How Does Parkinson's Disease Develop?
Pathophysiology is the study of the functional processes that occur in a disease. The pathophysiology of Parkinson’s disease (PD) is only partially understood, although considerable progress has been made. Pathophysiology continues to be an area for research, as scientists work to understand how and why PD develops and continue to search for ways to stop the progression of the disease.
Primary hallmarks: Loss of dopamine and presence of Lewy bodies
The primary pathologic hallmarks of PD are loss of neurons in an area of the brain called the substantia nigra pars compacta, and the presence of globs of a protein called alpha-synuclein found in neurons, called Lewy bodies.
Neurons in the substantia nigra pars compacta produce dopamine, a neurotransmitter (chemical messenger) that transmits signals from the substantia nigra to other parts of the brain. These other parts of the brain are collectively called the “basal ganglia”. Communication among neurons of the substantia nigra pars compacta and the basal ganglia produce smooth, purposeful movement. When the neurons in the substantia nigra are damaged in large numbers, the loss of dopamine prevents normal function in basal ganglia and causes the motor symptoms of PD: tremor, rigidity, impaired balance, and loss of spontaneous movement.1,3
Figure 1. Substantia nigra pars compacta
Alpha-Synuclein is a protein found exclusively in neurons. In PD, a-Synuclein is found in globs known as Lewy bodies that are found in neurons. Lewy bodies are found in dopaminergic neurons in the substantia nigra pars compacta and likely contribute to the death of these neurons. Lewy bodies can be found in other brain areas such as the amygdala, locus coeruleus, and raphe nucleus. These brain areas play a role in anxiety and depression. A brain area called the cortex is responsible for cognition, and executive function, i.e. the ability to plan for the future. Lewy bodies in this area of the brain are thought to cause dementia.
Interestingly, a study which examined the location of Lewy bodies in post-mortem brains of patients with early stages of PD to brains of patients with advanced stages of the disease, found that the Lewy bodies progress in a predictable manner from one brain region to another. This is called Braak staging. According to this staging system, Lewy bodies are initially found in the enteric nervous system, the medulla, and the olfactory bulb. The enteric nervous system is part of the autonomic nervous system that controls the gastrointestinal organs. The medulla is the part of the brain stem that regulates breathing, heart functions, and digestion. Finally, the olfactory bulb controls the sense of smell. Interestingly, constipation and reduced ability to smell are some of the earliest signs of PD. The presence of Lewy bodies in the substantia nigra pars compacta correlates with motor symptoms. In the late stages of PD, Lewy bodies are found in the cortex and are thought to contribute to dementia.
It is thought that preventing the progression of the formation of Lewy bodies from one brain region to another may halt the progression of the disease. However, much more research is required to determine if this hypothesis is correct.
How Parkinson’s disease affects neurons
In general, PD involves damage to neurons throughout the nervous system, and neural damage and death in different areas of the body create unique symptoms:
- Damage to neurons in the brainstem, the area of the brain right above the spinal cord likely contribute to sleep symptoms including REM sleep behavior disorder
- The substantia nigra pars compacta contains dopamine neurons – loss of neurons that produce dopamine causes impaired movement and balance
- Neurons of the olfactory bulb – loss of olfactory neurons causes reduced sense of smell
- The locus coeruleus contains noradrenergic neurons – noradrenergic neurons produce the neurotransmitter (chemical messenger) norepinephrine, which triggers the “fight or flight” response in the body; damage to these neurons can cause anxiety
- The raphe nucleus contains serotonergic neurons – serotonergic neurons produce the neurotransmitter (chemical messenger) serotonin, which has important roles in the movement of the intestines, sleep-wake cycles, and depression; damage to these neurons is believed to cause depression in people with PD
- Amygdala – damage to the neurons in the brain’s amygdala are believed to cause anxiety
- Autonomic nervous system - the autonomic nervous system controls many automatic functions, like breathing, heart beating, blood pressure, and the movements of the intestines; damage to the autonomic nervous system can cause symptoms such as constipation, increased salivation and sweat, and reduced blood pressure1,2,5,6