Ethical Aspects of Prodromal Synucleinopathy Prognostic Counseling

Abstract

Alpha-synucleinopathies can be identified in their prodromal phase, raising several ethical issues. In this review, we first provide definitions of prodromal α-synucleinopathies and discuss the importance of distinguishing between prodromes and risk factors. Next, we discuss the implications of a diagnosis of prodromal α-synucleinopathy and considerations regarding prognostic counseling in both clinical and research settings. We review available data on patient preferences regarding disclosure as well as providers' perspectives. We examine the pros and cons of disclosing a diagnosis of prodromal α-synucleinopathy, taking into consideration the differences between clinical and research settings. Asking about willingness to know in clinical and research settings and the shared decision-making process applied to prognostic counseling is discussed. Concerning research settings, ethical aspects regarding clinical trials are addressed. Availability of direct-to-consumer technologies will likely lead to novel contexts requiring prognostic counseling, and future neuroprotective or neuromodulating treatments may require further considerations on the timing, role, and importance of prognostic counseling. Recommendations on how to address ethical gaps should be a priority for patients, medical professional societies, and research workgroups. Ethical issues must be considered as an integral part of the overall clinical and research approach to prodromal synucleinopathies.

Keywords

RBD - REM sleep behavior disorder neurodegeneration - ethics - alpha-synuclein

^* Co-Primary Principal Authors

Publication History

Accepted Manuscript online:
24 January 2023

Article published online:
07 March 2023

• References

• 1 Galbiati A, Verga L, Giora E, Zucconi M, Ferini-Strambi L. The risk of neurodegeneration in REM sleep behavior disorder: a systematic review and meta-analysis of longitudinal studies. Sleep Med Rev 2019; 43: 37-46
• 2 McKeith IG, Ferman TJ, Thomas AJ. et al; prodromal DLB Diagnostic Study Group. Research criteria for the diagnosis of prodromal dementia with Lewy bodies. Neurology 2020; 94 (17) 743-755
• 3 Schaeffer E, Toedt I, Köhler S, Rogge A, Berg D. Risk disclosure in prodromal Parkinson's Disease. Mov Disord 2021; 36 (12) 2833-2839
• 4 Wenning GK, Stankovic I, Vignatelli L. et al. The Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy. Mov Disord 2022; 37 (06) 1131-1148
• 5 Berg D, Postuma RB, Adler CH. et al. MDS research criteria for prodromal Parkinson's disease. Mov Disord 2015; 30 (12) 1600-1611
• 6 Heinzel S, Berg D, Gasser T, Chen H, Yao C, Postuma RB. MDS Task Force on the Definition of Parkinson's Disease. Update of the MDS research criteria for prodromal Parkinson's disease. Mov Disord 2019; 34 (10) 1464-1470
• 7 Högl B, Stefani A, Videnovic A. Idiopathic REM sleep behaviour disorder and neurodegeneration—an update. Nat Rev Neurol 2018; 14 (01) 40-55
• 8 Iranzo A, Stefani A, Serradell M. et al; SINBAR (Sleep Innsbruck Barcelona) group. Characterization of patients with longstanding idiopathic REM sleep behavior disorder. Neurology 2017; 89 (03) 242-248
• 9 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 (08) 671-684
• 10 Yao C, Fereshtehnejad SM, Dawson BK. et al. Longstanding disease-free survival in idiopathic REM sleep behavior disorder: is neurodegeneration inevitable?. Parkinsonism Relat Disord 2018; 54: 99-102
• 11 Ju YE. Rapid eye movement sleep behavior disorder in adults younger than 50 years of age. Sleep Med 2013; 14 (08) 768-774
• 12 Postuma RB, Gagnon JF, Tuineaig M. et al. Antidepressants and REM sleep behavior disorder: isolated side effect or neurodegenerative signal?. Sleep 2013; 36 (11) 1579-1585
• 13 Beauchamp TL, Childress JF. Principles of Biomedical Ethics 8th ed. Oxford University Press; 2019: 512
• 14 Surbone A. Truth telling. Ann N Y Acad Sci 2000; 913: 52-62
• 15 Gossard TR, Teigen LN, Yoo S. et al. Patient values and preferences regarding prognostic counseling in isolated REM sleep behavior disorder. Sleep (Basel) 2022; 46 (01) zsac244
• 16 Fernández-Arcos A, Morenas-Rodríguez E, Santamaria J. et al. Clinical and video-polysomnographic analysis of rapid eye movement sleep behavior disorder and other sleep disturbances in dementia with Lewy bodies. Sleep 2019; 42 (07) zsz086
• 17 Howell MJ, Avidan AY, During E. et al. Clinical Practice Guideline for the Management of REM Behavior Disorder. Guideline. In press . Accessed December 13, 2022 at: https://aasm.org/clinical-resources/practice-standards/guidelines-in-development/
• 18 Feinstein MA, Sharp RR, Sandness DJ. et al. Physician and patient determinants of prognostic counseling in idiopathic REM sleep-behavior disorder. Sleep Med 2019; 62: 80-85
• 19 NAPS consortium for REM sleep behavior disorder. Accessed December 15, 2020 at: https://www.naps-rbd.org
• 20 Zhang H, Iranzo A, Högl B. et al. Risk factors for phenoconversion in rapid eye movement sleep behavior disorder. Ann Neurol 2022; 91 (03) 404-416
• 21 Alpinar-Sencan Z, Schicktanz S, Ulitsa N, Shefet D, Werner P. Moral motivation regarding dementia risk testing among affected persons in Germany and Israel. J Med Ethics 2022; 48 (11) 861-867
• 22 Schweda M, Kögel A, Bartels C, Wiltfang J, Schneider A, Schicktanz S. Prediction and early detection of Alzheimer's dementia: professional disclosure practices and ethical attitudes. J Alzheimers Dis 2018; 62 (01) 145-155
• 23 Green RC, Berg JS, Grody WW. et al; American College of Medical Genetics and Genomics. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 2013; 15 (07) 565-574
• 24 Malkani RG, Wenger NS. REM sleep behavior disorder as a pathway to dementia: if, when, how, what, and why should physicians disclose the diagnosis and risk for dementia. Curr Sleep Med Rep 2021; 7 (03) 57-64
• 25 Sperling RA, Rentz DM, Johnson KA. et al. The A4 study: stopping AD before symptoms begin?. Sci Transl Med 2014; 6 (228) 228fs13
• 26 Burns JM, Johnson DK, Liebmann EP, Bothwell RJ, Morris JK, Vidoni ED. Safety of disclosing amyloid status in cognitively normal older adults. Alzheimers Dement 2017; 13 (09) 1024-1030
• 27 National Academies of Sciences E. Medicine, Health, Medicine D, Board on Health Sciences P, Committee on the Return of Individual-Specific Research Results Generated in Research L. In: Downey AS, Busta ER, Mancher M, Botkin JR. eds. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: National Academies Press (US) Copyright 2018 by the National Academy of Sciences.; All rights reserved.; 2018
• 28 Molinuevo JL, Cami J, Carné X. et al. Ethical challenges in preclinical Alzheimer's disease observational studies and trials: results of the Barcelona summit. Alzheimers Dement 2016; 12 (05) 614-622
• 29 Mozersky J, Hartz S, Linnenbringer E. et al. Communicating 5-year risk of Alzheimer's disease dementia: development and evaluation of materials that incorporate multiple genetic and biomarker research results. J Alzheimers Dis 2021; 79 (02) 559-572
• 30 Gooblar J, Roe CM, Selsor NJ, Gabel MJ, Morris JC. Attitudes of research participants and the general public regarding disclosure of Alzheimer disease research results. JAMA Neurol 2015; 72 (12) 1484-1490
• 31 Ott BR, Pelosi MA, Tremont G, Snyder PJ. A survey of knowledge and views concerning genetic and amyloid PET status disclosure. Alzheimers Dement (N Y) 2016; 2 (01) 23-29
• 32 Caselli RJ, Langbaum J, Marchant GE. et al. Public perceptions of presymptomatic testing for Alzheimer disease. Mayo Clin Proc 2014; 89 (10) 1389-1396
• 33 Wikler EM, Blendon RJ, Benson JM. Would you want to know? Public attitudes on early diagnostic testing for Alzheimer's disease. Alzheimers Res Ther 2013; 5 (05) 43
• 34 Porteri C, Albanese E, Scerri C. et al; Geneva Task Force for the Roadmap of Alzheimer's Biomarkers. The biomarker-based diagnosis of Alzheimer's disease. 1-ethical and societal issues. Neurobiol Aging 2017; 52: 132-140
• 35 Vanderschaeghe G, Dierickx K, Vandenberghe R. Review of the Ethical issues of a biomarker-based diagnoses in the early stage of Alzheimer's disease. J Bioeth Inq 2018; 15 (02) 219-230
• 36 Roberts JS, Ferber R, Blacker D, Rumbaugh M, Grill JD. Advisory Group on Risk Evidence Education for Dementia (AGREED). Disclosure of individual research results at federally funded Alzheimer's disease research centers. Alzheimers Dement (N Y) 2021; 7 (01) e12213
• 37 Grill JD, Karlawish J. Disclosing Alzheimer disease biomarker results to research participants. JAMA Neurol 2022; 79 (07) 645-646
• 38 Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical?. JAMA 2000; 283: 2701-1110
• 39 World Health Organization. Optimizing brain health across the life course: WHO position paper. World Health Organization; 2022
• 40 Lang AE, Siderowf AD, Macklin EA. et al; SPARK Investigators. Trial of cinpanemab in early Parkinson's disease. N Engl J Med 2022; 387 (05) 408-420
• 41 Pagano G, Taylor KI, Anzures-Cabrera J. et al; PASADENA Investigators, Prasinezumab Study Group. Trial of prasinezumab in early-stage Parkinson's disease. N Engl J Med 2022; 387 (05) 421-432
• 42 Whone A. Monoclonal antibody therapy in Parkinson's disease—the end?. N Engl J Med 2022; 387 (05) 466-467
• 43 Postuma RB, Iranzo A, Hu M. et al. Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study. Brain 2019; 142 (03) 744-759
• 44 Postuma RB. Neuroprotective trials in REM sleep behavior disorder: the way forward becomes clearer. Neurology 2022; 99 (7, Suppl 1): 19-25
• 45 Halsband C, Zapf A, Sixel-Döring F, Trenkwalder C, Mollenhauer B. The REM sleep behavior disorder screening questionnaire is not valid in de novo Parkinson's disease. Mov Disord Clin Pract (Hoboken) 2018; 5 (02) 171-176
• 46 Stefani A, Mahlknecht P, Seppi K. et al. Consistency of “Probable RBD” diagnosis with the RBD screening questionnaire: a follow-up study. Mov Disord Clin Pract (Hoboken) 2016; 4 (03) 403-405
• 47 Stiasny-Kolster K, Sixel-Döring F, Trenkwalder C. et al. Diagnostic value of the REM sleep behavior disorder screening questionnaire in Parkinson's disease. Sleep Med 2015; 16 (01) 186-189
• 48 Jack Jr CR, Bennett DA, Blennow K. et al; Contributors. NIA-AA research framework: toward a biological definition of Alzheimer's disease. Alzheimers Dement 2018; 14 (04) 535-562
• 49 Johnson KA, Minoshima S, Bohnen NI. et al; Alzheimer's Association, Society of Nuclear Medicine and Molecular Imaging, Amyloid Imaging Taskforce. Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer's Association. Alzheimers Dement 2013; 9 (01) e-1-e-16
• 50 MacLeod R, Tibben A, Frontali M. et al; Editorial Committee and Working Group ‘Genetic Testing Counselling’ of the European Huntington Disease Network. Recommendations for the predictive genetic test in Huntington's disease. Clin Genet 2013; 83 (03) 221-231
• 51 Del Pozo Cruz B, Ahmadi M, Naismith SL, Stamatakis E. Association of daily step count and intensity with incident dementia in 78 430 adults living in the UK. JAMA Neurol 2022; 79 (10) 1059-1063