We (Suppl file) applaud the proposed frameworks for synucleinopathy staging: Neuronal α-Synuclein Disease Integrated Staging System (NSD-ISS)1 and SynNeurGe.2 Considering that isolated REM sleep behaviour disorder (iRBD) reflects an evolving synucleinopathy with eventual phenoconversion to Parkinson’s disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy (MSA) in most cases,3 we seek to pose several questions in the context of rapidly evolving seed amplification assay (SAA) testing for detection of PD/DLB (SLBD) and MSA (SMSA) seeds of misfolded α-synuclein (Figure).
What are the implications of negative SAA results? Because a significant minority of iRBD cases are SLBD-,4 it is unknown if these cases 1) represent a false negative test (i.e., brainstem synuclein pathology is present but SAA is negative), 2) have MSA and are SMSA+, or 3) represent a non-synucleinopathy etiology. Furthermore, it is unknown if there are iRBD cases who are SLBD- SMSA- and become SLBD+ or SMSA+ later.
Using “D+” to denote dopamine deficiency per dopamine transporter imaging, what is the frequency of S+ and/or D+ in iRBD, and what do each of these scenarios represent? The majority of iRBD cases are D-,5 and there are insufficient longitudinal data to determine if and when the status changes to D+, nor any correlation to eventual overt phenotype. One might predict that iRBD cases who are SLBD+ D- are more likely to phenoconvert to DLB, whereas those who are SLBD+ D+ are more likely to phenoconvert to PD. Because the pattern of functional impairment and findings on outcome measures are likely different between these eventualities, developing optimal trial design will be challenging.
Will trials for disease-modifying therapies in iRBD require SLBD+ D+ status for enrollment? Individuals with iRBD who are SLBD+ D+ likely have high risk of phenoconversion to PD, and therefore this trial design may be justified. The unfortunate result of this approach is that iRBD cases who are SLBD- and/or D-, who may be more likely to develop DLB or MSA than PD, would be under-represented in trials.
As representatives of the RBD scientific community who desire neuroprotective clinical trials to be designed for all persons with an underlying synucleinopathy, we urge others to address these questions to advance the solid foundations that these staging schemes have provided.1,2 iRBD represents a critical window of opportunity to intervene, and more longitudinal clinical and biomarker data in iRBD will bolster optimal trial design with appropriate inclusion criteria and outcome measures for PD, DLB, and MSA.
Supplementary Material
Acknowledgements
Supported by NIH grants U19 AG071754 and R34 AG056639 for the North American Prodromal Synucleinopathy (NAPS) Consortium.
Disclosures
Boeve – Related to manuscript: supported by NIH grants U19 AG071754 and R34 AG056639. Unrelated to manuscript: investigator for clinical trials sponsored by Biogen, Alector, EIP Pharma, Cognition Therapeutics, Transposon, GE Healthcare; research support to institution from the Lewy Body Dementia Association, American Brain Foundation, Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program, Little Family Foundation, Ted Turner and Family
Davis – Related to manuscript: supported by NIH grant U19 AG071754. Unrelated to manuscript: Medical Monitor, Data Safety Monitoring Board, “Sing for Your Saunter” study (2022 - present); American Neurological Association Special Interest Group Co-Chair (2024)
Ju – Related to manuscript: supported by NIH grants U19 AG071754 and R34 AG056639; support from GE for DaTscan ligand for NAPS protocol. Unrelated to manuscript: personal consulting fees from Applied Cognition; personal honoraria from American Academy of Sleep Medicine, American Academy of Neurology, Standford University, Columbia University
Kantarci – Related to manuscript: supported by NIH grant U19 AG071754. Unrelated to manuscript: institutional research support from Alzheimer’s Disease Discovery Fund, Eli Lilly; consulting fees to institution from Biogen
Singer – Related to manuscript: supported by NIH grant U19 AG071754. Unrelated to manuscript: institutional research support from FDA, Michael J. Fox Foundation for Parkinson’s Disease, Sturm Foundation, Bishop Dr. Karl Golser Foundation; personal consulting fees from Amneal, Biohaven, Lundbeck, Vaxxinity; DSMB member for Theravance; President of the American Autonomic Society
Videnovic – Related to manuscript: supported by NIH grants U19 AG071754 and R34 AG056639; Unrelated to manuscript: personal consulting fees from CoA Therapeutics, Syneos Health, XW Pharma, Biogen; DSMB member for Alexion Pharmaceuticals; President of the International RBD Study Group
References
- 1.Simuni T, Chahine LM, Poston K, Brumm M, Buracchio T, Campbell M, Chowdhury S, Coffey C, Concha-Marambio L, Dam T, DiBiaso P, Foroud T, Frasier M, Gochanour C, Jennings D, Kieburtz K, Kopil CM, Merchant K, Mollenhauer B, Montine T, Nudelman K, Pagano G, Seibyl J, Sherer T, Singleton A, Stephenson D, Stern M, Soto C, Tanner CM, Tolosa E, Weintraub D, Xiao Y, Siderowf A, Dunn B, Marek K. A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research. Lancet Neurol. 2024. Feb;23(2):178–190. doi: 10.1016/S1474-4422(23)00405-2. PMID: 38267190. [DOI] [PubMed] [Google Scholar]
- 2.Höglinger GU, Adler CH, Berg D, Klein C, Outeiro TF, Poewe W, Postuma R, Stoessl AJ, Lang AE. A biological classification of Parkinson’s disease: the SynNeurGe research diagnostic criteria. Lancet Neurol. 2024. Feb;23(2):191–204. doi: 10.1016/S1474-4422(23)00404-0. PMID: 38267191. [DOI] [PubMed] [Google Scholar]
- 3.Postuma RB, Iranzo A, Hu M, Högl B, Boeve BF, Manni R, Oertel WH, Arnulf I, Ferini-Strambi L, Puligheddu M, Antelmi E, Cochen De Cock V, Arnaldi D, Mollenhauer B, Videnovic A, Sonka K, Jung KY, Kunz D, Dauvilliers Y, Provini F, Lewis SJ, Buskova J, Pavlova M, Heidbreder A, Montplaisir JY, Santamaria J, Barber TR, Stefani A, St Louis EK, Terzaghi M, Janzen A, Leu-Semenescu S, Plazzi G, Nobili F, Sixel-Doering F, Dusek P, Bes F, Cortelli P, Ehgoetz Martens K, Gagnon JF, Gaig C, Zucconi M, Trenkwalder C, Gan-Or Z, Lo C, Rolinski M, Mahlknecht P, Holzknecht E, Boeve AR, Teigen LN, Toscano G, Mayer G, Morbelli S, Dawson B, Pelletier A. Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study. Brain. 2019. Mar 1;142(3):744–759. doi: 10.1093/brain/awz030. PMID: 30789229 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Iranzo A, Mammana A, Muñoz-Lopetegi AS, Mayà G, Rossi M, Serradell M, Baiardi S, Arqueros A, Quadalti C, Perissinotti A, Ruggeri E, Cano JS, Gaig C, Parchi P. Misfolded α-Synuclein Assessment in the Skin and CSF by RT-QuIC in Isolated REM Sleep Behavior Disorder. Neurology. 2023. May 2;100(18):e1944–e1954. doi: 10.1212/WNL.0000000000207147. Epub 2023 Mar 17. PMID: 36931726 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Arnaldi D, Chincarini A, Hu MT, Sonka K, Boeve B, Miyamoto T, Puligheddu M, De Cock VC, Terzaghi M, Plazzi G, Tachibana N, Morbelli S, Rolinski M, Dusek P, Lowe V, Miyamoto M, Figorilli M, Verbizier D, Bossert I, Antelmi E, Meli R, Barber TR, Trnka J, Miyagawa T, Serra A, Pizza F, Bauckneht M, Bradley KM, Zogala D, McGowan DR, Jordan L, Manni R, Nobili F. Dopaminergic imaging and clinical predictors for phenoconversion of REM sleep behaviour disorder. Brain. 2021. Feb 12;144(1):278–287. doi: 10.1093/brain/awaa365. PMID: 33348363 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.