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

Parkinson's Disease, Lewy Body Clinical Trial

Official title:

Establishing Alpha-synuclein Real Time - Quaking Induced Conversion (RT-QuIC) Assay as a Diagnostic Technique in Rapid Eye Movement (REM) Sleep Behaviour Disorder (RBD)

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT04266457
• Other study ID #: AC20015
• Status: Withdrawn
• Start date: September 1, 2021
• Est. completion date: September 1, 2022

Study information

• Verified date: May 2021
• Source: University of Edinburgh
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: September 1, 2022
• Est. primary completion date: September 1, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Disease
• Mental Disorders
• Parkinson Disease
• Parkinson's Disease, Lewy Body
• REM Sleep Behavior Disorder
• Sleep Disorder Rem Sleep Behavior
• Sleep Wake Disorders

Intervention

Other:
• No Intervention
No Intervention

Locations

Country	Name	City	State
United Kingdom	The University of Edinburgh	Edinburgh	Lothian

Sponsors (2)

Lead Sponsor	Collaborator
University of Edinburgh	Weston Brain Institute

Country where clinical trial is conducted

United Kingdom, 

References & Publications (24)

Alberio T, Bossi AM, Milli A, Parma E, Gariboldi MB, Tosi G, Lopiano L, Fasano M. Proteomic analysis of dopamine and a-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. — View Citation

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). doi: 10.1093/sleep/zsx071. — View Citation

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. — View Citation

Braak H, Del Tredici K, Rüb 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. — View Citation

Doppler K, Jentschke HM, Schulmeyer L, Vadasz D, Janzen A, Luster M, Höffken 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. — View Citation

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. — View Citation

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. eCollection 2016 Oct. — View Citation

Foulds PG, Mitchell JD, Parker A, Turner R, Green G, Diggle P, Hasegawa M, Taylor M, Mann D, Allsop D. Phosphorylated a-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. — View Citation

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. — View Citation

Holmes TH, Rahe RH. The Social Readjustment Rating Scale. J Psychosom Res. 1967 Aug;11(2):213-8. — View Citation

Iranzo A, Tolosa E, Gelpi E, Molinuevo JL, Valldeoriola F, Serradell M, Sanchez-Valle R, Vilaseca I, Lomeña F, Vilas D, Lladó 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. — View Citation

Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991 Dec;14(6):540-5. — View Citation

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. — View Citation

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. — View Citation

Peelaerts W, Baekelandt V. ?-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. Review. — View Citation

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

Postuma RB, Gagnon JF, Bertrand JA, Génier 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. — View Citation

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. Review. — View Citation

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. — View Citation

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 a-synuclein BAC transgenic mouse. Neurobiol Dis. 2014 Feb;62:193-207. doi: 10.1016/j.nbd.2013.10.005. Epub 2013 Oct 10. — View Citation

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

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 1:275-289. doi: 10.1111/jnc.13449. Epub 2016 Feb 10. Review. — View Citation

Venda LL, Cragg SJ, Buchman VL, Wade-Martins R. a-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. Review. — View Citation

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. — View Citation

* Note: There are 24 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Presence of pathological a-synuclein within the cerebrospinal fluid (CSF)	The primary outcome measure will be either a positive/negative (binary) result from the a-syn RT-QuIC assay. A positive output confirms presence of pathological a-synuclein within the CSF.	0-24 months after sample taken