Plasma NfL, GFAP, and pTau181 in patients with isolated REM sleep behavior disorder

Idiopathic/isolated Rapid Eye Movement (REM) sleep behavior disorder (iRBD) is recognized as a prodromal stage of neurodegenerative diseases, particularly of α-synucleinopathies. The development of blood-based biomarkers enables the in vivo assessment of neuronal, glial, and Alzheimer's disease (AD)-related changes. This study aimed to analyze plasma levels of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and phosphorylated-Tau 181 (pTau181) in iRBD patients compared to healthy controls (HC) and AD patients.

In this cross-sectional study, iRBD patients were compared to age- and sex-matched HC and AD patients. All participants underwent cognitive and motor assessments. Plasma NfL, GFAP, and pTau181 levels were quantified using SIMOA (Quanterix, Billerica, MA). Analyses of covariance and Spearman correlation coefficients were used for group comparisons and correlation analyses.

The study included 44 iRBD patients (81.8% males, mean age 71.0 ± 6.4 years), 55 HC (66.3% males, mean age 69.1 ± 5.5 years), and 28 AD patients (82.1% males, mean age of 70.4 ± 6.7 years). iRBD patients showed significantly higher plasma NfL and GFAP levels and similar pTau181 levels compared to HC. Compared to AD patients, iRBD patients had lower levels of GFAP, NfL, and pTau181. In iRBD, GFAP and NfL levels were significantly correlated, while no correlations were observed between plasma biomarkers and clinical symptoms.

High plasma NfL and GFAP levels in iRBD patients reflect a possible ongoing neurodegenerative process. Normal pTau181 plasma levels in iRBD suggest that AD-related neurodegeneration is not present at this stage. Future studies on plasma markers predicting phenoconversion are crucial for setting neuroprotective interventions in iRBD patients. Statement of Significance This study identifies plasma biomarkers that reflect neurodegeneration in idiopathic/isolated REM sleep behavior disorder (iRBD), a prodromal stage of α-synucleinopathies. Higher plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) levels in iRBD patients compared to healthy controls suggest early neuronal and glial degeneration, while similar phosphorylated-Tau 181 levels indicate an absence of Alzheimer's disease co-pathology. These findings support the utility of NfL and GFAP as potential blood-based markers for tracking early neurodegenerative changes in iRBD. Further studies focusing on these markers in predicting disease progression could be instrumental in guiding timely neuroprotective interventions.