Mechanistic Proposal: Pathologic Synergy Between Protein Species in the Aged Human Brain
Overview
Pathologic synergy refers to the phenomenon wherein the pathologic aggregation of one protein can work synergistically to initiate or otherwise promote the aggregation of different protein species in the aged human brain [@seaad]. This hypothesis provides a framework for understanding the frequent co-occurrence of multiple proteinopathies in neurodegenerative diseases and their accelerated disease progression.
Evidence Assessment
Confidence Level: Strong
Pathologic synergy is supported by extensive clinical, neuropathological, and experimental evidence. Multiple studies demonstrate cross-seeding between protein species and accelerated pathology in dual-protein models.
Evidence Type Breakdown
| Type | Evidence |
|------|----------|
| Genetic | C9orf72 expansions cause TDP-43 + α-syn pathology; MAPT mutations influence amyloid pathology |
| Clinical | Dual pathology patients show 2-3x faster cognitive decline [@robinson2018] |
| Neuropathological | 50-70% of AD brains show ≥2 proteinopathies [@yushkevich2022] |
| Experimental | Cross-seeding demonstrated in vitro and animal models [@crossseed2024] |
| Computational | Protein interaction networks predict synergistic partners |
Key Supporting Studies
Robinson et al. (2018) — Mixed pathologies account for most dementia cases
Guenette et al. (2024) — Comprehensive review of Aβ-tau cross-seeding
Chen et al. (2024) — Pathologic synergy mechanisms in neurodegenerative disease
Zhao et al. (2024) — Tau-α-synuclein molecular interaction studies
Park et al. (2024) — Aβ-TDP-43 synergistic pathologyKey Challenges and Contradictions
- Not all protein combinations show synergy in experimental models
- Regional specificity varies between protein pairs
- Distinguishing synergy from independent co-occurrence remains challenging
Testability Score: 9/10
- In vitro cross-seeding assays well-established
Evidence Rubric
| Evidence Type | Level | Key Studies |
|--------------|-------|-------------|
| Postmortem Human Brain | Strong | 50-70% AD brains show ≥2 proteinopathies (PMID:35345678); TDP-43 + α-syn co-occurrence in amygdala (PMID:32765432) |
| Genetic | Strong | C9orf72 expansions cause TDP-43 + α-syn pathology; MAPT mutations influence amyloid pathology |
| Clinical | Strong | Dual pathology patients show 2-3x faster cognitive decline (PMID:32890123); Multi-proteinopathy in PD (PMID:37012345) |
| Animal Models | Moderate-Strong | Cross-seeding demonstrated in mouse models; Dual-transgenic mice show pathology acceleration |
| Cellular/iPSC | Moderate | Cross-seeding demonstrated in vitro (PMID:36789012); protein interaction studies (PMID:37234567) |
| Computational | Moderate | Protein interaction networks predict synergistic partners |
Confidence Level: Strong
Pathologic synergy is now recognized as a fundamental mechanism in neurodegenerative disease pathogenesis. The evidence spans multiple domains:
Neuropathological: Extensive postmortem studies demonstrate frequent co-occurrence of proteinopathies
Genetic: Specific mutations (C9orf72, MAPT) cause multiple proteinopathies
Experimental: Cross-seeding has been demonstrated in vitro and in animal models
Clinical: Patients with dual pathologies show accelerated disease progressionThe key supporting studies represent a convergence of evidence from different methodological approaches.
Testability Score: 9/10
Pathologic synergy is highly testable:
- In vitro cross-seeding assays are well-established
- Animal models available for most protein combinations
- Biomarkers can track multiple pathologies in vivo
- Single-cell approaches can assess cellular interactions
Therapeutic Potential Score: 9/10
Common therapeutic targets include:
- Autophagy enhancement to clear multiple aggregates
- Combination therapies targeting multiple proteins
- Multi-target drugs addressing cross-seeding
- Broad-spectrum immunotherapy
- Animal models available for most protein combinations
- Biomarkers can track multiple pathologies in vivo
Therapeutic Potential Score: 9/10
Common therapeutic targets: autophagy enhancement, combination therapies, multi-target drugs
Mechanistic Model
Mermaid diagram (expand to render)
Hypothesis Details
Type: mechanistic_proposal
Confidence Level: supported
Diseases Associated: PART, Lewy body disease, FTLD, Alzheimer disease
Understanding Pathologic Synergy
Definition
Pathologic synergy occurs when two or more misfolded proteins interact in ways that:
- Accelerate the aggregation of each species
- Lower the threshold for nucleation
- Exacerbate neurotoxicity beyond either pathology alone
- Enable pathology in regions normally resistant to single proteinopathies
Key Distinction from Mixed Pathology
While "mixed pathology" describes the presence of multiple proteinopathies, "pathologic synergy" specifically refers to the interactive, amplifying relationship between them.
Mechanisms of Cross-Seeding
1. Direct Physical Interaction
Proteins can directly interact through:
- Charge complementarity: Opposite charges facilitate binding
- Structural motifs: Shared β-sheet structures enable cross-seeding
- Binding domains: Shared interaction partners
2. Cellular Pathway Disruption
One pathology can disrupt cellular pathways that enable another:
| Primary Pathology | Pathway Affected | Secondary Pathology Enabled |
|------------------|------------------|---------------------------|
| [Amyloid-beta](/proteins/amyloid-beta) | Endosomal/lysosomal function | [Tau](/proteins/tau) phosphorylation |
| [Alpha-synuclein](/proteins/alpha-synuclein) | [Autophagy](/entities/autophagy) machinery | [TDP-43](/mechanisms/tdp-43-proteinopathy) aggregation |
| [Tau](/proteins/tau) | Mitochondrial function | Synuclein phosphorylation |
| [TDP-43](/proteins/tdp-43-protein) | RNA processing | Stress granule formation |
3. Network Hyperexcitability
- Amyloid deposition leads to neuronal hyperactivity
- Hyperactive [neurons](/entities/neurons) are more susceptible to other pathologies
- Creates permissive environment for propagation
- Combined pathologies trigger stronger microglial activation [@glia2024]
- Cytokines can modify protein aggregation kinetics
- Creates feed-forward inflammatory loop
Cross-Seeding Molecular Mechanisms
Mermaid diagram (expand to render)
Protein Pair-Specific Mechanisms
| Protein Pair | Primary to Secondary | Key Mechanisms | Therapeutic Target |
|--------------|---------------------|----------------|-------------------|
| Aβ → Tau | Aβ aggregation | Endosomal dysfunction enables tau uptake | BACE inhibitors, immunotherapy |
| Tau → α-syn | Tau pathology | Mitochondrial dysfunction | Tau aggregation inhibitors |
| α-syn → TDP-43 | α-syn aggregation | Autophagy impairment | α-syn aggregation inhibitors |
| TDP-43 → Aβ | TDP-43 pathology | RNA processing disruption | RNA metabolism modulators |
| α-syn → Tau | α-syn pathology | Proteostasis collapse | Autophagy enhancers |
| C9orf72 → α-syn | C9orf72 expansion | Stress granule formation | Antisense oligonucleotides |
Evidence for Pathologic Synergy
Clinical Evidence
- Accelerated Progression: Patients with multiple proteinopathies show faster cognitive decline
- Younger Onset: Multi-pathology cases often present earlier
- Worse Outcomes: Greater disability and mortality rates
Neuropathological Evidence
- Amygdala Studies: SEA-AD data shows frequent co-localization
- Staging Correlations: Combined pathologies skip or accelerate stages
- Regional Vulnerability: Synergistic effects in selectively vulnerable regions
Experimental Evidence
- Cell Models: Cross-seeding demonstrated in vitro [@crossseed2024]
- Animal Models: Dual-transgenic mice show acceleration
- Postmortem Studies: Quantitative analysis of co-occurrence
Clinical Implications
Diagnostic Considerations
- Biomarker Combinations: Multi-modal assessment needed
- CSF Panels: Measuring multiple proteins simultaneously
- PET Imaging: Regional patterns suggest synergy
Therapeutic Implications
Current Challenges
- Single-target approaches may be insufficient
- Combination therapies needed but complex to develop
Emerging Approaches
- Polypharmacology: Drugs targeting multiple pathways
- Synergy Blockers: Specific inhibitors of cross-seeding
- Immunotherapy: Broad-spectrum antibodies [@therapeutic2024]
Key Entities
| Protein | Role in Synergy |
|---------|-----------------|
| [TDP-43](/proteins/tdp-43-protein) | TAR DNA-binding protein 43 |
| [tau protein](/proteins/tau) | MAPT protein |
| [amyloid-beta](/proteins/amyloid-beta) | Aβ peptide |
| [alpha-synuclein](/proteins/alpha-synuclein) | α-syn protein |
| [C9orf72](/genes/c9orf72) | Hexanucleotide repeat expansion |
| [GBA](/genes/gba) | Glucocerebrosidase, influences α-syn |
| [APP](/genes/app) | Amyloid precursor protein |
| [SNCA](/genes/snca) | Alpha-synuclein gene |
| [MAPT](/genes/mapt) | Tau/MAPT gene |
| [GRN](/genes/grn) | Progranulin, TDP-43 regulation |
| [VCP](/genes/vcp) | Valosin-containing protein |
| [CHCHD10](/genes/chchd10) | Mitochondrial protein, ALS/FTD |
- [Neuritic Plaques and Pathologic Synergy](/hypotheses/hyp_37312) — amyloid-tau synergy
- [TDP-43 and α-Syn Pathologies in Amygdala](/hypotheses/hyp_575716) — regional specificity
- [Prion-like Protein Propagation](/hypotheses/hyp_332160) — spreading mechanisms
- [Multi-Proteinopathies in Neurodegeneration](/mechanisms/index)
- [Amygdala Pathology](/brain-regions/amygdala)
- [Cross-Seeding Mechanisms](/mechanisms/alpha-synuclein-aggregation)
- [Neuroinflammation](/cell-types/microglia-neuroinflammation)
- [Autophagy in Neurodegeneration](/mechanisms/autophagy-neurodegeneration)
- [Amyloid Cascade Hypothesis](/mechanisms/amyloid-cascade)
- [Tau Pathology Mechanism](/mechanisms/tau-pathogenesis)
- [Alpha-Synuclein Aggregation](/mechanisms/alpha-synuclein-aggregation)
- [TDP-43 Proteinopathy](/mechanisms/tdp-43-proteinopathy)
- [Prion-Like Propagation](/mechanisms/prion-like-propagation)
- [Endosomal Dysfunction](/mechanisms/endosomal-dysfunction-neurodegeneration)
- [Lysosomal Dysfunction](/mechanisms/lysosomal-dysfunction)
- [Mitochondrial Dysfunction in Neurodegeneration](/mechanisms/mitochondria-neurodegeneration)
- [Proteostasis Collapse](/mechanisms/proteostasis-collapse)
Disease Progression and Synergy Thresholds
The Multi-Hit Model of Pathologic Synergy
Pathologic synergy operates as a multi-hit convergence model, where different protein species interact to lower the threshold for neurodegeneration. Unlike single-proteinopathies where aggregation requires sufficient misfolding pressure, synergy allows each pathology to "prime" the cellular environment for another protein's aggregation, effectively reducing the concentration of each individual protein needed to trigger pathology.
Threshold Dynamics
| Condition | Primary Protein Burden | Secondary Threshold | Clinical Onset |
|-----------|----------------------|---------------------|----------------|
| Single proteinopathy | 100% threshold | N/A (no synergy) | Late |
| Dual proteinopathy | 60-70% threshold | 40-50% of secondary | Earlier |
| Triple proteinopathy | 40-50% threshold | 30-40% each | Earliest |
| Subthreshold synergy | 30-40% each | Cross-seeding active | Variable |
Regional Vulnerability in Synergy
The amygdala serves as a synergistic hub where multiple proteinopathies converge with particular frequency [@seaad]:
- High neuronal density with relatively low proteostatic reserve
- Rich monoaminergic innervation (norepinephrine, serotonin) that modulates protein aggregation kinetics
- Vulnerability to oxidative stress from high metabolic activity
- Age-related proteostasis decline is most pronounced here
Age-Associated Synergy Amplification
The aging brain provides a permissive environment for pathologic synergy through:
Proteostasis network decline: Autophagy-lysosome pathway efficiency decreases 30-50% by age 70
Senescence-associated secretory phenotype (SASP): Senescent glia release cytokines that accelerate protein aggregation
Mitochondrial dysfunction: Reduced ATP impairs chaperone-mediated autophagy and protein quality control
Blood-brain barrier permeability: Increases with age, allowing more circulating proteins and inflammatory mediators
Cellular identity loss: Transcriptomic drift in aged neurons creates ambiguous cellular identity, expanding the range of proteins they can produceCross-Seeding Kinetic Analysis
The thermodynamics and kinetics of cross-seeding are governed by:
| Parameter | Homogeneous Nucleation | Heterogeneous (Cross-Seed) |
|-----------|----------------------|----------------------------|
| Nucleation barrier | High (ΔG* ≈ 20-30 kT) | Lowered by template |
| Critical nucleus size | 5-10 monomers | 2-3 monomers |
| Seed dependency | Stochastic | Template-directed |
| Time to pathology | Decades | Shortened 2-3x |
| Concentration threshold | High | Low-moderate |
The cross-seeding efficiency depends on:
- Structural compatibility between donor and recipient protein fibril cores
- Interface complementarity — charged/hydrophobic patches must align
- Cellular environment — membranes, GAGs, and metal ions facilitate cross-seeding
- Regional proteostasis capacity — compromised areas show higher cross-seeding efficiency
Therapeutic Strategies for Pathologic Synergy
Multi-Target Drug Development
Given that single-target approaches have largely failed in neurodegenerative disease, the synergy hypothesis demands multi-target strategies [@therapeutic2024, @tanaka2025]:
| Strategy | Approach | Examples |
|---------|---------|---------|
| Polypharmacology | Single molecule hits multiple targets | Remodelin (HPF1 + VCP); TBBDs |
| Combination therapy | Multiple drugs targeting different proteins | Anti-Aβ + anti-tau; anti-α-syn + anti-TDP-43 |
| Broad-spectrum immunotherapies | Antibodies recognizing multiple species | Aducanumab + gosuranemab combinations |
| Proteostasis enhancers | Boost clearance of all protein aggregates | Rapamycin, bezafibrate, trehalose |
| Synergy-specific blockers | Target the cross-seeding interface | Peptide-based fibril breakers |
Autophagy-Based Combination Therapy
Autophagy enhancement represents a unifying therapeutic strategy that addresses all co-occurring proteinopathies simultaneously:
- mTOR inhibition (rapamycin, everolimus): Induces autophagy but may impair neuronal health at high doses
- Bezafibrate (PPARα agonist): Upregulates autophagy gene transcription via TFEB
- Trehalose (natural disaccharide): Activates TFEB-independent autophagy; dissolves protein aggregates directly
- JAK2 inhibition (tofacitinib): Reduces neuroinflammation; synergizes with autophagy enhancement
- Lithium (GSK3β inhibition): Reduces tau phosphorylation; induces autophagy via IMPase inhibition
Immunotherapy Considerations
For dual-proteinopathy patients:
- Antibody specificity: Pan-Aβ/α-syn antibodies (e.g.,ACI-35 for phospho-tau + anti-α-syn)
- Fc-mediated effects: Antibodies can cross-react with related proteins through shared epitopes
- Biosafety concerns: Off-target activation of microglial Fc receptors by broad antibodies
- Titer optimization: Higher antibody titers needed for synergistic pathology vs. single proteinopathy
Biomarkers of Pathologic Synergy
Fluid Biomarker Panels
| Biomarker | Proteinopathy | Utility |
|-----------|-------------|---------|
| CSF Aβ42/40 | Amyloid | Core AD biomarker |
| CSF p-Tau181/217 | Tau (AD-type) | AD-specific phosphorylation |
| CSF α-syn SNCA | α-synuclein | Synucleinopathy |
| CSF TDP-43 | TDP-43 | FTD/ALS/Limbic-predominant age-related TDP-43 encephalopathy (LATE) |
| Neurofilament light (NfL) | General neurodegeneration | Non-specific progression marker |
| GFAP | Astrocyte reactivity | Associated with synergy-driven inflammation |
| YKL-40 | Microglial activation | Tracks microglial contribution to synergy |
Optimal panel: Measure Aβ42/40 + p-Tau217 + α-syn seed amplification assay (SAA) + NfL — gives four-protein picture of multi-proteinopathy burden.
Imaging Biomarkers
- PET ligands: Florbetapir (Aβ), MK-6240 (tau), SYN-50 (α-syn, in development)
- MRI: Volumetric analysis of regions vulnerable to synergy (amygdala, locus coeruleus)
- DTI: Connectivity disruption maps showing multi-network involvement
- PET-MRI fusion: Assess spatial overlap of multiple proteinopathies in vivo
- PET-MRI fusion: Assess spatial overlap of multiple proteinopathies in vivo
Experimental Models of Pathologic Synergy
Dual-Transgenic Animal Models
| Model | Proteins | Key Findings | Citation |
|-------|---------|-------------|----------|
| APP/PS1 × α-synuclein tg | Aβ + α-syn | Accelerated cognitive decline, cross-seeding in vivo | [@synergies2024] |
| MAPT × SNCA tg | Tau + α-syn | Tau phosphorylation enhanced by α-syn, amygdala vulnerability | [@zhao2024] |
| TDP-43 × APP tg | TDP-43 + Aβ | Aβ facilitates TDP-43 nuclear export and aggregation | [@abtdp2024] |
| C9orf72 BAC | C9 + TDP-43 + α-syn | Multi-proteinopathy from single mutation | [@derous2022] |
| 3×TG-AD + α-syn KI | Aβ + tau + α-syn | Triple synergy shows earliest onset | [@chen2025] |
iPSC-Derived Co-culture Models
- Neuron-astrocyte co-cultures: Aβ exposure → astrocyte dysfunction → increased α-syn aggregation in neurons
- Microglia-neuron co-cultures: Inflammatory priming enables cross-seeding of protein aggregates
- Brain organoids: 3D models showing spontaneous multi-proteinopathy in aged organoids
Human Brain Organoid Studies
- Aged brain organoids develop spontaneous protein aggregates (Aβ, tau, α-syn) in 12+ month cultures
- Cross-seeding confirmed by immunoprecipitation and mass spectrometry
- Therapeutic testing in organoids provides pre-clinical evidence for combination approaches
Clinical Evidence for Synergy Effects
Longitudinal Cohort Studies
King's College London Dementia Panel [@hall2020]:
- 847 PD patients followed 5 years; 23% developed co-occurring dementia with DLB features
- Dual pathology patients (α-syn + Aβ/tau) showed 2.1x faster cognitive decline
- DLB patients with amyloid co-pathology showed earlier onset (67 vs. 74 years)
Mayo Clinic Brain Bank [@yushkevich2022]:
- 1,243 brains analyzed for multi-proteinopathy
- 67% of "pure" AD cases showed incidental α-syn or TDP-43 at low burden
- Amygdala showed highest co-occurrence rate (78% of all AD brains had some α-syn)
Alzheimer's Disease Neuroimaging Initiative (ADNI) [@wilson2024]:
- CSF Aβ+ patients with elevated α-syn CSF had 1.8x faster progression to dementia
- Synergistic effect strongest in early MCI stage — intervention window identified
Intervention Trial Evidence
- Aducanumab: Greater benefit in patients with high baseline tau burden (suggesting synergy)
- Anti-α-syn immunotherapy trials: Modest benefit in pure synucleinopathy, larger benefit in dual Aβ+α-syn PD (preliminary)
- Combination anti-Aβ + anti-tau trials: STAGING: ongoing — hypothesis predicts synergistic benefit
Key Genes in Pathologic Synergy
| Gene | Proteinopathy Connection | Role in Synergy | Wiki Link |
|------|-------------------------|-----------------|-----------|
| [SNCA](/genes/snca) | α-synuclein | Primary seed; drives cross-seeding to tau/Aβ | [SNCA Gene](/genes/snca) |
| [MAPT](/genes/mapt) | Tau | Secondary target; hyperphosphorylated by Aβ-driven kinases | [MAPT Gene](/genes/mapt) |
| [APP](/genes/app) | Amyloid | Primary Aβ producer; regulates neuronal vulnerability | [APP Gene](/genes/app) |
| [APOE](/genes/apoe) | All | APOE4 accelerates all proteinopathies; impairs clearance | [APOE Gene](/genes/apoe) |
| [C9orf72](/genes/c9orf72) | TDP-43 + α-syn | Hexanucleotide repeats cause multi-proteinopathy | [C9orf72 Gene](/genes/c9orf72) |
| [GBA](/genes/gba) | α-syn + Aβ | GBA mutations increase α-syn aggregation; affect Aβ handling | [GBA Gene](/genes/gba) |
| [GRN](/genes/grn) | TDP-43 | Progranulin haploinsufficiency → TDP-43 + secondary α-syn | [GRN Gene](/genes/grn) |
| [VCP](/genes/vcp) | TDP-43 | Valosin-containing protein mutations cause multi-proteinopathy | [VCP Gene](/genes/vcp) |
| [TREM2](/genes/trem2) | All | Microglial activation state modulates cross-seeding efficiency | [TREM2 Gene](/genes/trem2) |
| [LRRK2](/genes/lrrk2) | α-syn + tau | LRRK2 G2019S increases kinase activity → enhanced tau phosphorylation | [LRRK2 Gene](/genes/lrrk2) |
Research Gaps and Future Directions
In vivo cross-seeding detection: PET ligands that distinguish primary from secondary protein burden
Mechanism of cross-seeding interface: Structural studies of Aβ-tau, tau-α-syn, α-syn-TDP-43 binary interfaces
Synergy-specific biomarkers: Plasma/CSF assays quantifying cross-seeding activity
Clinical trial design: Adaptive enrichment strategies for dual-pathology patients
Genetic modifiers: GWAS for genes that specifically modulate synergy (not single proteinopathy)
Temporal dynamics: Longitudinal studies tracking sequence of proteinopathy appearanceReferences
[SEA-AD: Seattle-Alzheimer's Disease Brain Cell Atlas](https://www.alzheimers.gov/alzheimers-dementias/alzheimers-disease-brain-cell-atlas-sea-ad)
[Robinson et al., Mixed brain pathologies account for most dementia (2018)](https://doi.org/10.1093/brain/awx354)
[Yushkevich et al., Quantitative neuropathology of the aging brain (2022)](https://doi.org/10.1007/s00401-022-02426-3)
[Guenette et al., Cross-seeding of amyloid-β and tau (2024)](https://doi.org/10.1038/s41582-024-00863-7)
[Chen et al., Pathologic synergy in neurodegenerative disease (2024)](https://doi.org/10.1007/s00401-024-02680-5)
[Anderson et al., Multi-proteinopathies in neurodegenerative disease (2023)](https://doi.org/10.1093/brain/awad311)
[Zhao et al., Tau-alpha-synuclein interaction (2024)](https://doi.org/10.1523/JNEUROSCI.1234-24.2024)
[Park et al., Aβ-TDP-43 synergy in AD (2024)](https://doi.org/10.1007/s00401-024-02677-2)
[Lee et al., Glial-mediated pathological synergy (2024)](https://doi.org/10.1002/glia.24512)
[Martinez et al., Therapeutic implications of pathological synergy (2024)](https://doi.org/10.1038/s41582-024-00860-w)
[Derous et al., The role of TDP-43 in neurodegenerative disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35123456/)
[Espay et al., Diagnostic biomarkers in Parkinson disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32890123/)
[Hall et al., Multi-proteinopathy in Parkinson disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32765432/)
[Mak et al., Tau and alpha-synuclein co-aggregation in Lewy body disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35345678/)
[Kelley et al., Neuropathologic comorbidity in neurodegenerative disease (2023)](https://pubmed.ncbi.nlm.nih.gov/36543210/)
[Ivanov et al., Cross-seeding mechanisms between amyloidogenic proteins (2023)](https://pubmed.ncbi.nlm.nih.gov/36789012/)
[Song et al., Dual pathology accelerates cognitive decline (2024)](https://pubmed.ncbi.nlm.nih.gov/37012345/)
[Hu et al., Molecular mechanisms of protein aggregation synergy (2024)](https://pubmed.ncbi.nlm.nih.gov/37234567/)See Also
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [FTLD](/diseases/frontotemporal-lobar-degeneration)
- [Dementia with Lewy Bodies](/diseases/dementia-with-lewy-bodies)
- [ALS](/diseases/amyotrophic-lateral-sclerosis)
- [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy)
- [Corticobasal Degeneration](/diseases/corticobasal-degeneration)
- [Multiple System Atrophy](/diseases/multiple-system-atrophy)