103 results on '"Growdon, John"'
Search Results
2. Neuropathologic correlates of amyloid and dopamine transporter imaging in Lewy body disease.
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Shirvan, Julia MD, PhD, Clement, Nathan MD, Ye, Rong MD, Katz, Samantha, Schultz, Aaron PhD, Johnson, Keith A. MD, Gomez-Isla, Teresa MD, PhD, Frosch, Matthew MD, PhD, Growdon, John H. MD, Gomperts, Stephen N. MD, PhD, Shirvan, Julia, Clement, Nathan, Ye, Rong, Schultz, Aaron, Johnson, Keith A, Gomez-Isla, Teresa, Frosch, Matthew, Growdon, John H, and Gomperts, Stephen N
- Published
- 2019
- Full Text
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3. β-Glucocerebrosidase activity in -linked Parkinson disease: The type of mutation matters.
- Author
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Young Eun Huh, Ruby Chiang, Ming Sum, Locascio, Joseph J., Zhixiang Liao, Ganqiang Liu, Choudhury, Karbi, Kuras, Yuliya I., Tuncali, Idil, Videnovic, Aleksandar, Hunt, Ann L., Schwarzschild, Michael A., Hung, Albert Y., Herrington, Todd M., Hayes, Michael T., Hyman, Bradley T., Wills, Anne-Marie, Gomperts, Stephen N., Growdon, John H., Sardi, Sergio Pablo, and Scherzer, Clemens R.
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- 2020
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4. Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease
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Liu, Ganqiang, Peng, Jiajie, Liao, Zhixiang, Locascio, Joseph J., Corvol, Jean-Christophe, Zhu, Frank, Dong, Xianjun, Maple-Grødem, Jodi, Campbell, Meghan C., Elbaz, Alexis, Lesage, Suzanne, Brice, Alexis, Mangone, Graziella, Growdon, John H., Hung, Albert Y., Schwarzschild, Michael A., Hayes, Michael T., Wills, Anne-Marie, Herrington, Todd M., Ravina, Bernard, Shoulson, Ira, Taba, Pille, Kõks, Sulev, Beach, Thomas G., Cormier-Dequaire, Florence, Alves, Guido, Tysnes, Ole-Bjørn, Perlmutter, Joel S., Heutink, Peter, Amr, Sami S., van Hilten, Jacobus J., Kasten, Meike, Mollenhauer, Brit, Trenkwalder, Claudia, Klein, Christine, Barker, Roger A., Williams-Gray, Caroline H., Marinus, Johan, and Scherzer, Clemens R.
- Abstract
A key driver of patients’ well-being and clinical trials for Parkinson’s disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P= 2.78 × 10−11), identify suggestive evidence for TMEM108(HR = 2.86, P= 2.09 × 10−8) and WWOX(HR = 2.12, P= 2.37 × 10−8) as progression loci, and confirm associations for GBA(HR = 1.93, P= 0.0002) and APOE(HR = 1.48, P= 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility.
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- 2021
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5. Associations of Lower Caffeine Intake and Plasma Urate Levels with Idiopathic Parkinson’s Disease in the Harvard Biomarkers Study
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Bakshi, Rachit, Macklin, Eric A., Hung, Albert Y., Hayes, Michael T., Hyman, Bradley T., Wills, Anne-Marie, Gomperts, Stephen N., Growdon, John H., Ascherio, Alberto, Scherzer, Clemens R., and Schwarzschild, Michael A.
- Abstract
Two purines, caffeine and urate, have been associated with a reduced risk of idiopathic Parkinson’s disease (PD) in multiple cohorts and populations. The Harvard Biomarkers Study (HBS) is a longitudinal study designed to accelerate the discovery and validation of molecular diagnostic and progression markers of early-stage PD. To investigate whether these ‘reduced risk’ factors are associated with PD within this cohort, we conducted a cross-sectional, case-control study in 566 subjects consisting of idiopathic PD patients and healthy controls. Caffeine intake as assessed by a validated questionnaire was significantly lower in idiopathic PD patients compared to healthy controls in males (mean difference –125?mg/day, p?0.001) but not in females (mean difference –30?mg/day, p?=?0.29). A strong inverse association was also observed with plasma urate levels both in males (mean difference –0.46?mg/dL, p?=?0.017) and females (mean difference –0.45?mg/dL, p?=?0.001). Both analyses stratified for sex and adjusted for age, body mass index, and either urate level or caffeine consumption, respectively. These results highlight the robustness of caffeine intake and urate as factors inversely associated with idiopathic PD.
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- 2020
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6. Associations of Lower Caffeine Intake and Plasma Urate Levels with Idiopathic Parkinson’s Disease in the Harvard Biomarkers Study
- Author
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Bakshi, Rachit, Macklin, Eric A., Hung, Albert Y., Hayes, Michael T., Hyman, Bradley T., Wills, Anne-Marie, Gomperts, Stephen N., Growdon, John H., Ascherio, Alberto, Scherzer, Clemens R., and Schwarzschild, Michael A.
- Abstract
Two purines, caffeine and urate, have been associated with a reduced risk of idiopathic Parkinson’s disease (PD) in multiple cohorts and populations. The Harvard Biomarkers Study (HBS) is a longitudinal study designed to accelerate the discovery and validation of molecular diagnostic and progression markers of early-stage PD. To investigate whether these ‘reduced risk’ factors are associated with PD within this cohort, we conducted a cross-sectional, case-control study in 566 subjects consisting of idiopathic PD patients and healthy controls. Caffeine intake as assessed by a validated questionnaire was significantly lower in idiopathic PD patients compared to healthy controls in males (mean difference –125 mg/day, p < 0.001) but not in females (mean difference –30 mg/day, p = 0.29). A strong inverse association was also observed with plasma urate levels both in males (mean difference –0.46 mg/dL, p = 0.017) and females (mean difference –0.45 mg/dL, p = 0.001). Both analyses stratified for sex and adjusted for age, body mass index, and either urate level or caffeine consumption, respectively. These results highlight the robustness of caffeine intake and urate as factors inversely associated with idiopathic PD.
- Published
- 2020
- Full Text
- View/download PDF
7. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing
- Author
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Kunkle, Brian W., Grenier-Boley, Benjamin, Sims, Rebecca, Bis, Joshua C., Damotte, Vincent, Naj, Adam C., Boland, Anne, Vronskaya, Maria, van der Lee, Sven J., Amlie-Wolf, Alexandre, Bellenguez, Céline, Frizatti, Aura, Chouraki, Vincent, Martin, Eden R., Sleegers, Kristel, Badarinarayan, Nandini, Jakobsdottir, Johanna, Hamilton-Nelson, Kara L., Moreno-Grau, Sonia, Olaso, Robert, Raybould, Rachel, Chen, Yuning, Kuzma, Amanda B., Hiltunen, Mikko, Morgan, Taniesha, Ahmad, Shahzad, Vardarajan, Badri N., Epelbaum, Jacques, Hoffmann, Per, Boada, Merce, Beecham, Gary W., Garnier, Jean-Guillaume, Harold, Denise, Fitzpatrick, Annette L., Valladares, Otto, Moutet, Marie-Laure, Gerrish, Amy, Smith, Albert V., Qu, Liming, Bacq, Delphine, Denning, Nicola, Jian, Xueqiu, Zhao, Yi, Del Zompo, Maria, Fox, Nick C., Choi, Seung-Hoan, Mateo, Ignacio, Hughes, Joseph T., Adams, Hieab H., Malamon, John, Sanchez-Garcia, Florentino, Patel, Yogen, Brody, Jennifer A., Dombroski, Beth A., Naranjo, Maria Candida Deniz, Daniilidou, Makrina, Eiriksdottir, Gudny, Mukherjee, Shubhabrata, Wallon, David, Uphill, James, Aspelund, Thor, Cantwell, Laura B., Garzia, Fabienne, Galimberti, Daniela, Hofer, Edith, Butkiewicz, Mariusz, Fin, Bertrand, Scarpini, Elio, Sarnowski, Chloe, Bush, Will S., Meslage, Stéphane, Kornhuber, Johannes, White, Charles C., Song, Yuenjoo, Barber, Robert C., Engelborghs, Sebastiaan, Sordon, Sabrina, Voijnovic, Dina, Adams, Perrie M., Vandenberghe, Rik, Mayhaus, Manuel, Cupples, L. Adrienne, Albert, Marilyn S., De Deyn, Peter P., Gu, Wei, Himali, Jayanadra J., Beekly, Duane, Squassina, Alessio, Hartmann, Annette M., Orellana, Adelina, Blacker, Deborah, Rodriguez-Rodriguez, Eloy, Lovestone, Simon, Garcia, Melissa E., Doody, Rachelle S., Munoz-Fernadez, Carmen, Sussams, Rebecca, Lin, Honghuang, Fairchild, Thomas J., Benito, Yolanda A., Holmes, Clive, Karamujić-Čomić, Hata, Frosch, Matthew P., Thonberg, Hakan, Maier, Wolfgang, Roshchupkin, Gennady, Ghetti, Bernardino, Giedraitis, Vilmantas, Kawalia, Amit, Li, Shuo, Huebinger, Ryan M., Kilander, Lena, Moebus, Susanne, Hernández, Isabel, Kamboh, M. Ilyas, Brundin, RoseMarie, Turton, James, Yang, Qiong, Katz, Mindy J., Concari, Letizia, Lord, Jenny, Beiser, Alexa S., Keene, C. Dirk, Helisalmi, Seppo, Kloszewska, Iwona, Kukull, Walter A., Koivisto, Anne Maria, Lynch, Aoibhinn, Tarraga, Lluís, Larson, Eric B., Haapasalo, Annakaisa, Lawlor, Brian, Mosley, Thomas H., Lipton, Richard B., Solfrizzi, Vincenzo, Gill, Michael, Longstreth, W. T., Montine, Thomas J., Frisardi, Vincenza, Diez-Fairen, Monica, Rivadeneira, Fernando, Petersen, Ronald C., Deramecourt, Vincent, Alvarez, Ignacio, Salani, Francesca, Ciaramella, Antonio, Boerwinkle, Eric, Reiman, Eric M., Fievet, Nathalie, Rotter, Jerome I., Reisch, Joan S., Hanon, Olivier, Cupidi, Chiara, Andre Uitterlinden, A. G., Royall, Donald R., Dufouil, Carole, Maletta, Raffaele Giovanni, de Rojas, Itziar, Sano, Mary, Brice, Alexis, Cecchetti, Roberta, George-Hyslop, Peter St, Ritchie, Karen, Tsolaki, Magda, Tsuang, Debby W., Dubois, Bruno, Craig, David, Wu, Chuang-Kuo, Soininen, Hilkka, Avramidou, Despoina, Albin, Roger L., Fratiglioni, Laura, Germanou, Antonia, Apostolova, Liana G., Keller, Lina, Koutroumani, Maria, Arnold, Steven E., Panza, Francesco, Gkatzima, Olymbia, Asthana, Sanjay, Hannequin, Didier, Whitehead, Patrice, Atwood, Craig S., Caffarra, Paolo, Hampel, Harald, Quintela, Inés, Carracedo, Ángel, Lannfelt, Lars, Rubinsztein, David C., Barnes, Lisa L., Pasquier, Florence, Frölich, Lutz, Barral, Sandra, McGuinness, Bernadette, Beach, Thomas G., Johnston, Janet A., Becker, James T., Passmore, Peter, Bigio, Eileen H., Schott, Jonathan M., Bird, Thomas D., Warren, Jason D., Boeve, Bradley F., Lupton, Michelle K., Bowen, James D., Proitsi, Petra, Boxer, Adam, Powell, John F., Burke, James R., Kauwe, John S. K., Burns, Jeffrey M., Mancuso, Michelangelo, Buxbaum, Joseph D., Bonuccelli, Ubaldo, Cairns, Nigel J., McQuillin, Andrew, Cao, Chuanhai, Livingston, Gill, Carlson, Chris S., Bass, Nicholas J., Carlsson, Cynthia M., Hardy, John, Carney, Regina M., Bras, Jose, Carrasquillo, Minerva M., Guerreiro, Rita, Allen, Mariet, Chui, Helena C., Fisher, Elizabeth, Masullo, Carlo, Crocco, Elizabeth A., DeCarli, Charles, Bisceglio, Gina, Dick, Malcolm, Ma, Li, Duara, Ranjan, Graff-Radford, Neill R., Evans, Denis A., Hodges, Angela, Faber, Kelley M., Scherer, Martin, Fallon, Kenneth B., Riemenschneider, Matthias, Fardo, David W., Heun, Reinhard, Farlow, Martin R., Kölsch, Heike, Ferris, Steven, Leber, Markus, Foroud, Tatiana M., Heuser, Isabella, Galasko, Douglas R., Giegling, Ina, Gearing, Marla, Hüll, Michael, Geschwind, Daniel H., Gilbert, John R., Morris, John, Green, Robert C., Mayo, Kevin, Growdon, John H., Feulner, Thomas, Hamilton, Ronald L., Harrell, Lindy E., Drichel, Dmitriy, Honig, Lawrence S., Cushion, Thomas D., Huentelman, Matthew J., Hollingworth, Paul, Hulette, Christine M., Hyman, Bradley T., Marshall, Rachel, Jarvik, Gail P., Meggy, Alun, Abner, Erin, Menzies, Georgina E., Jin, Lee-Way, Leonenko, Ganna, Real, Luis M., Jun, Gyungah R., Baldwin, Clinton T., Grozeva, Detelina, Karydas, Anna, Russo, Giancarlo, Kaye, Jeffrey A., Kim, Ronald, Jessen, Frank, Kowall, Neil W., Vellas, Bruno, Kramer, Joel H., Vardy, Emma, LaFerla, Frank M., Jöckel, Karl-Heinz, Lah, James J., Dichgans, Martin, Leverenz, James B., Mann, David, Levey, Allan I., Pickering-Brown, Stuart, Lieberman, Andrew P., Klopp, Norman, Lunetta, Kathryn L., Wichmann, H-Erich, Lyketsos, Constantine G., Morgan, Kevin, Marson, Daniel C., Brown, Kristelle, Martiniuk, Frank, Medway, Christopher, Mash, Deborah C., Nöthen, Markus M., Masliah, Eliezer, Hooper, Nigel M., McCormick, Wayne C., Daniele, Antonio, McCurry, Susan M., Bayer, Anthony, McDavid, Andrew N., Gallacher, John, McKee, Ann C., van den Bussche, Hendrik, Mesulam, Marsel, Brayne, Carol, Miller, Bruce L., Riedel-Heller, Steffi, Miller, Carol A., Miller, Joshua W., Al-Chalabi, Ammar, Morris, John C., Shaw, Christopher E., Myers, Amanda J., Wiltfang, Jens, O’Bryant, Sid, Olichney, John M., Alvarez, Victoria, Parisi, Joseph E., Singleton, Andrew B., Paulson, Henry L., Collinge, John, Perry, William R., Mead, Simon, Peskind, Elaine, Cribbs, David H., Rossor, Martin, Pierce, Aimee, Ryan, Natalie S., Poon, Wayne W., Nacmias, Benedetta, Potter, Huntington, Sorbi, Sandro, Quinn, Joseph F., Sacchinelli, Eleonora, Raj, Ashok, Spalletta, Gianfranco, Raskind, Murray, Caltagirone, Carlo, Bossù, Paola, Orfei, Maria Donata, Reisberg, Barry, Clarke, Robert, Reitz, Christiane, Smith, A David, Ringman, John M., Warden, Donald, Roberson, Erik D., Wilcock, Gordon, Rogaeva, Ekaterina, Bruni, Amalia Cecilia, Rosen, Howard J., Gallo, Maura, Rosenberg, Roger N., Ben-Shlomo, Yoav, Sager, Mark A., Mecocci, Patrizia, Saykin, Andrew J., Pastor, Pau, Cuccaro, Michael L., Vance, Jeffery M., Schneider, Julie A., Schneider, Lori S., Slifer, Susan, Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Swerdlow, Russell H., Tang, Mitchell, Tanzi, Rudolph E., Trojanowski, John Q., Troncoso, Juan C., Van Deerlin, Vivianna M., Van Eldik, Linda J., Vinters, Harry V., Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Wilhelmsen, Kirk C., Williamson, Jennifer, Wingo, Thomas S., Woltjer, Randall L., Wright, Clinton B., Yu, Chang-En, Yu, Lei, Saba, Yasaman, Pilotto, Alberto, Bullido, Maria J., Peters, Oliver, Crane, Paul K., Bennett, David, Bosco, Paola, Coto, Eliecer, Boccardi, Virginia, De Jager, Phil L., Lleo, Alberto, Warner, Nick, Lopez, Oscar L., Ingelsson, Martin, Deloukas, Panagiotis, Cruchaga, Carlos, Graff, Caroline, Gwilliam, Rhian, Fornage, Myriam, Goate, Alison M., Sanchez-Juan, Pascual, Kehoe, Patrick G., Amin, Najaf, Ertekin-Taner, Nilifur, Berr, Claudine, Debette, Stéphanie, Love, Seth, Launer, Lenore J., Younkin, Steven G., Dartigues, Jean-Francois, Corcoran, Chris, Ikram, M. Arfan, Dickson, Dennis W., Nicolas, Gael, Campion, Dominique, Tschanz, JoAnn, Schmidt, Helena, Hakonarson, Hakon, Clarimon, Jordi, Munger, Ron, Schmidt, Reinhold, Farrer, Lindsay A., Van Broeckhoven, Christine, C. O’Donovan, Michael, DeStefano, Anita L., Jones, Lesley, Haines, Jonathan L., Deleuze, Jean-Francois, Owen, Michael J., Gudnason, Vilmundur, Mayeux, Richard, Escott-Price, Valentina, Psaty, Bruce M., Ramirez, Alfredo, Wang, Li-San, Ruiz, Agustin, van Duijn, Cornelia M., Holmans, Peter A., Seshadri, Sudha, Williams, Julie, Amouyel, Phillippe, Schellenberg, Gerard D., Lambert, Jean-Charles, and Pericak-Vance, Margaret A.
- Abstract
Risk for late-onset Alzheimer’s disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1,and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer’s or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer’s disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P= 1.32 × 10−7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
- Published
- 2019
- Full Text
- View/download PDF
8. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
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Sims, Rebecca, van der Lee, Sven J, Naj, Adam C, Bellenguez, Céline, Badarinarayan, Nandini, Jakobsdottir, Johanna, Kunkle, Brian W, Boland, Anne, Raybould, Rachel, Bis, Joshua C, Martin, Eden R, Grenier-Boley, Benjamin, Heilmann-Heimbach, Stefanie, Chouraki, Vincent, Kuzma, Amanda B, Sleegers, Kristel, Vronskaya, Maria, Ruiz, Agustin, Graham, Robert R, Olaso, Robert, Hoffmann, Per, Grove, Megan L, Vardarajan, Badri N, Hiltunen, Mikko, Nöthen, Markus M, White, Charles C, Hamilton-Nelson, Kara L, Epelbaum, Jacques, Maier, Wolfgang, Choi, Seung-Hoan, Beecham, Gary W, Dulary, Cécile, Herms, Stefan, Smith, Albert V, Funk, Cory C, Derbois, Céline, Forstner, Andreas J, Ahmad, Shahzad, Li, Hongdong, Bacq, Delphine, Harold, Denise, Satizabal, Claudia L, Valladares, Otto, Squassina, Alessio, Thomas, Rhodri, Brody, Jennifer A, Qu, Liming, Sánchez-Juan, Pascual, Morgan, Taniesha, Wolters, Frank J, Zhao, Yi, Garcia, Florentino Sanchez, Denning, Nicola, Fornage, Myriam, Malamon, John, Naranjo, Maria Candida Deniz, Majounie, Elisa, Mosley, Thomas H, Dombroski, Beth, Wallon, David, Lupton, Michelle K, Dupuis, Josée, Whitehead, Patrice, Fratiglioni, Laura, Medway, Christopher, Jian, Xueqiu, Mukherjee, Shubhabrata, Keller, Lina, Brown, Kristelle, Lin, Honghuang, Cantwell, Laura B, Panza, Francesco, McGuinness, Bernadette, Moreno-Grau, Sonia, Burgess, Jeremy D, Solfrizzi, Vincenzo, Proitsi, Petra, Adams, Hieab H, Allen, Mariet, Seripa, Davide, Pastor, Pau, Cupples, L Adrienne, Price, Nathan D, Hannequin, Didier, Frank-García, Ana, Levy, Daniel, Chakrabarty, Paramita, Caffarra, Paolo, Giegling, Ina, Beiser, Alexa S, Giedraitis, Vilmantas, Hampel, Harald, Garcia, Melissa E, Wang, Xue, Lannfelt, Lars, Mecocci, Patrizia, Eiriksdottir, Gudny, Crane, Paul K, Pasquier, Florence, Boccardi, Virginia, Henández, Isabel, Barber, Robert C, Scherer, Martin, Tarraga, Lluis, Adams, Perrie M, Leber, Markus, Chen, Yuning, Albert, Marilyn S, Riedel-Heller, Steffi, Emilsson, Valur, Beekly, Duane, Braae, Anne, Schmidt, Reinhold, Blacker, Deborah, Masullo, Carlo, Schmidt, Helena, Doody, Rachelle S, Spalletta, Gianfranco, Jr, W T Longstreth, Fairchild, Thomas J, Bossù, Paola, Lopez, Oscar L, Frosch, Matthew P, Sacchinelli, Eleonora, Ghetti, Bernardino, Yang, Qiong, Huebinger, Ryan M, Jessen, Frank, Li, Shuo, Kamboh, M Ilyas, Morris, John, Sotolongo-Grau, Oscar, Katz, Mindy J, Corcoran, Chris, Dunstan, Melanie, Braddel, Amy, Thomas, Charlene, Meggy, Alun, Marshall, Rachel, Gerrish, Amy, Chapman, Jade, Aguilar, Miquel, Taylor, Sarah, Hill, Matt, Fairén, Mònica Díez, Hodges, Angela, Vellas, Bruno, Soininen, Hilkka, Kloszewska, Iwona, Daniilidou, Makrina, Uphill, James, Patel, Yogen, Hughes, Joseph T, Lord, Jenny, Turton, James, Hartmann, Annette M, Cecchetti, Roberta, Fenoglio, Chiara, Serpente, Maria, Arcaro, Marina, Caltagirone, Carlo, Orfei, Maria Donata, Ciaramella, Antonio, Pichler, Sabrina, Mayhaus, Manuel, Gu, Wei, Lleó, Alberto, Fortea, Juan, Blesa, Rafael, Barber, Imelda S, Brookes, Keeley, Cupidi, Chiara, Maletta, Raffaele Giovanni, Carrell, David, Sorbi, Sandro, Moebus, Susanne, Urbano, Maria, Pilotto, Alberto, Kornhuber, Johannes, Bosco, Paolo, Todd, Stephen, Craig, David, Johnston, Janet, Gill, Michael, Lawlor, Brian, Lynch, Aoibhinn, Fox, Nick C, Hardy, John, Albin, Roger L, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Baldwin, Clinton T, Barnes, Lisa L, Barral, Sandra, Beach, Thomas G, Becker, James T, Bigio, Eileen H, Bird, Thomas D, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Burke, James R, Burns, Jeffrey M, Buxbaum, Joseph D, Cairns, Nigel J, Cao, Chuanhai, Carlson, Chris S, Carlsson, Cynthia M, Carney, Regina M, Carrasquillo, Minerva M, Carroll, Steven L, Diaz, Carolina Ceballos, Chui, Helena C, Clark, David G, Cribbs, David H, Crocco, Elizabeth A, DeCarli, Charles, Dick, Malcolm, Duara, Ranjan, Evans, Denis A, Faber, Kelley M, Fallon, Kenneth B, Fardo, David W, Farlow, Martin R, Ferris, Steven, Foroud, Tatiana M, Galasko, Douglas R, Gearing, Marla, Geschwind, Daniel H, Gilbert, John R, Graff-Radford, Neill R, Green, Robert C, Growdon, John H, Hamilton, Ronald L, Harrell, Lindy E, Honig, Lawrence S, Huentelman, Matthew J, Hulette, Christine M, Hyman, Bradley T, Jarvik, Gail P, Abner, Erin, Jin, Lee-Way, Jun, Gyungah, Karydas, Anna, Kaye, Jeffrey A, Kim, Ronald, Kowall, Neil W, Kramer, Joel H, LaFerla, Frank M, Lah, James J, Leverenz, James B, Levey, Allan I, Li, Ge, Lieberman, Andrew P, Lunetta, Kathryn L, Lyketsos, Constantine G, Marson, Daniel C, Martiniuk, Frank, Mash, Deborah C, Masliah, Eliezer, McCormick, Wayne C, McCurry, Susan M, McDavid, Andrew N, McKee, Ann C, Mesulam, Marsel, Miller, Bruce L, Miller, Carol A, Miller, Joshua W, Morris, John C, Murrell, Jill R, Myers, Amanda J, O'Bryant, Sid, Olichney, John M, Pankratz, Vernon S, Parisi, Joseph E, Paulson, Henry L, Perry, William, Peskind, Elaine, Pierce, Aimee, Poon, Wayne W, Potter, Huntington, Quinn, Joseph F, Raj, Ashok, Raskind, Murray, Reisberg, Barry, Reitz, Christiane, Ringman, John M, Roberson, Erik D, Rogaeva, Ekaterina, Rosen, Howard J, Rosenberg, Roger N, Sager, Mark A, Saykin, Andrew J, Schneider, Julie A, Schneider, Lon S, Seeley, William W, Smith, Amanda G, Sonnen, Joshua A, Spina, Salvatore, Stern, Robert A, Swerdlow, Russell H, Tanzi, Rudolph E, Thornton-Wells, Tricia A, Trojanowski, John Q, Troncoso, Juan C, Van Deerlin, Vivianna M, Van Eldik, Linda J, Vinters, Harry V, Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A, Wilhelmsen, Kirk C, Williamson, Jennifer, Wingo, Thomas S, Woltjer, Randall L, Wright, Clinton B, Yu, Chang-En, Yu, Lei, Garzia, Fabienne, Golamaully, Feroze, Septier, Gislain, Engelborghs, Sebastien, Vandenberghe, Rik, De Deyn, Peter P, Fernadez, Carmen Muñoz, Benito, Yoland Aladro, Thonberg, Hakan, Forsell, Charlotte, Lilius, Lena, Kinhult-Stählbom, Anne, Kilander, Lena, Brundin, RoseMarie, Concari, Letizia, Helisalmi, Seppo, Koivisto, Anne Maria, Haapasalo, Annakaisa, Dermecourt, Vincent, Fievet, Nathalie, Hanon, Olivier, Dufouil, Carole, Brice, Alexis, Ritchie, Karen, Dubois, Bruno, Himali, Jayanadra J, Keene, C Dirk, Tschanz, JoAnn, Fitzpatrick, Annette L, Kukull, Walter A, Norton, Maria, Aspelund, Thor, Larson, Eric B, Munger, Ron, Rotter, Jerome I, Lipton, Richard B, Bullido, María J, Hofman, Albert, Montine, Thomas J, Coto, Eliecer, Boerwinkle, Eric, Petersen, Ronald C, Alvarez, Victoria, Rivadeneira, Fernando, Reiman, Eric M, Gallo, Maura, O'Donnell, Christopher J, Reisch, Joan S, Bruni, Amalia Cecilia, Royall, Donald R, Dichgans, Martin, Sano, Mary, Galimberti, Daniela, St George-Hyslop, Peter, Scarpini, Elio, Tsuang, Debby W, Mancuso, Michelangelo, Bonuccelli, Ubaldo, Winslow, Ashley R, Daniele, Antonio, Wu, Chuang-Kuo, Peters, Oliver, Nacmias, Benedetta, Riemenschneider, Matthias, Heun, Reinhard, Brayne, Carol, Rubinsztein, David C, Bras, Jose, Guerreiro, Rita, Al-Chalabi, Ammar, Shaw, Christopher E, Collinge, John, Mann, David, Tsolaki, Magda, Clarimón, Jordi, Sussams, Rebecca, Lovestone, Simon, O'Donovan, Michael C, Owen, Michael J, Behrens, Timothy W, Mead, Simon, Goate, Alison M, Uitterlinden, Andre G, Holmes, Clive, Cruchaga, Carlos, Ingelsson, Martin, Bennett, David A, Powell, John, Golde, Todd E, Graff, Caroline, De Jager, Philip L, Morgan, Kevin, Ertekin-Taner, Nilufer, Combarros, Onofre, Psaty, Bruce M, Passmore, Peter, Younkin, Steven G, Berr, Claudine, Gudnason, Vilmundur, Rujescu, Dan, Dickson, Dennis W, Dartigues, Jean-François, DeStefano, Anita L, Ortega-Cubero, Sara, Hakonarson, Hakon, Campion, Dominique, Boada, Merce, Kauwe, John Keoni, Farrer, Lindsay A, Van Broeckhoven, Christine, Ikram, M Arfan, Jones, Lesley, Haines, Jonathan L, Tzourio, Christophe, Launer, Lenore J, Escott-Price, Valentina, Mayeux, Richard, Deleuze, Jean-François, Amin, Najaf, Holmans, Peter A, Pericak-Vance, Margaret A, Amouyel, Philippe, van Duijn, Cornelia M, Ramirez, Alfredo, Wang, Li-San, Lambert, Jean-Charles, Seshadri, Sudha, Williams, Julie, and Schellenberg, Gerard D
- Abstract
We identified rare coding variants associated with Alzheimer's disease in a three-stage case–control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10−4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10−8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10−10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases= 0.0059, MAFcontrols= 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10−10, OR = 1.43, MAFcases= 0.011, MAFcontrols= 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10−14, OR = 1.67, MAFcases= 0.0143, MAFcontrols= 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein–protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
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- 2017
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9. Massachusetts Alzheimer's Disease Research Center: Progress and challenges.
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Hyman, Bradley T., Growdon, John H., Albers, Mark W., Buckner, Randy L., Chhatwal, Jasmeer, Gomez-Isla, Maria Teresa, Haass, Christian, Hudry, Eloise, Jr.Jack, Clifford R., Johnson, Keith A., Khachaturian, Zaven S., Kim, Doo Yeon, Martin, Joseph B., Nitsch, Roger M., Rosen, Bruce R., Selkoe, Dennis J., Sperling, Reisa A., St George-Hyslop, Peter, Tanzi, Rudolph E., and Yap, Liang
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- 2015
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10. Biomarkers for Alzheimer's Disease and Parkinson's Disease.
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Bures, Jan, Kopin, Irwin, McEwen, Bruce, Pribram, Karl, Rosenblatt, Jay, Weiskranz, Lawrence, Fisher, Abraham, Memo, Maurizio, Stocchi, Fabrizio, Hanin, Israel, Growdon, John H., Irizarry, Michael C., and Scherzer, Clemens
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- 2008
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11. Tau Positron Emission Tomographic Imaging in the Lewy Body Diseases
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Gomperts, Stephen N., Locascio, Joseph J., Makaretz, Sara J., Schultz, Aaron, Caso, Christina, Vasdev, Neil, Sperling, Reisa, Growdon, John H., Dickerson, Bradford C., and Johnson, Keith
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IMPORTANCE: The causes of cognitive impairment in dementia with Lewy bodies (DLB) and Parkinson disease (PD) are multifactorial. Tau pathologic changes are commonly observed at autopsy in individuals with DLB and PD dementia, but their contribution to these diseases during life is unknown. OBJECTIVE: To contrast tau aggregation in DLB, cognitively impaired persons with PD (PD-impaired), cognitively normal individuals with PD (PD-normal), and healthy persons serving as control participants, and to evaluate the association between tau aggregation, amyloid deposition, and cognitive function. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study was conducted from January 1, 2014, to April 28, 2016, in a tertiary care center’s memory and movement disorders units. Twenty-four patients with Lewy body disease (7 DLB, 8 PD-impaired, and 9 PD-normal) underwent multimodal brain imaging, cognitive testing, and neurologic evaluation, and imaging measures were compared with those of an independently acquired group of 29 controls with minimal brain amyloid burden as measured with carbon 11–labeled Pittsburgh Compound B ([11C]PiB) positron emission tomography (PET). EXPOSURES: Imaging with fluorine 18–labeled AV-1451 ([18F]AV-1451) (formerly known as [18F]T807), [11C]PiB PET, magnetic resonance imaging (MRI), neurologic examination, and detailed cognitive testing using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale. MAIN OUTCOMES AND MEASURES: Main outcomes were differentiation of diagnostic groups on the basis of [18F]AV-1451 binding, the association of [18F]AV-1451 binding with [11C]PiB binding, and the association of [18F]AV-1451 binding with cognitive impairment. All but 3 individuals underwent amyloid imaging with [11C]PiB PET. The hypotheses being tested were formulated before data collection. Mini-Mental State Examination (range, 0-30, with 30 being best) and Clinical Dementia Rating scale sum-of-boxes scale (range, 0-18, with 0 being best) were used for assessment of cognitive function. RESULTS: In patients with DLB, cortical [18F]AV-1451 uptake was highly variable and greater than in the controls, particularly in the inferior temporal gyrus and precuneus. Foci of increased [18F]AV-1451 binding in the inferior temporal gyrus and precuneus were also evident in PD-impaired patients. Elevated cortical [18F]AV-1451 binding was observed in 4 of 17 patients with Lewy body disease with low cortical [11C]PiB retention. For DLB and PD-impaired patients, greater [18F]AV-1451 uptake in the inferior temporal gyrus and precuneus was associated with increased cognitive impairment as measured with the MMSE and the Clinical Dementia Rating scale sum-of-boxes score. CONCLUSIONS AND RELEVANCE: Patients with Lewy body disease manifest a spectrum of tau pathology. Cortical aggregates of tau are common in patients with DLB and in PD-impaired patients, even in those without elevated amyloid levels. When present, tau deposition is associated with cognitive impairment. These findings support a role for tau copathology in the Lewy body diseases.
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- 2016
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12. Rarity of the Alzheimer Disease–Protective APP A673T Variant in the United States
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Wang, Li-San, Naj, Adam C., Graham, Robert R., Crane, Paul K., Kunkle, Brian W., Cruchaga, Carlos, Murcia, Josue D. Gonzalez, Cannon-Albright, Lisa, Baldwin, Clinton T., Zetterberg, Henrik, Blennow, Kaj, Kukull, Walter A., Faber, Kelley M., Schupf, Nicole, Norton, Maria C., Tschanz, JoAnn T., Munger, Ronald G., Corcoran, Christopher D., Rogaeva, Ekaterina, Lin, Chiao-Feng, Dombroski, Beth A., Cantwell, Laura B., Partch, Amanda, Valladares, Otto, Hakonarson, Hakon, St George-Hyslop, Peter, Green, Robert C., Goate, Alison M., Foroud, Tatiana M., Carney, Regina M., Larson, Eric B., Behrens, Timothy W., Kauwe, John S. K., Haines, Jonathan L., Farrer, Lindsay A., Pericak-Vance, Margaret A., Mayeux, Richard, Schellenberg, Gerard D., Albert, Marilyn S., Albin, Roger L., Apostolova, Liana G., Arnold, Steven E., Barber, Robert, Barmada, M. Michael, Barnes, Lisa L., Beach, Thomas G., Becker, James T., Beecham, Gary W., Beekly, Duane, Bennett, David A., Bigio, Eileen H., Bird, Thomas D., Blacker, Deborah, Boeve, Bradley F., Bowen, James D., Boxer, Adam, Burke, James R., Buxbaum, Joseph D., Cairns, Nigel J., Cao, Chuanhai, Carlson, Chris S., Carroll, Steven L., Chui, Helena C., Clark, David G., Cribbs, David H., Crocco, Elizabeth A., DeCarli, Charles, DeKosky, Steven T., Demirci, F. Yesim, Dick, Malcolm, Dickson, Dennis W., Duara, Ranjan, Ertekin-Taner, Nilufer, Fallon, Kenneth B., Farlow, Martin R., Ferris, Steven, Frosch, Matthew P., Galasko, Douglas R., Ganguli, Mary, Gearing, Marla, Geschwind, Daniel H., Ghetti, Bernardino, Gilbert, John R., Glass, Jonathan D., Graff-Radford, Neill R., Growdon, John H., Hamilton, Ronald L., Hamilton-Nelson, Kara L., Harrell, Lindy E., Head, Elizabeth, Honig, Lawrence S., Hulette, Christine M., Hyman, Bradley T., Jarvik, Gail P., Jicha, Gregory A., Jin, Lee-Way, Jun, Gyungah, Kamboh, M. Ilyas, Karydas, Anna, Kaye, Jeffrey A., Kim, Ronald, Koo, Edward H., Kowall, Neil W., Kramer, Joel H., Kramer, Patricia, LaFerla, Frank M., Lah, James J., Leverenz, James B., Levey, Allan I., Li, Ge, Lieberman, Andrew P., Lopez, Oscar L., Lunetta, Kathryn L., Lyketsos, Constantine G., Mack, Wendy J., Marson, Daniel C., Martin, Eden R., Martiniuk, Frank, Mash, Deborah C., Masliah, Eliezer, McCormick, Wayne C., McCurry, Susan M., McDavid, Andrew N., McKee, Ann C., Mesulam, M. Marsel, Miller, Bruce L., Miller, Carol A., Miller, Joshua W., Montine, Thomas J., Morris, John C., Murrell, Jill R., Olichney, John M., Parisi, Joseph E., Perry, William, Peskind, Elaine, Petersen, Ronald C., Pierce, Aimee, Poon, Wayne W., Potter, Huntington, Quinn, Joseph F., Raj, Ashok, Raskind, Murray, Reiman, Eric M., Reisberg, Barry, Reitz, Christiane, Ringman, John M., Roberson, Erik D., Rosen, Howard J., Rosenberg, Roger N., Sano, Mary, Saykin, Andrew J., Schneider, Julie A., Schneider, Lon S., Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Tanzi, Rudolph E., Thornton-Wells, Tricia A., Trojanowski, John Q., Troncoso, Juan C., Tsuang, Debby W., Van Deerlin, Vivianna M., Van Eldik, Linda J., Vardarajan, Badri N., Vinters, Harry V., Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Williamson, Jennifer, Wishnek, Sarah, Woltjer, Randall L., Wright, Clinton B., Younkin, Steven G., Yu, Chang-En, and Yu, Lei
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IMPORTANCE: Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States. OBJECTIVE: To determine the frequency of the APP A673T variant in a large group of elderly cognitively normal controls and AD cases from the United States and in 2 case-control cohorts from Sweden. DESIGN, SETTING, AND PARTICIPANTS: Case-control association analysis of variant APP A673T in US and Swedish white individuals comparing AD cases with cognitively intact elderly controls. Participants were ascertained at multiple university-associated medical centers and clinics across the United States and Sweden by study-specific sampling methods. They were from case-control studies, community-based prospective cohort studies, and studies that ascertained multiplex families from multiple sources. MAIN OUTCOMES AND MEASURES: Genotypes for the APP A673T variant were determined using the Infinium HumanExome V1 Beadchip (Illumina, Inc) and by TaqMan genotyping (Life Technologies). RESULTS: The A673T variant genotypes were evaluated in 8943 US AD cases, 10 480 US cognitively normal controls, 862 Swedish AD cases, and 707 Swedish cognitively normal controls. We identified 3 US individuals heterozygous for A673T, including 1 AD case (age at onset, 89 years) and 2 controls (age at last examination, 82 and 77 years). The remaining US samples were homozygous for the alanine (A673) allele. In the Swedish samples, 3 controls were heterozygous for A673T and all AD cases were homozygous for the A673 allele. We also genotyped a US family previously reported to harbor the A673T variant and found a mother-daughter pair, both cognitively normal at ages 72 and 84 years, respectively, who were both heterozygous for A673T; however, all individuals with AD in the family were homozygous for A673. CONCLUSIONS AND RELEVANCE: The A673T variant is extremely rare in US cohorts and does not play a substantial role in risk for AD in this population. This variant may be primarily restricted to Icelandic and Scandinavian populations.
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- 2015
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13. Amyloid is linked to cognitive decline in patients with Parkinson disease without dementia.
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Gomperts SN, Locascio JJ, Rentz D, Santarlasci A, Marquie M, Johnson KA, Growdon JH, Gomperts, Stephen N, Locascio, Joseph J, Rentz, Dorene, Santarlasci, Andrea, Marquie, Marta, Johnson, Keith A, and Growdon, John H
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- 2013
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14. Amyloid is linked to cognitive decline in patients with Parkinson disease without dementia.
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Gomperts, Stephen N., Locascio, Joseph J., Rentz, Dorene, Santarlasci, Andrea, Marquie, Marta, Johnson, Keith A., and Growdon, John H.
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- 2013
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15. Novel Progranulin Mutation Detected in 2 Patients With FTLD.
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Skoglund, Lena, Matsui, Toshifumi, Freeman, Stefanie H., Wallin, Anders, Blom, Elin S., Frosch, Matthew P., Growdon, John H., Hyman, Bradley T., Lannfelt, Lars, Ingelsson, Martin, and Glaser, Anna
- Abstract
The article presents a study which investigates the progranulin gene (PGRN) mutation in patients with frontotemporal lobar degeneration (FTLD). It says that PGRN mutation accounts for ubiquitin-positive frontotemporal dementias (FTD) in which it introduces premature termination in the PGRN mRNA sequence. The study shows that genetic analysis of FTLD patients reveals a novel PGRN frameshift mutation and reduction of PGRN mRNA.
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- 2011
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16. Effects of simvastatin on cholesterol metabolism and Alzheimer disease biomarkers.
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Serrano-Pozo A, Vega GL, Lütjohann D, Locascio JJ, Tennis MK, Deng A, Atri A, Hyman BT, Irizarry MC, Growdon JH, Serrano-Pozo, Alberto, Vega, Gloria L, Lütjohann, Dieter, Locascio, Joseph J, Tennis, Marsha K, Deng, Amy, Atri, Alireza, Hyman, Bradley T, Irizarry, Michael C, and Growdon, John H
- Abstract
Preclinical and epidemiologic studies suggest a protective effect of statins on Alzheimer disease (AD). Experimental evidence indicates that some statins can cross the blood-brain barrier, alter brain cholesterol metabolism, and may ultimately decrease the production of amyloid-beta (Abeta) peptide. Despite these promising leads, clinical trials have yielded inconsistent results regarding the benefits of statin treatment in AD. Seeking to detect a biological signal of statins effect on AD, we conducted a 12-week open-label trial with simvastatin 40 mg/d and then 80 mg/d in 12 patients with AD or amnestic mild cognitive impairment and hypercholesterolemia. We quantified cholesterol precursors and metabolites and AD biomarkers of Abeta and tau in both plasma and cerebrospinal fluid at baseline and after the 12-week treatment period. We found a modest but significant inhibition of brain cholesterol biosynthesis after simvastatin treatment, as indexed by a decrease of cerebrospinal fluid lathosterol and plasma 24S-hydroxycholesterol. Despite this effect, there were no changes in AD biomarkers. Our findings indicate that simvastatin treatment can affect brain cholesterol metabolism within 12 weeks, but did not alter molecular indices of AD pathology during this short-term treatment. [ABSTRACT FROM AUTHOR]
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- 2010
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17. Effects of Simvastatin on Cholesterol Metabolism and Alzheimer Disease Biomarkers.
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Serrano-Pozo, Alberto, Vega, Gloria L., Lütjohann, Dieter, Locascio, Joseph J., Tennis, Marsha K., Amy Deng, Atri, Alireza, Hyman, Bradley T., Irizarry, Michael C., and Growdon, John H.
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Preclinical and epidemiologic studies suggest a protective effect of statins on Alzheimer disease (AD). Experimental evidence indicates that some statins can cross the blood-brain barrier, alter brain cholesterol metabolism, and may ultimately decrease the production of amyloid-13 (A3) peptide. Despite these promising leads, clinical trials have yielded inconsistent results regarding the benefits of statin treatment in AD. Seeking to detect a biological signal of statins effect on AD, we conducted a 12-week open-label trial with simvastatin 4Omg/d and then 8Omg/d in 12 patients with AD or amnestic mild cognitive impairment and hypercholesterolemia. We quantified cholesterol precursors and metabolites and AD biomarkers of AJ3 and tau in both plasma and cerebrospinal fluid at baseline and after the 12-week treatment period. We found a modest but significant inhibition of brain cholesterol biosynthesis after simvastatin treatment, as indexed by a decrease of cerebrospinal fluid lathosterol and plasma 24S-hydroxycholesterol. Despite this effect, there were no changes in AD biomarkers. Our findings indicate that simvastatin treatment can affect brain cholesterol metabolism within 12 weeks, but did not alter molecular indices of AD pathology during this short-term treatment. [ABSTRACT FROM AUTHOR]
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- 2010
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18. Long-term course and effectiveness of combination therapy in Alzheimer disease.
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Atri A, Shaughnessy LW, Locascio JJ, Growdon JH, Atri, Alireza, Shaughnessy, Lynn W, Locascio, Joseph J, and Growdon, John H
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Objective: To compare the real-world clinical effectiveness and long-term clinical trajectory in patients with Alzheimer disease (AD) treated with combination (COMBO) therapy consisting of cholinesterase-inhibitor (CI) plus memantine (MEM) versus CI alone versus no treatment with either.Methods: Three hundred eighty-two subjects with probable AD underwent serial clinical evaluations at a memory disorders unit. Cognition was assessed by the Information-Memory-Concentration subscale of the Blessed Dementia Scale (BDS) and function was assessed by the Weintraub Activities of Daily Living Scale (ADL) at 6-month intervals. One hundred forty-four subjects received standard care without CI or MEM (NO-RX), 122 received CI monotherapy, and 116 received COMBO therapy with CI plus MEM. Mean follow-up was 30 months (4.1 visits) and mean cumulative medication treatment time was 22.5 months. Rates of decline were analyzed using mixed-effects regression models, and Cohen's d effect sizes were calculated annually for years 1 to 4.Results: Covarying for baseline scores, age, education, and duration of illness, the COMBO group had significantly lower mean annualized rates of deterioration in BDS and ADL scores compared with the CI (P<0.001; Cohen's dBDS=0.10-0.34 and dADL=0.23-0.46 at 1 to 2 y) and NO-RX groups (P<0.001; Cohen's dBDS=0.56-0.73 and dADL=0.32-0.48 at 1 to 2 y). For the COMBO group, Cohen's d effect sizes increased with treatment duration. Similar comparisons significantly favored the CI over the NO-RX group on the BDS.Conclusions: COMBO therapy slows cognitive and functional decline in AD compared with CI monotherapy and no treatment. These benefits had small-to-medium effect sizes that increased with time on treatment and were sustained for years. [ABSTRACT FROM AUTHOR]- Published
- 2008
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19. Effects of Multiple Genetic Loci on Age at Onset in Late-Onset Alzheimer Disease: A Genome-Wide Association Study
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Naj, Adam C., Jun, Gyungah, Reitz, Christiane, Kunkle, Brian W., Perry, William, Park, Yo Son, Beecham, Gary W., Rajbhandary, Ruchita A., Hamilton-Nelson, Kara L., Wang, Li-San, Kauwe, John S. K., Huentelman, Matthew J., Myers, Amanda J., Bird, Thomas D., Boeve, Bradley F., Baldwin, Clinton T., Jarvik, Gail P., Crane, Paul K., Rogaeva, Ekaterina, Barmada, M. Michael, Demirci, F. Yesim, Cruchaga, Carlos, Kramer, Patricia L., Ertekin-Taner, Nilufer, Hardy, John, Graff-Radford, Neill R., Green, Robert C., Larson, Eric B., St. George-Hyslop, Peter H., Buxbaum, Joseph D., Evans, Denis A., Schneider, Julie A., Lunetta, Kathryn L., Kamboh, M. Ilyas, Saykin, Andrew J., Reiman, Eric M., De Jager, Philip L., Bennett, David A., Morris, John C., Montine, Thomas J., Goate, Alison M., Blacker, Deborah, Tsuang, Debby W., Hakonarson, Hakon, Kukull, Walter A., Foroud, Tatiana M., Martin, Eden R., Haines, Jonathan L., Mayeux, Richard P., Farrer, Lindsay A., Schellenberg, Gerard D., Pericak-Vance, Margaret A., Albert, Marilyn S., Albin, Roger L., Apostolova, Liana G., Arnold, Steven E., Barber, Robert, Barnes, Lisa L., Beach, Thomas G., Becker, James T., Beekly, Duane, Bigio, Eileen H., Bowen, James D., Boxer, Adam, Burke, James R., Cairns, Nigel J., Cantwell, Laura B., Cao, Chuanhai, Carlson, Chris S., Carney, Regina M., Carrasquillo, Minerva M., Carroll, Steven L., Chui, Helena C., Clark, David G., Corneveaux, Jason, Cribbs, David H., Crocco, Elizabeth A., DeCarli, Charles, DeKosky, Steven T., Dick, Malcolm, Dickson, Dennis W., Duara, Ranjan, Faber, Kelley M., Fallon, Kenneth B., Farlow, Martin R., Ferris, Steven, Frosch, Matthew P., Galasko, Douglas R., Ganguli, Mary, Gearing, Marla, Geschwind, Daniel H., Ghetti, Bernardino, Gilbert, John R., Glass, Jonathan D., Growdon, John H., Hamilton, Ronald L., Harrell, Lindy E., Head, Elizabeth, Honig, Lawrence S., Hulette, Christine M., Hyman, Bradley T., Jicha, Gregory A., Jin, Lee-Way, Karydas, Anna, Kaye, Jeffrey A., Kim, Ronald, Koo, Edward H., Kowall, Neil W., Kramer, Joel H., LaFerla, Frank M., Lah, James J., Leverenz, James B., Levey, Allan I., Li, Ge, Lieberman, Andrew P., Lin, Chiao-Feng, Lopez, Oscar L., Lyketsos, Constantine G., Mack, Wendy J., Martiniuk, Frank, Mash, Deborah C., Masliah, Eliezer, McCormick, Wayne C., McCurry, Susan M., McDavid, Andrew N., McKee, Ann C., Mesulam, Marsel, Miller, Bruce L., Miller, Carol A., Miller, Joshua W., Murrell, Jill R., Olichney, John M., Pankratz, Vernon S., Parisi, Joseph E., Paulson, Henry L., Peskind, Elaine, Petersen, Ronald C., Pierce, Aimee, Poon, Wayne W., Potter, Huntington, Quinn, Joseph F., Raj, Ashok, Raskind, Murray, Reisberg, Barry, Ringman, John M., Roberson, Erik D., Rosen, Howard J., Rosenberg, Roger N., Sano, Mary, Schneider, Lon S., Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Tanzi, Rudolph E., Thornton-Wells, Tricia A., Trojanowski, John Q., Troncoso, Juan C., Valladares, Otto, Van Deerlin, Vivianna M., Van Eldik, Linda J., Vardarajan, Badri N., Vinters, Harry V., Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Williamson, Jennifer, Wishnek, Sarah, Woltjer, Randall L., Wright, Clinton B., Younkin, Steven G., Yu, Chang-En, and Yu, Lei
- Abstract
IMPORTANCE: Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants. OBJECTIVES: To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium. DESIGN, SETTING, AND PARTICIPANTS: The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results were combined using a random-effects, inverse variance–weighted meta-analysis approach to determine whether they contribute to variation in AAO. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes. MAIN OUTCOMES AND MEASURES: Age at disease onset abstracted from medical records among participants with LOAD diagnosed per standard criteria. RESULTS: Analysis confirmed the association of APOE with earlier AAO (P = 3.3 × 10−96), with associations in CR1 (rs6701713, P = 7.2 × 10−4), BIN1 (rs7561528, P = 4.8 × 10−4), and PICALM (rs561655, P = 2.2 × 10−3) reaching statistical significance (P < .005). Risk alleles individually reduced AAO by 3 to 6 months. Burden analyses demonstrated that APOE contributes to 3.7% of the variation in AAO (R2 = 0.256) over baseline (R2 = 0.221), whereas the other 9 loci together contribute to 2.2% of the variation (R2 = 0.242). CONCLUSIONS AND RELEVANCE: We confirmed an association of APOE (OMIM 107741) variants with AAO among affected participants with LOAD and observed novel associations of CR1 (OMIM 120620), BIN1 (OMIM 601248), and PICALM (OMIM 603025) with AAO. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on AAO are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on AAO may be significant, additional genetic contributions to AAO are individually likely to be small.
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- 2014
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20. Unrecognized vitamin D3deficiency is common in Parkinson disease
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Ding, Hongliu, Dhima, Kaltra, Lockhart, Kaitlin C., Locascio, Joseph J., Hoesing, Ashley N., Duong, Karen, Trisini-Lipsanopoulos, Ana, Hayes, Michael T., Sohur, U. Shivraj, Wills, Anne-Marie, Mollenhauer, Brit, Flaherty, Alice W., Hung, Albert Y., Mejia, Nicte, Khurana, Vikram, Gomperts, Stephen N., Selkoe, Dennis J., Schwarzschild, Michael A., Schlossmacher, Michael G., Hyman, Bradley T., Sudarsky, Lewis R., Growdon, John H., and Scherzer, Clemens R.
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To conclusively test for a specific association between the biological marker 25-hydroxy-vitamin D3, a transcriptionally active hormone produced in human skin and liver, and the prevalence and severity of Parkinson disease (PD).
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- 2013
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21. A Phenotypic Change But Not Proliferation Underlies Glial Responses in Alzheimer Disease
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Serrano-Pozo, Alberto, Gómez-Isla, Teresa, Growdon, John H., Frosch, Matthew P., and Hyman, Bradley T.
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Classical immunohistochemical studies in the Alzheimer disease (AD) brain reveal prominent glial reactions, but whether this pathological feature is due primarily to cell proliferation or to a phenotypic change of existing resting cells remains controversial. We performed double-fluorescence immunohistochemical studies of astrocytes and microglia, followed by unbiased stereology-based quantitation in temporal cortex of 40 AD patients and 32 age-matched nondemented subjects. Glial fibrillary acidic protein (GFAP) and major histocompatibility complex II (MHC2) were used as markers of astrocytic and microglial activation, respectively. Aldehyde dehydrogenase 1 L1 and glutamine synthetase were used as constitutive astrocytic markers, and ionized calcium-binding adaptor molecule 1 (IBA1) as a constitutive microglial marker. As expected, AD patients had higher numbers of GFAP+astrocytes and MHC2+microglia than the nondemented subjects. However, both groups had similar numbers of total astrocytes and microglia and, in the AD group, these total numbers remained essentially constant over the clinical course of the disease. The GFAP immunoreactivity of astrocytes, but not the MHC2 immunoreactivity of microglia, increased in parallel with the duration of the clinical illness in the AD group. Cortical atrophy contributed to the perception of increased glia density. We conclude that a phenotypic change of existing glial cells, rather than a marked proliferation of glial precursors, accounts for the majority of the glial responses observed in the AD brain.
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- 2013
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22. Substantia Nigra Volume Loss Before Basal Forebrain Degeneration in Early Parkinson Disease
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Ziegler, David A., Wonderlick, Julien S., Ashourian, Paymon, Hansen, Leslie A., Young, Jeremy C., Murphy, Alex J., Koppuzha, Cecily K., Growdon, John H., and Corkin, Suzanne
- Abstract
OBJECTIVE To test the hypothesis that degeneration of the substantia nigra pars compacta (SNc) precedes that of the cholinergic basal forebrain (BF) in Parkinson disease (PD) using new multispectral structural magnetic resonance (MR) imaging tools to measure the volumes of the SNc and BF. DESIGN Matched case-control study. SETTING The Athinoula A. Martinos Imaging Center at the McGovern Institute for Brain Research, Massachusetts Institute of Technology (MIT), and the Massachusetts General Hospital/MIT Morris Udall Center of Excellence in Parkinson Disease Research. PATIENTS Participants included 29 patients with PD (Hoehn and Yahr [H&Y] stages 1-3) and 27 matched healthy control subjects. MAIN OUTCOME MEASURES We acquired multiecho T1-weighted, multiecho proton density, T2-weighted, and T2-weighted fluid-attenuated inversion recovery (FLAIR) sequences from each participant. For the SNc, we created a weighted mean of the multiple echoes, yielding a single volume with a high ratio of contrast to noise. We visualized the BF using T2-weighted FLAIR images. For each participant, we manually labeled the 2 structures and calculated their volumes. RESULTS Relative to the controls, 13 patients with H&Y stage 1 PD had significantly decreased SNc volumes. Sixteen patients with H&Y stage 2 or 3 PD showed little additional volume loss. In contrast, the BF volume loss occurred later in the disease, with a significant decrease apparent in patients having H&Y stage 2 or 3 PD compared with the controls and the patients having H&Y stage 1 PD. The latter group did not differ significantly from the controls. CONCLUSION Our results support the proposed neuropathological trajectory in PD and establish novel multispectral methods as MR imaging biomarkers for tracking the degeneration of the SNc and BF.
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- 2013
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23. Amyloid is linked to cognitive decline in patients with Parkinson disease without dementia
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Gomperts, Stephen N., Locascio, Joseph J., Rentz, Dorene, Santarlasci, Andrea, Marquie, Marta, Johnson, Keith A., and Growdon, John H.
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To determine whether amyloid burden, as indexed by Pittsburgh compound B (PiB) retention, identifies patients with Parkinson disease with mild cognitive impairment (PD-MCI) compared to those with normal cognition (PD-nl). A related aim is to determine whether amyloid burden predicts cognitive decline in a cohort of subjects with PD without dementia.
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- 2013
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24. Reactive Glia not only Associates with Plaques but also Parallels Tangles in Alzheimer's Disease
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Serrano-Pozo, Alberto, Mielke, Matthew L., Gómez-Isla, Teresa, Betensky, Rebecca A., Growdon, John H., Frosch, Matthew P., and Hyman, Bradley T.
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Senile plaques are a prominent pathological feature of Alzheimer's disease (AD), but little is understood about the association of glial cells with plaques or about the dynamics of glial responses through the disease course. We investigated the progression of reactive glial cells and their relationship with AD pathological hallmarks to test whether glial cells are linked only to amyloid deposits or also to tangle deposition, thus integrating both lesions as a marker of disease severity. We conducted a quantitative stereology-based post-mortem study on the temporal neocortex of 15 control subjects without dementia and 91 patients with AD, including measures of amyloid load, neurofibrillary tangles, reactive astrocytes, and activated microglia. We also addressed the progression of glial responses in the vicinity (≤50 μm) of dense-core plaques and tangles. Although the amyloid load reached a plateau early after symptom onset, astrocytosis and microgliosis increased linearly throughout the disease course. Moreover, glial responses correlated positively with tangle burden, whereas astrocytosis correlated negatively with cortical thickness. However, neither correlated with amyloid load. Glial responses increased linearly around existing plaques and in the vicinity of tangles. These results indicate that the progression of astrocytosis and microgliosis diverges from that of amyloid deposition, arguing against a straightforward relationship between glial cells and plaques. They also suggest that reactive glia might contribute to the ongoing neurodegeneration.
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- 2011
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25. Meta-analysis Confirms CR1, CLU, and PICALM as Alzheimer Disease Risk Loci and Reveals Interactions With APOE GenotypesCR1, CLU, and PICALM as AD Susceptibility Loci
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Jun, Gyungah, Naj, Adam C., Beecham, Gary W., Wang, Li-San, Buros, Jacqueline, Gallins, Paul J., Buxbaum, Joseph D., Ertekin-Taner, Nilufer, Fallin, M. Daniele, Friedland, Robert, Inzelberg, Rivka, Kramer, Patricia, Rogaeva, Ekaterina, St. George-Hyslop, Peter, Arnold, Steven E., Baldwin, Clinton T., Barber, Robert, Beach, Thomas, Bigio, Eileen H., Bird, Thomas D., Boxer, Adam, Burke, James R., Cairns, Nigel, Carroll, Steven L., Chui, Helena C., Clark, David G., Cotman, Carl W., Cummings, Jeffrey L., DeCarli, Charles, Diaz-Arrastia, Ramon, Dick, Malcolm, Dickson, Dennis W., Ellis, William G., Fallon, Kenneth B., Farlow, Martin R., Ferris, Steven, Frosch, Matthew P., Galasko, Douglas R., Gearing, Marla, Geschwind, Daniel H., Ghetti, Bernardino, Gilman, Sid, Giordani, Bruno, Glass, Jonathan, Graff-Radford, Neill R., Green, Robert C., Growdon, John H., Hamilton, Ronald L., Harrell, Lindy E., Head, Elizabeth, Honig, Lawrence S., Hulette, Christine M., Hyman, Bradley T., Jicha, Gregory A., Jin, Lee-Way, Johnson, Nancy, Karlawish, Jason, Karydas, Anna, Kaye, Jeffrey A., Kim, Ronald, Koo, Edward H., Kowall, Neil W., Lah, James J., Levey, Allan I., Lieberman, Andrew, Lopez, Oscar L., Mack, Wendy J., Markesbery, William, Marson, Daniel C., Martiniuk, Frank, Masliah, Eliezer, McKee, Ann C., Mesulam, Marsel, Miller, Joshua W., Miller, Bruce L., Miller, Carol A., Parisi, Joseph E., Perl, Daniel P., Peskind, Elaine, Petersen, Ronald C., Poon, Wayne, Quinn, Joseph F., Raskind, Murray, Reisberg, Barry, Ringman, John M., Roberson, Erik D., Rosenberg, Roger N., Sano, Mary, Schneider, Julie A., Schneider, Lon S., Seeley, William, Shelanski, Michael L., Smith, Charles D., Spina, Salvatore, Stern, Robert A., Tanzi, Rudolph E., Trojanowski, John Q., Troncoso, Juan C., Van Deerlin, Vivianna M., Vinters, Harry V., Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Woltjer, Randall L., Younkin, Steven G., Cantwell, Laura B., Dombroski, Beth A., Saykin, Andrew J., Reiman, Eric M., Bennett, David A., Morris, John C., Lunetta, Kathryn L., Martin, Eden R., Montine, Thomas J., Goate, Alison M., Blacker, Deborah, Tsuang, Debby W., Beekly, Duane, Cupples, L. Adrienne, Hakonarson, Hakon, Kukull, Walter, Foroud, Tatiana M., Haines, Jonathan, Mayeux, Richard, Farrer, Lindsay A., Pericak-Vance, Margaret A., and Schellenberg, Gerard D.
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- 2010
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26. Cognitive–Behavioral Therapy for Patients With Parkinson’s Disease and Comorbid Major Depressive Disorder
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Farabaugh, Amy, Locascio, Joseph J., Yap, Liang, Growdon, John, Fava, Maurizio, Crawford, Christine, Matthews, John, McCutchen, Jesse, Buchin, Jacqueline, Pava, Joel, and Alpert, Jonathan E.
- Abstract
Depression has been recognized as a common feature of Parkinson’s disease (PD), and is the most prevalent psychiatric disorder in PD patients.
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- 2010
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27. Pattern of Depressive Symptoms in Parkinson's Disease
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Farabaugh, Amy H., Locascio, Joseph J., Yap, Liang, Weintraub, Daniel, McDonald, William M., Agoston, Monica, Alpert, Jonathan E., Growdon, John, and Fava, Maurizio
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Depressive symptoms are common in Parkinson's disease (PD); however, it is unclear whether there are specific depressive symptom patterns in patients with PD and comorbid depression (dPD).
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- 2009
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28. Plasma Amyloid β-Protein and C-reactive Protein in Relation to the Rate of Progression of Alzheimer Disease
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Locascio, Joseph J., Fukumoto, Hiroaki, Yap, Liang, Bottiglieri, Teodoro, Growdon, John H., Hyman, Bradley T., and Irizarry, Michael C.
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OBJECTIVE To examine whether plasma markers of amyloid precursor protein metabolism (amyloid β-protein ending in Val-40 [Aβ40] and Ala-42 [Aβ42]), inflammation (high-sensitivity C-reactive protein), and folic acid metabolism (folic acid, vitamin B12, and total homocysteine levels) are associated with the rate of cognitive and functional decline in persons with Alzheimer disease. DESIGN Longitudinal study across a mean (SD) of 4.2 (2.6) years with assessments at approximately 6- to 12-month intervals. SETTING Outpatient care. PATIENTS A cohort of 122 patients having a clinical diagnosis of probable Alzheimer disease, each with at least 2 assessments across time. MAIN OUTCOME MEASURES Scores on the cognitive Information-Memory-Concentration subscale of the Blessed Dementia Scale and the functional Weintraub Activities of Daily Living Scale. RESULTS Low plasma levels of Aβ40, Aβ42, and high-sensitivity C-reactive protein were associated with a significantly more rapid cognitive decline, as indexed using the Blessed Dementia Scale, than were high levels. Low levels of Aβ42 and high-sensitivity C-reactive protein were significantly associated with more rapid functional decline on the Weintraub Activities of Daily Living Scale than were high levels. These plasma markers contributed about 5% to 12% of the variance accounted for on the Blessed Dementia Scale and the Activities of Daily Living Scale by fixed-effects predictors. Measures of folic acid metabolism were not associated with changes on either the Blessed Dementia Scale or the Activities of Daily Living Scale. CONCLUSIONS Plasma markers of amyloid precursor protein metabolism and C-reactive protein may be associated with the rate of cognitive and functional decline in patients with Alzheimer disease.Arch Neurol. 2008;65(6):776-785--
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- 2008
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29. Molecular Imaging With Pittsburgh Compound B Confirmed at Autopsy: A Case Report
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Bacskai, Brian J., Frosch, Matthew P., Freeman, Stefanie H., Raymond, Scott B., Augustinack, Jean C., Johnson, Keith A., Irizarry, Michael C., Klunk, William E., Mathis, Chester A., DeKosky, Steven T., Greenberg, Steven M., Hyman, Bradley T., and Growdon, John H.
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OBJECTIVE To determine the correspondence between uptake of Pittsburgh Compound B (PiB) in life and measures of β-amyloid (Aβ) in postmortem tissue analysis. PATIENT A 76-year-old man with a clinical diagnosis of dementia with Lewy bodies underwent fluorodeoxyglucose 18F and PiB positron emission tomographic brain scans. Imaging revealed marked region specific binding of PiB and abnormal fluorodeoxyglucose uptake. INTERVENTION Autopsy was performed 3 months after the PiB scan. RESULTS Autopsy confirmed the clinical diagnosis; in addition, there was severe cerebral amyloid angiopathy and only moderate numbers of parenchymal Aβ plaques. Biochemical measures revealed a positive correlation between Aβ levels and regional PiB binding. CONCLUSION This report confirms that PiB detects Aβ in the living patient and demonstrates that amyloid deposited as cerebral amyloid angiopathy can be the dominant source of signal.Arch Neurol. 2007;64:431-434 --
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- 2007
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30. Influence of Heterozygosity for Parkin Mutation on Onset Age in Familial Parkinson Disease: The GenePD Study
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Sun, Mei, Latourelle, Jeanne C., Wooten, G. Frederick, Lew, Mark F., Klein, Christine, Shill, Holly A., Golbe, Lawrence I., Mark, Margery H., Racette, Brad A., Perlmutter, Joel S., Parsian, Abbas, Guttman, Mark, Nicholson, Garth, Xu, Gang, Wilk, Jemma B., Saint-Hilaire, Marie H., DeStefano, Anita L., Prakash, Ranjana, Williamson, Sally, Suchowersky, Oksana, Labelle, Nancy, Growdon, John H., Singer, Carlos, Watts, Ray L., Goldwurm, Stefano, Pezzoli, Gianni, Baker, Kenneth B., Pramstaller, Peter P., Burn, David J., Chinnery, Patrick F., Sherman, Scott, Vieregge, Peter, Litvan, Irene, Gillis, Tammy, MacDonald, Marcy E., Myers, Richard H., and Gusella, James F.
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BACKGROUND The PARK2 gene at 6q26 encodes parkin, whose inactivation is implicated in an early-onset autosomal recessive form of Parkinson disease (PD). OBJECTIVE To evaluate the influence of heterozygosity for parkin mutation on onset age in a sample of families with at least 2 PD-affected members. DESIGN Clinical and genetic study. SETTING Twenty collaborative clinical sites. PATIENTS Patients with familial PD collected in the GenePD study. Studied families were selected for (1) affected sibling pairs sharing 2 alleles identical by state at PARK2 (D6S305) or (2) 1 or more family members with onset age younger than 54 years, regardless of D6S305 status. At least 1 member from each of 183 families underwent comprehensive screening for deletion/insertion variants and point mutations in PARK2. MAIN OUTCOME MEASURES Mutations in the parkin gene were screened by means of single-stranded conformation polymorphism and sequencing in all 12 coding exons and flanking intronic sequences for point mutations and duplex quantitative polymerase chain reaction in all exons for rearrangement, duplication, and deletion. RESULTS Mutations were found in 23 families (12.6% of those screened). Among the mutation-positive families, 10 (43%) contained compound heterozygotes; 3 (13%), homozygotes; and 10 (43%), heterozygotes. The onset age in patients with parkin gene mutations ranged from 20 to 76 years. Patients with 1 parkin mutation had an 11.7-year age at onset than did patients with none (P = .04), and patients with 2 or more parkin mutations had a 13.2-year decrease in age at onset compared with patients with 1 mutation (P = .04). CONCLUSIONS These data indicate that parkin mutations are not rare in multiply affected sibships, and that heterozygous mutation carrier status in PARK2 significantly influences age at onset of PD.Arch Neurol. 2006;63:826-832 --
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- 2006
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31. Elevation of Cystatin C in Susceptible Neurons in Alzheimer's Disease
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Deng, Amy, Irizarry, Michael C., Nitsch, Roger M., Growdon, John H., and Rebeck, G. William
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A common polymorphism in the cystatin C gene is associated with increased risk of developing Alzheimer's disease (AD). To explore possible neuropathological consequences of this genetic association, we examined expression of cystatin C in brains from 22 AD and 11 control patients by immunohistochemistry. In the temporal cortex of all AD brains, there was strong cystatin C immunostaining of neurons and activated glia, whereas staining was absent or minimal in 7 of the 11 control brains. Neuronal staining of cystatin C in AD brains was primarily limited to pyramidal neurons in cortical layers III and V, which are the neurons most susceptible to cell death in AD. The increase in cystatin C staining in AD was independent of cystatin C genotype. Immunostaining of cystatin C within neurons showed a punctate distribution, which co-localized with the endosomal/lysosomal proteinase, cathepsin B. A primarily glial source for cystatin C was suggested by parallel studies using in situhybridization of mouse brain. In human AD brain, there was little co-localization of cystatin C with parenchymal Aβ deposits, although a small fraction of cerebral blood vessels and neurofibrillary tangles were cystatin C-positive. The regional distribution of cystatin C neuronal immunostaining also duplicated the pattern of neuronal susceptibility in AD brains: the strongest staining was found in the entorhinal cortex, in the hippocampus, and in the temporal cortex; fewer pyramidal neurons were stained in frontal, parietal, and occipital lobes. These neuropathological observations reinforce the association between cystatin C and AD, and support a model of cystatin C involvement in the process of neuronal death in AD.
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- 2001
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32. The selective muscarinic M1 agonist AF102B decreases levels of total Aβ in cerebrospinal fluid of patients with Alzheimer's disease
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Nitsch, Roger M., Deng, Meihua, Tennis, Marsha, Schoenfeld, David, and Growdon, John H.
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β‐Amyloid (Aβ) deposits in diffuse and compact senile plaques in the brain are one of the defining histopathological features of Alzheimer's disease (AD). Preventing Aβ deposition is a goal of drug therapy for AD, because excessive amounts of Aβ may be toxic to neurons. In preclinical studies, activation of the muscarinic M1 receptor subtype inhibited Aβ secretion from cultured cells. To determine whether a similar sequence occurs in human beings, we administered the selective M1 agonist AF102B to 19 AD patients and measured total Aβ (Aβtotal) levels in cerebrospinal fluid (CSF) before and during treatment. Aβtotallevels in CSF decreased in 14 patients by 22%, increased in 3 patients, and were unchanged in 2 patients; the overall decrease in the group as a whole was statistically significant. To test the specificity of the M1 effect, we also measured the relative changes in Aβtotallevels in CSF during treatments in separate sets of AD patients with the acetylcholinesterase inhibitor physostigmine or the anti‐inflammatory drug hydroxychloroquine. CSF Aβtotallevels did not change significantly in the 9 AD patients in the physostigmine protocol or in the 10 AD patients in the hydroxychloroquine study. These data provide evidence that the activation of M1 receptors reduces Aβ levels in the CSF of AD patients. If this effect also occurs in brain, M1 agonists may have long‐term therapeutic benefits by lowering amyloid in AD. Ann Neurol 2000;48:913–918
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- 2000
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33. The selective muscarinic M1 agonist AF102B decreases levels of total Aβ in cerebrospinal fluid of patients with Alzheimer's disease
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Nitsch, Roger M., Deng, Meihua, Tennis, Marsha, Schoenfeld, David, and Growdon, John H.
- Abstract
β-Amyloid (Aβ) deposits in diffuse and compact senile plaques in the brain are one of the defining histopathological features of Alzheimer's disease (AD). Preventing Aβ deposition is a goal of drug therapy for AD, because excessive amounts of Aβ may be toxic to neurons. In preclinical studies, activation of the muscarinic M1 receptor subtype inhibited Aβ secretion from cultured cells. To determine whether a similar sequence occurs in human beings, we administered the selective M1 agonist AF102B to 19 AD patients and measured total Aβ (Aβ
total ) levels in cerebrospinal fluid (CSF) before and during treatment. Aβtotal levels in CSF decreased in 14 patients by 22%, increased in 3 patients, and were unchanged in 2 patients; the overall decrease in the group as a whole was statistically significant. To test the specificity of the M1 effect, we also measured the relative changes in Aβtotal levels in CSF during treatments in separate sets of AD patients with the acetylcholinesterase inhibitor physostigmine or the anti-inflammatory drug hydroxychloroquine. CSF Aβtotal levels did not change significantly in the 9 AD patients in the physostigmine protocol or in the 10 AD patients in the hydroxychloroquine study. These data provide evidence that the activation of M1 receptors reduces Aβ levels in the CSF of AD patients. If this effect also occurs in brain, M1 agonists may have long-term therapeutic benefits by lowering amyloid in AD. Ann Neurol 2000;48:913918- Published
- 2000
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34. Challenges and Opportunities in Linking Brain-Based Biomarkers to Person-Specific Variation in Cognition: Pumping Up the Volume
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Hedden, Trey and Growdon, John H.
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- 2015
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35. Modulation of Presenilin-1 Processing by Nitric Oxide during Apoptosis Induced by Serum Withdrawal and Glucose Deprivation
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GASPARINI, LAURA, GHIDONI, ROBERTA, ALBERICI, ANTONELLA C., BENUSSI, LUISA, MORATTO, DANIELE, TRABUCCHI, MARCO, GROWDON, JOHN H., NITSCH, ROGER M., and BINETTI, GIULIANO
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- 1999
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36. Presenilin 1 Protein Directly Interacts with Bcl-2*
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Alberici, Antonella, Moratto, Daniele, Benussi, Luisa, Gasparini, Laura, Ghidoni, Roberta, Gatta, Luisa Benerini, Finazzi, Dario, Frisoni, Giovanni Battista, Trabucchi, Marco, Growdon, John H., Nitsch, Roger M., and Binetti, Giuliano
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Presenilin proteins are involved in familial Alzheimer's disease, a neurodegenerative disorder characterized by massive death of neurons. We describe a direct interaction between presenilin 1 (PS1) and Bcl-2, a key factor in the regulation of apoptosis, by yeast two-hybrid interaction system, by co-immunoprecipitation, and by cross-linking experiments. Our data show that PS1 and Bcl-2 assemble into a macromolecular complex, and that they are released from this complex in response to an apoptotic stimulus induced by staurosporine. The results support the idea of cross-talk between these two proteins during apoptosis.
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- 1999
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37. The effect of alcohol on essential tremor
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GROWDON, JOHN H., SHAHANI, BHAGWAN T., and YOUNG, ROBERT R.
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Five patients with essential tremor had a dramatic diminution in tremor amplitude within 15 minutes of ingesting small doses of ethyl alcohol. The same patients were given equivalent amounts of ethyl alcohol infused into a brachial artery, and there was no decrease in tremor amplitude in the perfused limb. It is concluded that, in patients with essential tremor, ethanol acts in a specific fashion on sensitive structures within the central nervous system and has no effect on peripheral tremorogenic mechanisms. This provides additional evidence for a central mechanism in essential tremor, distinguishing it from other tremors arising primarily from oscillation in peripheral servo-loops.
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- 1975
38. Pupil Dilation to Tropicamide Is Not Specific for Alzheimer Disease
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Growdon, John H., Graefe, Karin, Tennis, Marsha, Hayden, Doug, Schoenfeld, David, and Wray, Shirley H.
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BACKGROUND: The extent of pupil dilation after instillation of a dilute tropicamide solution was proposed as a noninvasive neurobiological diagnostic test for Alzheimer disease (AD). Pupils in patients with AD dilated 23% vs only 5% in control subjects. OBJECTIVE: To determine whether pupil dilation in response to tropicamide distinguishes patients with AD from control subjects without dementia. METHODS: There were 50 patients with AD and 51 control subjects; no participant had primary ocular pathological conditions or took drugs that affected cholinergic tone. All participants received 1 drop of 0.01% tropicamide in 1 eye and 1 drop of 0.9% saline solution in the other eye in random order. Pupil measurements were obtained using a pupil and corneal reflection tracking system (RK-426 PC system, ISCAN Inc, Burlington, Mass) that illuminated the eye with a low-level infrared source and measured pupil diameters, fixation, and light level every 16.7 milliseconds during each 30-second measurement. Pupil measurements were obtained from each eye at baseline and 5, 10, 15, and 30 minutes after drop instillation. RESULTS: The increase in pupil size after tropicamide instillation was equal between patients with AD and control subjects. The mean (±SD) pupil diameter increased from 4.5±1.1 to 5.5±1.1 mm after 30 minutes in patients with AD and from 4.7±0.9 to 5.8±0.9 mm in control subjects. Anisocoria and the mean rate of dilation did not differ between patients with AD and control subjects. Eye color and corneal moisture did not affect these results. The extent of pupil dilation in patients with AD was not related to clinical estimates of dementia severity. CONCLUSION: Pupil dilation in response to instillation of 0.01% tropicamide is not useful as an antemortem diagnostic test for AD.
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- 1997
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39. Association of Decreased Paternal Age and Late-Onset Alzheimer's Disease: An Example of Genetic Imprinting?
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Farrer, Lindsay A., Cupples, L. Adrienne, Connor, Linda, Wolf, Philip A., and Growdon, John H.
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• Several studies have identified advanced maternal age as a risk factor for Alzheimer's disease. This study evaluated maternal and paternal age at birth of 237 patients with Alzheimer's disease, each of whom was matched to five control subjects based on sex, year of birth, survival age, and location of residence. It was found that decreased paternal age substantially increased the susceptibility to the common form of Alzheimer's disease that occurs after the age of 67 years, whereas advanced maternal age had a negligible effect on risk of Alzheimer's disease. The higher incidence of late-onset Alzheimer's disease among persons born to younger fathers is consistent with a genetic imprinting mechanism involving DNA methylation. The proposed model postulates a role for environmental agents in the pathogenesis of Alzheimer's disease and accounts for families that show an aggregation of cases but no apparent pattern of inheritance.
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- 1991
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40. Beta-Adrenergic Mechanisms in Action Tremor
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Young, Robert R., Growdon, John H., and Shahani, Bhagwan T.
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- 1975
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41. Oral Choline Administration to Patients with Tardive Dyskinesia
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Growdon, John H., Hirsch, Madelyn J., Wurtman, Richard J., and Wiener, William
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- 1977
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42. Unraveling the Mystery of Cognitive Changes in Old Age: Correlation of Neuropsychological Evaluation With Neuropathological Findings in the Extreme Old
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Silver, Margery, Newell, Kathy, Hyman, Bradley, Growdon, John, Hedley-Whyte, E. Tessa, and Perls, Thomas
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In order to understand what cognitive changes can be expected with aging versus those caused by disease, the New England Centenarian Study examined correlations between neuropsychological evaluation and neuropathological studies of centenarian subjects. Sixty-nine subjects were administered an extensive neuropsychological test battery designed for centenarians. Six brain donors from this group have subsequently died, and neuropathological studies of their brains have been performed to determine the presence of Alzheimer's disease (AD) and other pathological states. Of these six centenarians, three subjects had Clinical Dementia Rating scores of 0 and no dementia on neuropsychological testing, and subsequent neuropathology showed very limited AD changes. In fact, despite a range of neuropsychological findings, none of the subjects in this series met neuropathological criteria for a diagnosis of definite AD. Findings suggest that dementia is not inevitable with aging and that dementia in this age group is surprisingly often not attributable to AD.
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- 1998
43. A Model for Oral Dyskinesia in Rats
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GUNNE, LARS M. and GROWDON, JOHN H.
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Rats subjected to bifrontal cortical ablations developed vacuous chewing movements and jaw tremors that began 22 weeks after surgery, reached a peak rate of 4 to 8 per minute, and remained stable for an 8-week observation period. Chronic haloperidol administration to rats with bifrontal cortical ablations produced 15 to 20 movements per minute that persisted for 7 weeks after drug withdrawal. Drugs given to decrease dopaminergic, cholinergic, and γ-aminobutyric acid (GABA)-ergic neurotransmission suppressed the movements, whereas cholinergic agonists increased them. This model of oral dyskinesia in rats may be useful in developing drugs for the treatment of facial dyskinesias in humans.
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- 1982
44. Postural changes tremor and myoclonus in the rat immediately following injections of pchloroamphetamine
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GROWDON, JOHN H.
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A single dose of p-chloroamphetamine, 10 mg per kilogram, produced postural abnormalities, tremor, myoclonus, and autonomic signs in rats 5 minutes after intraperitoneal injection. This syndrome lasted 60 to 90 minutes, and its intensity was directly proportional to the amount of p-chloroamphetamine given over a 2 to 10 mg per kilogram range. Whole-brain levels of serotonin and 5-hydroxyindoleacetic acid were not altered during this interval, although both were reduced significantly 1 day later. Pretreatment with drugs that interfere with the uptake of p-chloroamphetamine into terminals of serotonergic neurons (fluoxetine), depress brain serotonin levels (p-chlorophenylalanine), or block serotonin receptors (methiothepin or methergoline) suppressed this syndrome, whereas drugs that antagonize the effects of dopamine, norepinephrine, and acetylcholine did not. These observations implicate serotonergic mechanisms and provide behavioral evidence of p-chloroamphetamine's immediate actions on serotonergic neurons in the central nervous system.
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- 1977
45. CSF vasopressin concentration is reduced in Alzheimer's disease
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Mazurek, Michael F., Growdon, John H., Beal, M. Flint, and Martin, Joseph B.
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The concentration of arginine vasopressin (AVP) was measured in cerebrospinal fluid (CSF) by radioimmunoassay. Serial dilution curves and reversed-phase high-pressure liquid chromatography (HPLC) showed that the material measured behaved identically to authentic vasopressin. Levels of CSF AVP were reduced by 37 in Alzheimer's disease, but were normal in Huntington's disease, normal-pressure hydrocephalus, and several other neurologic disorders. On direct comparison, the CSF AVP concentration was significantly lower in Alzheimer's disease than in normal-pressure hydrocephalus. Low CSF levels of AVP may therefore assist in the identification of demented patients who are not likely to benefit from ventricular shunting.
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- 1986
46. Cognitive Test Performance in Detecting, Staging, and Tracking Alzheimer's Disease
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Locascio, Joseph J., Growdon, John H., and Corkin, Suzanne
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OBJECTIVES: To identify the specific cognitive deficits that characterize Alzheimer's disease (AD) and determine which cognitive tests, or combination of tests, are best for detecting AD (ie, distinguishing patients with AD from normal control subjects), staging AD (ie, distinguishing different severities of dementia), and tracking disease progression. SUBJECTS: Patients with AD (n=123) and normal control subjects (n=60) of comparable age, education, and gender distribution. SETTING: Outpatient care. MEASURES: Ten cognitive tests of memory, language, visuospatial abilities, and reasoning; the Information, Memory and Concentration subtest of the Blessed Dementia Scale, and the total score on an activities of daily living questionnaire. DESIGN: Patients with AD were tested every 6 to 24 months over a span of up to 5.5 years. RESULTS: Patients with AD were significantly inferior to normal control subjects on all cognitive tests. The scores of patients with AD worsened over time. Delayed recall of stories and figures showed sharp deterioration to an early floor, consistent with the finding that these tests discriminated patients with mild AD from normal control subjects well but were poor for staging. Confrontation naming, semantic fluency, and immediate recognition of geometric figures showed steady linear decline across time for patients with AD, consistent with these tests being found best for staging dementia severity. CONCLUSIONS: We postulate that the pathologic bases of impairment in delayed recall are atrophy of cholinergic ventral forebrain neurons and partial deafferentation of the hippocampus, both of which occur early in the course of AD. Worsening language and visuospatial abilities likely reflect progressive loss of neocortical neurons and their connections.
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- 1995
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47. Rate of Progression of Alzheimer's Disease Is Associated With Genetic Risk
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Farrer, Lindsay A., Cupples, L. Adrienne, van Duijn, Cornelia M., Connor-Lacke, Linda, Kiely, Dan K., and Growdon, John H.
- Abstract
OBJECTIVE: To determine whether differences in genetic origin affect the clinical course of Alzheimer's disease (AD). The limited number of cases of AD linked to a known genetic abnormality is a major obstacle in determining whether the disorder is expressed differently in patients with familial AD and those with sporadic AD. DESIGN: Cross-sectional study. SETTING: Memory Disorders Unit of the Alzheimer's Disease Research Center at Massachusetts General Hospital, Boston. PARTICIPANTS: A total of 186 patients who had a clinical diagnosis of probable AD, family history information available for all first-degree relatives, and three or more outpatient visits were identified from a consecutive case series. MAIN OUTCOME MEASURE: Rate of decline on the Blessed Dementia Scale and the Activities of Daily Living Scale. RESULTS: We calculated the probability that an individual patient has a major genetic locus for AD (MGAD) using an algorithm that incorporates information from a genetic model and the individual's family. We measured cognitive and functional changes by the average annual rate of increase (slope) in scores for the Blessed Dementia Scale and Activities of Daily Living Scale, respectively. Multivariate analysis adjusted for age at onset, duration of illness at entry into the study, and education level indicated that scores on the Activities of Daily Living Scale worsened significantly faster in men with MGAD than in men with non-MGAD. No differences in Activities of Daily Living Scale slopes were observed among women with MGAD and non-MGAD. The slopes for Blessed Dementia Scale scores were similar in men and women regardless of the MGAD probability. CONCLUSIONS: Genetic factors may account for heterogeneity in rates of functional decline in AD. This study also illustrates the practical application of a probabilistic method that characterizes the genetic status of AD in an individual patient.
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- 1995
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48. Oral dyskinesia in rats following brain lesions and neuroleptic drug administration
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Gunne, Lars M., Growdon, John, and Glaeser, Bruce
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After 10–12 weeks of chronic haloperidol administration rats with frontal cortex ablations or lesions induced by intracerebroventricular injection of 6-hydroxydopamine developed vacuous chewing behavior at a fairly stable frequency (bifrontal ablations had 15–20, 6-hydroxy-dopamine lesioned rats 7–12 chewing movements/min). This behavior persisted for 10 weeks after the last injection of haloperidol decanoate. However, rats with frontal cortex lesions developed a low rate of vacuous chewings (4–8 chewings/min) even without haloperidol administration. Bilateral intrastriatal injections of kainic acid in combination with chronic haloperidol administration did not cause chewing movements in excess of unlesioned haloperidol-treated controls.
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- 1982
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49. CSF somatostatinlike immunoreactivity in dementia
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Beal, M. Flint, Growdon, John H., Mazurek, Michael F., and Martin, Joseph B.
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Concentrations of somatostatin-like immunoreactivity (SLI) in CSF were reduced in Alzheimer's disease (AD) and multi-infarct dementia (p< 0.01), but not in normal-pressure hydrocephalus, Parkinson's disease, and Huntington's disease. This suggests that reduced SLI content in AD cerebral cortex is reflected in CSF. Chromatographic characterization of CSF SLI showed no differences between AD and controls. Concentrations of SLI in AD patients overlapped those in both normal subjects and patients with multi-infarct dementia, so that changes in CSF SLI have no diagnostic specificity.
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- 1986
50. Vasopressin and Bradykinin Regulate Secretory Processing of the Amyloid Protein Precursor of Alzheimer's Disease
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Nitsch, Roger, Kim, Cindy, and Growdon, John
- Abstract
The amyloid protein precursor (APP) can be processed via several alternative processing pathways, α-secretase processing by cleavage within the amyloid β-peptide domain of APP is highly regulated by several external and internal signals including G protein-coupled receptors, protein kinase C and phospholipase A2. In order to demonstrate that G protein-coupled neuropeptide receptors for bradykinin and vasopressin can increase α-secretase processing of APP, we stimulated endogenously expressed bradykinin or vasopressin receptors in cell culture with the neuropeptides and measured the secreted ectodomain (APPs) in the conditioned media. Both bradykinin and vasopressin rapidly increased phosphatidylinositol (PI) turnover in PC-12 and in NRK-49F cells, indicating that these cell lines constitutively expressed functional PI-linked receptors for these neuropeptides. Both bradykinin and vasopressin readily stimulated APPs secretion. Increased APPs secretion was concentration-dependent and saturable, and it was blocked by receptor antagonists indicating specific receptor interaction of the peptides. The bradykinin-induced increase in APPs secretion in PC-12 cells was mediated by protein kinase C (PKC), whereas vasopressin receptors in NRK-49F cells were coupled to APP processing by PKC-independent signalling pathways. Our data show that neuropeptides can modulate APP processing in cell culture. In as much as increased α-secretase processing is associated with decreased formation of Aβ1–40, a major constituent of amyloid plaques, our findings suggest a possible role for modulating neuropeptide receptors as a strategy for altering amyloid metabolism in Alzheimer's disease brain.
- Published
- 1998
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