Progressive Supranuclear Palsy

Key points at a glance

Progressive supranuclear palsy (PSP) is a tauopathy characterized by aggregation of 4-repeat tau protein.
The annual incidence is about 5.3 per 100,000 people, and it commonly affects middle-aged and older adults aged 40 and above, especially those in their mid-60s.
Vertical gaze palsy (especially downward gaze impairment) is the most characteristic ophthalmologic finding, appearing over the course of the disease.
Postural instability and axial rigidity are prominent, and repeated backward falls distinguish it from Parkinson’s disease.
The hummingbird sign on MRI (marked atrophy of the midbrain on sagittal view) is a diagnostic clue.
There is no curative treatment; symptomatic therapy focusing on fall prevention, swallowing management, and multidisciplinary intervention is central.
Median survival from onset is 5–8 years, and pathological findings are required for definitive diagnosis.

1. What is Progressive Supranuclear Palsy?

Progressive Supranuclear Palsy (PSP) is a type of tauopathy primarily affecting the brainstem and basal ganglia. It is caused by the aggregation and accumulation of 4-repeat tau protein in neurons and glial cells. It is also called Steel-Richardson-Olszewski syndrome (ICD-10: G23.1).

Epidemiologically, the annual incidence is 5.3 per 100,000 people, and the prevalence in the United States is 1.39 per 100,000, with recent reports suggesting a prevalence of up to 7 per 100,000¹⁾. Onset age is 40 years or older, typically in the mid-60s, with a slight male predominance. Due to similarity to Parkinson’s disease, misdiagnosis rates are high, and pathological findings are required for definitive diagnosis, leading to possible underdiagnosis. Median survival from onset is 5–8 years¹⁾.

Q How is PSP different from Parkinson's disease?

PSP is characterized by axial rigidity, retrocollis, and poor response to levodopa, whereas Parkinson’s disease shows limb-predominant rigidity, stooped posture, and good response to levodopa. Postural instability also appears earlier in PSP. For details, see the section “Diagnosis and Testing Methods”.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

Difficulty reading: Difficulty reading books due to downward gaze palsy.
Dropping food: Inability to secure the lower visual field during meals, leading to frequent dropping of food (positive dirty tie sign)¹⁾.
Falls: Falling forward or backward, appearing to caregivers as if falling without attempting to brace themselves.
Visual problems: Many patients complain of photophobia (light sensitivity), and some wear sunglasses even indoors.
Dizziness and poor balance: Balance problems while walking are a common chief complaint.
Dysarthria: Speech becomes “growling” in nature, and may become difficult to understand as it progresses.
Cognitive decline: Patients may notice memory problems or difficulty reading¹⁾.

Clinical Findings (Findings Confirmed by Physician Examination)

Ocular Motor Findings

Oculomotor disturbance is the most important finding in PSP and changes over the course of the disease.

Vertical gaze palsy: Downward gaze impairment is particularly characteristic. It is often absent in the early stages and appears over time. The progression order is downward gaze impairment → upward gaze impairment → horizontal gaze impairment.
Slowing of downward saccades: Caused by damage to burst neurons in the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF). This finding is present from the early stage of the disease.
Preservation of the vestibulo-ocular reflex (VOR): Preserved in the early stages. If eye movements improve with Bell’s phenomenon or VOR, it suggests a supranuclear lesion.
Square wave jerks: Involuntary vertical eye deviations repeated.
Saccadic impairment: Slow vertical saccades. Non-targeted saccades are impaired earlier than targeted saccades.
Convergence insufficiency: Frequently coexists. Eventually, both eyes become fixed in a nearly midline to abducted position.
Eyelid findings: Lid retraction (surprised expression), apraxia of eyelid opening/closing, blepharospasm, lid lag.

Motor findings

Retrocollis: Characteristic neck extension posture in PSP (contrasting with the forward flexion in Parkinson’s disease).
Axial rigidity: Predominance of axial rigidity over limb rigidity.
Postural instability: Falling backward on the pull test.
Rocket sign: When trying to stand up quickly from a chair, the patient falls backward.
Wide-based gait: Walking with a broad stance.

Cognitive and behavioral findings

Apathy: A combination of high apathy scores and low agitation/anxiety scores on the NPI suggests PSP.
Applause sign: When asked to clap three times, the patient continues beyond three. An indicator of motor disinhibition.
Subcortical dementia: Slowed processing speed and impaired planning ability appear in later stages.

Q How do the eye symptoms of progressive supranuclear palsy progress?

It begins with downward gaze palsy, progresses to upward gaze palsy, and eventually to horizontal gaze palsy. Initially, the vestibulo-ocular reflex compensates for eye movements, but eventually both eyes become fixed near the midline, interfering with reading and eating.

3. Causes and Risk Factors

The majority of progressive supranuclear palsy cases are sporadic, and the exact cause is unknown.

Tauopathy: The 4-repeat tau protein encoded by the MAPT gene on chromosome 17q21 aggregates in the brainstem and basal ganglia. While the normal ratio of 3-repeat to 4-repeat tau is 1:1, in progressive supranuclear palsy, the 4-repeat form predominates (1:3).
Genetic factors: An association with the H1 haplotype of the MAPT gene is known (mild predisposition). Ten mutations in the MAPT gene have been reported, including the R5L mutation in exon 1. Familial clustering is rare but has been reported.
Drug/toxin-induced hypothesis: High incidence has been reported in specific regions such as Guam (neurotoxin from cycads), Guadeloupe (traditional medicine containing annonacin), and northern France (arsenic from chemical plants).
Risk factors: Age (over 40 years), male sex, family history.

4. Diagnosis and Examination Methods

Clinical Diagnostic Criteria

The following criteria are used for the clinical diagnosis of PSP.

NINDS-SPSP criteria: Criteria established by the National Institute of Neurological Disorders and Stroke and the Society for Progressive Supranuclear Palsy. Progression is a prerequisite, and definitive diagnosis is based on pathological findings.
MDS criteria (2017): Revised diagnostic criteria by the Movement Disorder Society (MDS). Includes subtype classification.

Subtype Classification

PSP is classified into several subtypes based on clinical phenotype.

Richardson Syndrome

Frequency: Classic type, accounting for 54% of all PSP cases.

Features: Early falls and postural instability are main symptoms. Supranuclear gaze palsy and cognitive impairment appear later.

Levodopa response: Poor.

PSP-Parkinsonism Type

Frequency: The subtype most easily confused with PD.

Features: Presents with tremor and asymmetry, with an initial moderate response to levodopa.

Course: Features of the RS type often become apparent after several years.

Other Subtypes

PSP-PAGF: Pure akinesia with gait freezing. Gait disturbance is predominant from the early stage. Unresponsive to levodopa.

PSP-PNFA/AOS: Progressive non-fluent aphasia/apraxia of speech type.

PSP-C: Cerebellar ataxia type.

Imaging tests

MRI is the most important imaging test and is also used to rule out cerebrovascular disease, hydrocephalus, and tumors.

Hummingbird sign: Sagittal T1 shows marked atrophy of the midbrain with relative preservation of the pons. This morphological change resembles the profile of a hummingbird¹⁾.
Morning glory sign / Mickey Mouse sign: Axial T2 shows shortening of the anteroposterior diameter of the midbrain and thinning of the cerebral peduncles¹⁾.
Midbrain/pons ratio: A value less than 0.52 suggests PSP, and case reports have reported a value of 0.44¹⁾.
Volumetric MRI: Useful for detecting atrophy of the superior cerebellar peduncle. It is reported to distinguish PSP from MSA and PD with 74% sensitivity and 94% specificity.
MRPI (Magnetic Resonance Parkinsonism Index): An index calculated as (midbrain/pons ratio) × (MCP/SCP ratio).

Definite Pathological Diagnostic Criteria (NINDS)

High density of neurofibrillary tangles and neuropil threads in at least 3 of the following: globus pallidus, substantia nigra, pons, and subthalamic nucleus.
Low to high density lesions in at least 3 of the following: oculomotor complex, dentate nucleus, striatum, and medulla oblongata.

Differential Diagnosis

Parkinson’s disease (PD): PSP shows greater postural instability, axial rigidity (PD is limb-predominant), and retrocollis (PD is antecollis), with poor response to levodopa. Early falls strongly suggest PSP.
Multiple system atrophy (MSA): MSA can mimic PSP. Severe autonomic dysfunction (orthostatic hypotension, urinary incontinence) appearing within 3 years of onset suggests MSA (OR: 2.7)²⁾.
Corticobasal degeneration (CBD): Differentiation is needed when accompanied by limb apraxia or alien hand sign.
SCA8 (spinocerebellar ataxia type 8): CTA/CTG repeat expansion in the ATXN8OS gene can present with a PSP-like phenotype⁴⁾.

Q What does PSP look like on MRI?

On sagittal T1-weighted imaging, marked atrophy of the midbrain with relative preservation of the pons creates the characteristic “hummingbird sign” ¹⁾. Axial T2-weighted imaging shows a shortened anteroposterior diameter of the midbrain and thinning of the cerebral peduncles (morning glory sign). A midbrain-to-pons ratio of less than 0.52 is suggestive of PSP.

5. Standard Treatment

There is currently no curative treatment for PSP, and no medication can reverse disease progression. Symptomatic treatment and a multidisciplinary team approach are the mainstays of therapy ¹⁾.

Pharmacotherapy

Levodopa: In the PSP-P subtype, there may be a moderate initial response. In Richardson syndrome (RS type), it is usually ineffective. In one case report, no improvement was seen after levodopa/carbidopa administration, and treatment was discontinued ¹⁾. In another case, levodopa 100 mg three times daily resulted in only a 15.8% improvement in MDS-UPDRS part III, and treatment was stopped ⁴⁾.
Management of depression: Bupropion and other agents may be used ⁵⁾.

Non-pharmacological therapy and symptomatic treatment

Fall prevention: Physical therapy, walking aids, and home environment modifications are top priority.
Management of dysphagia: Speech-language therapy and dietary texture modification (to prevent aspiration pneumonia).
Management of dysarthria: Speech-language therapy and introduction of communication aids.

Q Is there any medication effective for progressive supranuclear palsy?

There is no curative drug. In some subtypes (PSP-P), levodopa may be partially effective, but it is usually ineffective in the classic type (Richardson syndrome). Current treatment focuses on fall prevention, swallowing management, and multidisciplinary symptomatic therapy.

6. Pathophysiology and Detailed Pathogenesis

Abnormal Aggregation of Tau Protein

Tau protein is encoded by the MAPT gene on chromosome 17q21 and consists of 16 exons. Alternative splicing generates six isoforms. In progressive supranuclear palsy, 4-repeat tau predominates (3-repeat:4-repeat = 1:3), aggregating in neurons and glial cells of the brainstem and basal ganglia.

Neural circuit mechanisms of oculomotor dysfunction

Oculomotor dysfunction in PSP is explained by the following pathway impairments.

Slowing of downward saccades: Burst neurons in the riMLF (rostral interstitial nucleus of the medial longitudinal fasciculus) are damaged. Downward gaze signals are transmitted from the riMLF to the ipsilateral oculomotor and trochlear nuclei, so bilateral riMLF lesions cause downward gaze palsy.
Upward gaze palsy: Upward gaze signals are transmitted from the riMLF via the posterior commissure (PC) to both oculomotor nuclei. Lesions of the posterior commissure cause upward gaze palsy.
Square-wave jerks: Associated with dysfunction of the superior colliculus, brainstem omnipause neurons, and the fastigial nucleus of the cerebellum.

Affected neural circuits and pathology

The main neural pathways affected are as follows:

Dopaminergic nigrostriatal pathway: Deficits are common with Parkinson’s disease.
GABAergic and cholinergic pathways: Choline acetyltransferase activity in the striatum, substantia innominata, and cerebral cortex is reduced, contributing to some visual impairments.

Pathologically, atrophy of posterior fossa structures including the globus pallidus and depigmentation of the substantia nigra are observed macroscopically. Under light microscopy, neurofibrillary tangles and neuropil threads composed of straight filaments (average diameter 12–15 nm) are densely present (different from the paired helical filaments of Alzheimer’s disease). There are no amyloid deposits or plaques, which distinguishes this from Alzheimer’s disease.

7. Latest Research and Future Prospects (Reports from Research Stages)

tau-PET Early Diagnosis Biomarker Research

Katzdobler et al. (2023) conducted a multicenter study using [18F]PI-2620 tau-PET, comparing 78 patients with 4-repeat tauopathies (PSP, corticobasal syndrome), 79 patients with other neurodegenerative diseases, and 12 healthy controls ³⁾. Significant hypoperfusion was observed in the thalamus, caudate nucleus, and anterior cingulate cortex in patients with progressive supranuclear palsy. The AUC for perfusion pattern alone was 0.850, and for combined perfusion and tau pattern it reached 0.903 (exceeding tau alone at 0.864), with an AUC of 0.917 in an external validation dataset. Perfusion patterns correlated with the Progressive Supranuclear Palsy Rating Scale (R=0.402, p=0.0012) and activities of daily living (R=−0.431, p=0.0005), showing stronger correlation with clinical severity than tau patterns.

Decision Tree Algorithm for Identifying Progressive Supranuclear Palsy Mimics in MSA

Miki et al. (2021) reported in a retrospective study of 218 autopsy-confirmed MSA cases that 17 cases (7.8%) were clinically diagnosed as progressive supranuclear palsy mimics ²⁾. The probability of MSA increased approximately 2.3-fold (OR: 2.3) when any one of seven red flag features appeared within 10 years of onset. In particular, when severe autonomic dysfunction (orthostatic hypotension, urinary incontinence) appeared within 3 years of onset, the odds ratio of MSA versus progressive supranuclear palsy was 2.7. From this study, development of a decision tree algorithm for differentiation is also being attempted.

Association between SCA8 and progressive supranuclear palsy phenotype

Jiang et al. (2023) reported from China a case of SCA8 with CTA/CTG repeats of 131 or more (complete penetrance mutation) in the ATXN8OS gene presenting a progressive supranuclear palsy-like phenotype (the third case following two similar reports from Japan) ⁴⁾. Autopsy cases of SCA8 have confirmed 4-repeat tauopathy, suggesting a genetic and pathological link. Currently, widespread ATXN8OS genetic testing in patients with progressive supranuclear palsy is not supported.

8. References

Diogo C, Fernandes C, Luz L, et al. Frequent and Unexplained Falls: A Case of Progressive Supranuclear Palsy. Cureus. 2024;16(10):e72503.
Miki Y, Tsushima E, Foti SC, et al. Identification of multiple system atrophy mimicking Parkinson’s disease or progressive supranuclear palsy. Brain. 2021;144(4):1138-1151.
Katzdobler S, Nitschmann A, Barthel H, et al. Additive value of [18F]PI-2620 perfusion imaging in progressive supranuclear palsy and corticobasal syndrome. Eur J Nucl Med Mol Imaging. 2023;50(2):423-434.
Jiang L, Zhu W, Zhao G, Cao L. Spinocerebellar ataxia type 8 presents as progressive supranuclear palsy. Neurosciences (Riyadh). 2023;28(3):199-203.
Braun AA, Jung HH. Systematic review of phenotypes in McLeod syndrome and case report of a progressive supranuclear palsy in a female carrier. Orphanet J Rare Dis. 2024;19(1):312.

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