Parkinson’s disease (PD) represents a progressive neurodegenerative disorder associated with a spectrum of motor and non-motor symptoms (Bloem et al., 2021). Therein, apathy is one of the most common neuropsychiatric disturbances in PD, with a prevalence of nearly 40% (den Brok et al., 2015). It can be defined as a syndrome of primary motivational loss, which cannot be attributed to emotional distress, cognitive impairment, or diminished level of consciousness (Marin, 1991). Increasing studies have shown that apathy may be a sign of PD worsening as the disease progresses (den Brok et al., 2015; Pagonabarraga et al., 2015). Apathy can be a predictor of dementia and cognitive decline over time in PD (Dujardin et al., 2009), and it is associated with more severe motor symptoms (Liu et al., 2017), lower health-related quality of life (Skorvanek et al., 2013), and heavier caregiver burden (Leroi et al., 2012; Skorvanek et al., 2013; Eglit et al., 2021).

Abnormal iron metabolism might not only contribute to the pathogenesis of PD (Dexter et al., 1989; Riederer et al., 1989; Ward et al., 2014), but also be involved in apathy (Wang et al., 2016). Neuropathological studies have shown the accumulation of iron in the substantia nigra (SN) of patients with PD, and the iron concentrations in the region increase with disease severity (Dexter et al., 1989; Riederer et al., 1989). High concentrations of iron detected in brain could induce neurotoxicity, leading to the death of dopaminergic neurons (Ward et al., 2014). Many studies have indicated that the disturbance of iron metabolism plays a crucial role in non-motor symptoms in PD, including sleep disorder (Hu et al., 2015), restless legs syndrome (Li et al., 2019), depression and anxiety (Xu et al., 2018). However, only a few studies have focused on the relationship between iron metabolism and apathy in PD. A 2016 study found that iron levels in the cerebrospinal fluid (CSF) of patients with PD were positively correlated with the Apathy Scale (AS) scores, and iron overload may be involved in apathy in PD via oxidative stress (Wang et al., 2016). Therefore, there is an urgent call for similar studies with larger sample sizes to explore the clinical significance of iron in apathy in PD.

Although awareness of the prevalence of apathy and its effect on clinical outcomes for patients have increased recently, the nature of apathy and the subjectivity of this neuropsychiatric symptom make the accurate diagnosis difficult (Pagonabarraga et al., 2015). Therefore, we aim to determine the features of apathy and its association with iron metabolism in the Chinese PD population, and construct a simple and useful nomogram to predict the occurrence of apathy in PD.

Apathy was common in our Chinese cohort, which is associated with more severe motor and non-motor symptoms. To the best of our knowledge, lower serum TRF levels and TIBC were observed in apathetic patients with PD for the first time, and both were negatively associated with AS scores in male patients with PD. Therefore, the disturbance of iron metabolism may contribute to apathy in PD, especially among male patients. More importantly, we developed an objective and practical nomogram to assist clinicians in screening apathetic patients with PD.

About 49.25% of the 201 patients were apathetic in our study, which is similar to the findings of a Chinese study on 145 patients assessed by AS (Wang et al., 2016). The subjective motor experiences of daily living in apathetic patients were impaired, implying that these patients exhibit a more severe neurodegenerative pattern progression (den Brok et al., 2015; Pagonabarraga et al., 2015). Also, dopamine ascending pathways were reported to play critical roles in the pathophysiology of apathy in PD (Levy and Czernecki, 2006).

We also found that apathy in PD was related to worse cognitive function, which is consistent with previous studies (Liu et al., 2017; Brown et al., 2019). Neuroimaging studies have demonstrated that cognitive decline in apathetic patients with PD is strongly linked with significant gray and white matter loss in the frontal lobe areas and the insular region (Alzahrani et al., 2016). In addition, apathetic patients with PD had more severe depression and anxiety, worse sleep quality and more severe autonomic dysfunction than non-apathetic patients. These aspects may probably account for the poorer quality of life experienced by apathetic compared to non-apathetic patients, as previously reported (Skorvanek et al., 2013).

As far as we known, the difference in serum TRF concentration or TIBC between PD participants with and without apathy has not been reported yet. TRF is a glycoprotein that circulates iron in a soluble, non-toxic form and delivers it to other body tissues (Gkouvatsos et al., 2012), including the brain (Moos et al., 2007). Another biomarker, TIBC, is regarded as a parameter to evaluate the maximal capacity of serum to transport iron, which is proportional to the concentration of TRF in serum (Kasvosve and Delanghe, 2002). Due to the decreased TRF concentration, a lack of iron load to transferrin may allow non-transferrin-bound iron enters the pool of labile iron (Ashraf et al., 2020), leading to enhanced harmful lipid peroxide production. It was considered one of the reasons contributing to the death of dopaminergic neurons in PD (Ma et al., 2021). Furthermore, similar research has also revealed that iron level in the CSF is significantly higher and positively correlated with·OH level in apathetic patients with PD. The authors also speculated excessive iron may be involved in apathy via oxidative stress (Wang et al., 2016). However, the association between central and peripheral iron in PD has not been fully elucidated (Costa-Mallen et al., 2017; Ashraf et al., 2020). Costa-Mallen et al. (2017) found decreased iron in circulation in favor of iron accumulation in the substantia nigra pars compacta (SNpc). In this investigation, levels of TRF and TIBC were significantly lower in apathetic patients than that in non-apathetic patients, based on which, we speculated that the decrease in serum TRF level in apathetic patients may result from the accumulation of iron in the brain, suggesting that disrupted iron metabolism may be involved in apathy in PD.

In male patients with PD, further analyses indicated that AS scores increased with decreased TRF concentration or TIBC. Recently, there has been increased interest in sex-related differences in PD or brain iron metabolism. An imaging study conducted on healthy individuals showed a selective lower total subcortical brain iron levels in middle-aged women compared to men and young women (Persson et al., 2015). Previous studies have also demonstrated the regulatory role of estrogen in brain iron metabolism (Sohrabji, 2007; Grubić Kezele and Ćurko-Cofek, 2020). Tzu-Yun et al. found that estradiol via different estrogen receptors could diminish the iron overload-induced autophagy and injury in female and male mice, respectively (Chen et al., 2019). Furthermore, the results by Wang and colleagues suggested that the striatum of male mice was more sensitive to iron accumulation than that of female mice. This trend was similar to those previously observed in clinical studies, which showed that men have a much higher risk of developing PD than women (Grubić Kezele and Ćurko-Cofek, 2020), and they are more likely to be apathetic (Pagonabarraga et al., 2015). Sex-associated differences are common among patients with PD, and we believe that this would be valuable for a future study.

The other particular strength of our study is that we developed a novel practical model to identify patients with PD who had a high risk of apathy. Based on standard deviation along the nomogram, both TIBC concentration and HAMD scores were important predictors, while age, sex and SI concentration do not appear to play a role in predicting apathy in this model. Our findings revealed that patients with a lower TIBC level were at a higher risk of apathy. Meanwhile, a trend towards decreased serum iron was found in apathetic patients although this difference did not reach statistical significance. Lower serum iron may also be linked with apathy. Patients with iron deficiency anemia could present with apathy (Bourre, 2006). And a study on psychiatric patients also found that oral iron treatment could bring about a reduction in apathy and the likelihood of resorting to psychiatric admission (Kassir, 2017). TRF delivers iron to the brain from the blood by binding to TRF receptors at the blood–brain barrier (Ma et al., 2021). As discussed previously, the relationship between peripheral and central iron in PD is still unclear and some points of view are contradictory. A previous study showed that lower serum iron in patients with PD may result from progressive iron deposition in the SNpc (Costa-Mallen et al., 2017). Therefore, we speculated that lower TIBC and the trend towards decreased serum iron in apathetic patients might provide indirect evidence for brain iron overload. And the specific mechanism may involve the regulation of TRF receptors expression on the cells of the blood–brain barrier (Ma et al., 2021). However, both iron deficiency in peripheral and central systems were simultaneously observed in patients with PD by Piao et al. (2017). In summary, the disturbance of iron metabolism is definitively involved in the pathogenesis of PD, and may also play a role in apathy although further investigation is required.

In addition to TIBC level, patients with severe depression were also more likely to be apathetic, which is consistent with the study from Brown et al. (2019). A 4-year prospective cohort study demonstrated that a high Hamilton Depression Rating Scale (HDRS) score was a predictor of apathy in PD (Ou et al., 2020), which may result from shared pathophysiological mechanisms. Maillet et al. found that the serotonergic alteration within the bilateral ventral striatum and the right caudate nucleus may play a role in apathy as well as depression (Maillet et al., 2016). Moreover, it is worth noting that we did not confuse apathy with depression, although there is a large overlap between apathy and depression (Pagonabarraga et al., 2015). The results from the nomogram should be viewed with caution, that means when patients with PD have both depression and iron metabolism abnormality, clinicians need to be alert to the possibility of apathy.

Since apathy is frequently associated with greater cognitive decline, more severe motor symptoms and heavier caregiver burden (Pagonabarraga et al., 2015), it is a need for earlier intervention. But there is no standard treatment for apathy. Acetylcholinesterase inhibitors and dopamine agonists were reported to improve apathy in PD (Seppi et al., 2019). Based on our study, we believed that maintaining iron homeostasis could be a potential therapeutic target for apathy in PD. Notably, the results should be interpreted with caution and there is much work needed to be carried out.

Several limitations of our study should be acknowledged. Firstly, this is a single-center study evaluating Chinese patients, which needs multicenter clinical datasets to perform the external validation of the nomogram. Secondly, further longitudinal studies are warranted to determine predictors of apathy. Thirdly, cognitive function of each participant was evaluated only by CM-MMSE, and more cognitive tests such as the Montreal Cognitive Assessment should be used in future studies. Finally, the analysis presented here has not incorporated radiological findings of patients, which will help to further explore the neural structures and levels of iron in the brain related to apathetic patients with PD.

In summary, apathy in PD is related to more severe motor and non-motor impairment. Lower serum TRF concentration and TIBC were first reported in apathetic patients with PD, and both were negatively associated with AS scores in male patients with PD. These findings suggest that abnormal iron metabolism may serve as an underlying mechanism of apathy in PD. TIBC level in combination with HAMD scores could be effectively used for the prediction of apathy in PD.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by the Medical Ethics Committee of Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology. The patients/participants provided their written informed consent to participate in this study.

ZX, Y-jX, and J-tL contributed to study design. J-tL, YQ, H-lG, J-yL, Q-xQ, D-lW, and J-wZ contributed to data acquisition. J-tL, Z-jM, ZM, Y-jX, and ZX analyzed and extracted the data. J-tL, YQ, H-lG, Y-jX, and ZX wrote the manuscript. All authors contributed to the article and approved the submitted version.

This work was supported by the National Natural Science Foundation of China (grant number 81771376).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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