The second most frequently diagnosed neurodegenerative disease after Alzheimer’s Disease is Parkinson’s Disease (PD). PD onset is usually after the age of 60 and affects about five 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. Ptients 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 with death usually occurring from complications related to the disease rather than the disease itself. Although the symptoms and rate of disease progression can vary widely between patients, early treatment and management of PD can extend 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 respond to the neurotransmitter, or chemical messenger, dopamine die. The substantia nigra plays an important role in movement and dopaminergic neurons are involved in smooth muscle movement. 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 exerts its cytotoxic effects, 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 and slow the progression of PD motor symptoms are dopaminergic drugs. Levodopa (L-dopa), a synthetic precursor to dopamine, is commonly administered to patients in combination with another drug that prevents L-dopa’s conversion to its final form before it crosses the blood brain barrier, thus increasing the drug’s half-life. L-dopa use can have a number of side effects including eventual drug resistance, freezing of movement, and involuntary muscle movements called dyskinesia; therefore patients are typically maintained on the lowest possible dose. Another family of drugs used is called Monoamine Oxidase B inhibitors. These drugs act by inhibiting the breakdown of dopamine in the space between the neurons in the brain, effectively extending the effects of the dopamine that remains. 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 battery-operated device about the size of a stopwatch is implanted into the brain in order to use electrical stimulation to block the aberrant nerve signals that cause PD motor symptoms. The device is connected to a battery pack that is worn externally by the patient.
Research toward better PD therapies has as its basis a more thorough understanding of the disease. There are ongoing efforts to identify environmental triggers that might precipitate the disease in predisposed individuals. These triggers could include pesticides, herbicides, and heavy metals. There are also potentially protective factors such as caffeine. The nature and mechanism of alpha-synuclein aggregation toxicity, as well as ways to clear the aggregates from the brain is also an active area of investigation. As our understanding of the factors and mechanisms involved in PD pathogenesis continues to grow, as does our repertoire of potential drug targets and therapies.