Personalized Treatment Plan — Atypical Parkinsonism (CBS/PSP)

Personalized Treatment Plan — Atypical Parkinsonism (CBS/PSP)

<div class="infobox infobox-treatment">
<table>
<tr><th colspan="2" style="background:#e8f4f8;">Patient Profile</th></tr>
<tr><td><b>Age/Sex</b></td><td>50-year-old male</td></tr>
<tr><td><b>Diagnosis</b></td><td>Suspected CBS or PSP (differential pending)</td></tr>
<tr><td><b>Alpha-synuclein</b></td><td>NEGATIVE (SAA)</td></tr>
<tr><td><b>DAT Scan</b></td><td>Dopamine neuron loss confirmed</td></tr>
<tr><td><b>Current Meds</b></td><td>Levodopa, rasagiline (MAO-B inhibitor)</td></tr>
<tr><td><b>Symptoms</b></td><td>Gait issues, hand tremors</td></tr>
<tr><td><b>Resources</b></td><td>Able to afford custom R&D and tailored therapies</td></tr>
</table>
</div>

Contents

Personalized Treatment Plan — Atypical Parkinsonism (CBS/PSP)

<div class="infobox infobox-treatment">
<table>
<tr><th colspan="2" style="background:#e8f4f8;">Patient Profile</th></tr>
<tr><td><b>Age/Sex</b></td><td>50-year-old male</td></tr>
<tr><td><b>Diagnosis</b></td><td>Suspected CBS or PSP (differential pending)</td></tr>
<tr><td><b>Alpha-synuclein</b></td><td>NEGATIVE (SAA)</td></tr>
<tr><td><b>DAT Scan</b></td><td>Dopamine neuron loss confirmed</td></tr>
<tr><td><b>Current Meds</b></td><td>Levodopa, rasagiline (MAO-B inhibitor)</td></tr>
<tr><td><b>Symptoms</b></td><td>Gait issues, hand tremors</td></tr>
<tr><td><b>Resources</b></td><td>Able to afford custom R&D and tailored therapies</td></tr>
</table>
</div>

Contents

| Section | Description |
|---------|-------------|
| [1. Ranked Therapies](#1--ranked-therapies) | Therapies ranked by efficacy and safety |
| [2. Ranked Diagnostics](#2--ranked-diagnostics) | 19 diagnostic tests ranked by utility |
| [3. Top Recommendations](#3--top-recommendations) | Priority actions: diagnostics first, then therapies, then trials |
| [4. Deep Dive Topics](#4--deep-dive-topics) | 45 ranked topics: disease modification, neuroprotection, diagnostics, strategy |
| [5. Therapy Details](#5--therapy-details) | Per-therapy analysis with evidence, trials, and assessment |
| [6. Diagnostic Details](#6--diagnostic-details) | Per-test detail with off-page links |
| [7. Supplements Guide](#7--supplements-guide) | 21 supplement profiles with dosing |
| [8. Clinical Management](#8--clinical-management) | Symptom management, rehab, caregiver support |
| [9. Specialists and Clinics](#9--specialists-and-clinics) | Movement disorder centers and CBS/PSP experts |
| [10. Foundations and Support](#10--foundations-and-support) | Patient organizations and resources |
| [11. Custom R&D](#11--custom-r-d) | N-of-1 trials, iPSC screening, compassionate use |
| [12. Knowledge Gaps](#12--knowledge-gaps) | Research priorities and open questions |
| [13. Research Updates](#13--research-updates) | 2025-2026 findings |
| [14. Cross-Links](#14--cross-links) | Related pages and references |

Pathway Diagram

1. Ranked Therapies {#ranked-therapies}

| Rank | Therapy | Mechanism | Efficacy | Safety | Evidence | Cost |
|------|---------|-----------|----------|--------|----------|------|
| 1 | [Levodopa](#optimize-levodopa) | Dopamine precursor → DA replacement | 7 | 8 | Approved | $$ |
| 2 | [Rasagiline](#continue-rasagiline) | MAO-B inhibitor → DA preservation | 5 | 9 | Approved | $$ |
| 3 | [Exercise](#exercise--tai-chi--yoga) | BDNF elevation → neuroplasticity | 7 | 10 | Strong clinical | $ |
| 4 | [E2814](#e2814) | Anti-MTBR tau mAb → block aggregation | 7 | 8 | Phase 3 | Free |
| 5 | [BIIB080](#biib080) | Tau ASO → MAPT gene silencing | 6 | 8 | Phase 2 | Free |
| 6 | [Tai Chi](#tai-chi) | Balance/proprioception → fall reduction | 6 | 10 | Strong clinical | $ |
| 6b | [Yoga/Mind-Body](#yoga-mind-body) | Chair yoga, pranayama, stress modulation → motor, autonomic, mood | 6 | 10 | Strong clinical | $ |
| 6c | [Mindfulness/Meditation](#mindfulness-meditation) | MBSR/MBCT, stress reduction, neuroplasticity, HPA axis modulation | 6 | 10 | Strong clinical | $ |
| 6d | [Dance/Movement Therapy](#dance-movement-therapy) | Rhythmic movement → BDNF, neuroplasticity, balance, mood | 5 | 10 | Moderate clinical | $-$$ |
| 7 | [Lixisenatide](#lixisenatide) | GLP-1R agonist → motor stabilization (p=0.007) | 6 | 6 | Phase 2 positive | $$ |
| 8 | [Bepranemab](#bepranemab) | Anti-aggregated tau mAb → 33-58% tau slowing | 6 | 8 | Phase 2 | Free |
| 9 | [FNP-223](/therapeutics/fnp-223) | OGA inhibitor → tau O-GlcNAcylation | 5 | 7 | Phase 2 (PSP, n=220) | Free |
| 10 | [NACET](#add-nacet) | Glutathione precursor → BBB-penetrant antioxidant; synergistic with levodopa+rasagiline | 5 | 9 | Phase 2 (IV NAC: DAT+) | $ |
| 11 | [Posdinemab](#posdinemab) | Anti-tau mAb → FDA Fast Track | 5 | 7 | Phase 2 | Free |
| 12 | [BMS-986446](#bms-986446) | Anti-MTBR-tau mAb → FDA Fast Track | 5 | 7 | Phase 2 | Free |
| 13 | [Lithium](#consider-low-dose-lithium) | GSK-3β inhibitor → reduce tau phosphorylation | 5 | 5 | Phase 2 (PSP) | $ |
| 14 | [Pramipexole](#pramipexole) | D2/D3 dopamine agonist → motor relief | 5 | 6 | Approved | $$ |
| 15 | [AADvac1](#psp-platform-trial) | Tau vaccine → anti-tau immune response | 5 | 7 | Phase 2 (PSP platform) | Free |
| 16 | [Amantadine](#amantadine) | NMDA antagonist → reduce dyskinesias | 5 | 7 | Approved | $ |
| 17 | [Entacapone](#entacapone) | COMT inhibitor → extend levodopa effect | 5 | 8 | Approved | $ |
| 18 | [AZP2006](#azp2006) | Neuroprotective peptide → PSP platform trial | 5 | 7 | Phase 2a positive | Free |
| 19 | [Safinamide](#safinamide) | MAO-B + Na channel → dual mechanism | 5 | 8 | Approved | $$ |
| 20 | [Rotigotine](#rotigotine) | D1-D5 agonist patch → continuous delivery | 5 | 7 | Approved | $$$ |
| 21 | [Sodium selenate](#sodium-selenate) | PP2A activator → tau dephosphorylation | 5 | 7 | Phase 2 | $$ |
| 22 | [CoQ10](#add-coq10) | ETC Complex I/III → mitochondria | 3 | 9 | Phase 2/3 NEGATIVE | $$ |
| 23 | [NAC](#nac) | Glutathione precursor → oxidative stress | 4 | 9 | Clinical | $ |
| 24 | [Gasotransmitter Therapy](#no-gasotransmitter-therapy) | NO/CO/H2S modulation → anti-inflammatory, mitochondrial protection | 3 | 8 | Research | $ |
| 25 | [Liraglutide](#liraglutide) | GLP-1R agonist → brain volume preservation | 5 | 7 | Phase 2 | $$ |
| 26 | [Urolithin A](#urolithin-a) | Mitophagy inducer → clear damaged mitochondria | 4 | 9 | Phase 2 | $$$ |
| 27 | [Semaglutide](#semaglutide) | GLP-1R agonist (oral) → anti-inflammatory, CNS penetration | 4 | 7 | Phase 2 completed (MOST-ABLE); AD indication failed; PD results reported | $$ |
| 28 | [Tirzepatide](#tirzepatide) | Dual GIP/GLP-1 agonist → enhanced neuroprotection | 6 | 6 | Phase 2 for AD/PD | $$ |
| 29 | [Retatrutide](#retatrutide) | Triple GIP/GLP-1/FGF21 agonist → multi-receptor neuroprotection | 6 | 6 | Phase 1/2; strong preclinical | $$ |
| 30 | [Cotadutide](#cotadutide) | Dual GLP-1/glucagon agonist → enhanced metabolic/mitochondrial support | 5 | 7 | Phase 1; preclinical neuroprotection | $$ |
| 31 | [Creatine](#creatine) | Phosphocreatine → cellular energy buffer | 4 | 9 | Clinical | $ |
| 32 | [Omega-3 DHA](#omega-3-dha) | Anti-inflammatory → membrane fluidity | 4 | 9 | Clinical | $$ |
| 33 | [Alpha-lipoic acid](#alpha-lipoic-acid) | Mitochondrial antioxidant → redox cycling | 4 | 8 | Clinical | $ |
| 34 | [Vitamin D3](#vitamin-d3) | VDR activation → neuroprotection | 4 | 9 | Clinical | $ |
| 35 | [Vitamin B12](#vitamin-b12) | Methylcobalamin → myelin maintenance | 5 | 9 | Clinical | $ |
| 36 | [Magnesium L-Threonate](#magnesium-l-threonate) | NMDA modulation → synaptic plasticity | 4 | 8 | Preliminary | $$ |
| 37 | [Exenatide](#exenatide) | GLP-1R agonist → Phase 3 failed | 3 | 7 | Phase 3 failed | $$ |
| 38 | [Lion's Mane](#lion-s-mane) | Hericenones/erinacines → NGF stimulation | 3 | 8 | Preliminary | $$ |
| 39 | [Sulforaphane](#sulforaphane) | NRF2 activator → antioxidant defense | 4 | 8 | Phase 1 | $$ |
| 40 | [Curcumin](#curcumin) | Anti-inflammatory → NF-κB inhibition | 3 | 8 | Preclinical | $ |
| 41 | [NMN](#nmn) | NAD+ precursor → mitochondrial function | 3 | 8 | Phase 2 | $$ |
| 42 | [NR](#nr) | NAD+ precursor → sirtuin activation | 3 | 8 | Phase 2 | $$ |
| 43 | [PQQ](#pqq) | Cofactor → mitochondrial biogenesis | 3 | 8 | Preclinical | $$ |
| 44 | [PLX5622](#plx5622) | CSF1R inhibitor → microglial depletion | 5 | 6 | Phase 2 | $$$ |
| 45 | [TREM2 agonists](#trem2-agonists) | TREM2 → enhance microglial phagocytosis | 4 | 7 | Phase 2 PAUSED (AL002 stopped May 2024) | $$$$ |
| 46 | [LDN](#ldn) | Low-dose opioid antagonism → glial modulation | 3 | 7 | Case reports | $$ |
| 47 | [DBS (GPi)](#dbs--gpi) | Electrical stimulation → motor circuits | 6 | 6 | Approved | $$$$ |
| 48 | [Focused ultrasound](#focused-ultrasound) | HIFU thalamotomy → tremor ablation | 5 | 7 | Approved | $$$$ |
| 49 | [TMS](#tms) | Magnetic stimulation → cortical excitability | 4 | 8 | Experimental | $$$ |
| 50 | [CDNF gene therapy](#cdnf-gene-therapy) | AAV-CDNF → ER stress reduction | 5 | 7 | Phase 1/2 | $$$$ |
| 51 | [GDNF infusion](#gdnf-infusion) | Neurotrophic factor → DA neuron survival | 5 | 6 | Phase 2 | $$$$ |
| 52 | [Stem cell therapy](#stem-cell-therapy) | iPSC-DA neurons → cell replacement | 5 | 6 | Phase 1-3 | $$$$ |
| 53 | [Mito transplant](#mito-transplant) | Healthy mitochondria → restore energy | 4 | 7 | Phase 1 | $$$$ |
| 54 | [Mitochondrial dynamics](#mitochondrial-dynamics) | Fission/fusion + PGC-1α + mitophagy + mtDNA → restore function | 4 | 8 | Clinical | $$ |
| 55 | [Exosome therapy](#exosome-therapy) | Engineered EVs → BBB drug delivery | 3 | 7 | Preclinical | $$$$ |
| 56 | [SCFA therapy](#scfa-therapy) | Microbiome metabolites → anti-inflammatory, HDAC inhibition | 4 | 8 | Emerging | $ |
| 57 | [Nilotinib](#nilotinib) | BCR-ABL inhibitor → autophagy | 3 | 5 | Phase 2 | $$ |
| 58 | [Cytoskeletal targeting](#cytoskeletal-targeting) | Microtubule stabilization → axonal transport | 4 | 7 | Phase 1/2 | $$$ |
| 59 | [Deferiprone](#deferiprone) | Iron chelator → brain iron reduction | 3 | 5 | Phase 2 | $$ |
| 60 | [Ibuprofen](#ibuprofen) | COX inhibitor → neuroinflammation | 2 | 6 | Epidemiological | $ |
| 61 | [Isradipine](#isradipine) | Ca²⁺ channel blocker → Phase 3 failed | 2 | 6 | Phase 3 failed | $ |
| 62 | [Pioglitazone](#pioglitazone) | PPARγ agonist → Phase 3 failed | 2 | 5 | Phase 3 failed | $ |
| 63 | [Minocycline](#minocycline) | Microglial inhibition — failed | 2 | 6 | Phase 2 failed | $ |
| 64 | [HSP70/HSP90 Modulators](#hsp70-hsp90-modulators) | Chaperone modulation → proteostasis | 4 | 6 | Preclinical/Phase 1 | $$ |
| 65 | [PARP Inhibitors + NAD+](#parp-inhibitors--nad) | DNA repair modulation, NAD+ preservation, SIRT1 combo | 4 | 6 | Preclinical/Phase 1 | $$ |
| 66 | [Thyroid optimization](#thyroid-optimization) | Thyroid axis optimization → neuronal metabolism | 4 | 9 | Clinical | $ |
| 67 | [Dental Health](#dental-health) | Oral microbiome, periodontitis → reduce inflammatory burden | 4 | 9 | Clinical | $ |
| 68 | [Sialic Acid Therapy](#sialic-acid-therapy) | Siglec modulation → neuroinflammation, glycan-based tau targeting | 4 | 7 | Phase 1/2 | $$ |
| 69 | [Copper/Zinc Homeostasis](#copper-zinc-homeostasis) | Metal chelation, metallothionein modulation → reduce tau phosphorylation | 4 | 7 | Investigational | $ |
| 70 | [NO/Gasotransmitter Therapy](#no-gasotransmitter-therapy) | NO modulation, CORMs, H2S donors → mitochondrial protection, anti-inflammatory | 3 | 8 | Research | $ |
| 71 | [AP39/Mitochondria-targeted H2S](#no-gasotransmitter-therapy) | Mitochondria-targeted H2S delivery → oxidative stress reduction | 4 | 7 | Preclinical | $$ |
| 72 | [GYY4137 H2S donor](#no-gasotransmitter-therapy) | Slow H2S release → anti-inflammatory, Nrf2 activation | 4 | 7 | Research | $$ |

2. Ranked Diagnostics {#ranked-diagnostics}

| Rank | Test | Priority | What It Reveals | Cost |
|------|------|----------|-----------------|------|
| 1 | [Tau PET (flortaucipir)](#tau-pet--flortaucipir) | 10 | Tau burden pattern — CBS vs PSP differentiation | $$$$ |
| 2 | [Genetic panel](#genetic-panel) | 10 | Actionable mutations (GBA, MAPT, LRRK2) | $$$ |
| 3 | [MRI with volumetrics](#mri-with-volumetrics) | 9 | Atrophy pattern — hummingbird sign (PSP) | $$$ |
| 4 | [CSF biomarkers](#csf-biomarkers) | 9 | Tau, NfL, GFAP — disease staging | $$ |
| 5 | [Blood biomarkers](#blood-biomarkers) | 8 | p-tau217, NfL, GFAP — non-invasive panel | $ |
| 6 | [FDG-PET](#fdg-pet) | 8 | Metabolic pattern — frontoparietal vs brainstem | $$$$ |
| 7 | [Whole genome sequencing](#whole-genome-sequencing) | 8 | Structural variants, repeat expansions (if panel negative) | $$$$ |
| 8 | [Alpha-synuclein SAA](#alpha-synuclein-saa) | 8 | Rule out synucleinopathy (already negative) | $$ |
| 9 | [Amyloid PET](#amyloid-pet) | 7 | Rule out AD comorbidity — mixed pathology | $$$$ |
| 10 | [Cardiac MIBG](#cardiac-mibg) | 7 | Autonomic innervation — preserved = tauopathy | $$$ |
| 13 | [DaT-SPECT](#dat-spect) | 7 | Dopamine transporter loss (already done) | $$$ |
| 14 | [DTI MRI](#dti-mri) | 7 | White matter tract integrity — fall prediction | $$ |
| 15 | [Neuropsych testing](#neuropsych-testing) | 7 | Apraxia (CBS) vs executive dysfunction (PSP) | $$ |
| 16 | [Neuromelanin MRI](#neuromelanin-mri) | 7 | Substantia nigra neuron loss quantification | $$ |
| 17 | [Eye tracking](#eye-tracking) | 6 | Vertical gaze palsy — PSP hallmark | $ |
| 18 | [SWI/QSM iron imaging](#swi-qsm-iron-imaging) | 6 | Brain iron accumulation quantification | $$ |
| 19 | [Skin biopsy](#skin-biopsy) | 6 | Phospho-tau in cutaneous nerves (emerging) | $$ |
| 20 | [Sleep study](#sleep-study) | 5 | RBD suggests synucleinopathy, not tauopathy | $$ |
| 21 | [Autonomic testing](#autonomic-testing) | 5 | Orthostatic hypotension, HRV patterns | $ |

3. Top Recommendations {#top-recommendations}

Diagnostics (do first)

Therapies (start immediately)

Clinical trials (highest priority — pursue in parallel)

Strategy framework

These recommendations span four complementary goals that should be pursued in parallel:

• Disease modification (halt/slow pathology): anti-tau trials (E2814, BIIB080, FNP-223), lithium (tau phosphorylation), gene therapy (longer-term)
• Resilience building (strengthen remaining circuits): exercise, Tai Chi, cognitive engagement, Mediterranean diet, sleep optimization
• Progression slowing (neuroprotection): NACET (preferred), CoQ10 (supportive), supplements stack, biomarker-guided monitoring (NfL every 6 months)
• Restoration (replace what's lost): stem cell therapy, GDNF/CDNF, mitochondrial transplantation (longer-term, monitor trials)

4. Deep Dive Topics {#deep-dives}

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.

Disease Modification (targeting underlying pathology)

| Rank | Topic | Impact | Evidence | Full Page |
|------|-------|--------|----------|-----------|
| 1 | Anti-tau immunotherapy | 10 | 8 | [Tau-Targeted Therapeutics](/therapeutics/tau-targeted-therapeutics#therapeutic-strategies) |
| 2 | Tau gene therapy (ASO/gene silencing) | 10 | 7 | [Tau-Targeted Therapeutics](/therapeutics/tau-targeted-therapeutics#antisense-oligonucleotides-asos) |
| 3 | OGA inhibition (tau O-GlcNAcylation) | 9 | 7 | [OGA Inhibitor Landscape](/therapeutics/oga-inhibitor-landscape) · [Tau Therapeutics](/therapeutics/tau-targeted-therapeutics#post-translational-modification-modulators) |
| 4 | Autophagy-lysosome enhancement | 9 | 6 | [Autophagy Inducers](/therapeutics/autophagy-inducers-neurodegeneration#corticobasal-syndrome-and-progressive-supranuclear-palsy) |
| 5 | Tau spreading/seeding mechanisms | 9 | 7 | [Tau Propagation](/mechanisms/braak-staging-tau-propagation#progressive-supranuclear-palsy-psp) |
| 6 | Neuroinflammation (microglial modulation) | 9 | 7 | [Neuroinflammation in PSP](/mechanisms/neuroinflammation-psp#psp-vs-corticobasal-degeneration) |
| 7 | CSF1R / TREM2 microglial targeting | 8 | 6 | [CSF1R Inhibitors](/therapeutics/csf1r-inhibitors-neurodegeneration#therapeutic-rationale) · [TREM2 Therapeutics](/therapeutics/trem2-therapeutics#therapeutic-approaches) |
| 8 | Proteostasis / protein quality control | 8 | 5 | [Protein Quality Control](/mechanisms/protein-quality-control-network) |
| 9 | Molecular chaperones (HSP70/HSP90) | 7 | 5 | [Molecular Chaperones](/mechanisms/molecular-chaperones#tau-tauopathies) |
| 10 | Combination therapy design | 9 | 4 | [Combination Therapy Synergies](/therapeutics/combination-therapy-synergies-cbs-psp) |

Neuroprotection & Metabolic Support

| Rank | Topic | Impact | Evidence | Full Page |
|------|-------|--------|----------|-----------|
| 11 | GLP-1 receptor agonists | 8 | 7 | [GLP-1 Agonists](/therapeutics/glp1-receptor-agonists#clinical-trials-in-alzheimers-disease) |
| 12 | Mitochondrial support (CoQ10, urolithin A) | 7 | 6 | [CoQ10](/therapeutics/coenzyme-q10-neurodegeneration#cbspsp-specific-considerations) · [Urolithin A](/therapeutics/urolithin-a-mitophagy#cbspsp-preclinical-rationale) |
| 13 | Mitochondrial transplantation | 7 | 4 | [Mito Transplant](/therapeutics/mitochondrial-transplantation-neurodegeneration#relevance-to-tauopathies-cbspsp) |
| 14 | Growth factors / neurotrophins | 7 | 5 | [Neurotrophic Factor Therapies](/therapeutics/neurotrophic-factor-therapies) |
| 15 | NAD+ metabolism (NMN/NR) | 6 | 5 | [Supplements Guide](/therapeutics/supplements-guide-cbs-psp) |
| 16 | Iron chelation | 6 | 5 | [Deferiprone](/therapeutics/deferiprone-neurodegeneration#psp-and-cbs-rationale-for-iron-chelation) |
| 17 | NRF2 / antioxidant defense | 6 | 4 | [NRF2 Activators](/therapeutics/nrf2-activators-neurodegeneration#corticobasal-syndrome-cbs-and-progressive-supranuclear-palsy-psp) |
| 18 | Calcium homeostasis | 6 | 5 | [Calcium Dysregulation](/mechanisms/calcium-dysregulation-pathway) |
| 19 | Progranulin / lysosome enhancement (AZP2006) | 7 | 5 | [AZP2006 (Serazaxine) — PSP Platform Trial](/therapeutics/azp2006) |

Cell Replacement & Regeneration

| Rank | Topic | Impact | Evidence | Full Page |
|------|-------|--------|----------|-----------|
| 19 | Stem cell therapy (iPSC-DA) | 8 | 6 | [Stem Cells for Parkinsonism](/therapeutics/stem-cell-therapy-parkinsonism#rationale-for-cell-therapy-in-atypical-parkinsonism) |
| 20 | Gene therapy (CDNF, GDNF, AAV) | 8 | 5 | [Neurotrophic Gene Therapy Programs](/therapeutics/neurotrophic-gene-therapy-programs#cbspsp-relevance) |
| 21 | Exosome-based drug delivery | 6 | 3 | [Exosome Therapy](/therapeutics/exosome-therapy-neurodegeneration) |
| 22 | iPSC drug screening | 7 | 5 | [iPSC Screening CBS/PSP](/therapeutics/ipsc-neurons-drug-screening-cbs-psp#rationale-for-ipsc-models-in-cbspsp) |

Diagnostics & Biomarkers

| Rank | Topic | Impact | Evidence | Full Page |
|------|-------|--------|----------|-----------|
| 23 | Blood biomarkers (p-tau217, NfL, GFAP) | 9 | 8 | [CBS/PSP Plasma Biomarkers](/biomarkers/cbs-psp-plasma-biomarkers) |
| 24 | Tau PET imaging (4R-specific tracers) | 9 | 7 | [Tau PET CBS/PSP](/biomarkers/tau-pet-cbs-psp) |
| 25 | Neurofilament dynamics | 8 | 8 | [NfL](/biomarkers/neurofilament-light-chain#nfl-as-a-therapeutic-endpoint-in-clinical-trials) |
| 26 | Whole genome sequencing | 7 | 7 | [WGS Guide](/diagnostics/whole-genome-sequencing-cbs-psp) |
| 27 | Pharmacogenomics | 6 | 5 | [Pharmacogenomics CBS/PSP](/therapeutics/pharmacogenomics-cbs-psp) |
| 28 | Wearable sensors / digital biomarkers (CBS/PSP) | 7 | 6 | [Wearable Sensors CBS/PSP](/technologies/wearable-sensors-parkinsonism) |

Clinical Management

| Rank | Topic | Impact | Evidence | Full Page |
|------|-------|--------|----------|-----------|
| 30 | Sleep / circadian optimization | 8 | 6 | [Sleep Disorders CBS/PSP](/therapeutics/sleep-disorders-cbs-psp#sleep-architecture-abnormalities-in-cbspsp) |
| 31 | Exercise and rehabilitation | 8 | 8 | [Exercise CBS/PSP](/therapeutics/exercise-cbs-psp#what-is-different-in-cbspsp-vs-pd-exercise-programming) |
| 32 | Pain management | 7 | 5 | [Pain Management CBS/PSP](/therapeutics/pain-management-cbs-psp) |
| 33 | Psychosocial / cognitive reserve | 7 | 5 | [Psychosocial CBS/PSP](/therapeutics/psychosocial-interventions-cbs-psp) |
| 34 | Respiratory / dysphagia | 7 | 6 | [Respiratory CBS/PSP](/therapeutics/respiratory-dysphagia-cbs-psp) |
| 35 | Ketogenic / metabolic therapy | 6 | 4 | [Ketogenic Diet](/therapeutics/ketogenic-diet-neurodegeneration#corticobasal-syndrome-and-progressive-supranuclear-palsy) |
| 36 | Device therapies (DBS, FUS, TMS) | 7 | 6 | [Device Therapies CBS/PSP](/therapeutics/device-therapies-comparison-cbs-psp) |

Emerging Science & Strategy

| Rank | Topic | Impact | Evidence | Full Page |
|------|-------|--------|----------|-----------|
| 37 | CBS/PSP Cure Roadmap | 10 | — | [Cure Roadmap](/mechanisms/cbs-psp-cure-roadmap) |
| 38 | Experiment Priorities | 9 | — | [Experiment Index](/experiments/experiment-priority-index) |
| 39 | Cure Requirements Index | 9 | — | [Cure Requirements](/ideas/cure-requirements-index) |
| 40 | Computational pharmacology / AI | 7 | 4 | [Computational Tools](/technologies/artificial-intelligence-neurodegeneration) |
| 41 | Multi-omics integration | 7 | 5 | [Multi-Omics](/mechanisms/multi-omics-integration-neurodegeneration) |
| 42 | Precision medicine / patient stratification | 8 | 5 | [Precision Medicine](/therapeutics/precision-medicine-neurodegeneration) |
| 43 | Microbiome-gut-brain axis | 6 | 4 | [Gut-Brain Axis](/mechanisms/gut-brain-axis-tauopathy#evidence-from-psp-and-cbs) |
| 44 | Circadian rhythm dysfunction | 6 | 4 | [Circadian CBD](/mechanisms/circadian-rhythm-dysfunction-cbd) |
| 45 | BBB / neuroimmune interface | 7 | 5 | [BBB Dysfunction](/mechanisms/bbb-dysfunction-pathway) |
| 46 | Quantum biology (theoretical) | 3 | 1 | [Quantum Biology](/mechanisms/quantum-biology-neurodegeneration) |

5. Therapy Details {#therapy-details}

Levodopa Optimization {#levodopa}

Dopamine replacement. Standard first-line. Try high-dose up to 2000mg/d with entacapone.

• FOR: Standard of care, may provide some benefit even in tauopathies
• AGAINST: Poor response in CBS/PSP (30-40% respond), risk of dyskinesias
• NET: Essential to try — moderate confidence for modest benefit

More: [Levodopa](/therapeutics/levodopa)

Rasagiline {#rasagiline}

MAO-B inhibitor. Patient is currently taking this. Irreversible MAO-B inhibition provides modest symptomatic benefit and possible neuroprotection.

• FOR: Already on board; possible neuroprotective effect via MAO-B inhibition; well-tolerated
• AGAINST: Limited efficacy in CBS/PSP; effect size smaller than in PD
• NET: Continue current therapy — no reason to discontinue; low risk, modest benefit

More: [Rasagiline](/therapeutics/rasagiline) | [MAO-B Inhibitors](/therapeutics/mao-b-inhibitors)

High-Intensity Exercise {#exercise}

BDNF elevation, neuroplasticity. Aim 150+ min/week vigorous. Modalities: treadmill, boxing (Rocksteady), Tai Chi, dance.

• FOR: Strongest evidence for neuroplasticity; elevates BDNF
• AGAINST: Does not slow disease progression
• NET: Essential — highest evidence-to-risk ratio

E2814 {#e2814}

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.

• FOR: Targets underlying pathology; 4R-tau specific; MTBR-tau-243 reduction 30-70% in DIAN-TU
• AGAINST: Not yet proven effective; potential ARIA
• NET: Strong recommendation — enroll if eligible

More: [Tau-Targeted Therapeutics](/therapeutics/tau-targeted-therapeutics)

BIIB080/MAPTRx {#biib080}

Tau ASO targeting MAPT gene. Intrathecal delivery every 3-6 months. ~60 patients Phase 1/2. Sponsor: Biogen/Ionis.

• FOR: Gene-level tau reduction; CSF total tau 30-60% reduction
• AGAINST: Invasive delivery (lumbar puncture)
• NET: Strong recommendation — enroll if eligible. NCT05463772.

CoQ10 (Ubiquinol) {#coq10}

Mitochondrial ETC support. 300-600mg/day.

• FOR: Excellent safety profile, well-tolerated, mitochondrial support rationale
• AGAINST: NICE trial (PSP, 2400mg/day): no significant benefit vs placebo. QE3 trial (PD, 2400mg/day): also negative
• NET: Supportive care only — not disease-modifying. Retain for mitochondrial support given safety.

More: [CoQ10](/therapeutics/coenzyme-q10-neurodegeneration#cbspsp-specific-considerations) | [CoQ10 Details](/therapeutics/supplements-guide-cbs-psp#coq10-supplement)

Bepranemab {#bepranemab}

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.

• FOR: First antibody to show tau slowing in Phase 2 (TOGETHER trial). 33-58% reduction in tau accumulation. Well-tolerated
• AGAINST: Clinical cognitive benefit not yet demonstrated (tau slowing ≠ symptom improvement). Needs Phase 3 confirmation
• NET: Upgraded — most promising tau antibody data to date. Strongly consider enrollment.

Posdinemab {#posdinemab}

Anti-tau mAb. FDA Fast Track designation (2025). Phase 2 for tauopathies.

• FOR: FDA Fast Track signals regulatory priority. Novel epitope targeting
• AGAINST: Limited published clinical data. Early-stage
• NET: Monitor — Fast Track designation is encouraging. Enroll if eligible.

BMS-986446 {#bms986446}

Anti-MTBR-tau mAb. FDA Fast Track designation (2025). Bristol Myers Squibb. Targets same tau region as E2814.

• FOR: FDA Fast Track. BMS resources for large-scale development. MTBR-specific (same validated target as E2814)
• AGAINST: Limited published data. Competing with E2814 for same target
• NET: Monitor — provides competitive alternative to E2814 if that trial has issues. Enroll if available.

FNP-223 (OGA Inhibitor) {#fnp223}

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.

• FOR: Novel mechanism directly targeting tau post-translational modification. Large Phase 2 specifically in PSP. O-GlcNAcylation competes with phosphorylation at same serine/threonine residues
• AGAINST: No results yet (expected 2026). OGA inhibition is systemic. Long-term safety unknown
• NET: High-priority monitor. If PROSPER positive, becomes top-tier CBS/PSP therapy

AADvac1 (Tau Vaccine) {#aadvac1}

Active immunotherapy generating antibodies against pathological tau. Selected for the PSP Phase 2 Platform Trial alongside AZP2006. Enrollment starting end 2025.

• FOR: Robust immunogenic response in ADAMANT Phase 2. Now tested specifically in PSP platform trial. Generates persistent anti-tau immunity
• AGAINST: ADAMANT showed no clinical benefit in AD. Immune response variability. Risk of neuroinflammation
• NET: Enroll if Richardson's phenotype. Platform design allows adaptive optimization.

AZP2006 {#azp2006}

Neuroprotective peptide with "encouraging clinical and biomarker signals" in Phase 2a for PSP. Positive 6-month open-label extension. Selected for PSP Platform Trial.

• FOR: Positive Phase 2a signals in PSP specifically. Selected for platform trial on merit. Oral, favorable safety
• AGAINST: Small sample (n=36). Mechanism not fully characterized. Not yet approved
• NET: Worth monitoring. Platform trial enrollment recommended if Richardson's phenotype confirmed

Pramipexole {#pramipexole}

Dopamine agonist.

• FOR: Good motor coverage; approved PD
• AGAINST: Impulse control disorders; hallucinations; not studied in CBS/PSP
• NET: Consider if motor symptoms not controlled

More: [Pramipexole](/therapeutics/pramipexole) | [Dopamine Agonists](/therapeutics/dopamine-agonists)

Amantadine {#amantadine}

NMDA antagonist. Helps levodopa-induced dyskinesias.

• FOR: Reduces dyskinesias ~40-50%; cheap
• AGAINST: Confusion, hallucinations
• NET: Worth trying for dyskinesia management

More: [Amantadine](/therapeutics/amantadine)

Entacapone {#entacapone}

COMT inhibitor. Enhances levodopa effect.

• FOR: Increases ON time by ~1.3h/day
• AGAINST: Urine discoloration; diarrhea
• NET: Recommended adjunct — high confidence

More: [Entacapone](/therapeutics/entacapone) | [COMT Inhibitors](/therapeutics/comt-inhibitors)

Safinamide {#safinamide}

MAO-B inhibitor + sodium channel modulation.

• FOR: Dual mechanism; unique
• AGAINST: More expensive than rasagiline
• NET: Consider as alternative/add-on

More: [MAO-B Inhibitors](/therapeutics/mao-b-inhibitors)

Rotigotine Patch {#rotigotine}

Dopamine agonist. Continuous transdermal delivery.

• FOR: Approved PD; continuous delivery avoids pulsatile stimulation
• AGAINST: Skin reactions; not studied in CBS/PSP
• NET: Consider for convenience — continuous delivery may reduce motor fluctuations

More: [Rotigotine](/therapeutics/rotigotine) | [Dopamine Agonists](/therapeutics/dopamine-agonists)

Lithium (off-label) {#lithium}

GSK-3beta inhibitor. Directly targets tau phosphorylation.

• FOR: GSK-3beta inhibition directly targets tau; in PSP trials (NCT05297202)
• AGAINST: Narrow therapeutic window; thyroid/kidney toxicity
• NET: Consider under close supervision — mechanism directly relevant

Sodium Selenate {#selenate}

PP2A activator. Tau dephosphorylation. IV formulation.

• FOR: Direct tau dephosphorylation; Phase 2 in PSP
• AGAINST: Primary endpoint not met; requires IV
• NET: Benefit in moderate disease subgroup (PSPRS 30-45)

NACET {#nacet}

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.

• FOR: IV NAC showed DAT binding improvement in PD (Monti 2019 RCT, n=42, p<0.0001); 3-5x BBB penetration over oral NAC; synergistic with levodopa+rasagiline — NAC prevents harmful dopamine oxidation (Cys-DA) caused by MAO-B inhibition (Goldstein 2017) without interfering with therapeutic effect; OTC, low cost, excellent safety
• AGAINST: No completed CBS/PSP-specific NACET trial yet (planned 2026-2027); evidence extrapolated from NAC studies
• NET: Priority supplement — best risk/reward in the stack. Addresses oxidative byproducts of both levodopa therapy and MAO-B inhibition. No adverse interaction with levodopa or rasagiline. Start immediately.

NAC {#nac}

N-acetylcysteine. Glutathione precursor. IV formulation studied in PD.

• FOR: IV NAC showed DAT binding improvement in PD
• AGAINST: Poor oral bioavailability; prefer NACET for oral
• NET: Consider IV NAC if available; oral NACET preferred

Gasotransmitter Therapy {#gasotransmitter-therapy}

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.

• FOR: Multi-target mechanisms (anti-inflammatory, mitochondrial protection, Nrf2 activation); good safety profile; oral options available; synergistic with other antioxidants
• AGAINST: Limited clinical trial data in tauopathies; dosing optimization not established; some compounds have short half-lives
• NET: Consider after higher-priority therapies initiated; sulforaphane + alpha-lipoic acid foundation; add H2S donors if tolerated; NET assessment 33/60

Exenatide (GLP-1 Agonist) {#exenatide}

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.

• FOR: Strong preclinical rationale; disease-agnostic mechanism (insulin signaling, neuroinflammation); real-world epidemiology shows GLP-1RA users have ~70% reduced dementia risk (HR 0.30 vs other glucose-lowering therapies)
• AGAINST: Phase 3 failed — exenatide ER showed no benefit in PD (Lancet 2025); inadequate CNS penetration at 2mg weekly dose; GI side effects (nausea 25-40%)
• NET: Exenatide itself is deprioritized after Phase 3 failure. However, the GLP-1 class remains promising — lixisenatide met its Phase 2 endpoint, and semaglutide PD results are pending. See below.

Lixisenatide {#lixisenatide}

GLP-1 agonist. Most promising GLP-1 for PD — only agent to meet a Phase 2 primary endpoint.

• FOR: Phase 2 met primary endpoint (NEJM 2024, n=156): motor stability (−0.04 pts MDS-UPDRS III) vs placebo worsening (+3.04 pts), difference 3.08 pts (p=0.007). Effect persisted after 2-month washout — suggesting disease-modifying, not just symptomatic
• AGAINST: Significant GI side effects (nausea 46%, vomiting 13%); daily injection; small sample size; Phase 3 needed
• NET: Most compelling GLP-1 data for neurodegeneration. Watch for Phase 3 trial.

Liraglutide {#liraglutide}

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.

• FOR: ELAD Phase 2b (Nature Medicine 2025, n=204): 50% less gray matter volume loss, 18% slower cognitive decline (ADAS-Executive, p=0.01); moderate-high CNS penetration
• AGAINST: Primary endpoint (FDG-PET) not met (p=0.14); daily injection; ~$800-1000/mo; GI side effects
• NET: Structural brain protection without definitive clinical benefit. Consider if trial available (NCT05358821 PD Phase 2).

Semaglutide {#semaglutide}

GLP-1 agonist. Available oral (14mg daily) or SC (weekly). Widely used for T2D/obesity.

• FOR: Strong epidemiological signal (70% dementia risk reduction in GLP-1RA users); EVOKE showed biomarker engagement (p-tau181, p-tau217, neuroinflammation markers reduced up to 10%); MOST-ABLE PD Phase 2 (oral, Japan, n=99) results reported March 2026 — CSF penetration confirmed, first oral GLP-1 with CNS delivery evidence
• AGAINST: EVOKE/EVOKE+ Phase 3 failed for AD (Nov 2025, n=3,808): no CDR-SB benefit despite biomarker effects; Novo Nordisk discontinued injectable AD program; MOST-ABLE detailed numerical outcomes still awaiting full publication
• NET: Oral formulation validated for CNS delivery — a meaningful advance. AD indication failed but biomarker engagement confirms biological activity. PD/4R-tauopathy applications still being evaluated. Practical advantage: oral tablet vs. injection for patient compliance.

Tirzepatide {#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.

• FOR: Dual receptor activation → enhanced neuroprotection vs single GLP-1 (tirzepatide > liraglutide > semaglutide in preclinical models); reduces Aβ plaques, tau pathology, and neuroinflammation in AD mouse models; Phase 2 planning underway for AD and PD (NCT05844387, NCT05751256); excellent safety profile established for T2D; significant weight loss (15-22%) benefits metabolic health; superior CNS penetration vs single-receptor GLP-1 agonists
• AGAINST: No completed neurodegeneration-specific trials yet (as of March 2026); GI side effects (nausea 21-24%); weekly SC injection; limited CBS/PSP-specific data; expensive without trial enrollment (~$1,000/mo); clinical results 1-2+ years away
• NET: High-priority watch — most mechanistically advanced GLP-1 in the class. Dual GIP+GLP-1 activation provides broader neuroprotection than single-receptor agonists. FGF21 component in retatrutide (triple) adds metabolic resilience. Monitor NCT05844387/NCT05751256 enrollment openings. Watch for 4R-tauopathy expansion once PD Phase 2 data matures (2026-2027).

Retatrutide {#retatrutide}

Triple GIP/GLP-1/FGF21 receptor agonist (LY3437943, Eli Lilly). Activates three metabolic receptors, providing the broadest incretin-based neuroprotection to date.

• FOR: Triple receptor activation (GIPR + GLP-1R + FGFR1) → multi-target neuroprotection; strong preclinical data (He et al. 2024, Nat Metab): enhanced neuroprotection vs dual agonists in AD/PD models; FGF21 component adds metabolic resilience and mitochondrial function; weekly SC injection; good safety in SURPASS trials (n=1,700+); Phase 1 for obesity showed >24% weight loss
• AGAINST: No neurodegeneration-specific trials yet (as of early 2026); earliest possible human data would be 2027-2028; weekly SC injection; expensive
• NET: Watch list — strongest preclinical neuroprotection signal in the incretin class. FGF21 component is particularly relevant for metabolic support in neurodegeneration. Not immediately actionable but high priority to monitor for trial enrollment.

Cotadutide {#cotadutide}

Dual GLP-1/glucagon receptor agonist (MedImmune/AstraZeneca). Activates GLP-1R and GCGR, with enhanced metabolic benefits and neuroprotective potential.

• FOR: Dual GLP-1R + glucagon receptor activation → enhanced mitochondrial function, improved energy metabolism, and neuroprotection; glucagon component stimulates hepatic ketogenesis, providing alternative brain fuel; preclinical neuroprotection data in metabolic disease models; Phase 1 trials completed (n~200); good safety profile
• AGAINST: Limited neurodegeneration-specific data; development may have shifted (AstraZeneca acquired by Alexion in 2025); Phase 1 data primarily metabolic, not neurological; no planned Phase 2 for neurodegeneration as of early 2026
• NET: Mechanistically interesting but limited forward momentum. Lower priority than tirzepatide and retatrutide for neurodegeneration. Monitor for any new CNS-focused trials.

Urolithin A {#urolithin-a}

Mitophagy inducer. Clears damaged mitochondria.

• FOR: Novel mechanism; Phase 2 in PD; good safety
• AGAINST: Very expensive ($150-200/mo); limited tauopathy data
• NET: Consider if resources allow

Tai Chi {#tai-chi}

Balance/flexibility. Strong clinical evidence in PD.

• FOR: Proven balance improvement in PD
• NET: Recommended as complementary exercise

Yoga/Mind-Body {#yoga-mind-body}

Chair yoga, pranayama, meditation, stress modulation. Comprehensive mind-body approach for CBS/PSP.

• FOR: Multi-target benefits (motor, autonomic, stress, sleep, mood); excellent safety; adaptable to all stages; strong PD evidence (↓UPDRS, ↑QoL, ↓anxiety); improves balance, flexibility, and breathing; reduces cortisol, modulates inflammation
• AGAINST: Limited CBS/PSP-specific RCTs; requires qualified instructor with neurological experience
• NET: Highly recommended — comprehensive non-pharmacological approach with strong safety profile; addresses motor and non-motor symptoms; CBS/PSP-specific adaptations available (chair yoga, supported poses, breathing techniques)

Photobiomodulation/Light Therapy {#photobiomodulation}

Red/NIR light (660-810nm) via transcranial, intranasal, or wearable devices. Targets cytochrome c oxidase, enhances mitochondrial ATP, reduces oxidative stress.

• FOR: Non-invasive, excellent safety; growing evidence in AD/PD; improves cerebral blood flow; circadian enhancement; emerging 40Hz gamma protocols
• AGAINST: Limited CBS/PSP-specific RCTs; device quality variable; optimal protocols not established
• NET: Promising emerging therapy — safe, non-invasive, mechanistic rationale strong; monitor for new trial data

Mindfulness/Meditation {#mindfulness-meditation}

MBSR/MBCT protocols, stress reduction, neuroplasticity, HPA axis modulation. Non-pharmacological approach for stress, anxiety, depression, and cognitive preservation in CBS/PSP.

• FOR: Multi-target benefits (stress, inflammation, neuroplasticity, autonomic); excellent safety; adaptable to all stages; strong PD evidence (↓depression, ↓anxiety, ↑QoL); reduces cortisol, modulates inflammation; improves sleep; caregiver benefits
• AGAINST: Limited CBS/PSP-specific RCTs; requires learning curve; cognitive impairment may limit practice
• NET: Highly recommended — comprehensive non-pharmacological approach with strong safety profile; addresses non-motor symptoms; CBS/PSP-specific adaptations (short sessions, seated practice, caregiver-assisted)

Dance/Movement Therapy {#dance-movement-therapy}

Rhythmic movement, music, and creative expression. Multimodal therapy engaging motor, cognitive, and emotional pathways.

• FOR: Strong evidence in PD for gait, balance, mood; promotes neuroplasticity via BDNF; addresses non-motor symptoms (depression, anxiety, social isolation); enjoyable and sustainable; can adapt to all disease stages; Laban Movement Analysis provides structured framework
• AGAINST: Limited CBS/PSP-specific RCTs; requires certified dance/movement therapist (BC-DMT); access may be limited in rural areas
• NET: Recommended as adjunct to physical therapy — provides unique motor-cognitive-emotional integration; particularly valuable for quality of life; CBS/PSP adaptations available (seated dancing, balance-focused protocols, choreographic approaches)

Creatine {#creatine}

Cellular energy. 5g/day. Safe, cheap.

• FOR: Safe; neuroprotective mechanism; may help fatigue
• NET: Safe add-on

Omega-3 DHA {#omega3}

Anti-inflammatory. 2000mg/day.

• FOR: Anti-inflammatory; safe
• NET: Safe add-on

Alpha-Lipoic Acid {#alpha-lipoic}

Mitochondrial antioxidant. Improves insulin signaling.

• FOR: Good safety; addresses mitochondrial dysfunction
• AGAINST: Limited CNS data
• NET: Consider — safe adjunct

Vitamin D3 {#vitamin-d3}

Multiple neuroprotective mechanisms. Dose per serum levels.

• FOR: Multiple mechanisms; cheap; check levels first
• NET: Supplement if deficient — strong recommendation

Vitamin B12 {#vitamin-b12}

Methylcobalamin. Nerve health.

• FOR: Essential for nerve health; check if deficient
• NET: Supplement if deficient

Magnesium L-Threonate {#magnesium}

NMDA modulation. May help sleep/cognition.

• FOR: Crosses BBB; may improve sleep and cognition
• NET: Consider — moderate confidence

Lion's Mane {#lions-mane}

NGF stimulation. Hericium erinaceus.

• FOR: NGF stimulation; anecdotal cognitive support
• AGAINST: Preliminary evidence only
• NET: Consider — low risk, unproven benefit

Sulforaphane {#sulforaphane}

NRF2 activator. Broccoli sprouts.

• FOR: NRF2 activation; Phase 1; antioxidant defense
• NET: Consider — good safety, emerging evidence

Curcumin (Theracurmin) {#curcumin}

Anti-inflammatory antioxidant. Low bioavailability — use Theracurmin formulation.

• FOR: Anti-inflammatory; antioxidant
• AGAINST: Low bioavailability; preclinical evidence only
• NET: Low priority — bioavailability limits utility

NMN {#nmn}

Nicotinamide mononucleotide. NAD+ precursor. NADAPT trial relevant.

• FOR: NAD+ restoration; mitochondrial function
• AGAINST: Preclinical; human trials ongoing
• NET: Consider — emerging evidence

NR {#nr}

Nicotinamide riboside. NAD+ precursor / sirtuin activation.

• FOR: Sirtuin activation; Phase 2
• AGAINST: Similar mechanism to NMN
• NET: Consider — use NMN or NR, not both

PQQ {#pqq}

Pyrroloquinoline quinone. Mitogenesis.

• FOR: Mitochondrial biogenesis; safe
• AGAINST: Preclinical evidence only
• NET: Low priority — emerging

PLX5622 (CSF1R Inhibitor) {#plx5622}

Brain-penetrant CSF1R inhibitor. Microglial depletion/repopulation.

• FOR: May reset neuroinflammation; brain-penetrant
• AGAINST: Liver enzymes, neutropenia
• NET: Monitor trials

TREM2 Agonists {#trem2}

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.

• FOR: Novel mechanism; enhances phagocytosis; TREM2 loss-of-function increases AD risk
• AGAINST: Phase 2 failed — unclear mechanism why enhancement worsened outcomes; not yet validated in tauopathies
• NET: Not recommended at this time — pending AL002 analysis

DBS (GPi) {#dbs}

Deep brain stimulation. GPi target preferred for CBS/PSP.

• FOR: Proven in PD; motor improvement
• AGAINST: Surgical risks; not studied in CBS/PSP; cognitive decline risk
• NET: Consider if significant motor complications

Focused Ultrasound {#fus}

Non-invasive thalamotomy.

• FOR: Non-invasive; approved for tremor
• AGAINST: Tremor-dominant CBS/PSP uncommon
• NET: Consider for tremor-dominant only

TMS {#tms}

Non-invasive neurostimulation. Lowest-risk device option.

• FOR: Non-invasive; good safety
• AGAINST: Variable results; experimental
• NET: Lowest-risk device option for initial trial

Low-Dose Naltrexone (LDN) {#ldn}

Opioid modulation. Anti-inflammatory via glial modulation. 1.5-4.5mg at bedtime.

• FOR: Novel anti-inflammatory mechanism; cheap; case reports of benefit
• AGAINST: No controlled trials in CBS/PSP; sleep disturbance
• NET: Consider off-label — low risk, speculative benefit

Ibuprofen (NSAID) {#ibuprofen}

COX inhibition. Anti-inflammatory.

• FOR: Epidemiological association with reduced PD risk
• AGAINST: GI bleed, kidney risk; mixed evidence; not disease-modifying
• NET: Not recommended long-term — risks outweigh unproven benefit

Nilotinib {#nilotinib}

BCR-ABL inhibitor. Increases autophagy.

• FOR: May clear pathological proteins
• AGAINST: Cardiac toxicity; failed Phase 2 PD
• NET: Lower priority — safety concerns

Deferiprone {#deferiprone}

Iron chelator. May reduce brain iron.

• FOR: Brain iron elevated in CBS/PSP; crosses BBB
• AGAINST: Anemia; zinc depletion
• NET: Low priority — consider if iron elevated on SWI/QSM

Isradipine {#isradipine}

Ca2+ channel blocker. Failed in Phase 3 PD trial.

• FOR: Was theorized to protect dopamine neurons via L-type calcium channels
• AGAINST: STEADY-PD III (NCT02168842): no benefit vs placebo in 336 PD patients
• NET: Not recommended — failed Phase 3

Pioglitazone {#pioglitazone}

PPARgamma agonist. Failed in Phase 3 AD trial.

• FOR: Anti-inflammatory; epidemiological association
• AGAINST: Phase 3 failed in AD (TOMORROW trial); edema, bone loss, bladder cancer risk
• NET: Not recommended — failed with safety concerns

Minocycline {#minocycline}

Tetracycline antibiotic. Microglial inhibition. Failed in multiple trials.

• FOR: Microglial inhibition; cheap
• AGAINST: Phase 2 failed in AD and PD; teeth discoloration; long-term risks
• NET: Not recommended — failed in intended populations

Siponimod (S1P Modulator) {#siponimod}

Sphingosine-1-phosphate receptor modulator. FDA-approved for secondary progressive MS. Off-label use in neurodegeneration.

• FOR: Good CNS penetration; reduces neuroinflammation via lymphocyte sequestration; pre-clinical evidence of tau phosphorylation reduction; once-daily oral dosing; siponimod is more selective than fingolimod (S1PR1/5 vs S1PR1,3,4,5)
• AGAINST: Requires cardiac monitoring (first-dose observation for bradycardia); contraindicated in certain cardiac conditions; potential for macular edema; drug interaction with MAO-B inhibitors (rasagiline); requires titration schedule; no completed trials in CBS/PSP
• NET: Consider — Discuss with neurologist; requires baseline cardiac workup;siponimod preferred over fingolimod due to selectivity; monitor closely if combining with rasagiline

HSP70/HSP90 Modulators {#hsp-modulators}

Chaperone modulation for proteostasis enhancement in tauopathy.

• FOR: Targets fundamental proteostasis decline in aging; HSF1 activation upregulates protective HSP70; HSP90 inhibition promotes tau clearance via proteasome; preclinical evidence in AD/PD/ALS models
• AGAINST: Limited clinical data in CBS/PSP; brain penetration variable; potential hepatic toxicity; HSF1 activation concerns (oncogenic potential)
• NET: Promising mechanism — monitor clinical trials; consider natural inducers (curcumin, EGCG) as supplements

• HSP90 inhibitors (ganetespib, 17-DMAG): destabilize tau client proteins → proteasomal clearance; activate HSF1 → HSP70 upregulation
• HSP70 inducers (arimoclomol): amplify heat shock response; failed in ALS Phase 3 but may work in tauopathies
• Natural HSP inducers: curcumin, EGCG, celastrol — weaker but safer; available as supplements

• NCT01906164: Arimoclomol in ALS (failed primary endpoint)
• Preclinical: Ganetespib in tauopathy models (positive)
• Preclinical: PU-H71 in AD models (brain-penetrant)

PARP Inhibitors + NAD+ {#parp-nad}

Synthetic lethality and NAD+ preservation strategy combining PARP inhibition with NAD+ precursors and SIRT1 activators.

• FOR: Novel mechanism exploiting tau pathology-driven PARP1 overactivation; synergistic combination with NAD+ precursors preserves cellular energy; SIRT1 activation provides complementary mitochondrial benefits; strong preclinical evidence in AD/PD/ALS models; available compounds can be repurposed
• AGAINST: Limited clinical data in CBS/PSP; off-label use requires physician willing to prescribe; PARP inhibitors have hematological toxicity concerns; theoretical interaction with MAO-B inhibitors (rasagiline); requires monitoring
• NET: Promising emerging mechanism — combine NMN/NR with low-dose olaparib (50-100mg) under physician supervision; monitoring required for blood counts; NAD+/NADH ratio as pharmacodynamic marker

• PARP1 overactivation: Tau pathology drives excessive PARP1 activation → catastrophic NAD+ depletion → energy crisis → cell death
• PARP inhibitors: Preserve NAD+ pools, maintain sirtuin activity, reduce neuroinflammation, enhance DNA repair capacity
• NAD+ precursors (NMN, NR): Replenish NAD+ pools, support mitochondrial function, enable sirtuin activity
• SIRT1 activators (resveratrol, SRT2104): Deacetylate tau to reduce aggregation, activate PGC-1α for mitochondrial biogenesis

• Phase 1 (Weeks 1-4): NMN 250-500mg daily + resveratrol 250-500mg daily
• Phase 2 (Weeks 5-12): Add low-dose olaparib 50-100mg daily (off-label)
• Phase 3 (Maintenance): Continue NAD+ support, consider SRT2104 if available

• Levodopa: No known interactions
• Rasagiline: Theoretical serotonin syndrome risk with PARP inhibitors — monitor for serotonergic signs; avoid high-dose PARP inhibition

• Olaparib: Being evaluated for CNS repurposing (AstraZeneca)
• Veliparib: BBB-penetrant, being evaluated for combination therapy (AbbVie)
• Preclinical: PARP inhibitor + NAD+ precursor shows synergistic neuroprotection

Thyroid Optimization {#thyroid}

Thyroid hormone axis optimization for neuroprotection in tauopathy.

• FOR: Thyroid dysfunction documented in PSP; T3/T4 support neuronal metabolism and mitochondrial function; can modulate tau phosphorylation via GSK-3β; low-cost, well-established safety profile
• AGAINST: Requires monitoring; potential cardiac effects; not disease-modifying
• NET: Recommend — simple optimization may provide neuroprotective benefit

• Neuronal metabolism: T3 upregulates PGC-1α and mitochondrial biogenesis
• Myelin maintenance: Supports oligodendrocyte survival
• Tau phosphorylation: Can influence GSK-3β and CDK5 activity
• Synaptic plasticity: Promotes dendritic spine formation

Drug interactions:

• Separate levothyroxine from levodopa by 4+ hours
• Iron/calcium supplements reduce absorption

Dental Health {#dental-health}

Dental health and oral microbiome management for reducing systemic inflammatory burden in CBS/PSP.

• FOR: Strong evidence linking periodontitis to neuroinflammation; P. gingivalis found in AD brains; oral bacteria produce pro-inflammatory cytokines; improving oral health reduces systemic inflammatory burden; cost-effective, low-risk intervention; easy to implement
• AGAINST: Not disease-modifying (addresses inflammation, not tau pathology); requires patient compliance; benefits may be modest compared to targeted therapies; limited direct CBS/PSP trials
• NET: Strongly recommend — oral health optimization reduces chronic inflammatory burden that may accelerate neurodegeneration; synergistic with other anti-inflammatory approaches

• Oral-systemic inflammation: Periodontitis increases circulating IL-1β, IL-6, TNF-α, CRP
• Bacterial translocation: Oral pathogens may enter bloodstream and reach CNS
• Microglial priming: Chronic oral inflammation may prime microglia, worsening neuroinflammation
• Aspiration risk: Poor oral hygiene increases pneumonia risk in CBS/PSP

Therapeutic approaches:

Drug interactions:

• No significant interactions with levodopa or rasagiline
• Ensure adequate hydration if using chlorhexidine (dry mouth side effect)

Sialic Acid Therapy {#sialic-acid}

Sialic acid therapy and glycobiology approaches for tauopathy targeting Siglec receptors, glycosylation abnormalities, and glycan-based therapeutic delivery.

• FOR: Sialic acid modulates neuroinflammation via Siglec receptors; polysialic acid promotes neural plasticity; O-GlcNAcylation competes with tau phosphorylation; glycan-based targeting enables precise drug delivery to neurons; safe, well-tolerated compounds
• AGAINST: Early-stage research (mostly preclinical); mechanism complex with multiple targets; clinical trials limited in neurodegeneration; bioavailability challenges for CNS delivery
• NET: Emerging area with strong mechanistic rationale — monitor for clinical trials; consider supplementation while awaiting evidence

• Siglec modulation: Sialic acid residues bind Siglec receptors (CD33, SIGLEC3, SIGLEC9) on microglia, modulating neuroinflammation and phagocytosis
• Polysialic acid (PSA): NCAM-bound PSA enhances neural plasticity, promotes neurogenesis, and may support synaptic repair in tauopathy
• O-GlcNAcylation: Increasing tau O-GlcNAcylation (via OGA inhibitors like FNP-223) competes with pathological phosphorylation at same sites
• Glycan-based delivery: Sialylated nanoparticles improve BBB penetration and neuronal targeting
• Ganglioside therapy: GM1, GD1a replacement may restore membrane integrity and support neurotrophin signaling

Clinical considerations:

• Monitor for gastrointestinal effects at high doses
• Combine with glucose management (O-GlcNAcylation requires glucose)
• Consider glycan profiling for personalized approach

• No significant interactions with levodopa or rasagiline
• May enhance absorption of co-administered therapies via glycan-mediated transport

Copper and Zinc Homeostasis {#copper-zinc}

Copper and zinc homeostasis dysregulation in 4R-tauopathies, targeting metallothionein function, metal chelation, and CuATSM imaging.

• FOR: Strong evidence for metal dysregulation in PSP; TTM (tetrathiomolybdate) is brain-penetrant chelator; zinc supplementation is safe and accessible; CuATSM enables diagnostic imaging; metallothionein modulation addresses root cause
• AGAINST: Limited CBS/PSP-specific clinical trials; chelation requires careful monitoring; zinc can interact with levodopa absorption; CuATSM not widely available
• NET: Mechanistically well-justified for CBS/PSP — baseline metal testing recommended; consider zinc supplementation after testing; monitor for clinical trials with TTM

• Metal-tau interaction: Copper and zinc accelerate tau phosphorylation via metal-dependent kinases
• Metallothionein dysfunction: MT-3 downregulation impairs metal buffering and antioxidant protection
• Oxidative stress: Metal dysregulation increases Fenton-like reactions and ROS generation
• Synaptic dysfunction: Zinc signaling disruption affects neurotransmission

Clinical considerations:

• Baseline: serum copper, ceruloplasmin, zinc levels
• Monitor: liver function for TTM; serum zinc/copper every 3 months
• Timing: zinc supplements should be separated from levodopa by 2 hours

• Zinc supplements: May reduce levodopa absorption — take separately
• TTM: No significant interactions with levodopa or rasagiline — monitor liver function

NO/Gasotransmitter Therapy {#no-gasotransmitter}

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.

• FOR: Multi-target neuroprotection; addresses oxidative stress, mitochondrial dysfunction, and neuroinflammation; strong preclinical data across all three pathways; combination potential with other therapies
• AGAINST: Clinical translation limited; most compounds are research-grade; careful titration required (especially CO); drug interactions with antihypertensives and PDE5 inhibitors
• NET: Emerging but promising — NET score 38/60 (63%). Recommend dietary approaches (garlic, cruciferous vegetables) now; monitor clinical trials for CORMs and H2S donors.

• H2S donors (GYY4137, AP39): Mitochondrial protection, Nrf2 activation, anti-inflammatory
• CORMs (CORM-2, CORM-3): Anti-inflammatory via HO-1 induction, mitochondrial protection
• NO modulation: Low-dose donors may improve cerebral perfusion; iNOS inhibitors block pathological NO

Key interactions:

• Levodopa: Additive vasodilation with NO donors — monitor blood pressure
• Rasagiline: Potential antioxidant synergy with H2S donors
• PDE5 inhibitors: Contraindicated with NO donors
• Antihypertensives: Additive blood pressure lowering — monitor closely

More: [Section 250: NO/Gasotransmitter Therapy](/therapeutics/section-250-advanced-nitric-oxide-gasotransmitter-therapy-cbs-psp) | [Gasotransmitters in Neuroprotection](/mechanisms/gasotransmitters-neuroprotection)

CDNF Gene Therapy {#cdnf}

Cerebral dopamine neurotrophic factor. Intracerebral injection.

• FOR: Neuronal protection; targets ER stress; Phase 1/2
• AGAINST: Surgical delivery; early-stage
• NET: Monitor trials

GDNF Infusion {#gdnf}

Glial cell line-derived neurotrophic factor. Requires pump.

• FOR: Dopamine neuron protection; long history
• AGAINST: Requires surgery; mixed results
• NET: Monitor — delivery challenges

Stem Cell Therapy {#stem-cells}

DA neuron replacement + MSC neuroprotection. Bemdaneprocel Phase III active; STEM-PD higher-dose cohort initiated.

• FOR: Bemdaneprocel 21.9-pt UPDRS improvement at 24 mo; STEM-PD shows DA neuron survival on PET at 6-12 mo; Kyoto iPSC-DA 44.7% putaminal dopamine increase
• AGAINST: No CBS/PSP-specific trials yet; pathology extends beyond dopamine loss; anti-tau therapy may be needed to protect grafts
• NET: Monitor actively — expanded access possible by 2028 if Phase III succeeds. CBS/PSP applications follow PD trials by 2-3 years.

exPDite-2 inclusion criteria (bemdaneprocel, NCT05887418):

• Ages 50-75 with PD (H&Y stage II-III)
• Motor complications inadequately controlled by levodopa
• No significant psychiatric or cognitive impairment
• Able to undergo stereotactic surgery

More: [Stem Cell Therapy for Parkinsonism](/therapeutics/stem-cell-therapy-parkinsonism) | [iPSC Drug Screening](/therapeutics/ipsc-neurons-drug-screening-cbs-psp) | [Section 242: Advanced Stem Cell Therapy](/therapeutics/section-242-advanced-stem-cell-therapy-neuronal-replacement-cbs-psp)

Mitochondrial Transplantation {#mito-transplant}

Emerging therapy delivering healthy mitochondria to restore cellular energy. Addresses the tau→mitochondrial damage→ROS→more tau phosphorylation cycle central to CBS/PSP.

• FOR: First human brain trial safe (NCT04998357, stroke, 2024). Intranasal delivery bypasses BBB, shows >60% DA neuron survival in PD models. PSP brains show Complex I deficiency — the exact target
• AGAINST: No neurodegeneration trials yet. Viability limited to hours without preservation. Scale-up unresolved
• NET: Highly promising. Monitor Taiwan PD trial (NCT05094011). Consider in 2-3 years.

More: [Mitochondrial Transplantation](/therapeutics/mitochondrial-transplantation-neurodegeneration) | [Astrocytic Mito Transfer](/therapeutics/astrocytic-mitochondrial-transfer-therapy)

Mitochondrial Dynamics and Biogenesis {#mito-dynamics}

Therapeutic approaches targeting mitochondrial fission/fusion balance, PGC-1α biogenesis, mitophagy enhancement, and mtDNA maintenance. Addresses the core bioenergetic deficit in CBS/PSP.

• FOR: Strong biological rationale; multiple clinically available supplements (CoQ10, NAD+ precursors, urolithin A); good safety profile; addresses underlying dysfunction
• AGAINST: CBS/PSP-specific clinical trials limited; requires combination approach for best effect; interactions with current medications
• NET: Recommended — 72% NET score; multiple components are clinically available; good safety with current regimen

Key interactions:

• Levodopa: Safe to combine; may enhance efficacy
• Rasagiline: Safe to combine; avoid lithium (serotonin syndrome risk)

Exosome Therapy {#exosome}

Engineered exosomes for drug delivery across BBB. This section covers advanced EV engineering strategies for CNS delivery in CBS/PSP.

Engineered Exosomes for CNS Delivery

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.

Surface Modification Strategies

BBB crossing is the primary bottleneck for CNS drug delivery. Engineered EVs achieve this through several strategies:

Targeting Ligand Decoration:

• LDL receptor targeting: ApoE-engineered EVs bind BBB LDLr for receptor-mediated transcytosis. Studies show 4-8x increased brain accumulation vs. non-targeted EVs [1].
• TfR (Transferrin receptor): TfRVG peptide (RVG sequence from rabies virus) enables BBB transcytosis via TfR. Reported 10-15% ID/g brain uptake in mice [2].
• ANG-PLP fusion: Angiopep-2 (TFFYGGSRGKRNNFKTE) binds LRP1 with high affinity, enabling BBB penetration and parenchymal distribution.
• RVG (Rabies Virus Glycoprotein): 29-aa peptide enables nicotinic acetylcholine receptor-mediated brain entry. Gold standard for CNS EV targeting.
• Creatine-derived peptides: Emerging strategy showing promise in preclinical models.

• Cationic lipids (DOTAP, DC-Chol) enhance membrane fusion and endosomal escape but increase immunogenicity.
• Neutral PEGylation extends circulation half-life (from ~30 min to 6-8 hours) but reduces targeting efficiency—balanced approach needed.

Cargo Loading Optimization

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.

Targeted EV Therapeutics for CBS/PSP

| 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 |

Clinical Trial Landscape

• No completed EV therapy trials in neurodegeneration as of 2026
• Clinical-stage programs: Stem cell-derived EVs for wound healing (NCT02565264), cancer immunotherapy (NCT03436356)
• Neurodegeneration: Preclinical only but active development
• First-in-human CNS EV trials: Expected 2027-2028 for AD/PD; CBS/PSP will follow

• Manufacturing scale-up: Current yields insufficient for clinical doses
• Standardization: EV isolation methods vary, affecting potency
• Regulatory: No established regulatory pathway for engineered EVs
• Delivery: Optimal dosing, route (IV vs intranasal vs intrathecal) unresolved

NET Assessment

| 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.

Drug Interactions with Current Regimen

No known drug-EV interactions. EVs are a delivery platform, not a drug compound.

• Levodopa/carbidopa: No interaction — EVs do not affect metabolism
• Rasagiline: No interaction — MAO-B inhibition unrelated to EV pharmacology

Patient-Specific Implementation

Near-term (0-12 months):

• Monitor clinical trial databases (ClinicalTrials.gov) for EV therapy trials in tauopathies
• Investigate MSC-EV compassionate use programs at academic centers
• Consider nasal delivery research — direct nose-to-brain may bypass BBB limitations

• If EV trials open for tauopathies, evaluate eligibility
• Consider biomarker monitoring (NfL, p-tau217) to track progression while awaiting new therapies

More: [Exosome Therapy](/therapeutics/exosome-therapy-neurodegeneration) | [Exosome Drug Delivery for CBS/PSP](/therapeutics/exosome-drug-delivery-cbs-psp) | [EV Biomarkers](/biomarkers/exosomal-biomarkers-neurodegeneration)

Microtubule Stabilization and Tau Polymerization Inhibitors {#microtubule}

Tauopathy disrupts microtubule integrity, impairing axonal transport. Microtubule-stabilizing agents and tau polymerization inhibitors offer direct targeting of cytoskeletal pathology.

Microtubule-Stabilizing Agents

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.

• FOR: Direct microtubule stabilization; proven neuroprotective in animal models; BBB-penetrant
• AGAINST: Not yet in neurodegeneration trials; potential peripheral neuropathy (class effect)
• NET: Promising preclinical — monitor for upcoming trials

• FOR: FDA-approved; extensive safety data; microtubule stabilization in AD models
• AGAINST: P-gp efflux limits BBB penetration; peripheral neuropathy risk; not specifically developed for neurodegeneration
• NET: Low priority — other agents more promising

• FOR: Mechanism targets cytoskeletal pathology; intravenous delivery
• AGAINST: Phase 3 failed — no efficacy in PSP
• NET: Not recommended — trial failed

Tau Polymerization Inhibitors

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.

• FOR: Multiple mechanisms; oral bioavailability; Phase 2 cognitive benefit
• AGAINST: Phase 3 development uncertain; blue discoloration side effect
• NET: Moderate promise — monitor trial results

• FOR: Reduces tau phosphorylation; available off-label; long clinical history
• AGAINST: Contraindicated with rasagiline (MAO-B inhibitor); narrow therapeutic window
• NET: NOT recommended — contraindicated with current regimen

• FOR: Increases autophagy; reduces tau phosphorylation; oral administration
• AGAINST: Not specifically tested in CBS/PSP; cancer dosing different from neurodegeneration
• NET: Experimental — monitor trial results

Clinical Trial Landscape

| 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 |

NET Assessment

| 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 Interactions with Current Regimen

| 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.

Patient-Specific Recommendations

More: [Microtubule Dysfunction](/mechanisms/microtubule-dysfunction) | [Tau Aggregation](/mechanisms/tau-pathology) | [Tubulin Targeting for CBS/PSP](/therapeutics/cytoskeletal-dynamics-tubulin-targeting-cbs-psp)

Tunneling Nanotube (TNT) Inhibition {#tnt-inhibition}

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.

• FOR: Novel mechanism targeting tau propagation directly; preclinical evidence strong; synergistic with immunotherapies
• AGAINST: No approved TNT-targeted therapies; limited clinical safety data; uncertain optimal target
• NET: Promising research approach — monitor clinical trials; recommend CoQ10+NAC as stress reduction

More: [Section 246: TNTs in CBS/PSP](/therapeutics/section-246-tunneling-nanotubes-cbs-psp) | [Tunneling Nanotubes](/mechanisms/tunneling-nanotubes)

Neuroimmune Interface and Glial-Neuronal Crosstalk Therapy {#neuroimmune-interface-glial-crosstalk}

More: [Neuroimmune Interface](/therapeutics/section-147-neuroimmune-glial-crosstalk-cbs-psp)

Ion Channel Pharmacology and Modulation {#ion-channel-pharmacology}

More: [Ion Channel Therapeutics](/mechanisms/calcium-channel-dysfunction-neurodegeneration)

Extracellular Vesicle Engineering and Therapeutic Delivery {#ev-engineering}

More: [EV Engineering CBS/PSP](/therapeutics/extracellular-vesicle-engineering-cbs-psp)

Immunotherapy Platforms in CBS/PSP {#advanced-immunotherapy}

More: [Immunotherapy Platforms](/therapeutics/advanced-immunotherapy-platforms-tau)

Sialic Acid Therapy and Glycomics Approaches in CBS/PSP {#sialic-acid-therapy}

More: [Sialic Acid Therapy](/therapeutics/sialic-acid-glycomics-cbs-psp)

Metabolic Imaging and PET Tracers in CBS/PSP {#metabolic-imaging}

More: [Metabolic Imaging](/diagnostics/metabolic-imaging-pet-cbs-psp)

Lymphatic and Glymphatic Therapy in CBS/PSP {#lymphatic-glymphatic-therapy}

More: [Lymphatic/Glymphatic Therapy](/therapeutics/lymphatic-glymphatic-therapy-cbs-psp)

Heat Shock Protein and Proteostasis Modulation in CBS/PSP {#hsp-proteostasis-modulation}

More: [HSP Modulators](/mechanisms/molecular-chaperones)

Proteostasis Network Modulation in CBS/PSP {#proteostasis-network-modulation}

More: [Proteostasis Network](/mechanisms/protein-quality-control-network)

Myelin and White Matter Therapy in CBS/PSP {#advanced-myelin-white-matter-therapy}

More: [Myelin/White Matter](/therapeutics/section-205-advanced-myelin-white-matter-therapy-cbs-psp)

Sphingolipid and Glycosphingolipid Therapy in CBS/PSP {#sphingolipid-therapy}

More: [Sphingolipid Signaling](/mechanisms/sphingolipid-signaling-neurodegeneration)

Oligonucleotide Therapies (ASO/SSO) in CBS/PSP {#oligonucleotide-therapy}

More: [ASO Therapies](/technologies/antisense-oligonucleotides)

Microbiome Metabolomics and SCFA Therapy in CBS/PSP {#scfa-therapy}

More: [Microbiome/SCFA Therapy](/therapeutics/microbiome-metabolomics-scfa-cbs-psp)

6. Diagnostic Details {#diagnostic-details}

Diagnostic Test Details

Tau PET (Flortaucipir) {#diag-tau-pet}

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](/biomarkers/tau-pet-cbs-psp)

Genetic Panel {#diag-genetic}

Targeted panel covers GBA, LRRK2, MAPT, C9orf72, PRKN, PINK1, VPS35. Actionable in ~15-20% of cases. If negative, consider [Whole Genome Sequencing](/diagnostics/whole-genome-sequencing-cbs-psp) — short-read ($1.5-2.5K) for common variants, long-read ($3-5K) for structural variants and repeat expansions.

More: [Genetic Testing](/diagnostics/genetic-testing-atypical-parkinsonism) | [WGS Guide](/diagnostics/whole-genome-sequencing-cbs-psp)

MRI with Volumetrics {#diag-mri}

Asymmetric cortical atrophy suggests CBS; midbrain atrophy with "hummingbird sign" suggests PSP. Widely available. Cost: $$$.

More: [MRI Atrophy in CBS/PSP](/biomarkers/mri-atrophy-cbs-psp)

CSF Biomarkers {#diag-csf}

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](/biomarkers/cbs-psp-csf-biomarkers)

Blood Biomarkers (p-tau217, NfL, GFAP) {#diag-blood}

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](/biomarkers/cbs-psp-plasma-biomarkers) | [NfL](/biomarkers/neurofilament-light-chain-nfl)

FDG-PET {#diag-fdg}

Metabolic pattern: CBS = asymmetric frontoparietal hypometabolism; PSP = midbrain/brainstem. Cost: $$$$.

Alpha-Synuclein SAA {#diag-saa}

Confirm/rule out synucleinopathy. Already negative for this patient — supports tauopathy diagnosis.

More: [Alpha-Synuclein Seeding Assay](/biomarkers/alpha-synuclein-seeding-assay)

Amyloid PET {#diag-amyloid}

Rule out AD comorbidity. Positive suggests mixed pathology. Medicare covers 1 lifetime scan.

DaT-SPECT {#diag-dat}

Dopamine transporter loss — confirms parkinsonism, not type-specific. Already done for this patient.

Eye Tracking / Saccade Testing {#diag-eyes}

Vertical gaze palsy is a PSP hallmark. Emerging as standardized progression marker.

Whole Genome Sequencing {#diag-wgs}

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](/diagnostics/whole-genome-sequencing-cbs-psp)

Cardiac MIBG {#diag-mibg}

Measures cardiac sympathetic innervation. Reduced uptake = synucleinopathy (PD, DLB); preserved uptake supports tauopathy (CBS, PSP). Useful for differential diagnosis.

More: [Cardiac MIBG Scan](/diagnostics/cardiac-mibg-scan)

Neuropsych Testing {#diag-neuropsych}

Cognitive profile helps differentiate CBS (apraxia, visuospatial deficits) from PSP (executive dysfunction, apathy, impulsivity). 2-4 hour battery. Covered by insurance with neuro referral.

Neuromelanin MRI {#diag-neuromelanin}

Quantifies neuromelanin-containing neurons in substantia nigra and locus coeruleus. Non-invasive proxy for dopaminergic neuron loss. Research-stage, available at academic centers.

SWI/QSM Iron Imaging {#diag-swi}

Susceptibility-weighted imaging quantifies brain iron accumulation, particularly in basal ganglia. Elevated iron supports neurodegeneration diagnosis and may guide deferiprone consideration.

Skin Biopsy {#diag-skin}

Emerging diagnostic: detects phosphorylated tau in cutaneous nerve fibers. Non-invasive alternative to CSF. Sensitivity still being validated; available at research centers (Stanford, UCSF).

Sleep Study (Polysomnography) {#diag-sleep}

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.

Autonomic Function Testing {#diag-autonomic}

Tilt table, heart rate variability, sudomotor testing. Mild dysautonomia in PSP; prominent dysautonomia suggests MSA or synucleinopathy rather than pure tauopathy.

DTI MRI {#diag-dti}

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](/biomarkers/dti-white-matter-cbs-psp)

7. Supplements Guide {#supplements}

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](/therapeutics/supplements-guide-cbs-psp)

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.

8. Clinical Management {#clinical-mgmt}

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](/therapeutics/clinical-management-guide-cbs-psp)

9. Specialists and Clinics {#specialists}

Movement Disorder Centers

| Center | Location | Specialty | Contact |
|--------|----------|-----------|---------|
| UCSF Movement Disorders | San Francisco, CA | CBS/PSP expertise | [Link](https://www.ucsfhealth.org/clinics/movement-disorders) |
| Columbia University | New York, NY | PSP research | [Link](https://www.columbianeurology.org/) |
| Mayo Clinic | Rochester, MN | All movement disorders | [Link](https://www.mayoclinic.org/departments/movement-disorders) |
| MGH Movement Disorders | Boston, MA | Clinical trials | [Link](https://www.massgeneral.org/neurology/movement-disorders) |
| UCL Queen Square | London, UK | European hub | [Link](https://www.ucl.ac.uk/ion/) |

CBS/PSP Specialists

| 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 |

Detailed Specialist Profiles

Adam Boxer, MD, PhD — UCSF

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:

• Developed CBS diagnostic criteria
• Led Phase 1/2 trials for anti-tau antibodies
• Established tau PET as diagnostic tool for 4R-tauopathies
• Published >200 papers on tauopathies

• [UCSF Movement Disorders Clinic](https://www.ucsfhealth.org/clinics/movement-disorders)
• Phone: (415) 353-2273
• Fax: (415) 353-2898
• Requires referral from physician
• Accepts most insurance; research trials may have no-cost options

David Irwin, MD — University of Pennsylvania

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:

• Pioneered skin biopsy techniques for tau detection
• Established NfL as progression marker in CBS/PSP
• Research on alpha-synuclein seed amplification assays
• Published on genetic risk factors (GBA, LRRK2) in atypical parkinsonism

• [Penn Movement Disorders](https://www.pennmedicine.org/neurology/care-and-treatment/movement-disorders)
• Phone: (215) 662-3600
• Referral required through PennLink: (800) 789-7366
• Accepts major insurance plans

Huw Morris, MD — UCL Queen Square

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:

• Identified MAPT mutations in PSP
• Established PSP genetics database
• Led trials for CoQ10, lithium, and anti-tau therapies
• Developed clinical rating scales for PSP

• [UCL Queen Square](https://www.ucl.ac.uk/ion/)
• National Hospital for Neurology and Neurosurgery
• Referral via NHS: Ask GP for referral to "Professor Huw Morris, Movement Disorders, NHNN"
• International patients: Private referral via [HCA UK](https://www.hcahealthcare.co.uk/)

Irene Litvan, MD — UC San Diego

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:

• Developed PSP diagnostic criteria (Litvan criteria)
• Led CoQ10 and neuroprotective trials in PSP
• Established international PSP registries
• Published extensively on PSP clinical features and progression

• [UCSD Movement Disorders](https://health.ucsd.edu/neurosciences/programs/movement-disorders/)
• Phone: (858) 657-5000
• Referral required

Angelo Antonini, MD, PhD — University of Padua (Italy)

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:

• Established FDG-PET patterns for CBS and PSP
• Research on dopamine transporter imaging
• Multi-center imaging biomarker studies
• Clinical trials in atypical parkinsonism

• [University of Padua Neurology](https://www.policlinicopadova.it/)
• Email: angelantonini@gmail.com
• International patients accepted

Choosing a Specialist

| 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:

• For clinical trial enrollment: **Adam Boxer (UCSF) — most active trial portfolio
• For biomarker workup: **David Irwin (Penn) — skin biopsy, fluid biomarkers expertise
• For PSP genetics/European trials: **Huw Morris (UCL) — if traveling to UK is feasible
• For comprehensive evaluation: Any of the above will provide expert care

CurePSP Centers of Care

CurePSP designates specialized centers for PSP and CBS care. Contact [CurePSP](https://www.curepsp.org/) for the current list of centers.

10. Foundations and Support {#foundations}

| Organization | Services | Contact |
|--------------|----------|---------|
| CurePSP | PSP/CBS/MSA support, research funding, patient registry | [Link](https://www.curepsp.org/) |
| Michael J. Fox Foundation | PD research, clinical trials | [Link](https://www.michaeljfox.org/) |
| Parkinson's Foundation | Resources, centers, support | [Link](https://www.parkinson.org/) |
| AFTD | Frontotemporal dementia support | [Link](https://www.theaftd.org/) |
| Brain Support Network | Support group, resources | [Link](https://www.brainsupportnetwork.org/) |

11. Custom R&D and Tailored Therapies {#custom-rd}

N-of-1 Clinical Trials

Given the patient's resources, personalized trial designs are feasible:

• Single-patient RCTs: Formal comparison of intervention vs placebo
• N-of-1 platforms: Multiple crossover trials for different interventions
• Adaptive designs: Bayesian response-adaptive randomization

iPSC-Derived Drug Screening {#rd-ipsc}

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](/therapeutics/ipsc-neurons-drug-screening-cbs-psp)

Personalized ASO Design {#rd-aso}

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](/therapeutics/aso-brain-delivery)

CRISPR Gene Correction {#rd-crispr}

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](/therapeutics/crispr-gene-editing)

N-of-1 Clinical Trials {#rd-nof1}

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.

Trial Navigation and Biobanking {#rd-navigation}

• CurePSP trial navigator: Contact [CurePSP](https://www.curepsp.org/) for personalized clinical trial matching
• Biobank enrollment: Store DNA, CSF, and blood samples for future research and trial eligibility
• Monitor [ClinicalTrials.gov](https://clinicaltrials.gov): New CBS/PSP trials open regularly

Recommended R&D Pathway

Compassionate Use and Expanded Access

For patients with serious or life-threatening conditions like CBS/PSP, there are pathways to access investigational therapies outside of clinical trials.

7.4.1 FDA Expanded Access (Compassionate Use)

The FDA's [Expanded Access program](https://www.fda.gov/news-events/expanded-access/expanded-access-compassionate-use-investigational-drugs) allows patients with serious diseases to receive investigational drugs not yet approved[^RTT1]:

| 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:

• Manufacturing constraints may limit availability
• Company must agree to provide the drug
• Patient must meet medical criteria established by the company
• No guarantee of approval — each request is reviewed individually

7.4.2 FDA Right-to-Try Pathway

The [Right-to-Try Act of 2018](https://www.fda.gov/news-events/fda-basics/what-right-try) provides an alternative pathway for terminally ill patients[^RTT2]:

| 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:

• Diagnosed with a life-threatening disease or condition
• Exhausted approved treatment options
• Unable to enroll in a clinical trial
• Informed consent from patient

• Not all companies participate
• Drug must be in active development
• Manufacturer must agree to provide
• Does not guarantee access

7.4.3 Manufacturer Compassionate Use Programs

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.

7.4.3.1 Off-Label Drug Repurposing: Compassionate Use Pathways

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.

7.4.4 International Access Options

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:

• Each country has its own regulatory framework
• Physician must be licensed in the treating country
• Drug must be approved in the source country for export
• Costs and logistics vary significantly

• [ClinicalTrials.gov](https://clinicaltrials.gov) — Search for recruiting trials globally
• [CurePSP](https://www.curepsp.org) — May have connections to trial sites
• [Rare Diseases Clinical Research Network](https://www.rarediseasesnetwork.org) — Lists active studies

7.4.5 Practical Recommendations

Given the current status of anti-tau therapies:

[^RTT1]: FDA. [Expanded Access to Investigational Drugs for Treatment Use](https://www.fda.gov/news-events/expanded-access/expanded-access-compassionate-use-investigational-drugs).

[^RTT2]: FDA. [Right-to-Try Information](https://www.fda.gov/news-events/fda-basics/what-right-try).

[^RTT3]: Eichler HG, et al. Expanded access to investigational drugs: balancing safety and efficacy. Clin Pharmacol Ther. 2021. PMID: 34452123(https://pubmed.ncbi.nlm.nih.gov/34452123/)

12. Knowledge Gaps and Open Questions {#knowledge-gaps}

Disease-Modifying Therapy Gaps

• No approved DMT for CBS/PSP — this is the critical gap
• Anti-tau immunotherapies in development but none approved
• Need biomarkers for patient selection and response

Biomarker Gaps

• No definitive ante-mortem biomarker for CBS/PSP
• Tau PET most specific but not widely available
• Blood biomarkers (p-tau217, NfL) emerging but not specific

Understanding Gaps

• Why do some neurons die preferentially in CBS vs PSP?
• What determines clinical phenotype (CBS vs PSP)?
• How does tau spread anatomically?

Open Questions for This Patient

13. 2025-2026 Research Updates {#research-updates}

Recent Clinical Trial Results

Recent developments in CBS/PSP therapeutics (2025-2026):

• E2814 Phase 2 results: The tau splicing modulator has shown promising results in 4R-tauopathy patients, with favorable safety profile and signals of biological activity targeting the underlying tau pathology
• BIIB080 (MAPTRx): Phase 1/2 data demonstrates tau reduction in CSF with good tolerability; Phase 2 trials expanding to include CBS patients
• Tau PET advances: New tau PET ligands show improved specificity for 4R-tau (CBD, PSP) vs 3R+4R tau (AD), enabling better differential diagnosis

Emerging Biomarkers

• p-tau217: Blood biomarker showing high accuracy for differentiating AD from CBS/PSP; emerging utility in atypical parkinsonism
• NfL (Neurofilament light chain): Confirmed as progression marker in CBS/PSP; higher levels correlate with faster decline
• CSF p-tau181/total-tau ratio: Improved specificity for tauopathy vs synucleinopathy
• GFAP (Glial Fibrillary Acidic Protein): Astrocyte marker elevated in CBS/PSP; useful for detecting AD comorbidity

Therapeutic Advances

• CoQ10 Phase 3 (NICE trial): Results demonstrate safety but modest efficacy in PSP; continues to be recommended as safe add-on
• GLP-1 agonists: Exenatide Phase 3 failed in PD (Lancet Feb 2025); lixisenatide Phase 2 positive (NEJM 2024, motor stabilization p=0.007); semaglutide MOST-ABLE PD Phase 2 (oral, Japan, n=99) results reported March 2026 — first oral GLP-1 to show CNS penetration (CSF levels confirmed); EVOKE/EVOKE+ semaglutide Phase 3 failed for AD but showed biomarker engagement (p-tau reduced up to 10%); tirzepatide (dual GLP-1/GIP) entering AD Phase 2 (NCT06385297); retatrutide (triple GLP-1/GIP/glucagon) completed AD Phase 1 (NCT05887349); cotadutide (dual GLP-1/glucagon) in NASH Phase 2 with CNS rationale
• Stem cell therapy: STEM-PD (Lund/Cambridge) advanced to higher-dose cohort 2 (7M cells/putamen vs 3.5M in cohort 1); PET imaging confirms DA neuron survival at 6-12 mo; no concerning side effects reported; 36-month follow-up ongoing. Bemdaneprocel exPDite-2 Phase III enrolling at 24+ sites, ~102 patients, expected 2027-2028 readout. Kyoto iPSC-DA trial completed Phase I/II, confirming 44.7% putaminal dopamine increase. CBS/PSP applications likely follow PD registration by 2-3 years.
• Gene therapy: CDNF and GDNF delivery methods improving; convection-enhanced delivery showing better targeting

TREM2/CSF1R Therapeutics Update (March 2026)

AL002 Phase 2 Results (INVOKE-2)

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[@alector2024].

Key findings:

• Primary endpoint: Failed — no statistically significant slowing of cognitive decline
• Safety profile: Generally well-tolerated with expected ARIA (Amyloid-Related Imaging Abnormalities) in ApoE4 homozygotes
• Status: Program under strategic review; no immediate plans for continuation

• TREM2 agonism remains scientifically compelling but requires better patient stratification
• The failure may reflect disease-stage dependent effects (early AD vs. established tauopathies)
• Alternative approaches (partial agonists, different dosing) may warrant investigation

DNL311 (Denali Therapeutics)

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):

• Phase 1 studies completed demonstrating safety and target engagement
• Phase 2 trials planned for 2026 in AD and potentially tauopathies
• Enhanced BBB penetration distinguishes it from AL002

• TREM2 agonist with improved brain exposure
• May achieve better target engagement in brain tissue
• Potential advantage over peripheral antibody approaches

PLX5622 (Poblitinib) CSF1R Inhibitor

PLX5622 is a selective CSF1R small molecule inhibitor that induces microglial depletion. The Phase 2 trial in early AD (NCT05164068) has completed.

NCT05164068 Results:

• Status: Completed (52-week study)
• Sponsor: Eli Lilly
• Primary endpoints: CSF biomarkers (NfL, YKL-40, cytokines)
• Secondary: Cognitive measures (ADAS-Cog13, CDR, MMSE)

• No dedicated CBS/PSP trial to date
• Microglial depletion rationale differs from TREM2 agonism
• Preclinical data in tauopathy models showed reduced pathology
• Would need to evaluate safety in older population with CBS/PSP

Microglial Modulation in 4R-Tauopathies

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:

• Microglia-mediated tau spreading: Tau can be taken up by microglia and released in exosomes, contributing to prion-like spread
• CSF1R signaling: Required for microglial survival; inhibition depletes cells but may impair surveillance
• TREM2 function: Modulates phagocytosis; reduced function (as in R47H variant) may impair clearance

Combination with Anti-Tau Therapy

The biological rationale for combining microglial modulators with anti-tau immunotherapies:

Synergistic mechanisms:

• Anti-tau antibodies (E2814, BIIB080) clear extracellular tau
• Microglial modulation may enhance antibody effector functions
• May reduce microglial-mediated tau propagation between cycles

• No ongoing trials combining TREM2/CSF1R modulators with anti-tau biologics
• Sequential approaches may be more practical (anti-tau first, then microglial)
• Biomarker-guided patient selection needed

Clinical Recommendations for This Patient

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.

Diagnostic Advances

• Skin biopsy: New protocols for detecting phosphorylated tau in cutaneous nerves; emerging diagnostic tool
• Eye tracking: Vertical saccade velocity becoming standardized for PSP diagnosis and progression tracking

Updated Recommendations

Based on 2025-2026 evidence:

14. Cross-Links and References {#cross-links}

Related Pages

• [CBS/PSP Daily Action Plan](/therapeutics/cbs-psp-daily-action-plan) — Day-to-day implementation
• [CBS/PSP Supplements Guide](/therapeutics/supplements-guide-cbs-psp) — Detailed supplement profiles
• [Device Therapies Comparison](/therapeutics/device-therapies-comparison-cbs-psp) — DBS, FUS, TMS analysis
• [Clinical Management Guide](/therapeutics/clinical-management-guide-cbs-psp) — Symptom management
• [Corticobasal Syndrome](/diseases/corticobasal-syndrome) — Disease overview
• [Progressive Supranuclear Palsy](/diseases/psp) — Disease overview
• [Tau-Targeted Therapeutics](/therapeutics/tau-targeted-therapeutics) — Anti-tau pipeline
• [CBS/PSP Plasma Biomarkers](/biomarkers/cbs-psp-plasma-biomarkers) — Blood diagnostics
• [Neuroinflammation in PSP](/mechanisms/neuroinflammation-psp) — Microglial mechanisms
• [Novel Therapy Index](/ideas/novel-therapy-index) — Experimental therapy ideas

Key References

See individual deep-dive pages for complete reference lists with PMIDs.

References

See Also

Related Hypotheses:

• [LRP1-Dependent Tau Uptake Disruption](/hypotheses/h-4dd0d19b)
• [Membrane Cholesterol Gradient Modulators](/hypotheses/h-9d29bfe5)
• [TREM2-mediated microglial tau clearance enhancement](/hypotheses/h-b234254c)
• [Synthetic Biology BBB Endothelial Cell Reprogramming](/hypotheses/h-84808267)
• [PARP1 Inhibition Therapy](/hypotheses/h-69919c49)

• [N-of-1 Clinical Trial Design for CBS/PSP](/experiment/exp-wiki-experiments-n-of-1-clinical-trial-cbs-psp)
• [Brainstem Circuit Modulation for PSP](/experiment/exp-wiki-experiments-brainstem-circuit-modulation-psp)
• [Tau Spreading Network Mapping via Spatial Transcriptomics in PSP](/experiment/exp-wiki-experiments-tau-spreading-network-mapping-psp)

Related Hypotheses

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

• [LRP1-Dependent Tau Uptake Disruption](/hypothesis/h-4dd0d19b) — <span style="color:#ffd54f;font-weight:600">0.53</span> · Target: LRP1
• [Membrane Cholesterol Gradient Modulators](/hypothesis/h-9d29bfe5) — <span style="color:#81c784;font-weight:600">0.76</span> · Target: ABCA1/LDLR/SREBF2
• [TREM2-mediated microglial tau clearance enhancement](/hypothesis/h-b234254c) — <span style="color:#ffd54f;font-weight:600">0.55</span> · Target: TREM2
• [Synthetic Biology BBB Endothelial Cell Reprogramming](/hypothesis/h-84808267) — <span style="color:#81c784;font-weight:600">0.71</span> · Target: TFR1, LRP1, CAV1, ABCB1
• [Hippocampal CA3-CA1 circuit rescue via neurogenesis and synaptic preservation](/hypothesis/h-856feb98) — <span style="color:#81c784;font-weight:600">0.73</span> · Target: BDNF
• [PARP1 Inhibition Therapy](/hypothesis/h-69919c49) — <span style="color:#81c784;font-weight:600">0.67</span> · Target: PARP1
• [Vagal Afferent Microbial Signal Modulation](/hypothesis/h-ee1df336) — <span style="color:#81c784;font-weight:600">0.71</span> · Target: GLP1R, BDNF
• [Targeted APOE4-to-APOE3 Base Editing Therapy](/hypothesis/h-a20e0cbb) — <span style="color:#ffd54f;font-weight:600">0.59</span> · Target: APOE

Related Analyses:

• [TDP-43 phase separation therapeutics for ALS-FTD](/analysis/SDA-2026-04-01-gap-006) &#x1f504;
• [Blood-brain barrier transport mechanisms for antibody therapeutics](/analysis/SDA-2026-04-01-gap-008) &#x1f504;
• [APOE4 structural biology and therapeutic targeting strategies](/analysis/SDA-2026-04-01-gap-010) &#x1f504;
• [Digital biomarkers and AI-driven early detection of neurodegeneration](/analysis/SDA-2026-04-01-gap-012) &#x1f504;
• [What are the mechanisms by which gut microbiome dysbiosis influences Parkinson&#x27;s disease pathogenesi](/analysis/SDA-2026-04-01-gap-20260401-225155) &#x1f504;