Alex Iranzo1, Graham Fairfoul2, Anutra Chumbala Na Ayudhaya2, Monica Serradell3, Ellen Gelpi4, Isabel Vilaseca5, Raquel Sanchez-Valle6, Carles Gaig3, Joan Santamaria3, Eduard Tolosa7, Renata L Riha8, Alison J E Green9. 1. Sleep Disorders Center, Neurology Service, Hospital Clínic Barcelona, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. Electronic address: airanzo@clinic.cat. 2. National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK. 3. Sleep Disorders Center, Neurology Service, Hospital Clínic Barcelona, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. 4. Neurological Tissue Bank, Biobanc-Hospital Clinic, IDIBAPS, Barcelona, Spain; Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria. 5. Otorhinolaryngology Service, Hospital Clínic de Barcelona, Universitat de Barcelona, Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR), IDIBAPS, Centro de Investigación Biomédica en Red (CIBER) Enfermedades Respiratorias, Bunyola, Spain. 6. Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic Barcelona, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. 7. Parkinson's Disease and Movement Disorders Unit, Neurology Service, Hospital Clínic Barcelona, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. 8. Sleep Research Unit, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK. 9. National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK. Electronic address: alison.green@ed.ac.uk.
Abstract
BACKGROUND: Isolated rapid-eye-movement (REM) sleep behaviour disorder (IRBD) can be part of the prodromal stage of the α-synucleinopathies Parkinson's disease and dementia with Lewy bodies. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has high sensitivity and specificity for the detection of misfolded α-synuclein in patients with Parkinson's disease and dementia with Lewy bodies. We investigated whether RT-QuIC could detect α-synuclein in the CSF of patients with IRBD and be used as a biomarker of prodromal α-synucleinopathy. METHODS: In this longitudinal observational study, CSF samples were obtained by lumbar puncture from patients with video polysomnography-confirmed IRBD recruited at a specialised sleep disorders centre in Barcelona, Spain, and from controls free of neurological disease. CSF samples were stored until analysed using RT-QuIC. After lumbar puncture, participants were assessed clinically for neurological status every 3-12 months. Rates of neurological disease-free survival were estimated using the Kaplan-Meier method. Disease-free survival rates were assessed from the date of lumbar puncture to the date of diagnosis of any neurodegenerative disease, or to the last follow-up visit for censored observations. FINDINGS: 52 patients with IRBD and 40 healthy controls matched for age (p=0·20), sex (p=0·15), and duration of follow-up (p=0·27) underwent lumbar puncture between March 23, 2008, and July 16, 2017. The CSF α-synuclein RT-QuIC assay was positive in 47 (90%) patients with IRBD and in four (10%) controls, resulting in a sensitivity of 90·4% (95% CI 79·4-95·8) and a specificity of 90·0% (95% CI 76·9-96·0). Mean follow-up from lumbar puncture until the end of the study (July 31, 2020) was 7·1 years (SD 2·8) in patients with IRBD and 7·7 years (2·9) in controls. During follow-up, 32 (62%) patients were diagnosed with Parkinson's disease or dementia with Lewy bodies a mean 3·4 years (SD 2·6) after lumbar puncture, of whom 31 (97%) were α-synuclein positive at baseline. Kaplan-Meier analysis showed that patients with IRBD who were α-synuclein negative had lower risk for developing Parkinson's disease or dementia with Lewy bodies at 2, 4, 6, 8, and 10 years of follow-up than patients with IRBD who were α-synuclein positive (log-rank test p=0·028; hazard ratio 0·143, 95% CI 0·019-1·063). During follow-up, none of the controls developed an α-synucleinopathy. Kaplan-Meier analysis showed that participants who were α-synuclein negative (ie, five patients with IRBD plus 36 controls) had lower risk of developing Parkinson's disease or dementia with Lewy bodies at 2, 4, 6, 8 and 10 years after lumbar puncture than participants who were α-synuclein positive (ie, 47 patients with IRBD plus four controls; log-rank test p<0·0001; hazard ratio 0·024, 95% CI 0·003-0·177). INTERPRETATION: In patients with IRBD, RT-QuIC detects misfolded α-synuclein in the CSF with both sensitivity and specificity of 90%, and α-synuclein positivity was associated with increased risk of subsequent diagnosis of Parkinson's disease or dementia with Lewy bodies. Detection of α-synuclein in the CSF represents a potential prodromal marker of Parkinson's disease and dementia with Lewy bodies. If these findings are replicated in additional cohorts, detection of CSF α-synuclein by RT-QuIC could be used to enrich IRBD cohorts in neuroprotective trials, particularly when assessing interventions that target α-synuclein. FUNDING: Department of Health and Social Care Policy Research Programme, the Scottish Government, and the Weston Brain Institute.
BACKGROUND: Isolated rapid-eye-movement (REM) sleep behaviour disorder (IRBD) can be part of the prodromal stage of the α-synucleinopathies Parkinson's disease and dementia with Lewy bodies. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has high sensitivity and specificity for the detection of misfolded α-synuclein in patients with Parkinson's disease and dementia with Lewy bodies. We investigated whether RT-QuIC could detect α-synuclein in the CSF of patients with IRBD and be used as a biomarker of prodromal α-synucleinopathy. METHODS: In this longitudinal observational study, CSF samples were obtained by lumbar puncture from patients with video polysomnography-confirmed IRBD recruited at a specialised sleep disorders centre in Barcelona, Spain, and from controls free of neurological disease. CSF samples were stored until analysed using RT-QuIC. After lumbar puncture, participants were assessed clinically for neurological status every 3-12 months. Rates of neurological disease-free survival were estimated using the Kaplan-Meier method. Disease-free survival rates were assessed from the date of lumbar puncture to the date of diagnosis of any neurodegenerative disease, or to the last follow-up visit for censored observations. FINDINGS: 52 patients with IRBD and 40 healthy controls matched for age (p=0·20), sex (p=0·15), and duration of follow-up (p=0·27) underwent lumbar puncture between March 23, 2008, and July 16, 2017. The CSF α-synuclein RT-QuIC assay was positive in 47 (90%) patients with IRBD and in four (10%) controls, resulting in a sensitivity of 90·4% (95% CI 79·4-95·8) and a specificity of 90·0% (95% CI 76·9-96·0). Mean follow-up from lumbar puncture until the end of the study (July 31, 2020) was 7·1 years (SD 2·8) in patients with IRBD and 7·7 years (2·9) in controls. During follow-up, 32 (62%) patients were diagnosed with Parkinson's disease or dementia with Lewy bodies a mean 3·4 years (SD 2·6) after lumbar puncture, of whom 31 (97%) were α-synuclein positive at baseline. Kaplan-Meier analysis showed that patients with IRBD who were α-synuclein negative had lower risk for developing Parkinson's disease or dementia with Lewy bodies at 2, 4, 6, 8, and 10 years of follow-up than patients with IRBD who were α-synuclein positive (log-rank test p=0·028; hazard ratio 0·143, 95% CI 0·019-1·063). During follow-up, none of the controls developed an α-synucleinopathy. Kaplan-Meier analysis showed that participants who were α-synuclein negative (ie, five patients with IRBD plus 36 controls) had lower risk of developing Parkinson's disease or dementia with Lewy bodies at 2, 4, 6, 8 and 10 years after lumbar puncture than participants who were α-synuclein positive (ie, 47 patients with IRBD plus four controls; log-rank test p<0·0001; hazard ratio 0·024, 95% CI 0·003-0·177). INTERPRETATION: In patients with IRBD, RT-QuIC detects misfolded α-synuclein in the CSF with both sensitivity and specificity of 90%, and α-synuclein positivity was associated with increased risk of subsequent diagnosis of Parkinson's disease or dementia with Lewy bodies. Detection of α-synuclein in the CSF represents a potential prodromal marker of Parkinson's disease and dementia with Lewy bodies. If these findings are replicated in additional cohorts, detection of CSF α-synuclein by RT-QuIC could be used to enrich IRBD cohorts in neuroprotective trials, particularly when assessing interventions that target α-synuclein. FUNDING: Department of Health and Social Care Policy Research Programme, the Scottish Government, and the Weston Brain Institute.
Authors: Moriah R Arnold; David G Coughlin; Barbara H Brumbach; Denis S Smirnov; Luis Concha-Marambio; Carly M Farris; Yihua Ma; Yongya Kim; Edward N Wilson; Jeffrey A Kaye; Annie Hiniker; Randy L Woltjer; Doug R Galasko; Joseph F Quinn Journal: Ann Neurol Date: 2022-07-29 Impact factor: 11.274
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Authors: Neus Falgàs; Ignacio Illán-Gala; Isabel E Allen; Paige Mumford; Youssef M Essanaa; Michael M Le; Michelle You; Lea T Grinberg; Howard J Rosen; Thomas C Neylan; Joel H Kramer; Christine M Walsh Journal: PLoS One Date: 2021-05-26 Impact factor: 3.240
Authors: Mitchell G Miglis; Charles H Adler; Elena Antelmi; Dario Arnaldi; Luca Baldelli; Bradley F Boeve; Matteo Cesari; Irene Dall'Antonia; Nico J Diederich; Kathrin Doppler; Petr Dušek; Raffaele Ferri; Jean-François Gagnon; Ziv Gan-Or; Wiebke Hermann; Birgit Högl; Michele T Hu; Alex Iranzo; Annette Janzen; Anastasia Kuzkina; Jee-Young Lee; Klaus L Leenders; Simon J G Lewis; Claudio Liguori; Jun Liu; Christine Lo; Kaylena A Ehgoetz Martens; Jiri Nepozitek; Giuseppe Plazzi; Federica Provini; Monica Puligheddu; Michal Rolinski; Jan Rusz; Ambra Stefani; Rebekah L S Summers; Dallah Yoo; Jennifer Zitser; Wolfgang H Oertel Journal: Lancet Neurol Date: 2021-08 Impact factor: 44.182