A simple and effective screening strategy for early multiple system atrophy diagnosis and α-Synuclein forms in erythrocytes

Abstract

Background: Urinary dysfunction is an early manifestation of autonomic dysfunction in Multiple System Atrophy (MSA) and often precedes orthostatic hypotension. This study investigated the diagnostic efficacy of post-void residual (PVR) urine volume in differentiating possible MSA from early-stage Parkinson’s disease (PD) and sought to identify a feasible combination of autonomic nervous system indicators for clinical use. The distribution of α-Synuclein (α-Syn) forms in erythrocyte was preliminary explored. Methods: This study included 70 patients with MSA-P, 73 with MSA-C, and 71 with PD. All participants underwent assessments including bladder residual urine ultrasound, the supine-to-standing test (STS), external anal sphincter electromyography (EAS-EMG), brain MRI, Mini-Mental State Examination (MMSE), and Montreal Cognitive Assessment (MoCA). Receiver operating characteristic (ROC) curves determined the diagnostic value of PVR urine volume and other autonomic indicators for possible MSA. Immunofluorescence staining of α-Syn forms in red blood cells (RBCs) was also performed. Results: PVR urine volume, ΔSBP and ΔDBP (at 1 and 3 min), and EAS-EMG parameters were significantly increased in MSA-P and MSA-C patients compared to PD (p < 0.01), with similar differences observed between possible MSA-P/MSA-C and early-stage PD patients. ROC analysis showed that PVR urine volume had diagnostic value in differentiating possible MSA-P (AUC = 0.668, cut-off 24.5 mL) and MSA-C (AUC = 0.759, cut-off 47.5 mL) form early-stage PD patients. ΔSBP at 1 and 3 min also distinguished possible MSA-P (AUC = 0.702, 0.730) and MSA-C (AUC = 0.707, 0.718) from early-stage PD. Combining PVR urine volume and ΔSBP (at 1 and 3 min) further improved diagnostic accuracy, with an AUC of 0.817 (sensitivity 57.1%, specificity 96.8%) for possible MSA-P and an AUC of 0.794 (sensitivity 68.6%, specificity 87.1%) for MSA-C from early-stage PD. On a molecular level, oligo-α-Syn predominantly localized to RBC membrane fractions in MSA patients, while α-Syn pS129 was primarily detected in the RBC cytoplasm of PD patients. Conclusion: Combining PVR urine volume and ΔSBP (at 1 and 3 min) is an easily accessible and effective method for distinguishing possible MSA from early-stage PD. This combination should be considered for routine assessment in Parkinsonism. Distinct α-Syn forms distribution in erythrocytes could be considered as a useful biomarker for differential diagnosis.