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Parkinson's disease (PD) is a relentlessly progressive disorder. The symptoms are usually mild at onset, most frequently a resting tremor of a hand, but worsen steadily over years to cause severe disability in most cases. Indeed, much evidence suggests that the onset of the neurodegenerative process precedes the appearance of clinical symptoms by as much as a decade, and that the neurodegenerative process is well established by the time the disease is clinically apparent.
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The motor deficits—tremor, rigidity, bradykinesia, and gait impairment—are the most obvious features of the disorder, and have been mainly attributed to the progressive loss of dopaminergic neurons in the substantia nigra (SN). Consequently, the focus of PD therapy has been on the replacement of dopamine. This approach has, in some respects, been remarkably effective and has led to treatments, which can substantially improve both the duration and quality of life of patients affected by PD. Ultimately, however, the success of this approach is limited by the development of motor complications that are difficult to control with currently available treatments (see Chapter 16). In addition, patients develop a variety of nonmotor symptoms, including anosmia, sleep disorders, autonomic impairment, and cognitive impairment (see Chapter 14). These nonmotor symptoms are refractory to most current treatments, and frequently become the most significant source of disability.
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Recent pathological studies have revealed a spectrum of degeneration that corresponds with this broader range of symptomatology. Dopaminergic degeneration is only a part of a much broader process of PD-related neurodegeneration that may begin with pathology in the brainstem and then progress beyond the SN to cortical and subcortical regions (see Chapter 20).1 Given the complexity of these late-stage complications and the widespread neurodegenerative changes that underlie them, it is unlikely that it will be possible to control all of these symptoms with pharmacological replacement therapies and preventative strategies are required.
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It is important to recognize that the long, slow course of neurologic impairment in PD offers an important opportunity: if treatments that delay or prevent the neurodegenerative process are developed, they could be employed at an early stage of the disease to prevent the severely debilitating complications of advanced PD. Such a therapy, although not a cure, could convert PD into a disorder that is readily treatable and not a source of long-term disability. Indeed, it is likely technologies that can detect the disease process before the onset of visible symptoms will become practical in the near future. The main barrier to progress against PD is the lack of a meaningful neuroprotective treatment that can be applied after the disease is identified.
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A Definition of Neuroprotection
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In this chapter, we define “neuroprotective” therapies as those that slow or prevent further neurodegeneration of cell populations, both dopaminergic and nondopaminergic, which are affected in PD. This is a mechanistic definition, which focuses on the fundamental processes of brain degeneration in PD. It ...