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Progressive Supranuclear Palsy (PSP) Information

Ten Common Questions and Answers for Patients

What is Progressive Supranuclear Palsy (PSP)?

Progressive supranuclear palsy, or PSP, is an atypical parkinsonian syndrome (Parkinson-plus disorder) typically characterized by progressive, early-onset postural instability, frequent (unexplained) falls, problems with eye movement, axial (involving neck or trunk) rigidity, speech/swallow difficulty, and cognitive decline.[1] The lack of eye movements is characteristic and is called supranuclear gaze palsy. Other features may include a masked facial expression, decreased blink rate (stare), double vision, slowed movement (and thought), sloppy eating habits, monotone speech, lack of spontaneous conversation, grasping or imitative behaviors, and emotional lability (i.e., uncontrolled laughter or crying). Many of these features overlap with those of Parkinson disease, particularly early on in the course of disease, and can lead to confusion and misdiagnosis. Not all patients present in the same way and increasingly variants are recognized. If PSP is suspected, evaluation by a neurologist or movement disorders specialist familiar with this disorder is strongly recommended to confirm diagnosis and to provide proper care.

Who gets PSP? (Why me?)

PSP is one of the most common atypical parkinsonian syndromes, but still relatively rare and affects only about 3-6 in 100,000 individuals.[2] It is largely a sporadic disease, meaning it is not inherited or passed down from generation to generation, and only a few families to date have been identified with a familial form of PSP. However, genetics clearly plays a role in susceptibility and several genes have been identified and associated with PSP risk. These genes are not routinely tested for clinically, but are the subject of active research. In particular several studies have implicated the MAPT gene (the gene that encodes for the microtubular associated protein tau) and its H1 haplotype as a risk factor for PSP (and also Parkinson disease).[3-5] The MAPT H1 haplotype is common in the general population, though, and reinforces the idea that genetics and environmental factors likely interact to cause disease.  Environmental factors include toxins— from proximity or occupational exposure—smoking, infectious agents, level of activity, and even stress. Research is ongoing, but so far no specific environmental factor has been definitively linked to PSP.

What causes PSP?

Although the exact cause of PSP remains unknown, there is increasing knowledge about its pathology furthering insight into potential mechanisms of the disease. We know that one of the hallmarks of PSP is abnormal deposition of the microtubular associated protein tau (encoded by the MAPT gene) in brain.[6] Tau pathology is implicated in a number of neurodegenerative disorders including Alzheimer’s disease, frontotemporal dementias, corticobasal degeneration (CBD), and PSP. Interestingly, in PSP a four-repeat (4R) version of the tau protein is predominant versus a three-repeat (3R) version. Normally tau is a protein that associates with microtubules, structures that help support a neuron’s long processes. In disease tau becomes hyperphosphorylated (bunch of phosphates get added to it) and tends to accumulate and forms deposits in cells. Accumulation of hyperphosphorylated tau eventually is toxic to neurons leading to dysfunction and degeneration. Understanding the process of how tau goes from a “good” to a “bad” protein and contributes different neurodegenerative diseases is a major area of research. Targeting the “bad” tau in brain has also been the focus of recent therapeutic trials which so far have been unsuccessful (see below). These studies are only the beginning, though, and raise many questions such as when to treat (maybe much earlier), who to treat, and even if targeting tau is best. Other factors, such as neuro-inflammation and mitochondrial dysfunction, also play a role in the disease and may too be amenable for therapeutics in the future.

How is PSP diagnosed?

There is no one diagnostic test for PSP. The diagnosis remains primarily clinical, meaning that it is based on history, exam, and physician opinion. A diagnosis by a movement disorders-trained neurologist has been shown to correlate well with the pathological diagnosis.  Still, PSP is likely both underdiagnosed or misdiagnosed because the symptoms can be missed in some neurology clinics and overlap those of other neurological disorders such as Parkinson disease and amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease). If suspected, referral to a movement disorders neurologist such as those here at UF is highly recommended.  PSP can be diagnosed based on typical symptoms of early postural instability, falls, gaze problems, slowed movement, rigidity, speech/swallow problems, and cognitive decline. However, not all patients follow this pattern and variants are seen. Average age of onset is in mid-60’s and ranges. Progression of symptoms, typically more rapid than in Parkinson disease, and poor response to medications can both be supportive of diagnosis but not necessarily diagnostic.

While a thorough history and exam are most important, diagnostic testing can also be useful in supporting diagnosis. One of the most helpful tests is brain MRI (magnetic resonance imaging). Shrinkage or atrophy of the midbrain (top of the brainstem) has been found to be a fairly sensitive indicator of PSP. Looking at the brainstem from a side view image, the midbrain can appear “beaked” and the brainstem suggest a “hummingbird sign.”[7] Measurement of the midbrain size and ratio to other parts (pons) of the brainstem may be helpful in distinguishing PSP from Parkinson disease and another atypical parkinson disorder, multisystem atrophy (MSA).[8] Other tests that can be used include functional brain imaging, such as PET or SPECT, that look at brain activity which can be correlated with known areas of degeneration. However, these tests are not widely available, can be expensive, and are not frequently used. The future may be in functional MRI and diffusion tensor imaging (DTI) which looks at brain activity and connectivity. Here at UF, Dr. David Vaillancourt and colleagues are actively studying these imaging techniques to determine whether they can be used to identify PSP and other atypical parkinsonian syndrome from Parkinson disease.

Clinical testing of blood or other tissues (such as cerebral spinal fluid, CSF) for PSP is not done. So far the search for useful biomarkers in blood or CSF has not yielded a reliable test for PSP, but is a subject of active research. Genetic testing is currently done only for research.

How is PSP treated?

Unfortunately, there is no one pill or cure for PSP. Treatment is primarily supportive and may include a combination of medications and supportive therapies. A trial of the Parkinson drug carbidopa-levodopa (commonly known as Sinemet) is warranted in PSP and may require increased dose for effect. Treatment in some patients can improve the Parkinson symptoms including stiffness, rigidity, slowness, walking, balance, and even overall energy. That said, as the disease progresses even increased dose of carbidopa-levodopa may not be helpful and can cause undesirable side effects. There is limited evidence to suggest trial of another, older Parkinson medication called amantadine.[9] Alternative treatments may include use of muscle relaxants for rigidity, or direct muscle injections with botulinum toxin (e.g., Botox), which temporarily may relieve uncomfortable muscle contractions.

Combining these treatments with physical (PT) and occupational therapy (OT) is critical. Falls are a leading cause of injury, disability, functional dependence, and even death. Physical therapy can help with gait, balance, and fall prevention, as well as general mobility. Exercises to stretch muscles can help with mobility and prevent formation of contractures. Occupational therapy addresses activities of daily living, like dressing, grooming, and going to the bathroom, all essential for healthy living and maintaining independence. A comprehensive therapy evaluation is, therefore, crucial and can make a huge difference in quality of life.

Treating speech and swallow impairments is equally important. Speech in PSP can become difficult to produce and understand (i.e., softer, slurred, stuttering, etc.). Cognitive issues also contribute and affect responsiveness, verbal fluency, word-finding, and even comprehension. Speech therapy can address and help with each of these issues. Choking or swallow difficulty is very common in PSP and another potential hazard. Aspiration of food, liquids, or saliva can result in pneumonia and even death. As such, formal swallow evaluation is strongly recommended and should include regular follow-up exams. To help with swallowing recommendations may include compensatory strategies, exercises, and thickening agents for liquids.

Many other features of PSP are also amenable for treatment. Visual disturbance in PSP, such as blurred or double vision, should prompt referral to a neuro-ophthalmologist. Prism glasses are often helpful for diplopa (double vision). Bifocals can be problematic due to the downgaze limitation in PSP forcing one to look through the line separating near and far vision lenses. Separate glasses are sometimes better and needed for reading versus general activity. Involuntary eye closure, or blepharospasm, can reduce vision too and often responds well to botulinum toxin injections. Difficulty closing the eyes can also occur and dry the eyes out. Regular use of an eye lubricant is recommended to prevent drying and scarring of the cornea. Mood is a big problem in PSP too and may include anxiety, irritability, depression, apathy, and emotional incontinence (called pseudobulbar affect). Without treatment these issues can be quite frustrating, exacerbate symptoms, and complicate therapy. Although a neurologist can start therapy with an antidepressant, proper referral and treatment by a psychiatrist familiar with mood issues in parkinsonism is important. Cognitive decline and dementia in PSP can also be treated. Formal neuropsychiatric assessment is a good place to start and identify areas amenable for treatment. Medications may include dementia drugs like donepezil (Aricept), rivastigmine (Exelon), or memantine (Namenda) which have modest effect in improving cognition or slowing decline.[10,11]

What about natural therapies and supplements for PSP?

Supplements and vitamins are another topic that is frequently asked about. Surprisingly little is known about these in relation to PSP. Much of what we know is derived from studies on Parkinson disease and may not actually translate to PSP. There is good data recently on coenzyme Q10 (CoQ10), a supplement that helps with energy production in cells and functions also as an antioxidant. Supplementing the energy of brain cells with CoQ10 is thought to help prevent further loss or degeneration, and may slow disease progression. In PSP there is evidence that CoQ10 indeed increases brain energy metabolism and, at least in the short-term, improves symptoms including cognitive function.[12] CoQ10 is not a regulated drug and comes in many forms (tablet, gel tab, and liquid), resulting in differences in the dose need for effect. Speak to your doctor about recommended doses before taking, but generally 1200 mg/day is needed (can be divided). As for other vitamins there again is limited data. Vitamin E has been touted as an antioxidant, but there is no good evidence for benefit in PSP and increasing data suggests that high doses (above recommended daily allowance; note, similar data for beta carotene and vitamin A) may actually increase risk of death.[13] Therefore, we do not recommend specific vitamin supplementation unless you are determined deficient by your doctor.

What is my prognosis with PSP?

So far there is no cure for PSP. Progression of disease is faster than in Parkinson disease, but still over the course of years. Average length of survival from diagnosis ranges from 5-8 years and clearly varies for each patient. In the advanced stages of the disease most patients succumb to complications such as aspiration (swallowing down the windpipe), infection (pneumonia, urinary), and falls, fractures, or head injury. As such, we do all we can to prevent these complications through therapy and supportive care. End of life care, however, is important and we can help with palliative and hospice care decisions that can provide many benefits for the patient and family members. Although often an uncomfortable topic, early discussion with your doctor about end-of-life decisions such as life support, resuscitation, and feeding-tube is equally important and encouraged

What is on the horizon for treatments or a cure for PSP?

There is hope! Research on PSP and related disorders has exploded in recent years. We know now more about the pathology of PSP than ever thanks to the generosity of patients. However, the cause of this devastating disease remains unclear. There is active research though in many areas looking at the pathology and role of tau protein in disease, protein processing, genetics, environmental risk factors, biomarkers, brain imaging, and therapeutics for PSP.

Knowledge of tau pathology, in particular, has led to several recent clinical trials aimed at reduction of pathological phosphorylated tau and deposits in brain cells. Drugs that inhibit GSK-3 (glycogen synthesis kinase 3) have received much attention because GSK-3 phosphorylates tau and localizes to tau-positive neurofibrillary tangles (cellular deposits seen in several neurodegenerative disorders including PSP). Some candidate inhibitors recently studied include lithium, valproate, and nypta (NP031112). Unfortunately, so far none of these has been shown to have any effect on PSP. Most recently, the drug Davunetide was tested in a phase 2/3 trial by Allon Therapeutics. Davunetide reduces tau phosphorylation. The trial ended in the fall of 2012 and failed to show benefit. Despite these failures, it is important to note that if not for ongoing basic and translational research on PSP these trials would never have occurred. With increasing knowledge about the pathologic mechanisms of PSP new targets for therapeutics trials are inevitable.

Other areas that are being explored for potential therapeutics include stem cells, growth hormones, gene therapies (modulating genes or inactivating them, such as with antisense DNA), transcranial magnetic stimulation (TMS), and DBS (deep brain stimulation). For now, none of these are clinically proven and participation is limited to a trial if eligible. DBS in particular is not approved for PSP and largely thought not to be helpful. However, studies in Toronto, Canada (Dr. Lozano) are investigating targeting a very small area of the brainstem called the PPN (pedunculopontine nucleus) for gait problems in Parkinson’s disease and potential application to PSP.

What about disease markers for PSP?

Biomarkers are also actively being explored to help with diagnosing PSP and distinguish it from other Parkinsonian disorders. Biomarkers can be chemicals, molecules, and genetic information found in tissues such as blood or CSF that need to be both sensitive and specific for whatever disease you are testing. Although so far no one biomarker has been identified for PSP, it may be that set of molecules (molecular “fingerprint”) will be needed to accurately detect or predict disease. Early detection and the ability to correlate a marker with disease progression are both highly desirable. In addition to molecular markers, brain imaging is also being explored as a biomarker for PSP and its progression. Functional MRI and DTI are being used here at UF (Dr. David Vaillancourt) to do just that.

Where do I find more information on PSP?

Please feel free to contact me, Dr. Nikolaus McFarland, Director of the PSP/Atypical Parkinson’s Clinic, University of Florida Center for Movement Disorders and Neurorestoration (http://mdc.mbi.ufl.edu), nikolaus.mcfarland@neurology.ufl.edu for further information.

Dr. McFarland is recipient of the Wright/Falls/Simmons Professorship in PSP/Atypical Parkinson’s and funded by the NIH.

Some other sites for information include:

CurePSP (http://www.psp.org/)

National Institutes of Health (http://www.ninds.nih.gov/disorders/psp/psp.htm)

PSP Association (in UK) http://www.pspassociation.org.uk/

 

References

1. Litvan I, Mangone CA, McKee A, Verny M, Parsa A, et al. (1996) Natural history of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) and clinical predictors of survival: a clinicopathological study. J Neurol Neurosurg Psychiatry 60: 615-620.

2. Hoppitt T, Pall H, Calvert M, Gill P, Yao G, et al. (2011) A systematic review of the incidence and prevalence of long-term neurological conditions in the UK. Neuroepidemiology 36: 19-28.

3. Rademakers R, Melquist S, Cruts M, Theuns J, Del-Favero J, et al. (2005) High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy. Hum Mol Genet 14: 3281-3292.

4. Baker M, Litvan I, Houlden H, Adamson J, Dickson D, et al. (1999) Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet 8: 711-715.

5. Elbaz A, Ross OA, Ioannidis JP, Soto-Ortolaza AI, Moisan F, et al. (2011) Independent and joint effects of the MAPT and SNCA genes in Parkinson disease. Ann Neurol 69: 778-792.

6. Williams DR, Lees AJ (2009) Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges. Lancet Neurol 8: 270-279.

7. Oba H, Yagishita A, Terada H, Barkovich AJ, Kutomi K, et al. (2005) New and reliable MRI diagnosis for progressive supranuclear palsy. Neurology 64: 2050-2055.

8. Longoni G, Agosta F, Kostic VS, Stojkovic T, Pagani E, et al. (2011) MRI measurements of brainstem structures in patients with Richardson’s syndrome, progressive supranuclear palsy-parkinsonism, and Parkinson’s disease. Mov Disord 26: 247-255.

9. Nieforth KA, Golbe LI (1993) Retrospective study of drug response in 87 patients with progressive supranuclear palsy. Clin Neuropharmacol 16: 338-346.

10. Liepelt I, Gaenslen A, Godau J, Di Santo A, Schweitzer KJ, et al. (2010) Rivastigmine for the treatment of dementia in patients with progressive supranuclear palsy: Clinical observations as a basis for power calculations and safety analysis. Alzheimers Dement 6: 70-74.

11. Karakaya T, Fusser F, Prvulovic D, Hampel H (2012) Treatment options for tauopathies. Curr Treat Options Neurol 14: 126-136.

12. Stamelou M, Reuss A, Pilatus U, Magerkurth J, Niklowitz P, et al. (2008) Short-term effects of coenzyme Q10 in progressive supranuclear palsy: a randomized, placebo-controlled trial. Mov Disord 23: 942-949.

13. Bjelakovic G, Nikolova D, Gluud C (2013) Antioxidant supplements to prevent mortality. JAMA 310: 1178-1179.