What is Parkinson’s Disease?

What is Parkinson’s disease?

Meeting someone with a relative diagnosed with Parkinson is almost inevitable and usually this result in the following question: what is Parkinsons disease? The answer to this question began to be formulated in 1817 when James Parkinson wrote a text called “Essay on the Shaking Palsy”, describing the basic symptoms of this disease, tremors, and other motor system alterations. This clinical description would be the only description of Parkinson’s disease for more than a century. This would only change with numerous histopathological and neurological discoveries starting in the 1950s. Currently, Parkinson’s disease is described as a progressive neurodegenerative disease with particular histological and anatomical abnormalities and distinctive clinical characteristics that make it a separate disease from other neurodegenerative illnesses. However, there are lots of things that need to be investigated, in particular its etiology and a definitive treatment.

What is Parkinson's Disease?

Parkinson’s Disease is a neurodegenerative disease

Parkinson’s disease is described as a neurodegenerative disease. As the disease progresses there is a loss of structure and function of neuronal cells.  Neurodegenerative diseases are characterized by irreversible neuronal damage and as a consequence of this damage functional loss occurs. In Parkinson’s this damage occurs in several parts of the brain which include the locus coeruleus, substancia nigra, raphe nuclei, dorsal nucleus of the vagus, cortical areas and many other regions. It has been proposed that the degenerative process occurs first in the dorsal nucleus of the vagus and the olfactory bulb, later in the substancia nigra pars compacta and locus coeruleus, and finally in the cortical regions. This pattern of degeneration could explain the order of the clinical symptoms in patients with Parkinson’s disease. (Initially, the symptoms are almost exclusively motor but as the illness progresses there is alteration of other functions).

In Parkinson’s disease, the main area of neuronal loss is the substancia nigra pars compacta, a region involved in the neuronal control of movement through the nigrostriatal pathway.This region synthesizes melanin, which gives it a distinct dark coloring. Therefore, when there is neuronal loss in this region, macroscopically one can observe a depigmentation process. Another substance synthesized in this region is the neurotransmitter dopamine. This neurochemical characteristic is highly relevant to the pathophysiology and pharmacological treatment of the disease. Another clinically relevant aspect of the site of lesion is its unilateral location. This will result that the related clinical symptoms will be found counter laterally in the subject.  Finally, it is important to note initial symptoms to appear when at least 70 to 80% of the neurons in the substancia nigra are lost.

In histological samples of distinctive lesions occurring in Parkinson can be observed. These are intracellular inclusions with accumulation of protein structures in the nigrostriatal neurons. These inclusions are called “Lewy bodies” and are described as spherical and eosinophilic. The protein structures contained include the following: alpha-synuclein, ubiquitin, and alpha B crystalline. Of the three proteins, alpha-synuclein and ubiquitin are the most relevant in Parkinson’s disease because genetic alterations of the proteins are the cause of several hereditary forms of the disease. Also through immunohistochemicalstaining, the neuronal samples have demonstrated that alpha-synuclein is found central in the inclusion. In comparison ubiquitin is found diffusely in the inclusion. It is important to note that these inclusions are not exclusive to Parkinson’s disease and that the content within could vary in other diseases.

Histological samples have other peculiarities in the pattern of the lesions in Parkinson’s disease. One of these is the differences with normal age alterations in the neurons of the substancia nigra pars compacta. Normally as the aging process occurs there is a dorsomedial loss of neurons in this region. In the other hand, in Parkinson’s disease, the caudal and ventrolateral parts of the substancia nigra pars compacta are affected.  Another is the site in the neuron in which the process of degeneration begins. In Parkinson’s disease there tends to be initial affection of neuronal endings and afterward cell body lesion.

Apart from the histopathological characteristics, Parkinson’s disease also has distinct clinical characteristics.First of all, the patients tend to be between 50 and 70 years old when the symptoms show up. Also, it is a disease that is slightly found more often in men (given the 3:2, male to female ratio).  Finally, 95& percent of patients with Parkinson’s are described as sporadic case seen by absence of family history of the disease.

Its symptoms are also part of the distinct clinical characteristics. Symptoms in Parkinson’s are divided into two groups: motor symptoms and non-motor symptoms. As described previously, the illness tends, to begin with ipsilateral motor symptoms, later developing bilaterally in the motors symptoms and non-motor symptoms in the final stages of the disease.  The cardinal motor symptoms found in Parkinson are bradykinesia, rest tremor, rigidity and postural instability. Other minor motor symptoms include akinesia, hypomimia, micrographia, freezing of gait and many others. The non-motor symptoms include hyposmia or anosmia, constipation, apathy, fatigue and cognitive deterioration.

Bradykinesia or slow movements are commonly explained by the loss neurons in the substancia nigra. The motor function is regulated by two pathways involving the cortex and the basal ganglia: the direct pathway and the indirect pathway. The direct pathway has a promoting effect on movements, while the indirect inhibits movement. Through these pathways, neurons in the substancia nigra pars compact have an activating effect in the motor systems. The neurons of the substancia nigra innervate other neurons in a structure called the striatum.

In the striatum, there are two types of dopamine receptors: D2 (inhibitory receptor) and D1 (excitatory receptor). In areas where D1 is expressed, this region of the striatum will activate the direct pathway.  To support this effect there are D2 (inhibitory) expressed in the region of the striatum that activates the indirect pathway. Therefore, upon activation of the dopaminergic neurons in the substancia nigra pars compacta, it will result in activation of the direct pathway due to the D1 receptors and inactivation of indirect pathway due to the D2 receptors. However, due to the neuronal loss of dopaminergic neurons in the substancia nigra, this will not occur, result in movement inhibition and the motor symptoms associated with Parkinson’s disease.

In contrast, the other cardinal symptoms (tremor, rigidity and gait disturbances) pathophysiologic basis are not understood. There is numerous hypotheses for each but there is still lots of room for further studies. This is the same case for the non-motor symptoms. The hypothesis for these was previously stated, which involves the degeneration of cortical and limbic structures involved in the non-motor functions.

Given the diversity of the symptoms and varied combinations of them, it has been hypothesized that Parkinson’s disease has two distinct subtypes. The two subtypes are: tremor-dominant Parkinson’s disease and postural instability and gait difficulty Parkinson’s disease.  These two types have distinct clinical characteristics. The tremor dominant Parkinson’s disease tends to have an earlier development (20-40-year-old), genetic component and a good prognosis. In the other hand, posture instability and gait difficulty Parkinson’s disease occur after the sixth decade of life and earlier non-motor components.

Also, there are differences in the histological analysis. In the posture instability and gait difficulty Parkinson’s disease tends to have a greater neuronal loss and more cortical Lewy bodies. In contrast, tremor dominant Parkinson’s disease has lesions in the midbrain, specifically the retrorubral A8 field. However, it should be pointed out that there hasn’t been enough research on the subtypes, therefore more research needs to support this hypothesis in order for it to be accepted.

Having in mind the particular histological and anatomical abnormalities and distinct clinical characteristics allows one to differentiate Parkinson disease from other diseases. In particular one needs to distinguish Parkinson’s from other diseases causing Parkinsonism and other neurodegenerative diseases.

The symptoms commonly found in Parkinson’s disease are commonly grouped together as Parkinsonism and can be found secondary to other illnesses. One cause is intoxication with substances like organophosphate pesticides or 1-methyl-1-phenyl-1,2,3,6-tetrahidropiridina. La latter can mask like Parkinson’s disease however the patient’s history will reveal exposure to the causal agent, the chemical. Another environmental cause is infections. This is what is called as Oost-encephalitic Parkinsonism, which was observed in the early 1900s.  Like the name says, Post-encephalitic Parkinsonism also shares clinical similarities with Parkinson’s disease.  However, similar to a case of Parkinsonism induced by chemical components, a patient’s history could reveal exposure to a secondary cause.

Parkinson's Disease

Parkinson’s Disease

Other diseases that mimic Parkinson’s disease are Striatonigral degeneration and Progressive supranuclear palsy. All these diseases (Parkinson’s disease, Striatonigral degeneration and Progressive supranuclear palsy) have a degenerative process. However, there are going to be a difference at the histopathological level. Striatonigral degeneration will differ from Parkinson’s disease because the degeneration process is much more diffuse and lesions in the substancia nigra and the locus coeruleus tend to be less severe. It should be noted that Striatonigral degeneration also has intracellular inclusions of alpha-synuclein. But present with glial cell inclusion as well.

Progressive supranuclear palsy also as a greater diffuse pattern of neuronal cell degeneration.  Also, it has a severe mesencephalic roof atrophy, resulting in a Mickey Mouse shape due to the prominence of the cerebral peduncles. This disease is also different in the content of cell inclusion. Progressive supranuclear palsy, instead of accumulating alpha-synuclein, in accumulates tau proteins. Clinically it is important to observe if there are early imbalance or vertical gaze alterations because these are characteristics of Progressive supranuclear palsy. In contrast, these either appear in later stages of the disease or do not appear in the clinicin Parkinson’s disease.

Another neurodegenerative disease that needs to be differentiated from Parkinson’s disease, are Alzheimer’s, Pick’s disease and Dementia with Lewy bodies. Alzheimer’s disease can present Parkinsonism; this will happen after the cognitive alterations.  It could be oversimplified by saying that of cognitive and motor impairment appear inversely when comparing Alzheimer’s disease to Parkinson’s disease. This clinical difference can be associated with the location of the histopathological alterations. While Parkinson’s lesions are mainly found in the substancia nigra and the locus coeruleus, in Alzheimer’s there is generalized cortical atrophy. Also, the inclusions in Alzheimer’s vary because they contain intracellular tau proteins inclusions and extracellular beta amyloid plaques.

The last neurodegenerative disease, Dementia with Lewy bodies, can hard to differentiate from Parkinson’s disease. This is because of its similar histopathology and clinical characteristics. In the histopathological studies, both diseases present with similar Lewy bodies with alpha-synuclein. However, but the location varies as Dementia with Lewy bodies tends to present in a diffuse manner, with significant early cortical lesions. Clinically both disease present with lots parkinsonism, however, the early onset of hallucinations and limbic dysfunction can help differentiate Dementia with Lewy bodies.  Due to its incredible heterogeneous characteristics, Dementia with Lewy bodies, has been said to be a Lewy body variant of Alzheimer’s.

Finally, the greatest challenge is identifying mixed neurodegenerative diseases. Each neurodegenerative disease has its own particular symptoms that aids but sometimes two different neurodegenerative diseases can coexist. Alzheimer histopathological findings can be found in post-mortem investigation in 40% of patients diagnosed with Parkinson’s disease upon. There is no doubt that diagnosing clinically overlapping disorders can be a challenge to even expert clinicians. Therefore, these complex cases most of the time are found post-mortem.

Regardless of the similarities with other neurodegenerative diseases, Parkinson’s disease has a precise clinical definition that facilitates diagnosis. However, further research is needed to discover the precise pathogenic mechanisms involved. This would benefit great the treatment as current pharmacological therapy is barely successful. Only limited improvement of symptoms has been managed. Upon discovery of the precise pathogenic mechanism, it is possible that pharmacological agents could be designed to prevent or even reverse neurodegeneration occurring in Parkinson’s.

In order to know what a disease is, one needs to define it and use this definition to distinguish from other similar diseases. Parkinson’s disease can be quickly defined as a nonreversible progressive neurodegenerative disease with significant motor impairment. However, this definition is not enough due to the similarities to other neurodegenerative diseases. It is the distinct properties that will define a disease. In this case a nonreversible progressive neurodegenerative process that mainly affects the substancia nigra and the locus coeruleus but in final stages affect diverse parts of the brain. This results in initial motor function impairment followed by further motor dysfunction and as diseases progress impairment of non-motor systems such as cognitive, emotional and other neurological functions.