Multimodal biomarkers of Parkinson’s disease risk in essential tremor. (A prospective cohort study)

Objective. To identify clinical and neuroimaging biomarkers associated with Parkinson’s disease (PD) onset in patients with essential tremor plus (ET-plus) during prospective observation. Material and methods. This prospective observational cohort study included 159 patients diagnosed with essential tremor (ET), ET-plus, ET-PD, and idiopathic PD. The median observation period was 4.6 years. All participants underwent standardized neurological examinations and assessments, including the Unified Parkinson’s Disease Rating Scale Part III (UPDRS-III), Montreal Cognitive Assessment (MoCA), Scale for the Assessment and Rating of Ataxia (SARA), Unified Dystonia Rating Scale (UDRS), Fahn-Tolosa-Marin Tremor Rating Scale, Non-Motor Symptoms Scale (NMSS), olfactory testing, screening for probable REM sleep behavior disorder (RBD), Stroop test, forward and backward counting tests, Boston Naming Test, literal and semantic verbal fluency tests, transcranial sonography (TCS) of the substantia nigra, and magnetic resonance imaging (MRI) with nigrosome-1 assessment. Results. Conversion from ET-plus to PD occurred in 15 patients. The most significant predictors of conversion were hyperechogenicity of the substantia nigra on transcranial Doppler (TCD), absence of nigrosome-1 on MRI, probable REM sleep behavior disorder (RBD), and ET duration greater than 20 years. The predictive model demonstrated high discriminatory power (C-statistic 0.89). Clinically, patients who converted showed a combination of non-motor symptoms, cognitive decline, signs of nigrostriatal dysfunction, and more frequent resting tremor. Conclusions. The risk of Parkinson’s disease onset in patients with ET-plus is determined by a combination of multimodal biomarkers. The prospective identification of 15 patients who converted supports classifying this subgroup as a high-risk phenotype that warrants ongoing monitoring and comprehensive evaluation.