Problems with the body’s internal clock in Parkinson’s disease: causes, effects, and possible treatments

Parkinson’s Disease (PD) is a chronic and progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra, leading to motor symptoms that include bradykinesia, resting tremor, rigidity, and postural instability (Box 1). Nonmotor symptoms, including sleep disturbances, mood disorders, and cognitive decline, further complicate the disease’s clinical presentation¹. PD is estimated to affect over nine million people worldwide, and is the second most common neurodegenerative disease after Alzheimer’s disease (AD)². PD is an age-associated disorder and, as such, its prevalence is increasing significantly due to the overall ageing trends of the human population. Moreover, PD is a progressive disorder leading to increasing disability that requires exceptional efforts from caregivers and, therefore, has a tremendous socio-economic impact³. In 2017, in U.S. alone about one million individuals were diagnosed with PD for an estimated economic burden of $51.9 billion⁴.

In addition to the loss of dopaminergic neurons, another pathological hallmark of PD is the accumulation of Lewy bodies and Lewy neurites, neuronal cytoplasmic inclusions enriched in alpha-synuclein (aSyn), a protein of 140 amino acids that is abundant in the brain, and becomes insoluble for reasons we do not fully understand⁵.

Although most forms of PD are sporadic, the identification of genetic factors associated with PD has enabled significant progress in our understanding of the molecular mechanisms involved^6,7. Monogenic forms of PD, caused by a mutation in a single gene, account for only 3–5% of cases. However, a recent large-observational study involving over 12,000 patients, suggested that a genetic contribution—including both monogenic mutations and risk variants such as those in GBA1—can be identified in up to 15% of individuals with PD⁸. These findings underscore the relevance of genetic testing in clinical settings, which can support informed decisions for a variety of applications from diagnosis to prognosis of PD, and accordingly the development of targeted therapeutic approaches. The effect of mutations in PD-associated genes range from being “fully penetrant” (like SNCA triplications or missense variants causing monogenic PD forms), to conferring a “strong predisposition” to the disease (as SNCA duplications, or variants in LRRK2, VPS35, and CHCHD2), or to variants causing “medium predisposition”⁶. To date, over 200 PD-associated genes have been discovered which can interact with other risk factors such as ageing and environmental factors in the development of the pathology⁷. Among the environmental factors, exposure to pesticides such as paraquat or rotenone, or to metals such as iron and manganese, seem to considerably increase the incidence of PD, especially in those more directly exposed to these substances^9–12.

In understanding the pathogenesis of PD, extensive research has focused on the molecular mechanisms underlying neuronal death and dysfunction. Oxidative stress, mitochondrial dysfunction, and protein misfolding are central to the disease’s molecular pathology¹³. The accumulation of aSyn is hypothesized to contribute to neuronal dysfunction, toxicity, and cell death. These molecular insights have been instrumental in identifying potential therapeutic targets, though effective disease-modifying treatments remain elusive.

Emerging evidence suggests that the circadian clock, the body’s intrinsic timekeeping system, may play a critical role in the pathophysiology of PD. Circadian rhythms (CR), which regulate a wide array of physiological processes, including sleep-wake cycles, hormone release, and metabolic functions, are disrupted in PD patients^14,15. This disruption not only exacerbates the motor and nonmotor symptoms of PD but may also influence the progression of neurodegeneration. Understanding the link between circadian rhythms and PD could reveal therapeutic strategies that align treatment with the body’s natural rhythms, potentially improving outcomes and quality of life for patients.

The management of PD has traditionally focused on symptomatic relief through pharmacological and surgical interventions. Levodopa (Box 1) remains the gold-standard for the management of motor symptoms, while deep brain stimulation (DBS) is a surgical intervention that offers benefits for patients with advanced disease¹⁶. However, these treatments do not halt disease progression, and their effectiveness diminishes over time due to complications such as dyskinesias and motor fluctuations. As such, there is a pressing need for innovative approaches that not only alleviate symptoms but also modify the disease course, as well as identifying disease markers for early detection and monitoring.

One promising area of research is the exploration of CR in the management of PD. Given the pervasive influence of circadian clocks on biological functions, optimizing the timing of pharmacological interventions, physical therapy, and lifestyle modifications in accordance with circadian rhythms could enhance treatment efficacy and mitigate side effects. Chronotherapy, the alignment of treatment with the body’s natural rhythms, has shown potential in other chronic diseases such as hypertension¹⁷, asthma¹⁸ and could be a valuable strategy in PD management. Moreover, improving sleep and circadian function in PD patients may alleviate some of the nonmotor symptoms, such as depression and cognitive impairment¹⁹, thereby improving overall patient well-being.

In this review, we cover a wide range of potential medical-related applications of CR—spanning from its use as a biomarker, diagnostic or therapeutic approach while combining insights across cellular or animal models, and humans, with a particular focus on the PD field. By integrating such a broad range of aspects, we aimed to provide a deeper understanding of the connection between PD and CR abnormalities, offering insights that can guide future research and clinical applications, making this review a valuable resource for researchers and clinicians. We discuss the role of the circadian clock in PD, and whether disruptions in CR are merely a consequence of the disease or play a contributory role in its pathogenesis. Additionally, we provide a comprehensive literature summary for each key molecular mechanism associated with PD and connect them to the circadian clock. To avoid biases on our search, we used defined Medical Subject Headings (MeSH) terms and synonym keywords in the field of CR and PD, which allowed us to cover the entire literature and to summary and discuss here the relevant reports for our review. Finally, we will discuss the current state of PD management and the potential benefits of incorporating CR considerations into pharmacological and non-pharmacological therapeutic strategies. Understanding these intersections between time, molecular mechanisms of neurodegeneration, and therapy could pave the way for more personalized and effective treatment approaches for PD patients.

The circadian clock is an internal timekeeping system that orchestrates the daily rhythms of physiological processes in nearly all living organisms. In mammals, this clock is regulated by a central pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus, which is synchronized via environmental timing cues, known as “Zeitgebers”, the strongest being light for humans (see Box 2). The light is detected by a specialized set of neurons named intrinsically photosensitive retinal ganglion cells (ipRGCs) which are then transmitted to the SCN via the retinohypothalamic tract (see Box 2). The SCN, in turn, coordinates the body’s peripheral oscillators—found in virtually all tissues and cells—through intricate networks of neuronal and hormonal signals, ensuring synchronization of various physiological processes across the body²⁰. The circadian clock not only governs regulation of sleep-wake cycles, but also influences metabolism, hormone release, and even gene expression. Disruptions to this finely tuned system have been linked to various health disorders, including metabolic diseases, mood disorders, and neurodegenerative conditions like PD, underscoring the critical role of circadian rhythms in maintaining overall health²¹.

The core-clock TTFLs regulate further the circadian expression of clock-controlled genes (CCGs) by acting on E-boxes, D-boxes, RREs, or cAMP response elements (CREs). These CCGs govern a wide range of cellular functions, including cell cycle regulation, immune responses, and metabolism^25–27. It is estimated that between 20 and 50% of gene expression in mammals, including humans, exhibits circadian rhythmicity in at least one tissue, highlighting the pervasive influence of circadian clocks on physiological processes^28–30.

Disruption of the circadian system has been increasingly implicated in PD that may in part be explained with the degeneration in brain regions that regulate sleep and autonomic functions^31–35. Clinically, these brain changes may manifest with disrupted thermoregulation and abnormal blood pressure patterns^36,37. Postmortem studies revealed α-synuclein buildup and significant volume loss in the brainstem, particularly in the dorsal motor nucleus of the vagus, the region associated with gastrointestinal-autonomic regulation and the pontomesencephalic tegmentum, a region which consist of cholinergic, GABAergic, and glutamatergic neurons, found also linked to rapid eye movement sleep behavior disorder (RBD) symptoms^38–40. RBD causes abnormal behavior during the REM sleep stage and is recognized as a prodromal stage for PD⁴¹, affecting up to 80% of PD patients in later course of the disease⁴². In addition, atrophy of the SCN previously observed in histology experiments⁴³, which may explain the weakened body temperature and altered melatonin rhythms under the direct SCN control. Altogether, these underscore neurodegeneration in specific brain regions may contribute to the circadian alterations observed in PD patients. However, the precise role of circadian dysfunction in the onset and progression of these symptoms remains further to be elucidated.

In a retrospective observational clinical study involving 13 idiopathic PD (IPD) patients (Box 1) with H&Y stage I-III demonstrated the potential of actigraphy in clinical staging, showing that differences in activity patterns across PD stages could serve as biomarkers, pending validation in larger cohorts⁴⁹. Another study which analysed 7-day actigraphy data from 88 patients with idiopathic REM sleep behavior disorder (iRBD), alongside 44 non-RBD controls and 44 clinically diagnosed synucleinopathy patients, revealed significant disruptions in rest-activity patterns in iRBD patients⁵⁰. These disruptions included increased daytime napping, fragmented sleep, and lower overall physical activity levels⁵⁰. Monitoring these patterns could be crucial in predicting the progression of synucleinopathy, potentially facilitating earlier disease detection.

Furthermore, a study tracking 2930 men without a PD diagnosis at baseline over an 11-year follow-up period found that individuals at high risk for PD exhibited reduced amplitude, mesor and less robust sleep-wake cycles⁵¹. Stable rest-activity cycles have also been correlated with better cognitive performance, as demonstrated in a study of 35 PD patients⁵². Interestingly, these cognitive benefits were linked specifically to rest-activity stability, rather than sleep efficiency⁵², suggesting that endogenous circadian regulation, rather than homeostatic sleep regulation, plays a pivotal role in mediating cognitive abilities in PD.

Circadian disruptions in PD significantly impact hormonal secretion, including cortisol and melatonin, as well as core body temperature and blood pressure rhythms, all of which are directly regulated by the circadian clock^53,54. In a study involving 30 PD patients and 15 controls, plasma cortisol levels were found to be elevated in PD patients, whereas circulating melatonin was reduced despite no observable change in the phase of the rhythms⁵⁵. A recent systematic review investigating cortisol alterations in PD identified out of 21 studies assessed ten studies reported disrupted cortisol rhythms, with the majority (seven out of ten) indicating elevated cortisol levels⁵⁶. However, some studies failed to find significant changes or even observed opposite trends, highlighting the need for further research to validate these findings. Conversely, plasma melatonin levels have been shown to be significantly lower in PD patients compared to controls, as measured by radioimmunoassay in a study with 20 PD patients and 15 controls⁵⁷. Another study, which included PD patients undergoing medical treatment (N = 16), unmedicated patients (N = 13), and healthy controls (N = 27), revealed that medicated patients exhibited a longer phase angle of entrainment (see Box 2 for definition) indicating a larger time difference between phase of the circadian rhythm and the external cue, calculated by subtracting salivary dim light melatonin onset (DLMO) from habitual sleep onset⁵⁸. In addition, higher melatonin levels were observed compared to the non-medicated group⁵⁸. These findings suggest that alterations in melatonin rhythms could be influenced by dopaminergic treatments (Box 1).

While overall circadian patterns in core body temperature are generally preserved in PD, the mesor of core body temperature is lower in PD patients, particularly in those with co-existing depression^54,59. Additionally, more than 50% of PD patients exhibit abnormal blood pressure rhythms, including a phenomenon known as “reverse dipping”, where nighttime blood pressure is higher than daytime levels³⁴.

Recent advances in high-throughput sequencing and genomic analysis have significantly expanded our understanding of the molecular mechanisms underlying PD. In a genotyping study involving 1394 PD patients and 1342 controls, specific single nucleotide polymorphisms (SNPs) in circadian clock genes were found to be associated with distinct clinical manifestations of PD⁶⁰. For instance, the ARNTL rs900147 variant was significantly associated with tremor-dominant PD (see also Box 1), while the PER1 rs2225380 variant correlated with postural instability and gait difficulty-dominant PD (Box 1), suggesting that genetic variations in circadian clock genes may influence the clinical presentation of the disease.

Further supporting this notion, a study involving 646 PD patients and 352 controls identified the CLOCK gene rs1801260 polymorphism as being associated with a twofold increased risk of developing PD⁶¹. In the same population, the CLOCK-3111T/C variant was linked to motor fluctuations and sleep disorders⁶². These findings indicate that alterations in clock genes may impact mitochondrial bioenergetics, autophagy, and neuroendocrine function, thereby contributing to PD pathogenesis⁶³. For example, mutations in the parkin RBR E3 ubiquitin protein ligase (PRKN) gene have been correlated with the circadian regulation of mitochondrial function^64,65, while alterations in the antioxidative NAD-dependent deacetylase sirtuin-1 (SIRT1) gene have been shown to affect circadian rhythms and oxidative stress regulation, contributing to neurodegeneration⁶⁶.

In addition to polymorphisms, changes in clock gene expression profiles have been observed in PD patients. Decreased BMAL1, CLOCK, CRY1, PER1, and PER2 expression reported previously in the peripheral blood of PD patients (N = 326) compared to controls (N = 314)⁶⁷. Reduction in BMAL1 expression was further confirmed in whole-blood samples (N = 17 PD patients, N = 16 controls)⁶⁸ where a downregulation of BMAL2 was later reported in the same cohort⁶⁹ (Table 1). Additionally, Breen et al. documented disrupted circadian rhythms in PD patients, characterized by abolished BMAL1 rhythms and increased expression of PER2 and REV-ERBα (at 4 AM), in a group of 30 PD, and 15 controls⁵⁵. Interestingly, nocturnal BMAL1 expression was found to correlate with PD symptom severity, suggesting its potential as a predictive marker for disease progression⁶⁸.

Moreover, a recent study assessing peripheral clock-gene expression in hair samples from 17 PD patients undergoing dopaminergic therapy found that those who responded positively to evening bright light therapy (BLT) exhibited a phase shift in PER3 expression¹⁹ (see Box 2 for detailed definitions). This phase shift appeared to impede the restoration of circadian rhythms, potentially explaining improvements in sleep disturbances observed in these patients¹⁹. Our group has also contributed to this growing body of evidence by conducting a transcriptomics analysis of the circadian clock network, revealing weaker correlations in clock gene expression in PD patients (N = 205) compared to age- and sex-matched controls (N = 233), indicative of disrupted circadian regulatory mechanisms⁷⁰. Collectively, these findings underscore the significant impact of circadian disruptions in PD. Understanding these disruptions offers a promising avenue for developing targeted interventions aimed at restoring circadian function, ultimately enhancing the management of PD.

Ageing is a major factor for the development of PD, and is associated with a decline in the activity of the proteostasis network, possibly leading to increased aggregation and accumulation of aSyn, which is thought to impact on the function and viability of dopaminergic neurons⁷¹ (Box 1). However, it is still unclear whether such effects are due to a gain of toxic function due to aggregation, or due to a depletion of the normal function of aSyn, which is thought to be related to the trafficking and fusion of synaptic vesicles with the plasma membrane. Altered proteostasis is also responsible for synaptic dysfunction, which is thought to be an early event in PD⁷². The link between alterations in the circadian clock and loss of proteostasis has been suggested by the decreased expression of the clock genes CRY, NPAS2, and PER in a PD mouse model overexpressing human SNCA that shows age-related alterations in the hippocampal transcriptome⁷³. Another study reported decreased levels of the CLOCK protein in transgenic mice carrying a mutation in the LRRK2 gene, which is strongly implicated in familial and sporadic forms of PD⁷⁴. aSyn aggregation may also induce cell senescence, causing cell cycle arrest and triggering a powerful inflammatory response, thereby contributing to PD progression⁷⁵. In fact, altered levels of cellular senescence markers have been found in the SNc (Box 1) of postmortem human PD brain tissue⁷⁵. Consistently, senescent glial cells were shown to worsen the pathogenesis of PD by inducing chronic neuroinflammatory processes and by reducing aSyn clearance due to reduced autophagic activity⁷⁶.

Another major molecular alteration in PD is mitochondrial dysfunction, associated with selective dopaminergic neurodegeneration and ROS production (Fig. 1). In particular, inhibition of mitochondrial complex I by rotenone or MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), induces parkinsonism in humans and was shown to induce aSyn aggregation in various model systems⁷⁷. Mitochondria are major producers of reactive oxygen species (ROS) in the cell and, therefore, can stimulate inflammatory responses through the release of their constituents and metabolites into the cytosol or in the extracellular environment⁷⁸. The correlation between CR dysfunction and mitochondrial alterations has been demonstrated in fibroblasts from PD patients carrying Parkin mutations, which show an altered bioenergetic rhythmicity related to the deregulation of clock genes such as PER2⁶⁵. Moreover, in Drosophila models of PD, mutations in Parkin and in mitochondrial ligase (MUL1) affect CR of behavior and, in general, the molecular mechanism of the circadian clock⁷⁹ .

PD genetics has also provided important insight into the molecular underpinnings of the disease and have implicated pathways such as the ubiquitin proteasome system, autophagy, or vesicular transport^71,80. Genomic instability due to ageing, leads to nuclear DNA damage, and this has been described in several studies in PD^81,82. Moreover, DNA double- (DSBs) or single-strand breaks (SSBs) accumulate in the brains (and particularly in the midbrain) of patients with PD⁸³. Altered gene expression may also derive from a different epigenetic regulation which modifies gene expression without altering their sequence⁸⁴. The best-known epigenetic modification is DNA methylation, entailing the addition of a methyl group to a particular nucleotide (cytosine) in CpG islands. In PD, several laboratory studies have started to investigate the epigenetic landscape, but it is still unclear how this contributes to disease.

Other epigenetic modifications like those affecting chromatin remodeling (e.g., the different histone modifications)⁸⁵ or, at RNA level, those regulated by non-coding RNAs⁸⁶, or by epitranscriptomic modifications which affect translation by post-transcriptional chemical modifications of RNA molecules⁸⁷, may also play an important role in PD (Fig. 1). Among the latter, the most abundant modification is RNA-methylation at the N6-position of adenosine (m6A), which plays an important role in the epitranscriptomic regulation of pathways associated with PD, such as those related to motor function⁸⁸, or those related to regulating the death of dopaminergic neurons⁸⁹(Box 1). Interestingly, in PD brains, a significant reduction in the abundance of m6A-modified RNAs has been observed in three regions (frontal and cingulate gyrus cortices and hippocampus)⁹⁰ (Box 1). Some studies have investigated the correlation between clock genes and PD at the epigenetic level. Methylated promoters of the clock genes CRY and NPAS2 have been found in patients with PD⁹¹, and a high frequency of methylation in the CpG islands of circadian genes has been seen in patients with Dementia with Lewy bodies^92,93.

Additional studies will be necessary in order to determine the complex molecular mechanisms underlying PD, and to develop innovative and effective therapeutic strategies.

Exploring the impact of CR disruption in PD opens new avenues for therapeutic interventions ranging from pharmacological to non-pharmacological applications to restore circadian dynamics or using the clock profiles as biomarkers for disease monitoring and management. Animal models are indispensable for advancing our understanding of circadian disruptions in PD, particularly given the challenges associated with accessing brain tissue in human subjects. In Drosophila PD models, mutations in key genes like mitochondrial ubiquitin ligase 1 (mul1), that regulates mitochondrial integrity and fusion–fission processes, and parkin (park), which facilitates the ubiquitination of mitochondrial substrates, have been shown to prolong activity rhythms and alter core-clock machinery⁷⁹. Specifically, park1¹ mutants exhibited a phase delay of ~3 h in the rhythmic expression of per and tim genes, while the protein-level rhythmic activity of PER was completely abolished in both park1¹ and mul1^A6 mutants⁷⁹ (Table 1). Similarly, in rat models, disrupted circadian behaviors, physiological outputs, and altered circadian expression of Per2 have been observed^94,95.

In Bmal1 knockout mice injected with MPTP, a compound that selectively depletes dopaminergic neurons in the substantia nigra (Box 1), circadian dysregulation was associated with a significant reduction in dopaminergic neurons and transmitters, as well as altered inflammatory and antioxidative defense responses, as indicated by increased microglial and astrocyte activity⁹⁶. Another core-clock component, REV-ERBα influences energy metabolism and was found to protect against neuroinflammation in the MPTP-induced-mouse model of parkinsonism^97,98. Moreover, it inhibits the expression of the rate-limiting enzyme, tyrosine hydroxylase, required for dopamine biosynthesis thereby ensures circadian activity of dopaminergic neurons (Box 1) and regulates mood⁹⁹. In the 6-hydroxydopamine (6-OHDA) mouse model of parkinsonism, animals exhibited depression and anxiety symptoms, similar to human sundowning syndrome¹⁰⁰. Administering the Rev-Erbα antagonist SR8278 rescued these behaviors in a time-dependent manner, effective only at subjective dawn and not at dusk¹⁰⁰ suggesting that the restoration of circadian rhythms may help with neuropsychiatric symptoms in PD.

Currently we lack curative therapies for PD. Among the symptomatic treatment options, levodopa (L-3,4-Dioxyphenylalanine, L-DOPA), a precursor to dopamine, is the most widely used (Box 1)¹⁰¹. L-DOPA is used as a replacement for the reduced levels of dopamine in the brain, with the aim to counteract the bradykinetic symptoms that are typical of PD. It is used in combination with peripheral decarboxylase inhibitors such as carbidopa or benserazide, which prevent its premature metabolization to dopamine by the enzyme aromatic L-amino acid decarboxylase (AADC), before reaching the brain¹⁰². Interestingly, these dopaminergic treatments affect CR of PD patients by phasing forward, for example, the melatonin rhythm¹⁰³.

In humans, melatonin is one of the best studied compounds in the context of restoring circadian dynamics, which has been shown to enhance subjective sleep quality in PD and to exhibit antioxidative properties^104,105. A slight improvement in nocturnal sleep in PD patients taking 50 mg of melatonin (in comparison to 5 mg placebo) has been observed, though the improvement was short-term (roughly 10 min)¹⁰⁶. Medeiros and colleagues on the other hand observed improved subjective sleep quality in PD patients taking a much lower dose (3 mg/day) of melatonin for a month, despite no significant change was detected in polysomnography (PSG) results¹⁰⁷. Delgado-Lara et al. reported increased BMAL1 gene expression in PD patients who were administered 25 mg of melatonin for 3 months, particularly in the morning, suggesting the improvement in PD symptom management is linked to restoration of core-clock machinery¹⁰⁸. In a recent systematic review where seven randomized controlled trials were assessed, melatonin was suggested as a safe and well-tolerated compound for the management of insomnia in PD patients albeit there was no improvement in daytime sleepiness or RBD symptoms¹⁰⁹. Other evidence showed a positive improvement of motor and nonmotor PD symptoms (including sleep disorders) in PD patients following treatment with cannabis¹¹⁰. With the development of new pharmacological compounds, such as small-molecule modulators, a restoration of disrupted CR has been explored. For example, compounds that inhibit casein kinases led to period-lengthening effects in human osteosarcoma cells (U2OS) and mouse embryonic fibroblasts (MEFs)¹¹¹, proposed to be linked to neuroprotective actions of CKI-δ encoded by CSNK1D. CKI directly acts on core-clock post-translational modifications by phosphorylation of PER²³ pending to be validated further in vivo. Despite these exciting developments, the exact molecular mechanisms behind clock disruption and PD are yet to be further elucidated. Moreover, clinical studies that take individual circadian rhythms into account are scarce, and further research in this field is timely.

The number of clinical trials in this overlap has remained consistently scarce (N_{total publications} = 6) (Fig. 2). The persistent scarcity of clinical trials in circadian research is due to need for time-series data, rather than a snapshot at a certain time-of-day, making them more costly and complex to conduct in clinical settings. For assessment of CR peripheral markers (e.g., hormonal levels such as cortisol, melatonin or core body temperature) are widely used to estimate the SCN phase due to its inaccessibility in humans, though they require time-series collection for accuracy^113,114. DLMO assessment is considered as gold-standard in the field, but DLMO values still govern inherent variability, and the procedure requires an overnight clinical stay, making it impractical for routine use. Emerging methods include high-dimensional assessments (e.g., DNA/transcriptome/metabolome profiling) or from sampling of physiological and environmental variables. Actigraphy and wearable devices (e.g., FitBit watches, Oura ring) are widespread used in this context which allow continuous monitoring of CR outputs (e.g., body temperature, heart rate, activity), but they do not capture underlying circadian gene and protein expression changes. To overcome this, several circadian gene expression assessment methods have been developed in recent years by our group and others^115–118. Using a non-invasive approach TimeTeller^® has been used to characterize molecular clock profiles from saliva samples^115,119. In an ongoing non-interventional, observational study, we planned to recruit 70 PD patients and 20 controls, to characterize the circadian profiles and identify the changes between the groups¹²⁰. While in vitro diagnostic (IVD) methodologies like TimeTeller^® offer a non-invasive, at-home solution using saliva samples, there is still no widely accepted common molecular tool to model CR based on core-clock gene expression, which is essential for precision medicine. This gap is particularly crucial in PD, where there is a lack of definitive diagnostic criteria and underscores the need for the development of new biomarkers to enhance early detection, accurate diagnosis, and effective monitoring of disease progression. Exploring CR alterations in this link holds potential essential not only for developing disease biomarkers but also for improving symptom management, understanding disease heterogeneity, and monitoring disease progression.

To complement pharmacological applications, the potential benefits of various non-pharmacological interventions have been investigated. In this context, BLT, which acts on retinal inputs to the circadian system, demonstrated improvements in sleep quality, insomnia, daytime sleepiness, depression, and motor symptoms in PD patients^121–126. Moreover, this therapy also counteracts the negative effects of dopamine treatment on sleep by modulating circadian rhythms¹⁹. BLT is believed to work by improving monoaminergic function and inhibiting circadian melatonin secretion, following exposure of the retina to light^127–131. This treatment has recently received a major boost with the development of standardized and customized protocols based on the patient’s personal chronotype¹³². In an early, pilot randomized placebo-controlled double-blind study with 36 PD patients who received BLT (see Box 2) in the morning for two weeks (30 min per day, 7500 Lux for treated group, whereas 950 lux for placebo) significant improvements in tremor and depression symptoms were reported¹²⁹. In another pioneering study, 12 IPD patients with nonmotor symptoms received BLT before bedtime (between 1000 and 1500 Lux for 60–90 min) over 2 to 5 weeks period, resulting in improvements in sleep onset and fragmentation, mood, and motor symptoms specifically for bradykinesia (Box 3) and rigidity¹²⁴. In a follow-up retro-perspective open-label study 129 PD patients under dopaminergic treatment were analysed and improvements in sleep, mood and motor symptoms were confirmed under similar BLT conditions but only for compliant patients, emphasizing the importance of continued light exposure for sustained benefits¹²⁵. Another clinical trial examined 31 PD patients receiving dopaminergic treatment, comparing BLT to dim-red light therapy over two weeks (1 h of BLT with 10,000 lux or dim-red LT with less than 300 lux between 09:00–11:00 and 17:00-19:00)¹²². Patients exposed to BLT showed enhanced sleep quality metrics, including reduced sleep fragmentation and daytime sleepiness, highlighting BLT’s potential in managing PD-related sleep disturbances¹²². In a recent retrospective open-label longitudinal study investigating the long-term impact of BLT administered before bedtime (1 h per day at 3000–4000 Lux for a period of 2 to 5 years) in 140 PD patients, ongoing improvements in insomnia, sleep quality, and nocturnal movement were observed¹²¹. Further studies are needed though to optimize the timing, duration, and parameters of light therapy for effective management of PD.

Physical exercise, which is bidirectionally influenced by circadian rhythms, plays a critical role in PD. Regular exercise can significantly improve motor functions, alleviate symptoms such as rigidity and bradykinesia (Box 1), and improve the overall quality of life for PD patients¹³³. High-intensity exercise acts in this regard, with significant improvements on the sleep quality of PD patients¹³⁴. Furthermore, in combination with an overnight and morning fast, exercise in the morning may slow the progression of PD by acting in cooperation with circadian rhythms to counteract mitochondrial dysfunctions, implicated in the pathogenesis of the disease¹³⁵.

Research in both animal models and humans suggests there might be an optimal time to maximize exercise benefits¹³⁶. Circadian variations in core body temperature, hormone levels, and muscle function affect exercise performance throughout the day¹³⁷. In addition, circadian variation in gene expression also influences athletic performance^136,138. In our recent study, which analysed the circadian profiles of core-clock genes among 15 healthy, physically active participants who performed physical activities at different times of the day, we identified PER2 peak timing as a key predictor for the timing of exercise performance¹¹⁵. Despite these significant advancements determining the best exercise timing remains complex due to various factors impacting exercise outcomes, including the type, intensity, duration, and frequency of exercise, impact on underlying metabolic circuits and specific symptoms being targeted^139,140. Underlying circadian disruptions unique to PD patients might further influence these outcomes. Activity trackers offer valuable insights in this context for the monitoring. A previous study highlighted that the step count is particularly useful to accurately assess daily variations in physical activity for PD patients after two days of data collection and can be used to optimize exercise prescriptions¹⁴¹. Moreover, a recent exploratory study using a hip-worn accelerometer found that individuals with PD who experience pain are notably less active (<4200 steps per day), depicting reduced activity levels especially in the morning hours¹⁴². Understanding such variations in CR may be used to personalize exercise schedules to maximize benefits for PD patients.

Neurodegenerative disorders, including PD, constitute a significant and growing challenge in our ageing global population. As we deepen our understanding of the molecular mechanisms underlying PD, it becomes increasingly clear that the circadian clock plays a pivotal role in the disease’s pathophysiology. Circadian disruptions not only exacerbate motor and nonmotor symptoms but also potentially accelerate disease progression by influencing key cellular processes such as mitochondrial function, oxidative stress, and neuroinflammation. Sleep problems (e.g., REM sleep behavior disorder), altered hormonal secretion, and disrupted core body temperature rhythms, emerge years before motor symptoms, as we also discussed in this review and could be used for the development of markers for this prodromal stage. Molecular evidence also strongly links circadian clock dysfunction to neurodegeneration, particularly through disruptions in core-clock genes (e.g., BMAL1 and PER2), and clock-controlled genes, which play critical roles in cellular homeostasis, mitochondrial function, and neuroinflammation. Furthermore, interventions to revert circadian changes, including BLT or melatonin supplements, have shown promising benefits in improving both motor and nonmotor symptoms. Thus, if circadian disruption were purely a consequence of PD, the observed benefits of circadian-based interventions would be less likely, suggesting a bidirectional relationship where circadian dysfunction may, in addition, accelerate disease onset and or progression, as well as symptoms. This review has highlighted the relevance of CR in PD, suggesting that time-of-day factors should be considered in both the research and clinical management of this condition.

Current PD management strategies primarily focus on symptomatic relief through pharmacological and surgical interventions. However, these approaches often overlook the importance of circadian alignment, which could offer a complementary avenue for improving treatment outcomes. Incorporating circadian-based therapies, such as timed light exposure, exercise, and meal timing, into treatment plans may enhance the efficacy of existing interventions, reduce side effects, and improve the overall quality of life of PD patients.

Looking forward, further research is needed to elucidate the exact mechanisms by which circadian disruptions contribute to PD and to develop personalized chronotherapeutic strategies. Future large-scale clinical trials should investigate the timing of drug administration and other pharmacological or non-pharmacological interventions to align with the individual circadian profiles of PD patients. Additionally, the exploration of biomarkers related to circadian rhythms could lead to earlier diagnosis and more precise monitoring of disease progression.

Hence, recognizing and integrating the circadian dimension in PD research and management holds great promise for advancing our understanding of the disease and enhancing the well-being of those affected. As we continue to explore this frontier, it is crucial to foster interdisciplinary collaborations that bridge the gap between chronobiology and neurology, ultimately paving the way for innovative treatments and improved patient care.