSM, CSF, Blood, MRS, dMRS
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. 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.
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.
Interventions
DIAGNOSTIC_TEST7T MRI scan
MRI-scanning of the brain using a 7T MRI scanner
DIAGNOSTIC_TESTCSF
CSF collection via lumbar puncture
DIAGNOSTIC_TESTBlood withdrawal
Blood is collected by doing a blood withdrawal
DIAGNOSTIC_TESTNeuropsychological assessment
Tests for memory, language, attention, executive functions, praxis, social cognition, visuoconstructive skills
DIAGNOSTIC_TESTClinical measures
Medical history, neurological assessment, neuropsychiatric inventory
Sponsors
Erasmus Medical Center
Leiden University Medical Center
Study design
Observational model
COHORT
Time perspective
CROSS_SECTIONAL
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Iron acccumulation biomarkers in CSF | At baseline | Biomarkers for iron accumulation (transferritin, ferritin, and iron) in CSF. |
| MR Spectroscopy in the lateral anterior cingulate cortex | At baseline | 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). |
| Diffusion weighted MR spectroscopy in the lateral anterior cingulate cortex | At baseline | 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). |
| Quantitative susceptibility mapping for iron localization and quantification | At baseline | 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. |
| Neurodegeneration biomarkers in blood | At baseline | Biomarkers for neurodegeneration (neurofilament light chain (NFL), total tau) in blood. |
| Neurodegeneration biomarkers in CSF | At baseline | Biomarkers for neurodegeneration (neurofilament light chain (NFL), total tau) in CSF. |
| Neuroinflammation biomarkers in CSF | At baseline | Biomarkers for neuroinflammation (YKL-40, TREM-1, TREM-2, IL-1, IL-6, TNF-α, GFAP, CHIT1) in CSF. |
| Iron accumulation biomarkers in blood | At baseline | Biomarkers for iron accumulation ( ferritin, and iron) in blood. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical and neuropsycological evaluation: Montreal Cognitive Assessment | At baseline and 1 year follow-up | 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. |
| Clinical and neuropsycological evaluation: Clinical dementia rating scale | At baseline and 1 year follow-up | 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. |
| Clinical evaluation: Parkinson's Disease Rating Score | At baseline and 1 year follow-up | 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. |
| Clinical evaluation: Neuropsychiatric assessment | At baseline and 1 year follow-up | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Markers for brain clearance: CSF | At baseline | Levels of total tau and AQP4 |
| 7T MR markers for brain clearance: CSF mobility | At baseline | Assessment of the CSF mobility in the perivascular spaces throughout the brain using a T2-weighted scan and diffusion weighted scans. |
| 7T MRI markers for brain clearance: prevalance of perivascular spaces | At baseline | 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. |
Countries
Netherlands
Outcome results
None listed