Cerebrospinal-fluid biomarkers for predicting phenoconversion in patients with isolated rapid-eye movement sleep behavior disorder

Abstract

Study Objectives Patients with isolated rapid-eye movement (REM) sleep behaviour disorder (iRBD) have an increased risk of developing neurodegenerative diseases. This study assessed cerebrospinal fluid (CSF) biomarkers of neurodegeneration and blood-brain barrier (BBB) alteration in iRBD patients compared to controls and ascertain whether these biomarkers may predict phenoconversion to alpha-synucleinopathies (Parkinson’s Disease – PD, Dementia with Lewy bodies – DLB, Multiple System Atrophy - MSA). Methods Patients and controls underwent between 2012-2016 a neurological assessment, a lumbar puncture for CSF biomarker analysis (β-amyloid42 - Aβ42; total-tau, and phosphorylated tau) and BBB alteration (CSF/serum albumin ratio). All iRBD patients were followed until 2021 and then classified into patients who converted to alpha-synucleinopathies (iRBD converters, cRBD) or not (iRBD non-converters, ncRBD). Results Thirty-four iRBD patients (mean age 67.12±8.14) and thirty-three controls (mean age 64.97±8.91) were included. At follow-up (7.63±3.40 years), eight patients were ncRBD and twenty-three patients were cRBD: eleven converted to PD, ten to DLB and two to MSA. IRBD patients showed lower CSF Aβ42 levels and higher CSF/serum albumin ratio than controls. Cox regression analysis showed that the phenoconversion rate increases with higher motor impairment (hazard ratio (HR)=1.23, p=0.032). CSF Aβ42 levels predicted phenoconversion to DLB (HR=0.67, p=0.038) and BBB alteration predicted phenoconversion to PD (HR=1.20,p =0.038). Discussion This study showed that low CSF Aβ42 levels and high BBB alteration may predict the phenoconversion to DLB and PD in iRBD patients, respectively. These findings highlight the possibility to discriminate phenoconversion in iRBD patients through CSF biomarkers, however further studies are needed.