Establishing Alpha-synuclein RT-QuIC Assay as a Diagnostic Technique in REM Sleep Behaviour Disorder

NCT ID: NCT04266457

Last Updated: 2022-10-18

Basic Information

• Recruitment Status: WITHDRAWN
• Study Classification: OBSERVATIONAL
• Study Start Date: 2021-09-01
• Study Completion Date: 2022-09-01

Brief Summary

We hypothesise that a real-time quaking induced conversion assay for the detection of pathological alpha-synuclein (α -syn RTQuIC) can be used to differentiate between cases of idiopathic REM-sleep behaviour disorder (RBD) and RBD that is symptomatic of prodromal α-synucleinopathies.

Detailed Description

This study will be the largest analysis of cerebrospinal fluid (CSF) α-synuclein in Rapid Eye Movement Behaviour Disorder (RBD) patients to date. In line with the The National CJD Research & Surveillance Unit (NCJDRSU)'s recent inclusion of a positive RT-QuIC for pathological prion protein in the diagnostic criteria for Creutzfeldt-Jakob Disease (CJD) [1], we aim to deploy this novel method to establish it as an accurate research and diagnostic resource in the assessment and prognosis of RBD. This research is transformative and has the potential to change practice.

Currently, there is no simple method with high sensitivity and specificity available which can identify patients who will go on to develop an α - synucleinopathy. Clinical assessment of a panel of markers (e.g. Postuma et al. 2015) are time-consuming and impractical in normal clinical settings, with the majority of patients presenting to sleep physicians, geriatricians, and non-specialised neurology clinics, both publicly and privately. This has a major impact on counselling strategies for RBD patients, appropriate follow-up, trials of novel neuro-protective agents in alpha-synucleinopathies before full-blown phenotype is manifest and enhancing understanding of pathways involved in RBD out-with the dopaminergic system.

RBD is a common, sometimes fatal disease (through injury to self/others) and treatments are indiscriminate regarding aetiology with limited evidence-base. A simple test using CSF (analogous to measuring CSF-orexin levels to diagnose narcolepsy+cataplexy) with high sensitivity and specificity is ideal. Thus, we believe that the central thesis of our work will not only inform subsequent behavioural, genetic and neuroimaging characterisation of our established RBD cohort, but will also translate the α-syn RT-QuIC concept into evidence-based and effective clinical practice.

Conditions

Sleep Disorder Rem Sleep Behavior; Parkinson's Disease, Lewy Body

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: CROSS_SECTIONAL

Interventions

No Intervention

No Intervention

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Patients diagnosed with Rapid Eye Movement Behaviour Disorder (RBD) using the International Classification of Sleep Disorders version 3 (ICSD-3) criteria [18] - Patients aged 18 years and over - Patient able to give written informed consent

Exclusion Criteria

• RBD secondary to medication or withdrawal state. - <18 years old - Inability to give written informed consent - Contraindication to lumbar puncture procedure (e.g. patients taking Warfarin)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Weston Brain Institute

OTHER

Sponsor Role: collaborator

University of Edinburgh

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Renata L Riha, MD

Role: PRINCIPAL_INVESTIGATOR

University of Edinburgh

Locations

The University of Edinburgh

Edinburgh, Lothian, United Kingdom

Countries

United Kingdom

References

Postuma RB, Gagnon JF, Bertrand JA, Genier Marchand D, Montplaisir JY. Parkinson risk in idiopathic REM sleep behavior disorder: preparing for neuroprotective trials. Neurology. 2015 Mar 17;84(11):1104-13. doi: 10.1212/WNL.0000000000001364. Epub 2015 Feb 13.

Reference Type: BACKGROUND

PMID: 25681454 (View on PubMed)

Iranzo A, Tolosa E, Gelpi E, Molinuevo JL, Valldeoriola F, Serradell M, Sanchez-Valle R, Vilaseca I, Lomena F, Vilas D, Llado A, Gaig C, Santamaria J. Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder: an observational cohort study. Lancet Neurol. 2013 May;12(5):443-53. doi: 10.1016/S1474-4422(13)70056-5. Epub 2013 Apr 3.

Reference Type: BACKGROUND

PMID: 23562390 (View on PubMed)

Boeve BF, Silber MH, Ferman TJ, Lin SC, Benarroch EE, Schmeichel AM, Ahlskog JE, Caselli RJ, Jacobson S, Sabbagh M, Adler C, Woodruff B, Beach TG, Iranzo A, Gelpi E, Santamaria J, Tolosa E, Singer C, Mash DC, Luca C, Arnulf I, Duyckaerts C, Schenck CH, Mahowald MW, Dauvilliers Y, Graff-Radford NR, Wszolek ZK, Parisi JE, Dugger B, Murray ME, Dickson DW. Clinicopathologic correlations in 172 cases of rapid eye movement sleep behavior disorder with or without a coexisting neurologic disorder. Sleep Med. 2013 Aug;14(8):754-62. doi: 10.1016/j.sleep.2012.10.015. Epub 2013 Mar 7.

Reference Type: BACKGROUND

PMID: 23474058 (View on PubMed)

Schenck CH, Boeve BF, Mahowald MW. Delayed emergence of a parkinsonian disorder or dementia in 81% of older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder: a 16-year update on a previously reported series. Sleep Med. 2013 Aug;14(8):744-8. doi: 10.1016/j.sleep.2012.10.009. Epub 2013 Jan 22.

Reference Type: BACKGROUND

PMID: 23347909 (View on PubMed)

Plomhause L, Dujardin K, Duhamel A, Delliaux M, Derambure P, Defebvre L, Monaca Charley C. Rapid eye movement sleep behavior disorder in treatment-naive Parkinson disease patients. Sleep Med. 2013 Oct;14(10):1035-7. doi: 10.1016/j.sleep.2013.04.018. Epub 2013 Jul 25.

Reference Type: BACKGROUND

PMID: 23890957 (View on PubMed)

Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003 Mar-Apr;24(2):197-211. doi: 10.1016/s0197-4580(02)00065-9.

Reference Type: BACKGROUND

PMID: 12498954 (View on PubMed)

Kim YK, Yoon IY, Kim JM, Jeong SH, Kim KW, Shin YK, Kim BS, Kim SE. The implication of nigrostriatal dopaminergic degeneration in the pathogenesis of REM sleep behavior disorder. Eur J Neurol. 2010 Mar;17(3):487-92. doi: 10.1111/j.1468-1331.2009.02854.x. Epub 2009 Nov 24.

Reference Type: BACKGROUND

PMID: 19968708 (View on PubMed)

Barber TR, Lawton M, Rolinski M, Evetts S, Baig F, Ruffmann C, Gornall A, Klein JC, Lo C, Dennis G, Bandmann O, Quinnell T, Zaiwalla Z, Ben-Shlomo Y, Hu MTM. Prodromal Parkinsonism and Neurodegenerative Risk Stratification in REM Sleep Behavior Disorder. Sleep. 2017 Aug 1;40(8):zsx071. doi: 10.1093/sleep/zsx071.

Reference Type: BACKGROUND

PMID: 28472425 (View on PubMed)

Puschmann A, Bhidayasiri R, Weiner WJ. Synucleinopathies from bench to bedside. Parkinsonism Relat Disord. 2012 Jan;18 Suppl 1:S24-7. doi: 10.1016/S1353-8020(11)70010-4.

Reference Type: BACKGROUND

PMID: 22166445 (View on PubMed)

Peelaerts W, Baekelandt V. a-Synuclein strains and the variable pathologies of synucleinopathies. J Neurochem. 2016 Oct;139 Suppl 1:256-274. doi: 10.1111/jnc.13595. Epub 2016 Mar 30.

Reference Type: BACKGROUND

PMID: 26924014 (View on PubMed)

Tyson T, Steiner JA, Brundin P. Sorting out release, uptake and processing of alpha-synuclein during prion-like spread of pathology. J Neurochem. 2016 Oct;139 Suppl 1(Suppl 1):275-289. doi: 10.1111/jnc.13449. Epub 2016 Feb 10.

Reference Type: BACKGROUND

PMID: 26617280 (View on PubMed)

El-Agnaf OM, Salem SA, Paleologou KE, Curran MD, Gibson MJ, Court JA, Schlossmacher MG, Allsop D. Detection of oligomeric forms of alpha-synuclein protein in human plasma as a potential biomarker for Parkinson's disease. FASEB J. 2006 Mar;20(3):419-25. doi: 10.1096/fj.03-1449com.

Reference Type: BACKGROUND

PMID: 16507759 (View on PubMed)

Tinsley RB, Kotschet K, Modesto D, Ng H, Wang Y, Nagley P, Shaw G, Horne MK. Sensitive and specific detection of alpha-synuclein in human plasma. J Neurosci Res. 2010 Sep;88(12):2693-700. doi: 10.1002/jnr.22417.

Reference Type: BACKGROUND

PMID: 20648655 (View on PubMed)

Foulds PG, Mitchell JD, Parker A, Turner R, Green G, Diggle P, Hasegawa M, Taylor M, Mann D, Allsop D. Phosphorylated alpha-synuclein can be detected in blood plasma and is potentially a useful biomarker for Parkinson's disease. FASEB J. 2011 Dec;25(12):4127-37. doi: 10.1096/fj.10-179192. Epub 2011 Aug 24.

Reference Type: BACKGROUND

PMID: 21865317 (View on PubMed)

Doppler K, Jentschke HM, Schulmeyer L, Vadasz D, Janzen A, Luster M, Hoffken H, Mayer G, Brumberg J, Booij J, Musacchio T, Klebe S, Sittig-Wiegand E, Volkmann J, Sommer C, Oertel WH. Dermal phospho-alpha-synuclein deposits confirm REM sleep behaviour disorder as prodromal Parkinson's disease. Acta Neuropathol. 2017 Apr;133(4):535-545. doi: 10.1007/s00401-017-1684-z. Epub 2017 Feb 8.

Reference Type: BACKGROUND

PMID: 28180961 (View on PubMed)

Fairfoul G, McGuire LI, Pal S, Ironside JW, Neumann J, Christie S, Joachim C, Esiri M, Evetts SG, Rolinski M, Baig F, Ruffmann C, Wade-Martins R, Hu MT, Parkkinen L, Green AJ. Alpha-synuclein RT-QuIC in the CSF of patients with alpha-synucleinopathies. Ann Clin Transl Neurol. 2016 Aug 28;3(10):812-818. doi: 10.1002/acn3.338. eCollection 2016 Oct.

Reference Type: BACKGROUND

PMID: 27752516 (View on PubMed)

Li SX, Wing YK, Lam SP, Zhang J, Yu MW, Ho CK, Tsoh J, Mok V. Validation of a new REM sleep behavior disorder questionnaire (RBDQ-HK). Sleep Med. 2010 Jan;11(1):43-8. doi: 10.1016/j.sleep.2009.06.008. Epub 2009 Nov 30.

Reference Type: BACKGROUND

PMID: 19945912 (View on PubMed)

Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991 Dec;14(6):540-5. doi: 10.1093/sleep/14.6.540.

Reference Type: BACKGROUND

PMID: 1798888 (View on PubMed)

Holmes TH, Rahe RH. The Social Readjustment Rating Scale. J Psychosom Res. 1967 Aug;11(2):213-8. doi: 10.1016/0022-3999(67)90010-4. No abstract available.

Reference Type: BACKGROUND

PMID: 6059863 (View on PubMed)

Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, Poewe W, Sampaio C, Stern MB, Dodel R, Dubois B, Holloway R, Jankovic J, Kulisevsky J, Lang AE, Lees A, Leurgans S, LeWitt PA, Nyenhuis D, Olanow CW, Rascol O, Schrag A, Teresi JA, van Hilten JJ, LaPelle N; Movement Disorder Society UPDRS Revision Task Force. Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord. 2008 Nov 15;23(15):2129-70. doi: 10.1002/mds.22340.

Reference Type: BACKGROUND

PMID: 19025984 (View on PubMed)

White C, Hill EA, Morrison I, Riha RL. Diagnostic delay in REM sleep behavior disorder (RBD). J Clin Sleep Med. 2012 Apr 15;8(2):133-6. doi: 10.5664/jcsm.1762.

Reference Type: BACKGROUND

PMID: 22505857 (View on PubMed)

Alberio T, Bossi AM, Milli A, Parma E, Gariboldi MB, Tosi G, Lopiano L, Fasano M. Proteomic analysis of dopamine and alpha-synuclein interplay in a cellular model of Parkinson's disease pathogenesis. FEBS J. 2010 Dec;277(23):4909-19. doi: 10.1111/j.1742-4658.2010.07896.x. Epub 2010 Oct 26.

Reference Type: BACKGROUND

PMID: 20977677 (View on PubMed)

Venda LL, Cragg SJ, Buchman VL, Wade-Martins R. alpha-Synuclein and dopamine at the crossroads of Parkinson's disease. Trends Neurosci. 2010 Dec;33(12):559-68. doi: 10.1016/j.tins.2010.09.004. Epub 2010 Oct 18.

Reference Type: BACKGROUND

PMID: 20961626 (View on PubMed)

Taylor TN, Potgieter D, Anwar S, Senior SL, Janezic S, Threlfell S, Ryan B, Parkkinen L, Deltheil T, Cioroch M, Livieratos A, Oliver PL, Jennings KA, Davies KE, Ansorge O, Bannerman DM, Cragg SJ, Wade-Martins R. Region-specific deficits in dopamine, but not norepinephrine, signaling in a novel A30P alpha-synuclein BAC transgenic mouse. Neurobiol Dis. 2014 Feb;62:193-207. doi: 10.1016/j.nbd.2013.10.005. Epub 2013 Oct 10.

Reference Type: BACKGROUND

PMID: 24121116 (View on PubMed)

Other Identifiers

AC20015

Identifier Type: -

Identifier Source: org_study_id