FTD-ALS Spectrum

FTD-ALS Spectrum

Overview

The FTD-ALS Spectrum represents a clinical, genetic, and pathological continuum between Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). This overlap syndrome reflects the shared underlying biology of TDP-43 proteinopathy and common genetic determinants, particularly hexanucleotide repeat expansions in the [C9orf72](/genes/c9orf72) gene.[@neumann2022] Patients may present with features of either condition, or develop both syndromes sequentially, with approximately 15% of ALS patients meeting criteria for FTD and up to 50% exhibiting subclinical cognitive or behavioral changes^[1]^[2]^.

The spectrum encompasses a continuum from pure behavioral variant FTD (bvFTD) or ALS to the combined syndrome where patients manifest characteristics of both conditions. This overlap has significant implications for diagnosis, treatment strategies, and clinical trial design^[3]^.

Epidemiology

Prevalence and Incidence

• ALS incidence: 1-2 per 100,000 person-years globally
• FTD incidence: 4-15 per 100,000 persons aged 45-64 years
• FTD-ALS overlap: 5-15% of ALS patients have comorbid FTD
• Gender distribution: Male predominance (1.3-1.5:1 for ALS; 1:1 for FTD)
• Age of onset: Typically 50-65 years for both conditions

Population-based studies show that the FTD-ALS spectrum accounts for a substantial proportion of both FTD and ALS cases, with the greatest overlap observed in patients with the C9orf72 hexanucleotide repeat expansion^[4]^.

Genetic Architecture

Major Genes

...

FTD-ALS Spectrum

Overview

The FTD-ALS Spectrum represents a clinical, genetic, and pathological continuum between Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). This overlap syndrome reflects the shared underlying biology of TDP-43 proteinopathy and common genetic determinants, particularly hexanucleotide repeat expansions in the [C9orf72](/genes/c9orf72) gene.[@neumann2022] Patients may present with features of either condition, or develop both syndromes sequentially, with approximately 15% of ALS patients meeting criteria for FTD and up to 50% exhibiting subclinical cognitive or behavioral changes^[1]^[2]^.

The spectrum encompasses a continuum from pure behavioral variant FTD (bvFTD) or ALS to the combined syndrome where patients manifest characteristics of both conditions. This overlap has significant implications for diagnosis, treatment strategies, and clinical trial design^[3]^.

Epidemiology

Prevalence and Incidence

• ALS incidence: 1-2 per 100,000 person-years globally
• FTD incidence: 4-15 per 100,000 persons aged 45-64 years
• FTD-ALS overlap: 5-15% of ALS patients have comorbid FTD
• Gender distribution: Male predominance (1.3-1.5:1 for ALS; 1:1 for FTD)
• Age of onset: Typically 50-65 years for both conditions

Population-based studies show that the FTD-ALS spectrum accounts for a substantial proportion of both FTD and ALS cases, with the greatest overlap observed in patients with the C9orf72 hexanucleotide repeat expansion^[4]^.

Genetic Architecture

Major Genes

| Gene | Location | Protein Function | FTD-ALS Association |
|------|----------|------------------|---------------------|
| [C9orf72](/genes/c9orf72) | 9p21 | DENN domain protein, Rab guanine nucleotide exchange | Most common cause of familial FTD-ALS (30-40%) |
| [TARDBP](/genes/tardbp) | 1p36 | TDP-43 RNA-binding protein | 3-5% of familial ALS, rare FTD |
| [FUS](/genes/fus) | 16p11 | Fused in sarcoma, RNA-binding protein | 3-5% of familial ALS, rare FTD |
| [GRN](/genes/grn) | 17q21 | Progranulin, secreted growth factor | ~20% of familial FTD, rare ALS |
| [MAPT](/genes/mapt) | 17q21 | Tau microtubule stabilization | FTDP-17, rare ALS overlap |
| TBK1 | 12p13 | TANK-binding kinase 1 | Autophagy/mitophagy regulation |

C9orf72 Hexanucleotide Repeat Expansion

The most significant genetic link in the FTD-ALS spectrum is the hexanucleotide repeat expansion in the first intron of [C9orf72](/genes/c9orf72)^[5]^:

• Normal repeats: <30
• Pathological repeats: >30 (typically 60-1000)
• Penetrance: Age-dependent, with most carriers developing symptoms by age 80
• Mechanisms: Three proposed pathogenic mechanisms:

1. RNA toxicity: Repeat-expanded RNA forms nuclear foci that sequester RNA-binding proteins

Dipeptide repeat (DPR) proteins: Translation of repeat RNA produces toxic DPRs (GA, GP, PA, PR, GR)

Reduced expression: Repeat expansion leads to reduced C9orf72 mRNA and protein levels

TARDBP Mutations

[TARDBP](/genes/tardbp) encodes TDP-43, the major protein accumulating in ALS and most FTD subtypes^[6]^:

• Over 50 pathogenic mutations identified, predominantly in the C-terminal glycine-rich domain
• Mutations cause TDP-43 mislocalization from nucleus to cytoplasm
• Leads to cytoplasmic aggregation and loss of nuclear function
• Both ALS and FTD cases show TDP-43 pathology (type B for ALS, type A for bvFTD)

FUS Mutations

[FUS](/genes/fus) (Fused in Sarcoma) is an RNA-binding protein with prion-like properties^[7]^:

• Mutations account for ~3-5% of familial ALS
• Rarely associated with FTD
• FUS pathology characterized by basophilic inclusions
• Earlier age of onset compared to other ALS genetic subtypes

Pathophysiology

TDP-43 Proteinopathy

The hallmark pathological feature of FTD-ALS is the accumulation of phosphorylated TDP-43 in neurons^[8]^:

TDP-43 Pathology Classification:
├── ALS: Type B (skeletal muscle, motor neurons, spinal cord)
│ └── Cytoplasmic inclusions, loss of nuclear TDP-43
├── bvFTD: Type A (frontal cortex)
│ └── Short dystrophic neurites, neuronal perikarya
└── ALS-FTD: Combined patterns
└── Overlapping features

TDP-43 is a 414-amino acid nuclear protein that functions in:

• RNA splicing and stability
• mRNA transport
• MicroRNA biogenesis
• Stress granule formation

In FTD-ALS, TDP-43 undergoes:

Hyperphosphorylation

C-terminal truncation

Ubiquitination

Mislocalization to cytoplasm

Formation of insoluble aggregates

Protein Aggregation Patterns

| Protein | FTD Subtype | ALS | FTD-ALS |
|---------|------------|-----|---------|
| TDP-43 | Type A/B | +++ | +++ |
| FUS | Type E (rare) | + | + |
| Tau | Type D (rare) | - | - |
| α-Synuclein | - | + | + |

RNA Metabolism Defects

RNA dysregulation is central to FTD-ALS pathogenesis:

RNA foci formation: C9orf72 repeat-expanded RNA forms nuclear RNA foci that sequester RBPs (hnRNPA1, hnRNPA2B1, Pur-α)

Splicing defects: TDP-43 loss-of-function causes aberrant splicing of thousands of neuronal transcripts

Transport deficits: Impaired axonal mRNA transport contributes to neurodegeneration

MicroRNA dysregulation: Altered miRNA profiles in ALS and FTD

Nucleocytoplasmic Transport Defects

C9orf72 repeat expansions cause nucleocytoplasmic transport dysfunction:

Repeat Expansion → RNA Foci → RBP Sequestration
↓
Importin/Exportin Dysregulation
↓
Nuclear Pore Complex Stress
↓
Impaired Nuclear Import/Export
↓
TDP-43 Mislocalization

Neuroinflammation

Microglial activation and neuroinflammation are prominent in FTD-ALS:

• Increased TREM2 expression in microglia
• Complement system activation (C1q, C3)
• Pro-inflammatory cytokine elevation (IL-6, TNF-α)
• Astrocyte reactivity (A1 phenotype)
• The C9orf72 expansion itself may modulate microglial function through the innate immune system

Clinical Presentation

FTD-ALS Phenotypes

The clinical spectrum encompasses multiple phenotypes:

1. ALS with Dementia (ALS-FTD)

• Progressive muscle weakness and atrophy
• Bulbar dysfunction (dysarthria, dysphagia)
• Behavioral changes (disinhibition, apathy)
• Executive dysfunction
• Mean survival: 2-3 years from symptom onset

2. FTD with Motor Neuron Involvement

• Behavioral variant FTD presentation
• Subsequent development of muscle weakness
• Less aggressive progression than pure ALS
• Survival: 5-10 years from symptom onset

3. Progressive Bulbar Palsy with Cognitive Decline

• Initial bulbar presentation (dysarthria, dysphagia)
• Later cognitive/behavioral changes
• Often associated with C9orf72 expansion

4. Corticobasal Syndrome/ALS Overlap

• Asymmetric rigidity
• Apraxia
• Myoclonus
• Progressive motor decline

Diagnostic Criteria

ALS Diagnostic Criteria (Awaji-Shima)

• Presence of progressive motor decline
• Evidence of upper and/or lower motor neuron signs in at least one region
• Electrophysiological evidence of denervation

FTD Diagnostic Criteria (Neary et al.)

• Core diagnostic features:
• Insidious onset
• Gradual progression
• Early loss of social conduct
• Early loss of insight
• Early signs of disinhibition
• Early apathy or loss of empathy
• Early loss of planning/judgment

FTD-ALS Overlap Diagnosis

• Meet criteria for both ALS and FTD, OR
• Have ALS with cognitive/behavioral impairment meeting at least 2 FTD criteria, OR
• Have FTD with emergent motor neuron signs

Cognitive and Behavioral Profile

| Domain | FTD-ALS | Pure ALS | Pure FTD |
|--------|---------|---------|----------|
| Executive function | +++ | ++ | +++ |
| Language | ++ | + | +++ |
| Memory | + | ++ | ++ |
| Visuospatial | + | + | + |
| Behavior | +++ | + | +++ |
| Social cognition | +++ | + | +++ |

Diagnosis and Biomarkers

Neuroimaging

[MRI](/technologies/mri-neurodegeneration) findings in FTD-ALS:

• Frontotemporal atrophy (especially poles and insula)
• Motor cortex atrophy
• Posterior frontal lobe asymmetry
• DTI: Reduced fractional anisotropy in frontal and motor tracts
• MRS: Elevated choline/creatine ratio in motor cortex

Neurophysiology

• EMG: Denervation potentials, fibrillation signs
• NCS: Often normal in pure ALS
• Transcranial magnetic stimulation: Reduced cortical excitability

Fluid Biomarkers

| Biomarker | FTD-ALS | Clinical Utility |
|----------|---------|-----------------|
| NfL (neurofilament light) | Elevated | Disease progression |
| pNfH (phosphorylated neurofilament heavy) | Elevated | Diagnostic specificity |
| TDP-43 (CSF) | Elevated | Disease activity |
| Progranulin (plasma) | Reduced in GRN carriers | Genetic screening |
| C9orf72 DPR (CSF) | Elevated | Disease-specific |

Genetic Testing

• C9orf72 hexanucleotide repeat analysis (standard of care)
• TARDBP sequencing
• FUS sequencing
• GRN sequencing (if progranulin low)
• MAPT sequencing (if FTDP-17 suspected)

Management

Pharmacological Approaches

Riluzole

• Primary FDA-approved ALS therapy
• 50mg twice daily
• Modulates glutamate transmission
• Small survival benefit (~2-3 months)

Edaravone (Radicava)

• Free radical scavenger
• IV infusion for 10 days monthly
• Indicated for early-stage ALS
• Modest functional benefit

Amyotrophic Lateral Sclerosis-Specific Management

For FTD-ALS patients:

• Acetylcholinesterase inhibitors: Avoid (may worsen behavioral symptoms)
• Memantine: Not recommended
• SSRIs: For behavioral symptoms (e.g., sertraline, citalopram)
• Antipsychotics: For severe agitation (use cautiously due to fall risk)

Non-Pharmacological Management

Nutritional Support

• Weight monitoring (weekly)
• Early PEG placement recommended
• High-calorie supplements
• Hydration management

Respiratory Support

• Pulmonary function monitoring (FVC, MIP)
• Non-invasive ventilation
• Cough assist devices
• Secretion management

Multidisciplinary Care

• Neurology: Coordinate care
• Pulmonology: Respiratory management
• Gastroenterology: Nutrition support
• Psychiatry: Behavioral management
• Physical therapy: Mobility support
• Occupational therapy: ADL preservation
• Speech pathology: Communication support
• Social work: Caregiver support

Experimental Therapies

Gene-Specific Approaches

| Target | Approach | Stage |
|--------|----------|-------|
| C9orf72 | Antisense oligonucleotides | Phase 1-2 |
| SOD1 | Tofersen (ASO) | Approved |
| TARDBP | Gene therapy | Preclinical |
| FUS | Gene therapy | Preclinical |
| TDP-43 | Small molecules | Discovery |

Stem Cell Therapies

• Mesenchymal stem cells (Phase 2-3)
• Neural stem cells (Phase 1)

Clinical Trials

Active and recent trials in FTD-ALS:

• NCT03098597: Tofersen for SOD1-ALS (completed, positive)
• NCT05055052: C9orf72 ASO (Phase 1/2)
• NCT05637863: Rapamycin for FTD-ALS (Phase 2)
• NCT05887308: Gene therapy for FUS-ALS (Phase 1)

Disease Progression and Prognosis

Natural History

| Parameter | FTD-ALS | Pure ALS | Pure FTD |
|-----------|---------|---------|----------|
| Age of onset | 55-65 | 55-65 | 55-75 |
| Duration (ALS) | 2-3 years | 2-4 years | 7-10 years |
| Duration (FTD) | Ongoing | - | 7-10 years |
| Cause of death | Respiratory failure | Respiratory failure | Complications |

Prognostic Factors

Negative prognostic factors:

• Age >60 at onset
• Bulbar onset
• Rapid progression
• Early cognitive/behavioral impairment
• Low baseline FVC
• Weight loss >10% at baseline
• C9orf72 expansion (for ALS component)

Neutral factors:

• Limb onset
• Male sex
• Early nutritional support

Animal Models

C9orf72 Models

• Mouse: BAC transgenic models with human C9orf72 and expanded repeats
• Drosophila: Drosophila models showing DPR toxicity
• iPSC-derived neurons: Patient-derived neurons demonstrating RNA foci and DPR production

TARDBP Models

• Transgenic mice: TDP-43 A315T, M337V mutations
• Conditional models: Inducible TDP-43 expression

Research Directions

Emerging Areas

Biomarker development: Blood-based NfL, pNfH for disease monitoring

Gene therapy: Antisense oligonucleotides for C9orf72, TARDBP, FUS

Targeted protein degradation: AUTOTAC, PROTAC approaches for TDP-43

Immunotherapy: TDP-43 vaccination strategies

Regenerative approaches: Stem cell replacement

Unmet Needs

• Earlier diagnosis
• Disease-modifying therapies
• Better biomarkers for clinical trials
• Understanding of phenotypic modifiers
• Integration of FTD and ALS clinical trial designs

Connections to Other Neurodegenerative Diseases

Alzheimer's Disease

The FTD-ALS spectrum connects to AD through:

• Shared TDP-43 pathology in ~30% of AD cases
• Common genetic risk factors (APOE)
• Overlapping behavioral phenotypes
• Microglial activation patterns

The intersection of TDP-43 pathology in AD (termed ["limbic-predominant age-related TDP-43 encephalopathy" or LATE](/mechanisms/late-neurodegeneration)) represents a key link between proteinopathies^[1]^. Recent studies demonstrate that TDP-43 pathology in AD follows a predictable staging pattern, beginning in the amygdala and spreading to the hippocampus and neocortex, similar to the progression of tau pathology^[2]^.

Key molecular intersections include:

• Mitochondrial dysfunction: Both conditions show impaired complex I activity and reduced ATP production
• Autophagy-lysosomal pathway: VPS35, GRN, and other genes implicated in both conditions
• Neuroinflammation: Shared microglial activation patterns with TREM2, CD33, and PLD3 as common risk factors
• RNA metabolism: Common defects in splicing and RNA transport

Parkinson's Disease

• C9orf72 expansion in some PD cases (~3-5% of PD with dementia)
• α-Synuclein pathology in ~5% of ALS-FTD
• Shared mitochondrial dysfunction through PINK1/Parkin pathway
• Overlapping therapeutic targets ( autophagy enhancers, mitochondrial protectors)

The relationship between [Parkinson's disease](/diseases/parkinsons-disease) and FTD-ALS is complex^[3]^. While these are traditionally considered separate proteinopathies (α-synuclein vs. TDP-43), hybrid cases exist where patients present with both Lewy bodies and TDP-43 inclusions^[4]^. Clinical features can include:

• Parkinsonian rigidity and bradykinesis with concurrent cognitive decline
• Lewy body dementia with motor neuron signs
• Rapid eye movement sleep behavior disorder as a shared prodromal feature

Corticobasal Degeneration

• Overlapping phenotypes (rigidity, apraxia, alien limb)
• TDP-43 pathology in ~30% of CBD cases
• Shared motor features with ALS
• Common tau pathology in some cases^[5]^

CBD was originally considered a tauopathy, but approximately 30% of cases show TDP-43 pathology, establishing a link to FTD-ALS^[6]^. The clinical syndrome includes:

• Asymmetric rigidity and dystonia
• Apraxia (especially limb-kinesthetic)
• Cortical sensory loss
• Alien limb phenomenon
• Cognitive decline meeting FTD criteria in ~30% of cases

Huntington's Disease

The overlap between [Huntington's disease](/diseases/huntingtons) and FTD-ALS is rare but documented:

• [C9orf72](/genes/c9orf72) expansion in some HD families
• CAG repeat length may modify TDP-43 pathology
• Shared mechanism involves RNA toxicity and dipeptide repeat proteins
• Behavioral changes in HD overlap with FTD phenotype^[7]^

Animal Models

C9orf72 Models

Mouse Models

• BAC transgenic models: Express human C9orf72 with expanded repeats
• knock-in models: Human repeat expansion knocked into endogenous mouse locus
• Phenotypes: Cognitive deficits, motor impairment, RNA foci, DPR deposits
• Therapeutic testing: Used for ASO efficacy studies

Drosophila Models

• Repeat expression models: Hexanucleotide repeat in Drosophila
• Phenotypes: Neurodegeneration, reduced lifespan
• Mechanism studies: RNA foci and DPR toxicity validated

iPSC-Derived Models

• Patient-derived neurons: Motor neurons from FTD-ALS patient iPSCs
• Phenotypes: RNA foci, DPR production, TDP-43 mislocalization
• Drug screening: Platform for high-throughput screening^[8]^

TARDBP Models

Transgenic Mouse Models

• TDP-43 A315T: First ALS-causing mutation identified
• TDP-43 M337V: Common mutation showing progressive phenotype
• Conditional models: Inducible TDP-43 expression for temporal studies

Phenotypes

• Progressive motor impairment
• Muscle denervation and atrophy
• Cytoplasmic TDP-43 inclusions
• Premature death

FUS Models

Transgenic Models

• FUS R521C: Most common pathogenic mutation
• FUS P525L: Associated with early-onset ALS

Phenotypes

• Rapid disease progression
• FUS-positive basophilic inclusions
• Stress granule abnormalities

Neuroimaging Biomarkers

Structural MRI

| Finding | FTD-ALS | Pure ALS | Pure FTD |
|---------|---------|---------|----------|
| Frontotemporal atrophy | +++ | + | +++ |
| Motor cortex atrophy | +++ | +++ | + |
| Precentral gyrus | ++ | +++ | + |
| Pallidum/putamen | ++ | + | + |
| Brainstem | + | + | + |

Advanced MRI Techniques

Diffusion Tensor Imaging (DTI)

• Fractional anisotropy reduction in:
• Corpus callosum
• Corticospinal tracts
• Frontotemporal white matter
• Apparent diffusion coefficient increase
• Useful for tracking disease progression

Resting-State fMRI

• Default mode network disruption
• Salience network hyperconnectivity (early)
• Motor network hypoconnectivity (progression)

PET Imaging

• FDG-PET: Hypometabolism in frontal/temporal regions
• PiB-PET: May show amyloid in FTD-ALS/AD overlap
• TAU-PET: Minimal uptake (distinguishes from AD)

Electrophysiological Biomarkers

Transcranial Magnetic Stimulation (TMS)

• Short-interval intracortical inhibition (SICI): Reduced
• Motor evoked potential (MEP) amplitude: Increased
• Cortical silent period: Shortened

Nerve Conduction Studies

• Typically normal in pure ALS-FTD
• May show reduced amplitudes in ALS component

EMG Findings

• Fibrillation potentials
• Positive sharp waves
• Fasciculation potentials
• Reduced recruitment

Proteomics and Metabolomics

Protein Biomarker Panels

| Protein | Change | Specificity | Stage |
|---------|-------|-------------|-------|
| NfL | 3-10x elevation | Moderate | All stages |
| pNfH | 2-5x elevation | High | Progressive |
| TDP-43 (total) | Elevated | Moderate | Active disease |
| pTDP-43 | Elevated | High | Pathology |
| CHIT1 | Elevated | High | Microglia |
| NFL | 3-10x elevation | Moderate | All stages |

Metabolomic Changes

• Energy metabolism: Reduced TCA cycle intermediates
• Amino acids: Elevated glutamate, reduced GABA
• Lipids: Altered phospholipid profile
• Nucleotides: Reduced ATP, elevated ADP

Pharmacological Management

FDA-Approved Therapies

Riluzole (Rilutek)

• Mechanism: Glutamate release inhibition, sodium channel block
• Dosing: 50mg twice daily
• Efficacy: 2-3 month survival benefit
• Side effects: Nausea, fatigue, liver enzyme elevation

Edaravone (Radicava)

• Mechanism: Free radical scavenger
• Dosing: 60mg IV infusion, 10 days monthly
• Efficacy: Slowed functional decline in early disease
• Side effects: Bruising, gait disturbance, headaches

Off-Label Therapies

Cognitive/Behavioral symptoms

• SSRIs: Sertraline (25-150mg), citalopram (10-40mg)
• SNRIs: Venlafaxine (75-225mg)
• Atypical antipsychotics: Quetiapine (25-100mg) - Monitor QTc

Motor symptoms

• Baclofen: Spasticity (10-30mg TID)
• Tizanidine: Spasticity (2-8mg TID)
• Benzodiazepines: Clonazepam (0.5-2mg) - for myoclonus

Sleep disturbances

• Melatonin: 1-10mg bedtime
• Mirtazapine: 15-45mg bedtime
• Low-dose trazodone: 25-100mg bedtime

Multidisciplinary Care Model

Core Team Members

| Specialist | Role | Frequency |
|------------|-----|-----------|
| Neurologist | Care coordination | Monthly |
| Pulmonologist | Respiratory care | Monthly |
| Gastroenterologist | Nutrition/PEG | As needed |
| Psychiatrist | Behavioral management | Monthly |
| Physical therapist | Mobility | Weekly |
| Occupational therapist | ADL | Weekly |
| Speech therapist | Communication | Weekly |
| Dietitian | Nutrition | Monthly |
| Social worker | Support services | Monthly |
| Palliative care | Quality of life | As needed |

Caregiver Support

• Education and training
• Respite care arrangements
• Support groups
• Financial counseling
• Legal planning (advanced directives)

Health Economics

Cost of Illness

| Category | Annual Cost (USD) |
|----------|------------------|
| Direct medical | $50,000-150,000 |
| Direct non-medical | $20,000-50,000 |
| Informal care | $30,000-100,000 |
| Productivity loss | $40,000-80,000 |
| Total | $140,000-380,000 |

Cost Drivers

• Hospitalizations
• Assistive devices
• Home modifications
• Caregiver time
• Medications

Public Health Implications

Epidemiology Summary

• Global ALS cases: ~400,000
• Global FTD cases: ~1.2 million
• FTD-ALS overlap: ~50,000-100,000
• Annual deaths (ALS): ~100,000 worldwide

Health Policy Needs

• Specialist workforce development
• Care infrastructure investment
• Research funding priorities
• Drug access policies

See Also

• [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
• [Frontotemporal Dementia](/diseases/frontotemporal-dementia)
• [C9orf72](/genes/c9orf72)
• [TARDBP](/genes/tardbp)
• [FUS](/genes/fus)
• [TDP-43 Proteinopathy](/mechanisms/tdp-43-proteinopathy)
• [Motor Neuron Disease](/diseases/motor-neuron-disease)
• [C9orf72 Hexanucleotide Repeat Expansion](/mechanisms/c9orf72-hexanucleotide-repeat-expansion)

External Links

• [PMC](https://pubmed.ncbi.nlm.nih.gov/)
• [OMIM](https://www.omim.org/)
• [ALS Association](https://www.alsassociation.org/)
• [AFTD](https://www.theaftd.org/)

Pathway Diagram

References

[Rascovsky et al., Sensitivity of revised criteria for the diagnosis of ALS-FTD (2011)](https://pubmed.ncbi.nlm.nih.gov/21819955/)

[Burrell et al., The intersection of ALS and FTD (2016)](https://pubmed.ncbi.nlm.nih.gov/27252821/)

[Abramzon et al., The Overlap of ALS and FTD (2020)](https://pubmed.ncbi.nlm.nih.gov/32890129/)

[Tout et al., TDP-43 pathology in ALS-FTD: Mechanistic and therapeutic implications (2020)](https://pubmed.ncbi.nlm.nih.gov/32050172/)

[Gomes et al., C9orf72 hexanucleotide repeats in FTD-ALS: New insights (2023)](https://pubmed.ncbi.nlm.nih.gov/37393283/)

[Wang et al., FUS mutations in FTD-ALS: Pathogenesis and mechanisms (2022)](https://pubmed.ncbi.nlm.nih.gov/35675189/)

[Neumann et al., TDP-43 proteinopathies (2022)](https://pubmed.ncbi.nlm.nih.gov/35284597/)

[Lomen-Hoerth et al., Amyotrophic lateral sclerosis: Concepts and classification (2002)](https://pubmed.ncbi.nlm.nih.gov/11809844/)

[Strong et al., Consensus on classification of ALS-FTD (2009)](https://pubmed.ncbi.nlm.nih.gov/19133856/)

[Irwin et al., Frontotemporal dementia and ALS: A clinicopathological continuum (2009)](https://pubmed.ncbi.nlm.nih.gov/19663657/)

[Neary et al., Frontotemporal lobar degeneration: Consensus (2000)](https://pubmed.ncbi.nlm.nih.gov/10896618/)

[Pascual-Fontan et al., TARDBP mutations in FTD-ALS (2015)](https://pubmed.ncbi.nlm.nih.gov/26365982/)