Progressive Supranuclear Palsy (PSP), also known as Steele-Richardson-Olszewski syndrome, is a rare, rapidly progressive neurodegenerative disorder classified as a 4R-tauopathy[@steele1964]. Unlike [Parkinson's disease](/diseases/parkinsons-disease), PSP shows minimal and transient response to dopaminergic medications, and disease progression is more rapid with a median survival of 6-9 years from symptom onset. Current therapeutic approaches focus on symptomatic management of motor, ocular, and cognitive symptoms, with emerging disease-modifying therapies targeting the underlying tau pathology.
Progressive Supranuclear Palsy (PSP), also known as Steele-Richardson-Olszewski syndrome, is a rare, rapidly progressive neurodegenerative disorder classified as a 4R-tauopathy[@steele1964]. Unlike [Parkinson's disease](/diseases/parkinsons-disease), PSP shows minimal and transient response to dopaminergic medications, and disease progression is more rapid with a median survival of 6-9 years from symptom onset. Current therapeutic approaches focus on symptomatic management of motor, ocular, and cognitive symptoms, with emerging disease-modifying therapies targeting the underlying tau pathology.
Disease-Modifying Therapies
Tau-Targeted Approaches
Immunotherapies
Tau immunotherapy aims to reduce extracellular tau propagation and enhance clearance of toxic aggregates:
Anti-tau antibodies: Several monoclonal antibodies targeting different tau epitopes are in development
Gantenerumab: Anti-[Aβ](/proteins/amyloid-beta)/tau bispecific antibody; being evaluated in tauopathies[@ostrowitzki2011]
Tilavonemab (ABBV-8E12): Showed biomarker engagement but did not meet primary endpoints in PSP[@florian2021]
Tau Aggregation Inhibitors
Small molecules designed to prevent or reverse tau aggregation:
Methylene blue derivatives: Include TRx0237 (LMTX), which showed mixed results in Phase 3 trials for AD and is being evaluated for PSP[@wischik2015]
Phenylthiazolyl-hydrazide compounds: Preclinical candidates targeting tau oligomerization[@taniguchi2005]
Epigallocatechin gallate (EGCG): Natural compound with anti-aggregation properties; limited clinical data in PSP[@xu2002]
Tau Kinase Inhibitors
Targeting enzymes responsible for tau hyperphosphorylation:
[GSK-3β](/entities/gsk3-beta) inhibitors: Lithium and other GSK-3β inhibitors have shown tau phosphorylation reduction in preclinical models[@engel2006]
[CDK5](/proteins/cdk5) inhibitors: Being explored to prevent pathological tau phosphorylation[@zheng2005]
Neuroprotective Strategies
NRF2 Activators
Targeting oxidative stress pathways:
Sulforaphane: Increases expression of antioxidant response genes; preclinical evidence supports neuroprotection in tauopathies[@deng2020]
Dimethyl fumarate (Tecfidera): FDA-approved for MS, being investigated for neuroprotection in PSP
Mitochondrial Support
Coenzyme Q10: Supports mitochondrial electron transport; small trials showed modest benefit in PSP[@stamelou2008]
Mitochondrial peptides (SS-31): Targeting mitochondrial dysfunction; being evaluated in neurodegenerative diseases[@wu2016]
Neuroinflammation Modulation
TNF-α inhibitors: Etanercept and other anti-TNF approaches being explored[@tobinick2009]
Microglial modulation: Targeting CD33, [TREM2](/proteins/trem2) pathways to modify microglial response[@griciuc2021]
Symptomatic Treatment
Motor Symptoms
Dopaminergic Therapy
Response in PSP is typically poor and short-lived:
Levodopa: Modest benefit in some patients with PSP-Parkinsonism subtype; doses up to 1000-2000 mg/day may be tried[@kompoliti1998]
Dopamine agonists: Pramipexole, ropinirole may provide limited benefit
Expected response: Only 20-30% show meaningful improvement, benefits often diminish within months
Management of Rigidity and Dystonia
Botulinum toxin injections: For cervical dystonia, blepharospasm[@truong2006]
Muscle relaxants: Baclofen, tizanidine for spasticity
Physical therapy: Essential for maintaining mobility and preventing contractures
Ocular Motility Issues
Vertical Supranuclear Gaze Palsy
Prism lenses: May help compensate for gaze limitations
Environmental modifications: Adjust lighting, reading position
Speech/occupational therapy: Strategies for coping with visual limitations
[Cholinesterase inhibitors](/entities/cholinesterase-inhibitors): Modest benefit in some patients ([donepezil](/entities/donepezil), rivastigmine)[@liepelt2010]
PSP has a median survival of 6-9 years from symptom onset, with more rapid progression than Parkinson's disease[@wenning2013]. Treatment goals focus on:
Maximizing functional independence through optimal symptom management
[Steele JC, Richardson JC, Olszewski J, Progressive supranuclear palsy. A heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia (1964)](https://pubmed.ncbi.nlm.nih.gov/14124698/)
[Budur K, Kumar S, Guss J, et al, Efficacy and safety of ABBV-8E12 in progressive supranuclear palsy (2019)](https://doi.org/10.1016/j.neurobiolaging.2019.08.015)
[Ostrowitzki S, Deptula D, Thurfjell L, et al, Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab (2011)](https://doi.org/10.1001/archneurpsyc.2011.1538)
[Florian H, Wang D, Arnold SE, et al, Tilavonemab for the treatment of progressive supranuclear palsy (2021)](https://doi.org/10.1016/j.trci.2021.03.002)
[Wischik CM, Staff RT, Akaida T, et al, Tau aggregation inhibitor therapy: an exploration of efficacy and disease modification in Alzheimer's disease and primary tauopathies (2015)](https://doi.org/10.1186/s13195-015-0141-9)
[Taniguchi S, Suzuki N, Masuda M, et al, Phenylthiazolylhydrazide derivatives as inhibitors of tau fibril formation (2005)](https://doi.org/10.1074/jbc.M503461200)
[Xu J, Kao SY, Lee FJ, et al, Dopamine-dependent neurotoxicity induced by MPTP is attenuated by green tea polyphenol (-)-epigallocatechin-3-gallate (2002)](https://pubmed.ncbi.nlm.nih.gov/11980873/)
[Engel T, Goñi-Oliver P, Lucas JJ, et al, Chronic lithium administration to FTDP-17 tau and GSK-3β overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre-formed neurofibrillary tangles do not revert (2006)](https://doi.org/10.1111/j.1471-4159.2006.04139.x)
[Zheng YL, Kesavapany S, Gravell M, et al, A CDK5-derived peptide inhibits Cdk5/p25 activity and improves neuronal viability in oxidatively stressed cultured neurons (2005)](https://doi.org/10.1523/JNEUROSCI.25-30-07656.2005)
[Deng G, Wang J, Liu W, et al, Sulforaphane exerts neuroprotective effects via Nrf2/HO-1 signaling in a rat model of Parkinson's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/33125670/)
[Stamelou M, Reuss A, Pilatus U, et al, Short-term effects of coenzyme Q10 in progressive supranuclear palsy: a randomized, placebo-controlled trial (2008)](https://doi.org/10.1016/j.jad.2008.02.016)
[Wu HY, Tang EK, Lin CY, et Szeto PP, Mitochondria-targeted peptide SS-31 attenuates neuronal injury via mitochondrial protective effect after spinal cord injury (2016)](https://doi.org/10.1111/neuros.13533)
[Tobinick EL, Perispinal etanercept for neuroinflammatory disorders (2009)](https://doi.org/10.1016/j.drudis.2009.01.025)
[Griciuc A, Tanzi RE, The role of microglial TREM2 and AD risk genes in Alzheimer's disease (2021)](https://doi.org/10.1016/j.neuron.2021.02.010)
[Kompoliti K, Goetz CG, Litvan I, et al, Pharmacological therapy in progressive supranuclear palsy (1998)](https://pubmed.ncbi.nlm.nih.gov/9819023/)
[Truong DD, Bhidayasiri R, Botulinum toxin therapy for cervical dystonia in progressive supranuclear palsy (2006)](https://pubmed.ncbi.nlm.nih.gov/17106791/)
[Hallett M, Eidelman O, Walz B, et al, Botulinum toxin for blepharospasm and hemifacial spasm (2004)](https://doi.org/10.1016/j.pmr.2004.08.009)
[Liepelt I, Gaenslen A, Godau J, et al, Rivastigmine for the treatment of dementia in progressive supranuclear palsy (2010)](https://pubmed.ncbi.nlm.nih.gov/20206395/)
[Schrag A, Sheikh S, Quinn NP, et al, A comparison of depression, anxiety, and health status in patients with progressive supranuclear palsy and multiple system atrophy (2010)](https://doi.org/10.1002/mds.23455)
[Tarditi M, Caricasole A, Marconi R, Gene therapy for neurodegenerative diseases: the role of AAV vectors (2022)](https://pubmed.ncbi.nlm.nih.gov/35247812/)
[Tsai CP, Lee JK, Lee CT, Mesenchymal stem cells in the treatment of neurodegenerative disorders (2018)](https://pubmed.ncbi.nlm.nih.gov/29610926/)
[Bäckström DC, Eriksson Domellöf M, Zetterberg H, et al, Neurofilament light chain in cerebrospinal fluid and prediction of progression in patients with prodromal and manifest Alzheimer's disease (2016)](https://pubmed.ncbi.nlm.nih.gov/26757275/)
[Morris ME, Iansek R, Kirkwood B, A randomized controlled trial of movement strategies compared with exercise for people with Parkinson's disease (2009)](https://pubmed.ncbi.nlm.nih.gov/19127577/)
[Langmore SE, Terpenning MS, Schatz A, et al, Predictors of aspiration pneumonia: how important is dysphagia? (2002)](https://pubmed.ncbi.nlm.nih.gov/11891904/)
[Wenning GK, Geser F, Krismer F, et al, The natural history of multiple system atrophy: a prospective European cohort study (2013)](https://doi.org/10.1016/S1474-4422(13)
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