Background

Progressive Supranuclear Palsy (PSP) is a rare neurodegenerative disorder affecting approximately 6 in every 100,000 people. It primarily affects individuals over the age of 60 and is characterised by a progressive deterioration of motor and cognitive functions. First described in the 1960s, PSP is often misdiagnosed initially due to its resemblance to other movement disorders such as Parkinson's disease, especially early in the disorder. However, its distinct clinical features, including early and prominent eye movement abnormalities, set it apart. It is an atypical Parkinsonian syndrome, which comprises a group of movement disorders characterised by a resting tremor, rigidity and slowness of movement. PSP progresses more rapidly than Parkinson’s disease, and as a result, it presents unique challenges in diagnosis and management.

Despite its rarity, PSP profoundly impacts individuals and their families, with symptoms gradually worsening over time and severely affecting quality of life. The exact cause of PSP remains elusive, although research suggests a combination of genetic predisposition, environmental factors, and abnormalities in tau protein accumulation within the brain. These factors are described in more detail below.

This article aims to provide a comprehensive understanding of PSP, delving into its causes, symptoms, diagnosis, management strategies, and ongoing research efforts. By shedding light on this often overlooked condition, we hope to raise awareness, increase early diagnosis, and ultimately improve the outcomes of those affected by PSP.

Causes of progressive supranuclear palsy

Genetic factors

Genetic factors play a significant role in the development of PSP. While PSP is typically considered a sporadic disorder, meaning it occurs without any clear family history, research has identified certain genetic changes that may increase an individual’s susceptibility to developing the disease. Specifically, alterations in the MAPT gene, which encodes the TAU protein, have been implicated in inherited cases of PSP.¹ 

Additionally, other genetic variations have been associated with an increased risk of developing PSP. However, their precise contribution to the development of the disease requires further investigation. Understanding the genetic underpinnings of PSP not only enhances our knowledge of the disease mechanisms but also holds potential implications for genetic counselling and the development of targeted therapies in the future.

Role of TAU proteins

TAU proteins play a central role in the disease's development. These proteins are normally found in the brain and help stabilize microtubules, which are important structures that are essential for maintaining the structure and function of healthy nerve cells. However, in PSP TAU proteins undergo abnormal changes, leading to their aggregation and accumulation within nerve cells. These proteins disrupt healthy functioning of nerve cells and eventually cause cell death. This cell death is particularly prominent in the regions of the brain responsible for movement control and cognition. 

The accumulation of TAU protein and resulting loss of nerve cells in specific brain regions contributes to the progressive deterioration of motor and cognitive abilities characteristic of PSP.² Moreover, the distribution of TAU protein in PSP differs from other diseases involving TAU, such as Alzheimer's disease. This highlights the distinct underlying features of this condition.³ Understanding the role of TAU proteins in PSP development is crucial for developing targeted therapeutic strategies aimed at halting or slowing the progression of this disorder.

Environmental influences 

While the exact cause of PSP is not fully understood, environmental factors have been implicated in its development. Environmental influences such as exposure to toxins, certain chemicals, pesticides and heavy metals have been suggested as potential contributors to PSP. Studies have shown correlations between environmental toxins and neurodegenerative diseases, including PSP⁴, although direct causality is yet to be fully established. Additionally, lifestyle factors such as diet, exercise habits and occupation may also play a role in the onset or progression of PSP.⁵ Further research is needed to determine the specific environmental factors and mechanisms involved in the development of PSP, which could pave the way for targeted prevention strategies and interventions aimed at reducing the burden of this condition.

Symptoms of progressive supranuclear palsy

Motor symptoms 

PSP manifests as a range of motor symptoms that progressively worsen over time, severely impacting an individual's mobility and independence. One of the hallmark features of PSP is postural instability, where individuals experience difficulty maintaining balance and frequently fall backwards whilst walking without the typical protective reflexes. 

Additionally, PSP patients exhibit distinctive eye movement abnormalities, including slowed or restricted eye movement issues looking up or down and controlling eyelids. This can lead to problems with focusing on and tracking objects.⁶ 

Muscle stiffness and rigidity, akin to Parkinson’s disease, are common, affecting various body parts. This contributes to atypical posture with a backwards lean and extended neck, contrasting the forward stooped posture seen in Parkinson’s patients. Conversely, muscle weakness may also occur, particularly in the later stages of the disease, leading to difficulty with activities such as walking, climbing stairs and even swallowing. 

Speech may also become slurred and difficult to understand due to impaired muscle control in the face and throat. These motor symptoms collectively result in significant functional impairment, reducing mobility, increasing the risk of falls and impacting the overall quality of life for individuals living with PSP.

Cognitive symptoms

Cognitive impairment is a significant aspect of PSP, impacting various cognitive domains and contributing to an increased disease burden. Individuals with PSP often experience executive dysfunction, marked by difficulties in planning, problem-solving and maintaining attention. Memory impairment may also manifest, affecting both short-term and long-term memory. Language deficits such as word-finding difficulties and reduced verbal fluency are common, leading to communication challenges. Additionally, visuospatial impairment can affect an individual's ability to perceive and interpret visual information accurately.⁷ These cognitive symptoms often exacerbate the functional limitations imposed by PSP's motor manifestations, further diminishing the individual's independence and quality of life. Understanding the cognitive aspects of PSP is crucial for comprehensive management and support, highlighting the need for tailored interventions to address these specific challenges

Summary

Progressive Supranuclear Palsy (PSP), is a neurodegenerative disorder characterised by the accumulation of abnormal TAU protein in the brain. While the exact cause of PSP remains unclear, research indicates a combination of genetic predisposition, environmental factors and TAU pathology contribute to its development. This rare condition primarily affects individuals over the age of 60, with symptoms gradually worsening over time. Motor symptoms include difficulties with balance and coordination, stiffness, and involuntary eye movements, particularly difficulty looking downward. Non-motor symptoms may include cognitive impairment, behavioural changes, and sleep disturbances. PSP is often misdiagnosed initially due to its resemblance to other movement disorders like Parkinson's disease, highlighting the importance of understanding its unique clinical features. Early recognition of PSP symptoms is crucial for appropriate management and care, as there is currently no cure. Ongoing research aims to unravel the underlying mechanisms of PSP and develop targeted treatments to improve outcomes for those affected by this debilitating condition.