The Role of the Coagulation Pathway at the Synapse in Prion Diseases

NCT02480725 | Unknown

• 1 other identifier: 1702-14 SMC
• Study Type: observational
• Target: 50
• Locations: 0 countries
• Sites: N/A

Brief Summary

The study hypothesis is that that the deleterious effect of prions on the brain may be mediated (at least partially) by activation of serine proteases involved in the coagulation system. If this is true, then measurement of the activity of the coagulation system may be a marker of disease onset (in at higher risk individuals such as E200K\* carriers) and for disease progression or activity in affected individuals. In addition, modulation of the coagulation system activity may be a potential tool for therapeutic intervention. \*E200K- E200K mutation (Glu to Lys substitution) in the prion protein gene

Conditions

Creutzfeldt-Jakob Syndrome

Keywords

CJD; CSF; prion; thrombin

Outcome Measures

Primary Outcomes (1)

• Thrombin activity assay

  10 years

Study Arms (3)

CJD (Creutzfeldt-Jakob disease) patients

Prior to inclusion in the study a senior neurologist will interview the patient and will verify that he fully understands the objectives of the study and he is mentally qualified to sign the informed consent form (severely demented patients who will not be able to adequately consider the participation in the study will be excluded). Cognitive performance will be evaluated using the Mini-mental Status Examination and Frontal Assessment Battery scales. No clinical data other than the cognitive assessment and those needed for the clinical work up will be especially collected for this study. We plan to collect CSF samples for thrombin activity assay.

non-CJD patients with a type of dementia

Prior to inclusion in the study a senior neurologist will interview the patient and will verify that he fully understands the objectives of the study and he is mentally qualified to sign the informed consent form (severely demented patients who will not be able to adequately consider the participation in the study will be excluded). Cognitive performance will be evaluated using the Mini-mental Status Examination and Frontal Assessment Battery scales. No clinical data other than the cognitive assessment and those needed for the clinical work up will be especially collected for this study. We plan to collect CSF samples for thrombin activity assay.

Procedure: collect CSF (Cerebrospinal fluid) sample

CSF samples of non-CJD patient used as control

CSF samples : Thrombin activity will be assayed.

Interventions

collect CSF (Cerebrospinal fluid) sample PROCEDURE

collecting CSF samples for thrombin activity assay

non-CJD patients with a type of dementia

Eligibility Criteria

• Age: 35 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

CJD and non-CJD patients

You may qualify if:

• Patient undergoing lumbar puncture test as part of the investigation of cognitive decline.

You may not qualify if:

• Patients on anticoagulation or those who have contraindication for undergoing lumbar puncture.

Sponsors & Collaborators

• Sheba Medical Center: lead
• Prof. Zerr , Prion Referral Center , University of Gottingen, Germany: collaborator

Related Publications (29)

• Prusiner SB. Molecular biology of prion diseases. Science. 1991 Jun 14;252(5012):1515-22. doi: 10.1126/science.1675487.

  PMID: 1675487 BACKGROUND

• Harris DA, Lele P, Snider WD. Localization of the mRNA for a chicken prion protein by in situ hybridization. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4309-13. doi: 10.1073/pnas.90.9.4309.

  PMID: 8483948 BACKGROUND

• Windl O, Dempster M, Estibeiro P, Lathe R. A candidate marsupial PrP gene reveals two domains conserved in mammalian PrP proteins. Gene. 1995 Jul 4;159(2):181-6. doi: 10.1016/0378-1119(95)00064-d.

  PMID: 7622046 BACKGROUND

• Bueler H, Aguzzi A, Sailer A, Greiner RA, Autenried P, Aguet M, Weissmann C. Mice devoid of PrP are resistant to scrapie. Cell. 1993 Jul 2;73(7):1339-47. doi: 10.1016/0092-8674(93)90360-3.

  PMID: 8100741 BACKGROUND

• Collinge J, Whittington MA, Sidle KC, Smith CJ, Palmer MS, Clarke AR, Jefferys JG. Prion protein is necessary for normal synaptic function. Nature. 1994 Jul 28;370(6487):295-7. doi: 10.1038/370295a0.

  PMID: 8035877 BACKGROUND

• Tobler I, Gaus SE, Deboer T, Achermann P, Fischer M, Rulicke T, Moser M, Oesch B, McBride PA, Manson JC. Altered circadian activity rhythms and sleep in mice devoid of prion protein. Nature. 1996 Apr 18;380(6575):639-42. doi: 10.1038/380639a0.

  PMID: 8602267 BACKGROUND

• Aucouturier P, Geissmann F, Damotte D, Saborio GP, Meeker HC, Kascsak R, Kascsak R, Carp RI, Wisniewski T. Infected splenic dendritic cells are sufficient for prion transmission to the CNS in mouse scrapie. J Clin Invest. 2001 Sep;108(5):703-8. doi: 10.1172/JCI13155.

  PMID: 11544275 BACKGROUND

• Pan KM, Baldwin M, Nguyen J, Gasset M, Serban A, Groth D, Mehlhorn I, Huang Z, Fletterick RJ, Cohen FE, et al. Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):10962-6. doi: 10.1073/pnas.90.23.10962.

  PMID: 7902575 BACKGROUND

• Ellis V, Daniels M, Misra R, Brown DR. Plasminogen activation is stimulated by prion protein and regulated in a copper-dependent manner. Biochemistry. 2002 Jun 4;41(22):6891-6. doi: 10.1021/bi025676g.

  PMID: 12033920 BACKGROUND

• Epple G, Schleuning WD, Kettelgerdes G, Kottgen E, Gessner R, Praus M. Prion protein stimulates tissue-type plasminogen activator-mediated plasmin generation via a lysine-binding site on kringle 2. J Thromb Haemost. 2004 Jun;2(6):962-8. doi: 10.1111/j.1538-7836.2004.00675.x.

  PMID: 15140132 BACKGROUND

• Fischer MB, Roeckl C, Parizek P, Schwarz HP, Aguzzi A. Binding of disease-associated prion protein to plasminogen. Nature. 2000 Nov 23;408(6811):479-83. doi: 10.1038/35044100.

  PMID: 11100730 BACKGROUND

• Praus M, Kettelgerdes G, Baier M, Holzhutter HG, Jungblut PR, Maissen M, Epple G, Schleuning WD, Kottgen E, Aguzzi A, Gessner R. Stimulation of plasminogen activation by recombinant cellular prion protein is conserved in the NH2-terminal fragment PrP23-110. Thromb Haemost. 2003 May;89(5):812-9.

  PMID: 12719777 BACKGROUND

• Deininger MH, Trautmann K, Magdolen V, Luther T, Schluesener HJ, Meyermann R. Cortical neurons of Creutzfeldt-Jakob disease patients express the urokinase-type plasminogen activator receptor. Neurosci Lett. 2002 May 10;324(1):80-2. doi: 10.1016/s0304-3940(02)00168-4.

  PMID: 11983300 BACKGROUND

• Zerr I, Bodemer M, Kaboth U, Kretzschmar H, Oellerich M, Armstrong VW. Plasminogen activities and concentrations in patients with sporadic Creutzfeldt-Jakob disease. Neurosci Lett. 2004 Nov 23;371(2-3):163-6. doi: 10.1016/j.neulet.2004.08.063.

  PMID: 15519749 BACKGROUND

• Almeida LM, Basu U, Khaniya B, Taniguchi M, Williams JL, Moore SS, Guan LL. Gene expression in the medulla following oral infection of cattle with bovine spongiform encephalopathy. J Toxicol Environ Health A. 2011;74(2-4):110-26. doi: 10.1080/15287394.2011.529061.

  PMID: 21218340 BACKGROUND

• Chapman J. Coagulation in inflammatory diseases of the central nervous system. Semin Thromb Hemost. 2013 Nov;39(8):876-80. doi: 10.1055/s-0033-1357482. Epub 2013 Oct 9.

  PMID: 24108468 BACKGROUND

• Maggio N, Shavit E, Chapman J, Segal M. Thrombin induces long-term potentiation of reactivity to afferent stimulation and facilitates epileptic seizures in rat hippocampal slices: toward understanding the functional consequences of cerebrovascular insults. J Neurosci. 2008 Jan 16;28(3):732-6. doi: 10.1523/JNEUROSCI.3665-07.2008.

  PMID: 18199772 BACKGROUND

• Maggio N, Itsekson Z, Dominissini D, Blatt I, Amariglio N, Rechavi G, Tanne D, Chapman J. Thrombin regulation of synaptic plasticity: implications for physiology and pathology. Exp Neurol. 2013 Sep;247:595-604. doi: 10.1016/j.expneurol.2013.02.011. Epub 2013 Feb 27.

  PMID: 23454608 BACKGROUND

• Maggio N, Cavaliere C, Papa M, Blatt I, Chapman J, Segal M. Thrombin regulation of synaptic transmission: implications for seizure onset. Neurobiol Dis. 2013 Feb;50:171-8. doi: 10.1016/j.nbd.2012.10.017. Epub 2012 Oct 25.

  PMID: 23103417 BACKGROUND

• Shavit E, Beilin O, Korczyn AD, Sylantiev C, Aronovich R, Drory VE, Gurwitz D, Horresh I, Bar-Shavit R, Peles E, Chapman J. Thrombin receptor PAR-1 on myelin at the node of Ranvier: a new anatomy and physiology of conduction block. Brain. 2008 Apr;131(Pt 4):1113-22. doi: 10.1093/brain/awn005. Epub 2008 Feb 25.

  PMID: 18299297 BACKGROUND

• Shavit E, Michaelson DM, Chapman J. Anatomical localization of protease-activated receptor-1 and protease-mediated neuroglial crosstalk on peri-synaptic astrocytic endfeet. J Neurochem. 2011 Nov;119(3):460-73. doi: 10.1111/j.1471-4159.2011.07436.x. Epub 2011 Sep 23.

  PMID: 21854391 BACKGROUND

• Beilin O, Gurwitz D, Korczyn AD, Chapman J. Quantitative measurements of mouse brain thrombin-like and thrombin inhibition activities. Neuroreport. 2001 Aug 8;12(11):2347-51. doi: 10.1097/00001756-200108080-00013.

  PMID: 11496108 BACKGROUND

• Beilin O, Karussis DM, Korczyn AD, Gurwitz D, Aronovich R, Hantai D, Grigoriadis N, Mizrachi-Kol R, Chapman J. Increased thrombin inhibition in experimental autoimmune encephalomyelitis. J Neurosci Res. 2005 Feb 1;79(3):351-9. doi: 10.1002/jnr.20270.

  PMID: 15605378 BACKGROUND

• Beilin O, Karussis DM, Korczyn AD, Gurwitz D, Aronovich R, Mizrachi-Kol R, Chapman J. Increased KPI containing amyloid precursor protein in experimental autoimmune encephalomyelitis brains. Neuroreport. 2007 Apr 16;18(6):581-4. doi: 10.1097/WNR.0b013e328091c1e6.

  PMID: 17413661 BACKGROUND

• Itzekson Z, Maggio N, Milman A, Shavit E, Pick CG, Chapman J. Reversal of trauma-induced amnesia in mice by a thrombin receptor antagonist. J Mol Neurosci. 2014 May;53(1):87-95. doi: 10.1007/s12031-013-0200-8. Epub 2013 Dec 19.

  PMID: 24352712 BACKGROUND

• Bushi D, Chapman J, Katzav A, Shavit-Stein E, Molshatzki N, Maggio N, Tanne D. Quantitative detection of thrombin activity in an ischemic stroke model. J Mol Neurosci. 2013 Nov;51(3):844-50. doi: 10.1007/s12031-013-0072-y. Epub 2013 Jul 31.

  PMID: 23900720 BACKGROUND

• Cohen OS, Prohovnik I, Korczyn AD, Ephraty L, Nitsan Z, Tsabari R, Appel S, Rosenmann H, Kahana E, Chapman J. The Creutzfeldt-Jakob disease (CJD) neurological status scale: a new tool for evaluation of disease severity and progression. Acta Neurol Scand. 2011 Dec;124(6):368-74. doi: 10.1111/j.1600-0404.2011.01489.x. Epub 2011 Feb 8.

  PMID: 21303352 BACKGROUND

• Padilla D, Beringue V, Espinosa JC, Andreoletti O, Jaumain E, Reine F, Herzog L, Gutierrez-Adan A, Pintado B, Laude H, Torres JM. Sheep and goat BSE propagate more efficiently than cattle BSE in human PrP transgenic mice. PLoS Pathog. 2011 Mar;7(3):e1001319. doi: 10.1371/journal.ppat.1001319. Epub 2011 Mar 17.

  PMID: 21445238 BACKGROUND

• Llorens F, Zafar S, Ansoleaga B, Shafiq M, Blanco R, Carmona M, Grau-Rivera O, Nos C, Gelpi E, Del Rio JA, Zerr I, Ferrer I. Subtype and regional regulation of prion biomarkers in sporadic Creutzfeldt-Jakob disease. Neuropathol Appl Neurobiol. 2015 Aug;41(5):631-45. doi: 10.1111/nan.12175. Epub 2015 Apr 30.

  PMID: 25134744 BACKGROUND

Biospecimen

Retention: SAMPLES WITHOUT DNA

CSF samples

MeSH Terms

Conditions

Creutzfeldt-Jakob Syndrome; Insomnia, Fatal Familial

Condition Hierarchy (Ancestors)

Prion Diseases; Central Nervous System Infections; Infections; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Mental Disorders; Neurodegenerative Diseases; Sleep Initiation and Maintenance Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders

Study Officials

• Oren Cohen, Dr. (MD)

  Cheba Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Oren Cohen, Dr. (MD)

CONTACT

+972-52-6667584; coheno@asaf.health.gov.il

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: June 22, 2015
• First Posted: June 24, 2015
• Study Start: June 1, 2015
• Primary Completion: July 1, 2024
• Study Completion: July 1, 2025
• Last Updated: June 24, 2015

Record last verified: 2015-06