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2. Progress toward standardized diagnosis of vascular cognitive impairment: Guidelines from the Vascular Impairment of Cognition Classification Consensus Study

Author

Taragano, F.E., Kril, J., Cavalieri, M., Jellinger, K.A., Kovacs, G.G., Engelborghs, S., Lafosse, C., Bertolucci, P.H., Brucki, S., Caramelli, P., de Toledo Ferraz Alves, T.C., Bocti, C., Fulop, T., Hogan, D.B., Hsiung, G.R., Kirk, A., Leach, L., Robillard, A., Sahlas, D.J., Guo, Q., Tian, J., Hokkanen, L., Jokinen, H., Benisty, S., Deramecourt, V., Hauw, J., Lenoir, H., Tsatali, M., Tsolaki, M., Sundar, U., Coen, R.F., Korczyn, A.D., Altieri, M., Baldereschi, M., Caltagirone, C., Caravaglios, G., Di Carlo, A., Di Piero, V., Gainotti, G., Galluzzi, S., Logroscino, G., Mecocci, P., Moretti, D.V., Padovani, A., Fukui, T., Ihara, M., Mizuno, T., Kim, S.Y., Akinyemi, R., Baiyewu, O., Ogunniyi, A., Szczudlik, A., Bastos-Leite, A.J., Firmino, H., Massano, J., Verdelho, A., Kruglov, L.S., Ikram, M.K., Kandiah, N., Arana, E., Barroso-Ribal, J., Calatayud, T., Cruz-Jentoft, A.J., López-Pousa, S., Martinez-Lage, P., Mataro, M., Börjesson-Hanson, A., Englund, E., Laukka, E.J., Qiu, C., Viitanen, M., Biessels, G.J., de Leeuw, F.-E., den Heijer, T., Exalto, L.G., Kappelle, L.J., Prins, N.D., Richard, E., Schmand, B., van den Berg, E., van der Flier, W.M., Bilgic, B., Allan, L.M., Archer, J., Attems, J., Bayer, A., Blackburn, D., Brayne, C., Bullock, R., Connelly, P.J., Farrant, A., Fish, M., Harkness, K., Ince, P.G., Langhorne, P., Mann, J., Matthews, F.E., Mayer, P., Pendlebury, S.T., Perneczky, R., Peters, R., Smithard, D., Stephan, B.C., Swartz, J.E., Todd, S., Werring, D.J., Wijayasiri, S.N., Wilcock, G., Zamboni, G., Au, R., Borson, S., Bozoki, A., Browndyke, J.N., Corrada, M.M., Crane, P.K., Diniz, B.S., Etcher, L., Fillit, H., Greenberg, S.M., Grinberg, L.T., Hurt, S.W., Lamar, M., Mielke, M., Ott, B.R., Perry, G., Powers, W.J., Ramos-Estebanez, C., Reed, B., Roberts, R.O., Romero, J.R., Saykin, A.J., Seshadri, S., Silbert, L., Stern, Y., Zarow, C., Skrobot, Olivia A., Black, Sandra E., Chen, Christopher, DeCarli, Charles, Erkinjuntti, Timo, Ford, Gary A., Kalaria, Rajesh N., O'Brien, John, Pantoni, Leonardo, Pasquier, Florence, Roman, Gustavo C., Wallin, Anders, Sachdev, Perminder, Skoog, Ingmar, Ben-Shlomo, Yoav, Passmore, Anthony P., Love, Seth, and Kehoe, Patrick G.

Published
2018
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3. The Vascular Impairment of Cognition Classification Consensus Study

Author

Taragano, F.E., Kril, J., Cavalieri, M., Jellinger, K.A., Kovacs, G.G., Engelborghs, S., Lafosse, C., Bertolucci, P.H., Brucki, S., Caramelli, P., de Toledo Ferraz Alves, T.C., Bocti, C., Fulop, T., Hogan, D.B., Hsiung, G.R., Kirk, A., Leach, L., Robillard, A., Sahlas, D.J., Guo, Q., Tian, J., Hokkanen, L., Jokinen, H., Benisty, S., Deramecourt, V., Hauw, J., Lenoir, H., Tsatali, M., Tsolaki, M., Sundar, U., Coen, R.F., Korczyn, A.D., Altieri, M., Baldereschi, M., Caltagirone, C., Caravaglios, G., Di Carlo, A., DI Piero, V., Gainotti, G., Galluzzi, S., Logroscino, G., Mecocci, P., Moretti, D.V., Padovani, A., Fukui, T., Ihara, M., Mizuno, T., Kim, S.Y., Akinyemi, R., Baiyewu, O., Ogunniyi, A., Szczudlik, A., Bastos-Leite, A.J., Firmino, H., Massano, J., Verdelho, A., Kruglov, L.S., Ikram, M.K., Kandiah, N., Arana, E., Barroso-Ribal, J., Calatayud, T., Cruz-Jentoft, A.J., López-Pousa, S., Martinez-Lage, P., Mataro, M., Börjesson-Hanson, A., Englund, E., Laukka, E.J., Qiu, C., Viitanen, M., Biessels, G.J., de Leeuw, F.-E., den Heijer, T., Exalto, L.G., Kappelle, L.J., Prins, N.D., Richard, E., Schmand, B., van den Berg, E., van der Flier, W.M., Bilgic, B., Allan, L.M., Archer, J., Attems, J., Bayer, A., Blackburn, D., Brayne, C., Bullock, R., Connelly, P.J., Farrant, A., Fish, M., Harkness, K., Ince, P.G., Langhorne, P., Mann, J., Matthews, F.E., Mayer, P., Pendlebury, S.T., Perneczky, R., Peters, R., Smithard, D., Stephan, B.C., Swartz, J.E., Todd, S., Werring, D.J., Wijayasiri, S.N., Wilcock, G., Zamboni, G., Au, R., Borson, S., Bozoki, A., Browndyke, J.N., Corrada, M.M., Crane, P.K., Diniz, B.S., Etcher, L., Fillit, H., Greenberg, S.M., Grinberg, L.T., Hurt, S.W., Lamar, M., Mielke, M., Ott, B.R., Perry, G., Powers, W.J., Ramos-Estebanez, C., Reed, B., Roberts, R.O., Romero, J.R., Saykin, A.J., Seshadri, S., Silbert, L., Stern, Y., Zarow, C., Skrobot, Olivia A., O'Brien, John, Black, Sandra, Chen, Christopher, DeCarli, Charles, Erkinjuntti, Timo, Ford, Gary A., Kalaria, Rajesh N., Pantoni, Leonardo, Pasquier, Florence, Roman, Gustavo C., Wallin, Anders, Sachdev, Perminder, Skoog, Ingmar, Ben-Shlomo, Yoav, Passmore, Anthony P., Love, Seth, and Kehoe, Patrick G.

Published
2017
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6. Multicenter F-18-PI-2620 PET for in vivo staging of tau pathology in progressive supranuclear palsy

Author

Rullmann, M., additional, Brendel, M., additional, Schroeter, M.L., additional, Saur, D., additional, Rumpf, J.J., additional, Levin, J., additional, Perneczky, R., additional, Tiepolt, S., additional, Patt, M., additional, Mueller, A., additional, Villemagne, V.L., additional, Classen, J., additional, Stephens, A.W., additional, Kovacs, G.G., additional, Sabri, O., additional, and Barthel, H., additional

Published
2022
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7. Type II beta-amyloid 42 Filaments from Human Brain

Author

Yang, Y., primary, Arseni, D., additional, Zhang, W., additional, Huang, M., additional, Lovestam, S.K.A., additional, Schweighauser, M., additional, Kotecha, A., additional, Murzin, A.G., additional, Peak-Chew, S.Y., additional, Macdonald, J., additional, Lavenir, I., additional, Garringer, H.J., additional, Gelpi, E., additional, Newell, K.L., additional, Kovacs, G.G., additional, Vidal, R., additional, Ghetti, B., additional, Falcon, B., additional, Scheres, S.H.W., additional, and Goedert, M., additional

Published
2021
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8. Argyrophilic grain disease type 1 tau filament

Author

Shi, Y., primary, Zhang, W., additional, Yang, Y., additional, Murzin, A.G., additional, Falcon, B., additional, Kotecha, A., additional, van Beers, M., additional, Tarutani, A., additional, Kametani, F., additional, Garringer, H.J., additional, Vidal, R., additional, Hallinan, G.I., additional, Lashley, T., additional, Saito, Y., additional, Murayama, S., additional, Yoshida, M., additional, Tanaka, H., additional, Kakita, A., additional, Ikeuchi, T., additional, Robinson, A.C., additional, Mann, D.M.A., additional, Kovacs, G.G., additional, Revesz, T., additional, Ghetti, B., additional, Hasegawa, M., additional, Goedert, M., additional, and Scheres, S.H.W., additional

Published
2021
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9. Limbic-predominant neuronal inclusion body 4R tauopathy type 2 tau filament

Author

Shi, Y., primary, Zhang, W., additional, Yang, Y., additional, Murzin, A.G., additional, Falcon, B., additional, Kotecha, A., additional, van Beers, M., additional, Tarutani, A., additional, Kametani, F., additional, Garringer, H.J., additional, Vidal, R., additional, Hallinan, G.I., additional, Lashley, T., additional, Saito, Y., additional, Murayama, S., additional, Yoshida, M., additional, Tanaka, H., additional, Kakita, A., additional, Ikeuchi, T., additional, Robinson, A.C., additional, Mann, D.M.A., additional, Kovacs, G.G., additional, Revesz, T., additional, Ghetti, B., additional, Hasegawa, M., additional, Goedert, M., additional, and Scheres, S.H.W., additional

Published
2021
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10. Globular glial tauopathy type 2 tau filament

Author

Shi, Y., primary, Zhang, W., additional, Yang, Y., additional, Murzin, A.G., additional, Falcon, B., additional, Kotecha, A., additional, van Beers, M., additional, Tarutani, A., additional, Kametani, F., additional, Garringer, H.J., additional, Vidal, R., additional, Hallinan, G.I., additional, Lashley, T., additional, Saito, Y., additional, Murayama, S., additional, Yoshida, M., additional, Tanaka, H., additional, Kakita, A., additional, Ikeuchi, T., additional, Robinson, A.C., additional, Mann, D.M.A., additional, Kovacs, G.G., additional, Revesz, T., additional, Ghetti, B., additional, Hasegawa, M., additional, Goedert, M., additional, and Scheres, S.H.W., additional

Published
2021
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11. Globular glial tauopathy type 1 tau filament

Author

Shi, Y., primary, Zhang, W., additional, Yang, Y., additional, Murzin, A.G., additional, Falcon, B., additional, Kotecha, A., additional, van Beers, M., additional, Tarutani, A., additional, Kametani, F., additional, Garringer, H.J., additional, Vidal, R., additional, Hallinan, G.I., additional, Lashley, T., additional, Saito, Y., additional, Murayama, S., additional, Yoshida, M., additional, Tanaka, H., additional, Kakita, A., additional, Ikeuchi, T., additional, Robinson, A.C., additional, Mann, D.M.A., additional, Kovacs, G.G., additional, Revesz, T., additional, Ghetti, B., additional, Hasegawa, M., additional, Goedert, M., additional, and Scheres, S.H.W., additional

Published
2021
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12. Limbic-predominant neuronal inclusion body 4R tauopathy type 1b tau filament

Author

Shi, Y., primary, Zhang, W., additional, Yang, Y., additional, Murzin, A.G., additional, Falcon, B., additional, Kotecha, A., additional, van Beers, M., additional, Tarutani, A., additional, Kametani, F., additional, Garringer, H.J., additional, Vidal, R., additional, Hallinan, G.I., additional, Lashley, T., additional, Saito, Y., additional, Murayama, S., additional, Yoshida, M., additional, Tanaka, H., additional, Kakita, A., additional, Ikeuchi, T., additional, Robinson, A.C., additional, Mann, D.M.A., additional, Kovacs, G.G., additional, Revesz, T., additional, Ghetti, B., additional, Hasegawa, M., additional, Goedert, M., additional, and Scheres, S.H.W., additional

Published
2021
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13. Progressive supranuclear palsy tau filament

Author

Shi, Y., primary, Zhang, W., additional, Yang, Y., additional, Murzin, A.G., additional, Falcon, B., additional, Kotecha, A., additional, van Beers, M., additional, Tarutani, A., additional, Kametani, F., additional, Garringer, H.J., additional, Vidal, R., additional, Hallinan, G.I., additional, Lashley, T., additional, Saito, Y., additional, Murayama, S., additional, Yoshida, M., additional, Tanaka, H., additional, Kakita, A., additional, Ikeuchi, T., additional, Robinson, A.C., additional, Mann, D.M.A., additional, Kovacs, G.G., additional, Revesz, T., additional, Ghetti, B., additional, Hasegawa, M., additional, Goedert, M., additional, and Scheres, S.H.W., additional

Published
2021
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14. Argyrophilic grain disease type 2 tau filament

Author

Shi, Y., primary, Zhang, W., additional, Yang, Y., additional, Murzin, A.G., additional, Falcon, B., additional, Kotecha, A., additional, van Beers, M., additional, Tarutani, A., additional, Kametani, F., additional, Garringer, H.J., additional, Vidal, R., additional, Hallinan, G.I., additional, Lashley, T., additional, Saito, Y., additional, Murayama, S., additional, Yoshida, M., additional, Tanaka, H., additional, Kakita, A., additional, Ikeuchi, T., additional, Robinson, A.C., additional, Mann, D.M.A., additional, Kovacs, G.G., additional, Revesz, T., additional, Ghetti, B., additional, Hasegawa, M., additional, Goedert, M., additional, and Scheres, S.H.W., additional

Published
2021
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15. Globular glial tauopathy type 3 tau filament

Author

Shi, Y., primary, Zhang, W., additional, Yang, Y., additional, Murzin, A.G., additional, Falcon, B., additional, Kotecha, A., additional, van Beers, M., additional, Tarutani, A., additional, Kametani, F., additional, Garringer, H.J., additional, Vidal, R., additional, Hallinan, G.I., additional, Lashley, T., additional, Saito, Y., additional, Murayama, S., additional, Yoshida, M., additional, Tanaka, H., additional, Kakita, A., additional, Ikeuchi, T., additional, Robinson, A.C., additional, Mann, D.M.A., additional, Kovacs, G.G., additional, Revesz, T., additional, Ghetti, B., additional, Hasegawa, M., additional, Goedert, M., additional, and Scheres, S.H.W., additional

Published
2021
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19. Distribution patterns of tau pathology in progressive supranuclear palsy

Author

Kovacs, G.G. (Gabor), Lukic, M.J. (Milica Jecmenica), Irwin, D.J. (David J.), Arzberger, T. (T.), Respondek, G. (Gesine), Lee, E.B. (Edward B.), Coughlin, D. (David), Giese, A. (Armin), Grossman, M. (Murray), Kurz, C. (Carolin), McMillan, C.T. (Corey T.), Gelpi, E. (Ellen), Compta, Y. (Yaroslau), Swieten, J.C. (John) van, Laat, L.D. (Laura Donker), Troakes, C. (Claire), Al-Sarraj, S. (Safa), Robinson, J.L. (John L.), Roeber, S. (Sigrun), Xie, S.X. (Sharon X.), Lee, V.M.Y. (Virginia), Trojanowski, J.Q. (John Q.), Hoglinger, G. (Gunter), Kovacs, G.G. (Gabor), Lukic, M.J. (Milica Jecmenica), Irwin, D.J. (David J.), Arzberger, T. (T.), Respondek, G. (Gesine), Lee, E.B. (Edward B.), Coughlin, D. (David), Giese, A. (Armin), Grossman, M. (Murray), Kurz, C. (Carolin), McMillan, C.T. (Corey T.), Gelpi, E. (Ellen), Compta, Y. (Yaroslau), Swieten, J.C. (John) van, Laat, L.D. (Laura Donker), Troakes, C. (Claire), Al-Sarraj, S. (Safa), Robinson, J.L. (John L.), Roeber, S. (Sigrun), Xie, S.X. (Sharon X.), Lee, V.M.Y. (Virginia), Trojanowski, J.Q. (John Q.), and Hoglinger, G. (Gunter)

Abstract

Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PSP pathology. We evaluated heat maps and distribution patterns of neuronal, astroglial, and oligodendroglial tau pathologies and their combinations in different clinical subtypes of PSP in postmortem brains. We

Published
2020
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22. The Vascular Impairment of Cognition Classification Consensus Study

Author

Skrobot, Olivia A., primary, O'Brien, John, additional, Black, Sandra, additional, Chen, Christopher, additional, DeCarli, Charles, additional, Erkinjuntti, Timo, additional, Ford, Gary A., additional, Kalaria, Rajesh N., additional, Pantoni, Leonardo, additional, Pasquier, Florence, additional, Roman, Gustavo C., additional, Wallin, Anders, additional, Sachdev, Perminder, additional, Skoog, Ingmar, additional, Taragano, F.E., additional, Kril, J., additional, Cavalieri, M., additional, Jellinger, K.A., additional, Kovacs, G.G., additional, Engelborghs, S., additional, Lafosse, C., additional, Bertolucci, P.H., additional, Brucki, S., additional, Caramelli, P., additional, Toledo Ferraz Alves, T.C., additional, Bocti, C., additional, Fulop, T., additional, Hogan, D.B., additional, Hsiung, G.R., additional, Kirk, A., additional, Leach, L., additional, Robillard, A., additional, Sahlas, D.J., additional, Guo, Q., additional, Tian, J., additional, Hokkanen, L., additional, Jokinen, H., additional, Benisty, S., additional, Deramecourt, V., additional, Hauw, J., additional, Lenoir, H., additional, Tsatali, M., additional, Tsolaki, M., additional, Sundar, U., additional, Coen, R.F., additional, Korczyn, A.D., additional, Altieri, M., additional, Baldereschi, M., additional, Caltagirone, C., additional, Caravaglios, G., additional, Di Carlo, A., additional, DI Piero, V., additional, Gainotti, G., additional, Galluzzi, S., additional, Logroscino, G., additional, Mecocci, P., additional, Moretti, D.V., additional, Padovani, A., additional, Fukui, T., additional, Ihara, M., additional, Mizuno, T., additional, Kim, S.Y., additional, Akinyemi, R., additional, Baiyewu, O., additional, Ogunniyi, A., additional, Szczudlik, A., additional, Bastos‐Leite, A.J., additional, Firmino, H., additional, Massano, J., additional, Verdelho, A., additional, Kruglov, L.S., additional, Ikram, M.K., additional, Kandiah, N., additional, Arana, E., additional, Barroso‐Ribal, J., additional, Calatayud, T., additional, Cruz‐Jentoft, A.J., additional, López‐Pousa, S., additional, Martinez‐Lage, P., additional, Mataro, M., additional, Börjesson‐Hanson, A., additional, Englund, E., additional, Laukka, E.J., additional, Qiu, C., additional, Viitanen, M., additional, Biessels, G.J., additional, Leeuw, F.‐E., additional, Heijer, T., additional, Exalto, L.G., additional, Kappelle, L.J., additional, Prins, N.D., additional, Richard, E., additional, Schmand, B., additional, Berg, E., additional, Flier, W.M., additional, Bilgic, B., additional, Allan, L.M., additional, Archer, J., additional, Attems, J., additional, Bayer, A., additional, Blackburn, D., additional, Brayne, C., additional, Bullock, R., additional, Connelly, P.J., additional, Farrant, A., additional, Fish, M., additional, Harkness, K., additional, Ince, P.G., additional, Langhorne, P., additional, Mann, J., additional, Matthews, F.E., additional, Mayer, P., additional, Pendlebury, S.T., additional, Perneczky, R., additional, Peters, R., additional, Smithard, D., additional, Stephan, B.C., additional, Swartz, J.E., additional, Todd, S., additional, Werring, D.J., additional, Wijayasiri, S.N., additional, Wilcock, G., additional, Zamboni, G., additional, Au, R., additional, Borson, S., additional, Bozoki, A., additional, Browndyke, J.N., additional, Corrada, M.M., additional, Crane, P.K., additional, Diniz, B.S., additional, Etcher, L., additional, Fillit, H., additional, Greenberg, S.M., additional, Grinberg, L.T., additional, Hurt, S.W., additional, Lamar, M., additional, Mielke, M., additional, Ott, B.R., additional, Perry, G., additional, Powers, W.J., additional, Ramos‐Estebanez, C., additional, Reed, B., additional, Roberts, R.O., additional, Romero, J.R., additional, Saykin, A.J., additional, Seshadri, S., additional, Silbert, L., additional, Stern, Y., additional, Zarow, C., additional, Ben‐Shlomo, Yoav, additional, Passmore, Anthony P., additional, Love, Seth, additional, and Kehoe, Patrick G., additional

Published
2016
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23. Genetic Creutzfeldt-Jakob disease mimicking variant Creutzfeldt-Jakob disease

Author

Kovacs, G.G., Horvath, S., Strobel, T., Puskas, M., Bakos, A., Summers, D.M., Will, R.G., and Budka, H.

Subjects
Prions -- Genetic aspects, Creutzfeldt-Jakob disease -- Genetic aspects, Creutzfeldt-Jakob disease -- Case studies, Genetic variation -- Case studies, Magnetic resonance imaging -- Analysis, Health, Psychology and mental health
Published
2009

24. The need to unify neuropathological assessments of vascular alterations in the ageing brain: Multicentre survey by the BrainNet Europe consortium

Author

Alafuzoff, I., Gelpi, E., Al-Sarraj, S., Arzberger, T., Attems, J., Bodi, I., Bogdanovic, N., Budka, H., Bugiani, O., Englund, E., Ferrer, I., Gentleman, S., Giaccone, G., Graeber, M.B., Hortobagyi, T., Hoeftberger, R., Ironside, J.W., Jellinger, K., Kavantzas, N., King, A., Korkolopoulou, P., Kovacs, G.G., Meyronet, D., Monoranu, C., Parchi, P., Patsouris, E., Roggendorf, W., Rozemuller, A.J.M., Seilhean, D., Streichenberger, N., Thal, D.R., Wharton, S.B., Kretzschmar, H., University of Zurich, Alafuzoff, Irina, Pathology, NCA - Neurodegeneration, Alafuzoff I., Gelpi E., Al-Sarraj S., Arzberger T., Attems J., Bodi I., Bogdanovic N., Budka H., Bugiani O., Englund E., Ferrer I., Gentleman S., Giaccone G., Graeber M.B., Hortobagyi T., Höftberger R., Ironside J.W., Jellinger K., Kavantzas N., King A., Korkolopoulou P., Kovács G.G., Meyronet D., Monoranu C., Parchi P., Patsouris E., Roggendorf W., Rozemuller A., Seilhean D., Streichenberger N., Thal D.R., Wharton S.B., and Kretzschmar H.

Subjects
Aging, 1303 Biochemistry, 10208 Institute of Neuropathology, 610 Medicine & health, Klinikai orvostudományok, Severity of Illness Index, Specimen Handling, DIAGNOSTIC CRITERIA, 1307 Cell Biology, 1302 Aging, 1311 Genetics, Surveys and Questionnaires, 1312 Molecular Biology, Humans, VASCULAR DEMENTIA, Staining and Labeling, Brain, Reproducibility of Results, Orvostudományok, 1310 Endocrinology, BRAIN BANKING, Cerebrovascular Disorders, Cerebrovascular Circulation, 570 Life sciences, biology, Dementia, NEUROPATHOLOGY
Abstract

Here, we summarise the results after carrying out a large survey regarding the assessment of vascular alterations, both vessel changes and vascular lesions in an inter-laboratory setting. In total, 32 neuropathologists from 22 centres, most being members of BrainNet Europe (BNE), participated by filling out a questionnaire with emphasis on assessment of common vascular alterations seen in the brains of aged subjects. A certain level of harmonisation has been reached among BNE members regarding sectioning of the brain, harvesting of brain tissue for histology and staining used when compared to the survey carried out in 2006 by Pantoni and colleagues. The most significant variability was seen regarding the assessment of severity and of clinical significance of vascular alterations. Two strategies have recently been recommended regarding the assessment of vascular alterations in aged and demented subjects. The National Institute on Aging - Alzheimer's Association (NIA-AA) recommends the assessment of hippocampal sclerosis, vascular brain injury and microvascular lesions in 12 regions. Although this strategy will be easy to follow, the recommendations do not inform how the load of observed alterations should be assessed and when the observed lesions are of significance. Deramecourt and his colleagues recommend an assessment and semiquantitative grading of various pathologies in 4 brain regions. This strategy yielded a total score of 0 to 20 as an estimate of pathology load. It is, however, not clear which score is considered to be of clinical significance. Furthermore, in several BNE trials the semiquantitative assessment has yielded poor agreement rates; an observation that might negatively influence the strategy proposed by Deramecourt and his colleagues. In line with NIA-AA, a dichotomised approach of easily recognisable lesions in a standardised set of brain regions harvested for neuropathological assessment and applying reproducible sampling and staining strategies is recommended by BNE. However, a simple strategy regarding assessment of load of alteration is urgently needed to yield reproducible, and at the same time, comparable results between centres.

Published
2012
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25. A genome wide association study links glutamate receptor pathway to sporadic Creutzfeldt-Jakob disease risk

Author

Sanchez-Juan, P. (Pascual), Bishop, M.T. (Matthew), Kovacs, G.G. (Gabor), Calero, M. (Miguel), Aulchenko, Y.S. (Yurii), Ladogana, A. (Anna), Boyd, A. (Alison), Lewis, V. (Victoria), Ponto, C. (Claudia), Calero, O. (Olga), Poleggi, A. (Anna), Carracedo, A. (Angel), Lee, S.J. (Sven) van der, Ströbel, T. (Thomas), Rivadeneira Ramirez, F. (Fernando), Hofman, A. (Albert), Haik, S., Combarros, O. (Onofre), Berciano, J. (José), Uitterlinden, A.G. (André), Collins, S.J. (Steven), Budka, H. (Herbert), Brandel, J-P. (Jean-Philippe), Laplanche, J.-L. (Jean-Louis), Pocchiari, M. (Maurizio), Zerr, I. (Inga), Knight, R. (Richard), Will, R.G. (Robert), Duijn, C.M. (Cornelia) van, Sanchez-Juan, P. (Pascual), Bishop, M.T. (Matthew), Kovacs, G.G. (Gabor), Calero, M. (Miguel), Aulchenko, Y.S. (Yurii), Ladogana, A. (Anna), Boyd, A. (Alison), Lewis, V. (Victoria), Ponto, C. (Claudia), Calero, O. (Olga), Poleggi, A. (Anna), Carracedo, A. (Angel), Lee, S.J. (Sven) van der, Ströbel, T. (Thomas), Rivadeneira Ramirez, F. (Fernando), Hofman, A. (Albert), Haik, S., Combarros, O. (Onofre), Berciano, J. (José), Uitterlinden, A.G. (André), Collins, S.J. (Steven), Budka, H. (Herbert), Brandel, J-P. (Jean-Philippe), Laplanche, J.-L. (Jean-Louis), Pocchiari, M. (Maurizio), Zerr, I. (Inga), Knight, R. (Richard), Will, R.G. (Robert), and Duijn, C.M. (Cornelia) van

Abstract

We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls

Published
2015
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27. Increased glucose metabolism and ATP level in brain tissue of Huntington's disease transgenic mice

Author

Olah, J., Kliveny, P., Gardian, G., Vecsey, L., Orosz, F., Kovacs, G.G., Westerhoff, H.V., Ovadi, J., and Molecular Cell Physiology

Subjects
SDG 10 - Reduced Inequalities
Abstract

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by multifarious dysfunctional alterations including mitochondrial impairment. In the present study, the formation of inclusions caused by the mutation of huntingtin protein and its relationship with changes in energy metabolism and with pathological alterations were investigated both in transgenic and 3-nitropropionic acid-treated mouse models for HD. The HD and normal mice were characterized clinically; the affected brain regions were identified by immunohistochemistry and used for biochemical analysis of the ATP-producing systems in the cytosolic and the mitochondrial compartments. In both HD models, the activities of some glycolytic enzymes were somewhat higher. By contrast, the activity of glyceraldehyde-3-phosphate dehydrogenase was much lower in the affected region of the brain compared to that of the control. Paradoxically, at the system level, glucose conversion into lactate was enhanced in cytosolic extracts from the HD brain tissue, and the level of ATP was higher in the tissue itself. The paradox could be resolved by taking all the observed changes in glycolytic enzymes into account, ensuing an experiment-based detailed mathematical model of the glycolytic pathway. The mathematical modelling using the experimentally determined kinetic parameters of the individual enzymes and the well-established rate equations predicted the measured flux and concentrations in the case of the control. The same mathematical model with the experimentally determined altered V-max values of the enzymes did account for an increase of glycolytic flux in the HD sample, although the extent of the increase was not predicted quantitatively. This suggested a somewhat altered regulation of this major metabolic pathway in HD tissue. We then used the mathematical model to develop a hypothesis for a new regulatory interaction that might account for the observed changes; in HD, glyceraldehyde-3-phosphate dehydrogenase may be in closer proximity (perhaps because of the binding of glyceraldehyde-3-phosphate dehydrogenase to huntingtin) with aldolase and engage in channelling for glyceraldehyde-3-phosphate. By contrast to most of the speculation in the literature, our results suggest that the neuronal damage in HD tissue may be associated with increased energy metabolism at the tissue level leading to modified levels of various intermediary metabolites with pathological consequences.

Published
2008
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28. Management of a twenty-first century brain bank: Experience in the BrainNet Europe consortium

Author

Bell, J.E. Alafuzoff, I. Al-Sarraj, S. Arzberger, T. Bogdanovic, N. Budka, H. Dexter, D.T. Falkai, P. Ferrer, I. Gelpi, E. Gentleman, S.M. Giaccone, G. Huitinga, I. Ironside, J.W. Klioueva, N. Kovacs, G.G. Meyronet, D. Palkovits, M. Parchi, P. Patsouris, E. Reynolds, R. Riederer, P. Roggendorf, W. Seilhean, D. Schmitt, A. Schmitz, P. Streichenberger, N. Schwalber, A. Kretzschmar, H.

Abstract

Collections of human postmortem brains gathered in brain banks have underpinned many significant developments in the understanding of central nervous system (CNS) disorders and continue to support current research. Unfortunately, the worldwide decline in postmortem examinations has had an adverse effect on research tissue procurement, particularly from control cases (non-diseased brains). Recruitment to brain donor programmes partially addresses this problem and has been successful for dementing and neurodegenerative conditions. However, the collection of brains from control subjects, particularly from younger individuals, and from CNS disorders of sudden onset, remains a problem. Brain banks need to adopt additional strategies to circumvent such shortages. The establishment of brain bank networks allows data on, and access to, control cases and unusual CNS disorders to be shared, providing a larger resource for potential users. For the brain banks themselves, inclusion in a network fosters the sharing of protocols and development of best practice and quality control. One aspect of this collective experience concerns brain bank management, excellence in which is a prerequisite not only for gaining the trust of potential donors and of society in general, but also for ensuring equitable distribution to researchers of high quality tissue samples. This review addresses the legal, ethical and governance issues, tissue quality, and health and safety aspects of brain bank management and data management in a network, as well as the needs of users, brain bank staffing, donor programs, funding issues and public relations. Recent developments in research methodology present new opportunities for researchers who use brain tissue samples, but will require brain banks to adopt more complex protocols for tissue collection, preparation and storage, with inevitable cost implications for the future. © Springer-Verlag 2008.

Published
2008

29. How a neuropsychiatric brain bank should be run: A consensus paper of Brainnet Europe II

Author

Schmitt, A. Bauer, M. Heinsen, H. Feiden, W. Falkai, P. Alafuzoff, I. Arzberger, T. Al-Sarraj, S. Bell, J.E. Bogdanovic, N. Brück, W. Budka, H. Ferrer, I. Giaccone, G. Kovacs, G.G. Meyronet, D. Palkovits, M. Parchi, P. Patsouris, E. Ravid, R. Reynolds, R. Riederer, P. Roggendorf, W. Schwalber, A. Seilhean, D. Kretzschmar, H.

Abstract

The development of new molecular and neurobiological methods, computer-assisted quantification techniques and neurobiological investigation methods which can be applied to the human brain, all have evoked an increased demand for post-mortem tissue in research. Psychiatric disorders are considered to be of neurobiological origin. Thus far, however, the etiology and pathophysiology of schizophrenia, depression and dementias are not well understood at the cellular and molecular level. The following will outline the consensus of the working group for neuropsychiatric brain banking organized in the Brainnet Europe II, on ethical guidelines for brain banking, clinical diagnostic criteria, the minimal clinical data set of retrospectively analyzed cases as well as neuropathological standard investigations to perform stageing for neurodegenerative disorders in brain tissue. We will list regions of interest for assessments in psychiatric disorder, propose a dissection scheme and describe preservation and storage conditions of tissue. These guidelines may be of value for future implementations of additional neuropsychiatric brain banks world-wide. © 2006 Springer-Verlag.

Published
2007

30. Progress toward standardized diagnosis of vascular cognitive impairment: Guidelines from the Vascular Impairment of Cognition Classification Consensus Study.

Author

Skrobot, Olivia A., Black, Sandra E., Chen, Christopher, DeCarli, Charles, Erkinjuntti, Timo, Ford, Gary A., Kalaria, Rajesh N., O'Brien, John, Pantoni, Leonardo, Pasquier, Florence, Roman, Gustavo C., Wallin, Anders, Sachdev, Perminder, Skoog, Ingmar, Taragano, F.E., Kril, J., Cavalieri, M., Jellinger, K.A., Kovacs, G.G., and Engelborghs, S.

Abstract

Introduction: Progress in understanding and management of vascular cognitive impairment (VCI) has been hampered by lack of consensus on diagnosis, reflecting the use of multiple different assessment protocols. A large multinational group of clinicians and researchers participated in a two‐phase Vascular Impairment of Cognition Classification Consensus Study (VICCCS) to agree on principles (VICCCS‐1) and protocols (VICCCS‐2) for diagnosis of VCI. We present VICCCS‐2. Methods: We used VICCCS‐1 principles and published diagnostic guidelines as points of reference for an online Delphi survey aimed at achieving consensus on clinical diagnosis of VCI. Results: Six survey rounds comprising 65–79 participants agreed guidelines for diagnosis of VICCCS‐revised mild and major forms of VCI and endorsed the National Institute of Neurological Disorders–Canadian Stroke Network neuropsychological assessment protocols and recommendations for imaging. Discussion: The VICCCS‐2 suggests standardized use of the National Institute of Neurological Disorders–Canadian Stroke Network recommendations on neuropsychological and imaging assessment for diagnosis of VCI so as to promote research collaboration. [ABSTRACT FROM AUTHOR]

Published
2018
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31. Intensity of human prion disease surveillance predicts observed disease incidence

Author

Klug, G.M. (Genevieve), Wand, H. (Handan), Simpson, M. (Marion), Boyd, A. (Alison), Law, M. (Matthew), Masters, C. (Colin), Mateǰ, R. (Radoslav), Howley, R. (Rachel), Farrell, M. (Michael), Breithaupt, M., Zerr, I. (Inga), Duijn, C.M. (Cornelia) van, Ibrahim-Verbaas, C.A. (Carla), Mackenzie, J., Will, R.G. (Robert), Brandel, J-P. (Jean-Philippe), Alperovitch, A. (Annick), Budka, H. (Herbert), Kovacs, G.G. (Gabor), Jansen, G.H. (Gerard), Coulthard, M. (Michael), Collins, S.J. (Steven), Klug, G.M. (Genevieve), Wand, H. (Handan), Simpson, M. (Marion), Boyd, A. (Alison), Law, M. (Matthew), Masters, C. (Colin), Mateǰ, R. (Radoslav), Howley, R. (Rachel), Farrell, M. (Michael), Breithaupt, M., Zerr, I. (Inga), Duijn, C.M. (Cornelia) van, Ibrahim-Verbaas, C.A. (Carla), Mackenzie, J., Will, R.G. (Robert), Brandel, J-P. (Jean-Philippe), Alperovitch, A. (Annick), Budka, H. (Herbert), Kovacs, G.G. (Gabor), Jansen, G.H. (Gerard), Coulthard, M. (Michael), and Collins, S.J. (Steven)

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 notifi cations, 14-3-3 protein diagnostic test referrals and neuropathological examinations of suspect cases) signi ficantly 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 sur

Published
2013
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32. Health professions and risk of sporadic Creutzfeldt- Jakob disease, 1965 to 2010

Author

Alcalde-Cabero, E., Almazán-Isla, J., Brandel, J-P. (Jean-Philippe), Breithaupt, M., Catarino, J., Collins, S.J. (Steven), Haybäck, J., Höftberger, R. (Romana), Kahana, E., Kovacs, G.G. (Gabor), Ladogana, A. (Anna), Mitrová, E. (Eva), Molesworth, A., Nakamura, Y., Pocchiari, M. (Maurizio), Popovic, M., Ruiz-Tovar, M., Taratuto, A., van Duin, C., Yamada, M., Will, R.G. (Robert), Zerr, I. (Inga), Pedro-Cuesta, J. (Jesús) de, Alcalde-Cabero, E., Almazán-Isla, J., Brandel, J-P. (Jean-Philippe), Breithaupt, M., Catarino, J., Collins, S.J. (Steven), Haybäck, J., Höftberger, R. (Romana), Kahana, E., Kovacs, G.G. (Gabor), Ladogana, A. (Anna), Mitrová, E. (Eva), Molesworth, A., Nakamura, Y., Pocchiari, M. (Maurizio), Popovic, M., Ruiz-Tovar, M., Taratuto, A., van Duin, C., Yamada, M., Will, R.G. (Robert), Zerr, I. (Inga), and Pedro-Cuesta, J. (Jesús) de

Abstract

In 2009, a pathologist with sporadic Creutzfeldt- Jakob Disease (sCJD) was reported to the Spanish registry. This case prompted a request for information on health-related occupation in sCJD cases from countries participating in the European Creutzfeldt Jakob Disease Surveillance network (EuroCJD). Responses from registries in 21 countries revealed that of 8,321 registered cases, 65 physicians or dentists, two of whom were pathologists, and another 137 healthcare workers had been identified with sCJD. Five countries reported 15 physicians and 68 other health professionals among 2,968 controls or non-cases, suggesting no relative excess of sCJD among healthcare professionals. A literature review revealed: (i) 12 case or small case-series reports of 66 health professionals with sCJD, and (ii) five analytical studies on health-related occupation and sCJD, where statistically significant findings were solely observed for persons working at physicians' offices (odds ratio: 4.6 (95 CI: 1.2-17.6)). We conclude that a wide spectrum of medical specialities and health professions are represented in sCJD cases and that the data analysed do not support any overall increased occupational risk for health professionals. Nevertheless, there may be a specific risk in some professions associated with direct contact with high human-infectivity tissue.

Published
2012

33. This title is unavailable for guests, please login to see more information.

Author

Alazuloff, I., Parkkinen, L., Al-Sarraj, S., Arzberger, T., Bell, J., Bodi, I., Bogdanovic, N., Budka, H., Ferrer, I., Gelpi, E., Gentleman, S., Giaccone, G., Kamphorst, W., King, A., Korkolopoulou, P., Kovacs, G.G., Larionov, S., Meyronet, D., Monoranu, C., Morris, J., Parchi, P., Patsouris, E., Roggendorf, W., Seilhaen, D., Streichenberger, N., Thal, D.R., Kretzschmar, H., Alazuloff, I., Parkkinen, L., Al-Sarraj, S., Arzberger, T., Bell, J., Bodi, I., Bogdanovic, N., Budka, H., Ferrer, I., Gelpi, E., Gentleman, S., Giaccone, G., Kamphorst, W., King, A., Korkolopoulou, P., Kovacs, G.G., Larionov, S., Meyronet, D., Monoranu, C., Morris, J., Parchi, P., Patsouris, E., Roggendorf, W., Seilhaen, D., Streichenberger, N., Thal, D.R., and Kretzschmar, H.

Published
2008

34. Management of a twenty-first century brain bank: experience in the BrainNet Europe consortium.

Author

Bell, J., Alazuloff, I., Al-Sarraj, S., Arzberger, T., Bogdanovic, N., Budka, H., Dexter, D.T., Falkai, P., Ferrer, I., Gelpi, E., Gentleman, S., Giaccone, G., Huitinga, I., Ironside, J.W., Klioueva, N.M., Kovacs, G.G., Meyronet, D., Palkkovits, M., Parchi, P., Patsouris, E., Reynolds, R., Riederer, P., Roggendorf, W., Seilhaen, D., Schmitt, A., Schmitz, P., Streichenberger, N., Schwalber, A., Kretzschmar, H., Bell, J., Alazuloff, I., Al-Sarraj, S., Arzberger, T., Bogdanovic, N., Budka, H., Dexter, D.T., Falkai, P., Ferrer, I., Gelpi, E., Gentleman, S., Giaccone, G., Huitinga, I., Ironside, J.W., Klioueva, N.M., Kovacs, G.G., Meyronet, D., Palkkovits, M., Parchi, P., Patsouris, E., Reynolds, R., Riederer, P., Roggendorf, W., Seilhaen, D., Schmitt, A., Schmitz, P., Streichenberger, N., Schwalber, A., and Kretzschmar, H.

Published
2008

49. 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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50. Identification of novel risk loci and causal insights for sporadic Creutzfeldt-Jakob disease: a genome-wide association study

Author

Gabor G. Kovacs, Stephanie A. Booth, Sebastian Brandner, Penny Norsworthy, Anna Ladogana, Akin Nihat, Herbert Budka, Saima Zafar, Helen Speedy, Antonio Salas, Parvin Ahmed, Holger Hummerich, Gerard H. Jansen, Tze How Mok, Michael D. Geschwind, Beata Sikorska, Maurizio Pocchiari, Christiane Stehmann, Sabina Capellari, Jean-Louis Laplanche, Sven J. van der Lee, Emma Jones, Jean-Charles Lambert, Olga Calero, Pierluigi Gambetti, Ewa Golanska, Serena Aneli, Richard Knight, Giuseppe Matullo, Pawel P. Liberski, Athanasios Dimitriadis, Jerome Whitfield, Hata Karamujić-Čomić, Federico Martinón-Torres, Emmanuelle Viré, Jiri G. Safar, Tracy Campbell, Pascual Sánchez-Juan, Katie Glisic, Anna Bartoletti-Stella, Carla A. Ibrahim-Verbaas, Adriano Aguzzi, Anna Poleggi, Aili Golubjatnikov, Karl Frontzek, Jean Phillipe Brandel, Phillipe Amouyel, Parmjit S. Jat, Zane Jaunmuktane, Simon Mead, Steven J. Collins, Inga Zerr, Liam Quinn, Piero Parchi, Janis Blevins, Elodie Bouaziz-Amar, Brian S. Appleby, Shannon Sarros, Jacqueline M. Linehan, Miguel Calero, Michael B. Coulthart, Stéphane Haïk, John Collinge, James Uphill, Cornelia M. van Duijn, Diseases, Network Centre for Biomedical Research in Neurodegenerative, Jones E., Hummerich H., Vire E., Uphill J., Dimitriadis A., Speedy H., Campbell T., Norsworthy P., Quinn L., Whitfield J., Linehan J., Jaunmuktane Z., Brandner S., Jat P., Nihat A., How Mok T., Ahmed P., Collins S., Stehmann C., Sarros S., Kovacs G.G., Geschwind M.D., Golubjatnikov A., Frontzek K., Budka H., Aguzzi A., Karamujic-Comic H., van der Lee S.J., Ibrahim-Verbaas C.A., van Duijn C.M., Sikorska B., Golanska E., Liberski P.P., Calero M., Calero O., Sanchez-Juan P., Salas A., Martinon-Torres F., Bouaziz-Amar E., Haik S., Laplanche J.-L., Brandel J.-P., Amouyel P., Lambert J.-C., Parchi P., Bartoletti-Stella A., Capellari S., Poleggi A., Ladogana A., Pocchiari M., Aneli S., Matullo G., Knight R., Zafar S., Zerr I., Booth S., Coulthart M.B., Jansen G.H., Glisic K., Blevins J., Gambetti P., Safar J., Appleby B., Collinge J., Mead S., Universidad de Cantabria, Neurology, Amsterdam Neuroscience - Neurodegeneration, and Epidemiology

Subjects
0301 basic medicine, epidemiology [Creutzfeldt-Jakob Syndrome], Tau protein, Single-nucleotide polymorphism, Genome-wide association study, diagnosis [Creutzfeldt-Jakob Syndrome], Disease, genetics [Genetic Loci], methods [Genome-Wide Association Study], Polymorphism, Single Nucleotide, Creutzfeldt-Jakob Syndrome, PRNP, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Humans, Genetic Predisposition to Disease, ddc:610, genetics [Genetic Predisposition to Disease], Genotyping, Exome sequencing, Genetics, biology, Odds ratio, genetics [Creutzfeldt-Jakob Syndrome], 030104 developmental biology, Genetic Loci, epidemiology [Genetic Predisposition to Disease], biology.protein, genetics [Polymorphism, Single Nucleotide], Neurology (clinical), 030217 neurology & neurosurgery, Genome-Wide Association Study, Human
Abstract

Background Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the PRNP gene that encodes prion protein are strong risk factors for sCJD but, although the condition has similar heritability to other neurodegenerative disorders, no other genetic risk loci have been confirmed. We aimed to discover new genetic risk factors for sCJD, and their causal mechanisms. Methods We did a genome-wide association study of sCJD in European ancestry populations (patients diagnosed with probable or definite sCJD identified at national CJD referral centres) with a two-stage study design using genotyping arrays and exome sequencing. Conditional, transcriptional, and histological analyses of implicated genes and proteins in brain tissues, and tests of the effects of risk variants on clinical phenotypes, were done using deep longitudinal clinical cohort data. Control data from healthy individuals were obtained from publicly available datasets matched for country. Findings Samples from 5208 cases were obtained between 1990 and 2014. We found 41 genome-wide significant single nucleotide polymorphisms (SNPs) and independently replicated findings at three loci associated with sCJD risk; within PRNP (rs1799990; additive model odds ratio [OR] 1·23 [95% CI 1·17–1·30], p=2·68 × 10 −15; heterozygous model p=1·01 × 10 −135), STX6 (rs3747957; OR 1·16 [1·10–1·22], p=9·74 × 10 −9), and GAL3ST1 (rs2267161; OR 1·18 [1·12–1·25], p=8·60 × 10 −10). Follow-up analyses showed that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 are associated with increased expression of the major transcripts in disease-relevant brain regions. Interpretation We present, to our knowledge, the first evidence of statistically robust genetic associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism as molecular causal mechanisms. Risk SNPs in STX6 are shared with progressive supranuclear palsy, a neurodegenerative disease associated with misfolding of protein tau, indicating that sCJD might share the same causal mechanisms as prion-like disorders. Funding Medical Research Council and the UK National Institute of Health Research in part through the Biomedical Research Centre at University College London Hospitals National Health Service Foundation Trust.

Published
2020
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