Pathophysiology

The Parkinson's-Reversing Breakthrough

Is There A Cure for Parkinson Disease

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Sleep disorders related to PD are multifactorial, and the causation is complex and largely unknown. Degeneration of central sleep regulatory neurons either due to a direct or an indirect effect of dopaminergic cell loss in the brainstem and related thalamo-cortical pathways, is implicated (17,19,20). A preclinical pathological staging of PD has been proposed by Braak (21). It has been traditionally believed that the pathological process of degeneration of dopaminergic neurons starts in the sub-stantia nigra; however, Braak (21) proposed an alternative, as he has introduced the concept of a six-stage pathological process, beginning at clearly designated "induction sites." In Braak stage 1 of PD, there is degeneration of the olfactory bulb and the anterior olfactory nucleus, which may clinically manifest as olfactory dysfunction. Progression of the pathological process to the lower brainstem occurs in Braak stage 2, which are key areas mediating nonmotor symptoms such as olfaction, sleep home-ostasis, and other autonomic features. The brainstem areas, particularly the raphe nucleus (serotonin), locus ceruleus (norepinephrine), and pedunculopontine nucleus (PPN), play a major role in the sleep-wake cycle and mediate the so-called flip-flop switch that mediates thalamo-cortical arousal (22). The clinico-pathological correlations are becoming increasingly evident. There is strong evidence that symptoms such as olfactory dysfunction and sleep disturbances such as RBD or EDS may precede the development of motor symptoms in PD, thus correlating with Braak stages 1 and 2 (2,23-25).

Degeneration of brainstem nuclei, such as the locus ceruleus, raphe nuclei, and the PPN, plays a critical role in thalamo-cortical arousal and the sleep-wake cycle and leads to dysregulation of basic REM and non-REM sleep architecture (19,20,26,27). Clinically, the manifestations are insomnia, parasomnias, and EDS. The latter may be dependent on dysfunction of the flip-flop switch proposed by Saper et al. (22,28), suggesting that the brain can be either "off" [promoting sleep by activating the ventrolateral preoptic area (VLPO) thought to be a sleep-promoting center] or "on" [promoting wakefulness by activation of the tubero-mamillary nucleus (TMN), which is the wake-promoting area along with locus ceruleus and the raphe nuclei] (22). Regulators of the internal rhythm between the two switches are via the suprachiasmatic nucleus and also possibly, hypocretin 1 (orexin), a hypothalamic peptide (28,29). Hypocretin 1 is virtually undetectable in narcolepsy and may have a complex relationship with the dopaminergic systems in the basal ganglia (17). The hypocretin neurons, for instance, project to the dopaminergic neurons in the substantia nigra (17). Hypocretin-1 could function as an external regulator of the flip-flop switch promoting wakefulness, and dopaminergic dysfunction caused by neuronal degeneration can destabilize this switch and its regulators, promoting rapid transitions to sleep intruding on wakefulness. Although hypocretin-1 insufficiency has not been confirmed by studies of cere-brospinal fluid in three patients with PD and EDS associated with the use of dopamine agonists, one study reported low hypocretin-1 levels in the ventricular fluid of advanced PD patients (30,31).

Other nocturnal disabilities in PD arise from causes secondary to progression of disease, causing "destructuring of sleep" and motor complications generated by dopaminergic treatment (32). Examples of the latter include nocturnal akinesia, early morning dystonia, and EDS. The cause of restless legs syndrome (RLS) in PD is unknown. Sleep-disordered breathing is being increasingly recognized in PD and may reflect a combination of central and peripheral mechanisms (7,18).

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