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Pathology
Anatomical
The basal ganglia, a group of brain structures innervated by the dopaminergic system, are the most seriously affected brain areas in PD.[41] The main pathological characteristic of PD is cell death in the substantia nigra and, more specifically, the ventral (front) part of the pars compacta, affecting up to 70% of the cells by the time death occurs.[8]
Macroscopic alterations can be noticed on cut surfaces of the brainstem, where neuronal loss can be inferred from a reduction of neuromelanin pigmentation in the substantia nigra and locus coeruleus.[42] The histopathology (microscopic anatomy) of the substantia nigra and several other brain regions shows neuronal loss and Lewy bodies in many of the remaining nerve cells. Neuronal loss is accompanied by death of astrocytes (star-shaped glial cells) and activation of the microglia (another type of glial cell). Lewy bodies are a key pathological feature of PD.[42]
Pathophysiology
The primary symptoms of Parkinson's disease result from greatly reduced activity of dopamine-secreting cells caused by cell death in the pars compacta region of the substantia nigra.[41]
There are five major pathways in the brain connecting other brain areas with the basal ganglia. These are known as the motor,oculo-motor, associative, limbic and orbitofrontal circuits, with names indicating the main projection area of each circuit.[41] All of them are affected in PD, and their disruption explains many of the symptoms of the disease since these circuits are involved in a wide variety of functions including movement, attention and learning.[41] Scientifically, the motor circuit has been examined the most intensively.[41]
A particular conceptual model of the motor circuit and its alteration with PD has been of great influence since 1980, although some limitations have been pointed out which have led to modifications.[41] In this model, the basal ganglia normally exert a constant inhibitory influence on a wide range of motor systems, preventing them from becoming active at inappropriate times. When a decision is made to perform a particular action, inhibition is reduced for the required motor system, thereby releasing it for activation. Dopamine acts to facilitate this release of inhibition, so high levels of dopamine function tend to promote motor activity, while low levels of dopamine function, such as occur in PD, demand greater exertions of effort for any given movement. Thus, the net effect of dopamine depletion is to produce hypokinesia, an overall reduction in motor output.[41] Drugs that are used to treat PD, conversely, may produce excessive dopamine activity, allowing motor systems to be activated at inappropriate times and thereby producing dyskinesias.[41]
Brain cell death
There is speculation of several mechanisms by which the brain cells could be lost.[44] One mechanism consists of an abnormal accumulation of the protein alpha-synuclein bound to ubiquitin in the damaged cells. This insoluble protein accumulates inside neurones forming inclusions called Lewy bodies.[8][45] According to the Braak staging, a classification of the disease based on pathological findings, Lewy bodies first appear in the olfactory bulb, medulla oblongata and pontine tegmentum, with individuals at this stage being asymptomatic. As the disease progresses, Lewy bodies later develop in the substantia nigra, areas of the midbrain and basal forebrain, and in a last step the neocortex.[8] These brain sites are the main places of neuronal degeneration in PD; however, Lewy bodies may not cause cell death and they may be protective.[44][45] In people with dementia, a generalized presence of Lewy bodies is common in cortical areas. Neurofibrillary tangles and senile plaques, characteristic of Alzheimer's disease, are not common unless the person is demented.[42]
Other cell-death mechanisms include proteosomal and lysosomal system dysfunction and reduced mitochondrial activity.[44] Iron accumulation in the substantia nigra is typically observed in conjunction with the protein inclusions. It may be related to oxidative stress, protein aggregation and neuronal death, but the mechanisms are not fully understood.[46]