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.

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.

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

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.