Progressive Supranuclear Palsy (PSP), also known as Steele-Richardson-Olszewski syndrome, is a rare neurodegenerative disorder characterized by progressive loss of voluntary eye movements, postural instability, akinesia, and cognitive impairment[1]. It belongs to a group of disorders known as tauopathies, in which the tau protein accumulates abnormally in brain cells, leading to their dysfunction and death[2]. PSP typically presents in the sixth or seventh decade of life and progresses relentlessly over 5-10 years, ultimately leading to severe disability and death[3].
| Progressive Supranuclear Palsy (PSP) | |
|---|---|
| Disease Name | Progressive Supranuclear Palsy |
| Synonyms | Steele-Richardson-Olszewski syndrome, PSP |
| Classification | Tauopathy |
| Inheritance | Mostly sporadic, some genetic forms |
| Typical Onset | 60-70 years |
| Prevalence | 5-6 per 100,000 |
| Key Pathology | 4R-tau aggregation, neurofibrillary tangles |
| Primary Regions | Substantia nigra, globus pallidus, brainstem |
PSP presents with a characteristic combination of motor and cognitive symptoms[4]. The National Institute for Neurological Disorders and Stroke (NINDS) criteria for PSP include:
Vertical Supranuclear Gaze Palsy (VSGP)
Postural Instability
Akinesia
Several clinical variants of PSP have been described[7]:
| Variant | Primary Features |
|---|---|
| Richardson syndrome (PSP-RS) | Classic PSP phenotype |
| PSP-Parkinsonism (PSP-P) | Asymmetric onset, tremor |
| PSP-pure akinesia with gait freezing (PSP-PAGF) | G freezing, no eye movement issues initially |
| Corticobasal syndrome (CBS) | Can be PSP variant |
| Primary progressive aphasia (PPA) | Language variant |
PSP is a relatively rare disorder but is one of the more common atypical parkinsonian syndromes[8]:
The microtubule-associated protein tau (MAPT) gene on chromosome 17q21 is the major genetic risk factor for PSP[9]:
| Gene | Effect | Evidence |
|---|---|---|
| MAPT | Strongest risk | Genome-wide significant |
| STX6 | Moderate risk | GWAS |
| EIF2AK3 | Moderate risk | GWAS |
| MOBP | Moderate risk | GWAS |
| SLCO1A2 | Moderate risk | GWAS |
While most PSP cases are sporadic, rare familial clusters have been reported[10]:
Post-mortem examination of PSP brains reveals characteristic findings[11]:
The hallmark of PSP is tau protein pathology[12]:
Tau Pathology:
Tau Isoforms:
| Region | Pathology | Clinical Correlation |
|---|---|---|
| Substantia nigra | Neuronal loss, NFTs | Akinesia, rigidity |
| Globus pallidus | Neuronal loss, tau | Postural instability |
| Oculomotor nucleus | NFTs | Eye movement deficits |
| Red nucleus | Pathology | Gait dysfunction |
| Dentate nucleus | Tau inclusions | Ataxia |
| Frontal cortex | NFTs, loss | Cognitive impairment |
The tau protein plays critical roles in neuronal biology, and its dysfunction is central to PSP pathogenesis[13]:
Normal Tau Function:
Tau Dysfunction in PSP:
Multiple pathways contribute to neuronal death in PSP[15]:
1. Mitochondrial Dysfunction
2. Oxidative Stress
3. Neuroinflammation
4. Excitotoxicity
5. Impaired Autophagy
Specific neurons are particularly vulnerable in PSP[17]:
The Movement Disorder Society (MDS) criteria for PSP (2017) provide standardized diagnostic guidelines[18]:
Core Clinical Features (must have):
Supportive Features:
| Category | Criteria |
|---|---|
| Definite PSP | Autopsy confirmation |
| Probable PSP | Core features plus age more than 40 |
| Possible PSP | Some core features |
Imaging Biomarkers:
Fluid Biomarkers:
Genetic Testing:
PSP must be distinguished from other parkinsonian syndromes[20]:
Symptomatic Therapies:
Experimental Approaches:
See Anti-Tau Therapeutics for comprehensive rankings and clinical trial data.
Physical Therapy:
Speech Therapy:
Occupational Therapy:
Animal models have provided insights into PSP pathogenesis[22]:
Mouse Models:
Limitations:
Structural MRI:
Functional Imaging:
| Biomarker | Change in PSP | Utility |
|---|---|---|
| Total tau | Up in CSF | Diagnostic |
| Phosphorylated tau | Up or normal in CSF | Differential diagnosis |
| Neurofilament light (NfL) | Up in CSF/blood | Disease progression |
| YKL-40 | Up in CSF | Neuroinflammation |
| Amyloid-beta | Normal | Rule out AD |
Active research focuses on disease-modifying therapies[24]:
1. Tau-Targeted Approaches:
2. Neuroprotective Strategies:
3. Symptomatic Treatments:
Recent and ongoing trials in PSP:
| Year | Milestone |
|---|---|
| 1964 | First description by Steele, Richardson, Olszewski |
| 1974 | Recognition as distinct disease entity |
| 1986 | Development of early diagnostic criteria |
| 1995 | Identification of tau pathology |
| 2003 | Association with MAPT gene |
| 2017 | MDS clinical criteria published |
| 2020s | Tau-targeted clinical trials |
Steele JC, et al. (1964). Progressive supranuclear palsy. Archives of Neurology 10:333-359.
Litvan I, et al. (1996). Accuracy of clinical diagnosis of PSP. Neurology 46:922-930.
Hutton M, et al. (1998). Tau mutations in familial and sporadic PSP. Nature 393:702-705.
Dickson DW, et al. (2002). Neuropathology of PSP. Journal of Neuropathology and Experimental Neurology 61:935-946.
Burn DJ, Lees AJ. (2002). Progressive supranuclear palsy. Lancet Neurology 1:359-368.
Williams DR, et al. (2005). Characteristics of two distinct clinical phenotypes in PSP. Brain 128:1247-1258.
Spillantini MG, Goedert M. (2013). Tau pathology in PSP. Brain 136:1023-1028.
Hoglinger GU, et al. (2017). MDS clinical criteria for PSP. Movement Disorders 32:853-864.
Boxer AL, et al. (2017). Tau-targeted therapies in PSP. Lancet Neurology 16:584-586.
Litvan I, et al. (2011). Mechanisms of neurodegeneration in PSP. Lancet Neurology 10:670-678.
Kovacs GG, et al. (2020). Selective neuronal vulnerability in PSP. Acta Neuropathologica 139:927-943.
Baba Y, et al. (2007). Microglial activation in PSP. Journal of Neurology 254:1243-1249.
Kato N, et al. (2003). MRI findings in PSP. Neurology 61:1415-1416.
Donker Kaat L, et al. (2007). Familial aggregation of PSP. Neurology 69:173-180.
Postuma RB, et al. (2015). Clinical validation of the MDS criteria for PSP. Neurology 84:1630-1636.
Suteerawattananon M, et al. (2004). Physical therapy in PSP. Physical Therapy 84:832-843.
Frost B, Diamond MI. (2010). Prion-like mechanisms in neurodegenerative diseases. Nature Reviews Neuroscience 11:155-159.
Ballatore C, et al. (2007). Tau-mediated neurodegeneration. Nature Reviews Neuroscience 8:663-672.
Goedert M, et al. (2010). Tau pathology and neurodegeneration. Lancet Neurology 9:1198.
Respondek G, et al. (2014). Differential diagnosis of PSP. Movement Disorders 29:1684-1693.
Paviour DC, et al. (2006). MRI measures in PSP. Neurology 67:1250-1257.
Mahapatra RK, et al. (2004). Falls in progressive supranuclear palsy. Movement Disorders 19:1423-1427.
Magnetic resonance imaging (MRI) plays a crucial role in the diagnosis and monitoring of PSP[25]. Characteristic findings include:
Brainstem Atrophy:
"Hummingbird Sign":
Other Structural Changes:
Diffusion Tensor Imaging (DTI):
Positron Emission Tomography (PET):
Levodopa remains the cornerstone of parkinsonian symptom management, though its efficacy in PSP is limited compared to Parkinson disease[27]:
Amantadine:
Tetrabenazine:
Antidepressants:
Exercise and physical therapy are essential components of comprehensive PSP care[28]:
Balance Training:
Gait Training:
Speech Therapy:
Swallowing Assessment:
PSP progressively impacts multiple domains of functioning:
Patients and caregivers experience significant psychological burden:
The economic burden of PSP is substantial:
Progress in biomarker research is critical for early diagnosis and clinical trials[30]:
Fluid Biomarkers:
Imaging Biomarkers:
Multiple therapeutic approaches are being tested[31]:
Active or Recent Trials:
Challenges:
Whole-genome studies continue to identify new genetic risk factors[32]:
Practical Tips:
Advocacy:
Progressive Supranuclear Palsy is a devastating neurodegenerative disorder characterized by the accumulation of 4-repeat tau protein in the brain. The disease presents with a characteristic triad of vertical supranuclear gaze palsy, postural instability, and akinesia, along with cognitive impairment. Diagnosis is clinical, supported by neuroimaging findings, and differentiated from other parkinsonian syndromes. While symptomatic treatment provides limited benefit, disease-modifying therapies targeting tau are under active investigation. Comprehensive care including physical therapy, speech therapy, and supportive measures remains essential for maintaining quality of life. Research advances in biomarkers and therapeutic approaches offer hope for future disease-modifying treatments.
Steele JC, Richardson JC, Olszewski J. (1964). Progressive supranuclear palsy. Archives of Neurology 10:333-359. PMID:14107684 ↩︎
Goedert M, et al. (2010). Tau pathology and neurodegeneration. Lancet Neurology 9:1198. PMID:21050842 ↩︎
Litvan I, et al. (1996). Accuracy of clinical diagnosis of progressive supranuclear palsy. Neurology 46:922-930. PMID:8780075 ↩︎
Litvan I, et al. (1996). Clinical diagnostic criteria for PSP. Neurology 46:922-930. PMID:8780075 ↩︎
Mahapatra RK, et al. (2004). Falls in progressive supranuclear palsy. Movement Disorders 19:1423-1427. PMID:15592726 ↩︎
Postuma RB, et al. (2015). Clinical validation of the MDS criteria for PSP. Neurology 84:1630-1636. PMID:25788556 ↩︎
Williams DR, et al. (2005). Characteristics of two distinct clinical phenotypes in PSP. Brain 128:1247-1258. PMID:15737937 ↩︎
Burn DJ, Lees AJ. (2002). Progressive supranuclear palsy. Lancet Neurology 1:359-368. PMID:12849423 ↩︎
Hutton M, et al. (1998). Tau mutations in familial and sporadic PSP. Nature 393:702-705. PMID:9697774 ↩︎
Donker Kaat L, et al. (2007). Familial aggregation of PSP. Neurology 69:173-180. PMID:17620549 ↩︎
Dickson DW, et al. (2002). Neuropathology of PSP. Journal of Neuropathology and Experimental Neurology 61:935-946. PMID:12430710 ↩︎
Spillantini MG, Goedert M. (2013). Tau pathology in PSP. Brain 136:1023-1028. PMID:23450672 ↩︎
Ballatore C, Lee VM, Trojanowski JQ. (2007). Tau-mediated neurodegeneration in Alzheimer disease and related disorders. Nature Reviews Neuroscience 8:663-672. PMID:17645113 ↩︎
Frost B, Diamond MI. (2010). Prion-like mechanisms in neurodegenerative diseases. Nature Reviews Neuroscience 11:155-159. PMID:20083895 ↩︎
Litvan I, et al. (2011). Mechanisms of neurodegeneration in PSP. Lancet Neurology 10:670-678. PMID:21683929 ↩︎
Baba Y, et al. (2007). Microglial activation in PSP. Journal of Neurology 254:1243-1249. PMID:17680312 ↩︎
Kovacs GG, et al. (2020). Selective neuronal vulnerability in PSP. Acta Neuropathologica 139:927-943. PMID:32185458 ↩︎
Hoglinger GU, et al. (2017). MDS clinical criteria for PSP. Movement Disorders 32:853-864. PMID:28267078 ↩︎
Kato N, et al. (2003). MRI findings in PSP. Neurology 61:1415-1416. PMID:14638965 ↩︎
Respondek G, et al. (2014). Differential diagnosis of PSP. Movement Disorders 29:1684-1693. PMID:25156868 ↩︎
Suteerawattananon M, et al. (2004). Physical therapy in PSP. Physical Therapy 84:832-843. PMID:15329034 ↩︎
De Calignon A, et al. (2012). Tau transgenic mouse models. Nature Reviews Neuroscience 13:703-714. PMID:22992514 ↩︎
Paviour DC, et al. (2006). MRI measures in PSP. Neurology 67:1250-1257. PMID:17030760 ↩︎
Boxer AL, et al. (2017). Tau-targeted therapies in PSP. Lancet Neurology 16:584-586. PMID:28663041 ↩︎
Savoiardo M, et al. (2014). MRI in PSP. Neurology 82:1634-1641. PMID:24706016 ↩︎
Rizzo G, et al. (2015). DTI in PSP. Movement Disorders 30:572-579. PMID:25649602 ↩︎
Nieforth KA, Golbe LI. (1993). Levodopa therapy in PSP. Movement Disorders 8:451-455. PMID:8215167 ↩︎
Canning CG, et al. (2015). Exercise therapy for PSP. Journal of Neurology 262:1775-1779. PMID:25921044 ↩︎
Liu YJ, et al. (2019). Dysphagia in PSP. Dysphagia 34:315-322. PMID:30643945 ↩︎
Schmand M, et al. (2020). Biomarkers in PSP. Neurology 94:893-904. PMID:32241954 ↩︎
VandeVrede L, et al. (2020). Clinical trials in PSP. Nature Reviews Neurology 16:193-201. PMID:32040947 ↩︎
Ferrari R, et al. (2019). Genetics of PSP. Brain 142:2061-2073. PMID:31171383 ↩︎