Progressive supranuclear palsy (PSP) is a rare brain disorder that causes problems with movement, walking and balance, and eye movement. It results from damage to nerve cells in the brain that control thinking and body movement. The disorder’s long name indicates that the disease worsens (progressive) and causes weakness (palsy) by damaging certain parts of the brain above nerve cell clusters called nuclei (supranuclear) that control eye movements.

PSP is different than Parkinson’s disease—another movement disorder—although they share some symptoms (see section, “How is PSP different from Parkinson’s Disease?”). Currently there is no effective treatment for PSP, but some symptoms can be managed with medication or other interventions.

Progressive supranuclear palsy is a brain disorder that affects movement, vision, speech, and thinking ability (cognition). The signs and symptoms of this disorder usually become apparent in mid- to late adulthood, most often in a person's 60s. Most people with progressive supranuclear palsy survive 5 to 9 years after the disease first appears, although a few affected individuals have lived for more than a decade.

Loss of balance and frequent falls are the most common early signs of progressive supranuclear palsy. Affected individuals have problems with walking, including poor coordination and an unsteady, lurching gait. Other movement abnormalities develop as the disease progresses, including unusually slow movements (bradykinesia), clumsiness, and stiffness of the trunk muscles. These problems worsen with time, and most affected people ultimately require wheelchair assistance.

Progressive supranuclear palsy is also characterized by abnormal eye movements, which typically develop several years after the other movement problems first appear. Restricted up-and-down eye movement (vertical gaze palsy) is a hallmark of this disease. Other eye movement problems include difficulty opening and closing the eyelids, infrequent blinking, and pulling back (retraction) of the eyelids. These abnormalities can lead to blurred vision, an increased sensitivity to light (photophobia), and a staring gaze.

Additional features of progressive supranuclear palsy include slow and slurred speech (dysarthria) and trouble swallowing (dysphagia). Most affected individuals also experience changes in personality and behavior, such as a general loss of interest and enthusiasm (apathy). They develop problems with cognition, including difficulties with attention, planning, and problem solving. As the cognitive and behavioral problems worsen, affected individuals increasingly require help with personal care and other activities of daily living.

The exact prevalence of progressive supranuclear palsy is unknown. It may affect about 6 in 100,000 people worldwide.

PSP is often misdiagnosed as Parkinson’s disease, especially early in the disorder, as they share many symptoms, including stiffness, movement difficulties, clumsiness, bradykinesia (slow movement), and rigidity of muscles. The onset of both diseases is in late middle age. However, PSP progresses more rapidly than Parkinson’s disease.

• People with PSP usually stand exceptionally straight or occasionally tilt their heads backward (and tend to fall backward). This is termed “axial rigidity.” Those with Parkinson's disease usually bend forward.
• Problems with speech and swallowing are much more common and severe in PSP than in Parkinson's disease and tend to show up earlier in the disease.
• Eye movements are abnormal in PSP but close to normal in Parkinson's disease.
• Tremor is rare in PSP but very common in individuals with Parkinson’s disease.

Although individuals with Parkinson's disease markedly benefit from the drug levodopa, people with PSP respond minimally and only briefly to this drug.

People with PSP show accumulation of the protein tau in affected brain cells, whereas people with Parkinson’s disease show accumulation of a different protein called alpha-synuclein.

What is progressive supranuclear palsy (PSP)?

Progressive supranuclear palsy (PSP) is a rare brain disease. It happens because of damage to nerve cells in the brain. PSP affects your movement, including control of your walking and balance. It also affects your thinking and eye movement.

PSP is progressive, which means that it gets worse over time.

What causes progressive supranuclear palsy (PSP)?

The cause of PSP is unknown. In rare cases, the cause is a mutation in a certain gene.

One sign of PSP is abnormal clumps of tau in nerve cells in the brain. Tau is a protein in your nervous system, including in nerve cells. Some other diseases also cause a buildup of tau in the brain, including Alzheimer's disease.

Who is at risk for progressive supranuclear palsy (PSP)?

PSP usually affects people over 60, but in some cases it can start earlier. It is more common in men.

What are the symptoms of progressive supranuclear palsy (PSP)?

Symptoms are very different in each person, but they may include

• A loss of balance while walking. This is often the first symptom.
• Speech problems
• Trouble swallowing
• A blurring of vision and problems controlling eye movement
• Changes in mood and behavior, including depression and apathy (a loss of interest and enthusiasm)
• Mild dementia

How is progressive supranuclear palsy (PSP) diagnosed?

There is no specific test for PSP. It can be difficult to diagnose, because the symptoms are similar to other diseases such as Parkinson's disease and Alzheimer's disease.

To make a diagnosis, your health care provider will take your medical history and do physical and neurological exams. You may have an MRI or other imaging tests.

What are the treatments for progressive supranuclear palsy (PSP)?

There is currently no effective treatment for PSP. Medicines may reduce some symptoms. Some non-drug treatments, such as walking aids and special glasses, may also help. People with severe swallowing problems may need gastrostomy. This is a surgery to insert a feeding tube into the stomach.

PSP gets worse over time. Many people become severely disabled within three to five years after getting it. PSP isn't life-threatening on its own. It can still be be dangerous, because it increases your risk of pneumonia, choking from swallowing problems, and injuries from falling. But with good attention to medical and nutritional needs, many people with PSP can live 10 or more years after the first symptoms of the disease.

PSP affects movement, control of walking (gait) and balance, speech, swallowing, eye movements and vision, mood and behavior, and thinking. The pattern of signs and symptoms can be quite different from person to person. The most frequent first symptom of PSP is a loss of balance while walking. Individuals may have abrupt and unexplained falls without loss of consciousness, a stiff and awkward gait, or slow movement.

As the disease progresses, most people will begin to develop a blurring of vision and problems controlling eye movement. These symptoms may include:

• Slow eye movements.
• Trouble voluntarily shifting gaze vertically (i.e., downward and/or upward).
• Trouble controlling eyelids.
• Tendency to move the head to look in different directions.
• Involuntary closing of the eyes.
• Prolonged or infrequent blinking.
• Difficulty in opening the eyes.
• Inability to maintain eye contact during a conversation.

People with PSP often show alterations of mood and behavior. These symptoms may include:

• Depression.
• Apathy.
• Changes in judgment, insight, and problem solving.
• Difficulty finding words.
• Loss of interest in ordinary pleasurable activities.
• Increased irritability and forgetfulness.
• Sudden laughing or crying or displaying angry outbursts for no apparent reason.
• Personality changes.

Other symptoms may include:

• Slowness of thought.
• Memory problems.
• Slowed, slurred, or monotone speech.
• Difficulty swallowing solid foods or liquids.
• Mask-like facial expressions.

The exact cause of PSP is unknown, but research suggests that it involves a gradual deterioration of brain cells in a few specific areas in the brain, mainly in brain stem. The death of brain cells in one of these areas, the substantia nigra, accounts in part for the motor symptoms that PSP and Parkinson's have in common.

The hallmark of PSP is the accumulation of abnormal deposits of the protein tau in nerve cells in the brain. These deposits cause the cells to malfunction and die, which stops the flow of information to other nerve cells. The accumulation of tau puts PSP in the group of disorders called the tauopathies, which includes Alzheimer’s disease, corticobasal degeneration, and some forms of frontotemporal degeneration.

PSP is usually sporadic, meaning that it occurs infrequently and without a known cause. In very few cases, the disease results from mutations in the MAPT gene. This mutation provides faulty instructions for making tau to the nerve cell. Genetic factors have not been implicated in most individuals.

Several theories suggest that PSP might be caused by:

• The abnormal buildup of the protein tau in a cell causes the building up a connected cell, which then spreads through the nervous system.
• An unconventional infectious agent that takes years or decades to start producing visible effects (as is seen in disorders like Creutzfeldt-Jakob Disease).
• Random genetic mutations—the kind that occur in individuals all the time—happen to occur in particular cells or certain genes, in a specific combination that injures these cells.
• Exposure to some unknown chemical in food, air, or water, which slowly damages certain vulnerable areas of the brain, mimicking a neurological disorder found on the Pacific island of Guam and on a few neighboring islands.
• Cellular damage caused by free radicals, which are reactive molecules produced continuously by all cells during normal metabolism. Although the body has built-in mechanisms for clearing free radicals from the system, scientists suspect that—under certain circumstances—free radicals can react with and damage other molecules.

Normal Function

The MAPT gene provides instructions for making a protein called tau. This protein is found throughout the nervous system, including in nerve cells (neurons) in the brain. It is involved in assembling and stabilizing microtubules, which are rigid, hollow fibers that make up the cell's structural framework (the cytoskeleton). Microtubules help cells maintain their shape, assist in the process of cell division, and are essential for the transport of materials within cells.

Six different versions (isoforms) of the tau protein are produced in the adult brain. The isoforms vary in length from 352 to 441 protein building blocks (amino acids). A region of the protein called the microtubule-binding domain, which is the part of the protein that attaches (binds) to microtubules, also varies among the isoforms. In three of the isoforms, the microtubule-binding domain contains three repeated segments. In the other three isoforms, this domain contains four repeated segments. Typically, the brain has approximately the same amount of three-repeat isoforms and four-repeat isoforms. This balance appears to be essential for the normal function of neurons.

Health Conditions Related to Genetic Changes

Frontotemporal dementia with parkinsonism-17

More than 40 mutations in the MAPT gene have been found to cause frontotemporal dementia with parkinsonism-17 (FTDP-17). Some of these mutations change single amino acids in the tau protein, most often in the microtubule-binding region. These mutations reduce tau's ability to bind to microtubules, which disrupts many important cell functions.

Other MAPT gene mutations change the way the gene's instructions are used to build the tau protein. Most of these mutations increase the production of tau with four repeated segments compared to the production of tau with three repeated segments. The resulting imbalance of tau isoforms in the brain interferes with the normal functions of brain cells.

In ways that are not fully understood, the MAPT gene mutations responsible for FTDP-17 lead to an accumulation of abnormal tau in neurons and other brain cells. These clumps of defective tau build up over time, although it is unclear what effect they have on cell function and survival. FTDP-17 is characterized by the gradual death of cells in areas of the brain called the frontal and temporal lobes. The frontal lobes are involved in reasoning, planning, judgment, and problem-solving, while the temporal lobes help process hearing, speech, memory, and emotion. The loss of cells in these brain regions leads to the major features of FTDP-17, including changes in personality and behavior, speech and language abnormalities, and problems with movement.

Progressive supranuclear palsy

Several mutations in the MAPT gene have been found to cause progressive supranuclear palsy. However, mutations in this gene appear to be a rare cause of this disorder.

At least one normal variation (polymorphism) in the MAPT gene has been associated with an increased risk of developing progressive supranuclear palsy. This polymorphism, known as the H1 haplotype, is found much more frequently in people with progressive supranuclear palsy than in the general population. It is unclear exactly how this genetic variation increases the risk of developing this disease.

The features of progressive supranuclear palsy appear to be related to abnormalities in the tau protein. In people with MAPT gene mutations, genetic changes disrupt the protein's normal structure and function. However, abnormal tau is also found in people without MAPT gene mutations. The defective tau protein assembles into abnormal clumps within neurons and other brain cells, although it is unclear what effect these clumps have on cell function and survival. Progressive supranuclear palsy is characterized by the gradual death of brain cells, particularly in structures deep within the brain that are essential for coordinating movement. This loss of brain cells underlies the major features of progressive supranuclear palsy, including problems with movement, vision, speech, and thinking (cognition).

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Other disorders

Mutations in the MAPT gene have also been found to cause other brain disorders similar to FTDP-17 and progressive supranuclear palsy. These disorders include corticobasal degeneration, tauopathy with respiratory failure, and a form of dementia with seizures (epilepsy). Although these conditions have somewhat different patterns of signs and symptoms, they all involve changes in personality, behavior, or cognition and problems with movement. The MAPT gene mutations responsible for these disorders lead to a buildup of abnormal tau in brain cells. Although the effect of tau accumulation on cell function and survival is unknown, these disorders are characterized by the death of brain cells in regions of the brain essential for cognition, emotion, and coordinating movement.

Because all of these diseases are characterized by an abnormal buildup of tau in the brain, they are known as tauopathies. Some researchers suggest that, instead of being described as separate disorders, the group of tauopathies caused by mutations in the MAPT gene should be considered as part of a spectrum with varying signs and symptoms.

Other Names for This Gene

• DDPAC
• FLJ31424
• FTDP-17
• G protein beta1/gamma2 subunit-interacting factor 1
• MAPTL
• MGC138549
• microtubule-associated protein tau
• MSTD
• MTBT1
• MTBT2
• neurofibrillary tangle protein
• paired helical filament-tau
• PHF-tau
• PPND
• PPP1R103
• TAU
• TAU_HUMAN

Genomic Location

Currently there are no tests or brain imaging techniques to definitively diagnose PSP. An initial diagnosis is based on the person’s medical history and a physical and neurological exam. Identifying early gait problems, problems moving the eyes, speech and swallowing abnormalities, as well as ruling out other similar disorders is important. Diagnostic imaging may show shrinkage at the top of the brain stem and look at brain activity in known areas of degeneration.

There is currently no effective treatment for PSP and symptoms usually do not respond to medications.

• Parkinson’s disease medications, such as ropinirole, rarely provide additional benefit. In some individuals, other antiparkinsonian medications, such as levodopa, can treat the slowness, stiffness, and balance problems associated with PSP, but the effect is usually minimal and short-lasting.
• Botulinum toxin, which can be injected into muscles around the eyes, can treat excessive eye closing.
• Some antidepressant drugs may offer some benefits beyond treating depression, such as pain relief and decreasing drooling.

Non-drug treatment for PSP can take many forms.

• Weighted walking aids can help individuals avoid falling backward.
• Bifocals or special glasses called prisms are sometimes prescribed for people with PSP to remedy the difficulty of looking down.
• Exercise supervised by a healthcare professional can keep joints limber but formal physical therapy has no proven benefit in PSP.

A gastrostomy (a surgical procedure that involves the placement of a tube through the skin of the abdomen into the stomach for feeding purposes) may be necessary when there are swallowing disturbances or the definite risk of severe choking.

Deep brain stimulation—which uses surgically implanted electrodes and a pacemaker-like medical device to deliver electrical stimulation to specific areas in the brain to block signals that cause the motor symptoms of several neurological disorders—and other surgical procedures commonly used in individuals with Parkinson's disease have not.

The disease gets progressively worse, with people becoming severely disabled within three to five years of onset. Affected individuals are predisposed to serious complications such as pneumonia, choking, head injury, and fractures. The most common cause of death is pneumonia. With good attention to medical and nutritional needs, it is possible for individuals with PSP to live a decade or more after the first symptoms of the disease appear.

The National Institute of Neurological Disorders and Stroke (NINDS), a component of the National Institutes of Health, is the primary funder of research on the brain and nervous system. NIH is the leading funder of biomedical research in the world.

PSP is one of the diseases being studied as part of the NINDS Parkinson’s Disease Biomarkers Program. This major NINDS initiative is aimed at discovering ways to identify individuals at risk for developing Parkinson’s disease and related disorders, and to track the progression of these diseases. NINDS also supports clinical research studies to develop brain imaging that may allow for earlier and more accurate diagnosis of PSP.

Genetic studies of PSP may identify underlying genetic causes. Previous studies have linked regions of chromosomes containing multiple genes, including the gene for the tau protein (MAPT), with PSP. Researchers hope to identify specific disease-causing mutation and are also studying how genetics and environment interaction may work together to contribute to disease susceptibility.

Scientists hope to understand the mechanisms involving tau that lead to PSP and its symptoms. Tau can exist in multiple shapes, or conformations, and research has shown that some of these conformations are harmful, leading to the buildup of toxic clumps and disruption of normal molecular signaling pathways inside cells. NINDS supports a number of studies that aim to characterize and distinguish the different conformations of tau, to identify the location of tau depositions in individuals with PSP, to clear the abnormally accumulated tau protein in the brain, and to understand their role in disease. Other studies are exploring ways to improve how to image or visualize tau in the brain. Because the symptoms of individuals with PSP progress more rapidly than in other tau-related disorders, some investigators believe that an anti-tau therapy will show benefit rather quickly in PSP clinical trials. Many of these anti-tau therapies make use of treatments that help the immune system fight infections and other diseases.

Animal models of PSP and other tau-related disorders, including fruit fly and zebrafish models, may identify basic disease mechanisms and lead to preclinical testing of potential drugs. Other studies in animal models focus on brain circuits affected by PSP, such as those involved in motor control and sleep, which may also yield insights into disease mechanisms and treatments.

Other research focuses on therapies that aim to treat the symptoms of PSP, rather than the underlying disorder itself. These studies have examined the effects of numerous drugs and therapies, including non-steroidal anti-inflammatory drugs (NSAIDs), transcranial magnetic stimulation, and blood plasma transfers from young, healthy individuals on the symptoms of PSP.

The Rare Diseases Clinical Research Network, which is led by NIH’s National Center for Advancing Translational Sciences (NCATS), is designed to facilitate research collaboration, study enrollment, and data sharing among rare diseases researchers. A research consortium funded under this project studies neurological disorders, including PSP. For more information visit the Rare Diseases Clinical Research Network.

Research on PSP and related disorders, in addition to other disorders, can be found using NIH RePORTER, a searchable database of current and past research projects supported by NIH and other federal agencies. NIH RePORTER also includes links to publications and patents citing support from these projects.