10.1.1 Epidemiology

Parkinson’s disease (PD) is a progressive neurodegenerative condition that is characterized by the presence of bradykinesia and at least one of three additional features including resting tremor, postural instability, and rigidity. ¹ It is primarily a disease of the elderly, affecting one percent of the population over the age of 60; however, young-onset cases diagnosed before the age of 40 years do occur and may be associated with certain genetic mutations. A male predominance exceeding 60% has been consistently noted. Whether there are racial differences, including the possibility that Caucasians are at greater risk than Asians and African Americans, is controversial.

PD is the result of the interaction amongst several genetic and environmental factors. ² Epidemiological studies link pesticide exposure, well water consumption, welding, and military exposure to Agent Orange with an increased risk of developing PD. Less than 10% of cases are linked to a monogenetic cause. There are five identified autosomal dominant genetic inheritance patterns and five with autosomal recessive patterns. Beyond these rare disease-causing mutations, there are now several well-characterized risk modifying genes. ³ In 2010, the estimated economic burden of PD in the United States was $14.4 billion, and this burden likely will continue to increase. ⁴

10.1.2 Pathology

PD is associated with a loss of dopaminergic cells and reduced pigmentation in the substantia nigra pars compacta of the midbrain. By the time the patient presents with initial motor features, 60–70% of these dopaminergic neurons have already been lost. Microscopy at autopsy shows the presence of Lewy bodies. These are round cytoplasmic inclusions containing pathological forms of the protein alpha-synuclein.

The classical description of PD as a pure motor disorder resulting from isolated dopaminergic cell degeneration has been substantially modified in recent years. According to the Braak hypothesis, first published in 2003, abnormal alpha-synuclein accumulates in a spreading geographic fashion. The olfactory bulbs and lower brainstem are affected early, followed by the midbrain, then the symptom onset advances rostrally to those caused sequentially by disease involving the subcortical regions and basal ganglia, and finally involving selected cortical regions. ⁵ This pattern may explain the timing and sequence of symptom onset, and why, for example, olfactory dysfunction may predate motor features, while cognitive impairment appears later in the disease course. Another important implication of this theory is that dopaminergic dysfunction is only a small part of a more complex disease process involving the serotonergic, noradrenergic, and cholinergic systems, giving rise to non-motor features such as autonomic, sleep, mood, and, of course, cognitive symptoms.

10.2.1 Motor Features of PD

Bradykinesia is essential for the diagnosis of PD. It can manifest in many ways, including slowed movements, reduced amplitude or decrement with repetitive movements, diminished facial expression (hypomimia), soft speaking (hypophonia), or small handwriting (micrographia). Patients may also have asymmetric muscle rigidity, resting tremor, and postural abnormalities that manifest as a stooped and tilted trunk with flexion at the elbows and knees. Postural instability is the inability to recover balance once it is perturbed. A narrow stance, shuffling, short steps, reduced arm swing, and en-bloc turning are characteristic of a parkinsonian gait. Ambulation is further complicated by freezing (hesitations and sticking of the feet to the floor, particularly when walking through doorways or changing direction), and festination (increasing forward momentum as the center of gravity propels the body forward).

10.2.2 Non-motor Features of PD

Dopamine deficiency leads to the motor features of PD; however, dysfunction among other neurotransmitter systems results in several common and debilitating non-motor symptoms. ^{6 , 7} One of the early signs of PD, often noted in retrospect, is olfactory dysfunction. This has been explored as an early predictive marker in asymptomatic family members of affected individuals. ⁸ Serotonergic dysfunction can manifest early in “pre-motor” PD, resulting in REM sleep behavior disorder that often predates classical motor symptoms, as well as causing mood disorders such as depression and anxiety. Patients may also experience sympathetic (noradrenergic) and parasympathetic (cholinergic) nervous system dysfunction. Symptoms of this are constipation, gastroparesis, urinary frequency and urgency, sexual dysfunction, and orthostatic hypotension. Other common non-motor symptoms are fatigue, daytime sleepiness, apathy and a variety of sensory complaints including pain. Any of these can profoundly impact quality of life. Cognitive decline and psychosis are late complications that will reduce quality of life and cause a loss of independence. ^{9 , 10}