This study comprehensively explored the independent risk factors, including demographic and clinical characteristics and relevant PD-associated MSD evaluations for the first time. Univariate analysis demonstrated that the MSD phenotype was associated with a lower educational level and a greater amount of manual labor, and a monolingual speaking background. These findings were partially in accordance with those of similar studies that focused mainly on the demographic characteristics and relevant evaluations in other types of SD [22–25]. Moreover, multivariate logistic regression analysis revealed a lower educational level as an independent risk factor for PD-associated MSD. Several studies on the neural mechanisms underlying motor speech control [15, 16, 26, 27] have hypothesized that a higher educational level might play a negative role in the occurrence and aggravation of PD-associated MSD. Previous MRI examinations have shown that lesions in cognitive-relevant cortical areas, especially those closely associated with educational level within the prefrontal lobe, frequently occur in SD patients [28–30]. Given that educational level is usually positively associated with high-level cognitive function, this finding might partially explain why there were more PD patients with low educational levels in the MSD group in the present study [31–34].
Additionally, both univariate and multivariate logistic regression analyses revealed a higher occurrence of frontal lesions in the MSD group, indicating that frontal lesions are another important independent risk factor for PD-associated MSD. This is could also explain our speculation that PD patients in the MSD group were more prone to cognitive impairment since frontal lesions have been reported as a risk factor for the development of cognitive dysfunction [35–38]. Additionally, the higher occurrence of frontal lesions in the MSD group might also be attributed to a lack of sufficient plastic repair in some cortical areas following PD, especially in the frontal lobe, a well-known key area for central modulation during speech motor processing. On the other hand,secondary damage remote from the basal ganglia, an indispensible fiber pathway and subcortical interconnecting structure, could occur in the frontal lobe [39–41]. Therefore, future prospective clinical and neuroimaging studies are necessary to confirm these relationships and provide new insights into the neuroplastic repair in cortical areas.
Previous studies have systematically explored the relationship between MSD and cardinal motor symptoms. Moustafa et al. found that motor symptoms such as gait disturbance share similar clinical profiles and neural bases with MSD [42]. Majdinasab et al. found that tremor was the only aspect of motor symptoms that influenced MSD among PD patients [43]. However, in the present study, the UPDRS motor sum, tremor, and PIGD score were all ruled out following the univariate analysis. The difference between our study and that of Majdinasab et al. might be in the different disease stages. Patients in the previous study were predominantly in the early stage of PD, when motor symptoms are common, while our patients were in more progressive stages of PD. Additionally, both MSD and other motor symptoms are partly under the modulation of the extrapyramidal system, which causes similar neuropathological changes.
In the present study, univariate analysis showed that the NMM burden was slightly greater in the MSD group than in the non-MSD group, which was consistent with our speculation that MSD and NMM share similar neuropathological mechanisms. We found that the MSD group had a higher NMMSS domain 5 score (attention/memory) than the non-MSD group. Cognitive function impairment, including attention, memory, and executive functions, are common in PD patients; therefore, the cause and effect relationship between cognitive impairment and MSD requires in-depth examination. In terms of neural substrates, the frontal lobe is predominantly considered as the key modulation area responsible for the neural coding of high-level cognitive function and as a positive influencer of cognitive integration, which explains the attention and memory impairment in the MSD group [44–46]. In addition to the anatomical findings, we also speculate that MSD and cognitive impairment might share a similar pathophysiological process. Consistent with several previous findings, we found that the invalidation of anti-PD medication was more remarkable in PD patients who developed MSD and other NMMs than in tremor-dominant patients. These findings indicate that the root cause of MSD and other NMMs might involve non-dopaminergic neurons and non-dopaminergic transmitter disorders, such as long-term neurodegeneration induced by a gradual loss of cholinergic neurons [10, 12 and 47). Generally, we reasoned that the MSD group was likely to experience more cognitive dysfunction since speech motor modulation and cognitive functions are likely to share common neural anatomy and neurodegenerative processes. In the present study, attention/memory impairment was retained after removal of the potential risk factor (perceptual problems) from the multivariate logistic regression analysis, suggesting that there may be a strong correlation between high-level cognitive function (especially attention and memory) and MSD in PD patients. This finding demonstrated that a detailed scale for neuroimaging evaluation of attention and memory, as well as valid cognitive treatment for the improvement of attention and memory, might improve the prognosis of MSD in PD patients. Moreover, determining the cause and effect relationship between MSD and attention/memory impairment in PD could help determine the detailed neurophysiologic and neuropathological mechanisms underlying the abnormal speech motor modulation. In addition, although we evaluated attention and memory as two separate high-level cognitive functions, it was difficult to separate the two different cognitive subtypes in the MSD and non-MSD groups. This could be attributed to the fact that a majority of the patients manifested with mixed dysfunction of the two cognitive subtypes, or that speech modulation involves the two cognitive subtypes. Nonetheless, we have to acknowledge that we just assessed patients’ attention or memory capacity via a single subjective question in NMSS, respectively. Therefore, lack of some direct objective cognition tests might bring about some limitation to present study. In the future study, we plan to carry out some direct objective cognition measurements to further explore the potential relationship between cognition and MSD in PD patients.
Several different studies have reported that speech is a multisensory process in which auditory perception plays a key role [48–51]. Additionally, some studies have reported that MSD patients are more likely to suffer more from perceptual disorder; however, the elaborate relationship and mechanism involved in PD-associated perceptual problems are unknown [52–54]. In the present study, univariate analysis showed a greater burden of perceptual problems in the MSD group than in the non-MSD group, but multivariate logistic regression analysis excluded perceptual problems as an independent risk factor for PD-associated MSD. However, as in the previous study, we did not explicitly define perceptual problems based on specific sensory function disorders. Therefore, studies with larger sample sizes and more comprehensive methods for evaluation of specific sensory disorders are necessary to confirm the relationship between perceptual problems and PD-associated MSD and to determine if more severe perceptual problems are related to a higher likelihood of MSD in PD patients.
Limitations
Tough we have tried our best to improve our present study, there are still some limitation as follows. Firstly, as mentioned in Discussion section, we just evaluated attention/memory capacity by a single item subjective question, respectively. This might make our study less objective, in that cognition tests were missing. Secondly, there was a little shortage in our neuroimaging method. We have successfully prevented missing MRI data, however, we just measured the occurrence of lesion within any a lobe rather than the number or the volume of lesions. This might make our present study ambiguous that we have not appropriately utilized our MRI data. It is helpful for our addition of limitation to readers that they will be more objective to interpret our present study.