Parkinson’s disease (PD) is a neurodegenerative disease characterized by slowly progressive symptoms of resting tremor, rigidity, akinesia/bradykinesia, and postural instability.

      PD is the second most common neurodegenerative disease after Alzheimer disease.

      PD affects about 2% of the population over 60 years.

      Incidence rates of PD are 8 to 18 per 100,000 person-years.³ In 3% to 5% of patients with parkinsonism, the onset is before the age of 40 years.⁴ Figure 4.1 compares young-onset PD with juvenile parkinsonism.^5,6

      Age is the single most consistent risk factor. Figure 4.2 outlines factors that have been reported to increase and decrease the risk for developing PD.^3,7–24

      Although the majority of cases of PD are sporadic, there are known and increasingly reported genetic and familiar forms of PD (Figure 4.3; Tables 4.1 and 4.2).^25–35

      Most inherited forms of PD present at a younger age.

      Braak and colleagues have challenged this idea and introduced a six-stage pathologic process (Figure 4.4).³⁷

              In this staging system, degeneration of dopaminergic neurons in the substantia nigra occurs in stage 3 (see Figure 4.4; Figure 4.5).

      The mechanism responsible for neuronal degeneration is probably multifactorial and based on a combination of genetic and environmental factors (Figure 4.6).³⁸

      Alteration in the direct pathway leading to PD (Figures 4.7 and 4.8)

              In normal subjects, dopaminergic neurons in the substantia nigra, pars compacta (SNc) act to excite inhibitory neurons in the direct pathway (see Figure 4.7).

      Alteration in the indirect pathway leading to PD (Figure 4.9)

              In normal subjects, dopaminergic neurons in the SNc act to inhibit excitatory neurons in the indirect pathway.

              In PD, there is dopaminergic cell loss in the SNc, resulting in increased striatal inhibition of the GPe. The reduced inhibition of the STN results in increased excitation of the GPi, which in turn results in excess inhibition of the thalamus. The final pathway would be a reduced activation of the motor cortex.

      Although several agents have been tested to evaluate their neuroprotective effect in PD, none has been definitively shown to slow disease progression (Table 4.3).^39–62

      Currently, the clinical data for neuroprotective agents for patients with early PD are conflicting and inconclusive.

      Clinical endpoints available are readily confounded by agents that also carry symptomatic effects.

      The diagnosis of PD remains clinical to this day (Figure 4.10). The UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria have been used as a gold standard diagnostic tool in PD research (Table 4.4).⁶³

      At present, there is no biological marker that unequivocally confirms the diagnosis of PD.

              Imaging and other ancillary tests have been utilized (clinically or in PD research) to help confirm the diagnosis of PD (Table 4.5).

              Recently, DaTscan has been approved by the US Food and Drug Administration (FDA) to differentiate neurodegenerative parkinsonism (eg, PD) from nonneurodegenerative parkinsonism (eg, essential tremor, vascular parkinsonism, drug-induced parkinsonism) (Figure 4.11). However, DaTscan is unable to differentiate PD from other Parkinsonplus syndromes (eg, progressive supranuclear palsy, multiple system atrophy, dementia with Lewy bodies).

      The PD motor presentation can be divided into two phenotypes (Figure 4.12).

              Akinetic–rigid syndrome or postural instability gait dysfunction subtype (PIGD)

              Tremor-predominant subtype

      Certain clinical features, such as resting tremor, asymmetry of parkinsonian motor symptoms, and good response to levodopa, strongly suggest PD rather than a Parkinson-plus syndrome (Figure 4.13).

      The akinetic–rigid syndrome or PIGD subtype is more challenging to differentiate from other Parkinson-plus syndromes.

      There is currently no biomarker to assess the severity of PD.

      The severity of PD is based mainly on the clinical features.