Circadian and sleep disorders in Parkinson's disease

Abstract

Impaired sleep and alertness, initially recognized by James Parkinson in his famous monograph “An Essay on the Shaking Palsy” in 1817, is one of the most common and disabling nonmotor symptoms of Parkinson's disease (PD). It is only recently, however, that sleep disturbances in PD have received the attention of medical and research community. Dopamine, the major neurotransmitter implicated in the pathogenesis of PD, plays a pivotal role in the regulation of sleep and circadian homeostasis. Sleep dysfunction affects up to 90% of patients with PD, and may precede the onset of the disease by decades. Sleep dysfunction in PD may be categorized into disturbances of overnight sleep and daytime alertness. Etiology of impaired sleep and alertness in PD is multifactorial. Co-existent primary sleep disorders, medication side effects, overnight re-emergence of motor symptoms, and primary neurodegeneration itself, are main causes of sleep disruption and excessive daytime sleepiness among patients with PD. Increasing body of evidence suggests that the circadian system becomes dysregulated in PD, which may lead to poor sleep and alertness. Treatment options are limited and frequently associated with unwanted side effects. Further studies that will examine pathophysiology of sleep dysfunction in PD, and focus on novel treatment approaches are therefore very much needed. In this article we review the role of dopamine in regulation of sleep and alertness and discuss main sleep and circadian disturbances associated with PD.

Introduction

Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting about 300 per 100,000 people. Motor hallmarks of the disease are tremor, rigidity, bradykinesia, and impaired balance. Non-motor symptoms, such as depression, psychiatric disorders, impairment of the sleep–wake cycle, and autonomic dysfunction, are prominent causes of disability in the PD population. The characteristic pathologic finding in PD is degeneration of dopaminergic neurons in the substantia nigra with formation of Lewy bodies (Cardoso et al., 2005). It is estimated that motor cardinal symptoms of PD emerge once approximately 60% of nigral neurons have been lost and dopaminergic striatal content reduced by 80%. Degeneration of nigrostriatal dopaminergic neurons follows a distinct topographic pattern: loss of dopamine (DA) is greater in the rostral than caudal striatum, and the putamen is more severely affected than the caudate nucleus (Fahn et al., 1971). Among dopaminergic receptors, which are classified in into a D1-family (D1, D5 receptors) and a D2-family (D2, D3, D4 receptors), D1 and D2 receptors have a central role in the pathogenesis of PD. In addition to the substantia nigra, other brain areas are also affected in PD, including the locus ceruleus, dorsal motor nucleus of the vagus and the pedunculopontine nucleus (Jellinger, 2003). Degeneration of these regions likely begins prior to degeneration of the substantia nigra (Braak et al., 2003), and accounts for many of the non-motor features seen in PD. The non-motor features of PD have only recently been the target of therapeutic interventions (Wulff et al., 2010), although several studies suggest that non-motor symptoms of PD may have greater impact on the quality of life measures than motor symptoms (Aarsland et al., 2005, Karlsen et al., 1999, Shulman et al., 2001). Sleep dysfunction, initially recognized by James Parkinson in his famous monograph “An Essay on the Shaking Palsy,” is one of the most striking non-motor symptoms of PD. It is only recently that sleep disturbances in PD have received the attention of the medical and research community. In this manuscript we discuss the role of dopamine in the regulation of the sleep–wake cycle and circadian timekeeping as well as outline clinical implications of circadian and sleep dysfunction in PD.