PSP & Corticobasal Degeneration

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are tauopathies that share a 4R-tau predominant pathology but produce distinctive clinical syndromes. PSP is the most common atypical parkinsonian disorder, with vertical gaze palsy, axial rigidity, and frontal cognitive features. CBD typically presents as asymmetric apraxia with alien limb and parkinsonism, though clinical-pathologic correlations are imperfect. Both diseases are classified within FTLD-tau and represent important examples of selective 4R tauopathy. This page covers PSP and CBD pathology and clinical-pathologic correlations.

Progressive Supranuclear Palsy (PSP)

Gross Pathology

  • Atrophy of midbrain (with characteristic “hummingbird” or “Mickey Mouse” appearance on sagittal MRI).
  • Pallor of substantia nigra and subthalamic nucleus.
  • Atrophy of frontal cortex (especially superior frontal, premotor).
  • Cerebellar dentate atrophy.
  • Variable thalamic atrophy.

Histology

  • 4R-tau predominant tauopathy.
  • Globose neurofibrillary tangles: in subcortical neurons; round, more compact than AD tangles.
  • Tufted astrocytes: tau-positive astrocytes with radiating tufts of tau-positive processes. Characteristic for PSP (also seen in CBD).
  • Oligodendroglial coiled bodies: tau-positive coiled tau in oligodendrocyte cytoplasm.
  • Neuropil threads: tau-positive.
  • Selective vulnerability:
    • Subthalamic nucleus.
    • Globus pallidus.
    • Substantia nigra.
    • Pedunculopontine nucleus.
    • Rostral interstitial nucleus of MLF (substrate of vertical gaze palsy).
    • Dentate nucleus.
    • Locus coeruleus.
    • Frontal cortex (especially superior).

Clinical Phenotypes (MDS-PSP 2017 Criteria)

  • PSP-Richardson syndrome (classical): vertical gaze palsy + early postural instability + axial rigidity + frontal cognitive features.
  • PSP-Parkinsonism (PSP-P): asymmetric tremor, mild bradykinesia; mimics PD.
  • PSP-Pure akinesia with gait freezing (PSP-PGF): predominantly gait + freezing.
  • PSP-Frontal (PSP-F): behavioral / cognitive predominance; bvFTD-like.
  • PSP-Corticobasal syndrome (PSP-CBS): PSP pathology presenting clinically as CBS.
  • PSP-Speech/language (PSP-SL): apraxia of speech, nfvPPA-like.
  • PSP-Cerebellar (PSP-C): cerebellar predominant; rare.

Hummingbird Sign on MRI

Sagittal midbrain atrophy with relative preservation of pons creates a profile resembling a hummingbird. Highly suggestive of PSP.

Mickey Mouse Sign

Axial midbrain atrophy creates a “Mickey Mouse” appearance (two large lateral cerebral peduncle “ears” with shrunken midbrain “head”).

Corticobasal Degeneration (CBD)

Gross Pathology

  • Asymmetric cortical atrophy (frontal, parietal predominantly; perirolandic, supplementary motor area, premotor).
  • Asymmetric basal ganglia atrophy.
  • Substantia nigra pallor.

Histology

  • 4R-tau predominant tauopathy.
  • Ballooned (achromatic) neurons: enlarged neurons with eccentric nuclei, pale cytoplasm, loss of Nissl substance. Especially in cortex.
  • Astrocytic plaques: tau-positive plaque-like aggregations centered on astrocytes; characteristic for CBD (distinct from PSP tufted astrocytes).
  • Coiled bodies: in oligodendrocytes.
  • Neuropil threads: tau-positive, dense.
  • Selective vulnerability: frontal/parietal cortex, basal ganglia, substantia nigra, thalamus.

Clinical Syndromes

  • Corticobasal syndrome (CBS): asymmetric rigidity + apraxia + cortical sensory loss + alien limb phenomenon + parkinsonism + sometimes dystonia, myoclonus.
  • Cognitive features: executive dysfunction, behavioral.

Clinical-Pathologic Mismatch

CBD pathology does not always present as CBS, and CBS clinically can have other underlying pathologies:

  • About 50% of CBS patients have CBD pathology.
  • 20% have AD pathology.
  • 15% have PSP pathology.
  • 15% have FTLD-TDP or other.

Conversely, CBD pathology can present as: CBS, bvFTD, PSP-like syndrome, nfvPPA, posterior cortical atrophy.

Distinguishing PSP from CBD Pathologically

Feature PSP CBD
Tau isoform 4R predominant 4R predominant
Distribution Subcortical (basal ganglia, brainstem, dentate) Cortical + subcortical, often asymmetric
Tangle morphology Globose Variable; often pretangle
Astrocytes Tufted astrocytes (radiating tufts) Astrocytic plaques (centered on astrocyte)
Ballooned neurons Rare Common (especially in cortex)
Subthalamic nucleus Severely affected Less affected
Asymmetry Symmetric Often asymmetric

Imaging

  • PSP:
    • Hummingbird sign on sagittal MRI (midbrain atrophy).
    • Mickey Mouse sign on axial.
    • Increased magnetic resonance parkinsonism index (MRPI).
    • Tau PET (flortaucipir): increasing midbrain/basal ganglia uptake.
  • CBD:
    • Asymmetric cortical atrophy (frontoparietal).
    • Asymmetric basal ganglia atrophy.
    • Tau PET signal in cortex.

Genetics

  • MAPT H1 haplotype: associated with both PSP and CBD; common variant.
  • Rare familial cases with MAPT mutations.
  • Most cases are sporadic.

Treatment

  • No disease-modifying therapy.
  • L-dopa modest response in some PSP-P; minimal in CBD.
  • Botulinum toxin for dystonia, blepharospasm.
  • Falls prevention.
  • Anti-tau immunotherapies (gosuranemab and others) failed phase 3 trials but research continues.
  • Supportive care.

🔍 Did You Know?

The vertical gaze palsy of PSP reflects a precise anatomic substrate: the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) in the rostral midbrain, which generates vertical saccades. Tau pathology accumulates in this nucleus early in PSP, producing the classical vertical gaze palsy that gives the disease its name. Downgaze is typically affected first, with patients having trouble looking down at the floor when walking (predisposing to falls) — followed by upgaze paresis. The combination of vertical gaze palsy + axial rigidity + early postural instability + frontal cognitive features is highly suggestive of PSP-Richardson syndrome (the classical phenotype). The clinical examination point: have the patient look at your finger above and below their eyes; in PSP the saccades become slow and incomplete, especially downward. Patients often compensate by tilting the head down to maintain visual access to the floor and feet. The pathology of PSP also affects the subthalamic nucleus (substrate of the axial rigidity and bradykinesia), pedunculopontine nucleus (postural instability, REM sleep disturbance), and frontal cortex (cognitive features) — explaining the full clinical syndrome. The 2017 MDS-PSP criteria recognized that PSP encompasses several phenotypes beyond the classical Richardson syndrome, each reflecting different distributions of the same underlying 4R tau pathology. The lesson: in any older patient with parkinsonism, test vertical gaze early. Slow vertical saccades + falls within the first year of parkinsonism = PSP until proven otherwise.

Pitfalls and Pearls

  • PSP: 4R tauopathy + globose tangles + tufted astrocytes + coiled bodies; midbrain atrophy (hummingbird sign).
  • CBD: 4R tauopathy + ballooned neurons + astrocytic plaques + coiled bodies; asymmetric cortical atrophy.
  • Tufted astrocytes: PSP. Astrocytic plaques: CBD. (Distinguishing histologic feature.)
  • PSP-Richardson syndrome: vertical gaze palsy + early postural instability + axial rigidity + frontal cognitive.
  • CBS clinically ≠ CBD pathologically: CBS has many causes (CBD ~50%, AD ~20%, PSP ~15%, FTLD-TDP).
  • Downgaze affected first in PSP: falls predispose.
  • Hummingbird sign: sagittal midbrain atrophy = PSP.
  • Mickey Mouse sign: axial midbrain atrophy = PSP.
  • MAPT H1 haplotype: PSP and CBD risk variant.
  • Apraxia + alien limb + asymmetric rigidity: think CBS (any underlying pathology).
  • Pure akinesia with gait freezing variant of PSP: subtle; falls + freezing without classical PSP features.
  • PSP-F: behavioral predominant; bvFTD-like.
  • No L-dopa response: distinguishes PSP/CBS from PD.
  • Anti-tau immunotherapy trials: ongoing; phase 3 trials so far disappointing.

References

  1. Love S, Budka H, Ironside JW, Perry A, eds. Greenfield’s Neuropathology. 9th ed. CRC Press; 2015.
  2. Höglinger GU, Respondek G, Stamelou M, et al. Clinical diagnosis of progressive supranuclear palsy: the Movement Disorder Society criteria. Mov Disord. 2017;32(6):853-864.
  3. Dickson DW, Bergeron C, Chin SS, et al. Office of Rare Diseases neuropathologic criteria for corticobasal degeneration. J Neuropathol Exp Neurol. 2002;61(11):935-946.
  4. Armstrong MJ, Litvan I, Lang AE, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology. 2013;80(5):496-503.
  5. Williams DR, Lees AJ. Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges. Lancet Neurol. 2009;8(3):270-279.
  6. Kovacs GG, Ghetti B, Goedert M. Classification of diseases with accumulation of tau protein. Neuropathol Appl Neurobiol. 2022;48(3):e12792.