Parkinson’s Disease

The second most frequently diagnosed neurodegenerative disease after Alzheimer’s Disease is Parkinson’s Disease (PD). PD is usually diagnosed after the age of 60 and affects about seven million people globally. This number is expected to keep rising as the population ages.

PD is primarily a movement disorder. Its typical motor system symptoms include resting limb tremors, stiffness and rigidity, a slowness of intentional movement (bradykinesia), disrupted balance and a characteristic, forward-falling gait. Non-motor symptoms of PD may include depression, anxiety and dementia. Additionally, the medications used to manage PD can cause a suite of neuropsychiatric side effects including psychosis and impulsive behaviors. Patients often subsequently develop a form of dementia, dominated by problems in processing complex information. A related illness, Dementia with Lewy Bodies, combines many of the motor symptoms of PD with hallucinations, behavioral disturbances, and dementia.

PD is a chronic, progressive disease. Although the symptoms and rate of disease progression can vary widely between patients, early treatment and management of PD can significantly extend the duration of a patient’s ability to live independently.

In the brains of PD patients, neurons in the substantia nigra area of the brain that produce the neurotransmitter, or chemical messenger, dopamine die. The substantia nigra plays an important role in movement and dopaminergic neurons facilitate smooth movements. PD brains also have Lewy bodies in some of the affected dopaminergic neurons. Lewy bodies are dense protein bodies with clumps of the protein alpha–synuclein, a protein whose normal function in the brain involves regulating neurotransmitter release and transport of important factors around the cell. The Lewy bodies spread through the brain in a stereotyped manner as the disease progresses.

PD can be either familial (about 10%) or apparently sporadic. As with many diseases, a complex interplay of genetics and environment is likely to be responsible for PD. While environmental triggers such as head injury, herbicides, and pesticides are being studied for potentially increasing the risk of sporadic PD, more information about its etiology has come from the discovery of mutations in particular genes associated with both familial and sporadic PD, most notably mutations in alpha-synuclein, the major constituent of Lewy bodies, and leucine-rich repeat kinase 2 (LRRK2), a cell signaling protein. It is not well understood how the aggregation of alpha-synuclein in Lewy bodies contributes to dopaminergic neuron death and PD pathology, but experiments have shown that aggregation of this protein in neurons is followed by cell death and aggregation inhibitors prevent this cell death. It is also not clear how LRRK2 contributes to brain cell degeneration, although it is likely through its role as a signaling protein and potentially by interacting with alpha-synuclein. 

The most common first-line therapies to control PD motor symptoms are dopaminergic drugs, such as Levodopa (L-dopa), a precursor to dopamine. It is typically administered to patients in combination with a drug that prevents L-dopa’s conversion to dopamine before it crosses the blood-brain barrier, thus increasing L-dopa’s half-life while reducing the side effect of nausea from extra dopamine outside the brain. L-dopa use can have a number of side effects, including eventual involuntary muscle movements called dyskinesia. Therefore, patients are typically maintained on the lowest effective dose. Other families of drugs similarly work to boost brain dopamine signaling by blocking its breakdown or mimicking its actions. Treatment for non-motor symptoms of PD, such as walking difficulty, sleep and mood disorders and dementia have been more elusive and include anti-psychotics and cholinesterase inhibitors for dementia and stimulants for daytime sleep issues.

When motor symptoms of PD can’t be adequately controlled by medication, surgery may be an option. In deep brain stimulation surgery, a small battery-operated device is implanted to generate electrical pulses that block aberrant nerve signals underlying PD motor symptoms.

Research toward better PD therapies has as its basis a more thorough understanding of the disease. There are ongoing efforts to identify environmental modify disease risk in predisposed individuals. These potential modulators include dietary or lifestyle factors such as caffeine and exercise. The nature and mechanism of alpha-synuclein aggregation toxicity, as well as ways to clear the aggregates from the brain are also active areas of investigation. As our understanding of the factors and mechanisms involved in PD pathogenesis grows, so does our repertoire of potential drug targets and therapies.