CoChat
Sign Up
Cited by 64Parkinson's Disease Mechanisms and TreatmentsNeuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatments

Emerging Immunotherapies for Parkinson Disease

Open access
Zella, Samis M. A., Metzdorf, Judith, Ciftci, Emine, Ostendorf, Friederike, Muhlack, Siegfried, Gold, Ralf, Tönges, Lars·2019·Neurology and Therapy
DOI 10.1007/s40120-018-0122-zPMC PMC6534677
Open this paper in CoChat — free accountOpen PDF

Abstract

Symptomatic treatment options for Parkinson disease have steadily improved, and individualized therapeutic approaches are becoming established for every stage of the disease. However, disease-modifying therapy with a causal approach is still unavailable. The central causative role of alpha-synuclein pathology, including its progressive spread to most areas of the CNS, has been widely recognized, and a strong involvement of immune responses has recently been discovered. New immunologic technologies have been shown to effectively prevent the progression of alpha-synuclein pathology in animal models. These approaches have recently been translated into the first human clinical trials, representing a novel starting point for the causal therapy of Parkinson disease. In this review, the pathomechanistic role of alpha-synuclein and its influence on the surrounding cellular environment are analyzed with a strong focus on immune responses and neuroinflammation. The potential of novel immunotherapeutic approaches that reduce the burden of alpha-synuclein pathology in the CNS is critically evaluated, and currently ongoing human clinical trials are presented. The clinical development of these new immunotherapies is progressing rapidly and gives reason to hope that a causal therapy of Parkinson disease could be possible in the foreseeable future.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1007/s40120-018-0122-z

Cites

7 of 7 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Three vaccines, AFFITOPE PD01A, AFFITOPE PD03A, and UB-312, are ongoing Phase II clinical trials.

    “Three of the vaccines, AFFITOPE PD01A, AFFITOPE PD03A, and UB-312, are ongoing Phase II clinical trials.49,558”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [558]

    The Active Immunization Strategies section says active anti-alpha-synuclein vaccines had only been studied in Phase I human trials. It identifies PD01A and PD03A as Phase I vaccines and says their clinical efficacy still needed to be demonstrated in Phase II studies, contrary to the claim that Phase II trials were ongoing. A search for UB-312 found no passage addressing it. (LLM, conf=0.90)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 69

  1. [1]Poewe W Seppi K Tanner CM Halliday GM Brundin P Volkmann J Parkinson disease Nat Rev Dis Primers. 2017 3 17013 10.1038/nrdp.2017.13 28332488 · DOI · Paper page
  2. [2]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 24 2 197 211 10.1016/S0197-4580(02)00065-9 12498954 · DOI · Paper page
  3. [3]Klingelhoefer L Reichmann H Pathogenesis of Parkinson disease—the gut-brain axis and environmental factorS NAT REV NEUROL. 2015 11 11 625 636 10.1038/nrneurol.2015.197 26503923 · DOI · Paper page
  4. [4]Walsh DM Selkoe DJ A critical appraisal of the pathogenic protein spread hypothesis of neurodegeneration Nat Rev Neurosci 2016 17 4 251 260 10.1038/nrn.2016.13 26988744 PMC6701169 · DOI
  5. [5]Tönges L Metzdorf J Zella S Parkinson's disease and neuroinflammation—Cellular pathology, mechanisms and therapeuticoptions Fortschr Neurol Psychiatr. 2018 86 S 01 S10 S20 10.1055/s-0044-101608 30016808 · DOI
  6. [6]Chitnis T Weiner HL CNS inflammation and neurodegeneration J Clin Invest. 2017 127 10 3577 3587 10.1172/JCI90609 28872464 PMC5617655 · DOI
  7. [7]Bendor JT Logan TP Edwards RH The function of alpha-synuclein Neuron 2013 79 6 1044 1066 10.1016/j.neuron.2013.09.004 24050397 PMC3866954 · DOI · Paper page
  8. [8]Braak H del Tredici K Neuropathological staging of brain pathology in sporadic Parkinson’s disease: separating the wheat from the chaff J Parkinsons Dis. 2017 7 S1 S71 S85 10.3233/JPD-179001 28282810 PMC5345633 · DOI · Paper page
  9. [9]Barbour R Kling K Anderson JP Banducci K Cole T Diep L Red blood cells are the major source of alpha-synuclein in blood Neurodegener Dis. 2008 5 2 55 59 10.1159/000112832 18182779 · DOI
  10. [10]Doppler K Jentschke HM Schulmeyer L Vadasz D Janzen A Luster M Dermal phospho-alpha-synuclein deposits confirm rem sleep behaviour disorder as prodromal Parkinson’s disease Acta Neuropathol. 2017 133 4 535 545 10.1007/s00401-017-1684-z 28180961 PMC5348554 · DOI
  11. [11]Dauer W Przedborski S Parkinson’s disease: mechanisms and models Neuron 2003 39 6 889 909 10.1016/S0896-6273(03)00568-3 12971891 · DOI · Paper page
  12. [12]Baba M Nakajo S Tu PH Tomita T Nakaya K Lee VM Aggregation of alpha-synuclein in lewy bodies of sporadic Parkinson’s disease and dementia with lewy bodies Am J Pathol. 1998 152 4 879 884 9546347 PMC1858234
  13. [13]Trinh J Farrer M Advances in the genetics of Parkinson disease Nat Rev Neurol. 2013 9 8 445 454 10.1038/nrneurol.2013.132 23857047 · DOI
  14. [14]Burré J Sharma M Tsetsenis T Buchman V Etherton MR Südhof TC Alpha-synuclein promotes snare-complex assembly in vivo and in vitro Science. 2010 329 5999 1663 1667 10.1126/science.1195227 20798282 PMC3235365 · DOI
  15. [15]Wong YC Krainc D Alpha-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies Nat Med 2017 23 2 1 13 10.1038/nm.4269 PMC8480197 28170377 · DOI · Paper page
  16. [16]Bridi JC Hirth F Mechanisms, of alpha-synuclein induced synaptopathy in Parkinson’s disease Front Neurosci. 2018 12 80 10.3389/fnins.2018.00080 29515354 PMC5825910 · DOI
  17. [17]Sudhof TC A molecular machine for neurotransmitter release: synaptotagmin and beyond Nat Med 2013 19 10 1227 1231 10.1038/nm.3338 24100992 · DOI
  18. [18]Lashuel HA Overk CR Oueslati A Masliah E The, many faces, of alpha-synuclein: from structure and toxicity to therapeutic target Nat Rev Neurosci 2013 14 1 38 48 10.1038/nrn3406 23254192 PMC4295774 · DOI
  19. [20]Bergstrom AL Kallunki P Fog K Development, of passive immunotherapies for synucleinopathies Mov Disord 2016 31 2 203 213 10.1002/mds.26481 26704735 · DOI
  20. [21]Burre J Sharma M Sudhof TC Definition of a molecular pathway mediating alpha-synuclein neurotoxicity J Neurosci. 2015 35 13 5221 5232 10.1523/JNEUROSCI.4650-14.2015 25834048 PMC4380997 · DOI
  21. [22]Marques O Outeiro TF Alpha-synuclein: from secretion to dysfunction and death Cell Death Dis. 2012 3 E350 10.1038/cddis.2012.94 22825468 PMC3406593 · DOI
  22. [23]Volpicelli-Daley LA Luk KC Patel TP Tanik SA Riddle DM Stieber A Exogenous alpha-synuclein fibrils induce lewy body pathology leading to synaptic dysfunction and neuron death Neuron 2011 72 1 57 71 10.1016/j.neuron.2011.08.033 21982369 PMC3204802 · DOI · Paper page
  23. [24]Volpicelli-Daley LA Luk KC Lee VM Addition, of exogenous alpha-synuclein preformed fibrils to primary neuronal cultures to seed recruitment of endogenous alpha-synuclein to lewy body and lewy neurite-like aggregates Nat Protoc 2014 9 9 2135 2146 10.1038/nprot.2014.143 25122523 PMC4372899 · DOI · Paper page
  24. [25]Brahic M Bousset L Bieri G Melki R Gitler AD Axonal transport and secretion of fibrillar forms of alpha-synuclein, ABETA42 peptide and httexon 1 Acta Neuropathol. 2016 131 4 539 548 10.1007/s00401-016-1538-0 26820848 PMC4789229 · DOI
  25. [26]Mao X Ou MT Karuppagounder SS Kam TI Yin X Xiong Y Pathological alpha-synuclein transmission initiated by binding lymphocyte-activation gene 3 Science. 2016 353 6307 aah3374 10.1126/science.aah3374 27708076 PMC5510615 · DOI
  26. [28]Diogenes MJ Dias RB Rombo DM Vicente Miranda H Maiolino F Guerreiro P Extracellular alpha-synuclein oligomers modulate synaptic transmission and impair LTP via NMDA-receptor activation J Neurosci. 2012 32 34 11750 11762 10.1523/JNEUROSCI.0234-12.2012 22915117 PMC6703775 · DOI
  27. [29]Peelaerts W Bousset L van der Perren A Moskalyuk A Pulizzi R Giugliano M Alpha-synuclein strains cause distinct synucleinopathies after local and systemic administration Nature 2015 522 7556 340 344 10.1038/nature14547 26061766 · DOI · Paper page
  28. [30]Luk KC Kehm V Carroll J Zhang B O’Brien P Trojanowski JQ Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice Science 2012 338 6109 949 953 10.1126/science.1227157 23161999 PMC3552321 · DOI · Paper page
  29. [31]Tonges L Szego EM Hause P Saal KA Tatenhorst L Koch JC Alpha-synuclein mutations impair axonal regeneration in models of Parkinson’s disease Front Aging Neurosci. 2014 6 239 25309425 PMC4159996
  30. [35]Dexter DT Jenner P Parkinson disease: from pathology to molecular disease mechanisms Free Radic Biol Med. 2013 62 132 144 10.1016/j.freeradbiomed.2013.01.018 23380027 · DOI
  31. [36]Gustafsson G Lindstrom V Rostami J Nordstrom E Lannfelt L Bergstrom J Alpha-synuclein oligomer-selective antibodies reduce intracellular accumulation and mitochondrial impairment in alpha-synuclein exposed astrocytes J Neuroinflammation. 2017 14 1 241 10.1186/s12974-017-1018-z 29228971 PMC5725978 · DOI
  32. [37]Soulet D Rivest S Microglia Curr Biol 2008 18 12 R506 R508 10.1016/j.cub.2008.04.047 18579087 · DOI
  33. [38]Wolf SA Boddeke HW Kettenmann H Microglia in physiology and diseaSE Annu Rev Physiol. 2017 79 619 643 10.1146/annurev-physiol-022516-034406 27959620 · DOI · Paper page
  34. [39]Hoffmann A Ettle B Bruno A Kulinich A Hoffmann AC Von Wittgenstein J Alpha-synuclein activates BV2 microglia dependent on its aggregation state Biochem Biophys Res Commun. 2016 479 4 881 886 10.1016/j.bbrc.2016.09.109 27666480 · DOI
  35. [41]Hoenen C Gustin A Birck C Kirchmeyer M Beaume N Felten P Alpha-synuclein proteins promote pro-inflammatory cascades in microglia: stronger effects of the A53T mutant PLoS One 2016 11 9 E0162717 10.1371/journal.pone.0162717 27622765 PMC5021287 · DOI · Paper page
  36. [42]Bergström AL Kallunki P Fog K Development, of passive immunotherapies for synucleinopathies Mov Disord 2016 31 2 203 213 10.1002/mds.26481 26704735 · DOI
  37. [43]Bruck D Wenning GK Stefanova N Fellner L Glia and alpha-synuclein in neurodegeneration: a complex interaction Neurobiol Dis. 2016 85 262 274 10.1016/j.nbd.2015.03.003 25766679 PMC4730552 · DOI
  38. [44]Games D Valera E Spencer B Rockenstein E Mante M Adame A Reducing C-TERMINAL-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson’s disease-like models J Neurosci 2014 34 28 9441 9454 10.1523/JNEUROSCI.5314-13.2014 25009275 PMC4087215 · DOI
  39. [45]Mandler M Valera E Rockenstein E Mante M Weninger H Patrick C Active immunization against alpha-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multiple system atrophy Mol Neurodegener. 2015 10 10 10.1186/s13024-015-0008-9 25886309 PMC4411775 · DOI
  40. [46]Sardi SP Cedarbaum JM Brundin P Targeted therapies for Parkinson’s disease: from genetics to the clinic Mov Disord 2018 33 5 684 696 10.1002/mds.27414 29704272 PMC6282975 · DOI
  41. [47]Rockenstein E Mallory M Hashimoto M Song D Shults CW Lang I Differential neuropathological alterations in transgenic mice expressing alpha-synuclein from the platelet-derived growth factor and Thy-1 promoters J Neurosci Res 2002 68 5 568 578 10.1002/jnr.10231 12111846 · DOI · Paper page
  42. [48]Masliah E Rockenstein E Adame A Alford M Crews L Hashimoto M Effects of alpha-synuclein immunization in a mouse model of Parkinson’s disease Neuron 2005 46 6 857 868 10.1016/j.neuron.2005.05.010 15953415 · DOI · Paper page
  43. [49]Lobello K Ryan JM Liu E Rippon G Black R Targeting Beta amyloid: a clinical review of immunotherapeutic approaches in Alzheimer's disease Int J Alzheimers Dis. 2012 2012 628070 10.1155/2012/628070 22292124 PMC3265072 · DOI
  44. [50]Ghochikyan A Petrushina I Davtyan H Hovakimyan A Saing T Davtyan A Immunogenicity of epitope vaccines targeting differenT B cell antigenic determinants of human α-synuclein: feasibility study Neurosci Lett 2014 560 86 91 10.1016/j.neulet.2013.12.028 24361548 PMC3928627 · DOI
  45. [51]Mandler M Valera E Rockenstein E Weninger H Patrick C Adame A Next-generation active immunization approach for synucleinopathies: implications for parkinson’s disease clinical trials Acta Neuropathol 2014 127 6 861 879 10.1007/s00401-014-1256-4 24525765 PMC4034750 · DOI
  46. [52]Villadiego J Labrador-Garrido A Franco JM Leal-Lasarte M De Genst EJ Dobson CM Immunization with Α-Synuclein/Grp94 reshapes peripheral immunity and suppresses microgliosis in a chronic Parkinsonism model GLIA. 2018 66 1 191 205 10.1002/glia.23237 29024008 · DOI
  47. [53]Kingwell K Zeroing in on neurodegenerative Α-synuclein Nat Rev Drug Discov. 2017 16 6 371 373 10.1038/nrd.2017.95 28559555 · DOI
  48. [54]Valera E Masliah E Immunotherapy for neurodegenerative diseases: focus on Α-synucleinopathies Pharmacol Ther 2013 138 3 311 322 10.1016/j.pharmthera.2013.01.013 23384597 PMC3925783 · DOI · Paper page
  49. [55]Affiris announces encouraging long-term data from a series of first-in-human studies using Affitope® PD01A targeting oligomeric alpha-synuclein in early Parkinson’s disease Patients [Press Release]. 2018.
  50. [56]Affiris announces top line results of first-in-human clinical study using AFFITOPE®PD03A, Confirming immunogenicity and safety profile In Parkinson’s disease patients [Press Release]. 2017. http://www.affiris.com/news/affiris-announces-top-line-results-of-first-in-human-clinical-study-using-affitope/.
  51. [57]Masliah E Rockenstein E Mante M Crews L Spencer B Adame A Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of lewy body disease PLoS One 2011 6 4 E19338 10.1371/journal.pone.0019338 21559417 PMC3084838 · DOI
  52. [58]Mishizen-Eberz AJ Norris EH Giasson BI Hodara R Ischiropoulos H Lee VM Cleavage of alpha-synuclein by calpain: potential role in degradation of fibrillized and nitrated species of alpha-synuclein Biochemistry 2005 44 21 7818 7829 10.1021/bi047846q 15909996 · DOI
  53. [59]Tofaris GK Garcia Reitböck P Humby T Lambourne SL O’Connell M Ghetti B Pathological changes in dopaminergic nerve cells of the substantia nigra and olfactory bulb in mice transgenic for truncated human alpha-synuclein(1-120): implications for lewy body disorders J Neurosci 2006 26 15 3942 3950 10.1523/JNEUROSCI.4965-05.2006 16611810 PMC6673887 · DOI
  54. [60]Bae EJ Lee HJ Rockenstein E Ho DH Park EB Yang NY Antibody-aided clearance of extracellular Α-synuclein prevents cell-to-cell aggregate transmission J Neurosci 2012 32 39 13454 13469 10.1523/JNEUROSCI.1292-12.2012 23015436 PMC3752153 · DOI · Paper page
  55. [61]Fleming SM Salcedo J Fernagut PO Rockenstein E Masliah E Levine MS Early and progressive sensorimotor anomalies in mice overexpressing wild-type human alpha-synuclein J Neurosci 2004 24 42 9434 9440 10.1523/JNEUROSCI.3080-04.2004 15496679 PMC6730110 · DOI
  56. [62]Shahaduzzaman M Nash K Hudson C Sharif M Grimmig B Lin X anti-human Α-synuclein N-terminal peptide antibody protects against dopaminergic cell death and ameliorates behavioral deficits in an aav-α-synuclein rat model of Parkinson’s Disease PLoS One 2015 10 2 E0116841 10.1371/journal.pone.0116841 25658425 PMC4319932 · DOI
  57. [63]Tran HT Chung CH Iba M Zhang B Trojanowski JQ Luk KC Α-synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration Cell Rep. 2014 7 6 2054 2065 10.1016/j.celrep.2014.05.033 24931606 PMC4410967 · DOI
  58. [64]Kahle PJ Neumann M Ozmen L Muller V Jacobsen H Schindzielorz A Subcellular localization of wild-type and Parkinson’s disease-associated mutant alpha-synuclein in human and transgenic mouse brain J Neurosci 2000 20 17 6365 6373 10.1523/JNEUROSCI.20-17-06365.2000 10964942 PMC6772969 · DOI
  59. [65]Lindström V Fagerqvist T Nordström E Eriksson F Lord A Tucker S Immunotherapy targeting α-synuclein protofibrils reduced pathology iN (THY-1)-H[A30P] α-synuclein mice Neurobiol Dis 2014 69 134 143 10.1016/j.nbd.2014.05.009 24851801 · DOI
  60. [66]Gustafsson G Eriksson F Möller C Da Fonseca TL Outeiro TF LannfelT L Cellular uptake of α-synuclein oligomer-selective antibodies is enhanced by the extracellular presence of α-synuclein and mediated via Fcγ ReceptorS Cell Mol Neurobiol 2017 37 1 121 131 10.1007/s10571-016-0352-5 26961542 PMC11482100 · DOI
  61. [67]El-Agnaf O Overk C Rockenstein E Mante M Florio J Adame A Differential effects of immunotherapy with antibodies targeting α-synuclein oligomers and fibrils in a transgenic model of synucleinopathy Neurobiol Dis 2017 104 85 96 10.1016/j.nbd.2017.05.002 28476636 PMC5954414 · DOI
  62. [68]Schenk DB Koller M Ness DK Griffith SG Grundman M Zago W First-in-human assessment of PRX002, an anti-alpha-synuclein monoclonal antibody, in healthy volunteers Mov Disord. 2017 32 2 211 218 10.1002/mds.26878 27886407 PMC5324684 · DOI
  63. [69]Jankovic J Goodman I Safirstein B Marmon TK Schenk DB Koller M Safety and tolerability of multiple ascending doses of PRX002/RG7935, an anti-α-synuclein monoclonal antibody, in patients with parkinson disease: a randomized clinical trial JAMA Neurol. 2018 75 10 1206 1214 10.1001/jamaneurol.2018.1487 29913017 PMC6233845 · DOI
  64. [72]Bioarctic enters into collaboration with abbvie for parkinson disease research [Press Release]. 2018. https://www.bioarctic.se/en/section/media/press-releases/
  65. [74]Zepp F Principles of vaccination Methods Mol Biol 2016 1403 57 84 10.1007/978-1-4939-3387-7_3 27076125 · DOI
  66. [75]Guy B The perfect mix: recent progress in adjuvant research Nat Rev Microbiol 2007 5 7 505 517 10.1038/nrmicro1681 17558426 · DOI
  67. [76]Tabira T Immunization therapy for alzheimer disease: a comprehensive review of active immunization strategies Tohoku J Exp Med 2010 220 2 95 106 10.1620/tjem.220.95 20139660 · DOI
  68. [77]Penninkilampi R Brothers HM Eslick GD Safety and efficacy of anti-amyloid-beta immunotherapy in Alzheimer’s disease: a systematic review and meta-analysis J Neuroimmune Pharmacol. 2017 12 1 194 203 10.1007/s11481-016-9722-5 28025724 · DOI
  69. [78]Brys I Halje P Scheffer-Teixeira R Varney M Newman-Tancredi A Petersson P Neurophysiological effects in cortico-basal ganglia-thalamic circuits of antidyskinetic treatment with 5-HT1A receptor biased agonists Exp Neurol. 2018 302 155 168 10.1016/j.expneurol.2018.01.010 29339052 · DOI

Cited by

Sorted by citations

Authors
Zella, S. M. A., Metzdorf, J., Ciftci, E., Ostendorf, F., Muhlack, S., Gold, R., & Tönges, L.
Affiliations
St. Josef-Hospital (DE)
Corresponding author
Tönges, Lars
ORCID
Venue
Neurology and Therapy
Publisher
Springer Science and Business Media LLC
Published
2018-12-11
Volume
8
Issue
1
Pages
29-44
ISSN
  • 2193-6536 (ISSN-L)
  • 2193-8253
DOI
10.1007/s40120-018-0122-z
PMC
PMC6534677
OpenAlex
W2905442324
Cited by
64
References
7
Citations by year
2026: 2 · 2025: 5 · 2024: 4 · 2023: 10 · 2022: 8 · 2021: 10 · 2020: 17 · 2019: 8
FWCI
1.38
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurology and Therapy (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
Parkinson's disease, immunotherapy, alpha-synuclein, neuroinflammation, disease-modifying therapy, causal therapy, immune response, clinical trials, neurodegeneration

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review