Personalized Treatment Plan — Atypical Parkinsonism (CBS/PSP)

Contents

Pathway Diagram

flowchart TD
    Personalized_Treatment_Plan___["Personalized Treatment Plan - Atypical Parkinsonism (CBS/PSP"] -->|"references"| LRP1["LRP1"]
    Personalized_Treatment_Plan___["Personalized Treatment Plan - Atypical Parkinsonism (CBS/PSP"] -->|"references"| BACE1["BACE1"]
    Personalized_Treatment_Plan___["Personalized Treatment Plan - Atypical Parkinsonism (CBS/PSP"] -->|"references"| GFAP["GFAP"]
    Personalized_Treatment_Plan___["Personalized Treatment Plan - Atypical Parkinsonism (CBS/PSP"] -->|"references"| BDNF["BDNF"]
    Personalized_Treatment_Plan___["Personalized Treatment Plan - Atypical Parkinsonism (CBS/PSP"] -->|"references"| PARP1["PARP1"]
    Personalized_Treatment_Plan___["Personalized Treatment Plan - Atypical Parkinsonism (CBS/PSP"] -->|"references"| HDAC["HDAC"]
    Personalized_Treatment_Plan___["Personalized Treatment Plan - Atypical Parkinsonism (CBS/PSP"] -->|"references"| SIRT1["SIRT1"]
    Personalized_Treatment_Plan___["Personalized Treatment Plan - Atypical Parkinsonism (CBS/PSP"] -->|"references"| TREM2["TREM2"]
    classDef gene fill:#1a3a2a,stroke:#4caf50,color:#e0e0e0
    classDef therapeutic fill:#1a3a3a,stroke:#80cbc4,color:#e0e0e0
    class Personalized_Treatment_Plan___ therapeutic
    class LRP1 gene
    class BACE1 gene
    class GFAP gene
    class BDNF gene
    class PARP1 gene
    class HDAC gene
    class SIRT1 gene
    class TREM2 gene

1. Ranked Therapies {#ranked-therapies}

2. Ranked Diagnostics {#ranked-diagnostics}

3. Top Recommendations {#top-recommendations}

Diagnostics (do first)

1. Tau PET — Single most important step. Differentiate CBS vs PSP. Emerging 4R-specific tracers (PI-2620) may improve sensitivity.

2. Genetic panel — GBA/LRRK2/MAPT variants actionable in ~15-20%. If negative, consider WGS.

3. Blood biomarkers — p-tau217 + NfL + GFAP panel ($400-600). NfL >60 pg/mL = rapid decline.

4. Repeat alpha-synuclein SAA — Confirm negative at reference lab (Amprion).

Therapies (start immediately)

5. Optimize levodopa — Up to 2000mg/day with entacapone. 30-40% of PSP patients respond transiently.

6. Continue rasagiline — Already on board. Possible neuroprotective effect (ADAGIO trial data).

7. Exercise + Tai Chi + Yoga — High-intensity 150+ min/week. Tai Chi for balance/fall reduction. Yoga (chair or supported) for flexibility, breathing, stress. Strongest evidence-to-risk ratio.

8. Add NACET — 600mg 2x/day. BBB penetration 3-5x over NAC. Synergistic with levodopa+rasagiline: prevents harmful DA oxidation from MAO-B inhibition (Goldstein 2017). IV NAC showed DAT improvement (Monti 2019). OTC, safe.

9. Add CoQ10 — Phase 3 negative (NICE PSP, QE3 PD). Supportive only.

10. Consider low-dose lithium — 0.3-0.5 mM with renal/thyroid monitoring. GSK-3β inhibition directly targets tau phosphorylation. PSP trial recruiting (NCT05297202).

Clinical trials (highest priority — pursue in parallel)

11. E2814 — Top priority. Phase 2 anti-tau biologic for 4R-tauopathies (DIAN-TU Phase 3 for AD). 39 sites worldwide.

12. BIIB080 — Tau ASO. Gene-level tau reduction. Phase 2. Intrathecal every 3-6 months.

13. PSP Platform Trial — AADvac1 (tau vaccine) + AZP2006 selected. Enrollment starting end 2025. Strongly consider if Richardson’s phenotype.

14. FNP-223 PROSPER — OGA inhibitor. Phase 2 in PSP completed recruitment (220 patients). Novel tau PTM mechanism. Results 2026.

15. Lixisenatide — Only GLP-1 to meet Phase 2 endpoint (NEJM 2024, p=0.007). Disease-modifying signal persisted after washout. Enroll if Phase 3 opens.

16. Tirzepatide — Dual GLP-1/GIP agonist. Phase 2 in early AD (NCT06385297) and PD (NCT05751256). Monitor for 4R-tauopathy expansion.

17. Semaglutide — Oral GLP-1, MOST-ABLE PD Phase 2 completed (March 2026). CSF penetration confirmed — first oral GLP-1 to show CNS delivery. AD failed but biomarker engagement validates mechanism.

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)

Neuroprotection & Metabolic Support

Cell Replacement & Regeneration

Diagnostics & Biomarkers

Clinical Management

Emerging Science & Strategy

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

Pooled effect size in PSP: d=0.23 (small). NCT03744468 Phase 2 (75 PD): no significant diff vs placebo.

More: 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

ADAGIO trial (NCT00256204): 1mg/day delayed need for symptomatic therapy in early PD (HR 0.82, p=0.02). No CBS/PSP-specific trials.

More: Rasagiline | MAO-B Inhibitors

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

More: Exercise for CBS/PSP | Exercise-Induced Myokines | Rehabilitation Guide

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

DIAN-TU data: CSF pTau217 ~50% reduction at 2 years. 39 sites worldwide. NCT05615614.

More: 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.

More: Tau-Targeted Therapeutics

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.

Phase 3 trials definitively negative for disease modification in both PSP and PD.

More: CoQ10 | CoQ10 Details

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.

More: Tau-Targeted Therapeutics

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.

More: Tau-Targeted Therapeutics

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.

More: Tau-Targeted Therapeutics

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

More: FNP-223 (Ferrer OGA Inhibitor) — dedicated therapeutic page

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.

More: CurePSP Platform Trial

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

More: AZP2006 (Serazaxine) — PSP Platform Trial

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

NCT03022088 Phase 4 (415 PD): significant improvement (d=0.45).

More: Pramipexole | 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

NCT03882892 Phase 4 (52 PD): significant dyskinesia reduction (d=0.68).

More: 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

NCT01567415 Phase 4 (168 PD): ON time +1.3h/day (p<0.001).

More: Entacapone | 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

NCT01023880 Phase 3 (544 PD): UPDRS improvement 2.6 pts (p=0.02).

More: 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

NCT00474638 Phase 3 (395 PD): UPDRS improvement -6.8 pts (p<0.001).

More: Rotigotine | 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

More: Lithium Therapy

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)

NCT02434588 Phase 2 (93 PSP): primary not met (p=0.14); subgroup -4.2 pts vs +1.1 placebo (p=0.01, d=0.68). CSF p-tau181 reduced 18%.

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.

More: NACET Details | Supplements Guide

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

More: NAC for Neurodegeneration | NACET Details

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

More: Section 250: Advanced Gasotransmitter Therapy

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.

More: GLP-1 Receptor Agonists — full comparison table, dosing, combination considerations, and trial details for all GLP-1 agonists

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.

More: GLP-1 Receptor Agonists

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).

More: Liraglutide | GLP-1 Receptor Agonists

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.

More: GLP-1 Receptor Agonists | Tirzepatide

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).

More: Tirzepatide | GLP-1 Receptor Agonists

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.

More: Tirzepatide | GLP-1 Receptor Agonists

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.

More: GLP-1 Receptor Agonists

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

More: Urolithin A | Urolithin A Details

Tai Chi {#tai-chi}

Balance/flexibility. Strong clinical evidence in PD.

• FOR: Proven balance improvement in PD

• NET: Recommended as complementary exercise

More: Tai Chi | Exercise for CBS/PSP

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)

More: Section 230: Advanced Mindfulness and Meditation | Section 231: Advanced Yoga and Mind-Body Therapy | Section 233: Advanced VR and Immersive Technology | Section 234: Advanced Acupuncture and TCM | Section 238: Advanced Aromatherapy and Olfactory Stimulation | Section 240: Advanced Narrative Therapy and Life Review

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

More: Section 243: Advanced Light Therapy

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)

More: Section 230: Advanced Mindfulness and Meditation

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)

More: Section 228: Advanced Dance/Movement Therapy

Creatine {#creatine}

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

• FOR: Safe; neuroprotective mechanism; may help fatigue

• NET: Safe add-on

More: Creatine | Creatine Details

Omega-3 DHA {#omega3}

Anti-inflammatory. 2000mg/day.

• FOR: Anti-inflammatory; safe

• NET: Safe add-on

More: Omega-3 Details

Alpha-Lipoic Acid {#alpha-lipoic}

Mitochondrial antioxidant. Improves insulin signaling.

• FOR: Good safety; addresses mitochondrial dysfunction

• AGAINST: Limited CNS data

• NET: Consider — safe adjunct

More: Alpha-Lipoic Acid | Alpha-Lipoic Details

Vitamin D3 {#vitamin-d3}

Multiple neuroprotective mechanisms. Dose per serum levels.

• FOR: Multiple mechanisms; cheap; check levels first

• NET: Supplement if deficient — strong recommendation

More: Vitamin D3 Details

Vitamin B12 {#vitamin-b12}

Methylcobalamin. Nerve health.

• FOR: Essential for nerve health; check if deficient

• NET: Supplement if deficient

More: Vitamin B12 Details

Magnesium L-Threonate {#magnesium}

NMDA modulation. May help sleep/cognition.

• FOR: Crosses BBB; may improve sleep and cognition

• NET: Consider — moderate confidence

More: Magnesium Details

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

More: Lion’s Mane Details

Sulforaphane {#sulforaphane}

NRF2 activator. Broccoli sprouts.

• FOR: NRF2 activation; Phase 1; antioxidant defense

• NET: Consider — good safety, emerging evidence

More: NRF2 Activators | Sulforaphane Details

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

More: Curcumin Details

NMN {#nmn}

Nicotinamide mononucleotide. NAD+ precursor. NADAPT trial relevant.

• FOR: NAD+ restoration; mitochondrial function

• AGAINST: Preclinical; human trials ongoing

• NET: Consider — emerging evidence

More: NMN Details

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

More: NR Details

PQQ {#pqq}

Pyrroloquinoline quinone. Mitogenesis.

• FOR: Mitochondrial biogenesis; safe

• AGAINST: Preclinical evidence only

• NET: Low priority — emerging

More: PQQ Details

PLX5622 (CSF1R Inhibitor) {#plx5622}

Brain-penetrant CSF1R inhibitor. Microglial depletion/repopulation.

• FOR: May reset neuroinflammation; brain-penetrant

• AGAINST: Liver enzymes, neutropenia

• NET: Monitor trials

More: CSF1R Inhibitors

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

More: TREM2 Therapeutics

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

More: Device Therapies

Focused Ultrasound {#fus}

Non-invasive thalamotomy.

• FOR: Non-invasive; approved for tremor

• AGAINST: Tremor-dominant CBS/PSP uncommon

• NET: Consider for tremor-dominant only

More: Device Therapies

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

More: Device Therapies

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

More: Anti-Inflammatory Therapy

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

More: Anti-Inflammatory Therapy

Nilotinib {#nilotinib}

BCR-ABL inhibitor. Increases autophagy.

• FOR: May clear pathological proteins

• AGAINST: Cardiac toxicity; failed Phase 2 PD

• NET: Lower priority — safety concerns

More: Nilotinib

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

More: Deferiprone

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

More: Calcium Channel Blockers

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

More: PPAR Agonists

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

More: Minocycline

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

More: Section 191: Advanced Lipid Signaling

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

Mechanisms:

• 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

Clinical trials:

• NCT01906164: Arimoclomol in ALS (failed primary endpoint)

• Preclinical: Ganetespib in tauopathy models (positive)

• Preclinical: PU-H71 in AD models (brain-penetrant)

More: HSP90 Inhibitors | HSP70 Inducers | Molecular Chaperones

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

Mechanisms:

• 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

Therapeutic protocol:

• 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

Drug interactions with current regimen:

• Levodopa: No known interactions

• Rasagiline: Theoretical serotonin syndrome risk with PARP inhibitors — monitor for serotonergic signs; avoid high-dose PARP inhibition

Clinical trials:

• Olaparib: Being evaluated for CNS repurposing (AstraZeneca)

• Veliparib: BBB-penetrant, being evaluated for combination therapy (AbbVie)

• Preclinical: PARP inhibitor + NAD+ precursor shows synergistic neuroprotection

More: Synthetic Lethality and PARP Inhibition | PARP Inhibitor Therapy | NAD+ Metabolism

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

Mechanisms:

• 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

Assessment protocol:

1. TSH, Free T4, Free T3, thyroid antibodies

2. Target: TSH 1.0-2.5 mIU/L (mid-normal range)

3. If TSH elevated: Consider levothyroxine 25-50 mcg daily

Drug interactions:

• Separate levothyroxine from levodopa by 4+ hours

• Iron/calcium supplements reduce absorption

More: Hormone Neuroprotection

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

Mechanisms:

• 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

Assessment protocol:

1. Dental examination: Periodontal status, caries, existing restorations

2. Oral microbiome testing: Consider bacterial panel (P. gingivalis, F. nucleatum)

3. Inflammatory markers: Baseline CRP, IL-6

Therapeutic approaches:

1. Professional dental care: Cleanings every 3-4 months (vs. typical 6 months)

2. Daily oral hygiene: Soft toothbrush, floss, antimicrobial mouthwash

3. Xylitol: 5-10g daily in divided doses — reduces S. mutans, increases salivary flow

4. Oil pulling: Coconut/sesame oil swish 10-15 min daily — reduces bacterial load

5. Antimicrobial rinses: Chlorhexidine 0.12% twice daily for active periodontitis

Drug interactions:

• No significant interactions with levodopa or rasagiline

• Ensure adequate hydration if using chlorhexidine (dry mouth side effect)

More: Dental Health and Oral Microbiome

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

Mechanisms:

• 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

Therapeutic approaches:

1. Oral sialic acid supplementation (N-acetylneuraminic acid): 500-1000mg daily, supports glycosylation

2. OGA inhibitors (FNP-223, Threprozine): Increase tau O-GlcNAcylation (already in pipeline as FNP-223)

3. Siglec modulators: CD33/SIGLEC3 antagonists (see CD33 modulation)

4. Polysialic acid delivery: PSA-NCAM targeting for neural repair

5. Ganglioside therapy: GM1 supplementation (clinical trials in PD)

Clinical considerations:

• Monitor for gastrointestinal effects at high doses

• Combine with glucose management (O-GlcNAcylation requires glucose)

• Consider glycan profiling for personalized approach

Drug interactions:

• No significant interactions with levodopa or rasagiline

• May enhance absorption of co-administered therapies via glycan-mediated transport

More: Glycomics Therapy CBS/PSP | CD33 Modulation | Gangliosides

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

Mechanisms:

• 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

Therapeutic approaches:

1. Zinc supplementation: 15-30 mg elemental zinc daily (after baseline testing)

2. Tetrathiomolybdate (TTM): 20-40 mg/day PO — brain-penetrant copper chelator

3. Clioquinol/PBT2: Metal-protein attenuating compounds (clinical trials)

4. Metallothionein inducers: EGCG, sulforaphane to boost endogenous MT expression

5. CuATSM PET imaging: If available — assess regional copper metabolism

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

Drug interactions:

• Zinc supplements: May reduce levodopa absorption — take separately

• TTM: No significant interactions with levodopa or rasagiline — monitor liver function

More: Copper/Zinc Homeostasis CBS/PSP | Copper Homeostasis | Zinc Homeostasis

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.

Key mechanisms:

• 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

Evidence: Gasotransmitter pathways impaired in PSP brains

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

Phased approach:

1. Immediate: Garlic and cruciferous vegetables; sulforaphane supplementation

2. Medium-term: Monitor for clinical trials of CORMs, H2S donors in neurodegeneration

3. Long-term: Evaluate combination protocols as new agents become available

More: Section 250: NO/Gasotransmitter Therapy | Gasotransmitters in 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

More: Gene Therapy | Section 241: Advanced Gene Therapy/CRISPR

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

More: Neurotrophic Factor Therapies

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

For CBS/PSP consideration: A dedicated tauopathy trial would likely follow successful PD registration. Patient should:

1. Monitor trial progress at clinicaltrials.gov

2. Contact BlueRock Medical Affairs for expanded access inquiries

3. Consider autologous iPSC option via research programs (Japan, Cell Therapy Center) — ~12-month turnaround, $50-100K

More: Stem Cell Therapy for Parkinsonism | iPSC Drug Screening | Section 242: Advanced Stem Cell Therapy

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 | Astrocytic Mito Transfer

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

Evidence: PGC-1α pathway impaired in CBD

Key interactions:

• Levodopa: Safe to combine; may enhance efficacy

• Rasagiline: Safe to combine; avoid lithium (serotonin syndrome risk)

More: Section 194: Mitochondrial Dynamics Therapy | Mitochondrial Biogenesis Inducers | NAD+ Boosters

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.

Surface Charge Modulation:

• 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

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

Key barriers to clinical translation:

• 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

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

EV-based delivery could potentially enhance delivery of other therapeutics (e.g., co-delivery with CoQ10, sulforaphane) but this is theoretical.

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

Medium-term (1-3 years):

• If EV trials open for tauopathies, evaluate eligibility

• Consider biomarker monitoring (NfL, p-tau217) to track progression while awaiting new therapies

Current action: None — this is a watchlist therapy. Do not pursue off-label EV therapy at this time.

More: Exosome Therapy | Exosome Drug Delivery for CBS/PSP | EV Biomarkers

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

Paclitaxel (Taxol): Well-established oncology agent. Neurotoxicity concerns limit CNS application, but novel formulations (nanoparticle, nab-paclitaxel) may improve CNS penetration.

• 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

DAVP (Davunetide): Octapeptide derived from activity-dependent neuroprotective protein (ADNP). Promotes microtubule stabilization, neuroprotection. Failed in Phase 3 for PSP (NCT01013480).

• 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

Lithium: GSK-3β inhibitor reducing tau phosphorylation, also affects tau aggregation. CBS/PSP patient has contraindications (MAO-B inhibitor — serotonin syndrome risk).

• 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

Nilotinib: Tyrosine kinase inhibitor (BCR-ABL) repositioned for neurodegeneration. Increases autophagy, reduces alpha-synuclein and tau. Phase 2 in PD (NCT03238988).

• 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

NET Assessment

Total NET Assessment: 16/40 = 40% (low due to limited clinical evidence)

Drug Interactions with Current Regimen

Key Finding: Lithium is contraindicated with rasagiline due to serotonin syndrome risk. Methylene blue should be used with caution.

Patient-Specific Recommendations

1. Monitor for trials: Epothilone D or next-generation microtubule stabilizers

2. Avoid lithium: Contraindicated with MAO-B inhibitor

3. Consider methylene blue: If future trials positive, low-dose formulation

4. Current priority: Low — other therapeutic approaches have stronger evidence

More: Microtubule Dysfunction | Tau Aggregation | Tubulin Targeting for 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

Approaches:

1. Fasudil (ROCK inhibitor): May reduce TNT formation; used clinically for vasospasm

2. CoQ10 + NAC: Stress reduction to decrease TNT formation (recommended now)

3. Anti-tau immunotherapy: Blocks extracellular tau available for TNT transfer

More: Section 246: TNTs in CBS/PSP | Tunneling Nanotubes

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

More: Neuroimmune Interface

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

More: Ion Channel Therapeutics

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

More: EV Engineering CBS/PSP

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

More: Immunotherapy Platforms

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

More: Sialic Acid Therapy

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

More: Metabolic Imaging

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

More: Lymphatic/Glymphatic Therapy

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

More: HSP Modulators

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

More: Proteostasis Network

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

More: Myelin/White Matter

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

More: Sphingolipid Signaling

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

More: ASO Therapies

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

More: Microbiome/SCFA Therapy

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

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 — short-read (1.5-2.5K) for common variants, long-read (3-5K) for structural variants and repeat expansions.

More: Genetic Testing | WGS Guide

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

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

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 | 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

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

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

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

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

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

9. Specialists and Clinics {#specialists}

Movement Disorder Centers

CBS/PSP Specialists

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

How to Refer:

• UCSF Movement Disorders Clinic

• Phone: (415) 353-2273

• Fax: (415) 353-2898

• Requires referral from physician

• Accepts most insurance; research trials may have no-cost options

Clinical Trial Enrollment: Contact UCSF Clinical Trials Office at (415) 514-1234 or email neurologyTrials@ucsf.edu

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

How to Refer:

• Penn Movement Disorders

• Phone: (215) 662-3600

• Referral required through PennLink: (800) 789-7366

• Accepts major insurance plans

Research Contact: Email d-irwin@pennmedicine.upenn.edu for trial information

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

How to Refer:

• UCL Queen Square

• 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

Clinical Trials: Contact UCL Clinical Trials Gateway: trials@ucl.ac.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

How to Refer:

• UCSD 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

How to Refer:

• University of Padua Neurology

• Email: angelantonini@gmail.com

• International patients accepted

Choosing a Specialist

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 for the current list of centers.

10. Foundations and Support {#foundations}

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

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

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

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 for personalized clinical trial matching

• Biobank enrollment: Store DNA, CSF, and blood samples for future research and trial eligibility

• Monitor ClinicalTrials.gov: New CBS/PSP trials open regularly

Recommended R&D Pathway

1. Complete diagnostic workup first — tau PET, genetic panel, WGS

2. Enroll in E2814 trial — closest mechanism match for 4R-tauopathy

3. Pursue iPSC screening — can test 100+ compounds on patient-specific neurons

4. Store biosamples — DNA, CSF, blood for future trial eligibility

5. Monitor for trial eligibility — CurePSP navigator service

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 allows patients with serious diseases to receive investigational drugs not yet approved¹:

Process for E2814, BIIB080, Bepranemab:

1. Contact the manufacturer directly — Eisai (E2814), Biogen (BIIB080), UCB (bepranemab)

2. Physician submits application — Treating neurologist completes company-specific forms

3. FDA reviews — Typically 1-4 weeks for individual patient requests

4. Institutional approval — Hospital IRB must approve

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 provides an alternative pathway for terminally ill patients²:

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

Limitations:

• 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:

Notes on Specific Drugs:

• E2814 (Eisai): This tau-targeting antibody specifically targets 4R-tau, making it highly relevant for CBS/PSP. Eisai has not publicly announced a compassionate use program. Patients should contact the company directly to inquire about expanded access.

• BIIB080/MAPTRx (Biogen): The antisense oligonucleotide that reduces tau production. Biogen has historically offered expanded access for some programs but no formal program exists for BIIB080. Direct inquiry recommended.

• Bepranemab (UCB): Anti-tau antibody targeting aggregated tau. UCB has not announced compassionate use programs for bepranemab. Contact the company for availability.

Note: Drug companies often handle compassionate use requests through their Medical Affairs departments. Direct contact is the best way to inquire about current availability and application processes.

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:

Process for Off-Label Access:

1. Consult with treating neurologist — Discuss risks/benefits

2. Check insurance coverage — Some insurers cover off-label use with prior authorization

3. Consider clinical trials — Some trials allow prior treatments

4. Document medical necessity — Letter of medical necessity helps with insurance

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:

Country-Specific Pathways:

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

Resources:

• ClinicalTrials.gov — Search for recruiting trials globally

• CurePSP — May have connections to trial sites

• Rare Diseases Clinical Research Network — Lists active studies

7.4.5 Practical Recommendations

Given the current status of anti-tau therapies:

1. Priority: Enroll in clinical trials — The most reliable pathway to access E2814, BIIB080, or bepranemab

2. Contact company Medical Affairs — Inquire about any expanded access programs or protocols

3. Monitor clinicaltrials.gov — New sites and trials open regularly

4. Engage a clinical trial navigator — Organizations like CurePSP can help identify options

5. Consider international trials — Some trials may have sites in other countries with easier access

6. Work with treating physician — They can help navigate regulatory requirements

7. Document all communications — Keep records of all sponsor contacts

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

1. Can tau PET definitively distinguish CBS from PSP? — Distinct patterns exist but overlap requires clinical correlation

2. Should alpha-synuclein SAA be repeated? — Sensitivity varies by lab; consider repeat at Amprion reference lab

3. Optimal levodopa dose for tauopathy? — 30-40% respond transiently; trial up to 2000mg/d warranted

4. Could GBA/LRRK2 mutations explain atypical presentation? — GBA associated with faster progression; affects trial eligibility

5. Role of neuroinflammation? — Microglial activation prominent in tauopathies; LDN and PLX5622 are candidates

6. Mixed pathology? — Amyloid PET can rule out AD comorbidity; affects treatment selection

7. Can prion-like tau spreading be slowed? — Anti-tau immunotherapies may slow; early intervention likely more effective

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^{2Alector Inc. AL002 Clinical Trial Results. 2024 Annual Report2024Open reference}.

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

Implications for CBS/PSP:

• 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

Mechanism:

• 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)

Implications for CBS/PSP:

• 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

Therapeutic strategies:

1. Microglial depletion (PLX5622): Controversial — may remove both harmful and protective functions

2. TREM2 agonism (AL002, DNL311): Enhance native clearance mechanisms (PAUSED post-AL002)

3. CSF1R modulation: Partial inhibition rather than depletion

4. Combination with anti-tau therapy: Rationale for combining with E2814 or BIIB080

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

Current trial designs:

• 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:

1. AL002: Not recommended — Phase 2 failed, program under review

2. DNL311: Monitor for Phase 2 enrollment; may represent improved approach

3. PLX5622: No CBS/PSP trial available; discuss off-label risks/benefits with clinician

4. Anti-tau + microglia approach: Prioritize anti-tau trials (E2814, BIIB080) now; microglial approaches remain experimental

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:

1. Tau PET remains the gold standard for differential diagnosis but blood p-tau217 may serve as accessible screening

2. Genetic testing increasingly important — GBA and LRRK2 variants found in more CBS patients than previously recognized

3. Anti-tau immunotherapies remain the most promising disease-modifying approach; prioritize trial enrollment

4. Exercise continues to have strongest evidence for symptomatic benefit; high-intensity protocols preferred

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

Related Pages

• CBS/PSP Daily Action Plan — Day-to-day implementation

• CBS/PSP Supplements Guide — Detailed supplement profiles

• Device Therapies Comparison — DBS, FUS, TMS analysis

• Clinical Management Guide — Symptom management

• Corticobasal Syndrome — Disease overview

• Progressive Supranuclear Palsy — Disease overview

• Tau-Targeted Therapeutics — Anti-tau pipeline

• CBS/PSP Plasma Biomarkers — Blood diagnostics

• Neuroinflammation in PSP — Microglial mechanisms

• Novel Therapy Index — Experimental therapy ideas

Key References

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

1. Chen T et al. DPP10: a voltage gated potassium channel associated protein is abnormally expressed in neurodegenerative diseases. Brain. 2014

2. Song et al., Potassium Channel Dysfunction in Parkinson’s Disease (2017)

3. Lowe et al., Flortaucipir F 18: FDA approval and clinical use (2024)

4. Malpetti et al., Tau PET imaging in 4R tauopathies: PSP and CBD (2024)

5. Chen et al., Tau PET in progressive supranuclear palsy: Systematic review (2024)

6. Boellaard et al., Evaluation of novel 4R tau-selective PET tracers (2024)

7. Koga et al., Prognostic and diagnostic utility of tau PET in PSP and CBS (2024)

8. Nicastro et al., Flortaucipir PET in PSP: Retrospective analysis (2024)

9. Respondek et al., Tau PET patterns in atypical parkinsonism (2023)

10. Passamonti et al., AV-1451 PET in PSP and CBS (2017)