CellSwarm-AD: A Multi-Scale Agent-Based Framework for Virtual Alzheimer's Disease Trials.

Parkinson’s disease (PD) is a neurodegenerative disorder pathologically characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the midbrain and the formation of Lewy bodies composed of α-synuclein (α-syn) []. In addition to the classical motor symptoms, sleep disorders and circadian rhythm disruption among the non-motor symptoms (NMS) are widely present in the prodromal stage of PD and significantly impair patients’ quality of life [,]. Contemporary conceptualizations of Parkinson’s disease have undergone a paradigm shift from a purely motor disorder to a systemic, multi-dimensional disease entity in which non-motor symptoms (NMS) constitute core diagnostic and prognostic dimensions rather than secondary manifestations. The evolving NMS spectrum—encompassing circadian rhythm disruption, rapid eye movement sleep behavior disorder (RBD), olfactory dysfunction, autonomic dysregulation, and neuropsychiatric features—often precedes the emergence of cardinal motor symptoms by years to decades, providing a critical window for early disease identification and neuroprotective intervention. The temporal sequence of prodromal NMS, anchored by isolated RBD as the strongest conversion predictor (>80% phenoconversion to α-synucleinopathy within 10–15 years), has been further refined by the integration of chronobiological biomarkers (blunted melatonin rhythmicity, attenuated circadian amplitude) and gut microbiota dysbiosis signatures, collectively informing a precision medicine framework for individualized risk stratification and chronotherapeutic management. Mammalian circadian rhythms are governed by the suprachiasmatic nucleus (SCN) of the hypothalamus as the master pacemaker, which maintains an oscillation period of approximately 24 h through a transcription–translation feedback loop (TTFL) composed of core clock genes including , , , and []. This system regulates a variety of physiological processes such as sleep–wake cycles, hormonal secretion, body temperature, metabolism, and immunity. Recent studies have revealed a bidirectional relationship between PD and CRD: on one hand, degeneration of the rhythm system accelerates the progression of PD pathology through mechanisms such as imbalanced dopamine biosynthesis, impaired α-syn clearance, oxidative stress, and neuroinflammation [,]; on the other hand, PD pathology itself disrupts the rhythm system by impairing the SCN and related neural pathways [,]. This review focuses on the bidirectional mechanisms and rhythm-targeted clinical diagnostic and therapeutic strategies. Whereas previous reviews have predominantly addressed the unidirectional impact of CRD on PD, this review synthesizes recent evidence supporting a bidirectional feedback-loop model linking CRD and PD and highlights emerging chronobiomarkers and chronotherapeutic strategies.