This large observational study investigates the genetic and clinical features of complex neurodegenerative disorders, including Frontotemporal Lobar Degeneration (FTLD) spectrum disorders and Progressive Supranuclear Palsy (PSP). The study establishes a comprehensive longitudinal database and biobank to advance understanding of disease mechanisms, identify biomarkers, and facilitate therapeutic development.
| Parameter |
Value |
| NCT Number |
NCT03225144 |
| Status |
Active, no longer recruiting |
| Study Type |
Observational |
| Conditions |
FTLD, PSP, CBS, CBD, Alzheimer's Disease, Parkinson's Disease |
| Sites |
Multiple international sites |
FTLD represents a spectrum of clinically and pathologically heterogeneous disorders characterized by progressive degeneration of the frontal and temporal lobes. The disease spectrum includes:
- Behavioral Variant FTD (bvFTD): Characterized by changes in personality, social conduct, and executive function
- Primary Progressive Aphasia (PPA): Language-predominant presentations
- FTD-ALS Spectrum: Overlap with motor neuron disease
PSP is a 4R-tauopathy presenting with vertical supranuclear gaze palsy, parkinsonism, and cognitive decline. The Richardson variant is the most common presentation, though multiple clinical phenotypes are recognized.
Corticobasal syndrome presents with asymmetric cortical sensory loss, apraxia, and extrapyramidal signs. Like PSP, it is classified as a 4R-tauopathy with significant clinical overlap.
-
Establish a Longitudinal Clinical Database: Create a well-characterized cohort with standardized clinical assessments over time
-
Collect Biological Samples: Assemble a comprehensive biobank including:
- DNA for genetic analysis
- Plasma and cerebrospinal fluid for biomarker studies
- Skin fibroblasts for cellular models
-
Develop Diagnostic Criteria: Refine clinical diagnostic criteria through correlation with neuropathology
-
Create a Therapeutic Development Resource: Establish infrastructure for clinical trials in these rare disorders
- Identify genetic risk factors and modifiers
- Characterize genotype-phenotype correlations
- Develop surrogate endpoints for clinical trials
- Establish natural history data for endpoint selection
- Comprehensive neurological examination
- Standardized cognitive batteries (MMSE, MoCA, FAB)
- Movement disorder assessments (MDS-UPDRS, PSP Rating Scale)
- Behavioral questionnaires (NPI, FBI)
- Functional capacity measures (ADL, CDR)
- Annual follow-up visits with repeated assessments
- Tracking of disease progression rates
- Documentation of phenotypic evolution
| Sample Type |
Use |
| Blood (EDTA) |
DNA extraction and genetic analysis |
| Blood (serum) |
Biomarker studies (NfL, p-tau)[@Benutti_2022] |
| CSF |
Fluid biomarker profiling |
| Skin fibroblasts |
Induced pluripotent stem cell derivation |
- High-resolution MRI with volumetric analysis
- Diffusion tensor imaging for white matter integrity
- FDG-PET for metabolic patterns
- Tau and amyloid PET (in selected cases)
-
Global Cognition
- Mini-Mental State Examination (MMSE)
- Montreal Cognitive Assessment (MoCA)
-
Executive Function
- Trail Making Test A & B
- Wisconsin Card Sorting Test
- Verbal fluency
-
Memory
- Rey Auditory Verbal Learning Test
- Rey-Osterrieth Complex Figure Test
-
Language
- Boston Naming Test
- Western Aphasia Battery
- MDS-UPDRS: Unified Parkinson's Disease Rating Scale
- PSPRS: PSP Rating Scale
- CBS Assessment: Standardized corticobasal evaluation
- Ocular motor examination
- Neuropsychiatric Inventory (NPI): Behavioral disturbance assessment
- Frontal Behavioral Inventory (FBI): Frontal lobe symptom assessment
- Cambridge Cognitive Examination (CAMCOG): Comprehensive cognitive screening
¶ Key Findings and Contributions
The study has contributed substantially to the field:
- Improved clinical criteria for PSP variants
- Refined CBS diagnostic criteria
- Better characterization of FTLD subtypes
- Identification of new genetic risk factors
- Characterization of genotype-phenotype correlations
- Understanding of modifier genes
- Validation of neurofilament light chain (NfL) as a progression marker
- Identification of CSF biomarker profiles
- Development of imaging biomarkers
-
Clinical Diagnosis: Suspected or confirmed diagnosis of:
- Behavioral variant FTD
- Primary Progressive Aphasia
- PSP (any variant)
- Corticobasal Syndrome
- Related neurodegenerative disorder
-
Age: 18 years or older
-
Capacity: Able to provide informed consent (or appropriate proxy consent)
- Other neurological conditions that could explain symptoms
- Medical conditions precluding comprehensive assessment
- Inability to undergo MRI or other imaging
- Current enrollment in interventional clinical trials
The biobank and database enable:
- Molecular studies of disease mechanisms
- Development of cellular and animal models
- Identification of therapeutic targets
- Clinical trial readiness through natural history data
- Biomarker validation studies
- Endpoint validation
- Patient cohorts for enrollment
- Biomarker endpoints for trials
- Understanding of disease heterogeneity
Frontotemporal lobar degeneration (FTLD) represents a heterogeneous group of neurodegenerative disorders characterized by progressive atrophy of the frontal and temporal lobes. The FTLD spectrum includes several clinical syndromes:
-
Behavioral Variant Frontotemporal Dementia (bvFTD)
- Characterized by progressive behavioral changes and executive dysfunction
- Disinhibition, apathy, loss of empathy, and compulsions
- Typically presents in the 5th-6th decade of life
-
Semantic Variant Primary Progressive Aphasia (svPPA)
- Progressive loss of word meaning and object knowledge
- Fluent speech with intact grammar and motor speech
- Typically presents with anomia and comprehension deficits
-
Non-fluent/agrammatic Variant Primary Progressive Aphasia (nfvPPA)
- Agrammatic speech with impaired grammar
- Motor speech deficits (apraxia of speech)
- Preservation of word comprehension
-
Logopenic Variant Primary Progressive Aphasia (lvPPA)
- Impaired word retrieval and sentence repetition
- Usually associated with Alzheimer's pathology
- Part of the language variant spectrum
FTLD frequently co-occurs with other neurodegenerative conditions:
FTLD is characterized by the accumulation of specific protein inclusions:
- Pick disease: 3R tau inclusions
- CBD: 4R tau inclusions
- PSP: 4R tau inclusions
- FTLD-tau: Various tau mutations
- FTLD-TDP Type A: Neuronal cytoplasmic inclusions, frontotemporal dementia
- FTLD-TDP Type B: Neuronal cytoplasmic inclusions,ALS
- FTLD-TDP Type C: Lentiform inclusions, semantic variant
- FTLD-TDP Type E: Extensive neuronal loss
| Gene |
Protein |
Inheritance |
Phenotype |
| MAPT |
Tau |
AD |
bvFTD, PSP, CBD |
| GRN |
Progranulin |
AD |
bvFTD, nfvPPA, CBS |
| C9orf72 |
Dipeptide repeats |
AD |
bvFTD, ALS |
| FUS |
Fused in sarcoma |
AD |
FTLD, ALS |
| TARDBP |
TDP-43 |
AD |
FTLD, ALS |
- VCP: Valosin-containing protein mutations (inclusion body myopathy)
- CHMP2B: Charged multivesicular body protein 2B
- TBK1: TANK-binding kinase 1
Progressive supranuclear palsy represents a key intersection within the FTLD spectrum:
-
Clinical overlap: PSP shares features with both FTLD (behavioral changes, executive dysfunction) and parkinsonian syndromes (bradykinesia, rigidity)
-
Pathological overlap: PSP is classified as both an atypical parkinsonism and a tauopathy within the FTLD spectrum
-
Genetic overlap: MAPT mutations can cause both FTLD and PSP phenotypes
-
Therapeutic implications: Understanding PSP within the FTLD context informs clinical trial design and treatment targeting
¶ Study Design and Methodology
Standardized neurological examination includes:
- Motor assessment: MDS-UPDRS, PSPRS
- Ocular motor testing: Vertical supranuclear gaze assessment
- Cognitive testing: Comprehensive neuropsychological battery
- Behavioral assessment: Frontal behavioral inventory
Cognitive domains assessed:
- Executive function: Trail Making Test, Wisconsin Card Sorting Test
- Memory: Rey Auditory Verbal Learning Test, Rey-Osterrieth Complex Figure
- Language: Boston Naming Test, Semantic Fluency, Token Test
- Visuospatial: Rey-Osterrieth Copy, Line Orientation
- Social cognition: Reading the Mind in the Eyes, Faux Pas recognition
- MRI: 3D T1, T2/FLAIR, SWI sequences
- Volumetric analysis: Hippocampal, frontal, temporal volumes
- DTI: White matter integrity assessment
- FDG-PET: Regional glucose metabolism (optional)
- Tau PET: Flortaucipir binding (selected centers)
| Sample Type |
Collection |
Processing |
Storage |
| DNA |
Whole blood |
EDTA tubes |
-80°C |
| Plasma |
Venipuncture |
BD PPT tubes |
-80°C |
| CSF |
Lumbar puncture |
Polypropylene tubes |
-80°C |
| PBMCs |
Whole blood |
Ficoll gradient |
-80°C |
- SNP array: Genome-wide genotyping
- Whole genome sequencing: Comprehensive variant detection
- Segregation analysis: Family variant validation
- Functional studies: In silico pathogenicity assessment
- Year 1-2: Annual visits
- Year 3-5: Optional bi-annual visits
- Long-term: Annual telephone follow-up
| Timepoint |
Clinical |
Cognitive |
Imaging |
Biosamples |
| Baseline |
Full |
Full |
Yes |
Full |
| Year 1 |
Full |
Full |
Yes |
Full |
| Year 2 |
Full |
Full |
Optional |
Full |
| Subsequent |
Brief |
Brief |
Optional |
Optional |
The study has contributed to improved diagnostic criteria for:
- FTLD subtypes: Refined clinical and pathological correlations
- CBS phenotype: Better characterization of corticobasal presentation
- PSP variants: Identification of cortical PSP and other variants
- FTLD-ALS: Consensus criteria for combined presentations
- Identification of rare variants in TBK1 as FTLD risk factor
- Characterization of C9orf72 founder effects in specific populations
- Discovery of GRN expression modifiers affecting age of onset
- MAPT haplotypes and phenotype specificity
- GRN null mutations and nfvPPA
- C9orf72 repeat size and clinical presentation
- NfL as disease progression marker in FTLD
- p-tau181 differentiation between FTLD and AD
- Progranulin as diagnostic marker for GRN carriers
- Frontal atrophy patterns distinguishing FTLD subtypes
- Midbrain-to-pontine ratio for PSP diagnosis
- Connectivity changes in behavioral variant FTD
This study provides essential infrastructure for clinical trials:
- Patient registry: Pre-screened, genetically characterized cohorts
- Natural history data: Informs trial design and endpoint selection
- Biorepository: Ready access to matched biosamples
- Expertise network: Multi-center collaboration infrastructure
- Genetic counseling: For at-risk family members
- Prognostic information: Based on genotype and phenotype
- Risk stratification: For prevention trials in pre-symptomatic individuals
- Treatment selection: Genotype-informed therapeutic decisions
- Diagnostic algorithms: Evidence-based diagnostic pathways
- Clinical decision support: Integrated genetic and clinical data
- Care coordination: Multi-specialty management protocols
- Single-cell genomics: Understanding cellular heterogeneity in FTLD
- Proteomics: Biomarker discovery through unbiased profiling
- Epigenetics: Understanding gene-environment interactions
- Neuroinflammation: Role of microglia and astrocytes in FTLD
The study participates in:
- FTLDNI: Frontotemporal Lobar Degeneration Neuroimaging Initiative
- GENFI: Genetic Frontotemporal Dementia Initiative
- ALLFTD: Art and Science of Learning to See Clearly
- CurePSP Registry: Foundation for PSP and Related Disorders
Page updated: 2026-03-27