In the present study, fatigue problems were found in more than half of the PD patients (59.46 %) in northeastern China, which is consistent with previous reports [
3,
22‐
24]. Moreover, fatigue appeared to be related with prolonged disease duration, increased disease severity, enhanced depressive symptoms, serious sleep disturbance, and the development of motor symptoms, except tremors. A univariate logistic regression analysis demonstrated that fatigue was significantly associated with several clinical characteristics of PD patients. Among the variables examined, only sleep disturbance was identified as an independent risk factor for fatigue. In addition, fatigue remission was found in 43.04 % of fatigued patients taking dopaminergic drugs. The development of DDNRF was associated with an older age and depressive symptoms, and depression severity was an independent risk factor for dopaminergic drug non-responsive fatigue. Our findings provide basic evidence for understanding the clinical significance of the non-motor symptom of fatigue in PD.
Sleep disturbance is an independent risk factor for fatigue in PD patients
Sleep is necessary for the maintenance of mammalian homeostasis. Additionally, sleep is one of the most crucial determinants of fatigue severity [
25]. In the general population, high-quality sleep is associated with less fatigue [
26,
27]. Sleep disturbance has been associated with fatigue in several disorders, including cancer [
28], multiple sclerosis [
29] and traumatic brain injury [
30]. In addition, it was reported that dissatisfaction with sleep, and not sleep itself, was associated with fatigue in psychotic patients [
31].
Although the mechanisms of sleep abnormalities and fatigue have not yet been clarified, increased inflammatory cytokine release has been associated with poor sleep conditions and fatigue [
32]. Specifically, the production of interleukin (IL)-1β and tumor necrosis factor (TNF)-α promotes non-rapid eye movement sleep (NREMS) under physiological and inflammatory conditions. Disturbed NREMS is associated with abnormal cyclic alternating pattern (CAP) rates and electroencephalogram arousals, and it is correlated with fatigue and sleepiness [
33]. IL-1β and TNF-α alter neuronal excitability and induce symptoms associated with sleep loss by binding to their neural receptors, which subsequently regulate neurotransmitters or neuromodulators [
34]. Moreover, the neurotransmitter serotonin governs sleep-wake behavior [
35], and a reduction of serotonin transporters was found in subjects with fatigue syndrome [
36]. These findings suggest that serotoninergic functions may play pivotal roles in controlling sleep and fatigue.
Fatigue, sleep disturbance and depression are the primary neuropsychiatric manifestations of PD, and they are related to patient quality of life [
37,
38]. In this study, a logistic regression analysis revealed that sleep disturbance is the only independent factor for fatigue in PD patients, which is in accordance with the findings of a previous study [
6]. Emerging lines of evidence indicate that sleep disorder treatment is effective for improving fatigue in patients with multiple sclerosis [
39,
40]. Similarly, the management of sleep loss may provide a valuable approach for improving fatigue in PD patients. It has been proposed that fatigue stems at least in part from disturbed cytokine production in diseases such as PD [
41]. Indeed, elevated secretion of IL-1β and TNF-α have been detected in the cerebrospinal fluid (CSF) of PD patients with sleep problems [
42]. The circulating level of IL-1β is also increased in PD patients with fatigue [
43]. Pavese et al. indicated that in addition to increased inflammatory cytokine production, fatigue in PD patients might result from serotonergic (5-hydroxytryptamine, 5-HT) dysfunction in the basal ganglia and limbic circuitry [
44]. Considering the crucial roles that cytokine release and serotonergic functioning play in regulating sleep and fatigue, we hypothesize that sleep disturbance and fatigue may share a similar mechanism in the pathogenesis of PD, with abnormal cytokine release and serotonergic dysfunction being the primary components of this mechanism. Future studies should explore the molecular mechanisms involved in this process.
Dopamine imbalance is associated with fatigue in PD patients
Another important finding of the current study was that dopaminergic medication improved fatigue in 43.04 % of PD patients with fatigue problems, whereas more than half of the fatigued patients were not responsive to dopaminergic medication. This result is consistent with ELLDOPA study [
45], which showed that levodopa/carbidopa is effective in reducing the progression of fatigue in drug naïve PD patients [
12]. Moreover, the study of ADAGIO [
46] also showed that rasagiline was associated with significantly less progression of fatigue compared with placebo over a 9-month period in drug naïve patients with PD [
47]. Both carbidopa/levodopa and rasagiline are dopaminergic drugs, which increase the extracellular levels of dopamine. Thus, we infer dopamine dysfunction may involve in the pathogenesis of fatigue in PD. The effects we observed might be due to enhanced dopaminergic neurotransmission, indicating the therapeutic value of dopaminergic treatment for fatigue relief in PD. However, according to the univariate logistic regression and correlation analysis performed in our study, there are no significant associations among fatigue, fatigue severity, remission rate, and dopaminergic medication dosage because a no dose-effect correlation was detected between levodopa and fatigue. Hence, levodopa may play a role in the mechanism underlying the development of fatigue, which is consistent with other current results. The dopamine imbalance hypothesis of fatigue was recently presented in multiple sclerosis and other neurological disorders [
48]. Thus, restoring dopamine levels in the CNS by means of dopaminergic medication, such as levodopa, might be an essential strategy for the treatment of fatigue in PD.
Depression is an independent risk factor for dopaminergic drug non-responsive fatigue
Depression is another prominent non-motor symptom in PD [
49]. Fatigue in PD is often associated with depression, using a logistic regression model, we further demonstrated that depression was the only independent factor for the efficacy of dopaminergic medication in treating fatigue in PD patients, which might imply crosstalk between depression, fatigue and dopamine insufficiency.
Pavese et al. found that compared with patients without fatigue, PD patients with fatigue showed greatly reduced serotonin transporter binding in the basal ganglia and limbic circuitry, as well as a significant reduction in dopamine uptake in the caudate and insula [
44]. These results demonstrate that even though a dysfunctional serotonergic pathway plays a predominant role in fatigue, reduced dopaminergic functioning also contributes to the incidence of fatigue [
44]. Hence, both dopaminergic and serotonergic pathways contribute to fatigue in PD patients. Interestingly, other studies have indicated that excessive 5-HT also induced fatigue. Indeed, increased 5-HT and decreased dopamine concentrations were detected in the brain in a rat model of exercise-induced fatigue [
50]. These findings imply that the level of 5-HT may not be a determinant, and maintaining the balance between serotonergic and dopaminergic function is key for fatigue relief. Hence, dopamine administration may improve fatigue only in PD patients who have a functional serotonergic system with normal 5-HT concentrations and receptor functioning, which is consistent with our results. In other words, functional serotonergic pathway is necessary for dopamine to alleviate fatigue. Therefore, both 5-HT and dopamine should be considered during the treatment of PD fatigue. For instance, in the early stage of PD, a supplement of only 5-HT without levodopa medication may be insufficient for relieving fatigue, as levodopa is usually not prescribed early in PD due to the absence of obvious motor symptoms. Similarly, when fatigue is present with no obvious depression, a combined administration of levodopa with 5-HT, but not levodopa alone, may provide greater relief from fatigue. Thus, we hypothesize that dopaminergic medication is required, but not sufficient, for fatigue suppression in fatigued PD patients with moderate depression, and such treatment can restore serotonergic neurotransmission and serve as a combination therapy. This may offer an ideal strategy for the treatment of fatigue in PD patients.