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1. Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

Author

van der Lee, Sven J, Conway, Olivia J, Zettergren, Anna, Christensen, Kaare, Ertekin-Taner, Nilüfer, Scholz, Sonja W, Ramirez, Alfredo, Ruiz, Agustín, Slagboom, Eline, van der Flier, Wiesje M, Holstege, Henne, Mead, S., Synofzik, M., Andlauer, Till F M, van Swieten, J. C., Leber, I., Ferrari, R., Hernandez, D. G., Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B. J., Dobson-Stone, C., Schofield, P. R., Diez-Fairen, Monica, Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Simon-Sanchez, Javier, Binetti, G., Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Blesa, R., Landqvist Waldö, M., Lleó, Alberto, Nilsson, K., Nilsson, C., Mackenzie, I. R. A., Hsiung, G-Y R, Mann, D. M. A., Grafman, J., Morris, C. M., Attems, J., Griffiths, T. D., McKeith, I. G., Zetterberg, Henrik, Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Razquin, C., Ortega-Cubero, S., Alonso, E., Nygaard, Marianne, Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., St George-Hyslop, P., Rossi, G., Blauwendraat, Cornelis, Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C. M., Uphill, J., Collinge, J., Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., Savage, Jeanne E, van der Zee, J., Van Broeckhoven, C., Cappa, S. F., Hannequin, D., Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Mengel-From, Jonas, Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Jansen, Iris, Moreno-Grau, Sonia, Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Rizzu, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Wagner, Michael, Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Baker, M., Josephs, K. A., Fortea, Juan, Parisi, J. E., Seeley, W. W., Miller, B. L., Karydas, A. M., Rosen, H., Dopper, E. G. P., Seelaar, H., Logroscino, G., Capozzo, R., Novelli, V., Keogh, Michael J, Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H-H, Graff, C., Pasquier, F., Rollin, A., Blennow, Kaj, Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., Singleton, A. B., Hardy, J., Momeni, P., Coppola, G., Skoog, Ingmar, Varpetian, A., Foroud, T. M., Levey, A. I., Kukull, W. A., Mendez, M. F., Ringman, J., Chui, H., Cotman, C., DeCarli, C., Friese, Manuel A, Geschwind, D. H., Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, Carrasquillo, Minerva M, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Kleineidam, Luca, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W, van Berckel, Bart N M, Alcolea, Daniel, Wiendl, Heinz, van den Akker, Erik, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, DESGESCO, EADB, IFGC, IPDGC, RiMod-FTD, Bank, Netherlands Brain, Boeve, Bradley F, Hernández, Isabel, Petersen, Ronald C, Ferman, Tanis J, van Gerpen, Jay A, Reinders, Marcel J T, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, van Eijk, Kristel R, Boada, Mercè, Zettl, Uwe K, van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Stringa, Najada, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande A L, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Chen, Jason A, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild I A, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, GIFT, and Clarimón, Jordi

Subjects
0301 basic medicine, Dementia with Lewy bodies, Disease, Bioinformatics, Neurodegenerative disease, 0302 clinical medicine, Missense mutation, media_common, 2. Zero hunger, Longevity, Brain, Parkinson Disease, Phospholipase C Gamma 2, Biobank, 3. Good health, ddc, Frontotemporal Dementia, Microglia, Alzheimer's disease, Alzheimer’s disease, Amyotrophic lateral sclerosis, Frontotemporal dementia, Multiple sclerosis, PLCG2, Parkinson’s disease, Progressive supranuclear palsy, Lewy Body Disease, Risk, Multiple Sclerosis, media_common.quotation_subject, education, Neuroimaging, Genomics, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, Alzheimer Disease, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Alleles, Phospholipase C gamma, business.industry, Amyotrophic Lateral Sclerosis, Correction, medicine.disease, 030104 developmental biology, Mutation, Dementia, Neurology (clinical), business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target. The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.

Published
2019
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2. CXCR4involvement in neurodegenerative diseases

Author

Bonham, Luke W, Karch, Celeste M, Ferrari, Raffaele, Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., van der Zee, J., Cruts, M., Van Broeckhoven, C., Cappa, S. F., Leber, I., Hannequin, D., Hardy, John, Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Momeni, Parastoo, Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Höglinger, Günter, Rizzu, P., Heutink, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Maletta, R., Frangipane, F., Cupidi, C., Müller, Ulrich, Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Rademakers, R., Baker, M., Dickson, D. W., Graff-Radford, N. R., Petersen, R. C., Hess, Christopher P, Knopman, D., Josephs, K. A., Boeve, B. F., Parisi, J. E., Seeley, W. W., Miller, B. L., Karydas, A. M., Rosen, H., van Swieten, J. C., Dopper, E. G. P., Sugrue, Leo P, Seelaar, H., Pijnenburg, Y. A. L., Scheltens, P., Logroscino, G., Capozzo, R., Novelli, V., Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Dillon, William P, Sorrentino, P., Kristiansen, M., Chiang, H-H, Graff, C., Pasquier, F., Rollin, A., Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Schellenberg, Gerard D, Pickering-Brown, S., Singleton, A. B., Hardy, J., Momeni, P., Miller, Bruce L, Fan, Chun C, Andreassen, Ole A, Dale, Anders M, Barkovich, A James, Yokoyama, Jennifer S, Desikan, Rahul S, Consortium, International FTD-Genomics, Consortium, International Parkinson’s Disease Genetics, Project, International Genomics of Alzheimer’s, Ferrari, R., Hernandez, D. G., Tan, Chin, Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B. J., Dobson-Stone, C., Schofield, P. R., Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Geier, Ethan G, Thompson, E., Haan, E., Hernández, I., Ruiz, A., Boada, M., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Wang, Yunpeng, Binetti, G., Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Clarimón, J., Lleó, A., Wen, Natalie, Blesa, R., Waldö, M Landqvist, Nilsson, K., Nilsson, C., Mackenzie, I. R. A., Hsiung, G-Y R, Mann, D. M. A., Grafman, J., Morris, C. M., Attems, J., Broce, Iris J, Griffiths, T. D., McKeith, I. G., Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Pastor, P., Li, Yi, Razquin, C., Ortega-Cubero, S., Alonso, E., Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Barkovich, Matthew J, Rogaeva, E., George-Hyslop, P St, Rossi, G., Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C. M., Uphill, J., Collinge, J., Mead, S., Bonham, Luke W., Karch, Celeste M., Fan, Chun C., Tan, Chin, Geier, Ethan G., Wang, Yunpeng, Wen, Natalie, Broce, Iris J., Li, Yi, Barkovich, Matthew J., Ferrari, Raffaele, Hardy, John, Momeni, Parastoo, Höglinger, Günter, Müller, Ulrich, Hess, Christopher P., Sugrue, Leo P., Dillon, William P., Schellenberg, Gerard D., Miller, Bruce L., Andreassen, Ole A., Dale, Anders M., Barkovich, A. Jame, Yokoyama, Jennifer S., Desikan, Rahul S., Hernandez, D. G., Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B. J., Dobson-Stone, C., Schofield, P. R., Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Haan, E., Hernández, I., Ruiz, A., Boada, M., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Binetti, G., Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Clarimón, J., Lleó, A., Blesa, R., Waldö, M. Landqvist., Nilsson, K., Nilsson, C., Mackenzie, I. R. A., Hsiung, G. -Y. R., Mann, D. M. A., Grafman, J., Morris, C. M., Attems, J., Griffiths, T. D., Mckeith, I. G., Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Pastor, P., Razquin, C., Ortega-Cubero, S., Alonso, E., Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., George-Hyslop, P. St., Rossi, G., Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C. M., Uphill, J., Collinge, J., Mead, S., Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., Van Der Zee, J., Cruts, M., Van Broeckhoven, C., Cappa, S. F., Leber, I., Hannequin, D., Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Rizzu, P., Heutink, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Rademakers, R., Baker, M., Dickson, D. W., Graff-Radford, N. R., Petersen, R. C., Knopman, D., Josephs, K. A., Boeve, B. F., Parisi, J. E., Seeley, W. W., Karydas, A. M., Rosen, H., Van Swieten, J. C., Dopper, E. G. P., Seelaar, H., Pijnenburg, Y. A. L., Scheltens, P., Logroscino, G., Capozzo, R., Novelli, V., Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H. -H., Graff, C., Pasquier, F., Rollin, A., Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., Singleton, A. B., Rademakers, Rosa, International FTD-Genomics Consortium (IFGC), International Parkinsons Disease Genetics Consortium (IPDGC), and International Genomics of Alzheimers Project (IGAP)

Subjects
0301 basic medicine, Aging, Gene Expression, Genome-wide association study, metabolism [Microglia], Neurodegenerative, Bioinformatics, Alzheimer's Disease, Transgenic, Mice, 0302 clinical medicine, Risk Factors, Receptors, 2.1 Biological and endogenous factors, Psychology, Gene Regulatory Networks, Aetiology, Alzheimer's Disease Related Dementias (ADRD), 0303 health sciences, Gene Regulatory Network, Parkinson's Disease, International Genomics of Alzheimer’s Project, Neurodegeneration, Brain, Neurodegenerative Diseases, Single Nucleotide, International Parkinson’s Disease Genetics Consortium, Frontotemporal Dementia (FTD), Psychiatry and Mental Health, Neurological, Public Health and Health Services, Tauopathy, Microglia, Frontotemporal dementia, Human, Receptors, CXCR4, Tau protein, Clinical Sciences, Mice, Transgenic, Computational biology, Biology, Polymorphism, Single Nucleotide, Article, CXCR4 protein, human, Progressive supranuclear palsy, lcsh:RC321-571, Cellular and Molecular Neuroscience, 03 medical and health sciences, Rare Diseases, Text mining, Genetic predisposition, medicine, Genetics, Acquired Cognitive Impairment, Animals, Humans, Genetic Predisposition to Disease, ddc:610, Polymorphism, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, 030304 developmental biology, CXCR4, Neurodegenerative Disease, Animal, business.industry, Risk Factor, International FTD-Genomics Consortium, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), medicine.disease, genetics [Receptors, CXCR4], Brain Disorders, Genome-Wide Association Study, 030104 developmental biology, metabolism [Brain], genetics [Neurodegenerative Diseases], Expression quantitative trait loci, biology.protein, Dementia, Human medicine, metabolism [Receptors, CXCR4], business, 030217 neurology & neurosurgery
Abstract

Neurodegenerative diseases likely share common underlying pathobiology. Although prior work has identified susceptibility loci associated with various dementias, few, if any, studies have systematically evaluated shared genetic risk across several neurodegenerative diseases. Using genome-wide association data from large studies (total n = 82,337 cases and controls), we utilized a previously validated approach to identify genetic overlap and reveal common pathways between progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson’s disease (PD) and Alzheimer’s disease (AD). In addition to the MAPT H1 haplotype, we identified a variant near the chemokine receptor CXCR4 that was jointly associated with increased risk for PSP and PD. Using bioinformatics tools, we found strong physical interactions between CXCR4 and four microglia related genes, namely CXCL12, TLR2, RALB, and CCR5. Evaluating gene expression from post-mortem brain tissue, we found that expression of CXCR4 and microglial genes functionally related to CXCR4 was dysregulated across a number of neurodegenerative diseases. Furthermore, in a mouse model of tauopathy, expression of CXCR4 and functionally associated genes was significantly altered in regions of the mouse brain that accumulate neurofibrillary tangles most robustly. Beyond MAPT, we show dysregulation of CXCR4 expression in PSP, PD, and FTD brains, and mouse models of tau pathology. Our multi-modal findings suggest that abnormal signaling across a ‘network’ of microglial genes may contribute to neurodegeneration and may have potential implications for clinical trials targeting immune dysfunction in patients with neurodegenerative diseases.

Published
2017
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3. Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies

Author

Broce, Iris, Karch, Celeste M., Wen, Natalie, Fan, Chun C., Wang, Yunpeng, Hong Tan, Chin, Kouri, Naomi, Ross, Owen A., Höglinger, Günter U., Muller, Ulrich, Hardy, John, Momeni, Parastoo, Hess, Christopher P., Dillon, William P., Miller, Zachary A., Bonham, Luke W., Rabinovici, Gil D., Rosen, Howard J., Schellenberg, Gerard D., Franke, Andre, Karlsen, Tom H., Veldink, Jan H., Ferrari, Raffaele, Yokoyama, Jennifer S., Miller, Bruce L., Andreassen, Ole A., Dale, Anders M., Desikan, Rahul S., Sugrue, Leo P., Ferrari R, Hernandez DG, Nalls MA, Rohrer JD, Ramasamy A, Kwok JBJ, Dobson-Stone C, Brooks WS, Schofield PR, Halliday GM, Hodges JR, Piguet O, Bartley L, Thompson E, Haan E, Hernández I, Ruiz A, Boada M, Borroni B, Padovani A, Cruchaga C, Cairns NJ, Benussi L, Binetti G, Ghidoni R, Forloni G, Galimberti D, Fenoglio C, Serpente M, Scarpini E, Clarimón J, Lleó A, Blesa R, Waldö ML, Nilsson K, Nilsson C, Mackenzie IRA, Hsuing GYR, Mann DMA, Grafman J, Morris CM, Attems J, Griffiths TD, McKeith IG, Thomas AJ, Pietrini P, Huey ED, Wasserman EM, Baborie A, Jaros E, Tierney MC, Pastor P, Razquin C, Ortega-Cubero S, Alonso E, Perneczky E, Diehl-Schmid J, Alexopoulos P, Kurz A, Rainero I, Rubino E, Pinessi L, Rogaeva E, St George-Hyslop P, Rossi G, Tagliavini F, Giaccone G, Rowe JB, Schlachetzki JCM, Uphill J, Collinge J, Mead S, Danek A, Van Deerlin VM, Grossmann M, Trojanowski JQ, van der Zee J, Deschamps W, Van Langenhove T, Cruts M, Van Broeckhoven C, Cappa SF, Le Ber I, Hannequin D, Golfier V, Vercelletto M, Brice A, Nacmias B, Sorbi S, Bagnoli S, Piaceri I, Nielsen JE, Hjermind LE, Riemenschneider M, Mayhaus M, Ibach B, Gasparoni G, Pichler S, Gu W, Rossor MN, Fox NC, Warren JD, Spillantini MG, Morris HR, Rizzu P, Heutnik P, Snowden J, Rollinson S, Richardson A, Gerhard A, Bruni AC, Maletta R, Frangipane F, Cupidi C, Bernardi L, Anfossi M, Gallo M, Conidi ME, Smirne N, Rademakers R, Baker M, Dickson DW, Graff-Radford NR, Peterson RC, Knopman D, Josephs KA, Boeve BF, Parisi JE, Seeley WW, Miller BL, Karydas AM, Rosen H, van Swieten JC, Dopper EGP, Seelaar H, Pijnenburg YAL, Scheltens P, Logroscino G, Capozzo R, Novelli V, Puca AA, Franceschi M, Postiglione A, Milan G, Sorrentino P, Kristiansen M, Chiang HH, Graff C, Pasquier F, Rollin A, Deramecourt V, Lebert F, Kapogiannis D, Ferucci L, Pickering-Brown S, Singleton AB, Hardy J, Momeni P., Broce, Iris [0000-0003-4932-1430], Karch, Celeste M [0000-0002-6854-5547], Wang, Yunpeng [0000-0001-9831-1090], Tan, Chin Hong [0000-0002-0980-9936], Kouri, Naomi [0000-0002-6841-9882], Hess, Christopher P [0000-0002-5132-5302], Miller, Zachary A [0000-0002-5991-3053], Bonham, Luke W [0000-0002-2533-1266], Veldink, Jan H [0000-0001-5572-9657], Dale, Anders M [0000-0002-6126-2966], Desikan, Rahul S [0000-0002-4151-6017], Sugrue, Leo P [0000-0001-7315-4519], Apollo - University of Cambridge Repository, Neurology, Human genetics, Amsterdam Neuroscience - Neurodegeneration, Divisions, Rademakers, Rosa, Int FTD-Genomics Consortium, Broce, Iri, Karch, Celeste M., Wen, Natalie, Fan, Chun C., Wang, Yunpeng, Hong Tan, Chin, Kouri, Naomi, Ross, Owen A., Höglinger, Günter U., Muller, Ulrich, Hardy, John, Momeni, Parastoo, Hess, Christopher P., Dillon, William P., Miller, Zachary A., Bonham, Luke W., Rabinovici, Gil D., Rosen, Howard J., Schellenberg, Gerard D., Franke, Andre, Karlsen, Tom H., Veldink, Jan H., Ferrari, Raffaele, Yokoyama, Jennifer S., Miller, Bruce L., Andreassen, Ole A., Dale, Anders M., Desikan, Rahul S., Sugrue, Leo P., Ferrari, R, Hernandez, Dg, Nalls, Ma, Rohrer, Jd, Ramasamy, A, Kwok, Jbj, Dobson-Stone, C, Brooks, W, Schofield, Pr, Halliday, Gm, Hodges, Jr, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, Nj, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Waldö, Ml, Nilsson, K, Nilsson, C, Mackenzie, Ira, Hsuing, Gyr, Mann, Dma, Grafman, J, Morris, Cm, Attems, J, Griffiths, Td, Mckeith, Ig, Thomas, Aj, Pietrini, P, Huey, Ed, Wasserman, Em, Baborie, A, Jaros, E, Tierney, Mc, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, E, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, St George-Hyslop, P, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, Jb, Schlachetzki, Jcm, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, Vm, Grossmann, M, Trojanowski, Jq, van der Zee, J, Deschamps, W, Van Langenhove, T, Cruts, M, Van Broeckhoven, C, Cappa, Sf, Le Ber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, Je, Hjermind, Le, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, Mn, Fox, Nc, Warren, Jd, Spillantini, Mg, Morris, Hr, Rizzu, P, Heutnik, P, Snowden, J, Rollinson, S, Richardson, A, Gerhard, A, Bruni, Ac, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Anfossi, M, Gallo, M, Conidi, Me, Smirne, N, Rademakers, R, Baker, M, Dickson, Dw, Graff-Radford, Nr, Peterson, Rc, Knopman, D, Josephs, Ka, Boeve, Bf, Parisi, Je, Seeley, Ww, Miller, Bl, Karydas, Am, Rosen, H, van Swieten, Jc, Dopper, Egp, Seelaar, H, Pijnenburg, Yal, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, Aa, Franceschi, M, Postiglione, A, Milan, G, Sorrentino, P, Kristiansen, M, Chiang, Hh, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebert, F, Kapogiannis, D, Ferucci, L, Pickering-Brown, S, Singleton, Ab, Hardy, J, and Momeni, P.

Subjects
0301 basic medicine, Linkage disequilibrium, Gene Expression, Genome-wide association study, Neurodegenerative, Medical and Health Sciences, Motor Neuron Diseases, 0302 clinical medicine, Medicine and Health Sciences, 2.1 Biological and endogenous factors, Corticobasal degeneration, genetics [Genetic Predisposition to Disease], genetics [Frontotemporal Dementia], Genetics, Medicine (all), Neurodegenerative Diseases, Single Nucleotide, Genomics, General Medicine, Middle Aged, Colitis, LRRK2, 3. Good health, Neurology, Manchester Institute for Collaborative Research on Ageing, Frontotemporal Dementia, Neurological, Medicine, Research Article, Frontotemporal dementia, ResearchInstitutes_Networks_Beacons/MICRA, Immunology, Rheumatoid Arthritis, Single-nucleotide polymorphism, Gastroenterology and Hepatology, Human leukocyte antigen, Biology, Autoimmune Disease, Polymorphism, Single Nucleotide, Autoimmune Diseases, 03 medical and health sciences, Rare Diseases, Rheumatology, Clinical Research, General & Internal Medicine, FTD GWA, Mental Health and Psychiatry, mental disorders, Acquired Cognitive Impairment, Genome-Wide Association Studies, medicine, Ulcerative Colitis, Humans, Inflammatory and Immune System, Genetic Predisposition to Disease, ddc:610, Polymorphism, Aged, Genetic association, Genome-Wide Association Study, International FTD-Genomics Consortium, Prevention, Arthritis, Human Genome, Inflammatory Bowel Disease, Amyotrophic Lateral Sclerosis, Neurosciences, Correction, Biology and Life Sciences, Computational Biology, nutritional and metabolic diseases, Human Genetics, Genome Analysis, medicine.disease, Brain Disorders, nervous system diseases, 030104 developmental biology, Genetic Loci, Genetics of Disease, Dementia, Clinical Immunology, Human medicine, Clinical Medicine, Digestive Diseases, 030217 neurology & neurosurgery
Abstract

Background Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. Methods and findings Using large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders—namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)—and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA) region on Chromosome (Chr) 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2), TBKBP1 (TBK1 binding protein 1), and PGBD5 (piggyBac transposable element derived 5). Functionally, we found that the expression of FTD–immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with FTD and is enriched in microglia/macrophages compared to other central nervous system cell types. The main study limitation is that the results represent only clinically diagnosed individuals. Also, given the complex interconnectedness of the HLA region, we were not able to define the specific gene or genes on Chr 6 responsible for our pleiotropic signal. Conclusions We show immune-mediated genetic enrichment specifically in FTD, particularly within the HLA region. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to FTD risk. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD., Rahul Desikan and colleagues use summary data from genome-wide association studies to investigate genetic overlap between frontotemporal dementia and a several immune-mediated diseases, and identify microglia and inflammation-associated genes that may play a role in FTD pathogenesis., Author summary Why was this study done? Frontotemporal dementia (FTD) is the leading cause of dementia in individuals less than 65 years old. Currently, there is no approved treatment of FTD and no diagnostic tests for predicting disease onset or measuring progression. Increasing evidence suggests that inflammation and immune system dysfunction play an important role in the pathogenesis of FTD. What did the researchers do and find? We used summary data from genome-wide association studies to investigate genetic overlap, or “pleiotropy,” between FTD and a variety of immune-mediated diseases. Through this approach, we found extensive FTD–immune genetic overlap within the HLA region on Chromosome 6, an area rich in genes related to microglial function, as well as in 3 genes not previously identified as contributing to the pathophysiology of FTD. Pointing to the functional relevance of these genetic results, we found that these candidate FTD–immune genes are differentially expressed in postmortem brains from patients with FTD compared to controls, and in microglia/macrophages compared with other central nervous system cells. Using bioinformatics tools, we explored protein and genetic interactions among our candidate FTD–immune genes. These results suggest that rather than a few individual loci, large portions of the HLA region may be associated with increased FTD risk. What do these findings mean? Immune dysfunction may play a role in the pathophysiology of a subset of FTD cases. For a subset of patients in whom immune dysfunction in general—and microglial activation in particular—is central to disease pathophysiology, anti-inflammatory treatment is an important area for further investigation.

Published
2018
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4. Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS

Author

Taskesen, E, Mishra, A, van der Sluis, S, Ferrari, R, Veldink, Jh, van Es MA4, Smit, Ab5, Posthuma, D1, 2, Hernandez DG, Pijnenburg Y., Nalls, Ma, Rohrer, Jd, Ramasamy, A, Kwok, Jbj, Dobson-Stone, C, Schofield, Pr, Halliday, Gm, Hodges, Jr, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, Nj, Benussi, L, Binetti, G, Ghidoni, Roberta, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Waldö, Ml, Nilsson, K, Nilsson, C, Mackenzie, Ira, Hsiung, Gr, Mann, Dma, Grafman, J, Morris, Cm, Attems, J, Griffiths, Td, Mckeith, Ig, Thomas, Aj, Pietrini, P, Huey, Ed, Wassermann, Em, Baborie, A, Jaros, E, Tierney, Mc, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, George-Hyslop, Ps, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, Jb, Schlachetzki, Jcm, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin VM, Grossman, M, Trojanowski, Jq, van der Zee, J, Van Broeckhoven, C, Cappa, Sf, Leber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, Je, Hjermind, Le, Riemenschneider, GUNNAR MARKUS, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, Mn, Fox, Nc, Warren, Jd, Spillantini, Mg, Morris, Hr, Rizzu, P, Heutink, P, Snowden, Js, Rollinson, S, Richardson, A, Gerhard, A, Bruni, Ac, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, Lara, Anfossi, M, Gallo, M, Conidi, Me, Smirne, N, Rademakers, R, Baker, M, Dickson, Dw, Graff-Radford, Nr, Petersen, Rc, Knopman, D, Josephs, Ka, Boeve, Bf, Parisi, Je, Seeley, Ww, Miller, Bl, Karydas, Am, Rosen, H, van Swieten JC, Dopper, Egp, Seelaar, H, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, Aa, Franceschi, M, Postiglione, Antonio, Milan, Gian Luca, Sorrentino, Paolo Luigi, Kristiansen, M, Chiang, Hh, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebouvier, T, Kapogiannis, D, Ferrucci, L, Pickering-Brown, S, Singleton, Ab, Hardy, J, Momeni, P., Rademakers, Rosa, International FTD-Genomics Consortium, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience - Neurodegeneration, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Human genetics, APH - Quality of Care, Midwifery Science, Divisions, Neurology, Amsterdam Reproduction & Development (AR&D), Mishra, A [0000-0002-8141-1543], van der Sluis, S [0000-0001-9958-7216], van Es, MA [0000-0002-7709-5883], Posthuma, D [0000-0001-7582-2365], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Candidate gene, Science, Genome-wide association study, Biology, Neurodegenerative, Article, 03 medical and health sciences, 0302 clinical medicine, Rare Diseases, SDG 3 - Good Health and Well-being, mental disorders, medicine, Journal Article, Acquired Cognitive Impairment, Genetics, 2.1 Biological and endogenous factors, Amyotrophic lateral sclerosis, Aetiology, General, Alzheimer's Disease Related Dementias (ADRD), Genetic association, Multidisciplinary, Genetic heterogeneity, International FTD-Genomics Consortium, Neurodegeneration, Human Genome, Neurosciences, nutritional and metabolic diseases, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), medicine.disease, nervous system diseases, Brain Disorders, Frontotemporal Dementia (FTD), 030104 developmental biology, DNA methylation, Neurological, Medicine, Dementia, Human medicine, ALS, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract

Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting the frontal and temporal lobes. Genome-wide association studies (GWAS) on FTD identified only a few risk loci. One of the possible explanations is that FTD is clinically, pathologically, and genetically heterogeneous. An important open question is to what extent epigenetic factors contribute to FTD and whether these factors vary between FTD clinical subgroup. We compared the DNA-methylation levels of FTD cases (n = 128), and of FTD cases with Amyotrophic Lateral Sclerosis (FTD-ALS; n = 7) to those of unaffected controls (n = 193), which resulted in 14 and 224 candidate genes, respectively. Cluster analysis revealed significant class separation of FTD-ALS from controls. We could further specify genes with increased susceptibility for abnormal gene-transcript behavior by jointly analyzing DNA-methylation levels with the presence of mutations in a GWAS FTD-cohort. For FTD-ALS, this resulted in 9 potential candidate genes, whereas for FTD we detected 1 candidate gene (ELP2). Independent validation-sets confirmed the genes DLG1, METTL7A, KIAA1147, IGHMBP2, PCNX, UBTD2, WDR35, and ELP2/SLC39A6 among others. We could furthermore demonstrate that genes harboring mutations and/or displaying differential DNA-methylation, are involved in common pathways, and may therefore be critical for neurodegeneration in both FTD and FTD-ALS.

Published
2017
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5. Immune-related genetic enrichment in frontotemporal dementia

Author

Broce, Iris, Karch, Celeste M., Wen, Natalie, Fan, Chun C., Wang, Yunpeng, Hong Tan, Chin, Kouri, Naomi, Ross, Owen A., Höglinger, Günter U., Muller, Ulrich, Hardy, John, Momeni, Parastoo, Hess, Christopher P., Dillon, William P., Miller, Zachary A., Bonham, Luke W., Rabinovici, Gil D., Rosen, Howard J., Schellenberg, Gerard D., Franke, Andre, Karlsen, Tom H., Veldink, Jan H., Ferrari, Raffaele, Yokoyama, Jennifer S., Miller, Bruce L., Andreassen, Ole A., Dale, Anders M., Desikan, Rahul S., Sugrue, Leo P., Ferrari, R, Hernandez, D G, Nalls, M A, Rohrer, J D, Ramasamy, A, Kwok, J B J, Dobson-Stone, C, Schofield, P R, Halliday, G M, Hodges, J R, Piguet, O, Bartley, L, Thompson, E, Haan, E, Hernández, I, Ruiz, A, Boada, M, Borroni, B, Padovani, A, Cruchaga, C, Cairns, N J, Benussi, L, Binetti, G, Ghidoni, R, Forloni, G, Albani, D, Galimberti, D, Fenoglio, C, Serpente, M, Scarpini, E, Clarimón, J, Lleó, A, Blesa, R, Landqvist Waldö, M, Nilsson, K, Nilsson, C, Mackenzie, I R A, Hsiung, G-Y R, Mann, D M A, Grafman, J, Morris, C M, Attems, J, Griffiths, T D, McKeith, I G, Thomas, A J, Pietrini, P, Huey, E D, Wassermann, E M, Baborie, A, Jaros, E, Tierney, M C, Pastor, P, Razquin, C, Ortega-Cubero, S, Alonso, E, Perneczky, R, Diehl-Schmid, J, Alexopoulos, P, Kurz, A, Rainero, I, Rubino, E, Pinessi, L, Rogaeva, E, George-Hyslop, P St, Rossi, G, Tagliavini, F, Giaccone, G, Rowe, J B, Schlachetzki, J C M, Uphill, J, Collinge, J, Mead, S, Danek, A, Van Deerlin, V M, Grossman, M, Trojanowski, J Q, der Zee, J van, Cruts, M, Broeckhoven, C Van, Cappa, S F, Leber, I, Hannequin, D, Golfier, V, Vercelletto, M, Brice, A, Nacmias, B, Sorbi, S, Bagnoli, S, Piaceri, I, Nielsen, J E, Hjermind, L E, Riemenschneider, M, Mayhaus, M, Ibach, B, Gasparoni, G, Pichler, S, Gu, W, Rossor, M N, Fox, N C, Warren, J D, Spillantini, M G, Morris, H R, Rizzu, P, Heutink, P, Snowden, J S, Rollinson, S, Richardson, A, Gerhard, A, Bruni, A C, Maletta, R, Frangipane, F, Cupidi, C, Bernardi, L, Anfossi, M, Gallo, M, Conidi, M E, Smirne, N, Rademakers, R, Baker, M, Dickson, D W, Graff-Radford, N R, Petersen, R C, Knopman, D, Josephs, K A, Boeve, B F, Parisi, J E, Seeley, W W, Miller, B L, Karydas, A M, Rosen, H, van Swieten, J C, Dopper, E G P, Seelaar, H, Pijnenburg, Y A L, Scheltens, P, Logroscino, G, Capozzo, R, Novelli, V, Puca, A A, Franceschi, M, Postiglione, A, Milan, G, Sorrentino, P, Kristiansen, M, Chiang, H-H, Graff, C, Pasquier, F, Rollin, A, Deramecourt, V, Lebouvier, T, Kapogiannis, D, Ferrucci, L, Pickering-Brown, S, Singleton, A B, Hardy, J, and Momeni, P

Subjects
Genetics, 0303 health sciences, business.industry, nutritional and metabolic diseases, Single-nucleotide polymorphism, Genome-wide association study, Disease, medicine.disease, nervous system diseases, 3. Good health, Progressive supranuclear palsy, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Immunology, Medicine, Corticobasal degeneration, Amyotrophic lateral sclerosis, business, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association, Frontotemporal dementia
Abstract

BackgroundConverging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed.Methods and findingsUsing large genome-wide association studies (GWAS) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs)jointlyassociated with ‘FTD-related disorders’ namely FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS) – and one or more immune-mediated diseases including Crohn’s disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis (PSOR). We found up to 270-fold genetic enrichment between FTD and RA and comparable enrichment between FTD and UC, T1D, and CeD. In contrast, we found only modest genetic enrichment between any of the immune-mediated diseases and CBD, PSP or ALS. At a conjunction false discovery rate (FDR) < 0.05, we identified numerous FTD-immune pleiotropic SNPs within the human leukocyte antigen (HLA)region on chromosome 6. By leveraging the immune diseases, we also found novel FTD susceptibility loci withinLRRK2(Leucine Rich Repeat Kinase 2), TBKBP1(TANK-binding kinase 1 Binding Protein 1), andPGBD5(PiggyBac Transposable Element Derived 5). Functionally, we found that expression of FTD-immune pleiotropic genes (particularly within theHLAregion) is altered in postmortem brain tissue from patients with frontotemporal dementia and is enriched in microglia compared to other central nervous system (CNS) cell types.ConclusionsWe show considerable immune-mediated genetic enrichment specifically in FTD, particularly within theHLAregion. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to risk for FTD. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.

Published
2017
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8. Genetic analysis suggests lysosomal and immune system involvement in frontotemporal dementia

Author

Ferrari, R., Hernandez, D. G., Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B. J., Dobson-Stone, C., Brooks, W. S., Eld, P. R. Schofi, Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Haan, E., Hernandez, I., Ruiz, A., Boada, M., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Binetti, G., Ghidoni, R., Forloni, G., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Clarimon, J., Lleo, A., Blesa, R., Waldoe, M. Landqvist, Nilsson, K., Nilsson, C., Mackenzie, I. R. A., Hsiung, G., Mann, D. M. A., Grafman, J., Morris, C. M., Attems, J., Ths, T. D. Griffi, Mckeith, I. G., Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Pastor, P., Razquin, C., Ortega-Cubero, S., Alonso, E., Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rubino, I. Rainero E., Pinessi, L., Rogaeva, E., St George-Hyslop, P., Rossi, G., Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C. M., Uphill, J., Collinge, J., Mead, S., Danek, A., Deerlin, V. M., Grossman, M., Trojanowski, J. Q., Zee, J., Deschamps, W., Langenhove, T., Cruts, M., Broeckhoven, C., Cappa, S. F., Le Ber, I., Hannequin, D., Golfier, V., Vercelletto, M., Alexis Brice, Nacmias, B., Sorbi, S., Bagnoli, S., Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Rizzu, P., Heutink, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Rademakers, R., Baker, M., Dickson, D. W., Graff-Radford, N. R., Petersen, R. C., Knopman, D., Josephs, K. A., Boeve, B. F., Parisi, J. E., Seeley, W. W., Miller, B. L., Karydas, A. M., Rosen, H., Swieten, J. C., Dopper, E. G. P., Seelaar, H., Pijnenburg, Y. A., Scheltens, P., Logroscino, G., Capozzo, R., Novelli, V., Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H. H., Graff, C., Pasquier, F., Rollin, A., Deramecourt, V., Lebert, F., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., Hardy, J., Momeni, P., and Singleton, A. B.

9. More than two-hundred and fifty FTD patients looking for genes: results from Italian FTD Network

Author

Alberici, A., Nacmias, B., Logroscino, G., Bruni, A., Tagliavini, F., Ghidoni, R., Galimberti, D., Bonanni, L., Cagnin, A., Bozzali, M., Silani, V., Turrone, R., Ferrari, C., Lombardi, G., Bessi, V., Capozzo, R., Zecca, C., Arcuti, S., Cupidi, C., Bernardi, L., Smirne, N., Frangipane, F., Rossi, G., Caroppo, P., Pietro Tiraboschi, Benussi, L., Binetti, G., Ciani, M., Fostinelli, S., Arighi, A., Fenoglio, C., Fumagalli, G., Onofrj, M., Scarpini, E., Sorbi, S., Padovani, A., and Borroni, B.

10. Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia

Author

Bonham, Luke W., Steele, Natasha Z. R., Karch, Celeste M., Broce, Iris, Geier, Ethan G., Wen, Natalie L., Momeni, Parastoo, Hardy, John, Miller, Zachary A., Gorno-Tempini, Maria Luisa, Hess, Christopher P., Lewis, Patrick, Miller, Bruce L., Seeley, William W., Manzoni, Claudia, Desikan, Rahul S., Baranzini, Sergio E., Ferrari, Raffaele, Yokoyama, Jennifer S., Hernandez, D. G., Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B. J., Dobson-Stone, C., Schofield, P. R., Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Haan, E., Hernández, I., Ruiz, A., Boada, M., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Binetti, G., Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Clarimón, J., Lleó, A., Blesa, R., Landqvist Waldö, M., Nilsson, K., Nilsson, C., Mackenzie, I. R. A., Hsiung, G. -Y. R., Mann, D. M. A., Grafman, J., Morris, C. M., Attems, J., Griffiths, T. D., McKeith, I. G., Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Pastor, P., Razquin, C., Ortega-Cubero, S., Alonso, E., Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., St George-Hyslop, P., Rossi, G., Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C. M., Uphill, J., Collinge, J., Mead, S., Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., Van Der Zee, J., Cruts, M., Van Broeckhoven, C., Cappa, S. F., Leber, I., Hannequin, D., Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Rizzu, P., Heutink, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Rademakers, R., Baker, M., Dickson, D. W., Graff-Radford, N. R., Petersen, R. C., Knopman, D., Josephs, K. A., Boeve, B. F., Parisi, J. E., Karydas, A. M., Rosen, H., Van Swieten, J. C., Dopper, E. G. P., Seelaar, H., Pijnenburg, Y. A. L., Scheltens, P., Logroscino, G., Capozzo, R., Novelli, V., Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H. -H., Graff, C., Pasquier, F., Rollin, A., Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., and Singleton, A. B.

Subjects
631/208/199, 692/617/375/132, 692/617/375/365, article, 38/39, 631/208/205, 3. Good health
Abstract

The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA’s relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration.

11. Mitochondrial genome aberrations in skeletal muscle of patients with motor neuron disease

Author

Vittoria Petruzzella, L. Serlenga, Lucia Artuso, Isabella Laura Simone, Paola Favia, Rosa Capozzo, Giancarlo Logroscino, A. Amati, Stefano Zoccolella, Giuseppe Gasparre, Artuso L., Zoccolella S., Favia P., Amati A., Capozzo R., Logroscino G., Serlenga L., Simone I., Gasparre G., and Petruzzella V.

Subjects
Male, Pathology, medicine.medical_specialty, Mitochondrial DNA, SOD1, AMYOTROPHIC LATERAL, Pilot Projects, Mitochondrion, Biology, medicine.disease_cause, DNA, Mitochondrial, Pathogenesis, MTDNA, medicine, Humans, Amyotrophic lateral sclerosis, Motor Neuron Disease, Muscle, Skeletal, Mutation, Amyotrophic Lateral Sclerosis, Skeletal muscle, Motor neuron, Middle Aged, medicine.disease, medicine.anatomical_structure, Neurology, Genome, Mitochondrial, Female, Neurology (clinical), Gene Deletion
Abstract

Our objective was to assess the role of defects of mitochondrial function as contributing factors in the pathogenesis and/or progression of amyotrophic lateral sclerosis (ALS); mitochondrial genome structural alterations were investigated. DNA lesions, point alterations and gross rearrangements were screened by specific applications of real-time PCR including an optimized rapid gene-specific method for the accurate quantification of mitochondrial DNA (mtDNA) lesions as well as sequencing on skeletal muscle biopsies of three patients presenting with motor neuron disease. We found a higher frequency of mtDNA lesions, including multiple deletions, particularly in the only SOD1 mutated patient as well as in a patient negative for mutations in SOD1 but presenting a severe form of the disease. The occurrence and the extent of mtDNA lesions of the cases here presented were consistent in all the examined clinical phenotypes of ALS (SOD1 related ALS, bulbar onset, spinal onset) and correlated with the severity of clinical course of the illness and with the presence of SOD1 mutation as well. In conclusion, the strong association with mtDNA damages supports the hypothesis that mitochondrial dysfunction in skeletal muscle may contribute to the pathogenesis and progression of ALS.

Published
2012

12. Early and severe autonomic failure: broadening the clinical phenotype of type-2 spinocerebellar ataxia. A case report

Author

Giancarlo Logroscino, Giovanni Rizzo, M. De Mari, Carla Tortorella, Rosa Capozzo, Capozzo, R., Rizzo, G., De Mari, M., Tortorella, C., and Logroscino, G.

Subjects
Adult, Male, Spinocerebellar Ataxia, medicine.medical_specialty, Neurology, business.industry, medicine.disease, Phenotype, Pure Autonomic Failure, Spinocerebellar ataxia, Gait Ataxia, Physical therapy, Medicine, Neurology (clinical), business, Clinical phenotype, Pure autonomic failure, Neuroscience, Human, Neuroradiology
Published
2014
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13. Mitochondrial genome large rearrangements in the skeletal muscle of a patient with PMA

Author

Vittoria Petruzzella, Flora Guerra, Rosa Capozzo, Giancarlo Logroscino, Stefano Zoccolella, Isabella Laura Simone, Lucia Artuso, A. Amati, Zoccolella, S., Artuso, L., Capozzo, R., Amati, A., Guerra, F., Simone, I., Logroscino, G., and Petruzzella, V.

Subjects
MtDNA duplication, Genetics, medicine.diagnostic_test, business.industry, MtDNA copy number, Muscle weakness, Neurological examination, Anatomy, Electromyography, Motor neuron, Progressive muscular atrophy, medicine.disease, Spinal cord, Upper limb muscle weakness, Fasciculation, medicine.anatomical_structure, MtDNA deletion, Neurology, Motor neuron degeneration, medicine, Neurology (clinical), medicine.symptom, business
Abstract

Sir, Progressive muscular atrophy is a motor neuron disease (MND) characterized by selective lower motor neuron involvement [1]. MND pathogenesis is unknown and different mechanisms, including oxidative stress, may be involved [2]. Mitochondrial (mt) abnormalities have been observed in motor neurons of patients with MND [2], and MND patients carrying pathogenic mtDNA alteration have been reported [3]. A 63-year-old woman presented with a 4-year history of proximal upper limb muscle weakness and hypotrophy. Informed consent was obtained. Neurological examination revealed muscle weakness, hypotrophy and fasciculations with the absence of deep tendon reflexes in upper limbs. Cranial nerves and lower limbs function were normal. Laboratory examinations, SOD1, and SMA analysis were normal. Electromyography of the four limb muscles showed diffuse chronic denervation with fibrillations. Motor, sensory evoked potentials were normal. Magnetic Resonance Imaging (MRI) of brain was normal, whilst MRI of the spinal cord revealed cervical and lumbar disks protrusion. The muscular weakness slowly

Published
2012
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