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CSF Biomarkers May Distinguish MSA from Lewy-Body Alpha-Synucleinopathies Before the Onset of Debilitating Symptoms

By Harini Sarva, MD

Assistant Professor of Clinical Neurology, Weill Cornell Medical College

SYNOPSIS: In patients with autonomic failure, the combination of elevated neurofilament light and alpha-synuclein oligomers in the cerebrospinal fluid can distinguish between multiple system atrophy and Parkinson’s disease/dementia with Lewy bodies. Early diagnosis is critical for the development of treatment trials.

SOURCE: Singer W, Schmeichel AM, Shahnawaz M, et al. Alpha-synuclein oligomers and neurofilament light chain predict phenoconversion of pure autonomic failure. Ann Neurol 2021;89:1212-1220.

Thirty-two patients with clinically defined pure autonomic failure (PAF) using standardized tests, including thermoregulatory sweat test, were included in this prospective study. Baseline cerebrospinal fluid (CSF) samples were examined for neurofilament light chain and the presence of alpha-synuclein oligomers.

The majority of subjects were male with prominent symptoms of bladder and erectile dysfunction. In addition, rapid eye movement sleep behavior disorder (RBD) and anosmia or hyposmia were common. Patients were examined annually, and the mean follow-up time was 3.9 years. Nine patients phenoconverted to neurodegenerative disorders — multiple system atrophy (MSA) (5), Parkinson’s disease (PD) (2), and dementia with Lewy bodies (DLB) (2). The time to conversion was one to two years for MSA and between one and three years for PD and DLB.

Those who converted to MSA had fewer complaints of impaired smell, shorter disease duration at the time of enrollment, and higher upright catecholamine levels. Two of these subjects who came to autopsy had pathologically confirmed MSA. All phenoconverters had subtle motor signs. All who had converted to MSA had elevated CSF neurofilament light chain levels compared to none of the PD or DLB phenoconverters. The alpha-synuclein oligomer assay demonstrated that those who converted to MSA had lower maximum thioflavin fluorescence than those who converted to PD/DLB, consistent with previous reports of established ranges for these disorders. The reaction kinetics also were distinct between MSA and the PD/DLB phenoconverters, with the reaction plateau occurring in the assay at an earlier time point for those who eventually developed MSA.


MSA is a devastating, progressive, fatal disease with diverse clinical phenotypes. Clinical diagnosis often is delayed without obvious autonomic dysfunction. No disease-specific therapies exist. MSA is pathologically distinct from PD and DLB and much rarer than either of these conditions. Developing treatment trials is challenging. Although clinical markers, such as the presence of RBD, subtle motor signs, and impaired smell, can aid in predicting conversion of prodromal alpha-synuclein pathology to full-blown disease, relying on clinical characteristics alone is insufficient to diagnose early stage disease. Failure to make an early and accurate diagnosis will limit the chances for disease modification.

Reliable CSF biomarkers, such as the combination of neurofilament light and alpha-synuclein oligomer, to accurately distinguish MSA from PD/DLB will not only aid in the prognostication and counseling of patients, but also will help in the development of therapeutics while patients still are in the prodromal phase of pure autonomic failure, which has limited alpha-synuclein pathology. Although the sample size of this study was small and lacked extensive autopsy confirmation of diagnosis, the detailed evaluations, with both clinical and biomarker assessments, are strengths. Although distinguishing between PD and DLB still remains a challenge, the potential of CSF biomarkers in distinguishing between MSA and PD/DLB synucleinopathies can aid in improving the accurate and early diagnosis of patients who present with mild parkinsonian features.