Targeting sleep and the circadian system as a novel treatment strategy for Parkinson’s disease

Abstract

There is a growing appreciation of the wide range of sleep–wake disturbances that occur frequently in Parkinson’s disease. These are known to be associated with a range of motor and non-motor symptoms and significantly impact not only on the quality of life of the patient, but also on their bed partner. The underlying causes for fragmented sleep and daytime somnolence are no doubt multifactorial but there is clear evidence for circadian disruption in Parkinson’s disease. This appears to be occurring not only as a result of the neuropathological changes that occur across a distributed neural network, but even down to the cellular level. Such observations indicate that circadian changes may in fact be a driver of neurodegeneration, as well as a cause for some of the sleep–wake symptoms observed in Parkinson’s disease. Thus, efforts are now required to evaluate approaches including the prescription of precision medicine to modulate photoreceptor activation ratios that reflect daylight inputs to the circadian pacemaker, the use of small molecules to target clock genes, the manipulation of orexin pathways that could help restore the circadian system, to offer novel symptomatic and novel disease modifying strategies.

Efficacy of biologically-directed daylight therapy on sleep and circadian rhythm in Parkinson's disease: a randomised, double-blind, parallel-group, active-controlled, phase 2 clinical trial

“…To be most effective any light therapy must utilise spectra that target the pathological sites within the retina and circadian pathways. 18 Evidence-based anatomical and functional studies demonstrate that photosensitive melanopsin retinal ganglion cells in the eye undergo degeneration in PD, thereby contributing to circadian disruption and clinical symptoms. 19 , 20 Importantly, melanopsin cells together with rods and cone photoreceptors are responsible for relaying the ambient light information to the central clock via the retinohypothalamic tract to synchronise the circadian rhythm and modulate the sleep–wake cycle.…”