Progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is a late-onset neurodegenerative disease involving the gradual deterioration and death of specific volumes of the brain, linked to 4-repeat tau pathology. The condition leads to symptoms including loss of balance, slowing of movement, difficulty moving the eyes, and cognitive impairment. However, the earliest known case presenting clinical features consistent with PSP, along with pathological confirmation, was reported in France in 1951. Originally thought to be a more general type of atypical parkinsonism, PSP has been linked to distinct clinical phenotypes including PSP-Richardson's syndrome (PSP-RS), which is the most common sub-type of the disease. As PSP advances to a fully symptomatic stage, many PSP subtypes eventually exhibit the clinical characteristics of PSP-RS.

Other common early symptoms are changes in personality, general slowing of movement, and visual symptoms. The most common behavioural symptoms in patients with PSP include apathy, a lack of inhibition, anxiety, and a profound state of unease or dissatisfaction.

Later symptoms and signs can include, but do not necessarily include dementia (typically including loss of inhibition and ability to organize information), slurring of speech, difficulty swallowing, and difficulty moving the eyes, particularly in the vertical direction. The latter accounts for some of the falls experienced by these patients, as they find it difficult to look up or down.

Some of the other signs are poor eyelid function, contracture of the facial muscles, a backward tilt of the head with stiffening of the neck muscles, sleep disruption, urinary incontinence, and constipation.

The visual symptoms are of particular importance in the diagnosis of this disorder. Patients typically complain of difficulty reading due to the inability to look downwards. The ophthalmoparesis experienced by these patients mainly concerns voluntary eye movement and the inability to make vertical saccades, which is often worse with downward saccades. Patients tend to have difficulty looking down (a downgaze palsy) followed by the addition of an upgaze palsy. This vertical gaze paresis will correct when the examiner passively rolls the patient's head up and down as part of a test for the oculocephalic reflex. Involuntary eye movement, as elicited by Bell's phenomenon, for instance, may be closer to normal. Assessment of these square-wave jerks and diminished vertical saccades is especially useful for diagnosing progressive supranuclear palsy, because these movements set PSP patients apart from other parkinsonian patients.

Signs and symptoms of PSP-RS subtype

PSP-RS is characterized by a combination of motor, ocular, cognitive, and speech-related impairments, that typically emerge in early stages of the disease. Symptoms of PSP-RS usually begin after 60 and steadily progress over time. PSP-RS is also characterized by unresponsiveness to dopamine therapies often prescribed for those with Parkinson's disease. Patients can present initially with symptoms more characteristic of the PSP-Parkinson (PSP-P) subtype which is characterized by asymmetric rigidity, resting tremor, and are more responsive to dopamine therapies such as levadopa compared to PSP-RS. Clinical and pathological differences between PSP-P and PRSP-RS occur within the first year of the disease, with individuals with PSP-RS exhibiting faster progression of symptoms and lower survival rates after diagnosis. Diagnostic criteria distinguish between probable and possible PSP-RS, as definitive diagnosis requires post-mortem neuropathological confirmation. Additionally, patients present with axial rigidity, which is characterized by stiffness in the neck and body.

Ocular symptoms in PSP-RS

A defining feature of PSP-RS is vertical supranuclear gaze palsy, which is difficulty with voluntary downward gaze. Vertical supranuclear gaze palsy, a symptom characterized by decreased velocity and amplitude of vertical eye movements (saccades) is often the prominent diagnostic feature of PSP-RS. Approximately 40% of patients with PSP-RS experiencing supranuclear gaze palsy, but it may not present until 3–4 years after disease onset. Nearly all people with PSP received a copy of that variant from each parent, but this is true of about two-thirds of the general population. The H1 haplotype of the MAPT gene has been identified in approximately 94% of individuals with PSP, compared to around 78% in healthy adults. Therefore, the H1 haplotype appears to be necessary but not sufficient to cause PSP. Other genes, as well as environmental toxins, are being investigated as other possible contributors to the cause of PSP.

Additionally, the H2 haplotype, combined with vascular dysfunction, seems to be a factor of vascular progressive supranuclear palsy.

Genetic mechanisms in PSP-RS

Although there is a strong correlation between the H1 haplotype and PSP, the exact molecular mechanism remains unclear. Some individuals with PSP-RS have reported a family history of the disease, suggesting the possibility that genetic factors, such as the H1 haplotype, may contribute to inherited susceptibility in certain cases. The PSP-RS subtype is known for a buildup of the 4R tau protein, which does not dissolve properly and forms insoluble aggregates in the brain. In healthy brains, there is typically a balanced ratio of 3-repeat (3R) and 4-repeat (4R) tau isoforms, resulting from the regulated inclusion or exclusion of exon 10 on the MAPT gene.

Pathophysiology

thumb|The image illustrates abnormal aggregation of 4-repeat (4R) tau protein (blue) disrupting microtubule structures (red), which impairs neuronal stability and function. Tau accumulation is a key pathological hallmark of PSP-RS and contributes to neurodegeneration.

The affected brain cells are both neurons and glial cells. The neurons display neurofibrillary tangles (NFTs), which are clumps of tau protein, a normal part of a brain cell's internal structural skeleton. Their chemical composition is usually different, however, and is similar to that of tangles seen in corticobasal degeneration. Individuals with PSP typically exhibit reduced levels of total tau and phosphorylated tau in CSF compared to the elevated levels observed in Alzheimer's disease, but these levels are still higher than those found in healthy controls. Lewy bodies are seen in some cases, but whether this is a variant or an independent co-existing process is not clear, and in some cases, PSP can coexist with corticobasal degeneration, Parkinson's, and/or Alzheimer's disease, particularly with older patients. Additional pathological features include oligodendroglial coiled bodies, neuronal loss, and gliosis. Others consider them separate diseases. PSP has been shown occasionally to co-exist with Pick's disease.

Pathophysiology in PSP-RS subtypes

Tau pathology in PSP-RS is generally more severe than in other subtypes and frequently involves regions such as the basal ganglia, subthalamic nucleus, tectum, locus coeruleus, and dentate nucleus. The PPT sends cholinergic projections to several regions commonly affected by tau pathology in PSP, including the globus pallidus, substantia nigra, and pons.

Differential diagnosis

PSP is frequently misdiagnosed as Parkinson's disease because they both involve slowed movements and gait difficulty, with PSP being one of a collection of diseases referred to as Parkinson plus syndromes. Both Parkinson's and PSP have an onset in late middle age and involve slowing and rigidity of movement. However, several distinguishing features exist. Tremor is very common with Parkinson's, but rare with PSP. Speech and swallowing difficulties are more common and severe with PSP and the abnormal eye movements of PSP are essentially absent with PD. A poor response to levodopa, along with symmetrical onset can also help differentiate PSP from PD.

PSP can also be misdiagnosed as Alzheimer's disease because of the behavioral changes.

Chronic traumatic encephalopathy (CTE) shows many similarities with PSP, because both share the following attributes:

Accumulations of hyperphosphorylated tau protein in neurons or glial cells
Accumulation of tau-immunoreactive astrocytes
Involve the superficial cortical layers

Types

Based on the pathological findings in confirmed cases of PSP, it is divided into the following categories:

Classical Richardson syndrome (PSP-RS)
PSP-C

Diagnostic differences between PSP subtypes

PSP-RS is the most common subtype of PSP. In PSP-P features of Parkinson's Disease overlap with the clinical presentation of PSP and follows a more benign course. In both PSP-P and PSP-PAGF distribution of abnormal tau is relatively restricted to the brain stem. Frontal PSP initially presents with behavioral and cognitive symptoms, with or without ophthalmoparesis and then evolves into typical PSP. Cerebellar ataxia as the predominant early presenting feature is increasingly recognized as a very rare subtype of PSP (PSP-C) which is associated with severe neuronal loss with gliosis and higher densities of coiled bodies in the cerebellar dentate nucleus.

The humming-bird sign is a radiologic sign, indicative of midbrain degeneration, that supports an early diagnosis of both PSP-RS and PSP-P. One commonly used quantitative measure is the midbrain-to-pons area ratio, which is calculated by measuring the cross-sectional areas of the midbrain and pons on midsagittal MRI images. As a result, the ratio is markedly reduced in PSP-RS, distinguishing it from other neurodegenerative conditions such as Parkinson's disease, multiple system atrophy (MSA), and even PSP-P, which typically exhibit less pronounced midbrain atrophy. Early falls are also more common with PSP, especially with Richardson syndrome.

{| class="wikitable"

!Feature

!PSP-RS

!PSP-P

!Other PSP Subtypes (e.g., PSP-SL, PSP-CBS, PSP-F, PSP-PG)

|Prevalence

|5-7 per 100,000

24-54% of all PSP cases

|13-45% of all PSP cases

|Less than 50% of PSP cases collectively

|Onset and Progression]]

Management is only supportive because there is currently no known cure for PSP. PSP cases are often split into two subgroups, PSP-RS and PSP-P, where a short-term response to levodopa can be obtained. Dyskinesia is an occasional but rare complication of treatment. Other variants have been described. Botox can be used to treat neck dystonia and blepharospasm, but this can aggravate dysphagia.

Two studies have suggested that rivastigmine may help with cognitive aspects, but the authors of both studies have suggested that larger studies are needed. There is some evidence from small-scale studies that the hypnotic zolpidem may improve motor function and eye movements.

Current clinical trials focus on disease modifying treatments but there are currently no FDA approved disease modifying treatments for PSP-RS. There has been research in the use of robot-assisted gait training. Evidence-based approaches to rehabilitation in PSP are lacking and, currently the majority of research on the subject consists of case reports involving only a small number of patients.

Case reports of rehabilitation programs for patients with PSP generally include limb-coordination activities, tilt-board balancing, gait training, strength training with progressive resistive exercises, and isokinetic exercises and stretching of the neck muscles. Due to their tendency to fall backwards, the use of a walker, particularly one that can be weighted in the front, is recommended instead of a cane.

Prognosis

No effective treatment or cure has been found for PSP, although some of the symptoms can respond to nonspecific measures. The poor prognosis is predominantly attributed to the serious impact this condition has on the quality of life. Pneumonia is a frequent cause of death, often caused by accidental aspiration of food particles.

History

In 1877, Charcot described a 40-year-old woman who had rigid-akinetic parkinsonism, neck dystonia, dysarthria, and eye-movement problems. In 1951, Chavany and others reported the clinical and pathologic features of a 50-year-old man with a rigid and akinetic form of parkinsonism with postural instability, neck dystonia, dysarthria, and staring gaze.

Between 1877 and 1963, 22 well-documented case reports of PSP, although not described as a distinct disorder, had been identified in the literature of neurology. Progressive supranuclear palsy was first described as a distinct disorder by neurologists John Steele, John Richardson, and Jerzy Olszewski in 1963. They recognized the same clinical syndrome in eight patients, and described the autopsy findings in six of them.

France: Association PSP France, a nonprofit patient association set up in 1996 through the help of PSPA in the UK. It also gives support to French speaking patients in Quebec, Morocco, Algeria, Belgium and Lebanon
UK: PSPA, a national charity for information, patient support and research of PSP and CBD, set up in 1994
Ireland: PSPAI, an organization which aims to increase public awareness of PSP
US: CurePSP, a nonprofit organization for promoting awareness, care and research of PSP, CBD, MSA "and other prime of life neurodegenerative diseases"

In popular culture

In the 2020 American musical comedy-drama television series, Zoey's Extraordinary Playlist, the title character's father (Mitch Clarke, played by Peter Gallagher) has PSP.

Notable cases

Dudley Moore (1935–2002): English actor, comedian, musician and composer
Peter Sarstedt (1941–2017): English singer and songwriter
Jesse Jackson (1941–2026) American activist
Brian Lindstrom (1961–2026) American filmmaker
Phyllis Frelich (1944–2014): American Tony Award-winning actor
Richard Rainwater (1944–2015): American investor and philanthropist
Mary McCaslin (1946–2022): American singer and songwriter
Linda Ronstadt (b. 1946): American singer
Veena Sahasrabuddhe (1948–2016): Indian classical vocalist
Jeff Golub (1955–2015): American Rock and Jazz guitar musician
Lee Wei Ling (1955–2024): Singaporean neurologist
Jennifer Wexton (b. 1968): former US Representative