This study represents the first attempt to investigate the causal association between TMD and NDs using multiple complementary MR approaches. Based on the GWAS data, the study demonstrated a significant genetic predisposition of TMD to PD. However, no causal relationship was observed with AD, ALS, and MS. Compared with the findings of previous studies, these findings establish a significant correlation between TMD and PD and offer valuable insights for the early routine screening of PD in future clinical patients with TMD.
Our findings regarding the positive causal effect of TMD on PD are consistent with current research. A recent study in Korea used a large population data from the National Health Insurance Service Health Screening Cohort to perform two analyses to assess the interaction between TMD and PD [31]. One of them (Part I) included 4455 participants with TMD matched with 17,820 control participants and concluded that patients with TMD have a higher risk of developing PD. Another study by researchers in Taiwan supported this conclusion [32]. This study suggests that a significant proportion of participants with PD exhibit TMD symptoms before their PD diagnosis. In addition, patients with PD were more likely to have been diagnosed with TMD before their PD diagnosis compared with those without PD.
However, some observational studies have yielded contrasting findings. According to Verhoeff et al., a higher prevalence of TMD pain, sleep, and awake bruxism was observed when self-reported complaints of orofacial pain and dysfunction were assessed in patients with PD [33]. Furthermore, the co-occurrence of TMD and PD has been documented in a previous study, with certain studies suggesting a higher prevalence of TMD among patients with PD compared with the general population [34]. Therefore, the causal relationship between TMD and PD remains uncertain in observational studies because of the influence of environmental factors and genetic predispositions [35]. However, by employing MR analysis, our findings provided compelling genetic evidence suggesting that TMD may confer increased susceptibility to PD.
According to various observational studies and research analyses, several studies have reported the possible underlying pathological mechanisms between TMD and NDs. The TMJ is one of humans’ most critical and complex joints because it enables jaw movement and chewing [36]. Chewing enhances the activation of various brain regions, including the somatosensory cortex, supplementary motor area, insular cortex, prefrontal cortex, and hippocampus [37]. He et al. reported that patients with TMD exhibit aberrant cortical responses to tactile stimulation, impaired cognitive capacity, and motor performance, thereby highlighting the association between TMD and the central nervous system [38]. Dammann et al. observed that patients with TMD exhibit heightened anxiety traits, which are directly linked to the functional activation of the anterior insula [39]. In a recent review, 25 original magnetic resonance imaging studies were retrieved to investigate the neuropathophysiological manifestations of TMD-related pain, providing evidence for the peripheral and central neural bases of pain in patients with TMD [40]. These studies confirmed the relationship between TMD and the brain, which helped to deeply explore the inherent relationship between TMD and NDs.
NDs arise from many factors, including genetic mutations, neuronal apoptosis, mitochondrial dysfunction, protein aggregation, impaired protein degradation pathways, and glial cell-mediated innate immune responses [41]. Notably, much research is currently focused on ND treatment, surgical techniques, and the development of neuropharmaceuticals. In the future, by securing the collaboration of dental professionals, researchers can conduct a comprehensive study of the interconnections between NDs and TMD, encompassing the central nervous system as it relates to the teeth, muscles, and jaws. This will help promote academic crosscutting and provide valuable support for advancing therapeutic strategies targeting NDs.
Furthermore, TMD is frequently accompanied by synovial inflammation of TMJ, with interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α) being the most prominent pro-inflammatory cytokines detected in the synovial fluid of patients with TMD [42]. Notably, interleukin (IL)-1 is crucial as an inflammatory cytokine in ND pathogenesis [43]. IL-1 involvement in neurodegeneration, its ability to induce IL-6 production, and its capacity to stimulate inducible nitric oxide (iNOS) activity in astrocytes have been demonstrated [44]. Dysregulated expression of TNF-α results in the development of chronic inflammation, pronounced gliosis, synaptic degeneration, and glutamatergic neurotoxicity [45]. Persistent TNF-α upregulation has been observed in patients with AD, PD, MS, HIV-associated dementia, and ischaemia [46, 47]. For the inflammatory markers, IL-1β and TNF-α involved in the pathological process of TMD and ND, effectively controlling their release in the TMJ of patients with TMD may treat NDs. Further research in this field, such as exploring how to control the transfer of these inflammatory factors from the TMJ to the nervous system, is expected to promote the prevention of NDs, such as PD, in the oral field.
Our findings have implications for clinical and scientific research. As a potential causal risk factor for PD, TMD should be considered when preventing PD. When treating patients with TMD, oral professionals tend to pay more attention to TMD-related oral and maxillofacial diseases and less to NDs, such as PD. Dentists should be trained to master the basic knowledge of NDs under specific conditions to screen patients early and reduce their disease burden. It is essential to assess the risk of NDs when diagnosing patients with TMD and to consider early interventions if necessary. Furthermore, TMD can serve as a valuable factor for future studies on the causes of NDs through observation, clinical research, or genetic analysis.
To our knowledge, no MR studies of TMD and NDs have been reported. The primary benefits of this study compared with the individual-level data analysis from previous studies are as follows: First, MR analysis is a potent tool for investigating the causal relationship between exposure and outcomes, thereby enhancing our understanding of causation [19]. Eliminating endogeneity and bias caused by confounding variables was pivotal in this analysis. Compared with randomised controlled trials, MR analysis offers distinct advantages by effectively addressing potential confounding factors and reverse causality effects while minimising resource wastage [21]. Second, the data utilized in this study were obtained from a GWAS database and included only European population samples, thereby effectively reducing population heterogeneity bias. Third, the findings from this study may have important implications for healthcare policies as the discovery of a causal relationship between TMD and PD is anticipated that there will be a favorable influence on public health policies related to the prevention and management.
However, this study has some limitations. First, as all genetic variants were derived from European populations, the generalisability of the findings to other populations and races requires further validation. Second, the lack of data from the ND databases stratified by familial and sporadic diseases, age, and sex may affect causal estimates. Third, despite using the latest MR methodology and GWAS data, the relatively small sample size may have limited the study’s power. Therefore, further large-scale studies are required to verify our findings.