| Patient Profile | |
|---|---|
| Age/Sex | 50-year-old male |
| Diagnosis | Suspected CBS or PSP (differential pending) |
| Alpha-synuclein | NEGATIVE (SAA) |
| DAT Scan | Dopamine neuron loss confirmed |
| Current Meds | Levodopa, rasagiline (MAO-B inhibitor) |
| Symptoms | Gait issues, hand tremors |
| Resources | Able to afford custom R&D and tailored therapies |
| Section | Description |
|---|---|
| 1. Ranked Therapies | Therapies ranked by efficacy and safety |
| 2. Ranked Diagnostics | 19 diagnostic tests ranked by utility |
| 3. Top Recommendations | Priority actions: diagnostics first, then therapies, then trials |
| 4. Deep Dive Topics | 45 ranked topics: disease modification, neuroprotection, diagnostics, strategy |
| 5. Therapy Details | Per-therapy analysis with evidence, trials, and assessment |
| 6. Diagnostic Details | Per-test detail with off-page links |
| 7. Supplements Guide | 21 supplement profiles with dosing |
| 8. Clinical Management | Symptom management, rehab, caregiver support |
| 9. Specialists and Clinics | Movement disorder centers and CBS/PSP experts |
| 10. Foundations and Support | Patient organizations and resources |
| 11. Custom R&D | N-of-1 trials, iPSC screening, compassionate use |
| 12. Knowledge Gaps | Research priorities and open questions |
| 13. Research Updates | 2025-2026 findings |
| 14. Cross-Links | Related pages and references |
| Rank | Therapy | Mechanism | Efficacy | Safety | Evidence | Cost |
|---|---|---|---|---|---|---|
| 1 | Levodopa | Dopamine precursor → DA replacement | 7 | 8 | Approved | $$ |
| 2 | Rasagiline | MAO-B inhibitor → DA preservation | 5 | 9 | Approved | $$ |
| 3 | Exercise | BDNF elevation → neuroplasticity | 7 | 10 | Strong clinical | $ |
| 4 | E2814 | Anti-MTBR tau mAb → block aggregation | 7 | 8 | Phase 3 | Free |
| 5 | BIIB080 | Tau ASO → MAPT gene silencing | 6 | 8 | Phase 2 | Free |
| 6 | Tai Chi | Balance/proprioception → fall reduction | 6 | 10 | Strong clinical | $ |
| 6b | Yoga/Mind-Body | Chair yoga, pranayama, stress modulation → motor, autonomic, mood | 6 | 10 | Strong clinical | $ |
| 6c | Mindfulness/Meditation | MBSR/MBCT, stress reduction, neuroplasticity, HPA axis modulation | 6 | 10 | Strong clinical | $ |
| 6d | Dance/Movement Therapy | Rhythmic movement → BDNF, neuroplasticity, balance, mood | 5 | 10 | Moderate clinical | $ |
| 7 | Lixisenatide | GLP-1R agonist → motor stabilization (p=0.007) | 6 | 6 | Phase 2 positive | $$ |
| 8 | Bepranemab | Anti-aggregated tau mAb → 33-58% tau slowing | 6 | 8 | Phase 2 | Free |
| 9 | FNP-223 | OGA inhibitor → tau O-GlcNAcylation | 5 | 7 | Phase 2 (PSP, n=220) | Free |
| 10 | NACET | Glutathione precursor → BBB-penetrant antioxidant; synergistic with levodopa+rasagiline | 5 | 9 | Phase 2 (IV NAC: DAT+) | $ |
| 11 | Posdinemab | Anti-tau mAb → FDA Fast Track | 5 | 7 | Phase 2 | Free |
| 12 | BMS-986446 | Anti-MTBR-tau mAb → FDA Fast Track | 5 | 7 | Phase 2 | Free |
| 13 | Lithium | GSK-3β inhibitor → reduce tau phosphorylation | 5 | 5 | Phase 2 (PSP) | $ |
| 14 | Pramipexole | D2/D3 dopamine agonist → motor relief | 5 | 6 | Approved | $$ |
| 15 | AADvac1 | Tau vaccine → anti-tau immune response | 5 | 7 | Phase 2 (PSP platform) | Free |
| 16 | Amantadine | NMDA antagonist → reduce dyskinesias | 5 | 7 | Approved | $ |
| 17 | Entacapone | COMT inhibitor → extend levodopa effect | 5 | 8 | Approved | $ |
| 18 | AZP2006 | Neuroprotective peptide → PSP platform trial | 5 | 7 | Phase 2a positive | Free |
| 19 | Safinamide | MAO-B + Na channel → dual mechanism | 5 | 8 | Approved | $$ |
| 20 | Rotigotine | D1-D5 agonist patch → continuous delivery | 5 | 7 | Approved | $$$ |
| 21 | Sodium selenate | PP2A activator → tau dephosphorylation | 5 | 7 | Phase 2 | $$ |
| 22 | CoQ10 | ETC Complex I/III → mitochondria | 3 | 9 | Phase 2/3 NEGATIVE | $$ |
| 23 | NAC | Glutathione precursor → oxidative stress | 4 | 9 | Clinical | $ |
| 24 | Gasotransmitter Therapy | NO/CO/H2S modulation → anti-inflammatory, mitochondrial protection | 3 | 8 | Research | $ |
| 25 | Liraglutide | GLP-1R agonist → brain volume preservation | 5 | 7 | Phase 2 | $$ |
| 26 | Urolithin A | Mitophagy inducer → clear damaged mitochondria | 4 | 9 | Phase 2 | $$$ |
| 27 | Semaglutide | GLP-1R agonist (oral) → anti-inflammatory, CNS penetration | 4 | 7 | Phase 2 completed (MOST-ABLE); AD indication failed; PD results reported | $$ |
| 28 | Tirzepatide | Dual GIP/GLP-1 agonist → enhanced neuroprotection | 6 | 6 | Phase 2 for AD/PD | $$ |
| 29 | Retatrutide | Triple GIP/GLP-1/FGF21 agonist → multi-receptor neuroprotection | 6 | 6 | Phase 1/2; strong preclinical | $$ |
| 30 | Cotadutide | Dual GLP-1/glucagon agonist → enhanced metabolic/mitochondrial support | 5 | 7 | Phase 1; preclinical neuroprotection | $$ |
| 31 | Creatine | Phosphocreatine → cellular energy buffer | 4 | 9 | Clinical | $ |
| 32 | Omega-3 DHA | Anti-inflammatory → membrane fluidity | 4 | 9 | Clinical | $$ |
| 33 | Alpha-lipoic acid | Mitochondrial antioxidant → redox cycling | 4 | 8 | Clinical | $ |
| 34 | Vitamin D3 | VDR activation → neuroprotection | 4 | 9 | Clinical | $ |
| 35 | Vitamin B12 | Methylcobalamin → myelin maintenance | 5 | 9 | Clinical | $ |
| 36 | Magnesium L-Threonate | NMDA modulation → synaptic plasticity | 4 | 8 | Preliminary | $$ |
| 37 | Exenatide | GLP-1R agonist → Phase 3 failed | 3 | 7 | Phase 3 failed | $$ |
| 38 | Lion's Mane | Hericenones/erinacines → NGF stimulation | 3 | 8 | Preliminary | $$ |
| 39 | Sulforaphane | NRF2 activator → antioxidant defense | 4 | 8 | Phase 1 | $$ |
| 40 | Curcumin | Anti-inflammatory → NF-κB inhibition | 3 | 8 | Preclinical | $ |
| 41 | NMN | NAD+ precursor → mitochondrial function | 3 | 8 | Phase 2 | $$ |
| 42 | NR | NAD+ precursor → sirtuin activation | 3 | 8 | Phase 2 | $$ |
| 43 | PQQ | Cofactor → mitochondrial biogenesis | 3 | 8 | Preclinical | $$ |
| 44 | PLX5622 | CSF1R inhibitor → microglial depletion | 5 | 6 | Phase 2 | $$$ |
| 45 | TREM2 agonists | TREM2 → enhance microglial phagocytosis | 4 | 7 | Phase 2 PAUSED (AL002 stopped May 2024) | $$$$ |
| 46 | LDN | Low-dose opioid antagonism → glial modulation | 3 | 7 | Case reports | $$ |
| 47 | DBS (GPi) | Electrical stimulation → motor circuits | 6 | 6 | Approved | $$$$ |
| 48 | Focused ultrasound | HIFU thalamotomy → tremor ablation | 5 | 7 | Approved | $$$$ |
| 49 | TMS | Magnetic stimulation → cortical excitability | 4 | 8 | Experimental | $$$ |
| 50 | CDNF gene therapy | AAV-CDNF → ER stress reduction | 5 | 7 | Phase 1/2 | $$$$ |
| 51 | GDNF infusion | Neurotrophic factor → DA neuron survival | 5 | 6 | Phase 2 | $$$$ |
| 52 | Stem cell therapy | iPSC-DA neurons → cell replacement | 5 | 6 | Phase 1-3 | $$$$ |
| 53 | Mito transplant | Healthy mitochondria → restore energy | 4 | 7 | Phase 1 | $$$$ |
| 54 | Mitochondrial dynamics | Fission/fusion + PGC-1α + mitophagy + mtDNA → restore function | 4 | 8 | Clinical | $$ |
| 55 | Exosome therapy | Engineered EVs → BBB drug delivery | 3 | 7 | Preclinical | $$$$ |
| 56 | SCFA therapy | Microbiome metabolites → anti-inflammatory, HDAC inhibition | 4 | 8 | Emerging | $ |
| 57 | Nilotinib | BCR-ABL inhibitor → autophagy | 3 | 5 | Phase 2 | $$ |
| 58 | Cytoskeletal targeting | Microtubule stabilization → axonal transport | 4 | 7 | Phase 1/2 | $$$ |
| 59 | Deferiprone | Iron chelator → brain iron reduction | 3 | 5 | Phase 2 | $$ |
| 60 | Ibuprofen | COX inhibitor → neuroinflammation | 2 | 6 | Epidemiological | $ |
| 61 | Isradipine | Ca²⁺ channel blocker → Phase 3 failed | 2 | 6 | Phase 3 failed | $ |
| 62 | Pioglitazone | PPARγ agonist → Phase 3 failed | 2 | 5 | Phase 3 failed | $ |
| 63 | Minocycline | Microglial inhibition — failed | 2 | 6 | Phase 2 failed | $ |
| 64 | HSP70/HSP90 Modulators | Chaperone modulation → proteostasis | 4 | 6 | Preclinical/Phase 1 | $$ |
| 65 | PARP Inhibitors + NAD+ | DNA repair modulation, NAD+ preservation, SIRT1 combo | 4 | 6 | Preclinical/Phase 1 | $$ |
| 66 | Thyroid optimization | Thyroid axis optimization → neuronal metabolism | 4 | 9 | Clinical | $ |
| 67 | Dental Health | Oral microbiome, periodontitis → reduce inflammatory burden | 4 | 9 | Clinical | $ |
| 68 | Sialic Acid Therapy | Siglec modulation → neuroinflammation, glycan-based tau targeting | 4 | 7 | Phase 1/2 | $$ |
| 69 | Copper/Zinc Homeostasis | Metal chelation, metallothionein modulation → reduce tau phosphorylation | 4 | 7 | Investigational | $ |
| 70 | NO/Gasotransmitter Therapy | NO modulation, CORMs, H2S donors → mitochondrial protection, anti-inflammatory | 3 | 8 | Research | $ |
| 71 | AP39/Mitochondria-targeted H2S | Mitochondria-targeted H2S delivery → oxidative stress reduction | 4 | 7 | Preclinical | $$ |
| 72 | GYY4137 H2S donor | Slow H2S release → anti-inflammatory, Nrf2 activation | 4 | 7 | Research | $$ |
| Rank | Test | Priority | What It Reveals | Cost |
|---|---|---|---|---|
| 1 | Tau PET (flortaucipir) | 10 | Tau burden pattern — CBS vs PSP differentiation | $$$$ |
| 2 | Genetic panel | 10 | Actionable mutations (GBA, MAPT, LRRK2) | $$$ |
| 3 | MRI with volumetrics | 9 | Atrophy pattern — hummingbird sign (PSP) | $$$ |
| 4 | CSF biomarkers | 9 | Tau, NfL, GFAP — disease staging | $$ |
| 5 | Blood biomarkers | 8 | p-tau217, NfL, GFAP — non-invasive panel | $ |
| 6 | FDG-PET | 8 | Metabolic pattern — frontoparietal vs brainstem | $$$$ |
| 7 | Whole genome sequencing | 8 | Structural variants, repeat expansions (if panel negative) | $$$$ |
| 8 | Alpha-synuclein SAA | 8 | Rule out synucleinopathy (already negative) | $$ |
| 9 | Amyloid PET | 7 | Rule out AD comorbidity — mixed pathology | $$$$ |
| 10 | Cardiac MIBG | 7 | Autonomic innervation — preserved = tauopathy | $$$ |
| 13 | DaT-SPECT | 7 | Dopamine transporter loss (already done) | $$$ |
| 14 | DTI MRI | 7 | White matter tract integrity — fall prediction | $$ |
| 15 | Neuropsych testing | 7 | Apraxia (CBS) vs executive dysfunction (PSP) | $$ |
| 16 | Neuromelanin MRI | 7 | Substantia nigra neuron loss quantification | $$ |
| 17 | Eye tracking | 6 | Vertical gaze palsy — PSP hallmark | $ |
| 18 | SWI/QSM iron imaging | 6 | Brain iron accumulation quantification | $$ |
| 19 | Skin biopsy | 6 | Phospho-tau in cutaneous nerves (emerging) | $$ |
| 20 | Sleep study | 5 | RBD suggests synucleinopathy, not tauopathy | $$ |
| 21 | Autonomic testing | 5 | Orthostatic hypotension, HRV patterns | $ |
These recommendations span four complementary goals that should be pursued in parallel:
Curated index of the most impactful topics for understanding and treating CBS/PSP. Ranked by clinical impact and evidence strength. Click any topic for the full analysis.
| Rank | Topic | Impact | Evidence | Full Page |
|---|---|---|---|---|
| 1 | Anti-tau immunotherapy | 10 | 8 | Tau-Targeted Therapeutics |
| 2 | Tau gene therapy (ASO/gene silencing) | 10 | 7 | Tau-Targeted Therapeutics |
| 3 | OGA inhibition (tau O-GlcNAcylation) | 9 | 7 | OGA Inhibitor Landscape · Tau Therapeutics |
| 4 | Autophagy-lysosome enhancement | 9 | 6 | Autophagy Inducers |
| 5 | Tau spreading/seeding mechanisms | 9 | 7 | Tau Propagation |
| 6 | Neuroinflammation (microglial modulation) | 9 | 7 | Neuroinflammation in PSP |
| 7 | CSF1R / TREM2 microglial targeting | 8 | 6 | CSF1R Inhibitors · TREM2 Therapeutics |
| 8 | Proteostasis / protein quality control | 8 | 5 | Protein Quality Control |
| 9 | Molecular chaperones (HSP70/HSP90) | 7 | 5 | Molecular Chaperones |
| 10 | Combination therapy design | 9 | 4 | Combination Therapy Synergies |
| Rank | Topic | Impact | Evidence | Full Page |
|---|---|---|---|---|
| 11 | GLP-1 receptor agonists | 8 | 7 | GLP-1 Agonists |
| 12 | Mitochondrial support (CoQ10, urolithin A) | 7 | 6 | CoQ10 · Urolithin A |
| 13 | Mitochondrial transplantation | 7 | 4 | Mito Transplant |
| 14 | Growth factors / neurotrophins | 7 | 5 | Neurotrophic Factor Therapies |
| 15 | NAD+ metabolism (NMN/NR) | 6 | 5 | Supplements Guide |
| 16 | Iron chelation | 6 | 5 | Deferiprone |
| 17 | NRF2 / antioxidant defense | 6 | 4 | NRF2 Activators |
| 18 | Calcium homeostasis | 6 | 5 | Calcium Dysregulation |
| 19 | Progranulin / lysosome enhancement (AZP2006) | 7 | 5 | AZP2006 (Serazaxine) — PSP Platform Trial |
| Rank | Topic | Impact | Evidence | Full Page |
|---|---|---|---|---|
| 19 | Stem cell therapy (iPSC-DA) | 8 | 6 | Stem Cells for Parkinsonism |
| 20 | Gene therapy (CDNF, GDNF, AAV) | 8 | 5 | Neurotrophic Gene Therapy Programs |
| 21 | Exosome-based drug delivery | 6 | 3 | Exosome Therapy |
| 22 | iPSC drug screening | 7 | 5 | iPSC Screening CBS/PSP |
| Rank | Topic | Impact | Evidence | Full Page |
|---|---|---|---|---|
| 23 | Blood biomarkers (p-tau217, NfL, GFAP) | 9 | 8 | CBS/PSP Plasma Biomarkers |
| 24 | Tau PET imaging (4R-specific tracers) | 9 | 7 | Tau PET CBS/PSP |
| 25 | Neurofilament dynamics | 8 | 8 | NfL |
| 26 | Whole genome sequencing | 7 | 7 | WGS Guide |
| 27 | Pharmacogenomics | 6 | 5 | Pharmacogenomics CBS/PSP |
| 28 | Wearable sensors / digital biomarkers (CBS/PSP) | 7 | 6 | Wearable Sensors CBS/PSP |
| Rank | Topic | Impact | Evidence | Full Page |
|---|---|---|---|---|
| 30 | Sleep / circadian optimization | 8 | 6 | Sleep Disorders CBS/PSP |
| 31 | Exercise and rehabilitation | 8 | 8 | Exercise CBS/PSP |
| 32 | Pain management | 7 | 5 | Pain Management CBS/PSP |
| 33 | Psychosocial / cognitive reserve | 7 | 5 | Psychosocial CBS/PSP |
| 34 | Respiratory / dysphagia | 7 | 6 | Respiratory CBS/PSP |
| 35 | Ketogenic / metabolic therapy | 6 | 4 | Ketogenic Diet |
| 36 | Device therapies (DBS, FUS, TMS) | 7 | 6 | Device Therapies CBS/PSP |
| Rank | Topic | Impact | Evidence | Full Page |
|---|---|---|---|---|
| 37 | CBS/PSP Cure Roadmap | 10 | — | Cure Roadmap |
| 38 | Experiment Priorities | 9 | — | Experiment Index |
| 39 | Cure Requirements Index | 9 | — | Cure Requirements |
| 40 | Computational pharmacology / AI | 7 | 4 | Computational Tools |
| 41 | Multi-omics integration | 7 | 5 | Multi-Omics |
| 42 | Precision medicine / patient stratification | 8 | 5 | Precision Medicine |
| 43 | Microbiome-gut-brain axis | 6 | 4 | Gut-Brain Axis |
| 44 | Circadian rhythm dysfunction | 6 | 4 | Circadian CBD |
| 45 | BBB / neuroimmune interface | 7 | 5 | BBB Dysfunction |
| 46 | Quantum biology (theoretical) | 3 | 1 | Quantum Biology |
Dopamine replacement. Standard first-line. Try high-dose up to 2000mg/d with entacapone.
Pooled effect size in PSP: d=0.23 (small). NCT03744468 Phase 2 (75 PD): no significant diff vs placebo.
More: Levodopa
MAO-B inhibitor. Patient is currently taking this. Irreversible MAO-B inhibition provides modest symptomatic benefit and possible neuroprotection.
ADAGIO trial (NCT00256204): 1mg/day delayed need for symptomatic therapy in early PD (HR 0.82, p=0.02). No CBS/PSP-specific trials.
More: Rasagiline | MAO-B Inhibitors
BDNF elevation, neuroplasticity. Aim 150+ min/week vigorous. Modalities: treadmill, boxing (Rocksteady), Tai Chi, dance.
More: Exercise for CBS/PSP | Exercise-Induced Myokines | Rehabilitation Guide
Anti-tau mAb targeting MTBR. Phase 2 for 4R-tauopathies (NCT05615614). Part of DIAN-TU Phase 3 for AD. ~150 patients, monthly IV. Sponsor: Eisai.
DIAN-TU data: CSF pTau217 ~50% reduction at 2 years. 39 sites worldwide. NCT05615614.
More: Tau-Targeted Therapeutics
Tau ASO targeting MAPT gene. Intrathecal delivery every 3-6 months. ~60 patients Phase 1/2. Sponsor: Biogen/Ionis.
More: Tau-Targeted Therapeutics
Mitochondrial ETC support. 300-600mg/day.
Phase 3 trials definitively negative for disease modification in both PSP and PD.
More: CoQ10 | CoQ10 Details
Anti-tau mAb targeting aggregated tau. TOGETHER Phase 2 (80 weeks): slowed tau accumulation by 33-58% relative to placebo — first clinical demonstration of tau slowing. Sponsor: UCB.
More: Tau-Targeted Therapeutics
Anti-tau mAb. FDA Fast Track designation (2025). Phase 2 for tauopathies.
More: Tau-Targeted Therapeutics
Anti-MTBR-tau mAb. FDA Fast Track designation (2025). Bristol Myers Squibb. Targets same tau region as E2814.
More: Tau-Targeted Therapeutics
OGA inhibitor that increases tau O-GlcNAcylation, competing with pathological phosphorylation. PROSPER Phase 2 in PSP completed recruitment of 220 patients across 44 sites (EU, UK, US) in October 2025 — 2 months ahead of schedule. Sponsor: Ferrer.
More: FNP-223 (Ferrer OGA Inhibitor) — dedicated therapeutic page
Active immunotherapy generating antibodies against pathological tau. Selected for the PSP Phase 2 Platform Trial alongside AZP2006. Enrollment starting end 2025.
More: CurePSP Platform Trial
Neuroprotective peptide with "encouraging clinical and biomarker signals" in Phase 2a for PSP. Positive 6-month open-label extension. Selected for PSP Platform Trial.
More: AZP2006 (Serazaxine) — PSP Platform Trial
Dopamine agonist.
NCT03022088 Phase 4 (415 PD): significant improvement (d=0.45).
More: Pramipexole | Dopamine Agonists
NMDA antagonist. Helps levodopa-induced dyskinesias.
NCT03882892 Phase 4 (52 PD): significant dyskinesia reduction (d=0.68).
More: Amantadine
COMT inhibitor. Enhances levodopa effect.
NCT01567415 Phase 4 (168 PD): ON time +1.3h/day (p<0.001).
More: Entacapone | COMT Inhibitors
MAO-B inhibitor + sodium channel modulation.
NCT01023880 Phase 3 (544 PD): UPDRS improvement 2.6 pts (p=0.02).
More: MAO-B Inhibitors
Dopamine agonist. Continuous transdermal delivery.
NCT00474638 Phase 3 (395 PD): UPDRS improvement -6.8 pts (p<0.001).
More: Rotigotine | Dopamine Agonists
GSK-3beta inhibitor. Directly targets tau phosphorylation.
More: Lithium Therapy
PP2A activator. Tau dephosphorylation. IV formulation.
NCT02434588 Phase 2 (93 PSP): primary not met (p=0.14); subgroup -4.2 pts vs +1.1 placebo (p=0.01, d=0.68). CSF p-tau181 reduced 18%.
N-acetylcysteine ethyl ester. Glutathione precursor, 3-5x superior BBB penetration vs oral NAC (~60-70% bioavailability vs NAC's 6-10%). 600mg 2x/day.
More: NACET Details | Supplements Guide
N-acetylcysteine. Glutathione precursor. IV formulation studied in PD.
More: NAC for Neurodegeneration | NACET Details
Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) signaling modulation. Endogenous gasotransmitters regulate neuroinflammation, mitochondrial function, and protein homeostasis. Deficiencies in CBS/PSP suggest therapeutic potential.
More: Section 250: Advanced Gasotransmitter Therapy
GLP-1 receptor agonist. Insulin signaling rescue, anti-inflammatory, neuroprotective. Phase 3 failed in PD (Lancet Feb 2025, n=194, 96 weeks) — no significant benefit vs placebo despite promising Phase 2 signals. CSF analysis suggests insufficient brain penetration at tested dose.
More: GLP-1 Receptor Agonists — full comparison table, dosing, combination considerations, and trial details for all GLP-1 agonists
GLP-1 agonist. Most promising GLP-1 for PD — only agent to meet a Phase 2 primary endpoint.
More: GLP-1 Receptor Agonists
GLP-1 agonist. Daily SC injection. Higher CNS penetration than exenatide. ELAD trial in AD showed 50% less brain volume loss but missed primary metabolic endpoint.
More: Liraglutide | GLP-1 Receptor Agonists
GLP-1 agonist. Available oral (14mg daily) or SC (weekly). Widely used for T2D/obesity.
More: GLP-1 Receptor Agonists | Tirzepatide
Dual GIP/GLP-1 receptor agonist (marketed as Mounjaro® for T2D). Co-activates both GIP and GLP-1 receptors, providing synergistic neuroprotective effects beyond single GLP-1 agonists.
More: Tirzepatide | GLP-1 Receptor Agonists
Triple GIP/GLP-1/FGF21 receptor agonist (LY3437943, Eli Lilly). Activates three metabolic receptors, providing the broadest incretin-based neuroprotection to date.
More: Tirzepatide | GLP-1 Receptor Agonists
Dual GLP-1/glucagon receptor agonist (MedImmune/AstraZeneca). Activates GLP-1R and GCGR, with enhanced metabolic benefits and neuroprotective potential.
More: GLP-1 Receptor Agonists
Mitophagy inducer. Clears damaged mitochondria.
More: Urolithin A | Urolithin A Details
Balance/flexibility. Strong clinical evidence in PD.
More: Tai Chi | Exercise for CBS/PSP
Chair yoga, pranayama, meditation, stress modulation. Comprehensive mind-body approach for CBS/PSP.
More: Section 230: Advanced Mindfulness and Meditation | Section 231: Advanced Yoga and Mind-Body Therapy | Section 233: Advanced VR and Immersive Technology | Section 234: Advanced Acupuncture and TCM | Section 238: Advanced Aromatherapy and Olfactory Stimulation | Section 240: Advanced Narrative Therapy and Life Review
Red/NIR light (660-810nm) via transcranial, intranasal, or wearable devices. Targets cytochrome c oxidase, enhances mitochondrial ATP, reduces oxidative stress.
More: Section 243: Advanced Light Therapy
MBSR/MBCT protocols, stress reduction, neuroplasticity, HPA axis modulation. Non-pharmacological approach for stress, anxiety, depression, and cognitive preservation in CBS/PSP.
More: Section 230: Advanced Mindfulness and Meditation
Rhythmic movement, music, and creative expression. Multimodal therapy engaging motor, cognitive, and emotional pathways.
More: Section 228: Advanced Dance/Movement Therapy
Cellular energy. 5g/day. Safe, cheap.
More: Creatine | Creatine Details
Anti-inflammatory. 2000mg/day.
More: Omega-3 Details
Mitochondrial antioxidant. Improves insulin signaling.
More: Alpha-Lipoic Acid | Alpha-Lipoic Details
Multiple neuroprotective mechanisms. Dose per serum levels.
More: Vitamin D3 Details
Methylcobalamin. Nerve health.
More: Vitamin B12 Details
NMDA modulation. May help sleep/cognition.
More: Magnesium Details
NGF stimulation. Hericium erinaceus.
More: Lion's Mane Details
NRF2 activator. Broccoli sprouts.
More: NRF2 Activators | Sulforaphane Details
Anti-inflammatory antioxidant. Low bioavailability — use Theracurmin formulation.
More: Curcumin Details
Nicotinamide mononucleotide. NAD+ precursor. NADAPT trial relevant.
More: NMN Details
Nicotinamide riboside. NAD+ precursor / sirtuin activation.
More: NR Details
Pyrroloquinoline quinone. Mitogenesis.
More: PQQ Details
Brain-penetrant CSF1R inhibitor. Microglial depletion/repopulation.
More: CSF1R Inhibitors
Microglial activation therapy. AL002 (Alector/AbbVie) Phase 2 PAUSED (May 2024) — trial stopped after interim analysis showed worse outcomes in treatment arm vs placebo. AL003 under review. DNL311 (Denali) in Phase 1/2.
More: TREM2 Therapeutics
Deep brain stimulation. GPi target preferred for CBS/PSP.
More: Device Therapies
Non-invasive thalamotomy.
More: Device Therapies
Non-invasive neurostimulation. Lowest-risk device option.
More: Device Therapies
Opioid modulation. Anti-inflammatory via glial modulation. 1.5-4.5mg at bedtime.
More: Anti-Inflammatory Therapy
COX inhibition. Anti-inflammatory.
More: Anti-Inflammatory Therapy
BCR-ABL inhibitor. Increases autophagy.
More: Nilotinib
Iron chelator. May reduce brain iron.
More: Deferiprone
Ca2+ channel blocker. Failed in Phase 3 PD trial.
More: Calcium Channel Blockers
PPARgamma agonist. Failed in Phase 3 AD trial.
More: PPAR Agonists
Tetracycline antibiotic. Microglial inhibition. Failed in multiple trials.
More: Minocycline
Sphingosine-1-phosphate receptor modulator. FDA-approved for secondary progressive MS. Off-label use in neurodegeneration.
More: Section 191: Advanced Lipid Signaling
Chaperone modulation for proteostasis enhancement in tauopathy.
Mechanisms:
Clinical trials:
More: HSP90 Inhibitors | HSP70 Inducers | Molecular Chaperones
Synthetic lethality and NAD+ preservation strategy combining PARP inhibition with NAD+ precursors and SIRT1 activators.
Mechanisms:
Therapeutic protocol:
Drug interactions with current regimen:
Clinical trials:
More: Synthetic Lethality and PARP Inhibition | PARP Inhibitor Therapy | NAD+ Metabolism
Thyroid hormone axis optimization for neuroprotection in tauopathy.
Mechanisms:
Assessment protocol:
Drug interactions:
More: Hormone Neuroprotection
Dental health and oral microbiome management for reducing systemic inflammatory burden in CBS/PSP.
Mechanisms:
Assessment protocol:
Therapeutic approaches:
Drug interactions:
More: Dental Health and Oral Microbiome
Sialic acid therapy and glycobiology approaches for tauopathy targeting Siglec receptors, glycosylation abnormalities, and glycan-based therapeutic delivery.
Mechanisms:
Therapeutic approaches:
Clinical considerations:
Drug interactions:
More: Glycomics Therapy CBS/PSP | CD33 Modulation | Gangliosides
Copper and zinc homeostasis dysregulation in 4R-tauopathies, targeting metallothionein function, metal chelation, and CuATSM imaging.
Mechanisms:
Therapeutic approaches:
Clinical considerations:
Drug interactions:
More: Copper/Zinc Homeostasis CBS/PSP | Copper Homeostasis | Zinc Homeostasis
Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) are endogenously produced gasotransmitters with critical roles in neuronal survival, mitochondrial function, and neuroinflammation modulation.
Key mechanisms:
Evidence: Gasotransmitter pathways impaired in PSP brains [@gas-huang2024]; H2S reduces tau phosphorylation via GSK-3β inhibition [@gas-zhang2024]; CORM-3 protected neurons in MPTP model [@gas-wang2024].
Key interactions:
Phased approach:
More: Section 250: NO/Gasotransmitter Therapy | Gasotransmitters in Neuroprotection
Cerebral dopamine neurotrophic factor. Intracerebral injection.
More: Gene Therapy | Section 241: Advanced Gene Therapy/CRISPR
Glial cell line-derived neurotrophic factor. Requires pump.
More: Neurotrophic Factor Therapies
DA neuron replacement + MSC neuroprotection. Bemdaneprocel Phase III active; STEM-PD higher-dose cohort initiated.
| Trial | Phase | Status | Key Result |
|---|---|---|---|
| Bemdaneprocel (exPDite-2, NCT05887418) | Phase III | Enrolling (~102 pts, 24+ sites, exp. 2027-2028 readout) | 21.9-pt UPDRS-III improvement at 24 mo (Phase I/II) |
| STEM-PD (Lund/Cambridge, EU) | Phase I/IIa | Active — cohort 2 dosing | 100-200K surviving DA neurons at 12 mo; PET evidence of graft survival; no concerning side effects |
| Kyoto iPSC-DA (Japan, NCT04995081) | Phase I/II | Completed | 44.7% increase in putaminal dopamine; 12-month safety confirmed |
| STEM-PD Cohort 2 | Phase I/IIa | Dosing underway | Higher dose: 7M cells/putamen (14M total, vs 3.5M/putamen in cohort 1); first patient grafted during 2024 |
exPDite-2 inclusion criteria (bemdaneprocel, NCT05887418):
For CBS/PSP consideration: A dedicated tauopathy trial would likely follow successful PD registration. Patient should:
More: Stem Cell Therapy for Parkinsonism | iPSC Drug Screening | Section 242: Advanced Stem Cell Therapy
Emerging therapy delivering healthy mitochondria to restore cellular energy. Addresses the tau→mitochondrial damage→ROS→more tau phosphorylation cycle central to CBS/PSP.
| Trial | Phase | Key Result |
|---|---|---|
| NCT04998357 (UW) | Phase 1 | Safe — first human brain mito transplant |
| NCT05094011 (Taiwan) | Phase 1 | Protocol design (9 PD patients) |
More: Mitochondrial Transplantation | Astrocytic Mito Transfer
Therapeutic approaches targeting mitochondrial fission/fusion balance, PGC-1α biogenesis, mitophagy enhancement, and mtDNA maintenance. Addresses the core bioenergetic deficit in CBS/PSP.
Evidence: PGC-1α pathway impaired in CBD [@md-park2024]; Drp1 hyperactivation in PSP [@md-chen2024]; urolithin A shows promise in tauopathy models [@md-lee2024]; CoQ10 trials ongoing in PSP [@md-brown2024].
Key interactions:
More: Section 194: Mitochondrial Dynamics Therapy | Mitochondrial Biogenesis Inducers | NAD+ Boosters
Engineered exosomes for drug delivery across BBB. This section covers advanced EV engineering strategies for CNS delivery in CBS/PSP.
Engineered extracellular vesicles (EVs) represent a promising cell-free therapeutic delivery platform that addresses the blood-brain barrier challenge central to CBS/PSP treatment. Unlike traditional nanoparticle approaches, exosomes inherit natural brain-targeting properties from their parent cells and can be systematically engineered to enhance CNS penetration, cargo delivery, and target specificity.
EV Biology and Therapeutic Relevance
Exosomes (30-150 nm) are nanoscale vesicles secreted by most cell types, including neurons, astrocytes, microglia, and mesenchymal stem cells (MSCs). They carry parent-cell-derived surface proteins and can be loaded with therapeutic cargo—siRNA, ASOs, small molecules, proteins—that then deliver to recipient cells. The EV membrane provides natural protection from degradation and enables receptor-mediated transcytosis across the BBB.
BBB crossing is the primary bottleneck for CNS drug delivery. Engineered EVs achieve this through several strategies:
Targeting Ligand Decoration:
Surface Charge Modulation:
Electroporation: Standard method for siRNA/mRNA loading. Efficiency 10-30% depending on cargo size and EVs. Risk of EV aggregation at high voltage.
Sonication: Shear forces create temporary pores. Better for hydrophobic drugs (curcumin, paclitaxel). 2-5x more efficient than electroporation for small molecules.
Extrusion: Sequential extrusion through membranes (100nm→50nm→30nm) creates uniform EV-like particles. High loading (~40% for mRNA) but loses native EV proteins.
Chemical Conjugation: Covalent attachment of cargo to EV surface or luminal proteins. Enables sustained release but may alter biological activity.
Endogenous Loading: Engineer parent cells to produce cargo within EVs. Best for proteins and miRNA. Higher biological activity but longer development time.
| Approach | Cargo | Target | Status | Relevance |
|---|---|---|---|---|
| Anti-tau siRNA EVs | Anti-tau siRNA | Neurons (RVG) | Preclinical | High |
| GDNF EVs | GDNF protein | Dopaminergic neurons | Preclinical | High for CBS/PSP |
| BACE1 siRNA EVs | BACE1 siRNA | Neurons | Preclinical | Medium |
| Curcumin-loaded EVs | Curcumin | Generalized | Preclinical | Medium |
| MSC-EVs | miRNA cargo | Neuroprotection | Early clinical | High |
| iPSC-derived neuronal EVs | Therapeutic RNAs | Disease-specific | Research | High |
Key barriers to clinical translation:
| Criterion | Score | Rationale |
|---|---|---|
| Scientific rationale | 8/10 | Strong mechanistic basis; natural BBB-crossing ability |
| CBS/PSP-specific evidence | 3/10 | No CBS/PSP data; AD/PD preclinical only |
| Clinical readiness | 2/10 | No clinical trials in neurodegeneration |
| Manufacturing feasibility | 2/10 | Scale-up challenges; batch variability |
| Combination potential | 7/10 | Can carry ASOs, siRNA, small molecules |
| Safety profile | 6/10 | Cell-free reduces rejection; immune response possible |
| Total | 28/60 (47%) | Experimental — monitor development |
Recommendation: Track actively; consider joining trial if available; not yet ready for clinical implementation.
No known drug-EV interactions. EVs are a delivery platform, not a drug compound.
EV-based delivery could potentially enhance delivery of other therapeutics (e.g., co-delivery with CoQ10, sulforaphane) but this is theoretical.
Near-term (0-12 months):
Medium-term (1-3 years):
Current action: None — this is a watchlist therapy. Do not pursue off-label EV therapy at this time.
More: Exosome Therapy | Exosome Drug Delivery for CBS/PSP | EV Biomarkers
Tauopathy disrupts microtubule integrity, impairing axonal transport. Microtubule-stabilizing agents and tau polymerization inhibitors offer direct targeting of cytoskeletal pathology.
Epothilones (e.g., epothilone D, BMS-241027): Macrocyclic lactones that bind β-tubulin promoting polymerization. Blood-brain barrier penetration superior to taxanes. Showed promise in AD models but clinical development limited.
Paclitaxel (Taxol): Well-established oncology agent. Neurotoxicity concerns limit CNS application, but novel formulations (nanoparticle, nab-paclitaxel) may improve CNS penetration.
DAVP (Davunetide): Octapeptide derived from activity-dependent neuroprotective protein (ADNP). Promotes microtubule stabilization, neuroprotection. Failed in Phase 3 for PSP (NCT01013480).
Methylene Blue (Rember): Redox-active compound inhibiting tau aggregation. Showed cognitive benefit in moderate AD (NCT00473278). Multiple mechanisms: aggregation inhibition, mitochondrial function, monoamine oxidase inhibition.
Lithium: GSK-3β inhibitor reducing tau phosphorylation, also affects tau aggregation. CBS/PSP patient has contraindications (MAO-B inhibitor — serotonin syndrome risk).
Nilotinib: Tyrosine kinase inhibitor (BCR-ABL) repositioned for neurodegeneration. Increases autophagy, reduces alpha-synuclein and tau. Phase 2 in PD (NCT03238988).
| Agent | Mechanism | Trial | Phase | Status |
|---|---|---|---|---|
| Epothilone D | Microtubule stabilization | NCT01492374 | Phase 1 | Completed |
| Davunetide (DAVP) | Microtubule stabilization | NCT01013480 | Phase 3 | Failed |
| Methylene Blue | Tau aggregation | NCT01492374 | Phase 2 | Completed |
| Lithium | GSK-3β inhibition | NCT05297202 | Phase 2 | Recruiting |
| Intervention | Relevance | Evidence | Readiness | Score |
|---|---|---|---|---|
| Epothilones | High | Preclinical | Phase 1 | 5/10 |
| Methylene Blue | Moderate | Phase 2 | Available | 6/10 |
| Nilotinib | Moderate | Phase 2 | Available | 5/10 |
| Lithium | Moderate | Phase 2 | Contraindicated | 0/10 |
Total NET Assessment: 16/40 = 40% (low due to limited clinical evidence)
| Drug | Interaction | Severity | Management |
|---|---|---|---|
| Lithium | Serotonin syndrome with MAO-B | Contraindicated | DO NOT USE |
| Methylene Blue | Serotonin syndrome risk | Moderate | Avoid or monitor closely |
| Epothilones | No significant interactions | Low | Monitor neuropathy |
| Nilotinib | QT prolongation additive | Moderate | Monitor ECG |
Key Finding: Lithium is contraindicated with rasagiline due to serotonin syndrome risk. Methylene blue should be used with caution.
More: Microtubule Dysfunction | Tau Aggregation | Tubulin Targeting for CBS/PSP
Tunneling nanotubes (TNTs) are F-actin-based membrane channels that enable direct intercellular transfer of tau aggregates, contributing to the spread of pathology in 4R-tauopathies like CBS/PSP. Targeting TNT formation or tau transfer represents a novel therapeutic strategy.
Approaches:
More: Section 246: TNTs in CBS/PSP | Tunneling Nanotubes
More: Neuroimmune Interface
More: Ion Channel Therapeutics
More: EV Engineering CBS/PSP
More: Immunotherapy Platforms
More: Sialic Acid Therapy
More: Metabolic Imaging
More: Lymphatic/Glymphatic Therapy
More: HSP Modulators
More: Proteostasis Network
More: Myelin/White Matter
More: Sphingolipid Signaling
More: ASO Therapies
More: Microbiome/SCFA Therapy
Gold standard for visualizing tau distribution. CBS shows asymmetric cortical uptake; PSP shows midbrain/brainstem pattern. ~80% accuracy for CBS vs PSP differentiation. Cost: $$$$, limited to ~50 US centers.
More: Tau PET in CBS/PSP
Targeted panel covers GBA, LRRK2, MAPT, C9orf72, PRKN, PINK1, VPS35. Actionable in ~15-20% of cases. If negative, consider Whole Genome Sequencing — short-read ($1.5-2.5K) for common variants, long-read ($3-5K) for structural variants and repeat expansions.
More: Genetic Testing | WGS Guide
Asymmetric cortical atrophy suggests CBS; midbrain atrophy with "hummingbird sign" suggests PSP. Widely available. Cost: $$$.
More: MRI Atrophy in CBS/PSP
Total tau, p-tau181, p-tau217, NfL, GFAP panel. p-tau231 elevated in PSP. NfL tracks progression. Cost: $300-800.
More: CBS/PSP CSF Biomarkers
Minimally invasive. p-tau217 differentiates AD from CBS/PSP (low = pure tauopathy). NfL tracks progression (>60 pg/mL = rapid decline). GFAP indicates astrocyte activation. Combined panel ~$400-600.
More: CBS/PSP Plasma Biomarkers | NfL
Metabolic pattern: CBS = asymmetric frontoparietal hypometabolism; PSP = midbrain/brainstem. Cost: $$$$.
Confirm/rule out synucleinopathy. Already negative for this patient — supports tauopathy diagnosis.
More: Alpha-Synuclein Seeding Assay
Rule out AD comorbidity. Positive suggests mixed pathology. Medicare covers 1 lifetime scan.
Dopamine transporter loss — confirms parkinsonism, not type-specific. Already done for this patient.
Vertical gaze palsy is a PSP hallmark. Emerging as standardized progression marker.
If targeted genetic panel is negative, WGS can identify rare variants, structural changes, and repeat expansions not covered by panels. Short-read ($1.5-2.5K) for common variants; long-read ($3-5K) for structural variants and GBA1/ATXN2 repeat expansions. Consider if diagnostic uncertainty persists.
More: WGS Guide for CBS/PSP
Measures cardiac sympathetic innervation. Reduced uptake = synucleinopathy (PD, DLB); preserved uptake supports tauopathy (CBS, PSP). Useful for differential diagnosis.
More: Cardiac MIBG Scan
Cognitive profile helps differentiate CBS (apraxia, visuospatial deficits) from PSP (executive dysfunction, apathy, impulsivity). 2-4 hour battery. Covered by insurance with neuro referral.
Quantifies neuromelanin-containing neurons in substantia nigra and locus coeruleus. Non-invasive proxy for dopaminergic neuron loss. Research-stage, available at academic centers.
Susceptibility-weighted imaging quantifies brain iron accumulation, particularly in basal ganglia. Elevated iron supports neurodegeneration diagnosis and may guide deferiprone consideration.
Emerging diagnostic: detects phosphorylated tau in cutaneous nerve fibers. Non-invasive alternative to CSF. Sensitivity still being validated; available at research centers (Stanford, UCSF).
REM sleep behavior disorder (RBD) strongly suggests synucleinopathy (PD, DLB, MSA), NOT tauopathy. Absence of RBD is supportive of CBS/PSP diagnosis. Also assesses sleep architecture disruption common in neurodegeneration.
Tilt table, heart rate variability, sudomotor testing. Mild dysautonomia in PSP; prominent dysautonomia suggests MSA or synucleinopathy rather than pure tauopathy.
White matter tract integrity via fractional anisotropy. Predicts fall risk in PSP. Superior longitudinal fasciculus and corpus callosum particularly affected in CBS.
More: DTI White Matter CBS/PSP
A comprehensive evaluation of 21 supplements has been compiled for this patient, including dosing, formulation comparisons, drug interactions with levodopa/rasagiline, and cost estimates ($150-300/month).
Full guide: CBS/PSP Supplements Guide
Top picks: CoQ10 (Ubiquinol) 300-600mg/day, NACET 600mg 2x/day, Omega-3 DHA 2000mg/day, Creatine 5g/day, Vitamin D3 (dose per levels), Magnesium L-Threonate 2g/day.
Practical clinical management guidance covering neuropsychiatric symptoms, pain, complementary therapies, nutrition, sleep, autonomic dysfunction, caregiver support, rehabilitation, and insurance.
Full guide: Clinical Management Guide for CBS/PSP
| Center | Location | Specialty | Contact |
|---|---|---|---|
| UCSF Movement Disorders | San Francisco, CA | CBS/PSP expertise | Link |
| Columbia University | New York, NY | PSP research | Link |
| Mayo Clinic | Rochester, MN | All movement disorders | Link |
| MGH Movement Disorders | Boston, MA | Clinical trials | Link |
| UCL Queen Square | London, UK | European hub | Link |
| Specialist | Institution | Expertise |
|---|---|---|
| Adam Boxer, MD, PhD | UCSF | CBS/PSP clinical trials |
| David Irwin, MD | Penn | CBS/PSP, biomarkers |
| Huw Morris, MD | UCL Queen Square | PSP genetics and trials |
| Irene Litvan, MD | UC San Diego | PSP research |
| Angelo Antonini, MD, PhD | University of Padua | PET imaging |
Position: Professor of Neurology, UCSF Memory and Aging Center
Clinical Focus: Corticobasal syndrome, progressive supranuclear palsy, frontotemporal dementia
Research: Principal investigator for multiple tau immunotherapy trials (E2814, BIIB080). Pioneer in tau PET imaging for atypical parkinsonism. Leads the UCSF Atypical Parkinsonism Program.
Key Contributions:
How to Refer:
Clinical Trial Enrollment: Contact UCSF Clinical Trials Office at (415) 514-1234 or email neurologyTrials@ucsf.edu
Position: Assistant Professor of Neurology, Penn Neuroscience Center
Clinical Focus: CBS, PSP, biomarkers, neuropathology
Research: Focus on biomarker development for atypical parkinsonism, including fluid biomarkers (NfL, p-tau217), skin biopsy for tau detection, and CSF analysis. Collaborator on multiple clinical trials.
Key Contributions:
How to Refer:
Research Contact: Email d-irwin@pennmedicine.upenn.edu for trial information
Position: Professor of Clinical Neuroscience, UCL Institute of Neurology
Clinical Focus: PSP, CBS, Parkinson's disease genetics
Research: Leads the UCL PSP genetics program. Identified multiple genetic risk factors for PSP. Director of the Queen Square Movement Disorders Clinic. Principal investigator for multiple Phase 2/3 trials.
Key Contributions:
How to Refer:
Clinical Trials: Contact UCL Clinical Trials Gateway: trials@ucl.ac.uk
Position: Professor of Neurology, UC San Diego
Clinical Focus: PSP, multiple system atrophy, Parkinson's disease
Research: Leader in PSP clinical trials and rating scale development. Principal investigator for multiple therapeutic trials. Developed the PSP Rating Scale (PSPRS).
Key Contributions:
How to Refer:
Position: Professor of Neurology, University of Padua
Clinical Focus: PET imaging in parkinsonism, differential diagnosis
Research: World expert in FDG-PET and dopamine transporter imaging for differential diagnosis of atypical parkinsonism. Developed metabolic pattern classification for CBS/PSP/PD.
Key Contributions:
How to Refer:
| Factor | Adam Boxer (UCSF) | David Irwin (Penn) | Huw Morris (UCL) | Irene Litvan (UCSD) |
|---|---|---|---|---|
| Location | San Francisco, CA | Philadelphia, PA | London, UK | San Diego, CA |
| CBS Focus | ⭐⭐⭐⭐⭐ | ⭐⭐⭐⭐⭐ | ⭐⭐⭐ | ⭐⭐⭐⭐ |
| PSP Focus | ⭐⭐⭐⭐ | ⭐⭐⭐⭐ | ⭐⭐⭐⭐⭐ | ⭐⭐⭐⭐⭐ |
| Clinical Trials | ⭐⭐⭐⭐⭐ | ⭐⭐⭐⭐ | ⭐⭐⭐⭐⭐ | ⭐⭐⭐⭐ |
| Biomarkers | ⭐⭐⭐⭐ | ⭐⭐⭐⭐⭐ | ⭐⭐⭐ | ⭐⭐⭐ |
| Genetics | ⭐⭐⭐ | ⭐⭐⭐⭐ | ⭐⭐⭐⭐⭐ | ⭐⭐⭐ |
Recommendation for This Patient:
CurePSP designates specialized centers for PSP and CBS care. Contact CurePSP for the current list of centers.
| Organization | Services | Contact |
|---|---|---|
| CurePSP | PSP/CBS/MSA support, research funding, patient registry | Link |
| Michael J. Fox Foundation | PD research, clinical trials | Link |
| Parkinson's Foundation | Resources, centers, support | Link |
| AFTD | Frontotemporal dementia support | Link |
| Brain Support Network | Support group, resources | Link |
Given the patient's resources, personalized trial designs are feasible:
Patient's skin or blood cells → iPSC → differentiated into cortical neurons and dopaminergic neurons → screen 100+ candidate compounds for efficacy in patient-specific 4R-tau disease model. Timeline: 6-12 months. Institutions: Harvard/MIT, Stanford, UCSF, Kyoto.
More: iPSC Drug Screening for CBS/PSP
If genetic testing reveals a specific MAPT variant, a personalized antisense oligonucleotide can be designed to target that variant. Precedent: milasen (custom ASO for Batten disease, developed in <1 year). Timeline: 12-18 months. Requires molecular characterization of the variant + IND-enabling studies.
More: ASO Brain Delivery
If an actionable point mutation is found (e.g., MAPT, GBA), ex vivo CRISPR correction of patient iPSCs followed by differentiation and autologous transplant is theoretically possible. Timeline: 18-24 months. Currently research-stage; no approved neurodegeneration applications.
More: CRISPR Gene Editing
Given the patient's resources, formal single-patient randomized trials are feasible: crossover design comparing intervention vs placebo periods with biomarker endpoints (NfL, motor assessments). Can test multiple interventions sequentially. Academic partners: UCSF, Mayo, Penn.
For patients with serious or life-threatening conditions like CBS/PSP, there are pathways to access investigational therapies outside of clinical trials.
The FDA's Expanded Access program allows patients with serious diseases to receive investigational drugs not yet approved[1]:
| Pathway | Requirements | Timeline | Cost |
|---|---|---|---|
| Expanded Access (Individual) | Serious condition, no comparable options, physician application | 1-4 weeks review | Company may provide free; patient bears costs |
| Intermediate-size Population | Similar to individual, multiple patients | 1-3 months | Variable |
| Treatment IND | Broader access, typically at Phase 3 | 30 days | Variable |
Process for E2814, BIIB080, Bepranemab:
Key Considerations:
The Right-to-Try Act of 2018 provides an alternative pathway for terminally ill patients[2]:
| Aspect | Right-to-Try | Expanded Access |
|---|---|---|
| Eligible Patients | Life-threatening condition | Serious condition |
| Physician Requirement | Treats the patient | Any licensed physician |
| FDA Review | None | Required (1-4 weeks) |
| Institutional Review | Not required | Hospital IRB approval |
| Timeline | Faster | Slower |
Eligibility Requirements:
Limitations:
Based on publicly available information, the status of each drug:
| Drug | Company | Compassionate Use Status | Contact |
|---|---|---|---|
| E2814 | Eisai | No public program; contact Medical Affairs | Eisai Medical Information: 1-866-4EISAI, clinicaltrials@eisai.com |
| BIIB080 | Biogen | No public program; contact Medical Affairs | Biogen Medical: 1-800-456-2255, clinicaltrials@biogen.com |
| Bepranemab | UCB | No public program; contact Medical Affairs | UCB Medical Information, ucb.cares@ucb.com |
Notes on Specific Drugs:
E2814 (Eisai): This tau-targeting antibody specifically targets 4R-tau, making it highly relevant for CBS/PSP. Eisai has not publicly announced a compassionate use program. Patients should contact the company directly to inquire about expanded access.
BIIB080/MAPTRx (Biogen): The antisense oligonucleotide that reduces tau production. Biogen has historically offered expanded access for some programs but no formal program exists for BIIB080. Direct inquiry recommended.
Bepranemab (UCB): Anti-tau antibody targeting aggregated tau. UCB has not announced compassionate use programs for bepranemab. Contact the company for availability.
Note: Drug companies often handle compassionate use requests through their Medical Affairs departments. Direct contact is the best way to inquire about current availability and application processes.
For the off-label therapies identified in this treatment plan (baricitinib, rapamycin, senolytics, LDN, exenatide), compassionate use considerations differ from investigational biologics:
| Drug | Status | Compassionate Use Pathway | Key Considerations |
|---|---|---|---|
| Baricitinib | Approved (RA) | Off-label prescription | FDA-approved for RA; can prescribe for any condition; insurance may cover |
| Rapamycin | Approved (transplant) | Off-label prescription | Approved for transplant/TSC; off-label use common; monitoring required |
| Dasatinib + Quercetin | Not approved | Research compound + supplement | Dasatinib requires prescription; Quercetin is OTC; compounding pharmacy needed |
| Low-dose Naltrexone | Approved (high dose) | Off-label prescription | Requires compounding pharmacy; well-established off-label use |
| Exenatide | Approved (diabetes) | Off-label prescription | FDA-approved for T2D; can prescribe for neurodegeneration |
Process for Off-Label Access:
Off-Label Considerations by Drug:
Baricitinib: FDA-approved for rheumatoid arthritis. Neurologist can prescribe off-label for neuroinflammation. Requires baseline labs (CBC, liver enzymes) and monitoring for infection risk. Some insurers cover with prior auth for autoimmune conditions.
Rapamycin (Sirolimus): Approved for transplant rejection prevention. Off-label use for neurodegeneration is emerging. Requires monitoring of lipids, blood counts, and for signs of infection. Consider everolimus for better CNS penetration.
Dasatinib + Quercetin: Dasatinib requires prescription (cancer indication). Quercetin is available OTC as a supplement. Use a compounding pharmacy for standardized dosing. Several clinical trials recruiting (search "senolytic" on clinicaltrials.gov).
Low-Dose Naltrexone: Requires compounding pharmacy (low doses not commercially available). Well-established off-label use in autoimmune conditions. Low side effect profile. Typical dose 1-4.5mg at bedtime.
Exenatide: FDA-approved for Type 2 diabetes. Off-label for neurodegeneration. Can use Bydureon (weekly) or Byetta (twice daily). GI side effects common. Some movement disorder specialists use it for PD.
For patients willing to travel or access treatments abroad:
| Option | Description | Considerations |
|---|---|---|
| Clinical trial in other countries | Many trials are international | Travel costs, eligibility, visa |
| Named Patient Program | Some countries allow import for individual patients | Country-specific regulations |
| European hospitals | Some EU centers offer expanded access | May require physician referral |
| Clinical trial expansion sites | Companies adding new sites | Monitor clinicaltrials.gov for updates |
Country-Specific Pathways:
| Country | Pathway | Notes |
|---|---|---|
| United Kingdom | MHRA exceptional use | Similar to FDA expanded access |
| European Union | Named patient supply | Per EU member state regulations |
| Switzerland | Special approval | Swissmedic individual approval |
| Australia | Special access scheme | TGA special access category A/B |
| Canada | Special access program | Health Canada SAP |
Key Considerations:
Resources:
Given the current status of anti-tau therapies:
Recent developments in CBS/PSP therapeutics (2025-2026):
The AL002 trial (Alector/AbbVie), a humanized anti-TREM2 monoclonal antibody agonist, failed to meet its primary endpoint in November 2024. The Phase 2 trial enrolled 328 patients with early Alzheimer's disease and showed that patients in the treatment arm experienced worse outcomes compared to placebo on the CDR-SB (Clinical Dementia Rating-Sum of Boxes) measure[3].
Key findings:
Implications for CBS/PSP:
DNL311 is a TREM2-targeting bispecific antibody engineered with Denali's Transport Vehicle (TV) platform for enhanced brain penetration. Currently in Phase 1/2 development.
Status (March 2026):
Mechanism:
PLX5622 is a selective CSF1R small molecule inhibitor that induces microglial depletion. The Phase 2 trial in early AD (NCT05164068) has completed.
NCT05164068 Results:
Implications for CBS/PSP:
Given this patient's alpha-synuclein negative status (SAA negative) suggesting a pure tauopathy (CBS/PSP), the role of microglia in tau propagation is particularly relevant:
Key mechanisms:
Therapeutic strategies:
The biological rationale for combining microglial modulators with anti-tau immunotherapies:
Synergistic mechanisms:
Current trial designs:
Given the current evidence:
Bottom line: TREM2/CSF1R therapeutics for CBS/PSP remain in early experimental stages. AL002's failure highlights mechanism complexity. Focus on anti-tau biologics with established trial infrastructure while monitoring DNL311 and PLX5622 developments.
Based on 2025-2026 evidence:
See individual deep-dive pages for complete reference lists with PMIDs.