Progressive Supranuclear Palsy: Symptoms, Types, Causes and Treatment

Progressive supranuclear palsy (PSP) is a rare, complex neurodegenerative disorder that profoundly affects movement, vision, behavior, and cognition. Because its symptoms overlap with other neurological diseases, PSP often poses significant diagnostic and therapeutic challenges. In this article, we explore the hallmark symptoms, the various clinical types, underlying causes, and current as well as emerging treatments for this devastating condition.

Symptoms of Progressive Supranuclear Palsy

When PSP begins, its symptoms can be subtle and easily mistaken for other disorders, particularly Parkinson’s disease. Yet, as the disease progresses, a distinct constellation of features emerges. These include movement difficulties, characteristic eye problems, and cognitive or behavioral changes. Recognizing these symptoms early can be crucial for diagnosis, care planning, and support.

Domain	Example Symptom	Distinguishing Feature	Source
Motor	Early falls, gait instability	Often backward falls	1 2 5
Visual	Vertical gaze palsy, blurred vision	Difficulty moving eyes up/down	2 12
Cognitive	Executive dysfunction, apathy	Slow thought, impaired planning	1 5 9
Other	Dysphagia, speech problems	Swallowing, slurred speech	5 6 4

Table 1: Key Symptoms

Motor Symptoms

One of the earliest and most disabling symptoms is a tendency to fall, particularly backwards, often occurring years before diagnosis. Gait becomes slow and stiff, and balance is impaired even at rest. These motor symptoms are typically resistant to standard Parkinson’s treatments such as levodopa, which can help distinguish PSP from Parkinson’s disease 1 5 6. Rigidity and bradykinesia (slowness of movement) are frequently observed.

Visual and Eye Movement Abnormalities

Visual disturbances are a hallmark of PSP. The most distinctive is vertical supranuclear gaze palsy, where patients have difficulty moving their eyes up or down. This can progress to affect horizontal gaze as well 2 12. Other specific features include:

• Fixation instability
• Eyelid retraction (a “staring” appearance)
• Blepharospasm (uncontrolled eyelid closure)
• Difficulty opening or closing the eyelids (apraxia) 2

These visual signs help differentiate PSP from other movement disorders.

Cognitive and Behavioral Changes

Cognitive symptoms in PSP often involve executive dysfunction—problems with planning, multitasking, and abstract thinking. Memory is less affected than in Alzheimer’s disease, but apathy, depression, and slowed thinking are common 1 5 9. Behavioral symptoms may include irritability and anxiety, sometimes appearing years before the classic motor findings 1.

Other Symptoms

As the disease advances, patients may develop:

• Dysphagia (difficulty swallowing), increasing the risk of aspiration pneumonia
• Dysarthria (slurred or slow speech)
• Autonomic symptoms such as urinary incontinence or constipation, though these are less severe than in some similar disorders 4 5
• Sleep disturbances and, occasionally, visual hallucinations 3

The combination and progression of these symptoms make PSP one of the most challenging movement disorders to manage.

Types of Progressive Supranuclear Palsy

PSP is not a single disease but a spectrum of clinical syndromes. Understanding its types is crucial for accurate diagnosis, prognosis, and tailoring management strategies.

Type	Key Features	Prognosis/Progression	Source
Richardson’s	Early falls, eye palsy, cognitive decline	Fast progression, shorter survival	6 7 8 9 10
PSP-Parkinsonism	Asymmetric onset, tremor, partial levodopa response	Slower progression, may evolve to Richardson’s	6 8
PSP-Gait Freezing	Freezing of gait, fewer eye signs	Intermediate progression	3 8
Cortical Variants	Language/behavioral deficits	Variable, often slower	8 9 10

Table 2: PSP Types and Features

Richardson’s Syndrome (PSP-RS)

The classic and most common form, Richardson’s syndrome, is characterized by early postural instability, unexplained falls, vertical gaze palsy, and prominent cognitive changes 6 7 8. Progression is typically rapid, with significant disability developing within a few years.

PSP-Parkinsonism (PSP-P)

This variant can closely mimic Parkinson’s disease at onset, with asymmetric motor symptoms, tremor, and a modest initial response to levodopa 6. Over time, PSP-P often transitions to features of Richardson’s syndrome. Progression is generally slower, and survival may be longer than in PSP-RS 8.

PSP-Gait Freezing (PSP-PGF)

Marked by early and prominent freezing of gait, this type lacks the early eye movement abnormalities seen in classic PSP and has an intermediate prognosis 3 8.

Cortical and Other Variant Syndromes

Cortical variants include:

• PSP-Frontal (PSP-F): Frontal behavioral or cognitive syndromes
• PSP-Speech/Language (PSP-SL): Progressive speech and language difficulties
• PSP-Corticobasal (PSP-CBS): Symptoms overlapping with corticobasal syndrome 8 9 10

These forms may have slower progression and longer survival compared to Richardson’s syndrome 8.

Clinical and Pathological Correlation

Recent research confirms that different types of PSP correspond to varying patterns of brain involvement and tau pathology 9 10. Understanding these subtypes is critical for diagnosis, prognosis, and for inclusion in clinical trials 8 10.

Causes of Progressive Supranuclear Palsy

While the exact cause of PSP has not been fully determined, research has revealed much about its underlying disease mechanisms and risk factors. Both genetic and environmental aspects appear to contribute.

Factor	Example/Detail	Mechanism/Role	Source
Tau pathology	Abnormal tau protein aggregation	Neuronal dysfunction, cell death	10 13
Genetic risk	MAPT, LRRK2, DCTN1 mutations	Familial/sporadic PSP, age at onset	13 3
Environmental	Toxins (mitochondrial inhibitors)	Possible risk, not proven	11
Unknown	Sporadic cases	Most cases, multifactorial	11 13

Table 3: Major Causes and Risk Factors

Tau Protein Abnormalities

PSP is classified as a primary tauopathy—a disease characterized by abnormal accumulation of tau protein in the brain, especially the 4-repeat isoform 10 13. This tau aggregation disrupts normal neuronal function, leading to cell death in key regions such as the brainstem, basal ganglia, and frontal cortex 9 10. The distribution of tau pathology is closely linked to the clinical features and subtypes of PSP 9.

Genetic Factors

Although PSP is mostly sporadic, genetic studies have identified several risk factors:

• MAPT gene: The strongest genetic risk locus for PSP, involved in tau protein production. Certain MAPT mutations cause familial PSP and may result in earlier disease onset 13.
• Other genes: Mutations in LRRK2 and DCTN1 have been implicated in rare cases and may mimic PSP clinically 13.
• Some populations show higher rates of familial involvement and genetic variants, suggesting an inherited susceptibility in a subset of patients 3 13.

Environmental and Other Factors

Epidemiological studies suggest possible links between PSP and exposure to environmental toxins, particularly those that disrupt mitochondrial function, though clear causation has not been established 11. Most cases remain idiopathic, with no identifiable cause.

Pathophysiology and Disease Progression

The earliest changes in PSP occur in the brainstem and subcortical structures, progressing over time to involve the frontal cortex and other brain regions 7 14. This pattern explains the sequence of clinical symptoms and underpins efforts to develop better diagnostic tools and treatments.

Treatment of Progressive Supranuclear Palsy

While there is currently no cure for PSP, several strategies can help manage symptoms and improve quality of life. Research into disease-modifying therapies is ongoing, and a multidisciplinary approach remains central to care.

Approach	Example/Therapy	Benefit/Outcome	Source
Symptomatic	Levodopa, antidepressants	Modest/temporary improvement	5 6
Rehabilitation	Multidisciplinary therapy, MIRT	Improved mobility, balance	16 18
Emerging	Anti-tau antibodies (e.g., BIIB092, tilavonemab)	Trials ongoing, mixed results	15 17 10
Supportive	Speech/swallowing therapy, mobility aids	Quality of life, safety	5 16 18

Table 4: Treatment Modalities in PSP

Symptomatic and Supportive Therapies

• Medications: Agents such as levodopa (used for Parkinson’s disease) may provide limited benefit, particularly in PSP-P, but are generally less effective in PSP-RS 5 6. Antidepressants, and sometimes medications for movement symptoms or sleep, are also used.
• Rehabilitation: Intensive, aerobic, multidisciplinary, and goal-based programs—sometimes adapted from Parkinson’s disease protocols—can improve gait, balance, and reduce falls 16. The use of mobility aids such as walkers and wheelchairs becomes necessary as the disease progresses 5.
• Speech and swallowing therapy: Crucial for managing dysphagia and dysarthria, reducing aspiration risks, and maintaining nutrition 5 16 18.
• Occupational therapy: Aids in adapting the home environment and daily activities to the patient’s changing abilities.

Emerging and Investigational Therapies

• Tau-directed therapies: Since PSP is driven by abnormal tau protein, therapies targeting tau are being investigated. Anti-tau monoclonal antibodies (such as BIIB092 and tilavonemab) have been tested in clinical trials. Early data show these treatments are generally safe, but so far, no clear benefit in slowing disease progression has been demonstrated 15 17 10.
• Biomarker development: New imaging and cerebrospinal fluid biomarkers may help diagnose PSP earlier and track response to novel therapies 10 18.

The Importance of Multidisciplinary Care

Given PSP’s complexity, coordinated care from neurologists, rehabilitation specialists, speech and occupational therapists, and social workers is essential 16 18. This approach addresses both motor and non-motor symptoms, improves safety, and supports caregivers.

Research and Future Directions

• Ongoing clinical trials are targeting tau pathology and other mechanisms in PSP.
• Improved diagnostic criteria and early recognition of variant syndromes are opening opportunities for earlier interventions 10 18.
• The hope is that disease-modifying therapies will emerge from current research, benefiting not only PSP but possibly other tauopathies.

Conclusion

Progressive supranuclear palsy is a devastating, multifaceted neurodegenerative disease. While there is still much to learn, research has made important strides in understanding its symptoms, subtypes, causes, and treatment approaches.

Key Points:

• PSP presents with a combination of motor, visual, cognitive, and behavioral symptoms, often with early falls and distinctive eye movement abnormalities.
• Several clinical types exist, with Richardson’s syndrome being the classic form; other variants may progress more slowly.
• The disease is driven by abnormal tau protein accumulation, influenced by genetics (notably MAPT) and possibly environmental factors.
• Current treatments are symptomatic and supportive, with multidisciplinary rehabilitation playing a key role.
• Novel therapies targeting tau are under investigation, but an effective disease-modifying treatment remains elusive.

Prompt recognition, comprehensive care, and continuing research are vital to improving the outlook for people living with PSP and their families.