Understanding Parkinson’s disease

In order to effectively search for new treatment options, new methods of accurate and early diagnosis and improve existing disease management, we need to better understand the natural course of Parkinson’s disease. This can be challenging, because, as we will learn, Parkinson’s disease is a complex disease that can be caused by a combination of different factors.

Not just a movement disorder

Parkinson’s disease is a disorder that affects the central nervous system, where it causes ongoing and irreversible loss of nerve cells or neurons. The neural damage that builds up over time gradually results in barely noticeable and eventually readily observable changes to the functional and mental abilities, which in turn impact quality of life and wellness.

Most people know Parkinson’s disease as a movement disorder that causes typical difficulties in control of every day movements, mobility and posture, due to the loss of neurons associated with motor control or dopamine producing neurons. What is less well known is that other areas of the nervous system are also affected, resulting in a variety of non-motor symptoms that can even precede the onset of the typical motor symptoms by years.

Today, Parkinson’s disease is no longer considered just a movement disorder, butis more often referred to as a complex multisystem disorder, with extensive neural damage resulting in a wide range of different symptoms.

Clinical diagnosis

Current clinical confirmation of Parkinson’s disease is based on the presence of bradykinesia (or slowness of movement) and at least one other motor symptom, such as tremor, muscle rigidity (or stiffness) or balance problems. The gradual worsening of symptoms, one-sided onset and a positive response to Levodopa further strengthens the diagnosis. Clinicians also make sure the symptoms aren’t caused by a different neurological condition (differential diagnosis). A host of non-motor symptoms is also associated with Parkinson’s disease and can emerge at any point, even long before the motor symptoms. Around 60% of patients suffer from more than one non-motor symptom.

Tip of the iceberg

Symptoms of Parkinson’s disease vary from person to person, they change over time and include a combination of motor and non-motor features. Ultimately, symptoms are the result of the underlying disease processes and do not always faithfully reflect the status or progression of the disease.

We now know that the classic motor symptoms, traditionally thought to indicate the onset of Parkinson's disease, are just the tip of the iceberg. They actually represent a later phase of the disease course and can be preceded by several non-motor symptoms. One of the biggest challenges is to identify Parkinson’s disease before the traditional motor symptoms emerge.

The current clinical diagnostic criteria for Parkison’s disease include the presense of at least two of the cardinal motor symptoms.

Identification

In order to accurately identify Parkinson’s disease without clinical Parkinsonism, researchers are now focusing on biological markers that could provide clues about the underlying disease before it has emerged.

Biomarkers are objective or measurable indicators that can reflect a medical state (health or illness). There are 4 types of biomarkers in Parkinson’s disease: clinical, imaging, biochemical and genetic. Biomarkers could be used for diagnostics as well as prognostics, but they can also play an important role to determine if new treatments are actually effective.

No biomarker is currently available to accurately and consistently diagnose Parkinson’s disease. Combinations of biomarkers will most likely be needed to optimize new diagnostic methods.

Differentiation

Another major challenge to clinical prognosis and management is to differentiate between various clinical presentations of Parkinson’s disease. Combinations of symptoms may indicate different subtypes that could  have different rates of progression and require personalised treatment approaches.

For instance, tremor is a common symptom and anyone presenting primarily with this symptom would be classified as tremor dominant. Others might have more problems with walking and balance, as well as muscle stiffness and would be classified as akinetic-rigid or postural instability and gait difficulty. Cognition is so far the only non-motor classifier, but efforts are ongoing to also determine  accurate non-motor subtypes.

Damage has already been done

It is now believed that the Parkinson’s disease process has already started years if not decades before a clinical diagnosis can even be made based on the currently available criteria.

Because we do not have optimal methods of identification, this period of the diasease course is referred to as the prediagnostic phase.

The prediagnostic phase highlights an even more considerable delay in the identification of Parkinson’s disease than was currently the case. Many efforts are therefor underway for the development of new methods for early and accurate diagnosis, but also innovative treatment options that aim to slow, stop or even reverse the disease process.

Parkinson’s disease in the absence of Parkinsonism

During the prediagnostic phase the build up of neural damage has started, but the typical clinical symptoms have not yet developed (preclinical phase), are not specific to Parkinson's disease or are too subtle to meet current diagnostic criteria (prodromal phase).

Many of the motor symptoms only become obvious and a clinical diagnosis can be made, when the body is no longer able to compensate for the considerable damage that has already been done.

Although estimations vary, there are indications that 40% or more of the neurons associated with movement control have been lost once motor symptoms first emerge. It is now clear that Parkinson’s disease pathology has been able to spread virtually undetected for years.

The biggest challenge moving forward is to find ways to diagnose Parkinson’s disease in the absence of Parkinsonism in an effort to intervene earlier and minimise or preferably prevent neural damage from happening. The focus therefore is on identifying certain risk factors that could predict future development of Parkinson’s disease as well as biological markers that can indicate the presence of existing pathology, the rate of progression or the effectiveness of new treatments.

Where to begin?

The exact cause of Parkinson's disease is still not known and we’re not quite sure when the disease actually starts. The clinical diagnosis, traditionally considered the start point of the disease, is considerably delayed, but we’re unsure of the extent of this delay.

In an attempt to solve this puzzle, researchers are trying to get a better understanding of the factors (age, genetics, environment and lifestyle) and cellular mechanisms that can increase the risk of development and influence the rate of disease progression.

It is important to realize that any one factor is unlikely to be responsible for the cascade of events associated with Parkinson's disease. Some factors can increase the chances of development, while others lower this chance.

It is likely that multiple factors combine to increase the risk of developing Parkinson's disease. This could also explain why not everyone exposed to some factors develops Parkinson's disease and why the clinical presentation and rate of progression is so variable between persons.

A disease of old age

Aging is still believed to be the greatest risk factor for Parkinson's disease as the motor symptoms commonly emerge around the age of 60. The risk of developing Parkinson's disease increases with increasing age, affecting about 2-3% of those over 65 years of age.

It is believed that age related changes to our recovery from and adaptability to internal and external stress might increase our risk of developing Parkinson's disease.

Although older age is most typical for traditional Parkinson's disease symptoms to emerge, a number of people with Parkinson's disease develop symptoms well before the age of 40, referred to as young onset Parkinson's disease. When the onset occurs before the age of 21 it is referred to as juvenile Parkinson's disease.  

Apart from age, gender also seems to play a role with males having a slightly greater risk for developing Parkinson's disease.

Genetic predisposition

The majority of Parkinson's disease cases are referred to as idiopathic or sporadic Parkinson's disease, meaning with unknown cause. However, a  family history is associated with an increased risk of Parkinson's disease.

By studying rare forms of familial Parkinson's disease, multiple genes (made up of DNA) have been identified that are thought to play a role in the disease development. Alternations to these genes or genetic mutations cause changes to proteins involved in essential biological processes and mechanisms of our cells, thus increasing the risk for development.

Genome-wide association studies have identified several susceptibility genes and locations on chromosomes (loci) that could increase the risk of developing Parkinson's disease. One of the first genes to be linked to Parkinson's disease was the alpha synuclein or SNCA gene in a large family study. Since then this gene has also been linked to sporadic Parkinson's disease, in particular the formation of Lewy bodies. Lewy bodies are abnormal accumulation of proteins that develop inside nerve cells, likely contributing to Parkinson's disease and dementia.

Environmental factors

Strong evidence for the role of environmental risk factors came from the permanent Parkinson-inducing effects of a drug called MPTP, a byproduct of a synthetic opioid used in the 1980s. Similar to Parkinson's disease, the drug causes selective loss of dopaminergic cells in the brain, as well as the characteristic motor symptoms. Due to its effectiveness in recreating symptoms, MPTP is still used in many Parkinson’s disease models to date.

As MPTP has a similar chemical composition to the pesticide paraquat the link was made for a possible role of pesticides (including insecticides and herbicides) in developing Parkinson's disease. Other environmental risk factors have also been proposed, such as heavy metals, solvents, prior traumatic head injury, rural living and well water drinking.

A clear understanding of dose response relationships has yet to be found. In addition, experts agree that the risk of developing Parkinson's disease depends likely on an interaction between different genetic and environmental factors.

Lifestyle factors

Apart from genetic and environmental factors, some lifestyle factors have been associated with the development and progression of Parkinson’s disease.

Although the scientific literature is inconsistent, potential protective effects have been attributed to lifestyle factors like smoking, coffee and tea drinking and some anti inflammatory medication. Nutrition and physical activity are also known to be important to neuronal health. Stress, anxiety and depression on the other hand potentially increase the risk of developing Parkinson’s disease or its progression.

Uncovering the exact cause and effect relationships of these risk factors need considerably more attention. Many associations are based on observation and are likely the result of reverse causation. Meaning, a common error of mistaking cause for effect or the other way around. Just because something changed in the years leading up to diagnosis does not necessarily mean it is the cause for the disease to develop.

SHIFT IN FOCUS

A cure for Parkinson's disease remains to be found. Most symptoms can be controlled quite well for many years, however, long-term use of medications can result in treatment related complications.

Although, the current treatment options are able to effectively manage most symptoms, they do not impact the underlying disease process. In addition, it is now clear that the motor symptoms appear during a later stage. Instead of marking the beginning of the Parkinson's disease course, their onset marks a point where considerable damage has already been done.

Many scientific efforts are therefor ongoing to develop methods for earlier detection of Parkinson's disease, as well as new treatment options that aim to prevent damage from happening (neuroprotection) and to slow, stop or even reverse the disease (neuromodification).

LOCAL FACTS

  • There are an estimated 80,000 Australians living with Parkinson’s disease.
  • This estimation is likely underestimated due to under- or misdiagnosis, which ranges between 10-35%.
  • 24% of those affected are from Queensland.
  • Total number of people with Parkinson’s disease is set to double in the next15 years.
  • There are more males (53%) than females (47%) with Parkinson’s disease.
  • While 82% of those affected are aged over 65 years, 18% are of working age.
  • On average there are more than 31 new diagnoses every day.
  • Median disease duration is around 12 years from time of onset, but many live much longer.
  • The burden of disease is significant and Parkinson’s disease often leads to loss of independence and increased reliance on care and assistance.
  • Quality of Life is considerably impacted and estimations show an average need for 36 h/wk of informal care.

Any questions?

Get in touch with the Queensland Parkinson's Project