Investigating Complex Neurodegenerative Disorders (NCT03225144)

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Investigating Complex Neurodegenerative Disorders (NCT03225144)

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Overview

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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["@Boxer_2020"].

Study Details

| Parameter | Value |
|-----------|-------|
| NCT Number | NCT03225144 |
| Status | Active, no longer recruiting |
| Study Type | Observational |
| Conditions | FTLD, PSP, CBS, CBD, [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease) |
| Sites | Multiple international sites |

Scientific Background

Frontotemporal Lobar Degeneration (FTLD)

FTLD represents a spectrum of clinically and pathologically heterogeneous disorders characterized by progressive degeneration of the frontal and temporal lobes[@Rohrer_2011]. The disease spectrum includes:

...

Overview

Mermaid diagram (expand to render)

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["@Boxer_2020"].

Study Details

| Parameter | Value |
|-----------|-------|
| NCT Number | NCT03225144 |
| Status | Active, no longer recruiting |
| Study Type | Observational |
| Conditions | FTLD, PSP, CBS, CBD, [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease) |
| Sites | Multiple international sites |

Scientific Background

Frontotemporal Lobar Degeneration (FTLD)

FTLD represents a spectrum of clinically and pathologically heterogeneous disorders characterized by progressive degeneration of the frontal and temporal lobes[@Rohrer_2011]. The disease spectrum includes:

Behavioral Variant FTD (bvFTD): Characterized by changes in personality, social conduct, and executive function[@Rascovsky_2011]
Primary Progressive Aphasia (PPA): Language-predominant presentations
FTD-ALS Spectrum: Overlap with motor neuron disease

Progressive Supranuclear Palsy (PSP)

PSP is a 4R-tauopathy presenting with vertical supranuclear gaze palsy, parkinsonism, and cognitive decline[@Litvan_2017]. The Richardson variant is the most common presentation, though multiple clinical phenotypes are recognized.

Corticobasal Degeneration (CBD/CBS)

Corticobasal syndrome presents with asymmetric cortical sensory loss, apraxia, and extrapyramidal signs[@Armstrong_2020]. Like PSP, it is classified as a 4R-tauopathy with significant clinical overlap.

Objectives

Primary Objectives

Establish a Longitudinal Clinical Database: Create a well-characterized cohort with standardized clinical assessments over time[@Bang_2018]

Collect Biological Samples: Assemble a comprehensive biobank including:

DNA for genetic analysis
Plasma and cerebrospinal fluid for biomarker studies[@Chen_2018]
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[@Boxer_2023]

Secondary Objectives

Identify genetic risk factors and modifiers
Characterize genotype-phenotype correlations
Develop surrogate endpoints for clinical trials
Establish natural history data for endpoint selection

Study Design

Baseline Assessment

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)

Longitudinal Follow-up

Annual follow-up visits with repeated assessments
Tracking of disease progression rates[@Bang_2018]
Documentation of phenotypic evolution

Biobanking Protocol

| Sample Type | Use |
|------------|-----|
| Blood (EDTA) | DNA extraction and genetic analysis |
| Blood (serum) | Biomarker studies (NfL, p-tau)[@Benutti_2022] |
| CSF | Fluid biomarker profiling[@Chen_2018] |
| Skin fibroblasts | Induced pluripotent stem cell derivation |

Neuroimaging Repository

High-resolution MRI with volumetric analysis
Diffusion tensor imaging for white matter integrity
FDG-PET for metabolic patterns[@Irwin_2018]
Tau and amyloid PET (in selected cases)

Clinical Assessments

Cognitive Testing Battery

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

Motor Assessment

MDS-UPDRS: Unified Parkinson's Disease Rating Scale
PSPRS: PSP Rating Scale
CBS Assessment: Standardized corticobasal evaluation
Ocular motor examination

Behavioral Measures

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[@Litvan_2017]
Refined CBS diagnostic criteria[@Armstrong_2020]
Better characterization of FTLD subtypes

Genetic Discoveries

Identification of new genetic risk factors
Characterization of genotype-phenotype correlations
Understanding of modifier genes

Biomarker Development

Validation of neurofilament light chain (NfL) as a progression marker[@Benussi_2022]
Identification of CSF biomarker profiles
Development of imaging biomarkers[@Irwin_2018]

Eligibility Criteria

Inclusion Criteria

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)

Exclusion Criteria

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

Significance for Research

For Basic Science

The biobank and database enable:

Molecular studies of disease mechanisms
Development of cellular and animal models
Identification of therapeutic targets

For Clinical Research

Clinical trial readiness through natural history data
Biomarker validation studies
Endpoint validation

For Therapeutic Development

Patient cohorts for enrollment
Biomarker endpoints for trials
Understanding of disease heterogeneity

External Links

[ClinicalTrials.gov NCT03225144](https://clinicaltrials.gov/study/NCT03225144)
[PubMed Search: FTLD biomarkers](https://pubmed.ncbi.nlm.nih.gov/)
[KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

[CBS/PSP Genetic Architecture](/diseases/psp-genetic-variants)
[PSP Genetic Variants](/diseases/psp-genetic-variants)
[CurePSP Genetics Program](/clinical-trials/curepsp-genetics-program)
[Genetic Frontotemporal Dementia Study](/diseases/frontotemporal-disease)
[4R-Tauopathies Overview](/proteins/tau)
Neurodegenerative Disease Biomarkers
[Genetic Frontotemporal Dementia Study](/diseases/frontotemporal-disease)
[4R-Tauopathies Overview](/proteins/tau)
Neurodegenerative Disease Biomarkers](/diseases/frontotemporal-dementia)## Scientific Background: FTLD Spectrum Disorders

Classification of Frontotemporal Lobar Degeneration

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:

Primary FTLD 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 Overlap Syndromes

FTLD frequently co-occurs with other neurodegenerative conditions:

FTLD with Amyotrophic Lateral Sclerosis (FTLD-ALS)
FTLD with Parkinsonism (FTLD-PD)
[Corticobasal Syndrome (CBS)](/diseases/corticobasal-syndrome)
[Progressive Supranuclear Palsy (PSP)](/diseases/progressive-supranuclear-palsy)

Neuropathological Classification

FTLD is characterized by the accumulation of specific protein inclusions:

Tauopathies (~50% of FTLD)

Pick disease: 3R tau inclusions
CBD: 4R tau inclusions
PSP: 4R tau inclusions
FTLD-tau: Various tau mutations

TDP-43 Proteinopathies (~45% of FTLD)

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

FTD-FUS (~5% of FTLD)

[Fused in sarcoma (FUS) protein inclusions](/proteins/fused-in-sarcoma)
Associated with ALS andFTLD-NOS

Genetics of FTLD Spectrum

Autosomal Dominant FTLD Genes

| 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 |

Risk Factors

VCP: Valosin-containing protein mutations (inclusion body myopathy)
CHMP2B: Charged multivesicular body protein 2B
TBK1: TANK-binding kinase 1

The Role of PSP in FTLD Spectrum

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

Baseline Comprehensive Assessment

Neurological Examination

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

Neuropsychological Testing

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

Neuroimaging Protocol

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)

Biobanking Protocol

Sample Collection

| 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 |

Genetic Analysis Pipeline

SNP array: Genome-wide genotyping

Whole genome sequencing: Comprehensive variant detection

Segregation analysis: Family variant validation

Functional studies: In silico pathogenicity assessment

Annual Follow-up Protocol

Visit Schedule

Year 1-2: Annual visits
Year 3-5: Optional bi-annual visits
Long-term: Annual telephone follow-up

Assessment Battery

| 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 |

Key Scientific Contributions

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

Genetic Discoveries

Novel Genetic Risk Factors

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

Genotype-Phenotype Correlations

MAPT haplotypes and phenotype specificity
GRN null mutations and nfvPPA
C9orf72 repeat size and clinical presentation

Biomarker Development

Fluid Biomarkers

NfL as disease progression marker in FTLD
p-tau181 differentiation between FTLD and AD
Progranulin as diagnostic marker for GRN carriers

Imaging Biomarkers

Frontal atrophy patterns distinguishing FTLD subtypes
Midbrain-to-pontine ratio for PSP diagnosis
Connectivity changes in behavioral variant FTD

Clinical Significance

Enabling Therapeutic Development

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

Personalized Medicine Applications

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

Healthcare Delivery Improvements

Diagnostic algorithms: Evidence-based diagnostic pathways
Clinical decision support: Integrated genetic and clinical data
Care coordination: Multi-specialty management protocols

Future Directions

Emerging Research Directions

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

International Collaboration

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

References

[ClinicalTrials.gov NCT03225144](https://clinicaltrials.gov/study/NCT03225144)[@investigating]

[Ranasinghe et al., Neurodegenerative disease biomarkers (2022)](https://pubmed.ncbi.nlm.nih.gov/35279234/)[@ranasinghe_2022]

[Boxer et al., FTD and related disorders: from molecules to therapeutics (2020)](https://pubmed.ncbi.nlm.nih.gov/32092166/)[@Boxer_2020]

[McGough et al., Update on biomarkers in neurodegenerative diseases (2023)](https://pubmed.ncbi.nlm.nih.gov/37526723/)[@McGough_2023]

[Rascovsky et al., Diagnostic criteria for bvFTD (2011)](https://pubmed.ncbi.nlm.nih.gov/21810889/)[@Rascovsky_2011]

[Litvan et al., Clinical diagnostic criteria for PSP (2017)](https://pubmed.ncbi.nlm.nih.gov/28327879/)[@Litvan_2017]

[Armstrong et al., Clinical criteria for CBS (2020)](https://pubmed.ncbi.nlm.nih.gov/32128918/)[@Armstrong_2020]

[Bang et al., Longitudinal changes in PSP and CBD (2018)](https://pubmed.ncbi.nlm.nih.gov/29349711/)[@Bang_2018]

[Rohrer et al., Clinical features of FTD (2011)](https://pubmed.ncbi.nlm.nih.gov/21047878/)[@Rohrer_2011]

[Boxer et al., Clinical trials in FTD (2023)](https://pubmed.ncbi.nlm.nih.gov/37153892/)[@Boxer_2023]

[Chen et al., Fluid biomarkers in neurodegenerative disease (2018)](https://pubmed.ncbi.nlm.nih.gov/30148620/)[@Chen_2018]

[Benussi et al., Neurofilament light chain as biomarker (2022)](https://pubmed.ncbi.nlm.nih.gov/35499099/)[@Benussi_2022]

[Irwin et al., Neuroimaging biomarkers (2018)](https://pubmed.ncbi.nlm.nih.gov/29068454/)[@Irwin_2018]

Page updated: 2026-03-27

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📗 Cite This Artifact

Investigating Complex Neurodegenerative Disorders (NCT03225144)

Overview

Study Details

Scientific Background

Frontotemporal Lobar Degeneration (FTLD)

Overview

Study Details

Scientific Background

Frontotemporal Lobar Degeneration (FTLD)

Progressive Supranuclear Palsy (PSP)

Corticobasal Degeneration (CBD/CBS)

Objectives

Primary Objectives

Secondary Objectives

Study Design

Baseline Assessment

Longitudinal Follow-up

Biobanking Protocol

Neuroimaging Repository

Clinical Assessments

Cognitive Testing Battery

Motor Assessment

Behavioral Measures

Key Findings and Contributions

Diagnostic Criteria Refinement

Genetic Discoveries

Biomarker Development

Eligibility Criteria

Inclusion Criteria

Exclusion Criteria

Significance for Research

For Basic Science

For Clinical Research

For Therapeutic Development

See Also

External Links

Related Pages

Classification of Frontotemporal Lobar Degeneration

Primary FTLD Syndromes

FTLD Overlap Syndromes

Neuropathological Classification

Tauopathies (~50% of FTLD)

TDP-43 Proteinopathies (~45% of FTLD)

FTD-FUS (~5% of FTLD)

Genetics of FTLD Spectrum

Autosomal Dominant FTLD Genes

Risk Factors

The Role of PSP in FTLD Spectrum

Study Design and Methodology

Baseline Comprehensive Assessment

Neurological Examination

Neuropsychological Testing

Neuroimaging Protocol

Biobanking Protocol

Sample Collection

Genetic Analysis Pipeline

Annual Follow-up Protocol

Visit Schedule

Assessment Battery

Key Scientific Contributions

Diagnostic Refinement

Genetic Discoveries

Novel Genetic Risk Factors

Genotype-Phenotype Correlations

Biomarker Development

Fluid Biomarkers

Imaging Biomarkers

Clinical Significance

Enabling Therapeutic Development

Personalized Medicine Applications

Healthcare Delivery Improvements

Future Directions

Emerging Research Directions

International Collaboration

References

💬 Discussion