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1. Visual deep learning-based explanation for neuritic plaques segmentation in Alzheimer's Disease using weakly annotated whole slide histopathological images

Author

Jimenez, Gabriel, Kar, Anuradha, Ounissi, Mehdi, Ingrassia, Léa, Boluda, Susana, Delatour, Benoît, Stimmer, Lev, and Racoceanu, Daniel

Subjects
Electrical Engineering and Systems Science - Image and Video Processing, Computer Science - Machine Learning
Abstract

Quantifying the distribution and morphology of tau protein structures in brain tissues is key to diagnosing Alzheimer's Disease (AD) and its subtypes. Recently, deep learning (DL) models such as UNet have been successfully used for automatic segmentation of histopathological whole slide images (WSI) of biological tissues. In this study, we propose a DL-based methodology for semantic segmentation of tau lesions (i.e., neuritic plaques) in WSI of postmortem patients with AD. The state of the art in semantic segmentation of neuritic plaques in human WSI is very limited. Our study proposes a baseline able to generate a significant advantage for morphological analysis of these tauopathies for further stratification of AD patients. Essential discussions concerning biomarkers (ALZ50 versus AT8 tau antibodies), the imaging modality (different slide scanner resolutions), and the challenge of weak annotations are addressed within this seminal study. The analysis of the impact of context in plaque segmentation is important to understand the role of the micro-environment for reliable tau protein segmentation. In addition, by integrating visual interpretability, we are able to explain how the network focuses on a region of interest (ROI), giving additional insights to pathologists. Finally, the release of a new expert-annotated database and the code (\url{https://github.com/aramis-lab/miccai2022-stratifiad.git}) will be helpful for the scientific community to accelerate the development of new pipelines for human WSI processing in AD.

Published
2023
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2. Motor neuron pathology in CANVAS due to RFC1 expansions

Author

Huin, Vincent, Coarelli, Giulia, Guemy, Clément, Boluda, Susana, Debs, Rabab, Mochel, Fanny, Stojkovic, Tanya, Grabli, David, Maisonobe, Thierry, Gaymard, Bertrand, Lenglet, Timothée, Tard, Céline, Davion, Jean-Baptiste, Sablonnière, Bernard, Monin, Marie-Lorraine, Ewenczyk, Claire, Viala, Karine, Charles, Perrine, Ber, Isabelle Le, Reilly, Mary, Houlden, Henry, Cortese, Andrea, Seilhean, Danielle, Brice, Alexis, and Durr, Alexandra

Subjects
Quantitative Biology - Neurons and Cognition
Abstract

CANVAS caused by RFC1 biallelic expansions is a major cause of inherited sensory neuronopathy. Detection of RFC1 expansion is challenging and CANVAS can be associated with atypical features. We clinically and genetically characterized 50 patients, selected based on the presence of sensory neuronopathy confirmed by EMG. We screened RFC1 expansion by PCR, repeat-primed PCR, and Southern blotting of long-range PCR products, a newly developed method. Neuropathological characterization was performed on the brain and spinal cord of one patient. Most patients (88%) carried a biallelic (AAGGG)n expansion in RFC1. In addition to the core CANVAS phenotype (sensory neuronopathy, cerebellar syndrome, and vestibular impairment), we observed chronic cough (97%), oculomotor signs (85%), motor neuron involvement (55%), dysautonomia (50%), and parkinsonism (10%). Motor neuron involvement was found for 24 of 38 patients (63.1%). First motor neuron signs, such as brisk reflexes, extensor plantar responses, and/or spasticity, were present in 29% of patients, second motor neuron signs, such as fasciculations, wasting, weakness, or a neurogenic pattern on EMG in 18%, and both in 16%. Mixed motor and sensory neuronopathy was observed in 19% of patients. Among six non-RFC1 patients, one carried a heterozygous AAGGG expansion and a pathogenic variant in GRM1. Neuropathological examination of one RFC1 patient with an enriched phenotype, including parkinsonism, dysautonomia, and cognitive decline, showed posterior column and lumbar posterior root atrophy. Degeneration of the vestibulospinal and spinocerebellar tracts was mild. We observed marked astrocytic gliosis and axonal swelling of the synapse between first and second motor neurons in the anterior horn at the lumbar level. The cerebellum showed mild depletion of Purkinje cells, with empty baskets, torpedoes, and astrogliosis characterized by a disorganization of the Bergmann's radial glia. We found neuronal loss in the vagal nucleus. The pars compacta of the substantia nigra was depleted, with widespread Lewy bodies in the locus coeruleus, substantia nigra, hippocampus, entorhinal cortex, and amygdala. We propose new guidelines for the screening of RFC1 expansion, considering different expansion motifs. Here, we developed a new method to more easily detect pathogenic RFC1 expansions. We report frequent motor neuron involvement and different neuronopathy subtypes. Parkinsonism was more prevalent in this cohort than in the general population, 10% versus the expected 1% (p < .001). We describe, for the first time, the spinal cord pathology in CANVAS, showing the alteration of posterior columns and roots, astrocytic gliosis and axonal swelling, suggesting motor neuron synaptic dysfunction.

Published
2022
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3. Endemic parkinsonism: clusters, biology and clinical features

Author

Menšíková, Katerina, Steele, John C., Rosales, Raymond, Colosimo, Carlo, Spencer, Peter, Lannuzel, Annie, Ugawa, Yoshikazu, Sasaki, Ryogen, Giménez-Roldán, Santiago, Matej, Radoslav, Tuckova, Lucie, Hrabos, Dominik, Kolarikova, Kristyna, Vodicka, Radek, Vrtel, Radek, Strnad, Miroslav, Hlustik, Petr, Otruba, Pavel, Prochazka, Martin, Bares, Martin, Boluda, Susana, Buee, Luc, Ransmayr, Gerhard, and Kaňovský, Petr

Published
2023
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4. Reply to: Questioning the cycad theory of Kii ALS–PDC causation

Author

Menšíková, Katerina, Rosales, Raymond, Colosimo, Carlo, Spencer, Peter, Lannuzel, Annie, Ugawa, Yoshikazu, Sasaki, Ryogen, Giménez-Roldán, Santiago, Matej, Radoslav, Tuckova, Lucie, Hrabos, Dominik, Kolarikova, Kristyna, Vodicka, Radek, Vrtel, Radek, Strnad, Miroslav, Hlustik, Petr, Otruba, Pavel, Prochazka, Martin, Bares, Martin, Boluda, Susana, Buee, Luc, Ransmayr, Gerhard, and Kaňovský, Petr

Published
2024
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5. CAG repeat mosaicism is gene specific in spinocerebellar ataxias

Author

Kacher, Radhia, Lejeune, François-Xavier, David, Isabelle, Boluda, Susana, Coarelli, Giulia, Leclere-Turbant, Sabrina, Heinzmann, Anna, Marelli, Cecilia, Charles, Perrine, Goizet, Cyril, Kabir, Nisha, Hilab, Rania, Jornea, Ludmila, Six, Julie, Dommergues, Marc, Fauret, Anne-Laure, Brice, Alexis, Humbert, Sandrine, and Durr, Alexandra

Published
2024
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6. MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study

Author

Warner, Thomas T, Jaunmuktane, Zane, Boeve, Bradley F, Duara, Ranjan, Graff-Radford, Neill R, Josephs, Keith A, Knopman, David S, Koga, Shunsuke, Murray, Melissa E, Lyons, Kelly E, Pahwa, Rajesh, Petersen, Ronald C, Whitwell, Jennifer L, Grinberg, Lea T, Miller, Bruce, Schlereth, Athena, Spina, Salvatore, Grossman, Murray, Irwin, David J, Suh, EunRan, Trojanowski, John Q, Van Deerlin, Vivianna M, Wolk, David A, Connors, Theresa R, Dooley, Patrick M, Oakley, Derek H, Aldecoa, Iban, Balasa, Mircea, Gelpi, Ellen, Borrego-Écija, Sergi, Gascon-Bayarri, Jordi, Sánchez-Valle, Raquel, Sanz-Cartagena, Pilar, Piñol-Ripoll, Gerard, Bigio, Eileen H, Flanagan, Margaret E, Rogalski, Emily J, Weintraub, Sandra, Schneider, Julie A, Peng, Lihua, Zhu, Xiongwei, Chang, Koping, Troncoso, Juan C, Prokop, Stefan, Newell, Kathy L, Jones, Matthew, Richardson, Anna, Roncaroli, Federico, Snowden, Julie, Allinson, Kieren, Singh, Poonam, Serrano, Geidy E, Flowers, Xena E, Goldman, James E, Heaps, Allison C, Leskinen, Sandra P, Black, Sandra E, Masellis, Mario, King, Andrew, Al-Sarraj, Safa, Troakes, Claire, Hodges, John R, Kril, Jillian J, Kwok, John B, Piguet, Olivier, Roeber, Sigrun, Attems, Johannes, Thomas, Alan J, Evers, Bret M., Bieniek, Kevin F, Sieben, Anne A, Cras, Patrick P, De Vil, Bart B, Bird, Thomas, Castellani, Rudolph J, Chaffee, Ann, Franklin, Erin, Haroutunian, Vahram, Jacobsen, Max, Keene, Dirk, Latimer, Caitlin S, Metcalf, Jeff, Perrin, Richard J, Purohit, Dushyant P, Rissman, Robert A, Schantz, Aimee, Walker, Jamie, De Deyn, Peter P, Duyckaerts, Charles, Le Ber, Isabelle, Seilhean, Danielle, Turbant-Leclere, Sabrina, Ervin, John F, Nennesmo, Inger, Riehl, James, Nacmias, Benedetta, Finger, Elizabeth C, Blauwendraat, Cornelis, Nalls, Mike A, Singleton, Andrew B, Vitale, Dan, Cunha, Cristina, Wszolek, Zbigniew K, Valentino, Rebecca R, Scotton, William J, Roemer, Shanu F, Lashley, Tammaryn, Heckman, Michael G, Shoai, Maryam, Martinez-Carrasco, Alejandro, Tamvaka, Nicole, Walton, Ronald L, Baker, Matthew C, Macpherson, Hannah L, Real, Raquel, Soto-Beasley, Alexandra I, Mok, Kin, Revesz, Tamas, Christopher, Elizabeth A, DeTure, Michael, Seeley, William W, Lee, Edward B, Frosch, Matthew P, Molina-Porcel, Laura, Gefen, Tamar, Redding-Ochoa, Javier, Ghetti, Bernardino, Robinson, Andrew C, Kobylecki, Christopher, Rowe, James B, Beach, Thomas G, Teich, Andrew F, Keith, Julia L, Bodi, Istvan, Halliday, Glenda M, Gearing, Marla, Arzberger, Thomas, Morris, Christopher M, White, Charles L, 3rd, Mechawar, Naguib, Boluda, Susana, MacKenzie, Ian R, McLean, Catriona, Cykowski, Matthew D, Wang, Shih-Hsiu J, Graff, Caroline, Nagra, Rashed M, Kovacs, Gabor G, Giaccone, Giorgio, Neumann, Manuela, Ang, Lee-Cyn, Carvalho, Agostinho, Morris, Huw R, Rademakers, Rosa, Hardy, John A, Dickson, Dennis W, Rohrer, Jonathan D, and Ross, Owen A

Published
2024
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7. Visual Deep Learning-Based Explanation for Neuritic Plaques Segmentation in Alzheimer’s Disease Using Weakly Annotated Whole Slide Histopathological Images

Author

Jimenez, Gabriel, Kar, Anuradha, Ounissi, Mehdi, Ingrassia, Léa, Boluda, Susana, Delatour, Benoît, Stimmer, Lev, Racoceanu, Daniel, Goos, Gerhard, Founding Editor, Hartmanis, Juris, Founding Editor, Bertino, Elisa, Editorial Board Member, Gao, Wen, Editorial Board Member, Steffen, Bernhard, Editorial Board Member, Yung, Moti, Editorial Board Member, Wang, Linwei, editor, Dou, Qi, editor, Fletcher, P. Thomas, editor, Speidel, Stefanie, editor, and Li, Shuo, editor

Published
2022
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8. MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study

Author

Valentino, Rebecca R, primary, Scotton, William J, additional, Roemer, Shanu F, additional, Lashley, Tammaryn, additional, Heckman, Michael G, additional, Shoai, Maryam, additional, Martinez-Carrasco, Alejandro, additional, Tamvaka, Nicole, additional, Walton, Ronald L, additional, Baker, Matthew C, additional, Macpherson, Hannah L, additional, Real, Raquel, additional, Soto-Beasley, Alexandra I, additional, Mok, Kin, additional, Revesz, Tamas, additional, Christopher, Elizabeth A, additional, DeTure, Michael, additional, Seeley, William W, additional, Lee, Edward B, additional, Frosch, Matthew P, additional, Molina-Porcel, Laura, additional, Gefen, Tamar, additional, Redding-Ochoa, Javier, additional, Ghetti, Bernardino, additional, Robinson, Andrew C, additional, Kobylecki, Christopher, additional, Rowe, James B, additional, Beach, Thomas G, additional, Teich, Andrew F, additional, Keith, Julia L, additional, Bodi, Istvan, additional, Halliday, Glenda M, additional, Gearing, Marla, additional, Arzberger, Thomas, additional, Morris, Christopher M, additional, White, Charles L, additional, Mechawar, Naguib, additional, Boluda, Susana, additional, MacKenzie, Ian R, additional, McLean, Catriona, additional, Cykowski, Matthew D, additional, Wang, Shih-Hsiu J, additional, Graff, Caroline, additional, Nagra, Rashed M, additional, Kovacs, Gabor G, additional, Giaccone, Giorgio, additional, Neumann, Manuela, additional, Ang, Lee-Cyn, additional, Carvalho, Agostinho, additional, Morris, Huw R, additional, Rademakers, Rosa, additional, Hardy, John A, additional, Dickson, Dennis W, additional, Rohrer, Jonathan D, additional, Ross, Owen A, additional, Warner, Thomas T, additional, Jaunmuktane, Zane, additional, Boeve, Bradley F, additional, Duara, Ranjan, additional, Graff-Radford, Neill R, additional, Josephs, Keith A, additional, Knopman, David S, additional, Koga, Shunsuke, additional, Murray, Melissa E, additional, Lyons, Kelly E, additional, Pahwa, Rajesh, additional, Petersen, Ronald C, additional, Whitwell, Jennifer L, additional, Grinberg, Lea T, additional, Miller, Bruce, additional, Schlereth, Athena, additional, Spina, Salvatore, additional, Grossman, Murray, additional, Irwin, David J, additional, Suh, EunRan, additional, Trojanowski, John Q, additional, Van Deerlin, Vivianna M, additional, Wolk, David A, additional, Connors, Theresa R, additional, Dooley, Patrick M, additional, Oakley, Derek H, additional, Aldecoa, Iban, additional, Balasa, Mircea, additional, Gelpi, Ellen, additional, Borrego-Écija, Sergi, additional, Gascon-Bayarri, Jordi, additional, Sánchez-Valle, Raquel, additional, Sanz-Cartagena, Pilar, additional, Piñol-Ripoll, Gerard, additional, Bigio, Eileen H, additional, Flanagan, Margaret E, additional, Rogalski, Emily J, additional, Weintraub, Sandra, additional, Schneider, Julie A, additional, Peng, Lihua, additional, Zhu, Xiongwei, additional, Chang, Koping, additional, Troncoso, Juan C, additional, Prokop, Stefan, additional, Newell, Kathy L, additional, Jones, Matthew, additional, Richardson, Anna, additional, Roncaroli, Federico, additional, Snowden, Julie, additional, Allinson, Kieren, additional, Singh, Poonam, additional, Serrano, Geidy E, additional, Flowers, Xena E, additional, Goldman, James E, additional, Heaps, Allison C, additional, Leskinen, Sandra P, additional, Black, Sandra E, additional, Masellis, Mario, additional, King, Andrew, additional, Al-Sarraj, Safa, additional, Troakes, Claire, additional, Hodges, John R, additional, Kril, Jillian J, additional, Kwok, John B, additional, Piguet, Olivier, additional, Roeber, Sigrun, additional, Attems, Johannes, additional, Thomas, Alan J, additional, Evers, Bret M., additional, Bieniek, Kevin F, additional, Sieben, Anne A, additional, Cras, Patrick P, additional, De Vil, Bart B, additional, Bird, Thomas, additional, Castellani, Rudolph J, additional, Chaffee, Ann, additional, Franklin, Erin, additional, Haroutunian, Vahram, additional, Jacobsen, Max, additional, Keene, Dirk, additional, Latimer, Caitlin S, additional, Metcalf, Jeff, additional, Perrin, Richard J, additional, Purohit, Dushyant P, additional, Rissman, Robert A, additional, Schantz, Aimee, additional, Walker, Jamie, additional, De Deyn, Peter P, additional, Duyckaerts, Charles, additional, Le Ber, Isabelle, additional, Seilhean, Danielle, additional, Turbant-Leclere, Sabrina, additional, Ervin, John F, additional, Nennesmo, Inger, additional, Riehl, James, additional, Nacmias, Benedetta, additional, Finger, Elizabeth C, additional, Blauwendraat, Cornelis, additional, Nalls, Mike A, additional, Singleton, Andrew B, additional, Vitale, Dan, additional, Cunha, Cristina, additional, and Wszolek, Zbigniew K, additional

Published
2024
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11. Clinical and neuropathological diversity of tauopathy in MAPT duplication carriers

Author

Wallon, David, Boluda, Susana, Rovelet-Lecrux, Anne, Thierry, Manon, Lagarde, Julien, Miguel, Laetitia, Lecourtois, Magalie, Bonnevalle, Antoine, Sarazin, Marie, Bottlaender, Michel, Mula, Mathieu, Marty, Serge, Nakamura, Natsuko, Schramm, Catherine, Sellal, François, Jonveaux, Thérèse, Heitz, Camille, Le Ber, Isabelle, Epelbaum, Stéphane, Magnin, Eloi, Zarea, Aline, Rousseau, Stéphane, Quenez, Olivier, Hannequin, Didier, Clavaguera, Florence, Campion, Dominique, Duyckaerts, Charles, and Nicolas, Gaël

Published
2021
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13. Amyloid-β peptide signature associated with cerebral amyloid angiopathy in familial Alzheimer's disease with APPdup and Down syndrome.

Author

Kasri, Amal, Camporesi, Elena, Gkanatsiou, Eleni, Boluda, Susana, Brinkmalm, Gunnar, Stimmer, Lev, Ge, Junyue, Hanrieder, Jörg, Villain, Nicolas, Duyckaerts, Charles, Vermeiren, Yannick, Pape, Sarah E., Nicolas, Gaël, Laquerrière, Annie, De Deyn, Peter Paul, Wallon, David, Blennow, Kaj, Strydom, Andre, Zetterberg, Henrik, and Potier, Marie-Claude

Subjects
CEREBRAL amyloid angiopathy, ALZHEIMER'S disease, PEPTIDES, DOWN syndrome, POLYNEUROPATHIES, TAU proteins
Abstract

Alzheimer's disease (AD) is characterized by extracellular amyloid plaques containing amyloid-β (Aβ) peptides, intraneuronal neurofibrillary tangles, extracellular neuropil threads, and dystrophic neurites surrounding plaques composed of hyperphosphorylated tau protein (pTau). Aβ can also deposit in blood vessel walls leading to cerebral amyloid angiopathy (CAA). While amyloid plaques in AD brains are constant, CAA varies among cases. The study focuses on differences observed between rare and poorly studied patient groups with APP duplications (APPdup) and Down syndrome (DS) reported to have higher frequencies of elevated CAA levels in comparison to sporadic AD (sAD), most of APP mutations, and controls. We compared Aβ and tau pathologies in postmortem brain tissues across cases and Aβ peptides using mass spectrometry (MS). We further characterized the spatial distribution of Aβ peptides with MS-brain imaging. While intraparenchymal Aβ deposits were numerous in sAD, DS with AD (DS-AD) and AD with APP mutations, these were less abundant in APPdup. On the contrary, Aβ deposits in the blood vessels were abundant in APPdup and DS-AD while only APPdup cases displayed high Aβ deposits in capillaries. Investigation of Aβ peptide profiles showed a specific increase in Aβx-37, Aβx-38 and Aβx-40 but not Aβx-42 in APPdup cases and to a lower extent in DS-AD cases. Interestingly, N-truncated Aβ2-x peptides were particularly increased in APPdup compared to all other groups. This result was confirmed by MS-imaging of leptomeningeal and parenchymal vessels from an APPdup case, suggesting that CAA is associated with accumulation of shorter Aβ peptides truncated both at N- and C-termini in blood vessels. Altogether, this study identified striking differences in the localization and composition of Aβ deposits between AD cases, particularly APPdup and DS-AD, both carrying three genomic copies of the APP gene. Detection of specific Aβ peptides in CSF or plasma of these patients could improve the diagnosis of CAA and their inclusion in anti-amyloid immunotherapy treatments. [ABSTRACT FROM AUTHOR]

Published
2024
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16. C9ORF72 knockdown triggers FTD-like symptoms and cell pathology in mice

Author

Lopez-Herdoiza, Maria-Belen, primary, Bauché, Stephanie, additional, Wilmet, Baptiste, additional, Le Duigou, Caroline, additional, Roussel, Delphine, additional, Frah, Magali, additional, Béal, Jonas, additional, Devely, Gabin, additional, Boluda, Susana, additional, Frick, Petra, additional, Bouteiller, Delphine, additional, Dussaud, Sébastien, additional, Guillabert, Pierre, additional, Dalle, Carine, additional, Dumont, Magali, additional, Camuzat, Agnes, additional, Saracino, Dario, additional, Barbier, Mathieu, additional, Bruneteau, Gaelle, additional, Ravassard, Phillippe, additional, Neumann, Manuela, additional, Nicole, Sophie, additional, Le Ber, Isabelle, additional, Brice, Alexis, additional, and Latouche, Morwena, additional

Published
2023
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18. Golgi localization of SARS-CoV-2 spike protein and interaction with furin in cerebral COVID-19 microangiopathy: a clue to the central nervous system involvement?

Author

Boluda, Susana, Mokhtari, Karima, Mégarbane, Bruno, Annane, Djillali, Mathon, Bertrand, Cao, Albert, Adam, Clovis, Androuin, Alexandre, Bielle, Franck, Brochier, Guy, Charlotte, Frédéric, Chougar, Lydia, El Hachimi, Khalid Hamid, Eloit, Marc, Haïk, Stéphane, Hervé, Dominique, Kasri, Amal, Leducq, Valentin, Lehéricy, Stéphane, Levavasseur, Etienne, Lobsiger, Christian, Lorin De La Grandmaison, Geoffroy, Malet, Isabelle, Malissin, Isabelle, Marot, Stéphane, Marty, Serge, Pérot, Philippe, Plu, Isabelle, Prigent, Annick, Stimmer, Lev, Potier, Marie-Claude, Marcelin, Anne-Geneviève, Delatour, Benoît, Duyckaerts, Charles, Seilhean, Danielle, 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), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Raymond Poincaré [Garches], Université Paris-Saclay, Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-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), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL), Découverte de pathogènes – Pathogen discovery, Institut Pasteur [Paris] (IP), Université Sorbonne Paris Nord, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), The authors thank the Cohort COVID-19 Neurosciences (CoCo Neurosciences) study supported by APHP and funded by the generous support of the Federation Internationale de l’Automobile (FIA), the FIA Foundation and donors of Paris Brain Institute – ICM. The research leading to these results has received funding from Sorbonne University (PathoCoV project) and from the program 'Investissements d’avenir' ANR-10- IAIHU-06. This work benefited from equipment and services from the CELIS cell culture core facility (Paris Brain Institute), a platform receiving support from ANR-10- IAIHU-06 and ANR-11-INBS-0011-NeurATRIS. We thank for targeted NGS sequencing the Biomics Platform, C2RT, Institut Pasteur, Paris, France, supported by France Génomique (ANR-10-INBS-09-09), IBISA and the Illumina COVID-19 Projects’ offer., ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), and ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010)

Subjects
Furin, Blood-brain barrier (BBB), Original Paper, Microangiopathy, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Neuro-Covid, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], COVID-19
Abstract

In a neuropathological series of 20 COVID-19 cases, we analyzed six cases (three biopsies and three autopsies) with multiple foci predominantly affecting the white matter as shown by MRI. The cases presented with microhemorrhages evocative of small artery diseases. This COVID-19 associated cerebral microangiopathy (CCM) was characterized by perivascular changes: arterioles were surrounded by vacuolized tissue, clustered macrophages, large axonal swellings and a crown arrangement of aquaporin-4 immunoreactivity. There was evidence of blood-brain-barrier leakage. Fibrinoid necrosis, vascular occlusion, perivascular cuffing and demyelination were absent. While no viral particle or viral RNA was found in the brain, the SARS-CoV-2 spike protein was detected in the Golgi apparatus of brain endothelial cells where it closely associated with furin, a host protease known to play a key role in virus replication. Endothelial cells in culture were not permissive to SARS-CoV-2 replication. The distribution of the spike protein in brain endothelial cells differed from that observed in pneumocytes. In the latter, the diffuse cytoplasmic labeling suggested a complete replication cycle with viral release, notably through the lysosomal pathway. In contrast, in cerebral endothelial cells the excretion cycle was blocked in the Golgi apparatus. Interruption of the excretion cycle could explain the difficulty of SARS-CoV-2 to infect endothelial cells in vitro and to produce viral RNA in the brain. Specific metabolism of the virus in brain endothelial cells could weaken the cell walls and eventually lead to the characteristic lesions of COVID-19 associated cerebral microangiopathy. Furin as a modulator of vascular permeability could provide some clues for the control of late effects of microangiopathy., Free Neuropathology, Vol. 4 (2023)

Published
2023

19. 'Keeping the plates spinning': a qualitative study of the complexity, barriers, and facilitators to caregiving in heart failure with preserved ejection fraction.

Author

Pearson, Clare R, Forsyth, Faye, Khair, Eva, Sowden, Emma, Borja Boluda, Susana, Deaton, Christi, Optimise HFpEF Investigators, Chakravorty, Mollika, Maclachlan, Sophie, Kane, Edward, Odone, Jessica, Thorley, Natasha, Borja-Boluda, Susana, Wellwood, Ian, Blakeman, Thomas, Chew-Graham, Carolyn, Hossain, Muhammed, Sharpley, John, Gordon, Brain, and Taffe, Joanna

Subjects
CAREGIVER attitudes, SERVICES for caregivers, VENTRICULAR ejection fraction, RESEARCH methodology, INTERVIEWING, FAMILY roles, QUALITATIVE research, PSYCHOLOGY of caregivers, DESCRIPTIVE statistics, RESEARCH funding, THEMATIC analysis, JUDGMENT sampling, DATA analysis software, HEART failure, COMORBIDITY
Abstract

Aims: Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of all heart failure cases; yet remains poorly understood, diagnosed, and managed, which adds complexity to the carer role. No study to date has investigated the experiences of informal carers of people with HFpEF. The aim of this study was to explore the role and experiences of informal carers of people with HFpEF. Methods and results: A qualitative study using semi-structured interviews involving carers alone, patients alone, or carer/patient dyads. The interviews were part of a larger programme of research in HFpEF. Participants were recruited from three regions of England. Interviews were recorded, transcribed verbatim, and analysed thematically. Twenty-two interviews were conducted with 38 participants, 17 were informal carers. Three inter-related themes were identified: Theme 1, the complex nature of informal caregiving ('spinning plates'); Theme 2, the barriers to caregiving ('the spinning falters'); and Theme 3, the facilitators of caregiving ('keeping the plates spinning'). Conclusions: Informal carers play an important role in supporting people with HFpEF. The experience of caregiving in HFpEF is similar to that described for Heart Failure with reduced Ejection Fraction, but complicated by challenges of limited information and support specific to HFpEF, and high burden of multi-morbidity. Healthcare providers should assess the needs of informal carers as part of patient care in HFpEF. Carers and patients would benefit from improved information and co-ordinated management of HFpEF and multi-morbidities. Helping carers 'keep the plates spinning' will require innovative approaches and co-ordination across the care continuum. Graphical Abstract [ABSTRACT FROM AUTHOR]

Published
2023
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21. Relationship between Substantia Nigra Neuromelanin Imaging and Dual Alpha-Synuclein Labeling of Labial Minor in Salivary Glands in Isolated Rapid Eye Movement Sleep Behavior Disorder and Parkinson’s Disease

Author

Mangone, Graziella, primary, Houot, Marion, additional, Gaurav, Rahul, additional, Boluda, Susana, additional, Pyatigorskaya, Nadya, additional, Chalancon, Alizé, additional, Seilhean, Danielle, additional, Prigent, Annick, additional, Lehéricy, Stéphane, additional, Arnulf, Isabelle, additional, Corvol, Jean-Christophe, additional, Vidailhet, Marie, additional, Duyckaerts, Charles, additional, and Degos, Bertrand, additional

Published
2022
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23. Normal meninges harbor oncogenic somatic mutations in meningioma-driver genes.

Author

Boetto, Julien, Plu, Isabelle, Ducos, Yohan, Blouin, Antoine, Teranishi, Yu, Letournel, Franck, Martin-Négrier, Marie-Laure, Faisant, Maxime, Godfraind, Catherine, Maurage, Claude-Alain, Deramecourt, Vincent, Duchesne, Mathilde, Meyronnet, David, Delteil, Clémence, Rigau, Valérie, Vandenbos-Burel, Fanny, Seilhean, Danielle, Boluda, Susana, Chiforeanu, Dan Christian, and Marguet, Florent

Subjects
SOMATIC mutation, MENINGES, DURA mater, GENETIC variation
Abstract

The occurrence of I TRAF7 i mutations in the normal meninges also questions its intrinsic pathogenic value, since meningiomas frequently harbor a second co-mutation ( I KLF4 i SP I K409Q i sp or one of the main oncogenes of the PI3K pathway, I AKT1 i and I PIK3CA i ) [[1], [5]]. Meningioma oncogenesis is dominated by the occurrence of well-known driver gene mutations that form co-exclusive mutational groups, but 20% of meningiomas do not harbor any somatic mutation [[4]-[6]]. Variants are reported ordered by gene mutation frequency, and colored depending on the consequence of the mutation. d Summary of the four mutations present in the normal meninges in main driver genes for meningioma (NF2 and TRAF7). [Extracted from the article]

Published
2023
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25. Alterations of neuronal lysosomes in Alzheimer's disease and in APPxPS1-KI mice

Author

Androuin, Alexandre, Thierry, Manon, Boluda, Susana, Baskaran, Asha, Langui, Dominique, Duyckaerts, Charles, Potier, Marie-Claude, El Hachimi, Khalid Hamid, Delatour, Benoît, Marty, Serge, 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Marty, Serge

Subjects
Neurons, Amyloid beta-Peptides, electron microscopy, General Neuroscience, [SDV]Life Sciences [q-bio], Mice, Transgenic, General Medicine, amyloid-β, Lipofuscin, [SDV] Life Sciences [q-bio], Psychiatry and Mental health, Clinical Psychology, Amyloid beta-Protein Precursor, Disease Models, Animal, Mice, Alzheimer Disease, lysosome, Animals, Humans, Geriatrics and Gerontology, Lysosomes, Alzheimer’s disease
Abstract

International audience; Background: The cellular and molecular alterations associated with synapse and neuron loss in Alzheimer's disease (AD) remain unclear. In transgenic mouse models that express mutations responsible for familial AD, neuronal and synaptic losses occur in populations that accumulate fibrillar amyloid-β 42 (Aβ42) intracellularly.Objective: We aimed to study the subcellular localization of these fibrillar accumulations and whether such intraneuronal assemblies could be observed in the human pathology.Methods: We used immunolabeling and various electron microscopy techniques on APP x presenilin1 - knock-in mice and on human cortical biopsies and postmortem samples.Results: We found an accumulation of Aβ fibrils in lipofuscin granule-like organelles in APP x presenilin1 - knock-in mice. Electron microscopy of human cortical biopsies also showed an accumulation of undigested material in enlarged lipofuscin granules in neurons from AD compared to age-matched non-AD patients. However, in those biopsies or in postmortem samples we could not detect intraneuronal accumulations of Aβ fibrils, neither in the lipofuscin granules nor in other intraneuronal compartments.Conclusion: The intralysosomal accumulation of Aβ fibrils in specific neuronal populations in APPxPS1-KI mice likely results from a high concentration of Aβ42 in the endosome-lysosome system due to the high expression of the transgene in these neurons.

Published
2022

28. Motor neuron pathology in CANVAS due to RFC1 expansions

Author

Huin, Vincent, Coarelli, Giulia, Guemy, Clément, Boluda, Susana, Debs, Rabab, Mochel, Fanny, Stojkovic, Tanya, Grabli, David, Maisonobe, Thierry, Gaymard, Bertrand, Lenglet, Timothée, Tard, Céline, Davion, Jean-Baptiste, Sablonnière, Bernard, Monin, Marie-Lorraine, Ewenczyk, Claire, Viala, Karine, Charles, Perrine, Le Ber, Isabelle, Reilly, Mary, Houlden, Henry, Cortese, Andrea, Seilhean, Danielle, Brice, Alexis, Durr, Alexandra, 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), 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de référence des maladies rares neuromusculaires, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and University College of London [London] (UCL)

Subjects
[SDV.GEN]Life Sciences [q-bio]/Genetics, nervous system, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, CANVAS, sensory neuronopathy, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], cerebellar ataxia, motor neuron, parkinsonism, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; CANVAS caused by RFC1 biallelic expansions is a major cause of inherited sensory neuronopathy. Detection of RFC1 expansion is challenging and CANVAS can be associated with atypical features. We clinically and genetically characterized 50 patients, selected based on the presence of sensory neuronopathy confirmed by EMG. We screened RFC1 expansion by PCR, repeat-primed PCR, and Southern blotting of long-range PCR products, a newly developed method. Neuropathological characterization was performed on the brain and spinal cord of one patient. Most patients (88%) carried a biallelic (AAGGG)n expansion in RFC1. In addition to the core CANVAS phenotype (sensory neuronopathy, cerebellar syndrome, and vestibular impairment), we observed chronic cough (97%), oculomotor signs (85%), motor neuron involvement (55%), dysautonomia (50%), and parkinsonism (10%). Motor neuron involvement was found for 24 of 38 patients (63.1%). First motor neuron signs, such as brisk reflexes, extensor plantar responses, and/or spasticity, were present in 29% of patients, second motor neuron signs, such as fasciculations, wasting, weakness, or a neurogenic pattern on EMG in 18%, and both in 16%. Mixed motor and sensory neuronopathy was observed in 19% of patients. Among six non-RFC1 patients, one carried a heterozygous AAGGG expansion and a pathogenic variant in GRM1. Neuropathological examination of one RFC1 patient with an enriched phenotype, including parkinsonism, dysautonomia, and cognitive decline, showed posterior column and lumbar posterior root atrophy. Degeneration of the vestibulospinal and spinocerebellar tracts was mild. We observed marked astrocytic gliosis and axonal swelling of the synapse between first and second motor neurons in the anterior horn at the lumbar level. The cerebellum showed mild depletion of Purkinje cells, with empty baskets, torpedoes, and astrogliosis characterized by a disorganization of the Bergmann's radial glia. We found neuronal loss in the vagal nucleus. The pars compacta of the substantia nigra was depleted, with widespread Lewy bodies in the locus coeruleus, substantia nigra, hippocampus, entorhinal cortex, and amygdala. We propose new guidelines for the screening of RFC1 expansion, considering different expansion motifs. Here, we developed a new method to more easily detect pathogenic RFC1 expansions. We report frequent motor neuron involvement and different neuronopathy subtypes. Parkinsonism was more prevalent in this cohort than in the general population, 10% versus the expected 1% (p

Published
2021

29. The neuroCEB brainbank: a brief history (15 years!) of neuropathology

Author

artaud botté, marie claire, Leclere-Turbant, Sabrina, Duyckaerts, C, Martin Negrier, Marie Laure, Letourneur, Franck, Plu, Isabelle, Boluda, Susana, Seilhean, Danielle, and neuro-ceb

Subjects
[SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2021

31. P2X7-deficiency improves plasticity and cognitive abilities in a mouse model of Tauopathy

Author

Carvalho, Kevin, primary, Martin, Elodie, additional, Ces, Aurélia, additional, Sarrazin, Nadège, additional, Lagouge-Roussey, Pauline, additional, Nous, Caroline, additional, Boucherit, Leyna, additional, Youssef, Ihsen, additional, Prigent, Annick, additional, Faivre, Emilie, additional, Eddarkaoui, Sabiha, additional, Gauvrit, Thibaut, additional, Vieau, Didier, additional, Boluda, Susana, additional, Huin, Vincent, additional, Fontaine, Bertrand, additional, Buée, Luc, additional, Delatour, Benoît, additional, Dutar, Patrick, additional, Sennlaub, Florian, additional, Guillonneau, Xavier, additional, Blum, David, additional, and Delarasse, Cécile, additional

Published
2021
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35. Identification d’un nouvel arbovirus neurotrope en France : le virus Umbre

Author

Pérot, Philippe, Bielle, Franck, Bigot, Thomas, Foulongne, Vincent, Bolloré, Karine, Chrétien, Delphine, Gil, Patricia, Gutierrez, Serafin, L'Ambert, Grégory, Mokhtari, Karima, Hellert, Jan, Flamand, Marie, Tamietti, Carole, Coulpier, Muriel, Huard de Verneuil, Anne, Temmam, Sarah, Couderc, Thérèse, De Sousa Cunha, Edouard, Boluda, Susana, Plu, Isabelle, Delisle, Marie Bernadette, Bonneville, Fabrice, Brassat, David, Fieschi, Claire, Malphettes, Marion, Duyckaerts, Charles, Mathon, Bertrand, Demeret, Sophie, Seilhean, Danielle, Eloit, Marc, Pérot, Philippe, Découverte de pathogènes – Pathogen discovery, Institut Pasteur [Paris] (IP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Pathogenesis and Control of Chronic and Emerging Infections (PCCEI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université des Antilles (UA)-Etablissement français du don du sang [Montpellier], Animal, Santé, Territoires, Risques et Ecosystèmes (UMR ASTRE), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Département Systèmes Biologiques (Cirad-BIOS), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Entente Interdépartementale pour la démoustication du littoral méditerranéen (EID), Virologie Structurale - Structural Virology, Virologie UMR1161 (VIRO), École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Biologie des Infections - Biology of Infection, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service Neuroradiologie Diagnostique et Thérapeutique [CHU Toulouse], Pôle imagerie médicale [CHU Toulouse], 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), Immunologie clinique [CHU St-Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre national de référence des Agents Transmissibles Non Conventionnels, Institut de Veille Sanitaire (INVS), École nationale vétérinaire - Alfort (ENVA), Institut Pasteur [Paris], Laboratoire de Neuropathologie Raymond Escourolle, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Institut Pasteur [Paris]-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)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier )-Université de Montpellier (UM), École nationale vétérinaire d'Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anatomie et cytologie pathologiques [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Neuroradiologie Diagnostique et Thérapeutique [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Service de Neurochirurgie [CHU Pitié-Salpêtrière], and École nationale vétérinaire d'Alfort (ENVA)

Subjects
[SDV.EE]Life Sciences [q-bio]/Ecology, environment, métagénomique, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, moustiques, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], encéphalites, orthobunyavirus, [SDV.EE] Life Sciences [q-bio]/Ecology, environment, arbovirus, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], NGS, Umbre virus, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], virologie, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]
Abstract

International audience; Notre laboratoire a mis en place une collaboration avec le laboratoire de neuropathologie de l’hôpital de la Pitié-Salpêtrière pour explorer une série post-mortem de cas d’encéphalites humaines d’étiologie inconnue par un séquençage NGS profond et non ciblé du transcriptome, à la recherche de séquences de pathogènes. Le virus Umbre, un virus du genre orthobunyavirus, a été identifié chez deux patients immunodéprimés décédés en 2013 et 2019. Le virus infecte des neurones du cortex cérébral, la moelle épinière et le foie. Le virus Umbre a été décrit initialement dans les années 1950 dans des populations de moustiques Culex en zone Asie Pacifique, mais n’avait auparavant ni été isolé chez des mammifères (dont l’homme), ni détecté en Europe. Cette infection par le virus Umbre chez deux patients français, dont l’un vivait dans la région Occitanie et n’avait jamais voyagé en dehors de France métropolitaine, et l’autre avait fait une croisière en méditerranée avant l’apparition des symptômes, nous a amené à rechercher l’origine de la contamination dans des moustiques. Une investigation réalisée en partenariat avec le CIRAD de Montpellier et l’EID Méditerranée a permis d’identifier des séquences du genre orthobunyavirus très proches du virus Umbre dans des moustiques Culex de Camargue. Une enquête sérologique par un test développé à l’Institut Pasteur sur une population du sud de la France composée d’environ 300 personnes « contrôles » et d’une vingtaine de cas « encéphalites » n’a pas mis en évidence de réponse anticorps contre le virus Umbre. Ce résultat suggère que la fréquence de l’infection dans la population générale est au plus faible, ce qui ne reflète donc pas le risque pour les personnes immunodéprimées. Cette découverte d’un nouvel arbovirus responsable d’encéphalite, et son existence en France, présente un intérêt particulier en matière de santé publique.

Published
2021

36. Additional file 1 of Transmission of amyloid-beta and tau pathologies is associated with cognitive impairments in a primate

Author

Lam, Suzanne, Petit, Fanny, Hérard, Anne-Sophie, Boluda, Susana, Eddarkaoui, Sabiha, Guillermier, Martine, Buée, Luc, Duyckaerts, Charles, Haïk, Stéphane, Picq, Jean-Luc, and Dhenain, Marc

Subjects
ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, ComputingMilieux_COMPUTERSANDEDUCATION, Data_FILES, ComputerApplications_COMPUTERSINOTHERSYSTEMS
Abstract

Additional file 1. Supplementary table and figures.

Published
2021
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37. Heterogeneity of Alzheimer’s disease: Insight from a novel mouse model of amyloid and tau lesions based on the inoculation of human brain preparations

Author

Lam, Suzanne, Boluda, Susana, Herard, Anne‐sophie, Petit, Fanny, Duyckaerts, Charles, Delatour, Benoit, Haïk, Stéphane, Dhenain, Marc, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), 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)-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)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
Abstract

International audience; Background: A major challenge in clinical research is to better understand the heterogeneity of AD. Indeed, AD is heterogeneous regarding its origin, neuropathology and clinical expressions. While classical sporadic forms of AD (clAD) evolve over approximately 10 years, the "rapidly progressive form of AD" (rAD) is a non-genetic aggressive form associated with a rapid clinical decline that evolves over approximately 2 years (Schmidt et al., Arch Neurol. 2011). Several studies have shown that the experimental inoculation of brain samples with Aβ- and/or tau pathology into transgenic (tg) mouse models overexpressing mutant human APP or tau promotes either Aβ or tau aggregation in the brain of the recipient animal (Gary et al., Acta Neuropathol Com. 2019). The phenotype of the inoculated brains is moreover reproduced in the recipient host (Watts et al., PNAS. 2014). The aim of this work was to study the impact of the inoculations of rAD versus clAD-human brain preparations in tg mice mouse models of β-amyloidosis to explore the mechanisms associated to AD heterogeneity.

Published
2020

38. Induction of amyloid-β deposits from serially transmitted, histologically silent, Aβ seeds issued from human brains

Author

Herard, Anne-Sophie, Petit, Fanny, Gary, Charlotte, Guillermier, Martine, Boluda, Susana, Garin, Clément, Lam, Suzanne, Dhenain, Marc, Letournel, Franck, Martin-Negrier, Marie-Laure, Faisant, Maxime, Godfraind, Catherine, Maurage, Claude-Alain, Deramecourt, Vincent, Duchesne, Mathilde, Meyronnet, David, Maues De Paula, André, Rigau, Valérie, Burel-Vandenbos, Fanny, Duyckaerts, Charles, Seilhean, Danielle, Plu, Isabelle, Milin, Serge, Chiforeanu, Dan Christian, Laquerriere, Annie, Lannes, Béatrice, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), 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)-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)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), 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), Laboratoire de Neuropathologie Raymond Escourolle, 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 Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), France-Alzheimer Association, Fondation Vaincre Alzheimer, CEA bottom-up program, NeurATRIS - ANR-11-INBS-0011, Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Institut des Neurosciences de Montpellier (INM)

Subjects
Genetically modified mouse, Pathology, medicine.medical_specialty, Amyloid, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Iatrogenic Disease, Mice, Transgenic, Plaque, Amyloid, Endogeny, Context (language use), Hippocampal formation, β-amyloid pathology, Hippocampus, lcsh:RC346-429, Pathology and Forensic Medicine, Lesion, Amyloid beta-Protein Precursor, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Alzheimer Disease, Presenilin-1, medicine, Animals, Humans, lcsh:Neurology. Diseases of the nervous system, 030304 developmental biology, 0303 health sciences, Amyloid beta-Peptides, Tissue Extracts, Chemistry, Research, Amyloidosis, Brain, Human brain, Alzheimer's disease, medicine.disease, Immunohistochemistry, Disease Models, Animal, medicine.anatomical_structure, Neurology (clinical), medicine.symptom, Aβ transmission, Alzheimer’s disease, 030217 neurology & neurosurgery
Abstract

In humans, iatrogenic transmission of cerebral amyloid-β (Aβ)-amyloidosis is suspected following inoculation of pituitary-derived hormones or dural grafts presumably contaminated with Aβ proteins as well as after cerebral surgeries. Experimentally, intracerebral inoculation of brain homogenate extracts containing misfolded Aβ can seed Aβ deposition in transgenic mouse models of amyloidosis or in non-human primates. The transmission of cerebral Aβ is governed by the host and by the inoculated samples. It is critical to better characterize the propensities of different hosts to develop Aβ deposition after contamination by an Aβ-positive sample as well as to better assess which biological samples can transmit this lesion. Aβ precursor protein (huAPPwt) mice express humanized non-mutated forms of Aβ precursor protein and do not spontaneously develop Aβ or amyloid deposits. We found that inoculation of Aβ-positive brain extracts from Alzheimer patients in these mice leads to a sparse Aβ deposition close to the alveus 18 months post-inoculation. However, it does not induce cortical or hippocampal Aβ deposition. Secondary inoculation of apparently amyloid deposit-free hippocampal extracts from these huAPPwt mice to APPswe/PS1dE9 mouse models of amyloidosis enhanced Aβ deposition in the alveus 9 months post-inoculation. This suggests that Aβ seeds issued from human brain samples can persist in furtive forms in brain tissues while maintaining their ability to foster Aβ deposition in receptive hosts that overexpress endogenous Aβ. This work emphasizes the need for high-level preventive measures, especially in the context of neurosurgery, to prevent the risk of iatrogenic transmission of Aβ lesions from samples with sparse amyloid markers.

Published
2020

43. Phenotypes associated with MAPT duplications

Author

Wallon, David, primary, Bonnevalle, Antoine, additional, Rovelet‐Lecrux, Anne, additional, Lagarde, Julien, additional, Sarazin, Marie, additional, Bottlaender, Michel, additional, Sellal, François, additional, Jonveaux, Therese, additional, Heitz, Camille, additional, Magnin, Eloi, additional, Ber, Isabelle Le, additional, Epelbaum, Stéphane, additional, Quillard‐Muraine, Muriel, additional, Chastan, Mathieu, additional, Hannequin, Didier, additional, Boluda, Susana, additional, Rousseau, Stéphane, additional, Richard, Anne‐Claire, additional, Quenez, Olivier, additional, Charbonnier, Camille, additional, Duyckaerts, Charles, additional, Campion, Dominique, additional, and Nicolas, Gaël, additional

Published
2020
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45. Huntington’s disease alters human neurodevelopment

Author

Barnat, Monia, primary, Capizzi, Mariacristina, additional, Aparicio, Esther, additional, Boluda, Susana, additional, Wennagel, Doris, additional, Kacher, Radhia, additional, Kassem, Rayane, additional, Lenoir, Sophie, additional, Agasse, Fabienne, additional, Braz, Barbara Y., additional, Liu, Jeh-Ping, additional, Ighil, Julien, additional, Tessier, Aude, additional, Zeitlin, Scott O., additional, Duyckaerts, Charles, additional, Dommergues, Marc, additional, Durr, Alexandra, additional, and Humbert, Sandrine, additional

Published
2020
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46. Identification of Umbre Orthobunyavirus as a Novel Zoonotic Virus Responsible for Lethal Encephalitis in 2 French Patients with Hypogammaglobulinemia

Author

Pérot, Philippe, primary, Bielle, Franck, additional, Bigot, Thomas, additional, Foulongne, Vincent, additional, Bolloré, Karine, additional, Chrétien, Delphine, additional, Gil, Patricia, additional, Gutiérrez, Serafín, additional, L’Ambert, Grégory, additional, Mokhtari, Karima, additional, Hellert, Jan, additional, Flamand, Marie, additional, Tamietti, Carole, additional, Coulpier, Muriel, additional, Huard de Verneuil, Anne, additional, Temmam, Sarah, additional, Couderc, Thérèse, additional, De Sousa Cunha, Edouard, additional, Boluda, Susana, additional, Plu, Isabelle, additional, Delisle, Marie Bernadette, additional, Bonneville, Fabrice, additional, Brassat, David, additional, Fieschi, Claire, additional, Malphettes, Marion, additional, Duyckaerts, Charles, additional, Mathon, Bertrand, additional, Demeret, Sophie, additional, Seilhean, Danielle, additional, and Eloit, Marc, additional

Published
2020
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49. Diagnosis of patients with heart failure with preserved ejection fraction in primary care: cohort study.

Author

Forsyth, Faye, Brimicombe, James, Cheriyan, Joseph, Edwards, Duncan, Hobbs, F.D. Richard, Jalaludeen, Navazh, Mant, Jonathan, Pilling, Mark, Schiff, Rebekah, Taylor, Clare J., Zaman, M. Justin, Deaton, Christi, Chakravorty, Mollika, Maclachlan, Sophie, Kane, Edward, Odone, Jessica, Thorley, Natasha, Borja‐Boluda, Susana, Wellwood, Ian, and Sowden, Emma

Subjects
HEART failure patients, PRIMARY care
Abstract

Aims: Heart failure with preserved ejection fraction (HFpEF) accounts for half of all heart failure (HF), but low awareness and diagnostic challenges hinder identification in primary care. Our aims were to evaluate the recruitment and diagnostic strategy in the Optimise HFpEF cohort and compare with recent recommendations for diagnosing HFpEF. Methods and results: Patients were recruited from 30 primary care practices in two regions in England using an electronic screening algorithm and two secondary care sites. Baseline assessment collected clinical and patient‐reported data and diagnosis by history, assessment, and trans‐thoracic echocardiogram (TTE). A retrospective evaluation compared study diagnosis with H2FPEF score and HFA‐PEFF diagnostic algorithm. A total of 152 patients (86% primary care, mean age 78.5, 40% female) were enrolled; 93 (61%) had HFpEF confirmed. Most participants had clinical features of HFpEF, but those with confirmed HFpEF were more likely female, obese, functionally impaired, and symptomatic. Some echocardiographic findings were diagnostic for HFpEF, but no difference in natriuretic peptide levels were observed. The H2FPEF and HFA‐PEFF scores were not significantly different by group, although confirmed HFpEF cases were more likely to have scores indicating high probability of HFpEF. Conclusions: Patients with HFpEF in primary care are difficult to identify, and greater awareness of the condition, with clear diagnostic pathways and specialist support, are needed. Use of diagnostic algorithms and scores can provide systematic approaches to diagnosis but may be challenging to apply in older multi‐morbid patients. Where diagnostic uncertainty remains, pragmatic decisions are needed regarding the value of additional testing versus management of presumptive HFpEF. [ABSTRACT FROM AUTHOR]

Published
2021
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