Progressive Supranuclear Palsy (PSP) is a progressive 4R tauopathy for which no FDA-approved disease-modifying therapies currently exist[1]. Treatment is multimodal, combining symptomatic pharmacotherapy, evidence-based neuroprotective supplementation, multidisciplinary rehabilitation, and — for eligible patients — clinical trial participation. This page consolidates the current treatment landscape for PSP, drawing on interventions ranked across an 8-dimension evidence rubric developed for the CBS/PSP Treatment Rankings.
The CBS/PSP Daily Action Plan provides implementable protocols. The CBS/PSP Rehabilitation Guide details non-pharmacological therapies.
Levodopa remains the first-line pharmacological trial for motor symptoms in PSP, despite limited efficacy compared to Parkinson's Disease[2]. PSP-Parkinsonism (PSP-P) patients are most likely to respond, with approximately 20-30% showing modest, transient benefit.
| Medication | Mechanism | Dosing | Evidence | Notes |
|---|---|---|---|---|
| Levodopa/carbidopa | Dopamine precursor | Up to 1000 mg/day | Limited | Trial warranted in all patients; declare non-response after adequate trial[2:1] |
| Amantadine | NMDA antagonist + DA release | 100-200 mg BID | Moderate | May improve rigidity and gait freezing; monitor for confusion[3] |
| Pramipexole | D2/D3 agonist | 0.375-1.5 mg/day | Weak | Impulse control side effects limit use |
Botulinum toxin injections are first-line for focal symptoms[4]:
| Symptom | First-Line | Second-Line | Notes |
|---|---|---|---|
| Depression | SSRIs (sertraline 50-200 mg, citalopram 10-20 mg) | Mirtazapine | Avoid tricyclics (anticholinergic burden)[5] |
| Apathy | Methylphenidate 5-20 mg/day | Modafinil 100-200 mg | Common and disabling; differentiate from depression |
| Pseudobulbar affect | Dextromethorphan/quinidine (Nuedexta) | SSRIs | Only FDA-approved treatment for pseudobulbar affect |
| Anxiety | SSRIs | Short-term low-dose benzodiazepines | Fall risk with benzodiazepines |
| Insomnia | Sleep hygiene + melatonin 3-5 mg | Low-dose trazodone 25-50 mg | Avoid anticholinergics and long-acting benzodiazepines |
| REM sleep behavior disorder | Melatonin 3-12 mg | Clonazepam 0.25-1 mg | Melatonin preferred due to fall risk |
Cholinergic deficits in the pedunculopontine nucleus (PPN) and cortical regions contribute to cognitive impairment in PSP[6]. However, evidence for cholinesterase inhibitors remains limited:
Dysphagia develops in most PSP patients and is the leading cause of death via aspiration pneumonia[7]:
A comprehensive ranking of 55 interventions is available on the CBS/PSP Treatment Rankings page. Key approaches are organized by evidence tier[8].
Mediterranean/MIND Diet (64/80)
The highest-ranked intervention. MIND diet combines Mediterranean and DASH dietary patterns, emphasizing leafy greens, berries, nuts, olive oil, fish, and whole grains while limiting red meat, sweets, and fried foods. PREDIMED-Plus and Rush MIND studies demonstrate sustained cognitive benefit[9]. For PSP patients with dysphagia, the CBS/PSP Daily Action Plan provides texture-modified MIND diet protocols.
Structured Exercise (62/80)
Physical exercise is the single most impactful non-pharmacological intervention[10]: 150+ minutes/week aerobic activity, 2x/week resistance training, and daily balance exercises. See CBS/PSP Rehabilitation Guide for stage-adapted protocols.
Rasagiline (60/80)
MAO-B inhibitor with potential neuroprotective properties beyond dopamine preservation. The NNIPPS trial showed a suggestive but non-significant trend toward slowed progression at 1 mg/day[11]. Rasagiline's propargylamine moiety activates anti-apoptotic pathways (Bcl-2 upregulation, PKC activation) independently of MAO-B inhibition.
Rapamycin (57/80)
mTORC1 inhibitor that restores autophagy-mediated tau clearance. Intermittent dosing protocol (5-6 mg once weekly) is under investigation based on geroscience longevity evidence and the PEARL trial framework[12]. Requires lipid and CBC monitoring.
Alpha-Lipoic Acid (56/80)
Mitochondrial antioxidant targeting Complex I deficiency, a hallmark of PSP pathology. R-enantiomer 600 mg/day with meals[13].
TUDCA/UDCA (56/80)
Bile acid chemical chaperones that reduce endoplasmic reticulum (ER) stress. AMX0035 (CENTAUR/PHOENIX trials) provides class evidence for neuroprotection in motor neuron disease; PSP shares ER stress pathology[14].
Low-Dose Lithium (55/80)
GSK-3β inhibitor that directly reduces tau phosphorylation at disease-relevant epitopes. 150-300 mg/day targeting serum levels of 0.3-0.6 mEq/L. Requires thyroid and renal monitoring[15].
Spermidine (55/80)
Natural polyamine that induces autophagy via EP300 inhibition and TFEB activation. Wheat germ extract 1.2 mg/day spermidine equivalent. SmartAge RCT demonstrated cognitive benefit in older adults[16].
| Intervention | Score | Key Mechanism | Dosing |
|---|---|---|---|
| Senolytics (D+Q) | 54/80 | Clear senescent glia → reduce SASP | Intermittent 2-day courses monthly |
| NAD+ Precursors | 53/80 | Mitochondrial NAD+ repletion | NMN 500 mg or NR 300 mg/day |
| Melatonin | 53/80 | Chronobiotic + antioxidant + tau kinase inhibition | 3-5 mg at bedtime |
| Urolithin A | 53/80 | Mitophagy induction via PINK1/Parkin | 500-1000 mg/day |
| Methylene Blue | 50/80 | Tau aggregation inhibitor + mitochondrial electron carrier | 8-16 mg/day (NOT with SSRIs) |
| CoQ10 | 48/80 | Complex I electron carrier | 400-1200 mg/day ubiquinol |
| Omega-3 DHA/EPA | 48/80 | SPM biosynthesis + membrane integrity | 2-4 g/day EPA+DHA |
| Curcumin | 40/80 | Tau anti-aggregation + NF-κB suppression | Bioavailable formulation required |
Physical therapy is the single most impactful intervention for PSP functional outcomes[10:1]:
Several monoclonal antibodies targeting tau are in clinical development for PSP[18]:
| Agent | Target | Phase | Status |
|---|---|---|---|
| Semorinemab (RO7105685) | N-terminal tau | Phase 2 | Completed in PSP |
| Tilavonemab (ABBV-8E12) | Aggregated tau | Phase 2 | Completed — no efficacy in PSP-RS[19] |
| Bepranemab (UCB0107) | Mid-domain tau | Phase 1/2 | Ongoing |
| E2814 | Microtubule-binding region | Phase 1/2 | DIAN-TU platform |
Optimal PSP management requires a coordinated team approach[22]:
| Team Member | Role | Frequency |
|---|---|---|
| Movement disorder neurologist | Diagnosis, pharmacotherapy, clinical trial enrollment | Every 3-6 months |
| Physical therapist | Gait, balance, exercise program | Weekly → biweekly |
| Occupational therapist | ADL adaptation, home safety, assistive devices | Monthly → as needed |
| Speech-language pathologist | Voice therapy, swallowing assessment, AAC | Weekly → monthly |
| Neuropsychologist | Cognitive assessment, behavioral strategies | Every 6-12 months |
| Social worker | Care coordination, financial planning, support resources | As needed |
| Palliative care specialist | Symptom management, advance directives, end-of-life planning | From diagnosis onward |
| Dietitian/nutritionist | Weight monitoring, diet modification, PEG timing | Every 3-6 months |
Early discussion of advance directives is critical given the predictable progression of PSP[23]:
Tracking disease progression in PSP requires multimodal assessment:[8:1]
| Domain | Assessment Tool | Frequency |
|---|---|---|
| Motor | PSP Rating Scale (PSPRS), Timed Up and Go | Every 3-6 months |
| Cognitive | MoCA, Frontal Assessment Battery | Every 6 months |
| Falls | Fall calendar, injurious fall tracking | Monthly |
| Dysphagia | VFSS, weight tracking | Every 6-12 months |
| Mood | GDS, NPI | Every 6 months |
| Quality of life | PSP-QoL, PDQ-39 | Every 6-12 months |
Sleep disorders are common in PSP and significantly impact quality of sleep and daytime functioning:[22:1]
Management strategies:
Blood-brain barrier (BBB) dysfunction is increasingly recognized as a significant contributor to progressive supranuclear palsy (PSP) pathogenesis. The neurovascular unit (NVU), comprising endothelial cells, pericytes, astrocytes, and neurons, maintains the BBB's selective permeability. In PSP, disruption of this unit allows peripheral immune cells, toxins, and inflammatory mediators to enter the central nervous system, potentially accelerating neurodegeneration.
Vascular Protective Agents
Anti-inflammatory Approaches
BBB Stabilizing Compounds
Pericyte-Targeted Therapies
| Marker | Source | Significance |
|---|---|---|
| Fibrinogen | CSF | Elevated indicates BBB breakdown |
| Albumin ratio | CSF/Serum | Elevated ratio suggests barrier leakage |
| MMP-9 | CSF | Matrix metalloproteinase degrades tight junctions |
| sICAM-1 | Serum | Endothelial activation marker |
| VEGF | CSF | Increased in barrier dysfunction |
Stem Cell Therapies
Gene Therapy
The BBB dysfunction in PSP interacts with other pathological mechanisms:
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