Characterization, Diagnosis, and History

Parkinson’s disease (PD) is a neurodegenerative disorder that impairs proper movement, and is the second most common neurodegenerative disorder behind Alzheimer’s.1 PD is also a part of the synucleinopathy family, meaning that it is a disease associated with the improper functioning of the alpha-synuclein protein within the brain. Although there remains no putative cure for Parkinson’s disease, our understanding of this disease has improved immensely, and will continue to improve into the foreseeable future. However, in order to fully grasp where we presently stand in terms of our knowledge of PD, and to assess where we will likely go into the future, it is important to take a look into the past and see what major advancements have been made in the identification and characterization of the disease. Thus, we still start at the very beginning of Parkinson’s disease’s story in order to get a better sense of how it has been characterized and defined throughout its history.

Brief History of Developments

            Although the symptoms of PD have been recognized for hundreds and hundreds of years, it was first characterized and described as a neurological disorder by James Parkinson in 1817 in his work titled “An Essay on the Shaking Palsy. Within this, Parkinson identified many of the more common symptoms such as tremor, slowed movements and gait impairments.2 Years later in 1886, Jean-Martin Charcot expanded upon Parkinson’s findings, identifying other symptomatic features such as bradykinesia, and coining the term Parkinson’s disease as opposed to paralysis agitans or shaking palsy. Not long after in 1899, Brissaud determined that the area of the brain that was likely being affected in PD patients was the substantia nigra, the area of the brain responsible for motor functions.3 Additionally, in 1912 Frederic Lewy identified what would become the cardinal feature of many synucleopathies and neurological disorders, the Lewy body.4 The Lewy body is an inclusion found within the brain of those suffering from Parkinson’s disease, and is composed of structurally altered neurofilament and various protein aggregates within the brain. This research laid out the groundwork for further studies into the more intricate biochemistry of this debilitating disease.

James Parkinson, the researcher who first characterized what was then known as shaking palsy in 1817.

            Some of this advanced research involved genetic studies of Parkinson’s disease, and in 1997, Polymeropolous identified a genetic mutation in the SNCA gene of one Italian kindred, and three unrelated Greek families who were all suffering from Parkinson’s. The SNCA gene is tied to the alpha-synuclein protein within neurons.5 This finding implicated other researchers to find out more about alpha-synuclein and its involvement in Parkinson’s disease. As a result, in the same year Spillantini discovered through antibody staining of Lewy bodies from idiopathic Parkinson’s, that alpha-synuclein is actually a main component of these inclusions.6 This finding opened the door to much of the alpha-synuclein focused research that has been conducted throughout the 21stcentury.

            Additionally, following the initial identification of the SNCA genetic mutation by Polymeropoulous in 1997, other SNCA missense mutations were identified which included the A53T mutant, A30P, E46K, H50Q, and G51D.7,8 Beyond the SNCA gene, more than 20 other genes and mutations of said genes have been identified as being causes of Parkinson’s disease. Some of the more well know genes include LRRK2, GBA, PINK-1, parkin, and DJ-1.9,10 Mutations of these genes results in disruption of typical dopaminergic neuron function in different ways, as opposed to SNCA which directly impacts alpha-synuclein protein.11

Clinical Diagnosis / Symptoms

            Parkinson’s disease impacts dopaminergic cells within the substantia nigra, and upon cellular disruption or death, the neurotransmitter dopamine’s production is significantly reduced. Dopamine within the substantia nigra is responsible for sending signals for movement.12 When this system is impaired we, the signs and symptoms of Parkinson’s disease begin to be observed. The hallmark symptoms include bradykinesia, tremor at rest, muscular rigidity, postural instability, loss of automatic movements, as well as many other less common movement impairments.13

            Patients are most often diagnosed with Parkinson’s disease based off of the observed symptoms. However, many other neurological disorders share similar symptoms, and as a result, diagnosis based solely off of visible symptoms is not always the most effective methods. Other less common methods that allow for more accurate diagnosis include what is known as a DaTscan. This is an imaging technique that is used to visualize the degeneration of dopamine within the substantia nigra. 125 physicians were surveyed regarding the efficacy of DaTscan, and it was reported that there was an overall increase in confidence of diagnosis as a result of the implementation of this imaging technology.14

            In terms of who is most at risk for Parkinson’s disease, the mean age of PD diagnosis is in the 70’s. However, due to the slow progression of the disease (average duration of 15 years), often times patients are first diagnosed upon the first sign of symptoms, and the disease may have been developing for years.15 16 It is estimated that major symptoms arise after 80% of the substantia nigra dopamine has been lost. This leaves a lot of time between the onset of disease and clinical diagnosis.

            Additionally, there are also cases of early onset Parkinson’s disease that can affect patients much younger than 70, as an estimated 3% of cases are identified initially in patients younger than age 50. Many early onset cases are the result of genetic mutations, which constitute 10% of the overall cases of PD, with sporadic / idiopathic making up the rest.17 Outside of genetic variation, age and unknown environmental factors make up the risk for PD, although it is unknown how alpha-synculein is aggregating and forming Lewy bodies during disease pathology.

Illustration of what a typical Parkinson’s patients symptoms may look like. The hunched over posture is very typical of these patients.

Parkinson’s Stages

            A staging system for Parkinson’s was introduced by Heiko Braak in 2003, and this system remains one of the main forms of staging used today.18 The stages are labeled from stage 1 to stage 6, and are identified by the following:

  • Stage 1: Disease initiated in the structures of the lower brainstem, in particular the dorsal motor nucleus. Thread-like alpha-synuclein aggregates are more common than Lewy bodies.
  • Stage 2: Characterized by additional lesions within the raphe nuclei, and the gigantocellular reticular nucleus of the medulla oblongata. Alpha-syn aggregates remain more prevalent than Lewy bodies.
  • Stage 3: Disease has infiltrated the substantia nigra, and Lewy body formation begins within the pars compacta. Lewy body numbers begin to rise.
  • Stage 4: Destruction and loss of dopaminergic neurons in the pars compacta begins. Pathology can be observed in the amygdala, and in the subnuclei of the thalamus.
  • Stage 5: The neocortex has begun to be effected by disease progression, and spread continues into the temporal, parietal, and frontal lobes of the brain. Cell death has become extensive throughout multiple parts of brain, specifically in areas responsible for movement.
  • The neocortex has been fully invaded by disease. The disease has reached its most dangerous, and most severe point throughout progression.


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