The significance of inflammation and biomarkers of neurodegeneration in essential tremor: a systematic review

INTRODUCTION: Essential tremor (ET) is one of the most prevalent yet mechanistically unresolved movement disorders. Although traditionally attributed to cerebellar dysfunction, accumulating evidence indicates the involvement of broader systemic processes, including neuroinflammation, immune dysregulation, and neurodegeneration. However, the role of inflammation in ET remains insufficiently defined, particularly regarding whether it constitutes a primary pathogenic mechanism or a secondary response. MATERIAL AND METHODS: This systematic review aimed to comprehensively evaluate current evidence on inflammatory, immune- related, and neurodegeneration-associated biomarkers in ET. A structured search of PubMed, Scopus, and Web of Science identified relevant studies published between 2000 and March 2026. Thirty-two studies fulfilled the inclusion criteria. RESULTS: Across clinical and molecular investigations, the available evidence was highly heterogeneous and frequently inconsistent. No reproducible inflammatory profile has been established, and reported alterations in cytokines, acute-phase proteins, and hematological indices varied substantially across cohorts. Although selected cytokines were associated with tremor severity and cognitive impairment, these associations lacked consistency and specificity. Similarly, biomarkers of neurodegeneration, including neurofilament light chain and α-synuclein, demonstrated variable and non-disease-specific alterations. Emerging evidence suggests the involvement of integrative mechanisms encompassing blood-brain barrier dysfunction, impaired glymphatic clearance, and gut-brain axis interactions, although direct evidence in ET remains limited. CONCLUSIONS: Current evidence does not support inflammation as a primary driver of ET and instead indicates that inflammatory processes may act as context-dependent modulators within a multifactorial disease framework. Further well-designed longitudinal and multimodal studies are required to clarify the causal role of inflammation and its relationship to neurodegenerative mechanisms in ET.