Table 2:
Summary of biomarker candidates in isolated RBD
| Subtype | Availability | Cost | Sensitivity and specificity | Remarks | |
|---|---|---|---|---|---|
|
| |||||
| Neurophysiology | |||||
| RSWA quantified by visual or automated methods (eg, SINBAR, rapid-eye-movement atonia index) | Diagnostic, prognostic, monitoring | High | Low | Diagnostic: 85–95% and 85–95%;97–105 prognostic: 78–89% and 61–70%5 | Robust data supporting both visual and automatic methods, with similar results despite differences in methods; few studies |
| Cyclic alternating pattern rate | Diagnostic, prognostic | Moderate | Moderate | NA | Only one study;8 special analyses of EEG required |
| Biomarkers obtained through artificial intelligence, machine learning, and deep neural network-based methods | Diagnostic, prognostic, combined | Low | High | Diagnostic: 91–98% and 93–94%; prognostic: AUC 78%9,10 | Few studies9,10 |
| Motor function | |||||
| Upper extremity alternate-tap test | Diagnostic, prognostic, monitoring, combined | High | Low | Year 0:100% and 83%;24 year –1: 92% and 86%; year –2: 88% and 89%; year –3: 91% and 86% | Easy to do; year 0=phenoconversion to PD or DLB; years –1, –2, –3=years before phenoconversion |
| Speech abnormalities quantified by means of acoustic analysis | Prognostic, monitoring | High | Low | 67% and 71%16 | Easy to do; only cross-sectional validation studies |
| Gait dysfunction by instrumental analysis | Prognostic, monitoring | Moderate | High | NA | Limited to few specialised centres; cross-sectional studies only |
| Wearable devices and smartphones | Prognostic, monitoring | High | Low | 92% and 90%18 | Cross-sectional validation studies only |
| Cognition | |||||
| Trail Making Test Part B | Diagnostic, prognostic, monitoring, combined | High | Low | Year 0: 100% and 83%;24 year –1: 92% and 86%; year –2: 88% and 89%; year –3: 91% and 86% | Only one longitudinal study; early identification of prodromal DLB; year 0=phenoconversion to DLB; years –1, –2, –3=years before phenoconversion |
| Semantic verbal fluency | Monitoring, diagnostic, prognostic, combined | High | Low | Year 0: 91% and 97%;24 year –1: 91% and 91%; year –2: 80% and 91%; year –3: 90% and 74% | Only one longitudinal study; cognitive change over time for prodromal DLB; year 0=phenoconversion to DLB; years –1, –2, –3=years before phenoconversion |
| Rey Auditory-Verbal Learning Test (immediate recall) | Diagnostic, prognostic, monitoring, combined | High | Low | Year 0: 92% and 89 %;24 year –1: 100% and 89%; year –2: 100% and 75%; year –3: 82% and 89% | Only one longitudinal study; cognitive change over time for prodromal DLB; year 0=phenoconversion to DLB; years –1, –2, –3=years prior to phenoconversion |
| Olfaction | |||||
| Odour identification testing (eg. Sniffin’ Sticks, UPSIT) | Diagnostic, prognostic, combined | High | Low | 86–91% and 76–88%106 | Easily done with conversion data between Sniffin and UPSIT available107 |
| Ophthalmic function | |||||
| Farnsworth-Munsell 100-Hue test | Diagnostic, prognostic | Moderate | Low | NA | Easily done; limited data |
| Optical coherence tomography (structural imaging of the parafoveal avascular zone) | Diagnostic, prognostic | Low | Moderate | NA | Highly promising for investigating other pathways at risk of early degeneration |
| Autonomic function | |||||
| Autonomic questionnaires | Diagnostic, prognostic, monitoring, combined | High | Low | NA | Easily done and can be easily repeated over time |
| Heart rate variability analysis | Diagnostic | High | Low | NA | Easily obtained from baseline vPSG; sensitive to artifact |
| Metaiodobenzylguanidine | Diagnostic | Moderate | Moderate | NA | Might help distinguish PD and DLB from MSA51 |
| Cardiovascular reflex testing | Diagnostic, prognostic, monitoring, combined | Low | Moderate | NA | Limited to few specialised centres; might help distinguish PD and DLB from MSA49 |
| Biofluids | |||||
| CSF RT-QuIC | Diagnostic, prognostic, monitoring | Low | Moderate | 100% and 98%55 | Somewhat invasive |
| Nasal swabs (olfactory mucosa) RT-QuIC | Diagnostic | Moderate | Moderate | 44·4% and 90%57 | Minimally invasive, ENT specialist needed for sampling |
| Serum neuronal exosomal α-synuclein | Diagnostic | Low | High | 95% and 93%59 | Most appealing serum marker sensitivity and specificity |
| Neuroimaging | |||||
| 123I-FP SPECT (dopamine transporter SPECT) | Diagnostic, prognostic, monitoring, combined | Moderate | Moderate | 29·3% and 100%71 | Low diagnostic value in differentiating patients with isolated RBD from controls; high prognostic value in identifying future phenoconverters; low prognostic value in identifying phenoconversion subtype; responsive to dopamine-oriented therapy |
| 18F-FDG PET | Diagnostic, monitoring, combined | Moderate | Moderate | 52·4% and 100%67,73 | Moderate diagnostic value in differentiating patients with isolated RBD from controls; high diagnostic potential in predicting α-synucleinopathy subtype but requires independent validation; possible prognostic value has yet to be shown in large series; useful for monitoring disease progression; possibly responsive to therapy |
| MRI for nigrosome, MRI for substantia nigra neuromelanin, MRI for cortical thinning, and MRI for DBM | Diagnostic, prognostic, combined | Moderate | Moderate | MRI nigrosome: 27·5–77% and 97–92·3%;74 MRI substantia nigra neuromelanin: 90% and 94%108 | Good diagnostic potential in differentiating patients with isolated RBD from controls (nigrosome, substantia nigra neuromelanin) as well as RBD subtype (ie, RBD with MCI or cortical thinning); possible prognostic value for DLB (DBM); all markers require independent study confirmation |
| Tissue biopsy | |||||
| Colon biopsy | Diagnostic | Low | Moderate | 24% and 100%82 | Invasive; poor sensitivity |
| Major salivary glands | Diagnostic | Low | Moderate | 89% and 100%83 | Invasive, surgeon needed for sampling; high sensitivity if glandular tissue obtained |
| Minor salivary glands | Diagnostic | Moderate | Moderate | 50% and 97%84 | Invasive, surgeon needed for sampling; poor sensitivity |
| Skin biopsy | Diagnostic, prognostic, monitoring, combined | Moderate | Moderate | 58%–87% and 100%35,86,87 | Easy to do, minimally invasive, but analysis requires expertise; might help distinguish PD and DLB from MSA51 |
| Genetic testing | |||||
| GBA variants | Prognostic | Moderate | Moderate | NA | Might help predict the rate of phenoconversion95 |
| SNCA 5′ variants | Prognostic | Moderate | Moderate | NA | Might help predict the rate of phenoconversion96 |
RSWA=rapid-eye-movement sleep without atonia. SINBAR=Sleep Innsbruck Barcelona group. AUC=area under the curve. PD=Parkinson’s disease. DLB=dementia with Lewy bodies. UPSIT=University of Pennsylvania smell identification test. vPSG=video polysomnography. MSA= multiple system atrophy. RT-QuIC=real-time quaking-induced conversion. ENT=ear nose and throat. 123I-FP=123I-ioflupane. 18F-FDG=18F-fluorodeoxyglucose. MCI=mild cognitive impairment. DBM=deformation-based morphometry. RBD=rapid-eye-movement sleep behaviour disorder.