What is Progressive Supranuclear Palsy (PSP)?

Progressive Supranuclear Palsy (PSP)

Progressive Supranuclear Palsy (PSP) is a rare, debilitating neurodegenerative disorder characterized primarily by postural instability, supranuclear gaze palsy, and varying degrees of cognitive, behavioral, and other movement symptoms, with frontotemporal lobar degeneration-PSP (FTLD-PSP) being the most common underlying pathology. 1

Clinical Presentation and Diagnostic Features

Core Clinical Features

• Postural instability and early falls: Often the earliest and most disabling symptom
• Supranuclear gaze palsy: Particularly vertical gaze abnormalities
  • Slowing of downward saccades is among the earliest and most specific diagnostic features 2
  • Decreased velocity of vertical saccades and absence of optokinetic nystagmus vertically
• Poor response to levodopa therapy: Distinguishes PSP from Parkinson's disease

Additional Clinical Manifestations

• Motor symptoms:
  • Bradykinesia
  • Rigidity
  • Low amplitude fast finger tapping 3
• Cognitive and behavioral changes:
  • Executive dysfunction
  • Apathy
  • Personality changes
• Bulbar symptoms:
  • Dysarthria
  • Dysphagia
  • Pseudobulbar affect
• Sleep disturbances:
  • Irregular sleep patterns 3

Pathophysiology

PSP is characterized by:

• Accumulation of 4R-tau protein aggregates in various brain regions 3
• Neuronal loss, gliosis, and tau-positive inclusions:
  • Neurofibrillary tangles
  • Tufted astrocytes
  • Coiled bodies
• Primary affected areas:
  • Brainstem
  • Basal ganglia
  • Subthalamic nucleus
  • Globus pallidus interna and externa
  • Pontine nuclei
  • Periaqueductal grey matter
  • Substantia nigra 4

Clinical Phenotypes

PSP shows clinical heterogeneity with several recognized phenotypes:

1. PSP-Richardson's syndrome (PSP-RS): The classic presentation
2. PSP-predominant Parkinsonism
3. PSP-predominant corticobasal syndrome
4. PSP-predominant speech/language disorder
5. PSP-progressive gait freezing
6. PSP-predominant frontal presentation 5

Diagnostic Evaluation

Neurological Examination

• Assessment of eye movements (particularly vertical saccades)
• Testing for optokinetic nystagmus
• Evaluation of postural stability and gait
• Assessment of cognitive function

Neuroimaging

• MRI Brain: Regional volume loss patterns, particularly midbrain atrophy ("hummingbird sign") 2
• FDG-PET/CT Brain: Hypometabolism in the medial frontal and anterior cingulate cortices, striatum, and midbrain
• Ioflupane SPECT/CT (DaTscan): Decreased radiotracer uptake in the striatum 2

Differential Diagnosis

PSP must be differentiated from:

• Parkinson's disease
• Multiple system atrophy
• Corticobasal degeneration
• Dementia with Lewy bodies
• Vascular parkinsonism 2

Disease Burden and Prognosis

• Mean age of onset: approximately 63 years 4
• Mean survival from symptom onset: 9 years 4
• Men are more frequently affected than women 4
• High burden on patients, caregivers, and healthcare systems across all phenotypes 5
• Most patients (67-100%) develop moderate-to-severe disease 5
• Patients typically require:
  • Multiple healthcare professionals (mean 3.6-4.4 across phenotypes)
  • At least one caregiver (mean 1.3-1.8 across phenotypes)
  • Visual and/or mobility aids (55-100%)
  • Home modifications (55-78%) 5

Management

Current Treatment Challenges

• No disease-modifying treatments are currently available 2
• Pharmacological therapy is challenging due to multiple neurotransmitter abnormalities 4
• Patients typically have minimal response and short duration of benefit from medications 4

Supportive Care

• Visual and mobility aids
• Home modifications
• Multidisciplinary care involving neurologists, physical therapists, occupational therapists, speech therapists, and other specialists

Experimental Approaches

• Deep brain stimulation has been explored but with variable outcomes and inherent risks 6
• Clinical trials targeting tau through various mechanisms:
  • Modulating post-translational modifications
  • Stabilizing interaction with microtubules
  • Enhancing clearance by immunotherapy 3

Special Considerations

Falls Prevention

• Falls are a major cause of morbidity in PSP
• Frequent fallers show deterioration of bulbar function and decreased ability to deal with distraction of attention under dual-task situations 7
• Preventive strategies should focus on:
  • Environmental modifications
  • Appropriate assistive devices
  • Caregiver education on fall prevention and management

Cognitive and Behavioral Management

• Early recognition and management of cognitive and behavioral symptoms
• Caregiver support and education about behavioral changes

End-of-Life Care

• Advanced care planning
• Palliative care considerations for this progressive, ultimately fatal condition