Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) may be twice as common as previously believed

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Two rare degenerative neurological disorders, namely Progressive Supranuclear Palsy (PSP) and CorticoBasal Degeneration (CBD), may be twice as common as previously thought, a UCL-led study finds.

Initial results from the PROSPECT study, published in JAMA Neurology, estimates that up to 10,000 people may be living with PSP & CBD in the UK.

The PROSPECT study is a longitudinal research program, funded by PSPA, which uses MRI scanning, blood and cerebrospinal fluid samples, genetics, and clinical assessments to find ways of tracking disease progression and improving diagnosis.

Baseline data from the first five years of the PROSPECT study has shown that 50% of people living with PSP had a delayed diagnosis because they initially presented with symptoms similar to other neurodegenerative conditions such as Parkinson’s disease and frontotemporal dementia.

The study, led by Professor Huw Morris and Dr Edwin Jabbari (both UCL Queen Square Institute of Neurology), found that the different forms of PSP & CBD had distinct patterns of clinical, cognitive, MRI and blood protein results that can be used to improve early and accurate diagnosis in the clinic.

Professor Morris said: “With the support of patients, carers and PSPA we have completed the primary stage of the PSP – PROPSECT study.

“Surprisingly, recently described rarer presentations of PSP are as frequent as the classical form of PSP, indicating that the disease may be twice as common as previously thought.

“We hope that this improved understanding of the disease spectrum will lead to better, earlier diagnosis and ultimately to better treatments.”

Now baselining of the initial data collection has been completed, the study is entering into the second phase which will provide one year follow up data on disease progression in participants.

As the study continues Prof Morris and his team of researchers hope to discover biomarkers and diagnostic tools which will enable better outcomes for people with PSP & CBD in the future.

This shows a brain scan from the study

MRI scan with area in green highlighting midbrain atrophy with preserved pontine volume which is characteristic of PSP. Image is credited to UCL.

Dr Wendy Edwards, Research Manager at PSPA, said: “The initial results of the PROSPECT study provide an exciting development in our fight against PSP & CBD.

PSP & CBD are regularly misdiagnosed with other neurodegenerative conditions such as Parkinson’s and Alzheimer’s due to the lack of specialist knowledge about these rare diseases.

These latest ground breaking findings give PSPA the ammunition we need to campaign for increased awareness, better diagnosis and improved care for those living with PSP & CBD.”

The PROSPECT study is the core research project of the UK PSP Research Network, which was established in 2012. The study began five years ago in 2014 and -will been funded by PSPA until 2023.

The aim of the study is to:

  • Expand recruitment to create the world’s largest PSP & CBD cohort
  • Improve diagnosis by discovering diagnostic markers of PSP & CBD
  • Better understand the progression of PSP & CBD to help define new treatments
  • Support upcoming clinical trials and ultimately accelerate the discovery of future treatments.

Alongside UCL, the PROSPECT study, represents a UK-wide collaborative effort with data also collected and analysed by Professor James Rowe (University of Cambridge), Professor Michele Hu (University of Oxford), Professor Nicola Pavese and Professor David Burn (Newcastle University), Professor Nigel Leigh (Brighton and Sussex Medical School) Dr Alistair Church (Royal Gwent Hospital) and Dr Chris Kobylecki and Dr Alex Gerhard (both University of Manchester).

Funding: Additional funding for the study has come from UCL, CBD Solution


History and Physical

Progressive supranuclear palsy is an akinetic-rigid form of parkinsonism. The onset of the disease is insidious and symmetric in most patients. Early in the course of the disease, motor abnormalities are typically axial, and not appendicular.

Gait difficulty and falls are the most common initial manifestation. Other modes of onset include non-specific dizziness, generalized motor slowing, and personality change. Only occasionally, the onset may be resting tremor.[26] 

As the disease progresses, other neurologic manifestations occur, including worsening parkinsonism, dysarthria, dysphagia, frontal cognitive difficulties, and eye movement abnormalities.

Although supranuclear ophthalmoplegia is the hallmark of progressive supranuclear palsy, some patients only manifest this late in the progression of the disease. Slowed vertical saccades may be the only eye movement manifestation early on.

There are a number of clinical subtypes of progressive supranuclear palsy including classic progressive supranuclear palsy-Richardson syndrome (PSP-RS), progressive supranuclear palsy-parkinsonism (PSP-P), progressive supranuclear palsy-pure akinesia with gait freezing (PSP-PAGF), progressive supranuclear palsy-corticobasal syndrome (PSP-CBS), progressive supranuclear palsy-behavioral variant of frontotemporal dementia (PSP-bvFTD) and progressive supranuclear palsy-progressive non-fluent aphasia (PSP-PNFA).[3]

Postural Instability and Falls

Patients with classic progressive supranuclear palsy, PSP-RS, have a stiff and broad-based gait, with an inclination to have their knees and trunk extended (as opposed to the flexed posture of idiopathic Parkinson disease), and arms slightly abducted.

Instead of turning en bloc, as seen in Parkinson disease, they tend to pivot quickly, which further increases their risk of falls. This is sometimes referred to as the “drunken sailor gait.” When they fall, it is usually backward due to a lack of postural reflexes.

Oculomotor Findings

Although extraocular movement abnormalities, specifically supranuclear ophthalmoplegia, is the hallmark of progressive supranuclear palsy, only a minority of patients present with gaze palsy. Often the first ocular motility abnormality noted on physical examination is impairment of vertical saccades. Eventually, most patients with progressive supranuclear palsy show slow or absent vertical saccades.[27][28][27] 

Typically, downgaze is affected before upgaze. Horizontal visually guided saccades .are also often impaired.[29] Symptomatic eye movement abnormalities begin at a median of 4 years after disease onset.[27][28][27] Other oculomotor findings in progressive supranuclear palsy include saccadic intrusions into fixation (“square wave jerks”), loss of optokinetic nystagmus (particularly in the vertical direction), loss of convergence, blepharospasm, and eyelid-opening apraxia.

The patient is often unable to suppress the horizontal vestibulo-ocular reflex.[28] The vestibulo-ocular reflex is present until late in the disease, but with disease progression and brainstem involvement, vestibulo-ocular reflexes may be lost. Eventually, supranuclear gaze palsy may be present in all directions, and toward the end of the disease, the eyes may be virtually immobile.

The combination of rare blinking, facial dystonia, and gaze abnormalities leads to the development of a classic facial expression of perpetual surprise or astonishment.[30] Vertical gaze impairment commonly leads to problems with reading, spilling food while eating, and contributes to falls while walking.[31]

Motor Involvement

Bradykinesia, with marked micrographia, are primary features of parkinsonism present in all types of progressive supranuclear palsy. Rigidity in patients with progressive supranuclear palsy is usually more apparent in axial than limb muscles, especially the neck and upper trunk. On examination, it can be demonstrated by resistance to passive movement of the neck.

There can be dystonia of the neck, typically retrocollis. The face of patients with progressive supranuclear palsy is often stiff, immobile, and deeply furrowed (the look of surprise) also due to dystonia.[21] 

About one-third of patients with progressive supranuclear palsy develop pyramidal signs, including hyperreflexia and Babinski signs. A jaw jerk and other frontal release signs can be present. Spastic dysarthria, dysphonia, and dysphagia can be profound in the middle to later stages of the disease.

Cognitive and Behavioral abnormalities

The neuropsychological profile of progressive supranuclear palsy primarily involves frontal lobe dysfunction. This includes impaired executive function making it difficult to shift between mental tasks,[32], and spontaneous motor behaviors, such as palilalia, motor perseveration, compulsive spitting, among others.

The presence of severe frontal cognitive deficits is a common finding in these patients.[33][34][35] Executive dysfunction may be the presenting symptom of progressive supranuclear palsy in some patients but is more characteristic of the later stages of the disease. Ideomotor apraxia may be a rare manifestation of progressive supranuclear palsy, although it is more common and severe in patients with corticobasal degeneration, a syndrome that can overlap clinically with progressive supranuclear palsy [36]

Behavioral abnormalities are also common in patients with progressive supranuclear palsy. In a case series of 22 patients with progressive supranuclear palsy, the most common behavioral symptoms were apathy (91%), disinhibition (36%), dysphoria (18%), and anxiety (18%).[37] One study of 188 patients with progressive supranuclear palsy demonstrated depression in 50% and anxiety in 37% [38], while another study of 74 patients with progressive supranuclear palsy reported obsessive-compulsive symptoms in 24%.[39] Impulsivity often induces patients to try to perform motor tasks that they are not able to do, such as get up and walk on their own. This can lead to falls.

Pseudobulbar palsy is another characteristic feature of progressive supranuclear palsy. Emotional incontinence is less common than in other forms of a pseudobulbar palsy,[21] but patients with progressive supranuclear palsy commonly manifest the characteristic hoarse groaning voice along with moaning. Speech perseveration and anomia can be observed.[30]

Sleep Disturbances

Early or late insomnia and difficulties in maintaining sleep have all been reported in patients with progressive supranuclear palsy. Marked rigidity may result in the inability to remain comfortable in bed, further contributing to sleep complaints. Rapid eye movement sleep behavior disorder (RBD) is infrequently associated with progressive supranuclear palsy.[40] This negative finding, similar to preserved olfaction, can be helpful in differentiating progressive supranuclear palsy, a tauopathy, from Parkinson disease and multiple system atrophy, both of which are synucleinopathies and commonly demonstrate symptoms of RBD.

Patients with the classic PSP-RS usually develop initial symptoms in their mid-60s, and the disease advances from symptom onset to death in 7 years, on average.[41] Clinical subtypes of PSP-P and PSP-PAGF have a more benign course with a survival period of a decade or more.[41] Both subtypes have an overall tau burden less than that of PSP-RS, and the distribution of abnormal tau is relatively limited to the brain stem.[42][43] The phenotypes of PSP-P and PSP-PAGF can be referred to as the “brain stem” variants of progressive supranuclear palsy, as opposed to the “cortical” variants which present with predominant cortical features including PSP-CBS, PSP-bvFTD, and PSP-PNFA.[3]


Source:
UCL
Media Contacts:
Henry Killworth – UCL
Image Source:
The image is credited to UCL.

Original Research: Open access
“Diagnosis Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Syndrome”. Edwin Jabbarin et al.
JAMA Neurology doi:10.1001/jamaneurol.2019.4347.

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