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1. Iatrogenic Creutzfeldt-Jakob disease with Amyloid-β pathology: an international study

Author: Ignazio Cali, Mark L. Cohen, Stéphane Haїk, Piero Parchi, Giorgio Giaccone, Steven J. Collins, Diane Kofskey, Han Wang, Catriona A. McLean, Jean-Philippe Brandel, Nicolas Privat, Véronique Sazdovitch, Charles Duyckaerts, Tetsuyuki Kitamoto, Ermias D. Belay, Ryan A. Maddox, Fabrizio Tagliavini, Maurizio Pocchiari, Ellen Leschek, Brian S. Appleby, Jiri G. Safar, Lawrence B. Schonberger, and Pierluigi Gambetti
Subjects: Amyloid-β, Pathology, iCJD, Cerebral amyloid angiopathy, Thioflavin S, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract The presence of pathology related to the deposition of amyloid-β (Aβ) has been recently reported in iatrogenic Creutzfeldt-Jakob disease (iCJD) acquired from inoculation of growth hormone (GH) extracted from human cadaveric pituitary gland or use of cadaveric dura mater (DM) grafts. To investigate this phenomenon further, a cohort of 27 iCJD cases – 21 with adequate number of histopathological sections – originating from Australia, France, Italy, and the Unites States, were examined by immunohistochemistry, amyloid staining, and Western blot analysis of the scrapie prion protein (PrPSc), and compared with age-group matched cases of sporadic CJD (sCJD), Alzheimer disease (AD) or free of neurodegenerative diseases (non-ND). Cases of iCJD and sCJD shared similar profiles of proteinase K-resistant PrPSc with the exception of iCJD harboring the “MMi” phenotype. Cerebral amyloid angiopathy (CAA), either associated with, or free of, Thioflavin S-positive amyloid core plaques (CP), was observed in 52% of 21 cases of iCJD, which comprised 37.5% and 61.5% of the cases of GH- and DM-iCJD, respectively. If only cases younger than 54 years were considered, Aβ pathology affected 41%, 2% and 0% of iCJD, sCJD and non-ND, respectively. Despite the patients’ younger age CAA was more severe in iCJD than sCJD, while Aβ diffuse plaques, in absence of Aβ CP, populated one third of sCJD. Aβ pathology was by far most severe in AD. Tau pathology was scanty in iCJD and sCJD. In conclusion, (i) despite the divergences in the use of cadaveric GH and DM products, our cases combined with previous studies showed remarkably similar iCJD and Aβ phenotypes indicating that the occurrence of Aβ pathology in iCJD is a widespread phenomenon, (ii) CAA emerges as the hallmark of the Aβ phenotype in iCJD since it is observed in nearly 90% of all iCJD with Aβ pathology reported to date including ours, and it is shared by GH- and DM-iCJD, (iii) although the contributions to Aβ pathology of other factors, including GH deficiency, cannot be discounted, our findings increase the mounting evidence that this pathology is acquired by a mechanism resembling that of prion diseases.
Published: 2018
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2. Genetic Testing in Prion Disease: Psychological Consequences of the Decisions to Know or Not to Know

Author: Mathias Schwartz, Jean-Philippe Brandel, Marie Lise Babonneau, Christilla Boucher, Elodie Schaerer, Stephane Haik, Jean Louis Laplanche, Marcela Gargiulo, and Alexandra Durr
Subjects: PRNP, presymptomatic testing, prion, psychological scales, anxiety, Genetics, QH426-470
Abstract: Purpose: Presymptomatic testing for susceptibility to genetic prion diseases is often delivered in difficult circumstances, as the index case is often dying when a genetic diagnosis is obtained. Since test requests in these diseases are very rare, the factors underlying decisions of relatives to be tested or not and the long-term psychological consequences are not reported.Methods: We contacted subjects who had consulted between 2004 and 2017 because a relative carried a pathological PRNP variant. Standardized psychological scales and semistructured interviews were proposed.Results: We did contact 19 of the 30 subjects who had consulted: 6 of 10 who did not undergo testing, 10 of 12 noncarriers, and 3 of 8 mutation carriers. Anxiety rates were high and similar between noncarriers and untested subjects.Conclusions: Living in a family with inherited prion disease produced psychological burden, regardless of the decision to undergo testing and its results. Decisions in favor of being testing did not allow relief of anxiety about the family disease. The dilemmatic decision not to know remained a burden to be coped with. Genetic counseling procedures should take into account all these situations, even that of noncarriers and that of untested.
Published: 2019
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3. The role of environmental factors on sporadic Creutzfeldt-Jakob disease mortality: evidence from an age-period-cohort analysis

Author: Angéline Denouel, Jean-Philippe Brandel, Danielle Seilhean, Jean-Louis Laplanche, Alexis Elbaz, and Stéphane Haik
Subjects: Epidemiology
Abstract: Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common form of prion diseases. The causes of sCJD are still unknown and exogenous factors may play a role. Worldwide, the number of patients with sCJD has progressively increased over time. This increase can be partly explained by increasing life expectancy and better case ascertainment, but a true increase in the number of sCJD cases cannot be excluded. We estimated mortality rates from sCJD in France (1992–2016) and studied variation in mortality rates by age, period, and time.We included all cases aged 45–89 years old who died with a probable/definite sCJD diagnosis based on the French national surveillance network. We used age-period-cohort (APC) Poisson regression models to study variation in mortality rates by sex, age, period, and time.A total of 2475 sCJD cases aged 45–89 years were included. Mortality rates increased with age, reached a peak between 75 and 79 years, and decreased thereafter. Mortality rates were higher in women than men at younger ages and lower at older ages. The full APC model with a sex×age interaction provided the best fit to the data, thus in favour of sex, age, period, and cohort effects on mortality rates. In particular, mortality rates increased progressively with successive birth cohorts.Based on 25 years of active surveillance in France, we show evidence for sex, age, period, and cohort effects on sCJD mortality. The identification of cohort effects suggests that environmental exposures may play a role in sCJD etiology.
Published: 2023
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4. Personality Assessment with Temperament and Character Inventory in Parkinson's Disease

Author: Mathilde Boussac, Christophe Arbus, Olivier Colin, Chloé Laurencin, Alexandre Eusebio, Elodie Hainque, Jean Christophe Corvol, Nathalie Versace, Olivier Rascol, Vanessa Rousseau, Estelle Harroch, Fabienne Ory-Magne, Margherita Fabbri, Caroline Moreau, Anne-Sophie Rolland, Béchir Jarraya, David Maltête, Sophie Drapier, Ana-Raquel Marques, Nicolas Auzou, Thomas Wirth, Mylène Meyer, Bruno Giordana, Mélissa Tir, Tiphaine Rouaud, David Devos, Christine Brefel-Courbon, Pr Luc Defebvre, Dr Nicolas Carriere, Dr Guillaume Grolez, Dr Guillaume Baille, Dr Kreisler, Pr Jean-Pierre Pruvo, Pr Leclerc, Dr Renaud Lopes, Dr Romain Viard, Dr Gregory Kuchcinski, Mr Julien Dumont, Pr Kathy Dujardin, Mme M. Delliaux, Mrs M. Brion, Dr Gustavo Touzet, Pr Nicolas Reyns, Pr Arnaud Delval, Mrs Valerie Santraine, Mrs Marie Pleuvret, Mrs Nolwen Dautrevaux, Mr Victor Laugeais, Thavarak Ouk, Camille Potey, Celine Leclercq, Elise Gers, Jean-Christophe Corvol, null Marie-Vidailhet, Marie-Laure Welter, Lucette Lacomblez, David Grabli, Emmanuel Roze, Yulia Worbe, Cécile Delorme, Hana You, Jonas Ihle, Raquel Guimeraes-Costa, Florence Cormier-Dequaire, Aurélie Méneret, Andréas Hartmann, Louise-Laure Mariani, Stéphane Lehericy, Virginie Czernecki, Fanny Pineau, Frédérique Bozon, Camille Huiban, Eve Benchetrit, Carine Karachi, Soledad Navarro, Philippe Cornu, Arlette Welaratne, Carole Dongmo-Kenfack, Lise Mantisi, Nathalie Jarry, Sophie Aix, Carine Lefort, Dr Tiphaine Rouaud, Pr Philippe Damier, Pr Pascal Derkinderen, Dr Anne-Gaelle Corbille, Dr Elisabeth Calvier-Auffray, Mrs Laetitia Rocher, Mrs Anne-Laure Deruet, Dr Raoul Sylvie, Dr Roualdes Vincent, Mrs Le Dily Séverine, Dr Ana Marques, Dr Berangere Debilly, Pr Franck Durif, Dr Philippe Derost, Dr Charlotte Beal, Carine Chassain, Laure Delaby, Tiphaine Vidal, Pr Jean Jacques Lemaire, Isabelle Rieu, Elodie Durand, Pr Alexandre Eusebio, Pr Jean-Philippe Azulay, Dr Tatiana Witjas, Dr Frédérique Fluchère, Dr Stephan Grimaldi, Pr Nadine Girard, Marie Delfini, Dr Romain Carron, Pr Jean Regis, Dr Giorgio Spatola, Camille Magnaudet, Dr Ansquer Solène, Dr Benatru Isabelle, Dr Colin Olivier, Pr Houeto Jl, Pr Guillevin Remy, Mrs Fradet Anne, Mrs Anziza Manssouri, Mrs Blondeau Sophie, Dr Richard Philippe, Dr Cam Philippe, Dr Page Philippe, Pr Bataille Benoit, Mrs Rabois Emilie, Mrs Guillemain Annie, Dr Drapier Sophie, Dr Frédérique Leh, Dr Alexandre Bonnet, Pr Marc Vérin, Dr Jean-Christophe Ferré, Mr Jean François Houvenaghel, Pr Claire Haegelen, Mrs Francoise Kestens, Mrs Solenn Ory, Pr Pierre Burbaud, Dr Nathalie Damon-Perriere, Pr Wassilios Meissner, Pr Francois Tison, Dr Stéphanie Bannier, Dr Elsa Krim, Pr Dominique Guehl, Sandrine Molinier-Blossier, Morgan Ollivier, Marion Lacoste, Marie Bonnet, Pr Emmanuel Cuny, Dr Julien Engelhardt, Olivier Branchard, Clotilde Huet, Julie Blanchard, Pr Rascol Olivier, Dr Christine Brefel Courbon, Dr Fabienne Ory Magne, Dr Marion Simonetta Moreau, Pr Christophe Arbus, Pr Fabrice Bonneville, Dr Jean Albert Lotterie, Marion Sarrail, Charlotte Scotto d’Apollonia, Pr Patrick Chaynes, Pr François Caire, Pr David Maltete, Dr Romain Lefaucheur, Dr Damien Fetter, Dr Nicolas Magne, Mrs Sandrine Bioux, Mrs Maud Loubeyre, Mrs Evangéline Bliaux, Mrs Dorothée Pouliquen, Pr Stéphane Derrey, Mrs Linda Vernon, Dr Frédéric Ziegler, Mathieu Anheim, Ouhaid Lagha-Boukbiza, Christine Tranchant, Odile Gebus, Solveig Montaut, S. Kremer, Nadine Longato, Clélie Phillips, Jimmy Voirin, Marie des Neiges Santin, Dominique Chaussemy, Dr Amaury Mengin, Dr Caroline Giordana, Dr Claire Marsé, Lydiane Mondot, Robin Kardous, Bernadette Bailet, Héloise Joly, Denys Fontaine, Dr Aurélie Leplus, Amélie Faustini, Vanessa Ferrier, Pr Pierre Krystkowiak, Dr Mélissa Tir, Pr Jean-Marc Constans, Sandrine Wannepain, Audrey Seling, Dr Michel Lefranc, Stéphanie Blin, Béatrice Schuler, Pr Stephane Thobois, Dr Teodor Danaila, Dr Chloe Laurencin, Pr Yves Berthezene, Dr Roxana Ameli, Helene Klinger, Dr Gustavo Polo, Patrick Mertens, A. Nunes, Elise Metereau, Dr Lucie Hopes, Dr Solène Frismand, Dr Emmanuelle Schmitt, Mrs Mylène Meyer, Mrs Céline Dillier, Pr Sophie Colnat, Mrs Anne Chatelain, Dr Jean- Philippe Brandel, Dr Cécile Hubsch, Dr Patte Karsenti, Dr Marie Lebouteux, Dr Marc Ziegler, Dr Christine Delmaire, Dr Julien Savatowky, Mrs Juliette Vrillac, Mrs Claire Nakache, Dr Vincent D'Hardemare, Mr Lhaouas Belamri, Dr Valérie Mesnage, Dr Cécilia Bonnet, Dr Jarbas Correa Lino, Dr Camille Decrocq, Dr Anne Boulin, Mrs Inès Barre, Mrs Jordane Manouvrier, Dr Bérénice Gardel, Pr Béchir Jarraya, Mrs Catherine Ziz, Mrs Lydie Prette, Mr Hassen Douzane, David Gay, Robin Bonicel, Fouzia El Mountassir, Clara Fischer, Jean-François Mangin, Marie Chupin, Yann Cointepas, Bertrand Accart, Patrick Gelé, Florine Fievet, Matthieu Chabel, Virginie Derenaucourt, Loïc Facon, Yanick Tchantchou Njosse, Dominique Deplanque, Alain Duhamel, Lynda Djemmane, Florence Duflot, Toulouse Neuro Imaging Center (ToNIC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier de Brive-la-Gaillarde (CH Brive), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), CHU Marseille, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Fondation Ophtalmologique Adolphe de Rothschild [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d’Excellence en Maladies Neurodégénératives (NeuroToul), CIC - Biotherapie - Toulouse, Institut National de la Santé et de la Recherche Médicale (INSERM), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Lille, Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Hôpital Foch [Suresnes], Neuroimagerie cognitive - Psychologie cognitive expérimentale (UNICOG-U992), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA), Institut Pascal (IP), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA), CHU Bordeaux [Bordeaux], Les Hôpitaux Universitaires de Strasbourg (HUS), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire de Nice (CHU Nice), CHU Amiens-Picardie, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), Centre hospitalier universitaire de Nantes (CHU Nantes), This work was supported by the France Parkinson charity and French Ministry of Health (PHRC national 2012). This is an ancillary study to Protocol ID: 2013-A00193-42, ClinicalTrials.gov: NCT02360683., Centre Hospitalier Brive-la-Gaillarde, and Hôpital P.P.-Riquet
Subjects: Personality Inventory, Temperament and character inventory, Parkinson's disease, Parkinson Disease, Personality Assessment, Antidepressive Agents, Neurology, Anti-Anxiety Agents, Fluctuating PD patients, Quality of Life, Humans, Neurology (clinical), Geriatrics and Gerontology, Temperament, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Personality
Abstract: International audience; INTRODUCTION: There is a growing interest in personality evaluation in Parkinson's disease (PD), following observations of specific temperaments in PD patients. Therefore, our objective was to evaluate personality dimensions from the Temperament and Character Inventory (TCI) in a cohort of fluctuating PD patients considered for deep brain stimulation. METHODS: Fluctuating PD patients from the PREDISTIM cohort were included. Description of TCI dimensions and comparison with a French normative cohort were performed. Pearson correlations between TCI dimensions and motor, behavioral and cognitive variables were investigated. Structural and internal consistency analysis of the TCI were further assessed. RESULTS: The 570 PD patients presented significant higher scores in Harm Avoidance, Reward Dependence, Persistence, Self-Directedness and Cooperativeness and significant lower scores in Self-Transcendence compared to the French normative cohort; only Novelty Seeking scores were not different. Harm Avoidance and Self-directedness scores were correlated with PDQ-39 total, HAMD, HAMA scores, and anxiolytic/antidepressant treatment. Novelty Seeking scores were correlated with impulsivity. Pearson correlations between TCI dimensions, principal component analysis of TCI sub-dimensions and Cronbach's alpha coefficients showed adequate psychometric proprieties. CONCLUSION: The TCI seems to be an adequate tool to evaluate personality dimensions in PD with good structural and internal consistencies. These fluctuating PD patients also have specific personality dimensions compared to normative French population. Moreover, Harm Avoidance and Self-Directedness scores are associated with anxio-depressive state or quality of life and, and Novelty Seeking scores with impulsivity.
Published: 2022
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5. New Ratios for the Detection and Classification of CJD in Multisequence MRI of the Brain.

Author: Marius George Linguraru, Nicholas Ayache, Miguel ángel González Ballester, éric Bardinet, Damien Galanaud, Stéphane Haïk, Baptiste Faucheux, Patrick Cozzone, Didier Dormont, and Jean-Philippe Brandel
Published: 2005
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6. The importance of ongoing international surveillance for Creutzfeldt–Jakob disease

Author: Inga Zerr, Anna Ladogana, Terri Lindsay, J. B. D. Mackenzie, Peter Hermann, Alison Green, Colin Smith, Suvankar Pal, Jean-Philippe Brandel, Maurizio Pocchiari, and Neil Watson
Subjects: 0301 basic medicine, medicine.medical_specialty, Internationality, Prions, Bovine spongiform encephalopathy, Disease, Creutzfeldt-Jakob Syndrome, Prion Diseases, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, mental disorders, Animals, Humans, Medicine, Intensive care medicine, Iatrogenic transmission, Prolonged incubation, business.industry, Transmission (medicine), Public health, Chronic wasting disease, medicine.disease, nervous system diseases, Variant cjd, 030104 developmental biology, Population Surveillance, Cattle, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: Creutzfeldt-Jakob disease (CJD) is a rapidly progressive, fatal and transmissible neurodegenerative disease associated with the accumulation of misfolded prion protein in the CNS. International CJD surveillance programmes have been active since the emergence, in the mid-1990s, of variant CJD (vCJD), a disease linked to bovine spongiform encephalopathy. Control measures have now successfully contained bovine spongiform encephalopathy and the incidence of vCJD has declined, leading to questions about the requirement for ongoing surveillance. However, several lines of evidence have raised concerns that further cases of vCJD could emerge as a result of prolonged incubation and/or secondary transmission. Emerging evidence from peripheral tissue distribution studies employing high-sensitivity assays suggests that all forms of human prion disease carry a theoretical risk of iatrogenic transmission. Finally, emerging diseases, such as chronic wasting disease and camel prion disease, pose further risks to public health. In this Review, we provide an up-to-date overview of the transmission of prion diseases in human populations and argue that CJD surveillance remains vital both from a public health perspective and to support essential research into disease pathophysiology, enhanced diagnostic tests and much-needed treatments.
Published: 2021
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7. Biomarkers and diagnostic guidelines for sporadic Creutzfeldt-Jakob disease

Author: Jean-Philippe Brandel, Gabor G. Kovacs, Anna Ladogana, Stéphane Haïk, Simon Mead, Gianluigi Zanusso, Inga Zerr, Byron Caughey, Franc Llorens, Katsuya Satoh, Maurizio Pocchiari, Michael D. Geschwind, Steven J. Collins, Peter Hermann, Alison Green, Piero Parchi, Suvankar Pal, Noriyuki Nishida, Brian S. Appleby, Hermann P., Appleby B., Brandel J.-P., Caughey B., Collins S., Geschwind M.D., Green A., Haik S., Kovacs G.G., Ladogana A., Llorens F., Mead S., Nishida N., Pal S., Parchi P., Pocchiari M., Satoh K., Zanusso G., and Zerr I.
Subjects: Genetic Markers, 0301 basic medicine, diagnosis, animal diseases, diagnosis [Creutzfeldt-Jakob Syndrome], Guidelines as Topic, Neuroimaging, Total tau, diagnostic imaging [Creutzfeldt-Jakob Syndrome], Disease, Bioinformatics, Sensitivity and Specificity, Article, Creutzfeldt-Jakob Syndrome, pre-symptomatic biomarkers, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Sporadic Creutzfeldt-Jakob disease, Humans, Medicine, ddc:610, business.industry, biomarkers, CSF, prion disease, Creutzfeldt-Jakob disease, diagnosis, RT-QuIC, PRNP, genetics [Creutzfeldt-Jakob Syndrome], nervous system diseases, 3. Good health, Clinical neurology, 030104 developmental biology, Clinical value, Biomarker (medicine), real-time quaking induced conversion (RT-QuIC), Neurology (clinical), Prion Proteins, analysis [Biomarkers], business, Biomarkers, 030217 neurology & neurosurgery
Abstract: Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal and potentially transmissible neurodegenerative disease caused by misfolded prion proteins (PrP(Sc)). To date, effective therapeutics are not available and accurate diagnosis can be challenging. Clinical diagnostic criteria employ a combination of characteristic neuropsychiatric symptoms, cerebrospinal fluid (CSF) proteins 14–3-3, MRI, and EEG. Supportive biomarkers such as high CSF total Tau may aid the diagnostic process. Discordant results of studies however, have led to controversies about the clinical value of some established surrogate biomarkers. The recent development and clinical application of disease-specific protein aggregation and amplification assays such as Real-time Quaking Induced Conversion (RT-QuIC) have constituted major breakthroughs for the confident pre-mortem diagnosis of sCJD. Updated criteria for the diagnosis of sCJD including RT-QuIC will improve early clinical confirmation, surveillance, assessment of PrP(Sc) seeding activity in different tissues, and trial monitoring. Moreover, emerging blood-based, prognostic, and potentially pre-symptomatic biomarker candidates are under current investigation.
Published: 2021
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8. Constant Transmission Properties of Variant Creutzfeldt-Jakob Disease in 5 Countries

Author: Abigail B. Diack, Diane Ritchie, Matthew Bishop, Victoria Pinion, Jean-Philippe Brandel, Stephane Haik, Fabrizio Tagliavini, Cornelia Van Duijn, Ermias D. Belay, Pierluigi Gambetti, Lawrence B. Schonberger, Pedro Piccardo, Robert G. Will, and Jean C. Manson
Subjects: Prion, strain, variant Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, Creutzfeldt-Jakob disease, CJD, Medicine, Infectious and parasitic diseases, RC109-216
Abstract: Variant Creutzfeldt-Jakob disease (vCJD) has been reported in 12 countries. We hypothesized that a common strain of agent is responsible for all vCJD cases, regardless of geographic origin. To test this hypothesis, we inoculated strain-typing panels of wild-type mice with brain material from human vCJD case-patients from France, the Netherlands, Italy, and the United States. Mice were assessed for clinical disease, neuropathologic changes, and glycoform profile; results were compared with those for 2 reference vCJD cases from the United Kingdom. Transmission to mice occurred from each sample tested, and data were similar between non-UK and UK cases, with the exception of the ranking of mean clinical incubation times of mouse lines. These findings support the hypothesis that a single strain of infectious agent is responsible for all vCJD infections. However, differences in incubation times require further subpassage in mice to establish any true differences in strain properties between cases.
Published: 2012
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9. Iatrogenic Creutzfeldt-Jakob Disease, Final Assessment

Author: Paul Brown, Jean-Philippe Brandel, Takeshi Sato, Yosikazu Nakamura, Jan MacKenzie, Robert G. Will, Anna Ladogana, Maurizio Pocchiari, Ellen W. Leschek, and Lawrence B. Schonberger
Subjects: Creutzfeldt-Jakob disease, dura mater, human growth hormone, iatrogenic disease, PRNP codon 129, variant Creutzfeldt-Jakob disease, Medicine, Infectious and parasitic diseases, RC109-216
Abstract: The era of iatrogenic Creutzfeldt-Jakob disease (CJD) has nearly closed; only occasional cases with exceptionally long incubation periods are still appearing. The principal sources of these outbreaks are contaminated growth hormone (226 cases) and dura mater grafts (228 cases) derived from human cadavers with undiagnosed CJD infections; a small number of additional cases are caused by neurosurgical instrument contamination, corneal grafts, gonadotrophic hormone, and secondary infection with variant CJD transmitted by transfusion of blood products. No new sources of disease have been identified, and current practices, which combine improved recognition of potentially infected persons with new disinfection methods for fragile surgical instruments and biological products, should continue to minimize the risk for iatrogenic disease until a blood screening test for the detection of preclinical infection is validated for human use.
Published: 2012
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10. Differentiation of sCJD and vCJD forms by automated analysis of basal ganglia intensity distribution in multisequence MRI of the brain-definition and evaluation of new MRI-based ratios.

Author: Marius George Linguraru, Nicholas Ayache, éric Bardinet, Miguel ángel González Ballester, Damien Galanaud, Stéphane Haïk, Baptiste Faucheux, J.-J. Hauw, Patrick Cozzone, Didier Dormont, and Jean-Philippe Brandel
Published: 2006
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11. Validation of Revised International Creutzfeldt-Jakob Disease Surveillance Network Diagnostic Criteria for Sporadic Creutzfeldt-Jakob Disease

Author: Neil Watson, Peter Hermann, Anna Ladogana, Angeline Denouel, Simone Baiardi, Elisa Colaizzo, Giorgio Giaccone, Markus Glatzel, Alison J. E. Green, Stéphane Haïk, Daniele Imperiale, Janet MacKenzie, Fabio Moda, Colin Smith, David Summers, Dorina Tiple, Luana Vaianella, Gianluigi Zanusso, Maurizio Pocchiari, Inga Zerr, Piero Parchi, Jean-Philippe Brandel, Suvankar Pal, Watson N., Hermann P., Ladogana A., Denouel A., Baiardi S., Colaizzo E., Giaccone G., Glatzel M., Green A.J.E., Haik S., Imperiale D., Mackenzie J., Moda F., Smith C., Summers D., Tiple D., Vaianella L., Zanusso G., Pocchiari M., Zerr I., Parchi P., Brandel J.-P., and Pal S.
Subjects: Male, revision, accuracy, diagnosis, sporadic Creutzfeldt-Jakob disease, specificity, Diagnostic Techniques, Neurological, General Medicine, sensitivity, Magnetic Resonance Imaging, Sensitivity and Specificity, Creutzfeldt-Jakob Syndrome, United Kingdom, Italy, Retrospective Studie, Germany, Population Surveillance, diagnostic criteria, Humans, Female, Autopsy, France, Retrospective Studies, Aged, Human
Abstract: Importance: Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly lethal disease. Rapid, accurate diagnosis is imperative for epidemiological surveillance and public health activities to exclude treatable differentials and facilitate supportive care. In 2017, the International CJD Surveillance Network diagnostic criteria were revised to incorporate cortical ribboning on magnetic resonance imaging and the real-time quaking-induced conversion (RT-QuIC) assay, developments that require multicenter evaluation. Objective: To evaluate the accuracy of revised diagnostic criteria through the retrospective diagnosis of autopsy-confirmed cases (referred to as in-life diagnosis). Design, Setting, and Participants: This diagnostic study used a 3-year clinicopathological series using all cases of autopsy-confirmed sCJD and a noncase group with alternative neuropathological diagnoses from national surveillance centers in the United Kingdom, France, Germany, and Italy. Data were collected from January 2017 to December 2019 and analyzed from January 2020 to November 2021. Main Outcomes and Measures: Sensitivity and specificity of revised diagnostic criteria and diagnostic investigations. Secondary analyses assessing sCJD subgroups by genotype, pathological classification, disease duration, and age. Results: A total of 501 sCJD cases and 146 noncases were included. Noncase diagnoses included neurodegenerative diseases, autoimmune encephalitis, and cerebral insults such as anoxia. Participants in the sCJD cases cohort were younger (mean [SD] age, 68.8 [9.8] years vs 72.8 [10.9] years; P .99). Among 223 cases and 52 noncases with the full panel of investigations performed, sensitivity of revised criteria (97.8%; 95% CI, 94.9%-99.3%) was increased compared with prior criteria (76.2%; 95% CI, 70.1%-81.7%; P .99). In 455 cases and 111 noncases, cortical ribboning was 67.9% sensitive (95% CI, 63.4%-72.2%) and 86.5% specific (95% CI, 78.7%-92.2%). In 274 cases and 77 noncases, RT-QuIC was 91.6% sensitive (95% CI, 87.7%-94.6%) and 100% specific (95% CI, 96.2%-100%). Investigation sensitivity varied with genetic and pathological features, disease duration, and age. Conclusions and Relevance: This diagnostic study demonstrated significantly improved sensitivity of revised sCJD diagnostic criteria with unaltered specificity. The revision has enhanced diagnostic accuracy for clinical care and surveillance..
Published: 2022
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12. Variant Creutzfeldt–Jakob Disease Diagnosed 7.5 Years after Occupational Exposure

Author: Isabelle Plu, Audrey Culeux, Elodie Bouaziz-Amar, Danielle Seilhean, Stéphane Haïk, M Bustuchina Vlaicu, Maxime Belondrade, Katarina Grznarova, Jean-Philippe Brandel, Daisy Bougard, Michèle Levasseur, Angeline Denouel, DIAMANT-BERGER, Valérie, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Groupe Hospitalier Nord Essonne [Longjumeau], Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Pathogénèse et contrôle des infections chroniques (PCCI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Hôpital Lariboisière-Fernand-Widal [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Pediatrics, medicine.medical_specialty, Brain chemistry, Fatal outcome, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, animal diseases, Disease, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, parasitic diseases, mental disorders, Variant Creutzfeldt–Jakob disease, medicine, [SDV.EE.SANT] Life Sciences [q-bio]/Ecology, environment/Health, 030212 general & internal medicine, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, medicine.diagnostic_test, business.industry, Technician, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Magnetic resonance imaging, General Medicine, nervous system diseases, Variant cjd, body regions, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Occupational exposure, business
Abstract: Variant CJD in a Laboratory Technician Variant Creutzfeldt–Jakob disease was identified in a technician who had cut her thumb while handling brain sections of mice infected with adapted BSE 7.5 yea...
Published: 2020
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13. 004 Validation of the diagnostic criteria for sporadic Creutzfeldt-Jakob disease

Author: Neil Watson, Jean-Philippe Brandel, Alison Green, Peter Hermann, Anna Ladogana, Maurizio Poc- chiari, Colin Smith, David Summers, Inga Zerr, and Suvankar Pal
Subjects: Psychiatry and Mental health, Surgery, Neurology (clinical)
Abstract: Sporadic Creutzfeldt-Jakob disease (sCJD) is the commonest form of CJD, a universally fatal and rapidly progressive human prion disease. sCJD typically presents with rapidly progressive dementia but can have diverse manifestations. The diagnosis can be challenging. Diagnostic criteria were revised in 2017 to include the real-time quaking-induced conversion (RT-QuIC) assay and cortical ribboning on magnetic resonance imaging (MRI). The aim of this study is to validate the diagnostic criteria, with the secondary aim of evaluating its impact on classification during life and hence case ascertainment. 501 deceased subjects with post-mortem (PM)-confirmed sCJD between 2017–2019 were included from the national registries of the UK, France, Germany and Italy. A control group of 146 subjects with alternative diagnoses at PM was included. Diagnostic test outcomes were recorded. RT-QuIC was 91.6% sensitive and 100% specific. MRI was the second most sensitive (86.8%) and specific (91.9%) investigation. Codon 129 had a significant impact on MRI changes in sCJD (pneilwatson@nhslothian.scot.nhs.uk27
Published: 2022
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14. A genome wide association study links glutamate receptor pathway to sporadic Creutzfeldt-Jakob disease risk.

Author: Pascual Sanchez-Juan, Matthew T Bishop, Gabor G Kovacs, Miguel Calero, Yurii S Aulchenko, Anna Ladogana, Alison Boyd, Victoria Lewis, Claudia Ponto, Olga Calero, Anna Poleggi, Ángel Carracedo, Sven J van der Lee, Thomas Ströbel, Fernando Rivadeneira, Albert Hofman, Stéphane Haïk, Onofre Combarros, José Berciano, Andre G Uitterlinden, Steven J Collins, Herbert Budka, Jean-Philippe Brandel, Jean Louis Laplanche, Maurizio Pocchiari, Inga Zerr, Richard S G Knight, Robert G Will, and Cornelia M van Duijn
Subjects: Medicine, Science
Abstract: We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109 sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after correction for multiple testing. Subsequently these five SNPs were genotyped in 2264 controls. The pooled analysis, including 1543 sCJD cases and 4203 controls, yielded two genome wide significant results: rs6107516 (p-value=7.62x10-9) a variant tagging the prion protein gene (PRNP); and rs6951643 (p-value=1.66x10-8) tagging the Glutamate Receptor Metabotropic 8 gene (GRM8). Next we analysed the data stratifying by country of origin combining samples from the pooled analysis with genotypes from the 1000 Genomes Project and imputed genotypes from the Rotterdam Study (Total n=12967). The meta-analysis of the results showed that rs6107516 (p-value=3.00x10-8) and rs6951643 (p-value=3.91x10-5) remained as the two most significantly associated SNPs. Rs6951643 is located in an intronic region of GRM8, a gene that was additionally tagged by a cluster of 12 SNPs within our top100 ranked results. GRM8 encodes for mGluR8, a protein which belongs to the metabotropic glutamate receptor family, recently shown to be involved in the transduction of cellular signals triggered by the prion protein. Pathway enrichment analyses performed with both Ingenuity Pathway Analysis and ALIGATOR postulates glutamate receptor signalling as one of the main pathways associated with sCJD. In summary, we have detected GRM8 as a novel, non-PRNP, genome-wide significant marker associated with heightened disease risk, providing additional evidence supporting a role of glutamate receptors in sCJD pathogenesis.
Published: 2014
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15. Glycoform-selective prion formation in sporadic and familial forms of prion disease.

Author: Xiangzhu Xiao, Jue Yuan, Stéphane Haïk, Ignazio Cali, Yian Zhan, Mohammed Moudjou, Baiya Li, Jean-Louis Laplanche, Hubert Laude, Jan Langeveld, Pierluigi Gambetti, Tetsuyuki Kitamoto, Qingzhong Kong, Jean-Philippe Brandel, Brian A Cobb, Robert B Petersen, and Wen-Quan Zou
Subjects: Medicine, Science
Abstract: The four glycoforms of the cellular prion protein (PrP(C)) variably glycosylated at the two N-linked glycosylation sites are converted into their pathological forms (PrP(Sc)) in most cases of sporadic prion diseases. However, a prominent molecular characteristic of PrP(Sc) in the recently identified variably protease-sensitive prionopathy (VPSPr) is the absence of a diglycosylated form, also notable in familial Creutzfeldt-Jakob disease (fCJD), which is linked to mutations in PrP either from Val to Ile at residue 180 (fCJD(V180I)) or from Thr to Ala at residue 183 (fCJD(T183A)). Here we report that fCJD(V180I), but not fCJD(T183A), exhibits a proteinase K (PK)-resistant PrP (PrP(res)) that is markedly similar to that observed in VPSPr, which exhibits a five-step ladder-like electrophoretic profile, a molecular hallmark of VPSPr. Remarkably, the absence of the diglycosylated PrP(res) species in both fCJD(V180I) and VPSPr is likewise attributable to the absence of PrP(res) glycosylated at the first N-linked glycosylation site at residue 181, as in fCJD(T183A). In contrast to fCJD(T183A), both VPSPr and fCJD(V180I) exhibit glycosylation at residue 181 on di- and monoglycosylated (mono181) PrP prior to PK-treatment. Furthermore, PrP(V180I) with a typical glycoform profile from cultured cells generates detectable PrP(res) that also contains the diglycosylated PrP in addition to mono- and unglycosylated forms upon PK-treatment. Taken together, our current in vivo and in vitro studies indicate that sporadic VPSPr and familial CJD(V180I) share a unique glycoform-selective prion formation pathway in which the conversion of diglycosylated and mono181 PrP(C) to PrP(Sc) is inhibited, probably by a dominant-negative effect, or by other co-factors.
Published: 2013
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16. Correction: Glycoform-Selective Prion Formation in Sporadic and Familial Forms of Prion Disease.

Author: Xiangzhu Xiao, Jue Yuan, Stéphane Haïk, Ignazio Cali, Yian Zhan, Mohammed Moudjou, Baiya Li, Jean-Louis Laplanche, Hubert Laude, Jan Langeveld, Pierluigi Gambetti, Tetsuyuki Kitamoto, Qingzhong Kong, Jean-Philippe Brandel, Brian A. Cobb, Robert B. Petersen, and Wen-Quan Zou
Subjects: Medicine, Science
Published: 2013
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17. An in vivo Caenorhabditis elegans model for therapeutic research in human prion diseases

Author: Jean-Philippe Brandel, Etienne Levavasseur, Stéphane Haïk, Nicolas Bizat, Sofian Laoues, Patrice Beaudry, Valeria Parrales, Julian Roussel, Nicolas Privat, Alexianne Gougerot, Philippe Ravassard, Sébastien Normant, and Jean-Louis Laplanche
Subjects: animal diseases, Transgene, Benzocaine, PrPSc Proteins, Context (language use), Biology, medicine.disease_cause, Protein Aggregation, Pathological, Prion Proteins, Prion Diseases, Animals, Genetically Modified, Piroxicam, Tubulin, Genetic model, medicine, Animals, Humans, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Mutation, Naloxone, Neurodegeneration, Brain, medicine.disease, biology.organism_classification, Phenotype, nervous system diseases, Cell biology, Disease Models, Animal, Neurology (clinical)
Abstract: Human prion diseases are fatal neurodegenerative disorders that include sporadic, infectious and genetic forms. Inherited Creutzfeldt-Jakob disease due to the E200K mutation of the prion protein-coding gene is the most common form of genetic prion disease. The phenotype resembles that of sporadic Creutzfeldt-Jakob disease at both the clinical and pathological levels, with a median disease duration of 4 months. To date, there is no available treatment for delaying the occurrence or slowing the progression of human prion diseases. Existing in vivo models do not allow high-throughput approaches that may facilitate the discovery of compounds targeting pathological assemblies of human prion protein or their effects on neuronal survival. Here, we generated a genetic model in the nematode Caenorhabditis elegans, which is devoid of any homologue of the prion protein, by expressing human prion protein with the E200K mutation in the mechanosensitive neuronal system. Expression of E200K prion protein induced a specific behavioural pattern and neurodegeneration of green fluorescent protein-expressing mechanosensitive neurons, in addition to the formation of intraneuronal inclusions associated with the accumulation of a protease-resistant form of the prion protein. We demonstrated that this experimental system is a powerful tool for investigating the efficacy of anti-prion compounds on both prion-induced neurodegeneration and prion protein misfolding, as well as in the context of human prion protein. Within a library of 320 compounds that have been approved for human use and cross the blood–brain barrier, we identified five molecules that were active against the aggregation of the E200K prion protein and the neurodegeneration it induced in transgenic animals. This model breaks a technological limitation in prion therapeutic research and provides a key tool to study the deleterious effects of misfolded prion protein in a well-described neuronal system.
Published: 2020

18. Genome-wide association study identifies risk variants for sporadic Creutzfeldt-Jakob disease in STX6 and GAL3ST1

Author: Anna Poleggi, John Collinge, Carla A. Ibrahim-Verbaas, Jean-Philippe Brandel, Emma Jones, Dimitriadis A, Anna Bartoletti-Stella, James Uphill, Christiane Stehmann, Mok Th, Gerard H. Jansen, Tracy Campbell, Zafar S, Holger Hummerich, van Duijn C, Jiri G. Safar, Ewa Golanska, Martinón-Torres F, Aili Golubjatnikov, Michael B. Coulthart, Zane Jaunmuktane, Beata Sikorska, Giuseppe Matullo, Miguel Calero, Jerome Whitfield, Sabina Capellari, Jean-Louis Laplanche, Kathleen Glisic, Gabor G. Kovacs, Richard Knight, Helen Speedy, Juan Ps, Olga Calero, Jean-Charles Lambert, Stéphane Haïk, Anna Ladogana, Akin Nihat, Stephanie A. Booth, Serena Aneli, Herbert Budka, Pawel P. Liberski, Piero Parchi, Shannon Sarros, Jacqueline M. Linehan, Sebastian Brandner, Maurizio Pocchiari, Ahmed P, Michael D. Geschwind, Fronztek K, Antonio Salas, Inga Zerr, Janis Blevins, Elodie Bouaziz-Amar, Brian S. Appleby, Steven J. Collins, P. Gambetti, Hata Karamujić-Čomić, Adriano Aguzzi, Philippe Amouyel, van der Lee S, Penny Norsworthy, Parmjit S. Jat, Liam Quinn, Emmanuelle Viré, and Simon Mead
Subjects: Genetics, 0303 health sciences, biology, animal diseases, Tau protein, STX6, Single-nucleotide polymorphism, Genome-wide association study, medicine.disease, 3. Good health, Progressive supranuclear palsy, PRNP, nervous system diseases, 03 medical and health sciences, 0302 clinical medicine, medicine, biology.protein, Gene, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract: Mammalian prions are lethal pathogens composed of fibrillar assemblies of misfolded prion protein. Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the gene that encodes prion protein (PRNP) are strong risk factors for sCJD, but although the condition has heritability similar to other neurodegenerative disorders, no other risk loci have yet been confirmed. By genome-wide association in European ancestry populations, we found three replicated loci (cases n=5208, within PRNP, STX6, and GAL3ST1) and two further unreplicated loci were significant in gene-wide tests (within PDIA4, BMERB1). Exome sequencing in 407 sCJD cases, conditional and transcription analyses suggest that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 and PDIA4 associate with increased expression of the major transcripts in disease-relevant brain regions. Alteration of STX6 expression does not modify prion propagation in a neuroblastoma cell model of mouse prion infection. We went on to analyse the proteins histologically in diseased tissue and examine the effects of risk variants on clinical phenotypes using deep longitudinal clinical cohort data. Risk SNPs in STX6, a protein involved in the intracellular trafficking of proteins and vesicles, are shared with progressive supranuclear palsy, a neurodegenerative disease associated with the misfolded protein tau. We present the first evidence of statistically robust associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism.
Published: 2020
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19. Étude de la mortalité de la maladie de Creutzfeldt–Jakob sporadique en France de 1992 à 2016 à l’aide d’un modèle âge–période–cohorte

Author: Angéline Denouel, Jean-Philippe Brandel, Alexis Elbaz, and Stephane Haik
Subjects: Neurology, Neurology (clinical)
Published: 2022
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20. Les marqueurs du liquide céphalo-rachidien pour le diagnostic des maladies à prions

Author: J.L. Laplanche, Arlette Welaratne, Katarina Grznarova, Laurène Peckeu, Jean-Philippe Brandel, Etienne Levavasseur, S. Haik, and Audrey Culeux
Subjects: 0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Neurology (clinical), 030217 neurology & neurosurgery
Abstract: Resume Les tests effectues dans le liquide cephalorachidien sont particulierement utiles pour differencier les maladies a prions d’autres demences degeneratives ou d’autres encephalopathies dont certaines potentiellement traitables. La recherche ou les dosages des proteines 14-3-3, tau ou S100b, utilises, depuis plusieurs annees, sont des marqueurs indirects qui ont une bonne sensibilite mais une specificite qui est loin d’atteindre 100 %. La possibilite maintenant de mettre en evidence directement la proteine prion anormale au moyen d’une methode d’amplification, la Real-Time Quaking-Induced Conversion (RT-QuIC), permet, surtout pour la forme sporadique de la maladie de Creutzfeldt–Jakob, une importante amelioration du diagnostic de probabilite. Meme si ceci a conduit en 2017 a la modification des criteres diagnostiques de surveillance, la RT-QuIC doit encore etre consideree comme une technique de recherche.
Published: 2018
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21. Susceptibility to Creutzfeldt-Jakob disease after human growth hormone treatment in France

Author: Jean-Philippe Brandel, Stéphane Haïk, Arlette Welaratne, Dominique Costagliola, and Laurène Peckeu
Subjects: Adult, Male, 0301 basic medicine, Adolescent, Attack rate, Physiology, Disease, Growth hormone, Creutzfeldt-Jakob Syndrome, Cohort Studies, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, Child, Proportional Hazards Models, Individual susceptibility, Dose-Response Relationship, Drug, Human Growth Hormone, business.industry, Human growth hormone, Infant, Newborn, Infant, Treatment characteristics, 030104 developmental biology, Child, Preschool, Epidemiological Monitoring, Multivariate Analysis, Cohort, Female, Disease Susceptibility, France, Neurology (clinical), business, 030217 neurology & neurosurgery, Hormone
Abstract: ObjectiveTo identify, among the available data concerning host characteristics and exposure, risk factors influencing the susceptibility for developing iatrogenic Creutzfeldt-Jakob disease (iCJD) in a cohort of patients treated with human cadaver-sourced growth hormone (hGH) in France.MethodsThis study included all 1,443 individuals treated in France with hGH from January 1982 to December 1985, out of which 119 cases of hGH-iCJD have been identified so far. We applied a 3 sequential step Cox analysis involving univariable, stepwise, and nonstepwise multivariable procedures. The variables studied were sex, age at hGH treatment initiation, and treatment characteristics (batches and doses).ResultsWhile no effect of age at treatment initiation was observed, a significant effect of sex on disease susceptibility was unexpectedly evidenced with a 2-fold increase of disease occurrence in male patients. This effect did not depend on differences of exposure between male and female patients. We identified 4 categories of hormone batches from high risk to no association with susceptibility. A relationship between the dose received from at-risk hormone batches and the attack rate (number of patients developing the disease among exposed individuals) was demonstrated.ConclusionsStudying the hGH-exposed patients in France provides epidemiologic evidence of a relationship between dose of inoculum and disease occurrence in humans and suggests an unexpected effect of sex on individual susceptibility.
Published: 2018
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22. Regulating factors of PrP glycosylation in Creutzfeldt-Jakob disease--implications for the dissemination and the diagnosis of human prion strains.

Author: Etienne Levavasseur, Isabelle Laffont-Proust, Emilie Morain, Baptiste A Faucheux, Nicolas Privat, Katell Peoc'h, Véronique Sazdovitch, Jean-Philippe Brandel, Jean-Jacques Hauw, and Stéphane Haïk
Subjects: Medicine, Science
Abstract: ObjectiveThe glycoprofile of pathological prion protein (PrP(res)) is widely used as a diagnosis marker in Creutzfeldt-Jakob disease (CJD) and is thought to vary in a strain-specific manner. However, that the same glycoprofile of PrP(res) always accumulates in the whole brain of one individual has been questioned. We aimed to determine whether and how PrP(res) glycosylation is regulated in the brain of patients with sporadic and variant Creutzfeldt-Jakob disease.MethodsPrP(res) glycoprofiles in four brain regions from 134 patients with sporadic or variant CJD were analyzed as a function of the genotype at codon 129 of PRNP and the Western blot type of PrP(res).ResultsThe regional distribution of PrP(res) glycoforms within one individual was heterogeneous in sporadic but not in variant CJD. PrP(res) glycoforms ratio significantly correlated with the genotype at codon 129 of the prion protein gene and the Western blot type of PrP(res) in a region-specific manner. In some cases of sCJD, the glycoprofile of thalamic PrP(res) was undistinguishable from that observed in variant CJD.InterpretationRegulations leading to variations of PrP(res) pattern between brain regions in sCJD patients, involving host genotype and Western blot type of PrP(res) may contribute to the specific brain targeting of prion strains and have direct implications for the diagnosis of the different forms of CJD.
Published: 2008
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23. Correction: Regulating Factors of PrP Glycosylation in Creutzfeldt-Jakob Disease - Implications for the Dissemination and the Diagnosis of Human Prion Strains.

Author: Etienne Levavasseur, Isabelle Laffont-Proust, Émilie Morain, Baptiste A. Faucheux, Nicolas Privat, Katell Peoc'h, Véronique Sazdovitch, Jean-Philippe Brandel, Jean-Jacques Hauw, and Stéphane Haïk
Subjects: Medicine, Science
Published: 2008
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24. Parkinson's disease polygenic risk score is not associated with impulse control disorders: A longitudinal study

Author: Vanessa Brochard, Fanny Artaud, Frédéric Bourdain, S. Sambin, Valérie Mesnage, O. Rascol, Clemens R. Scherzer, Fabienne Ory-Magne, Isabelle Rieu, Jean-Christophe Corvol, Fanny Pineau, Merry Mazmanian, Louise-Laure Mariani, Monica Roy, Hélène Bertrand, Marie Vidailhet, Graziella Mangone, Tiphaine Vidal, Benjamin Le Toullec, Bérangère Debilly, Sara Leder, Emmanuel Roze, Bertrand Degos, Samir Bekadar, Cecilia Bonnet, Genetic core: Alexis Brice, Jean-Philippe Brandel, Antoine Faurie-Grepon, Hana You, Monique Galitsky, Stephan Klebe, Julia Kraemmer, J. Ihle, Mostafa Hajji, Virginie Bayet, David Grabli, Richard Levy, P. Derkinderen, Hakima Manseur, Ll Mariani, Julie Socha, Suzanne Lesage, Florence Cormier-Dequaire, Statistical analyses, A. Marques, Fernando Pico, Khadija Tahiri, Andreas Hartmann, Stéphane Bernard, Olivier Rascol, Eve Benchetrit, Alexis Brice, Julia Muellner, F. Durif, Violaine Plante-Bordeneuve, Sponsor activities, J-C Corvol, Alain Mallet, Co-investigators, Coralie Villeret, Pascal Derkinderen, Franck Durif, Anne-Marie Bonnet, Neuropsychologists, Christine Brefel-Courbon, Mélissa Tir, A. Elbaz, Lucette Lacomblez, Alexis Elbaz, Elsa Pomies, F. Artaud, Principal investigators for sites, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), NS-Park/FCRIN Network, UMS 015, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Foch [Suresnes], Fondation A. Rothschild, Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Clermont-Ferrand, CHU Saint-Antoine [AP-HP], Centre Hospitalier de Versailles André Mignot (CHV), Hôpital Henri Mondor, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), ANR-10-IAIHU-06 MinistÃ¨re des Affaires Sociales et de la SantÃ©: AOR0810 Agence Nationale de SÃ©curitÃ© du MÃ©dicament et des Produits de SantÃ©, ANSM: ANSM-2013, This project was funded by grants from the French Ministry of Health (Programme Hospitalier de Recherche Clinique, AOR0810 ) and from the French Drug Agency (Agence Nationale de Sécurité et des Médicaments, ANSM-2013 ). The research leading to these results has received funding from the program ' Investissements d’Avenir ' ANR-10-IAIHU-06 . We want to express our gratitude to all the participants who made this study possible., ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Longitudinal study, Multifactorial Inheritance, Parkinson's disease, Movement disorders, Genome-wide association study, Disease, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Genetic predisposition, Humans, Longitudinal Studies, Age of Onset, Adverse effect, Generalized estimating equation, Aged, business.industry, Parkinson Disease, Middle Aged, medicine.disease, 3. Good health, Disruptive, Impulse Control, and Conduct Disorders, 030104 developmental biology, Neurology, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), France, Geriatrics and Gerontology, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: International audience; Objective: To examine the relationship between a Parkinson's disease (PD) polygenic risk score (PRS) and impulse control disorders (ICDs) in PD. Background: Genome wide association studies (GWAS) have brought forth a PRS associated with increased risk of PD and younger disease onset. ICDs are frequent adverse effects of dopaminergic drugs and are also more frequent in patients with younger disease onset. It is unknown whether ICDs and PD share genetic susceptibility. Methods: We used data from a multicenter longitudinal cohort of PD patients with annual visits up to 6 years (DIG-PD). At each visit ICDs, defined as compulsive gambling, buying, eating, or sexual behavior were evaluated by movement disorders specialists. We genotyped DNAs using the Megachip assay (Illumina) and calculated a weighted PRS based on 90 SNPs associated with PD. We estimated the association between PRS and prevalence of ICDs at each visit using Poisson generalized estimating equations, adjusted for dopaminergic treatment and other known risk factors for ICDs. Results: Of 403 patients, 185 developed ICDs. Patients with younger age at onset had a higher prevalence of ICDs (p < 0.001) as well as higher PRS values (p = 0.06). At baseline, there was no association between the PRS and ICDs (overall, p = 0.84). The prevalence of ICDs increased over time similarly across the quartiles of the PRS (overall, p = 0.88; DA users, p = 0.99). Conclusion: Despite younger disease onset being associated with both higher PRS and ICD prevalence, our findings are not in favor of common susceptibility genes for PD and ICDs.
Published: 2020
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25. Amplification techniques and diagnosis of prion diseases

Author: Stéphane Haïk, Jean-Louis Laplanche, Jean-Philippe Brandel, Etienne Levavasseur, Audrey Culeux, P. Lamy, Arlette Welaratne, Katarina Grznarova, A. Denouel, Nicolas Privat, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Pathology, medicine.medical_specialty, Diagnostic methods, Sporadic CJD, business.industry, animal diseases, [SDV]Life Sciences [q-bio], Creutzfeldt-Jakob Syndrome, nervous system diseases, 3. Good health, Variant cjd, Prion Diseases, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, Neurology, Molecular Diagnostic Techniques, mental disorders, medicine, Protein Misfolding Cyclic Amplification, Humans, 030212 general & internal medicine, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: Protein misfolding cyclic amplification assay (PMCA) and real-time quaking-induced conversion (RT-QuIC) are two amplification techniques based on the ability of PrPsc to induce a conformational change in PrP allowing the detection of minute amounts of PrPsc in body fluids or tissues. PMCA and RT-QuIC have different ability to amplify PrPsc from sporadic, variant and genetic forms of Creutzfeldt-Jakob disease (CJD). PMCA readily amplifies PrPsc from variant CJD (vCJD) tissue while RT-QuIC easily amplifies PrPsc from sporadic CJD (sCJD) patient tissues. In terms of diagnosis, this implies the possibility of distinguishing vCJD from sCJD and explains the wider use of RT-QuIC given the respective frequencies of vCJD and sCJD. The sensitivity values of RT-QuIC for the diagnosis of sCJD are comparable or higher than those of the other tests (EEG, MRI, detection of 14-3-3 or tau proteins in cerebrospinal fluid) but with a specificity close to 100%. These new diagnostic methods could also be useful for the diagnosis of other neurodegenerative diseases.
Published: 2019
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26. Examining the Reserve Hypothesis in Parkinson's Disease: A Longitudinal Study

Author: Lucette Lacomblez, Alexis Elbaz, Florence Cormier-Dequaire, David Grabli, Frédéric Bourdain, Jean-Philippe Brandel, Fabienne Ory-Magne, Franck Durif, Cecilia Bonnet, Pei-Chen Lee, Hana You, Pascal Derkinderen, Marie Vidailhet, Olivier Rascol, Jean-Christophe Corvol, Alexis Brice, A. Marques, Graziella Mangone, Fernando Pico, Christine Brefel-Courbon, Fanny Artaud, Valérie Mesnage, Stephan Klebe, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Pharmacologie Clinique et Neurosciences, CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d’Excellence en Maladies Neurodégénératives (NeuroToul), CHU Toulouse [Toulouse], Neuro-Psycho Pharmacologie des Systèmes Dopimanégiques sous-corticaux (NPsy-Sydo), CHU Clermont-Ferrand-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Neuropathies du système nerveux entérique et pathologies digestives, implication des cellules gliales entériques, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie, Hôpital Foch [Suresnes], Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of neurology, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Department of Epidemiology and Public Health, University College of London [London] (UCL), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service Pharmacologie Clinique [CHU Toulouse], Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Laboratoire d'Imagerie Biomédicale [Paris] (LIB), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Julius-Maximilians-Universität Würzburg (JMU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, Longitudinal study, medicine.medical_specialty, Parkinson's disease, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Medizin, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Cognition, Quality of life, medicine, Dementia, Humans, Cognitive Dysfunction, Longitudinal Studies, ComputingMilieux_MISCELLANEOUS, Aged, Depressive Disorder, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Proportional hazards model, business.industry, Depression, 4. Education, [SCCO.NEUR]Cognitive science/Neuroscience, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Parkinson Disease, Middle Aged, medicine.disease, 3. Good health, 030104 developmental biology, Neurology, Quality of Life, Anxiety, Female, Neurology (clinical), medicine.symptom, business, Cognition Disorders, 030217 neurology & neurosurgery, Cohort study
Abstract: BACKGROUND Whether reserve plays a role in Parkinson's disease (PD) patients has received less attention than in dementia and has been mainly examined in relation with cognitive function. OBJECTIVE To investigate whether reserve plays a role in the severity and progression of motor, cognitive, and nonmotor PD symptoms by examining whether education level (proxy of reserve) is associated with baseline performance and rate of progression. METHODS We used data from a longitudinal cohort of PD patients (≤5-year disease duration at baseline) annually followed up to 5 years (n = 393; 41% women; mean age = 62.3 years, standard deviation = 10.0; mean disease duration = 2.6 years, standard deviation = 1.5). We examined the relationship of education with time to reach Hoehn and Yahr stage ≥3 using Cox regression and with baseline severity and progression of motor (Movement Disorder Society-Unified Parkinson's Disease Rating Scale parts II and III, gait speed), cognitive (Mini-Mental State Examination), and nonmotor (depression, anxiety, nonmotor symptoms scale, quality of life) symptoms using mixed models. RESULTS Education level was not associated with age at onset or diagnosis. Compared with the low-education group, the incidence of Hoehn and Yahr ≥3.0 was 0.42 times lower (95% confidence interval, 0.22-0.82, P = 0.012) in the high-education group. Higher education was associated with better baseline motor function (P 0.15). Similar results were observed for cognition. Education was not associated with nonmotor symptoms. CONCLUSIONS Higher education is associated with better baseline motor/cognitive function in PD, but not with rate of decline, and with a lower risk of reaching Hoehn and Yahr ≥3 during the follow-up. Our observations are consistent with a passive reserve hypothesis for motor/cognitive symptoms. © 2019 International Parkinson and Movement Disorder Society.
Published: 2019
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27. First European case of Creutzfeldt-Jakob disease with a PRNP G114V mutation

Author: Stéphane Epelbaum, Aurélie Méneret, Camille Huiban, Elodie Bouaziz-Amar, Carole Azuar, Jean-Philippe Brandel, Louis Cousyn, David Grabli, Damien Galanaud, Danielle Seilhean, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neuropathologie [CHU Pitié Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob, Service de Neuroradiologie [CHU Pitié-Salpêtrière], Service de Neurologie [CHU Pitié-Salpêtrière], and IFR70-CHU Pitié-Salpêtrière [AP-HP]
Subjects: Adult, Male, Disease onset, Cognitive Neuroscience, animal diseases, Experimental and Cognitive Psychology, Disease, Neuropsychological Tests, 050105 experimental psychology, Creutzfeldt-Jakob Syndrome, Prion Proteins, PRNP, 03 medical and health sciences, 14.3.3, 0302 clinical medicine, Cerebrospinal fluid, Genetic, mental disorders, Total Tau Protein, Humans, 0501 psychology and cognitive sciences, Family history, Genetics, Atypical presentation, 05 social sciences, Creutzfeldt-Jakob disease, 3. Good health, Pedigree, nervous system diseases, Neuropsychology and Physiological Psychology, Phenotype, Mutation (genetic algorithm), Mutation, Prnp gene, Psychology, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Genetic Creutzfeldt-Jakob disease is due to mutations in the PRNP gene. Only two families with a PRNP G114V mutation have been described around the world. We report the first European case, who had no family history and initially presented with isolated deficit in hippocampus-dependent memory. Initial investigations were normal except for elevated total tau protein in the cerebrospinal fluid. He died 4 years after disease onset. This case highlights the diagnostic difficulties posed by genetic Creutzfeldt-Jakob disease, and shows that genetic analyses should be considered even in sporadic cases.
Published: 2019
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28. Factors Influencing the Incubation of an Infectious Form of Creutzfeldt-Jakob Disease

Author: Jean-Philippe Brandel, Laurène Peckeu, Elodie Amar, Arlette Welaratne, Stéphane Haïk, Dominique Costagliola, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Descartes - Paris 5 (UPD5), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Neuropathologie Raymond Escourolle, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)
Subjects: Microbiology (medical), Prions, [SDV]Life Sciences [q-bio], Iatrogenic Disease, Physiology, Disease, Growth hormone, Iatrogenic Creutzfeldt-Jakob disease, Communicable Diseases, Creutzfeldt-Jakob Syndrome, Prion Proteins, Incubation period, prion, 03 medical and health sciences, 0302 clinical medicine, Medicine, Humans, 030212 general & internal medicine, Incubation, business.industry, Transmission (medicine), Human growth hormone, nervous system diseases, 3. Good health, Somatropin, Infectious Diseases, human growth hormone, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: The French epidemics of iatrogenic Creutzfeldt-Jakob disease after growth hormone (GH) treatment provide an opportunity to understand factors governing the inter-human transmission of prions. The present analysis relying on truncated Weibull distribution supports a relationship between host genetics, dose of the at-risk GH, age at treatment onset, and duration of the incubation period.
Published: 2019
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29. Autoantibodies against the prion protein in individuals with

Author: Karl, Frontzek, Manfredi, Carta, Marco, Losa, Mirka, Epskamp, Georg, Meisl, Alice, Anane, Jean-Philippe, Brandel, Ulrike, Camenisch, Joaquín, Castilla, Stéphane, Haïk, Tuomas, Knowles, Ewald, Lindner, Andreas, Lutterotti, Eric Vallabh, Minikel, Ignazio, Roiter, Jiri G, Safar, Raquel, Sanchez-Valle, Dana, Žáková, Simone, Hornemann, Adriano, Aguzzi, and Gianluigi, Forloni
Subjects: Male, Heterozygote, animal diseases, Case-Control Studies, Null Hypothesis, Mutation, Humans, Female, Autoantigens, Prion Proteins, nervous system diseases, Autoantibodies
Abstract: OBJECTIVE: To determine whether naturally occurring autoantibodies against the prion protein are present in individuals with genetic prion disease mutations and controls, and if so, whether they are protective against prion disease. METHODS: In this case–control study, we collected 124 blood samples from individuals with a variety of pathogenic PRNP mutations and 78 control individuals with a positive family history of genetic prion disease but lacking disease-associated PRNP mutations. Antibody reactivity was measured using an indirect ELISA for the detection of human immunoglobulin G(1–4) antibodies against wild-type human prion protein. Multivariate linear regression models were constructed to analyze differences in autoantibody reactivity between (1) PRNP mutation carriers vs controls and (2) asymptomatic vs symptomatic PRNP mutation carriers. Robustness of results was examined in matched cohorts. RESULTS: We found that antibody reactivity was present in a subset of both PRNP mutation carriers and controls. Autoantibody levels were not influenced by PRNP mutation status or clinical manifestation of prion disease. Post hoc analyses showed anti-PrP(C) autoantibody titers to be independent of personal history of autoimmune disease and other immunologic disorders, as well as PRNP codon 129 polymorphism. CONCLUSIONS: Pathogenic PRNP variants do not notably stimulate antibody-mediated anti-PrP(C) immunity. Anti-PrP(C) immunoglobulin G autoantibodies are not associated with the onset of prion disease. The presence of anti-PrP(C) autoantibodies in the general population without any disease-specific association suggests that relatively high titers of naturally occurring antibodies are well-tolerated. CLINICALTRIALS.GOV IDENTIFIER: NCT02837705.
Published: 2019

30. Age at onset in genetic prion disease and the design of preventive clinical trials

Author: Michael D. Geschwind, Christiane Stehmann, Janna Kenny, Sabina Capellari, Ryusuke Ae, Sonia M Vallabh, Leonel T. Takada, Masahito Yamada, Piero Parchi, Tadashi Tsukamoto, Steven J. Collins, Jamie Fong, Nobuo Sanjo, Claudia Ponto, Jean Louis Laplanche, Inga Zerr, Tobias Knipper, Jean Philippe Brandel, Margaret C. Orseth, Peter Hermann, Yosikazu Nakamura, Simon Mead, Stéphane Haïk, Miguel Calero, Tetsuyuki Kitamoto, Tsuyoshi Hamaguchi, Jesús de Pedro-Cuesta, Ignazio Roiter, Roberto Chiesa, Eric Vallabh Minikel, Jiri G. Safar, Hidehiro Mizusawa, Minikel E.V., Vallabh S.M., Orseth M.C., Brandel J.-P., Haik S., Laplanche J.-L., Zerr I., Parchi P., Capellari S., Safar J., Kenny J., Fong J.C., Takada L.T., Ponto C., Hermann P., Knipper T., Stehmann C., Kitamoto T., Ae R., Hamaguchi T., Sanjo N., Tsukamoto T., Mizusawa H., Collins S.J., Chiesa R., Roiter I., de Pedro-Cuesta J., Calero M., Geschwind M.D., Yamada M., Nakamura Y., and Mead S.
Subjects: 0301 basic medicine, Adult, Male, Creutzfeldt-Jakob disease, human prions, PRNP gene, clinical trials, biomarkers, neurodegenerative diseases, Adolescent, Genotype, Penetrance, Disease, Kaplan-Meier Estimate, Bioinformatics, Article, Prion Proteins, PRNP, Prion Diseases, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Medicine, Humans, Young adult, Age of Onset, Child, Aged, Proportional Hazards Models, Aged, 80 and over, Clinical Trials as Topic, Surrogate endpoint, Proportional hazards model, business.industry, Middle Aged, 3. Good health, Clinical trial, 030104 developmental biology, Research Design, Mutation, Female, Neurology (clinical), Age of onset, business, 030217 neurology & neurosurgery
Abstract: ObjectiveTo determine whether preventive trials in genetic prion disease could be designed to follow presymptomatic mutation carriers to onset of disease.MethodsWe assembled age at onset or death data from 1,094 individuals with high penetrance mutations in the prion protein gene (PRNP) in order to generate survival and hazard curves and test for genetic modifiers of age at onset. We used formulae and simulations to estimate statistical power for clinical trials.ResultsGenetic prion disease age at onset varies over several decades for the most common mutations and neither sex, parent's age at onset, nor PRNP codon 129 genotype provided additional explanatory power to stratify trials. Randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials.ConclusionThe characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a postmarketing study could provide opportunities for subsequent determination of clinical benefit.
Published: 2019

31. Age of onset in genetic prion disease and the design of preventive clinical trials

Author: Piero Parchi, Hidehiro Mizusawa, Claudia Ponto, Nobuo Sanjo, Janna Kenny, Inga Zerr, Jean Louis Laplanche, Tobias Knipper, Miguel Calero, Jiri G. Safar, Yosikazu Nakamura, Stéphane Haïk, Simon Mead, Sabina Capellari, Leonel T. Takada, Ignazio Roiter, Christiane Stehmann, Tadashi Tsukamoto, Sonia M Vallabh, Jamie Fong, Tsuyoshi Hamaguchi, Masahito Yamada, Margaret C. Orseth, Eric Vallabh Minikel, Steven J. Collins, Michael D. Geschwind, Ryusuke Ae, Tetsuyuki Kitamoto, Jean Philippe Brandel, Peter Hermann, Roberto Chiesa, and Jesús de Pedro-Cuesta
Subjects: 0303 health sciences, medicine.medical_specialty, Surrogate endpoint, business.industry, Disease, 3. Good health, law.invention, Clinical trial, 03 medical and health sciences, 0302 clinical medicine, Drug development, Randomized controlled trial, law, Clinical endpoint, medicine, Biomarker (medicine), Age of onset, Intensive care medicine, business, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Regulatory agencies worldwide have adopted programs to facilitate drug development for diseases where the traditional approach of a randomized trial with a clinical endpoint is expected to be prohibitively lengthy or difficult. Here we provide quantitative evidence that this criterion is met for the prevention of genetic prion disease. We assemble age of onset or death data fromN=1,094 individuals with high penetrance mutations in the prion protein gene (PRNP), generate survival and hazard curves, and estimate statistical power for clinical trials. We show that, due to dramatic and unexplained variability in age of onset, randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials. Instead, the characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Biomarker-based trials may require post-marketing studies to confirm clinical benefit. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a post-marketing study could provide opportunities for subsequent determination of clinical benefit.
Published: 2018
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32. History of Prions and transmission of protein misfolding

Author: Jean-Jacques, Hauw, Stéphane, Haik, and Jean-Philippe, Brandel
Subjects: Humans, Neurodegenerative Diseases, History, 20th Century, Proteostasis Deficiencies, Prion Diseases
Abstract: Since J. Cuillé and P. L. Chelle successfully transmitted scrapie between sheep by experi- mental inoculation in 1936 and D. C. Gajdusek kuru and Creutzfeldt-Jakob disease to chimpanzee in 1966 and 1968, respectively, the nature of the agents causing these " slow virus diseases " remains a mystery. In 1982, S. Prusiner called them " PRIONs " (for " PROteinaceous INfectious particles ") because they appeared lacking the nucleic acids that would classify them viruses. Although infectious or genetic mechanisms were seldom found, most of the rare human PRION diseases appeared " sporadic ". They shared many clinical and neuropathological properties with human neurodegenerative diseases (slow development, prominent nervous system involvement, amyloid deposits, paucity of immune response) the mechanism of which was not considered usually infectious. In 1991, H. Braak showed, in Alzheimer's disease brain, the low spreading of neuropathological tau associated lesions along anatomic pathways. They appear long before the clinical signs. The abnor- mally misfolded proteins characteristics of many neurodegenerative diseases are thought to aggregate after an initial seeding. This leads to their cell-cell transmission and dissemina- tion through neuronal and extra-neuronalpathways, which unexpected extent is under study. Whether the seeding is infectious or not remains debated. This new paradigm for unders- tanding their natural history and phenotypic diversity, which has already led to assess the diagnostic value of skin biopsy, should open the door to new therapeutic approach.
Published: 2018

33. Variant Creutzfeldt-Jakob disease

Author: Jean-Philippe, Brandel and Richard, Knight
Subjects: Encephalopathy, Bovine Spongiform, Sex Factors, Age Factors, Animals, Brain, Humans, Cattle, Creutzfeldt-Jakob Syndrome, Diet
Abstract: Variant CJD (vCJD) was described first in the United Kingdom in 1996. It is a zoonotic form of human prion disease, originating from dietary contamination of human food with material from bovine spongiform encephalopathy (BSE)-affected cattle. It has important epidemiologic, clinical, and neuropathogic differences from other forms of human prion disease. Cases have occurred in several countries but the United Kingdom and France have been most affected. Following the decline in BSE in cattle and the dietary protective measures adopted, vCJD has become an extremely rare disease. However, important concerns remain about asymptomatic infection in human populations (especially the United Kingdom) and the possibility of human-to-human transmission via medical and surgical interventions. Definitive diagnosis depends on neuropathology, usually undertaken at autopsy, but sometimes on brain biopsy. Clinical diagnosis with a reasonable degree of likelihood is, however, possible based on the clinical features and the finding of the pulvinar sign on cerebral magnetic resonance. There are also emerging tests (including blood tests) that have promising sensitivity and specificity for vCJD. It is a progressive illness, inevitably fatal with no curative treatment.
Published: 2018

34. Neuropathology of iatrogenic Creutzfeldt–Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Abeta pathology

Author: Stéphane Haïk, Jean-Philippe Brandel, Véronique Sazdovitch, Charles Duyckaerts, Zehra Yilmaz, Laurène Peckeu, Emmanuel Comoy, Kunie Ando, Nicolas Privat, Aleksandra Maleska Maceski, Sylvain Lehmann, Elodie Amar, Danielle Seilhean, Jean Pierre Brion, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université libre de Bruxelles (ULB), Laboratoire d'histologie générale, de neuroanatomie et de neuropathologie [Bruxelles], Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), CEA [Fontenay-aux-Roses] (UGRA / SETA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Université Libre de Bruxelles [Bruxelles] (ULB), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), Plateforme de Protéomique Clinique, CHU Saint-Eloi, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: Adult, 0301 basic medicine, Pathology, medicine.medical_specialty, Tau pathology, [SDV]Life Sciences [q-bio], Iatrogenic Disease, tau Proteins, Neuropathology, Biology, Growth hormone, Creutzfeldt-Jakob Syndrome, Prion Proteins, Infectious Disease Incubation Period, Pathology and Forensic Medicine, Incubation period, Cohort Studies, Young Adult, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, mental disorders, Cadaver, medicine, Humans, Incubation, ComputingMilieux_MISCELLANEOUS, Immunoassay, Amyloid beta-Peptides, medicine.diagnostic_test, Human Growth Hormone, Transmission (medicine), Brain, medicine.disease, nervous system diseases, 3. Good health, 030104 developmental biology, France, Neurology (clinical), Tauopathy, Drug Contamination, 030217 neurology & neurosurgery
Abstract: Abeta deposits and tau pathology were investigated in 24 French patients that died from iatrogenic Creutzfeldt-Jakob disease after exposure to cadaver-derived human growth hormone (c-hGH) in the 1980s. Abeta deposits were found only in one case that had experienced one of the longest incubation periods. Three cases had also intracellular tau accumulation. The analysis of 24 batches of c-hGH, produced between 1974 and 1988, demonstrated for the first time the presence of Abeta and tau contaminants in c-hGH (in 17 and 6 batches, respectively). The incubation of prion disease was shorter in the French patients than the incubation times reported in two previously published British series. We interpreted the low incidence of Abeta in this French series as a consequence of the shorter incubation period observed in France, as compared to that observed in the United Kingdom. This concept suggested that a mean incubation period for the development of detectable Abeta deposits would be longer than 18 years after the first exposure. Moreover, we hypothesized that tau pathology might also be transmissible in humans.
Published: 2018
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35. La maladie de Parkinson est-elle une maladie à prion ?

Author: A.-G Corbillé, Stéphane Haïk, Pascal Derkinderen, Jean-Philippe Brandel, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre national de référence des Agents Transmissibles Non Conventionnels, Institut de Veille Sanitaire (INVS), Unité James-Parkinson, Neuropathies du système nerveux entérique et pathologies digestives, implication des cellules gliales entériques, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: α-Synuclein, 0303 health sciences, Maladie de Parkinson, Prions, Parkinson's disease, Synucleins, Parkinson Disease, Article, 3. Good health, nervous system diseases, Prion Diseases, 03 medical and health sciences, 0302 clinical medicine, Neurology, Humans, Neurology (clinical), 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Prion-like, 030304 developmental biology
Abstract: National audience; The accumulation of a specific protein in aggregated form is a common phenomenon in human neurodegenerative diseases. In Parkinson's disease, this protein is α-synuclein which is a neuronal protein of 143 amino acids. With a monomeric conformation in solution, it also has a natural capacity to aggregate into amyloid structures (dimers, oligomers, fibrils and Lewy bodies or neurites). It therefore fulfils the characteristics of a prion protein (different conformations, seeding and spreading). In vitro and in vivo experimental evidence in transgenic and wild animals indicates a prion-like propagation of Parkinson's disease. The sequential and predictive distribution of α-synuclein demonstrated by Braak et al. and its correlation with non-motor signs are consistent with the prion-like progression. Although the triggering factor causing the misfolding and aggregation of the target protein is unknown, Parkinson's disease is a highly relevant model for the study of these mechanisms and also to test specific treatments targeting the assemblies of α-synuclein and propagation from pre-motor phase of the disease. Despite this prion-like progression, there is currently no argument indicating a risk of human transmission of Parkinson's disease.; L'accumulation d'une protéine spécifique sous forme agrégée est un phénomène commun aux maladies neurodégénératives humaines. Dans la maladie de Parkinson, cette protéine est l'α-synucléine qui est une protéine neuronale de 143 acides aminés. De conformation monomérique en solution, elle possède également une capacité naturelle à s'agréger en structures amyloïdes (dimères, oligomères, fibrilles puis corps ou neurites de Lewy). Elle détient donc les caractéristiques d'une protéine prion (différentes conformations, initiation et dissémination d'un processus transconformationnel). De nombreux arguments expérimentaux in vitro et in vivo sur des animaux transgéniques ou sauvages sont en faveur d'une progression prion-like de la maladie de Parkinson. La diffusion séquentielle et prédictive de l'α-synucléine mise en évidence par Braak et al. et sa corrélation avec les signes non moteurs vont tout à fait dans le sens de cette progression prion-like. Même si le facteur déclenchant à l'origine du mauvais repliement et de l'agrégation de la protéine cible reste inconnu, la maladie de Parkinson est un modèle très pertinent pour l'étude de ces mécanismes et aussi pour tester des traitements spécifiques ciblant les assemblages d'α-synucléine et leur propagation dès la phase pré-motrice de la maladie. Malgré cette progression prion-like, il n'existe actuellement aucun argument indiquant un risque de transmission interhumaine de la maladie de Parkinson.
Published: 2015
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36. Prions et transconformation protéique: une perspective historique

Author: Jean-Philippe Brandel, Stéphane Haïk, and Jean-Jacques Hauw
Subjects: medicine.diagnostic_test, Amyloid, Mechanism (biology), Transmission (medicine), Scrapie, General Medicine, Disease, Biology, medicine.disease, Virology, Immune system, Skin biopsy, medicine, Kuru
Abstract: Since J. Cuille and P. L. Chelle successfully transmitted scrapie between sheep by experi- mental inoculation in 1936 and D. C. Gajdusek kuru and Creutzfeldt-Jakob disease to chimpanzee in 1966 and 1968, respectively, the nature of the agents causing these " slow virus diseases " remains a mystery. In 1982, S. Prusiner called them " PRIONs " (for " PROteinaceous INfectious particles ") because they appeared lacking the nucleic acids that would classify them viruses. Although infectious or genetic mechanisms were seldom found, most of the rare human PRION diseases appeared " sporadic ". They shared many clinical and neuropathological properties with human neurodegenerative diseases (slow development, prominent nervous system involvement, amyloid deposits, paucity of immune response) the mechanism of which was not considered usually infectious. In 1991, H. Braak showed, in Alzheimer's disease brain, the low spreading of neuropathological tau associated lesions along anatomic pathways. They appear long before the clinical signs. The abnor- mally misfolded proteins characteristics of many neurodegenerative diseases are thought to aggregate after an initial seeding. This leads to their cell-cell transmission and dissemina- tion through neuronal and extra-neuronalpathways, which unexpected extent is under study. Whether the seeding is infectious or not remains debated. This new paradigm for unders- tanding their natural history and phenotypic diversity, which has already led to assess the diagnostic value of skin biopsy, should open the door to new therapeutic approach.
Published: 2015
Full Text: View/download PDF

37. Additional file 6: Figure S4. of Iatrogenic Creutzfeldt-Jakob disease with Amyloid-β pathology: an international study

Author: Cali, Ignazio, Cohen, Mark, Haїk, Stéphane, Parchi, Piero, Giaccone, Giorgio, Collins, Steven, Kofskey, Diane, Wang, Han, McLean, Catriona, Jean-Philippe Brandel, Privat, Nicolas, Sazdovitch, Véronique, Duyckaerts, Charles, Tetsuyuki Kitamoto, Ermias Belay, Maddox, Ryan, Tagliavini, Fabrizio, Pocchiari, Maurizio, Leschek, Ellen, Appleby, Brian, Jiri Safar, Schonberger, Lawrence, and Gambetti, Pierluigi
Abstract: Quantitative estimates of Thioflavin S-positive Aβ CP affecting the cerebral cortex in subjects with iCJD and sporadic AD (sAD). A: the density of Aβ CP, expressed as the percentage of cerebral cortex area occupied, was 5 times greater in subjects with sAD than in iCJD. B: size of Aβ CP (N=500), expressed as diameter, was greater in patients with sAD than in those with iCJD. C and D: representative microscopic fields showing fewer and smaller CP (arrows) in iCJD (C) than sAD (D) where cluster of very large CP (dashed square) could be detected. Bar graphs are expressed as mean ± standard error of the mean (SEM) in A or as mean ± standard deviation in B. Student's t-test (two-tailed). (PDF 3338 kb)
Published: 2018
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38. Additional file 7: Figure S5. of Iatrogenic Creutzfeldt-Jakob disease with Amyloid-β pathology: an international study

Author: Cali, Ignazio, Cohen, Mark, Haїk, Stéphane, Parchi, Piero, Giaccone, Giorgio, Collins, Steven, Kofskey, Diane, Wang, Han, McLean, Catriona, Jean-Philippe Brandel, Privat, Nicolas, Sazdovitch, Véronique, Duyckaerts, Charles, Tetsuyuki Kitamoto, Ermias Belay, Maddox, Ryan, Tagliavini, Fabrizio, Pocchiari, Maurizio, Leschek, Ellen, Appleby, Brian, Jiri Safar, Schonberger, Lawrence, and Gambetti, Pierluigi
Subjects: cardiovascular system
Abstract: Size of blood vessels examined and semiquantitative evaluation of the percentage of the vessel wall perimeters occupied by Aβ deposits in subjects with iCJD and sporadic AD (sAD). A: scatter plot showing the similar sizes of the blood vessels from the subarachnoid spaces of frontal, occipital and cerebellar regions examined for the semiquantitative determinations made in B; size of individual vessels is measured as perimeter. B: the percentage of the blood vessel wall occupied by Aβ was significantly greater in iCJD than sAD. Bar graphs are expressed as mean±SEM. Student's t-test (two-tailed). (PDF 228 kb)
Published: 2018
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39. Additional file 4: Figure S2. of Iatrogenic Creutzfeldt-Jakob disease with Amyloid-β pathology: an international study

Author: Cali, Ignazio, Cohen, Mark, Haїk, Stéphane, Parchi, Piero, Giaccone, Giorgio, Collins, Steven, Kofskey, Diane, Wang, Han, McLean, Catriona, Jean-Philippe Brandel, Privat, Nicolas, Sazdovitch, Véronique, Duyckaerts, Charles, Tetsuyuki Kitamoto, Ermias Belay, Maddox, Ryan, Tagliavini, Fabrizio, Pocchiari, Maurizio, Leschek, Ellen, Appleby, Brian, Jiri Safar, Schonberger, Lawrence, and Gambetti, Pierluigi
Subjects: nervous system
Abstract: Histopathology of an atypical US iCJD (case 5, Table 1). A-C: HE staining. D and E: PrP immunohistochemistry. A: spongiform degeneration (SD) with large and confluent vacuoles typical of the sCJDMM2 subtype, but limited to layer II of the frontal cortex, and severe neuronal loss and gliosis affecting all layers. B: high magnification of the area highlighted in A showing SD with large vacuoles. C: severe loss of granule cells and gliosis of the cerebellum; Grl. L: granular layer; Mol. L: molecular layer. D and E: diffuse or “synaptic” PrP immunostaining in the frontal cortex (D), and molecular and granular layers of the cerebellum (E); A-C: HE staining. D and E: PrP immunohistochemistry with Ab 3F4. (PDF 30981 kb)
Published: 2018
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40. Additional file 3: Figure S1. of Iatrogenic Creutzfeldt-Jakob disease with Amyloid-β pathology: an international study

Author: Cali, Ignazio, Cohen, Mark, Haїk, Stéphane, Parchi, Piero, Giaccone, Giorgio, Collins, Steven, Kofskey, Diane, Wang, Han, McLean, Catriona, Jean-Philippe Brandel, Privat, Nicolas, Sazdovitch, Véronique, Duyckaerts, Charles, Tetsuyuki Kitamoto, Ermias Belay, Maddox, Ryan, Tagliavini, Fabrizio, Pocchiari, Maurizio, Leschek, Ellen, Appleby, Brian, Jiri Safar, Schonberger, Lawrence, and Gambetti, Pierluigi
Abstract: Kaplan–Meier estimates of iCJD and sCJD controls. A: survival graphs representing whole iCJD cohort and its GH- and DM-iCJD subsets as well as sCJD cases. B: survival graphs of 21 iCJD and all sCJD divided into two groups according to age: 54 years or younger (≤54y), and older than 54 years (> 54y). Median survivals are indicated on the X-axis in A and B (arrowheads). Significant differences in median survivals, determined by the log rank (Mantel-Cox), were found between GH-iCJD and sCJD (P=0.0017) (A) or DM-iCJD ≤ 54y and sCJD ≤ 54y (P=0.0027) (B). (PDF 2348 kb)
Published: 2018
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41. Additional file 5: Figure S3. of Iatrogenic Creutzfeldt-Jakob disease with Amyloid-β pathology: an international study

Author: Cali, Ignazio, Cohen, Mark, Haїk, Stéphane, Parchi, Piero, Giaccone, Giorgio, Collins, Steven, Kofskey, Diane, Wang, Han, McLean, Catriona, Jean-Philippe Brandel, Privat, Nicolas, Sazdovitch, Véronique, Duyckaerts, Charles, Tetsuyuki Kitamoto, Ermias Belay, Maddox, Ryan, Tagliavini, Fabrizio, Pocchiari, Maurizio, Leschek, Ellen, Appleby, Brian, Jiri Safar, Schonberger, Lawrence, and Gambetti, Pierluigi
Abstract: WB profile of resPrPSc from iCJD and sCJD controls using different WB systems for PrP detection. BHs from the frontal cortex (lanes 8-10) and cerebellum (lanes 1-7) treated with 100 U/ml PK (~2000 μg/ml) were probed with indicated Abs. PrP bands were resolved in 15% Tris-HCl, 8.7 cm-long (A-C and E) and 20 cm-long (D) gels, and visualized with near-infrared LI-COR system (A-D and E(i)) or chemiluminescence (E(ii) and E(iii)). A: profiles of resPrPSc from CJD obtained with an 8.7 cm-long gel are similar to those obtained with the 20 cm-long gels in Fig. 2. The unglycosylated resPrPSc ~21 kDa of type 1 (21), ~20 kDa of type i (i), ~19 kDa of type 2 (2) and ~18 kDa (18) are indicated. B: the ~20 kDa of type i (i) and ~21 kDa of type 1 (21) (lanes 3-8), but not the ~19 kDa band of type 2, immunoreact with Ab 12B2. Profile of resPrPSc from iCJDMMi (lane 5) is indistinguishable from that of CJDMVi+2 (lanes 3 and 4), but differs from those of iCJDMM1 and sCJDMM1 (lanes 6-8), as the ~21 kDa band predominates in these three conditions. C: only ~19 kDa (type 2), but not ~21 kDa (type 1) and ~20 kDa (type i) immunoreacted with Tohoku-2 (To-2). An ~18 kDa (18) band in CJDVV2 and CJDMVi+2, and an unidentified lower size fragment (large arrow) in all cases harboring type 2 were also detected. A non-specific band (indicated by three asterisks) was present in all tested samples. D: high resolution gel electrophoresis in 20-cm long gel revealing ~21 kDa (21) and the ~20 kDa band (i and arrowhead). E(i): enhanced image of dashed area in A showing the bands ~21 kDa (21), ~20 kDa (i and arrowhead), and ~19 kDa (19; lane 4). The detection of the resPrPSc ~20 kDa band in addition to the prominent ~21 kDa fragment in CJDMM1 is most likely due to our use of a high resolution electrophoretic systems. E(ii): profiles of unglycosylated resPrPSc from the same cases in E(i) visualized on film by chemiluminescence. Note that the three CJDMM1 (lanes 6-8) show only ~21 kDa bands. E(iii): the ~20 kDa and ~21 kDa bands visible in B (lanes 3-5) resolve as a single band of ~21 kDa (lanes 4 and 5) when visualized on film by chemiluminescence. (PDF 6122 kb)
Published: 2018
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42. Longitudinal analysis of impulse control disorders in Parkinson disease

Author: Jean-Christophe, Corvol, Fanny, Artaud, Florence, Cormier-Dequaire, Olivier, Rascol, Franck, Durif, Pascal, Derkinderen, Ana-Raquel, Marques, Frédéric, Bourdain, Jean-Philippe, Brandel, Fernando, Pico, Lucette, Lacomblez, Cecilia, Bonnet, Christine, Brefel-Courbon, Fabienne, Ory-Magne, David, Grabli, Stephan, Klebe, Graziella, Mangone, Hana, You, Valérie, Mesnage, Pei-Chen, Lee, Alexis, Brice, Marie, Vidailhet, Alexis, Elbaz, Antoine, Faurie-Grepon, Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Neuro-Psycho Pharmacologie des Systèmes Dopimanégiques sous-corticaux (NPsy-Sydo), CHU Clermont-Ferrand-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Neuropathies du système nerveux entérique et pathologies digestives, implication des cellules gliales entériques, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National Taiwan University [Taiwan] (NTU), Neurologie et thérapeutique expérimentale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Recherches épidémiologiques en neurologie et psychopathologie, Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Fédération des Maladies du Système Nerveux, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), INSERM UMR_S975, CIC AP-HP (pitie-Salpetriere)/inserm, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Department of Neurology, University Hospital of Würzburg-University Hospital of Würzburg, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Department of Neurology, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM)
Subjects: 0301 basic medicine, Male, Levodopa, Pediatrics, medicine.medical_specialty, Longitudinal study, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Medizin, Disease, Antiparkinson Agents, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Medicine, Humans, Cumulative incidence, Longitudinal Studies, Generalized estimating equation, ComputingMilieux_MISCELLANEOUS, Aged, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Parkinson Disease, Middle Aged, Confidence interval, 3. Good health, Discontinuation, Disruptive, Impulse Control, and Conduct Disorders, 030104 developmental biology, Dopamine Agonists, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug, Cohort study, Follow-Up Studies
Abstract: ObjectiveTo investigate the longitudinal dose-effect relationship between dopamine replacement therapy and impulse control disorders (ICDs) in Parkinson disease (PD).MethodsWe used data from a multicenter longitudinal cohort of consecutive patients with PD with ≤5 years' disease duration at baseline followed up annually up to 5 years. ICDs were evaluated during face-to-face semistructured interviews with movement disorder specialists. Generalized estimating equations and Poisson models with robust variance were used to study the association between several time-dependent definitions of dopamine agonist (DA) use, taking dose and duration of treatment into account, and ICDs at each visit. Other antiparkinsonian drugs were also examined.ResultsAmong 411 patients (40.6% women, mean age 62.3 years, average follow-up 3.3 years, SD 1.7 years), 356 (86.6%) took a DA at least once since disease onset. In 306 patients without ICDs at baseline, the 5-year cumulative incidence of ICDs was 46.1% (95% confidence interval [CI] 37.4–55.7, DA ever users 51.5% [95% CI 41.8–62.1], DA never users 12.4% [95% CI 4.8–30.0]). ICD prevalence increased from 19.7% at baseline to 32.8% after 5 years. ICDs were associated with ever DA use (prevalence ratio 4.23, 95% CI 1.78–10.09). Lifetime average daily dose and duration of treatment were independently associated with ICDs with significant dose-effect relationships. Similar analyses for levodopa were not in favor of a strong association. ICDs progressively resolved after DA discontinuation.ConclusionIn this longitudinal study of patients with PD characterized by a high prevalence of DA treatment, the 5-year cumulative incidence of ICDs was ≈46%. ICDs were strongly associated with DA use with a dose-effect relationship; both increasing duration and dose were associated with ICDs. ICDs progressively resolved after DA discontinuation.ClinicalTrials.gov identifier:NCT01564992.
Published: 2017
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43. Intensity of human prion disease surveillance predicts observed disease incidence

Author: Maren Breithaupt, Inga Zerr, Annick Alpérovitch, Robert G. Will, Steven J. Collins, Gerard H. Jansen, Rachel Howley, Marion Simpson, Michael Farrell, Michael Coulthard, Genevieve M Klug, Cornelia M. van Duijn, Handan Wand, Alison Boyd, Colin L. Masters, Jean-Philippe Brandel, Matthew Law, Gabor G. Kovacs, Jan Mackenzie, Herbert Budka, Radoslav Matěj, Carla A. Ibrahim-Verbaas, University of Zurich, Klug, Genevieve M J A, Epidemiology, and Neurology
Subjects: Canada, Pediatrics, medicine.medical_specialty, Population, 10208 Institute of Neuropathology, Surveillance Methods, 610 Medicine & health, Disease, Creutzfeldt-Jakob Syndrome, Prion Diseases, 2738 Psychiatry and Mental Health, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Public health surveillance, Epidemiology, medicine, Humans, Dementia, Public Health Surveillance, Registries, 030212 general & internal medicine, education, Psychiatry, Disease surveillance, education.field_of_study, business.industry, Incidence, Incidence (epidemiology), Australia, medicine.disease, 2746 Surgery, nervous system diseases, 3. Good health, Europe, Psychiatry and Mental health, 2728 Neurology (clinical), Epidemiological Monitoring, 570 Life sciences, biology, Surgery, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: Background Prospective national screening and surveillance programmes serve a range of public health functions. Objectively determining their adequacy and impact on disease may be problematic for rare disorders. We undertook to assess whether objective measures of disease surveillance intensity could be developed for the rare disorder sporadic Creutzfeldt–Jakob disease (CJD) and whether such measures correlate with disease incidence. Method From 10 countries with national human prion disease surveillance centres, the annual number of suspected prion disease cases notified to each national unit (n=17 610), referrals for cerebrospinal fluid (CSF) 14-3-3 protein diagnostic testing (n=28 780) and the number of suspect cases undergoing diagnostic neuropathological examination (n=4885) from 1993 to 2006 were collected. Age and survey year adjusted incidence rate ratios with 95% CIs were estimated using Poisson regression models to assess risk factors for sporadic, non-sporadic and all prion disease cases. Results Age and survey year adjusted analysis showed all three surveillance intensity measures (suspected human prion disease notifications, 14-3-3 protein diagnostic test referrals and neuropathological examinations of suspect cases) significantly predicted the incidence of sporadic CJD, non-sporadic CJD and all prion disease. Conclusions Routine national surveillance methods adjusted as population rates allow objective determination of surveillance intensity, which correlates positively with reported incidence for human prion disease, especially sporadic CJD, largely independent of national context. The predictive relationship between surveillance intensity and disease incidence should facilitate more rapid delineation of aberrations in disease occurrence and assessment of the adequacy of disease monitoring by national registries.
Published: 2013
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44. Region-specific protein misfolding cyclic amplification reproduces brain tropism of prion strains

Author: Jean-Philippe Brandel, Etienne Levavasseur, Jean-Louis Laplanche, Stéphane Haïk, Samia Hannaoui, Serfildan Yildirim, Danielle Seilhean, Nicolas Privat, Vincent Béringue, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Biochimie et Biologie Moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Université de Montpellier (UM), Institut national de Veille Sanitaire, Haik, Stephane, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Protein Folding, mice, Amyloid, PrPSc Proteins, animal diseases, [SDV]Life Sciences [q-bio], Scrapie, Mice, Transgenic, Protein aggregation, Biology, in-vitro, Biochemistry, Creutzfeldt-Jakob Syndrome, 03 medical and health sciences, 0302 clinical medicine, agent strain, propagation, medicine, Animals, Humans, Protein Isoforms, molecules, Proteostasis Deficiencies, Molecular Biology, creutzfeldt-jakob-disease, Tropism, scrapie, transmission, Brain, Molecular Bases of Disease, Cell Biology, Human brain, Virology, Fungal prion, Cell biology, nervous system diseases, 030104 developmental biology, medicine.anatomical_structure, variant, infectious prions, Protein Misfolding Cyclic Amplification, Protein folding, 030217 neurology & neurosurgery
Abstract: International audience; Human prion diseases such as Creutzfeldt-Jakob disease are transmissible brain proteinopathies, characterized by the accumulation of a misfolded isoform of the host cellular prion protein (PrP) in the brain. According to the prion model, prions are defined as proteinaceous infectious particles composed solely of this abnormal isoform of PrP (PrPSc). Even in the absence of genetic material, various prion strains can be propagated in experimental models. They can be distinguished by the pattern of disease they produce and especially by the localization of PrPSc deposits within the brain and the spongiform lesions they induce. The mechanisms involved in this strain-specific targeting of distinct brain regions still are a fundamental, unresolved question in prion research. To address this question, we exploited a prion conversion in vitro assay, protein misfolding cyclic amplification (PMCA), by using experimental scrapie and human prion strains as seeds and specific brain regions from mice and humans as substrates. We show here that region-specific PMCA in part reproduces the specific brain targeting observed in experimental, acquired, and sporadic Creutzfeldt-Jakob diseases. Furthermore, we provide evidence that, in addition to cellular prion protein, other region-and species-specific molecular factors influence the strain-dependent prion conversion process. This important step toward understanding prion strain propagation in the human brain may impact research on the molecular factors involved in protein misfolding and the development of ultrasensitive methods for diagnosing prion disease.
Published: 2017
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45. Accuracy of diagnosis criteria in patients with suspected diagnosis of sporadic Creutzfeldt-Jakob disease and detection of 14-3-3 protein, France, 1992 to 2009

Author: N. Delasnerie-Laupretre, Stéphane Haïk, Véronique Sazdovitch, Danielle Seilhean, Jean-Jacques Hauw, Charles Duyckaerts, Laurène Peckeu, Jean-Louis Laplanche, Jean-Philippe Brandel, D. Salomon, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Cellule Natl Reference Malad Creutzfeldt Jakob, Hôpital Universitaire Pitié Salpêtrière, Assistance Publique - Hôpitaux de Paris (AP - HP), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC), Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Service de Biochimie [AP-HP Hôpitaux Saint-Louis Lariboisière], Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de Neuropathologie Raymond Escourolle [CHU Pitié Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Académie nationale de médecine, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -CHU Pitié-Salpêtrière [APHP], Hôpital Universitaire Pitié Salpêtrière, Assistance Publique - Hôpitaux de Paris ( AP - HP ), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité ( CRESS (U1153 / UMR_A 1125) ), Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Recherche Agronomique ( INRA ), CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP)-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]-Assistance publique - Hôpitaux de Paris (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neuropathologie [CHU Pitié Salpêtrière], HAL UPMC, Gestionnaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 0301 basic medicine, Pathology, Epidemiology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Autopsy, Disease, Electroencephalography, Surveillance and Outbreak Report, Creutzfeldt-Jakob Syndrome, 0302 clinical medicine, Cerebrospinal fluid, medicine.diagnostic_test, Brain, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, Magnetic Resonance Imaging, 3. Good health, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, surveillance, Female, France, medicine.medical_specialty, Prions, Sensitivity and Specificity, Prion Proteins, prion, 03 medical and health sciences, Nervous system disease, Virology, mental disorders, medicine, Humans, 14-3-3 protein, business.industry, Public Health, Environmental and Occupational Health, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, biomarkers, Magnetic resonance imaging, medicine.disease, Creutzfeldt-Jakob disease, nervous system diseases, 030104 developmental biology, 14-3-3 Proteins, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, diagnosis criteria, business, 030217 neurology & neurosurgery
Abstract: International audience; Diagnostic criteria of Creutzfeldt–Jakob disease (CJD), a rare and fatal transmissible nervous system disease with public health implications, are determined by clinical data, electroencephalogram (EEG), detection of 14-3-3 protein in cerebrospinal fluid (CSF), brain magnetic resonance imaging and prion protein gene examination. The specificity of protein 14-3-3 has been questioned. We reviewed data from 1,572 autopsied patients collected over an 18-year period (1992–2009) and assessed whether and how 14-3-3 detection impacted the diagnosis of sporadic CJD in France, and whether this led to the misdiagnosis of treatable disorders. 14-3-3 detection was introduced into diagnostic criteria for CJD in 1998. Diagnostic accuracy decreased from 92% for the 1992–1997 period to 85% for the 1998–2009 period. This was associated with positive detections of 14-3-3 in cases with negative EEG and alternative diagnosis at autopsy. Potentially treatable diseases were found in 163 patients (10.5%). This study confirms the usefulness of the recent modification of diagnosis criteria by the addition of the results of CSF real-time quaking-induced conversion, a method based on prion seed-induced misfolding and aggregation of recombinant prion protein substrate that has proven to be a highly specific test for diagnosis of sporadic CJD.
Published: 2017
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46. Preclinical sporadic Creutzfeldt-Jakob disease in French blood donors: an epidemiologic model-based study

Author: Stéphane Haïk, Jean-Philippe Brandel, D. Salomon, I Capek, Josiane Pillonel, Lucie Léon, Joliette Coste, Annick Alpérovitch, and Véronique Vaillant
Subjects: Pediatrics, medicine.medical_specialty, education.field_of_study, business.industry, Immunology, Population, Hematology, Disease, Sporadic Creutzfeldt-Jakob disease, Clinical onset, Surgery, Increased risk, Blood donor, Donation, medicine, Immunology and Allergy, Preclinical stage, education, business
Abstract: BACKGROUND: A recent case-control study showed that transfusion recipients were at an increased risk of developing sporadic Creutzfeldt-Jakob disease (sCJD), suggesting that blood donors with silent preclinical sCJD could transmit the sCJD agent. We therefore estimated the annual number of French blood donors expected to have preclinical sCJD at the time of donation. STUDY DESIGN AND METHODS: We developed a mathematical model to estimate the number of blood donors who would subsequently develop sCJD, under various assumptions about how long their blood might be infective before clinical onset. The model used distributions by age group and sex for sCJD cases, blood donor population, French general population, and mortality in the general population. RESULTS: Using 1999 to 2008 data, modeling showed that, each year, a mean of 1.1 (standard deviation [SD], 0.3) donors were within 1 year of sCJD onset at the time of blood donation, 6.9 (SD, 0.5) donors were within 5 years, 18.0 (SD, 0.6) were within 10 years, and 33.4 (SD, 1.1) were within 15 years. CONCLUSION: Few donors are expected to be in the late preclinical stage of sCJD at the time of blood donation. This result and that of the worldwide absence of any epidemic increase in sCJD over the years indicate that this risk of transfusion-transmitted sCJD, if any, is likely to be very low.
Published: 2011
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47. Contents Vol. 37, 2011

Author: Pornpet Panjapiyakul, Monika Balzer-Geldsetzer, Hans-Ulrich Wittchen, Neşe Güler, Ülkü Türk Börü, Marcelo Schultz, Satz Mengensatzproduktion, Bernadette Boden-Albala, L. Fernando Gonzalez, Ana Sofia Costa, Julián Benito-León, Carlos Romero, Claudia Trenkwalder, Alexander Storch, Mustafa Taşdemir, Ahmed Jusabani, Susanne Gräber-Sultan, Maurice Giroud, Cédric Annweiler, Günther Deuschl, John F. Kurtzke, Rashmi Kumar, Mark Swai, Juha E. Jääskeläinen, Haydar Sur, William K. Gray, Stavropoula Tjoumakaris, Mikael von und zu Fraunberg, Martin Kronenbürger, J. Hernesniemi, Stéphane Haïk, Jaakko Rinne, Antti Ronkainen, Adam E. Handel, Roongroj Bhidayasiri, Terhi Huttunen, Arlette Welaratne, Sabine Nunnemann, Kiyan Heshmat-Ghahdarijani, William K. Wohlgemuth, Christine Schneider, Elif Dilaver Ayık, Christián Begué, Myunghee Cho Paik, Annamaija Riihinen, Sreeram V. Ramagopalan, Thanin Asawavichienjinda, Antti E. Lindgren, Julio R. Vieira, Albertine Aouaba, Alireza Minagar, Thomas Klockgether, Carlos D'Giano, Maren Bodden, Hervé Aube, Thomas Gasser, Kanittha Chimabutra, Jörg B. Schulz, Wolfgang H. Oertel, Eric Benzenine, Renu Srismith, Estefania Rojas, Véronique Vaillant, Isabelle Capek, Vahab Moradi, Yves Cottin, Luca Mascitelli, M.S.V. Elkind, Alexander Kurz, Hans Förstl, Arda Duman, Richard Dodel, Safieh Nonahal, Alberto R. Ramos, Chuanhui Dong, Sandra Röske, Timo Koivisto, Tatjana Rundek, Samart Tananyakul, Kammant Phanthumchinda, Nele Schmidt, Mitja I. Kurki, Chanvit Tharathep, Ana Lia Taratuto, Hannah Gardener, Oliver Riedel, Catherine Quantin, Guiqing Yao, Tibor Schuster, Jean-Philippe Brandel, Catherine Sackley, Marianne Zeller, Olivier Beauchet, Gustavo Sevlever, Chiadi U. Onyike, Anwar Rizvi, Ayşegül Kumaş, Luc Lorgis, Brit Mollenhauer, Daniela Berg, Horacio Martinetto, Yannick Béjot, Pascal Jabbour, Annick Alpérovitch, Elke Kalbe, Serhan Yıldırım, Siegfried Muhlack, Supaporn Choeytim, Melanie Calvert, Anupama Bhave, Janine Diehl-Schmid, Yolsilp Suchonwanich, Abbas Ghorbani, Carola Seifried, Talat Rizvi, Annika Spottke, Inga Liepelt-Scarfone, Ralph L. Sacco, Paramjit Gill, Hardev Pall, Mitchell S.V. Elkind, Karsten Witt, Thomas Müller, Benjamin Eaton, Masoud Etemadifar, Amir-Hadi Maghzi, Natnipa Wannachai, Aaron S. Dumont, Taavi Saavalainen, Richard Walker, Roli Bhargava, Ullrich Wüllner, Mark R. Goldstein, Sudaratana Limpabandhu, Rüdiger Hilker, Clinton B. Wright, Yeseon P. Moon, Thomas J Hoppitt, Dominique Salomon, Manuel J. Somoza, Druck Reinhardt Druck Basel, and Dirk Woitalla
Subjects: Traditional medicine, Epidemiology, business.industry, Medicine, Neurology (clinical), business
Published: 2011
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48. Iatrogenic Creutzfeldt–Jakob disease in Australia: time to amend infection control measures for pituitary hormone recipients?

Author: Steven J. Collins, Lawrence B. Schonberger, Alison Boyd, Jean-Philippe Brandel, Amelia McGlade, Colin L. Masters, and Genevieve M Klug
Subjects: Infertility, Pediatrics, medicine.medical_specialty, Iatrogenic Disease, Disease, Risk Assessment, Short stature, Creutzfeldt-Jakob Syndrome, Central nervous system disease, Pituitary Gland, Anterior, mental disorders, Health care, medicine, Humans, Infection control, Infection Control, Human Growth Hormone, Tissue Extracts, business.industry, Australia, General Medicine, medicine.disease, nervous system diseases, Surgery, Cohort, Anxiety, medicine.symptom, business
Abstract: From 1967, the Australian Human Pituitary Hormone Program offered treatment for short stature and infertility using human cadaver-acquired pituitary hormones (human growth hormone [hGH] and human pituitary gonadotrophin [hPG]). The program was suspended in 1985 when a growth-hormone recipient in the United States developed Creutzfeldt-Jakob disease (CJD), an incurable and rapidly progressive neurodegenerative disorder. Since this time, recipients have lived with the significant anxiety that they have an elevated risk of developing CJD. Furthermore, additional CJD infection control measures are required when recipients undergo some types of surgery. As it is 20 years since the last Australian pituitary hormone recipient developed CJD, we evaluated the risk for Australian recipients of developing iatrogenic CJD, and compared Australian data with data from New Zealand and selected other countries who had pituitary hormone programs. Our evaluation indicates that pituitary hormone recipients in Australia have the lowest risk of developing iatrogenic CJD, and that Australia is the only country not to have experienced ongoing CJD-related deaths. Thus, we believe that: in the Australian hGH recipient cohort, the risk of developing CJD is sufficiently low for this cohort to no longer require additional infection control measures in the health care setting; and in the Australian hPG recipient cohort, if another 5 years elapses with no further occurrence of CJD in this group, the hPG recipient cohort could also be considered as not requiring additional infection control measures in the health care setting. These recommendations should not be misunderstood as implying that there is no ongoing risk, but that the risk is acceptably low and generally in keeping with guidelines that stratify the risk.
Published: 2010
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49. Phénotype inhabituel d’une maladie de Creutzfeldt-Jakob d’origine génétique

Author: Jean-Philippe Brandel, Carole Azuar, Richard Levy, Louis Cousyn, Stéphane Epelbaum, Aurélie Méneret, and David Grabli
Subjects: Neurology, Neurology (clinical)
Abstract: Introduction La presentation atypique des formes genetiques de maladie de Creutzfeldt-Jakob (MCJ), en comparaison aux formes sporadiques, peut engendrer un retard diagnostique. Observation Nous rapportons le cas d’un patient de 39 ans, sans antecedent personnel ni familial, ayant installe sur 3 mois une amnesie hippocampique isolee d’aggravation rapidement progressive. Il ne presente pas de syndrome pyramidal, extrapyramidal ou cerebelleux. On ne note que de discretes myoclonies des extremites sous fluoxetine. Les IRM initiales sont normales, sans anomalie corticale ou du striatum en particulier. Les EEG repetes n’objectivent que des anomalies lentes theta diffuses sans complexe triphasique. L’analyse du LCR est sans particularite, avec une proteine 14.3.3 negative. La proteine Tau totale revient tres elevee a 1927 pg/mL (proteine phospho-tau et peptide beta amyloide normaux). Une mutation G114V du gene PRNP est mise en evidence a l’etat heterozygote. Le patient est decede apres 9 mois d’evolution. Discussion Un âge de debut plus precoce, une evolution plus lente et un tableau clinique polymorphe dependant de la mutation sont decrits dans les formes genetiques. L’IRM et l’EEG sont egalement plus souvent normaux. Certaines etudes tendent a montrer une meilleure specificite et sensibilite de la proteine Tau totale que la proteine 14.3.3 dans le LCR. Conclusion Les formes genetiques de MCJ peuvent se caracteriser par une clinique atypique et polymorphe, l’absence d’anomalies evocatrices IRM et EEG, et une proteine 14.3.3 negative dans le LCR.
Published: 2018
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50. Case report of Lewy body disease mimicking Creutzfeldt-Jakob disease in a 44-year-old man

Author: Katell Peoc'h, Eric Guedj, A. Vital, Fabienne Ory Magne, Michèle Puel, Suzanne Lesage, Pierre Payoux, Laure Saint-Aubert, Hervé Dumas, Christine Brefel Courbon, Jérémie Pariente, Jean-Philippe Brandel, Karolinska Institutet [Stockholm], Neurologie vasculaire, pathologie neuro-dégénérative et explorations fonctionnelles du système nerveux [Toulouse], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Imagerie cérébrale et handicaps neurologiques (ICHN), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neuroradiologie [CHU Toulouse], Service de Médecine Nucléaire [Toulouse], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), AP-HP Service de Biochimie, Fondation FondaMental, U942 Hôpital Lariboisière, Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pharmacologie Clinique, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Service de Médecine Nucléaire - Pierre-Paul Riquet [CHU Toulouse], Pôle imagerie médicale [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service Pharmacologie Clinique [CHU Toulouse], Pôle Santé publique et médecine publique [CHU Toulouse], Imagerie cérébrale et handicaps neurologiques, Université Paul Sabatier - Toulouse 3 (UPS) - Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [CHU Toulouse], Service de médecine nucléaire [CHU Toulouse], Cellule nationale de référence des maladies de Creutzfeldt-Jakob, Institut du Cerveau et de la Moëlle Epinière (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC) - Institut National de la Santé et de la Recherche Médicale (INSERM) - CHU Pitié-Salpêtrière [APHP] - Centre National de la Recherche Scientifique (CNRS), Université Bordeaux Segalen - Bordeaux 2 - CHU Bordeaux [Bordeaux] - Groupe hospitalier Pellegrin, Institut de Neurosciences de la Timone [Marseille] (INT), and Aix Marseille Université (AMU) - Assistance Publique - Hôpitaux de Marseille (APHM) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Lewy Body Disease, Male, medicine.medical_specialty, Pediatrics, Pathology, Neurology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Diagnostico diferencial, Dementia with Lewy bodies, Clinical Neurology, Case Report, Neuroimaging, Disease, Creutzfeldt-Jakob Syndrome, Delusions, 14–3–3 protein, Imaging, Diagnosis, Differential, 03 medical and health sciences, Fatal Outcome, 0302 clinical medicine, Parkinsonian Disorders, Fluorodeoxyglucose F18, Diagnosis, medicine, Genetics, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], business.industry, Brain, General Medicine, medicine.disease, Magnetic Resonance Imaging, 030227 psychiatry, 3. Good health, 14-3-3 Proteins, Young population, Positron-Emission Tomography, Neurology (clinical), Neurosurgery, Cognition Disorders, business, Lewy body disease, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract: Background Few patients are reported with dementia with Lewy bodies before fifty years-old, which may partly reflect the difficulty of accurate diagnosis in young population. We report the case of a 44-year-old male with pathologically confirmed sporadic dementia with Lewy bodies, who did not fulfil the revised clinical criteria for this disease. Case presentation We document this atypical case with clinical and cognitive evaluation, imaging, biochemistry, genetics and pathology investigations. Creutzfeldt-Jakob disease was first suspected in this patient with no previous medical history, who developed acute and rapid cognitive impairment, L-dopa-non-responsive parkinsonism, and delusion. Positive 14–3–3 protein was initially detected in cerebrospinal fluid and until the late stages of the disease. Severe atrophy with no diffusion hypersignal was found on structural MRI as well as an extensive hypometabolism on 18F-FDG-PET, in comparison to age-matched healthy volunteers. Genetic investigation found no alpha-synuclein gene mutation. The patient died within 5 years, and post-mortem examination found numerous Lewy bodies and Lewy neurites consistent with pure Lewy body disease. Conclusions This comprehensively described case illustrates that dementia with Lewy bodies can occur in young patients with atypical clinical presentation. Biochemistry and neuroimaging investigations can sometimes be insufficient to allow accurate diagnostic. More specific markers to support such diagnosis are needed. Electronic supplementary material The online version of this article (doi:10.1186/s12883-016-0643-y) contains supplementary material, which is available to authorized users.
Published: 2016
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