Neuroprotection in Parkinson's Disease: Are We Getting Close?
INTRODUCTION
Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease.1 In the United States alone, there are approximately 1 to 1.5 million people with PD.2-4 Most cases of PD are sporadic, or idiopathic; however, familial forms of the disease have been described, and genetic mutations that can cause PD have been identified.4 Regardless of the etiology, PD is a progressive, neurodegenerative disorder that causes motor and nonmotor dysfunction. Traditionally, PD has been characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, which results in reduced striatal dopamine5 and the classic motor deficits observed in the disease.4 However, it is now accepted that PD is a multisystem disorder and that neurodegeneration occurs in other regions of the brain and areas of the nervous system, including the autonomic6 and enteric7-10 nervous systems.
Topographic progression of PD
A key pathologic finding in PD is the presence of α-synuclein–containing protein inclusions, also known as Lewy bodies, within neurons.11 Further, the localization of Lewy bodies defines the 6-stage topographic progression of PD in the Braak staging system.12 According to the Braak model, Lewy body pathology begins in the dorsal motor nucleus of the glossopharyngeal and vagus nerves, the anterior olfactory nucleus, and the enteric nerve cell plexuses, rather than in the substantia nigra.12,13 Lewy body pathology in the brain then progressively extends in a rostral direction toward the neocortex,12 with each Braak stage correlating with advancing clinical characteristics of PD.14-16 Stages 1 and 2 correspond with the presence of early premotor symptoms; stages 3 and 4 with the symptomatic motor phase of PD, affecting the substantia nigra at stage 312; and stages 5 and 6 with cognitive decline.
While the Braak staging model of caudo-rostral progression of PD has been confirmed by several groups,16-20 it is also argued that progression of PD does not always comply with this pattern.16,19,21-23 Further, the localization of Lewy bodies and areas of neurodegeneration are not always coincidental,24 and Lewy body pathology is not observed in some genetic forms of PD that are clinically indistinguishable from sporadic PD.25-30 Additionally, the cognitive decline associated with PD has been noted in patients without Lewy body pathology, and Lewy body pathology is not always coincidental with cognitive decline.15,31 Thus, the relevance of Lewy bodies to the pathophysiology and many of the clinical symptoms of PD has not been fully defined.
Symptoms of PD
There are 3 cardinal motor signs of PD—rest tremor, bradykinesia/akinesia, and rigidity; postural instability, or imbalance, is sometimes considered the fourth cardinal motor feature, but it occurs late in the disease (Table 1).5,32 While the majority (70%-90%) of patients present with rest tremor,5,33 the most distinctive and disabling motor symptom of PD is often bradykinesia.5,32 However, patients with PD can exhibit a variety of motor and nonmotor symptoms (Table 1). Late-stage motor symptoms (eg, postural instability leading to falls) and nonmotor symptoms, including dementia and neuropsychiatric problems, emerge as PD progresses and are major causes of disability that do not respond to standard dopamine replacement therapy.34,35 Eventually, despite the fact that PD itself is not fatal, the disability associated with the late stages of PD often leads to fatal secondary complications, such as respiratory infections and cardiac disease.33,36,37 Indeed, mortality rates for those with PD are higher than those in various control populations.33,35-40
Table 1. Symptoms of Parkinson's Disease5,32,41-43
| Motor symptoms | Nonmotor symptoms |
|---|---|
Tremor at resta
|
Neuropsychiatric
|
PD, Parkinson's disease; REM, rapid eye movement. a Hallmark motor symptom of PD.
Current therapies for PD
Current treatment strategies (Figure 1) are primarily focused on the symptomatic management of PD. However, since robust symptomatic treatments for the disabling features of advanced disease (eg, dementia and imbalance) are not likely to become available in the foreseeable future, stopping or slowing disease progression by inhibiting the underlying mechanisms driving disease etiology or pathogenesis through the use of neuroprotective therapies beginning early in the disease process is a current goal in the management of PD.44,45
The gold standard in the treatment of PD remains levodopa in combination with a dopa decarboxylase inhibitor, such as carbidopa. However, despite treatment with this combination of drugs, PD continues to progress, and levodopa-related long-term adverse events emerge.46-50 Additional strategies include enhancing dopaminergic function through the use of dopamine receptor agonists (ie, ropinirole, pramipexole) and inhibition of dopamine metabolism with monoamine oxidase (MAO)-B inhibitors (ie, selegiline, rasagiline). Catechol-O-methyltransferase inhibitors (ie, entacapone, tolcapone) are used to prolong the levodopa peripheral half-life and thereby send more levodopa to the brain over a longer time (Figure 1).51,52 The antiviral medication amantadine, which may increase dopamine levels by enhancing release of dopamine,53-55 blocking dopamine reuptake,53,56,57 and increasing levels of the D2 dopamine receptor,57 is also used. All of these therapies have demonstrated efficacy in PD symptom management, and dopamine receptor agonists, MAO-B inhibitors, and amantadine can delay the need for levodopa therapy. Recent evidence indicating that several of these agents have promise as neuroprotective therapies will be reviewed in this module. The objective of this module is to provide healthcare professionals with current information regarding advances in the detection and diagnosis of PD, and to review clinical evidence supporting the possible neuroprotective effects of these therapies.
