Predictors of α-Synucleinopathies in Isolated Rapid Eye Movement Sleep Behavior Disorder

Study researchers evaluated the role of biomarkers in predicting conversion to clinically manifest α-synucleinopathies in patients with isolated REM sleep behavior disorder.

Reliable biomarkers may have an important role in predicting conversion to clinically manifest α-synucleinopathies in patients with isolated rapid eye movement sleep behavior disorder (RBD), and may be essential to predict α-synucleinopathies subtype and response to treatment, according to a review published in Neurology.

Previous studies have shown that RBD is a potential early sign of α-synucleinopathies, a group of neurodegenerative diseases characterized by the abnormal accumulation of α-synuclein in the brain, including Parkinson disease, dementia with Lewy bodies, and multiple system atrophy.

Potential biomarkers that predict conversion to clinically manifest α-synucleinopathies may aid in early diagnosis, assessment of response to therapy, and prediction of α-synucleinopathies subtypes. The current review focused on several biomarker categories and provided data on their potential usefulness and role in assessment of diagnosis, prognosis and response to disease-modifying therapy.

The potential biomarkers were classified to 10 categories, including neurophysiology, motor function, cognition, olfaction, ophthalmic function, autonomic function, biofluids, neuroimaging, tissue biopsy, and genetic testing.

These biomarkers may be used to confirm an underlying α-synucleinopathy and distinguish α-synucleinopathies subtypes (diagnostic), to predict rate of phenoconversion and disease severity (prognostic), to monitor the progression of neurodegeneration and response to treatment (monitoring or therapy-responsive), or to refine and enhance the diagnostic, prognostic, and monitoring capabilities (combined).

Rapid eye movement sleep without atonia recorded during video-polysomnography is the most readily available diagnostic biomarker. In patients with isolated RBD, motor abnormalities appear relatively late in the prodromal disease process and may suggest which patients are at greatest risk of phenoconversion in the near future. Quantitative motor tests are among the most powerful predictive markers of future phenoconversion.

Serum neuronal exosomal α-synuclein and spinal fluid real-time quaking-induced conversion may be used as valuable markers with high sensitivity and specificity.

There are no good imaging biomarkers to determine the neuropathological spread of α-synuclein in patients with isolated RBD. At this point, ¹²³I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (¹²³I-FPCIT) SPECT imaging is the most reliable prognostic marker of phenoconversion in this context.

Peripheral tissue biopsy, particularly skin biopsy, has shown great promise as an in-vivo diagnostic biomarker for isolated RBD. Transcutaneous core needle biopsy of the submandibular gland with ultrasound guidance may be helpful.

Combination of multiple biomarkers may provide important data for the diagnosis, prognosis, and monitoring response to therapy.

“Future research will focus on longitudinal outcome data of multiple biomarkers across multiple [centers] worldwide,” concluded the study researchers.


Miglis MG, Adler CH, Antelmi E, et al. Biomarkers of conversion to α-synucleinopathy in isolated rapid-eye-movement sleep behaviour disorder. Lancet Neurol. 2021;20(8):671-684. doi:10.1016/S1474-4422(21)00176-9