Herein, we investigated fatigue and related demographic and clinical features of patients with PSP using the PFS, which is a specified scale for assessing fatigue. We also investigated the relationship between fatigue and other NMS, such as depression, cognition, sleep disturbance, QoL, and dysautonomic symptom in PSP patients with PFS. Our study showed that depression was the factor strongly associated with fatigue in patients with PSP. We divided the patients with fatigue into two groups (primary and secondary) based on the presence of depression, and thereby, we were able to minimize the confounding effects of depressive mood.
Our study revealed that fatigue is the common NMS in patients with PSP (38.8%), but the prevalence of fatigue was much lower than that reported in previous studies (from 82.9–100%.) [2, 5–8]. Chaithra et al. investigated the NMS in patients with PSP using NMSS and reported that sleep/fatigue was the most common NMS in these patients, with a prevalence of 82.9% . Ou et al. also investigated the NMS in patients with PSP using NMSS and reported that 100% of these patients (27/27) had sleep/fatigue symptoms . However, none of these five studies used the specialized scale for assessing fatigue. Four out of the five studies used sleep/fatigue domains of NMSS [2, 5–7] and the other study used a simple question to investigate fatigue . Although the sleep/fatigue domain of NMSS consists of questions about sleep and fatigue, it might not be sufficient to assess fatigue. Our result, which showed a much lower prevalence of fatigue in patients with PSP, supports this contention. Interestingly, there were no differences in the sleep/fatigue domain of NMSS between the primary and non-fatigue groups. Only the secondary fatigue group, in which patients had fatigue and depression simultaneously, showed a higher NMSS sleep/fatigue domain score than the primary and non-fatigue groups (Supplementary Table S1 online). Furthermore, fatigue in patients with PSP was not related to sleep quality (PDSS). These results suggest that the sleep/fatigue domain of NMSS might not be useful in precisely detecting fatigue alone in patients with PSP. Contrary to previous studies, we used PFS, which is a specialized scale for the assessment of fatigue. Given the complexity and difficulty in assessing fatigue, our study presents a more reliable result regarding the prevalence of fatigue in patients with PSP.
The pathophysiology of fatigue in neurological diseases, including PD, has not been well studied [3, 4]. In PD, fatigue is believed to be an intrinsic symptom rather than a secondary or reactive symptom, because it may precede the motor symptoms and did not correlate with disease duration or motor disability [4, 13]. Previous studies investigating fatigue in PD suggest that fatigue is not simply related to the striatal dopaminergic system but is also associated with the imbalance between different neurotransmitters. Studies on PD suggest that the serotonergic system may contribute to the development of fatigue; however, further investigation is needed to explain the pathophysiology [13, 14]. As with PD, the present study showed that fatigue in patients with PSP is not associated with disease duration and disease severity (PSPRS). Instead, fatigue in patients with PSP showed a positive correlation with NMSS. Furthermore, a previous study investigating prodromal symptoms of PSP showed that 10% of patients with PSP had fatigue before the diagnosis of PSP, similar to that observed in PD . These results suggest that fatigue in PSP might not only be related to the dopaminergic system but also to the non-dopaminergic system, as in PD. However, there is a paucity of evidence regarding fatigue in PSP; therefore, further studies are required to understand the pathophysiology of fatigue in PSP.
The logistic regression model of the present study showed that BDI was associated with fatigue, but not with age, disease duration, PSPRS, cognitive function and excessive daytime sleepiness. We applied the results and divided patients into primary and secondary fatigue groups, rather than just following the previous secondary fatigue concept for PD . Both the primary fatigue and secondary fatigue groups had worse QoL (PDQ-39 SI) than the non-fatigue group, despite the lack of differences in PSP-related symptoms (PSPRS). Our results suggest that primary and secondary fatigue can worsen the QoL of patients with PSP. Thus, improving fatigue can help to improve the QoL of patients with PSP. Unfortunately, fatigue in parkinsonism is poorly understood, and its treatment is limited . Several medications such as methylphenidate, dopaminergic medications, and antidepressants have been suggested for the treatment of PD-associated fatigue . Generally, patients with PSP exhibit a poor response to dopaminergic replacement therapy, and this therapy has a limited effect on these patients . Given that secondary fatigue patients with depression have worse QoL than non-fatigue patients, antidepressants would be worth trying. However, there is no consensus on the definition of primary and secondary fatigue in PSP. Skorvanek et al. suggested primary and secondary fatigue in patients with PD, but this has not yet been investigated in patients with PSP . We divided the patients with fatigue based on the results of logistic regression analysis, but further investigation is needed in patients with PSP.
Several scales have been introduced for the assessment of fatigue. The PFS is a specialized scale for measuring fatigue in PD patients . However, not all scales, including PFS, have been validated for patients with PSP. We believe that PFS is the most reliable scale for assessing fatigue in patients with PSP, considering the clinical similarity between PSP and PD. Moreover, several scales have been suggested as an assessment tool for PSP in patients with PD, although these scales have not been validated in PSP .
In conclusion, fatigue is a common NMS in patients with PSP and is correlated with other NMS and QoL in these patients. The pathophysiology and clinical impact of fatigue in patients with PSP are largely unknown. The first step in the treatment of fatigue is the identification of symptoms and investigation of the associated factors. In this aspect, the present study provides meaningful insight into fatigue in patients with PSP. Further studies are needed to reveal the pathophysiology of fatigue in patients with PSP and to develop novel treatment modalities.