What is Progressive Supranuclear Palsy (PSP)?

Progressive Supranuclear Palsy (PSP)

Progressive Supranuclear Palsy (PSP) is a rare, neurodegenerative brain disorder characterized by postural instability with early falls, supranuclear gaze palsy (particularly affecting vertical eye movements), and various cognitive and behavioral symptoms. 1

Definition and Classification

PSP is a tauopathy - a neurodegenerative disorder characterized by abnormal accumulation of tau protein in the brain. It belongs to the family of "Parkinson-plus" syndromes or atypical Parkinsonisms, which demonstrate classic Parkinsonian features (bradykinesia and rigidity) along with additional clinical manifestations 1.

PSP is also known as Steele-Richardson-Olszewski syndrome and is the most common atypical Parkinsonism with a prevalence of approximately 5/100,000 1.

Pathophysiology

PSP is characterized by:

• Accumulation of 4R-tau protein aggregates in various brain regions 2
• Neuronal loss, gliosis, and tau-positive inclusions (neurofibrillary tangles, tufted astrocytes, coiled bodies) 2
• Primary involvement of the brainstem and basal ganglia 2
• Multiple affected anatomical sites including:
  • Subthalamic nucleus
  • Globus pallidus (internal and external)
  • Pontine nuclei
  • Periaqueductal gray matter
  • Substantia nigra 3

Clinical Presentation

Core Features

• Postural instability with early, unexplained falls (typically backward) 1, 2
• Vertical supranuclear gaze palsy (especially downward gaze) 1, 2
• Axial rigidity 1
• Bradykinesia 2
• Cognitive impairment 2

Ocular Symptoms

• Slow saccades (early in disease) 4
• Difficulty looking down (affecting reading, eating, walking downstairs) 4
• Fixation instability 4
• Lid retraction 4
• Blepharospasm 4
• Apraxia of eyelid opening and closing 4

Disease Progression

The typical disease course includes:

• Mean age of onset around 63 years 3
• Mean survival from symptom onset of approximately 9 years 3
• Early symptoms often precede diagnosis by several years:
  • First falls occur median 2.0 years before diagnosis
  • Unsteady gait/gait impairment appears median 1.2 years before diagnosis
  • Mobility problems develop median 0.8 years before diagnosis 5

Clinical Phenotypes

PSP presents with clinical heterogeneity, with several recognized phenotypes:

1. PSP-Richardson's syndrome (PSP-RS): The classic presentation with early falls, supranuclear gaze palsy, and postural instability 2, 6
2. PSP-predominant Parkinsonism: Features resembling Parkinson's disease 6
3. PSP-predominant corticobasal syndrome: Asymmetric limb rigidity and apraxia 6
4. PSP-predominant speech/language disorder: Primary language and speech difficulties 6
5. PSP-progressive gait freezing: Characterized by severe gait problems 6
6. PSP-predominant frontal presentation: Primarily behavioral and cognitive symptoms 6

Diagnostic Approach

Imaging

• MRI Brain: Preferred imaging modality 1

  • Characteristic findings include:
    • "Hummingbird sign" (midbrain atrophy)
    • "Morning glory sign" (concave upper surface of midbrain) 2
    • Regional volume loss patterns 1

• FDG-PET/CT Brain: May show hypometabolism in the medial frontal and anterior cingulate cortices, striatum, and midbrain 1

• Ioflupane SPECT/CT (DaTscan): Shows decreased radiotracer uptake in the striatum but cannot differentiate PSP from other parkinsonian syndromes 7

Clinical Diagnosis

Diagnosis is primarily clinical, based on:

• Progressive disorder
• Age at onset ≥40 years
• Vertical supranuclear gaze palsy
• Prominent postural instability with falls in the first year of disease onset 1, 2

Differential Diagnosis

PSP must be distinguished from:

• Parkinson's disease (PD)
• Multiple system atrophy (MSA)
• Corticobasal degeneration (CBD)
• Dementia with Lewy bodies (DLB)
• Vascular parkinsonism 1, 7, 2

Management and Healthcare Burden

Treatment Challenges

• No disease-modifying treatments are currently available 2
• Pharmacological therapy is challenging due to multiple neurotransmitter abnormalities affecting:
  • Dopamine
  • Acetylcholine
  • GABA
  • Norepinephrine systems 3
• Patients typically have minimal response and short duration of benefit from medications 3

Healthcare Resource Utilization

PSP places significant demands on healthcare systems:

• Multiple healthcare professionals required (mean 3.6-4.4 per patient) 6
• High use of:
  • Medications (100% of patients)
  • Imaging studies (99%)
  • Assistive devices (90%)
  • Supportive care (86%)
  • Surgeries and procedures (85%) 5

Caregiver Burden

• Most patients require at least one caregiver (mean 1.3-1.8 caregivers per patient) 6
• Home modifications are frequently needed (55-78% of patients) 6
• Visual and mobility aids are commonly required (55-100% of patients) 6

Emerging Therapies

Research is focusing on novel approaches targeting tau pathology:

• Modulating tau post-translational modifications
• Stabilizing tau interaction with microtubules
• Enhancing tau clearance through immunotherapy 2

These approaches may offer potential for slowing disease progression in the future.