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1. Prognostic relevance of gait-related cognitive functions for dementia conversion in amnestic mild cognitive impairment

Author

Tuena, C, Maestri, S, Serino, S, Pedroli, E, Stramba-Badiale, M, Riva, G, Silbert, L, Lind, B, Crissey, R, Kaye, J, Carter, R, Dolen, S, Quinn, J, Schneider, L, Pawluczyk, S, Becerra, M, Teodoro, L, Dagerman, K, Spann, B, Brewer, J, Fleisher, A, Vanderswag, H, Ziolkowski, J, Heidebrink, J, Zbizek-Nulph, L, Lord, J, Albers, C, Petersen, R, Mason, S, Knopman, D, Johnson, K, Villanueva-Meyer, J, Pavlik, V, Pacini, N, Lamb, A, Kass, J, Doody, R, Shibley, V, Chowdhury, M, Rountree, S, Dang, M, Stern, Y, Honig, L, Mintz, A, Ances, B, Morris, J, Winkfield, D, Carroll, M, Stobbs-Cucchi, G, Oliver, A, Creech, M, Mintun, M, Schneider, S, Geldmacher, D, Love, M, Griffith, R, Clark, D, Brockington, J, Marson, D, Grossman, H, Goldstein, M, Greenberg, J, Mitsis, E, Shah, R, Lamar, M, Samuels, P, Duara, R, Greig-Custo, M, Rodriguez, R, Albert, M, Onyike, C, Farrington, L, Rudow, S, Brichko, R, Kielb, S, Smith, A, Raj, B, Fargher, K, Sadowski, M, Wisniewski, T, Shulman, M, Faustin, A, Rao, J, Castro, K, Ulysse, A, Chen, S, Doraiswamy, P, Petrella, J, James, O, Wong, T, Borges-Neto, S, Karlawish, J, Wolk, D, Vaishnavi, S, Clark, C, Arnold, S, Smith, C, Jicha, G, Khouli, R, Raslau, F, Lopez, O, Oakley, M, Simpson, D, Porsteinsson, A, Martin, K, Kowalski, N, Keltz, M, Goldstein, B, Makino, K, Ismail, M, Brand, C, Thai, G, Pierce, A, Yanez, B, Sosa, E, Witbracht, M, Kelley, B, Nguyen, T, Womack, K, Mathews, D, Quiceno, M, Levey, A, Lah, J, Hajjar, I, Burns, J, Swerdlow, R, Brooks, W, Silverman, D, Kremen, S, Apostolova, L, Tingus, K, Lu, P, Bartzokis, G, Woo, E, Teng, E, Graff-Radford, N, Parfitt, F, Poki-Walker, K, Farlow, M, Hake, A, Matthews, B, Brosch, J, Herring, S, van Dyck, C, Mecca, A, Good, S, Macavoy, M, Carson, R, Varma, P, Chertkow, H, Vaitekunas, S, Hosein, C, Black, S, Stefanovic, B, Heyn, C, Hsiung, G, Kim, E, Mudge, B, Sossi, V, Feldman, H, Assaly, M, Finger, E, Pasternak, S, Rachinsky, I, Kertesz, A, Drost, D, Rogers, J, Grant, I, Muse, B, Rogalski, E, Robson, J, Mesulam, M, Kerwin, D, Wu, C, Johnson, N, Lipowski, K, Weintraub, S, Bonakdarpour, B, Pomara, N, Hernando, R, Sarrael, A, Rosen, H, Miller, B, Weiner, M, Perry, D, Turner, R, Reynolds, B, Mccann, K, Poe, J, Marshall, G, Sperling, R, Yesavage, J, Taylor, J, Chao, S, Coleman, J, White, J, Lane, B, Rosen, A, Tinklenberg, J, Belden, C, Atri, A, Clark, K, Zamrini, E, Sabbagh, M, Killiany, R, Stern, R, Mez, J, Kowall, N, Budson, A, Obisesan, T, Ntekim, O, Wolday, S, Khan, J, Nwulia, E, Nadarajah, S, Lerner, A, Ogrocki, P, Tatsuoka, C, Fatica, P, Fletcher, E, Maillard, P, Olichney, J, Decarli, C, Carmichael, O, Bates, V, Capote, H, Rainka, M, Borrie, M, Lee, T, Bartha, R, Johnson, S, Asthana, S, Carlsson, C, Perrin, A, Burke, A, Scharre, D, Kataki, M, Tarawneh, R, Hart, D, Zimmerman, E, Celmins, D, Miller, D, Ponto, L, Smith, K, Koleva, H, Shim, H, Nam, K, Schultz, S, Williamson, J, Craft, S, Cleveland, J, Yang, M, Sink, K, Ott, B, Drake, J, Tremont, G, Daiello, L, Ritter, A, Bernick, C, Munic, D, O'Connelll, A, Mintzer, J, Wiliams, A, Masdeu, J, Shi, J, Garcia, A, Newhouse, P, Potkin, S, Salloway, S, Malloy, P, Correia, S, Kittur, S, Pearlson, G, Blank, K, Anderson, K, Flashman, L, Seltzer, M, Hynes, M, Santulli, R, Relkin, N, Chiang, G, Lee, A, Lin, M, Ravdin, L, Tuena C., Maestri S., Serino S., Pedroli E., Stramba-Badiale M., Riva G., Silbert L. C., Lind B., Crissey R., Kaye J. A., Carter R., Dolen S., Quinn J., Schneider L. S., Pawluczyk S., Becerra M., Teodoro L., Dagerman K., Spann B. M., Brewer J., Fleisher A., Vanderswag H., Ziolkowski J., Heidebrink J. L., Zbizek-Nulph L., Lord J. L., Albers C. S., Petersen R., Mason S. S., Knopman D., Johnson K., Villanueva-Meyer J., Pavlik V., Pacini N., Lamb A., Kass J. S., Doody R. S., Shibley V., Chowdhury M., Rountree S., Dang M., Stern Y., Honig L. S., Mintz A., Ances B., Morris J. C., Winkfield D., Carroll M., Stobbs-Cucchi G., Oliver A., Creech M. L., Mintun M. A., Schneider S., Geldmacher D., Love M. N., Griffith R., Clark D., Brockington J., Marson D., Grossman H., Goldstein M. A., Greenberg J., Mitsis E., Shah R. C., Lamar M., Samuels P., Duara R., Greig-Custo M. T., Rodriguez R., Albert M., Onyike C., Farrington L., Rudow S., Brichko R., Kielb S., Smith A., Raj B. A., Fargher K., Sadowski M., Wisniewski T., Shulman M., Faustin A., Rao J., Castro K. M., Ulysse A., Chen S., Doraiswamy P. M., Petrella J. R., James O., Wong T. Z., Borges-Neto S., Karlawish J. H., Wolk D. A., Vaishnavi S., Clark C. M., Arnold S. E., Smith C. D., Jicha G. A., Khouli R. E., Raslau F. D., Lopez O. L., Oakley M. A., Simpson D. M., Porsteinsson A. P., Martin K., Kowalski N., Keltz M., Goldstein B. S., Makino K. M., Ismail M. S., Brand C., Thai G., Pierce A., Yanez B., Sosa E., Witbracht M., Kelley B., Nguyen T., Womack K., Mathews D., Quiceno M., Levey A. I., Lah J. J., Hajjar I., Burns J. M., Swerdlow R. H., Brooks W. M., Silverman D. H. S., Kremen S., Apostolova L., Tingus K., Lu P. H., Bartzokis G., Woo E., Teng E., Graff-Radford N. R., Parfitt F., Poki-Walker K., Farlow M. R., Hake A. M., Matthews B. R., Brosch J. R., Herring S., van Dyck C. H., Mecca A. P., Good S. P., MacAvoy M. G., Carson R. E., Varma P., Chertkow H., Vaitekunas S., Hosein C., Black S., Stefanovic B., Heyn C., Hsiung G. -Y. R., Kim E., Mudge B., Sossi V., Feldman H., Assaly M., Finger E., Pasternak S., Rachinsky I., Kertesz A., Drost D., Rogers J., Grant I., Muse B., Rogalski E., Robson J., Mesulam M. -M., Kerwin D., Wu C. -K., Johnson N., Lipowski K., Weintraub S., Bonakdarpour B., Pomara N., Hernando R., Sarrael A., Rosen H. J., Miller B. L., Weiner M. W., Perry D., Turner R. S., Reynolds B., MCCann K., Poe J., Marshall G. A., Sperling R. A., Johnson K. A., Yesavage J., Taylor J. L., Chao S., Coleman J., White J. D., Lane B., Rosen A., Tinklenberg J., Belden C. M., Atri A., Clark K. A., Zamrini E., Sabbagh M., Killiany R., Stern R., Mez J., Kowall N., Budson A. E., Obisesan T. O., Ntekim O. E., Wolday S., Khan J. I., Nwulia E., Nadarajah S., Lerner A., Ogrocki P., Tatsuoka C., Fatica P., Fletcher E., Maillard P., Olichney J., DeCarli C., Carmichael O., Bates V., Capote H., Rainka M., Borrie M., Lee T. -Y., Bartha R., Johnson S., Asthana S., Carlsson C. M., Perrin A., Burke A., Scharre D. W., Kataki M., Tarawneh R., Hart D., Zimmerman E. A., Celmins D., Miller D. D., Ponto L. L. B., Smith K. E., Koleva H., Shim H., Nam K. W., Schultz S. K., Williamson J. D., Craft S., Cleveland J., Yang M., Sink K. M., Ott B. R., Drake J., Tremont G., Daiello L. A., Drake J. D., Ritter A., Bernick C., Munic D., O'Connelll A., Mintzer J., Wiliams A., Masdeu J., Shi J., Garcia A., Newhouse P., Potkin S., Salloway S., Malloy P., Correia S., Kittur S., Pearlson G. D., Blank K., Anderson K., Flashman L. A., Seltzer M., Hynes M. L., Santulli R. B., Relkin N., Chiang G., Lee A., Lin M., Ravdin L., Tuena, C, Maestri, S, Serino, S, Pedroli, E, Stramba-Badiale, M, Riva, G, Silbert, L, Lind, B, Crissey, R, Kaye, J, Carter, R, Dolen, S, Quinn, J, Schneider, L, Pawluczyk, S, Becerra, M, Teodoro, L, Dagerman, K, Spann, B, Brewer, J, Fleisher, A, Vanderswag, H, Ziolkowski, J, Heidebrink, J, Zbizek-Nulph, L, Lord, J, Albers, C, Petersen, R, Mason, S, Knopman, D, Johnson, K, Villanueva-Meyer, J, Pavlik, V, Pacini, N, Lamb, A, Kass, J, Doody, R, Shibley, V, Chowdhury, M, Rountree, S, Dang, M, Stern, Y, Honig, L, Mintz, A, Ances, B, Morris, J, Winkfield, D, Carroll, M, Stobbs-Cucchi, G, Oliver, A, Creech, M, Mintun, M, Schneider, S, Geldmacher, D, Love, M, Griffith, R, Clark, D, Brockington, J, Marson, D, Grossman, H, Goldstein, M, Greenberg, J, Mitsis, E, Shah, R, Lamar, M, Samuels, P, Duara, R, Greig-Custo, M, Rodriguez, R, Albert, M, Onyike, C, Farrington, L, Rudow, S, Brichko, R, Kielb, S, Smith, A, Raj, B, Fargher, K, Sadowski, M, Wisniewski, T, Shulman, M, Faustin, A, Rao, J, Castro, K, Ulysse, A, Chen, S, Doraiswamy, P, Petrella, J, James, O, Wong, T, Borges-Neto, S, Karlawish, J, Wolk, D, Vaishnavi, S, Clark, C, Arnold, S, Smith, C, Jicha, G, Khouli, R, Raslau, F, Lopez, O, Oakley, M, Simpson, D, Porsteinsson, A, Martin, K, Kowalski, N, Keltz, M, Goldstein, B, Makino, K, Ismail, M, Brand, C, Thai, G, Pierce, A, Yanez, B, Sosa, E, Witbracht, M, Kelley, B, Nguyen, T, Womack, K, Mathews, D, Quiceno, M, Levey, A, Lah, J, Hajjar, I, Burns, J, Swerdlow, R, Brooks, W, Silverman, D, Kremen, S, Apostolova, L, Tingus, K, Lu, P, Bartzokis, G, Woo, E, Teng, E, Graff-Radford, N, Parfitt, F, Poki-Walker, K, Farlow, M, Hake, A, Matthews, B, Brosch, J, Herring, S, van Dyck, C, Mecca, A, Good, S, Macavoy, M, Carson, R, Varma, P, Chertkow, H, Vaitekunas, S, Hosein, C, Black, S, Stefanovic, B, Heyn, C, Hsiung, G, Kim, E, Mudge, B, Sossi, V, Feldman, H, Assaly, M, Finger, E, Pasternak, S, Rachinsky, I, Kertesz, A, Drost, D, Rogers, J, Grant, I, Muse, B, Rogalski, E, Robson, J, Mesulam, M, Kerwin, D, Wu, C, Johnson, N, Lipowski, K, Weintraub, S, Bonakdarpour, B, Pomara, N, Hernando, R, Sarrael, A, Rosen, H, Miller, B, Weiner, M, Perry, D, Turner, R, Reynolds, B, Mccann, K, Poe, J, Marshall, G, Sperling, R, Yesavage, J, Taylor, J, Chao, S, Coleman, J, White, J, Lane, B, Rosen, A, Tinklenberg, J, Belden, C, Atri, A, Clark, K, Zamrini, E, Sabbagh, M, Killiany, R, Stern, R, Mez, J, Kowall, N, Budson, A, Obisesan, T, Ntekim, O, Wolday, S, Khan, J, Nwulia, E, Nadarajah, S, Lerner, A, Ogrocki, P, Tatsuoka, C, Fatica, P, Fletcher, E, Maillard, P, Olichney, J, Decarli, C, Carmichael, O, Bates, V, Capote, H, Rainka, M, Borrie, M, Lee, T, Bartha, R, Johnson, S, Asthana, S, Carlsson, C, Perrin, A, Burke, A, Scharre, D, Kataki, M, Tarawneh, R, Hart, D, Zimmerman, E, Celmins, D, Miller, D, Ponto, L, Smith, K, Koleva, H, Shim, H, Nam, K, Schultz, S, Williamson, J, Craft, S, Cleveland, J, Yang, M, Sink, K, Ott, B, Drake, J, Tremont, G, Daiello, L, Ritter, A, Bernick, C, Munic, D, O'Connelll, A, Mintzer, J, Wiliams, A, Masdeu, J, Shi, J, Garcia, A, Newhouse, P, Potkin, S, Salloway, S, Malloy, P, Correia, S, Kittur, S, Pearlson, G, Blank, K, Anderson, K, Flashman, L, Seltzer, M, Hynes, M, Santulli, R, Relkin, N, Chiang, G, Lee, A, Lin, M, Ravdin, L, Tuena C., Maestri S., Serino S., Pedroli E., Stramba-Badiale M., Riva G., Silbert L. C., Lind B., Crissey R., Kaye J. A., Carter R., Dolen S., Quinn J., Schneider L. S., Pawluczyk S., Becerra M., Teodoro L., Dagerman K., Spann B. M., Brewer J., Fleisher A., Vanderswag H., Ziolkowski J., Heidebrink J. L., Zbizek-Nulph L., Lord J. L., Albers C. S., Petersen R., Mason S. S., Knopman D., Johnson K., Villanueva-Meyer J., Pavlik V., Pacini N., Lamb A., Kass J. S., Doody R. S., Shibley V., Chowdhury M., Rountree S., Dang M., Stern Y., Honig L. S., Mintz A., Ances B., Morris J. C., Winkfield D., Carroll M., Stobbs-Cucchi G., Oliver A., Creech M. L., Mintun M. A., Schneider S., Geldmacher D., Love M. N., Griffith R., Clark D., Brockington J., Marson D., Grossman H., Goldstein M. A., Greenberg J., Mitsis E., Shah R. C., Lamar M., Samuels P., Duara R., Greig-Custo M. T., Rodriguez R., Albert M., Onyike C., Farrington L., Rudow S., Brichko R., Kielb S., Smith A., Raj B. A., Fargher K., Sadowski M., Wisniewski T., Shulman M., Faustin A., Rao J., Castro K. M., Ulysse A., Chen S., Doraiswamy P. M., Petrella J. R., James O., Wong T. Z., Borges-Neto S., Karlawish J. H., Wolk D. A., Vaishnavi S., Clark C. M., Arnold S. E., Smith C. D., Jicha G. A., Khouli R. E., Raslau F. D., Lopez O. L., Oakley M. A., Simpson D. M., Porsteinsson A. P., Martin K., Kowalski N., Keltz M., Goldstein B. S., Makino K. M., Ismail M. S., Brand C., Thai G., Pierce A., Yanez B., Sosa E., Witbracht M., Kelley B., Nguyen T., Womack K., Mathews D., Quiceno M., Levey A. I., Lah J. J., Hajjar I., Burns J. M., Swerdlow R. H., Brooks W. M., Silverman D. H. S., Kremen S., Apostolova L., Tingus K., Lu P. H., Bartzokis G., Woo E., Teng E., Graff-Radford N. R., Parfitt F., Poki-Walker K., Farlow M. R., Hake A. M., Matthews B. R., Brosch J. R., Herring S., van Dyck C. H., Mecca A. P., Good S. P., MacAvoy M. G., Carson R. E., Varma P., Chertkow H., Vaitekunas S., Hosein C., Black S., Stefanovic B., Heyn C., Hsiung G. -Y. R., Kim E., Mudge B., Sossi V., Feldman H., Assaly M., Finger E., Pasternak S., Rachinsky I., Kertesz A., Drost D., Rogers J., Grant I., Muse B., Rogalski E., Robson J., Mesulam M. -M., Kerwin D., Wu C. -K., Johnson N., Lipowski K., Weintraub S., Bonakdarpour B., Pomara N., Hernando R., Sarrael A., Rosen H. J., Miller B. L., Weiner M. W., Perry D., Turner R. S., Reynolds B., MCCann K., Poe J., Marshall G. A., Sperling R. A., Johnson K. A., Yesavage J., Taylor J. L., Chao S., Coleman J., White J. D., Lane B., Rosen A., Tinklenberg J., Belden C. M., Atri A., Clark K. A., Zamrini E., Sabbagh M., Killiany R., Stern R., Mez J., Kowall N., Budson A. E., Obisesan T. O., Ntekim O. E., Wolday S., Khan J. I., Nwulia E., Nadarajah S., Lerner A., Ogrocki P., Tatsuoka C., Fatica P., Fletcher E., Maillard P., Olichney J., DeCarli C., Carmichael O., Bates V., Capote H., Rainka M., Borrie M., Lee T. -Y., Bartha R., Johnson S., Asthana S., Carlsson C. M., Perrin A., Burke A., Scharre D. W., Kataki M., Tarawneh R., Hart D., Zimmerman E. A., Celmins D., Miller D. D., Ponto L. L. B., Smith K. E., Koleva H., Shim H., Nam K. W., Schultz S. K., Williamson J. D., Craft S., Cleveland J., Yang M., Sink K. M., Ott B. R., Drake J., Tremont G., Daiello L. A., Drake J. D., Ritter A., Bernick C., Munic D., O'Connelll A., Mintzer J., Wiliams A., Masdeu J., Shi J., Garcia A., Newhouse P., Potkin S., Salloway S., Malloy P., Correia S., Kittur S., Pearlson G. D., Blank K., Anderson K., Flashman L. A., Seltzer M., Hynes M. L., Santulli R. B., Relkin N., Chiang G., Lee A., Lin M., and Ravdin L.

Abstract

Background: Increasing research suggests that gait abnormalities can be a risk factor for Alzheimer’s Disease (AD). Notably, there is growing evidence highlighting this risk factor in individuals with amnestic Mild Cognitive Impairment (aMCI), however further studies are needed. The aim of this study is to analyze cognitive tests results and brain-related measures over time in aMCI and examine how the presence of gait abnormalities (neurological or orthopedic) or normal gait affects these trends. Additionally, we sought to assess the significance of gait and gait-related measures as prognostic indicators for the progression from aMCI to AD dementia, comparing those who converted to AD with those who remained with a stable aMCI diagnosis during the follow-up. Methods: Four hundred two individuals with aMCI from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database were included. Robust linear mixed-effects models were used to study the impact of gait abnormalities on a comprehensive neuropsychological battery over 36 months while controlling for relevant medical variables at baseline. The impact of gait on brain measures was also investigated. Lastly, the Cox proportional-hazards model was used to explore the prognostic relevance of abnormal gait and neuropsychological associated tests. Results: While controlling for relevant covariates, we found that gait abnormalities led to a greater decline over time in attention (DSST) and global cognition (MMSE). Intriguingly, psychomotor speed (TMT-A) and divided attention (TMT-B) declined uniquely in the abnormal gait group. Conversely, specific AD global cognition tests (ADAS-13) and auditory-verbal memory (RAVLT immediate recall) declined over time independently of gait profile. All the other cognitive tests were not significantly affected by time or by gait profile. In addition, we found that ventricles size increased faster in the abnormal gait group compared to the normal gait group. In terms of prognosis, abno

Published
2023

5. Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference

Author

Young, A. L., Marinescu, R. V., Oxtoby, N. P., Bocchetta, M., Yong, K., Firth, N. C., Cash, D. M., Thomas, D. L., Dick, K. M., Cardoso, J., van Swieten, J., Borroni, B., Galimberti, D., Masellis, M., Tartaglia, M. C., Rowe, J. B., Graff, C., Tagliavini, F., Frisoni, G. B., Laforce, R., Finger, E., de Mendonca, A., Sorbi, S., Warren, J. D., Crutch, S., Fox, N. C., Ourselin, S., Schott, J. M., Rohrer, J. D., Alexander, D. C., Andersson, C., Archetti, S., Arighi, A., Benussi, L., Binetti, G., Black, S., Cosseddu, M., Fallstrom, M., Ferreira, C., Fenoglio, C., Freedman, M., Fumagalli, G. G., Gazzina, S., Ghidoni, R., Grisoli, M., Jelic, V., Jiskoot, L., Keren, R., Lombardi, G., Maruta, C., Meeter, L., Mead, S., van Minkelen, R., Nacmias, B., Oijerstedt, L., Padovani, A., Panman, J., Pievani, M., Polito, C., Premi, E., Prioni, S., Rademakers, R., Redaelli, V., Rogaeva, E., Rossi, G., Rossor, M., Scarpini, E., Tang-Wai, D., Thonberg, H., Tiraboschi, P., Verdelho, A., Weiner, M. W., Aisen, P., Petersen, R., Jack, C. R., Jagust, W., Trojanowki, J. Q., Toga, A. W., Beckett, L., Green, R. C., Saykin, A. J., Morris, J., Shaw, L. M., Khachaturian, Z., Sorensen, G., Kuller, L., Raichle, M., Paul, S., Davies, P., Fillit, H., Hefti, F., Holtzman, D., Mesulam, M. M., Potter, W., Snyder, P., Schwartz, A., Montine, T., Thomas, R. G., Donohue, M., Walter, S., Gessert, D., Sather, T., Jiminez, G., Harvey, D., Bernstein, M., Thompson, P., Schuff, N., Borowski, B., Gunter, J., Senjem, M., Vemuri, P., Jones, D., Kantarci, K., Ward, C., Koeppe, R. A., Foster, N., Reiman, E. M., Chen, K., Mathis, C., Landau, S., Cairns, N. J., Householder, E., Taylor-Reinwald, L., Lee, V., Korecka, M., Figurski, M., Crawford, K., Neu, S., Foroud, T. M., Potkin, S., Shen, L., Faber, K., Kim, S., Nho, K., Thal, L., Buckholtz, N., Albert, M., Frank, R., Hsiao, J., Kaye, J., Quinn, J., Lind, B., Carter, R., Dolen, S., Schneider, L. S., Pawluczyk, S., Beccera, M., Teodoro, L., Spann, B. M., Brewer, J., Vanderswag, H., Fleisher, A., Heidebrink, J. L., Lord, J. L., Mason, S. S., Albers, C. S., Knopman, D., Johnson, K., Doody, R. S., Villanueva-Meyer, J., Chowdhury, M., Rountree, S., Dang, M., Stern, Y., Honig, L. S., Bell, K. L., Ances, B., Carroll, M., Leon, S., Mintun, M. A., Schneider, S., Oliver, A., Marson, D., Griffith, R., Clark, D., Geldmacher, D., Brockington, J., Roberson, E., Grossman, H., Mitsis, E., de Toledo-Morrell, L., Shah, R. C., Duara, R., Varon, D., Greig, M. T., Roberts, P., Onyike, C., D'Agostino, D., Kielb, S., Galvin, J. E., Cerbone, B., Michel, C. A., Rusinek, H., de Leon, M. J., Glodzik, L., De Santi, S., Doraiswamy, P. M., Petrella, J. R., Wong, T. Z., Arnold, S. E., Karlawish, J. H., Wolk, D., Smith, C. D., Jicha, G., Hardy, P., Sinha, P., Oates, E., Conrad, G., Lopez, O. L., Oakley, M. A., Simpson, D. M., Porsteinsson, A. P., Goldstein, B. S., Martin, K., Makino, K. M., Ismail, M. S., Brand, C., Mulnard, R. A., Thai, G., Mc-Adams-Ortiz, C., Womack, K., Mathews, D., Quiceno, M., Diaz-Arrastia, R., King, R., Weiner, M., Martin-Cook, K., Devous, M., Levey, A. I., Lah, J. J., Cellar, J. S., Burns, J. M., Anderson, H. S., Swerdlow, R. H., Apostolova, L., Tingus, K., Woo, E., Silverman, D. H., P. H., Lu, Bartzokis, G., Graff-Radford, N. R., Parfitt, F., Kendall, T., Johnson, H., Farlow, M. R., Hake, A. M., Matthews, B. R., Herring, S., Hunt, C., van Dyck, C. H., Carson, R. E., Macavoy, M. G., Chertkow, H., Bergman, H., Hosein, C., Stefanovic, B., Caldwell, C., Hsiung, G. -Y. R., Feldman, H., Mudge, B., Assaly, M., Kertesz, A., Rogers, J., Bernick, C., Munic, D., Kerwin, D., Mesulam, M. -M., Lipowski, K., C. -K., Wu, Johnson, N., Sadowsky, C., Martinez, W., Villena, T., Turner, R. S., Reynolds, B., Sperling, R. A., Johnson, K. A., Marshall, G., Frey, M., Lane, B., Rosen, A., Tinklenberg, J., Sabbagh, M. N., Belden, C. M., Jacobson, S. A., Sirrel, S. A., Kowall, N., Killiany, R., Budson, A. E., Norbash, A., Johnson, P. L., Allard, J., Lerner, A., Ogrocki, P., Hudson, L., Fletcher, E., Carmichael, O., Olichney, J., Decarli, C., Kittur, S., Borrie, M., Lee, T. -Y., Bartha, R., Johnson, S., Asthana, S., Carlsson, C. M., Potkin, S. G., Preda, A., Nguyen, D., Tariot, P., Reeder, S., Bates, V., Capote, H., Rainka, M., Scharre, D. W., Kataki, M., Adeli, A., Zimmerman, E. A., Celmins, D., Brown, A. D., Pearlson, G. D., Blank, K., Anderson, K., Santulli, R. B., Kitzmiller, T. J., Schwartz, E. S., Sink, K. M., Williamson, J. D., Garg, P., Watkins, F., Ott, B. R., Querfurth, H., Tremont, G., Salloway, S., Malloy, P., Correia, S., Rosen, H. J., Miller, B. L., Mintzer, J., Spicer, K., Bachman, D., Pasternak, S., Rachinsky, I., Drost, D., Pomara, N., Hernando, R., Sarrael, A., Schultz, S. K., Ponto, L. L. B., Shim, H., Smith, K. E., Relkin, N., Chaing, G., Raudin, L., Smith, A., Fargher, K., Raj, B. A., Neylan, T., Grafman, J., Davis, M., Morrison, R., Hayes, J., Finley, S., Friedl, K., Fleischman, D., Arfanakis, K., James, O., Massoglia, D., Fruehling, J. J., Harding, S., Peskind, E. R., Petrie, E. C., Li, G., Yesavage, J. A., Taylor, J. L., and Furst, A. J.

Published
2018

15. Sex-dependent association of common variants of microcephaly genes with brain structure

Author

Rimol, L. M., Agartz, I., Djurovic, S., Brown, A. A., Roddey, J. C., Kahler, A. K., Mattingsdal, M., Athanasiu, L., Joyner, A. H., Schork, N. J., Halgren, E., Sundet, K., Melle, I., Dale, A. M., Andreassen, O. A., Weiner, M., Thal, L., Petersen, R., Jack, C. R., Jagust, W., Trojanowki, J., Toga, A. W., Beckett, L., Green, R. C., Gamst, A., Potter, W. Z., Montine, T., Anders, D., Bernstein, M., Felmlee, J., Fox, N., Thompson, P., Schuff, N., Alexander, G., Bandy, D., Koeppe, R. A., Foster, N., Reiman, E. M., Chen, K., Shaw, L., Lee, V. M.- Y., Korecka, M., Crawford, K., Neu, S., Harvey, D., Kornak, J., Kachaturian, Z., Frank, R., Snyder, P. J., Molchan, S., Kaye, J., Vorobik, R., Quinn, J., Schneider, L., Pawluczyk, S., Spann, B., Fleisher, A. S., Vanderswag, H., Heidebrink, J. L., Lord, J. L., Johnson, K., Doody, R. S., Villanueva-Meyer, J., Chowdhury, M., Stern, Yaakov, Honig, L. S., Bell, K. L., Morris, J. C., Mintun, M. A., Schneider, S., Marson, D., Griffith, R., Badger, B., Grossman, H., Tang, C., Stern, J., deToledo-Morrell, L., Shah, R. C., Bach, J., Duara, R., Isaacson, R., Strauman, S., Albert, M. S., Pedroso, J., Toroney, J., Rusinek, H., de Leon, M. J., De Santi, S. M., Doraiswamy, P. M., Petrella, J. R., Aiello, M., Clark, C. M., Pham, C., Nunez, J., Smith, C. D., Given II, C. A., Hardy, P., DeKosky, S. T., Oakley, M., Simpson, D. M., Ismail, M. S., Porsteinsson, A., McCallum, C., Cramer, S. C., Mulnard, R. A., McAdams-Ortiz, C., Diaz-Arrastia, R., Martin-Cook, K., DeVous, M., Levey, A. I., Lah, J. J., Cellar, J. S., Burns, J. M., Anderson, H. S., Laubinger, M. M., Bartzokis, G., Silverman, D. H. S., Lu, P. H., Fletcher, R., Parfitt, F., Johnson, H., Farlow, M., Herring, S., Hake, A. M., van Dyck, C. H., MacAvoy, M. G., Bifano, L. A., Chertkow, H., Bergman, H., Hosein, C., Black, S., Graham, S., Caldwell, C., Feldman, H., Assaly, M., Hsiung, G.-Y. R., Kertesz, A., Rogers, J., Trost, D., Bernick, C., Gitelman, D., Johnson, N., Mesulam, M., Sadowsky, C., Villena, T., Mesner, S., Aisen, P. S., Johnson, K. B., Behan, K. E., Sperling, R. A., Rentz, D. M., Johnson, K. A., Rosen, A., Tinklenberg, J., Ashford, W., Sabbagh, M., Connor, D., Obradov, S., Killiany, R., Norbash, A., Obisesan, T. O., Jayam-Trouth, A., Wang, P., Auchus, A. P., Huang, J., Friedland, R. P., DeCarli, C., Fletcher, E., Carmichael, O., Kittur, S., Mirje, S., Johnson, S. C., Borrie, M., Lee, T.-Y., Asthana, S., Carlsson, C. M., Potkin, S. G., Highum, D., Preda, A., Nguyen, D., Tariot, P. N., Hendin, B. A., Scharre, D. W., Kataki, M., Beversdorf, D. Q., Zimmerman, E. A., Celmins, D., Brown, A. D., Gandy, S., Marenberg, M. E., Rovner, B. W., Pearlson, G., Blank, K., Anderson, K., Saykin, A. J., Santulli, R. B., Pare, N., Williamson, J. D., Sink, K. M., Potter, H., Ashok Raj, B., Giordano, A., Ott, B. R., Wu, C.-K., Cohen, R., Wilks, K. L., and Alzheimer's Disease Neuroimaging Initiative

Subjects
Adult, Male, Microcephaly, Molecular Sequence Data, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Brain mapping, ASPM, Sex Factors, medicine, Animals, Humans, SNP, Genetic Predisposition to Disease, Genetics, Brain Mapping, Multidisciplinary, CDK5RAP2, Brain morphometry, Brain, Middle Aged, Biological Sciences, medicine.disease, Magnetic Resonance Imaging, Phenotype, Brain size, Female
Abstract

Loss-of-function mutations in the genes associated with primary microcephaly (MCPH) reduce human brain size by about two-thirds, without producing gross abnormalities in brain organization or physiology and leaving other organs largely unaffected [Woods CG, et al. (2005) Am J Hum Genet 76:717–728]. There is also evidence suggesting that MCPH genes have evolved rapidly in primates and humans and have been subjected to selection in recent human evolution [Vallender EJ, et al. (2008) Trends Neurosci 31:637–644]. Here, we show that common variants of MCPH genes account for some of the common variation in brain structure in humans, independently of disease status. We investigated the correlations of SNPs from four MCPH genes with brain morphometry phenotypes obtained with MRI. We found significant, sex-specific associations between common, nonexonic, SNPs of the genes CDK5RAP2 , MCPH1 , and ASPM , with brain volume or cortical surface area in an ethnically homogenous Norwegian discovery sample ( n = 287), including patients with mental illness. The most strongly associated SNP findings were replicated in an independent North American sample ( n = 656), which included patients with dementia. These results are consistent with the view that common variation in brain structure is associated with genetic variants located in nonexonic, presumably regulatory, regions.

Published
2009
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16. Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity

Author

Jahanshad, N., Rajagopalan, P., Hua, X., Hibar, D. P., Nir, T. M., Toga, A. W., Jack, C. R., Saykin, A. J., Green, R. C., Weiner, M. W., Medland, S. E., Montgomery, G. W., Hansell, N. K., McMahon, K. L., de Zubicaray, G. I., Martin, N. G., Wright, M. J., Thompson, P. M., the Alzheimer's Disease Neuroimaging Initiative, Weiner, M., Aisen, P., Petersen, R., Jagust, W., Trojanowski, J. Q., Beckett, L., Morris, J., Liu, E., Montine, T., Gamst, A., Thomas, R. G., Donohue, M., Walter, S., Gessert, D., Sather, T., Harvey, D., Kornak, J., Dale, A., Bernstein, M., Felmlee, J., Fox, N., Thompson, P., Schuff, N., Alexander, G., DeCarli, C., Bandy, D., Koeppe, R. A., Foster, N., Reiman, E. M., Chen, K., Mathis, C., Cairns, N. J., Taylor-Reinwald, L., Trojanowki, J. Q., Shaw, L., Lee, V. M. Y., Korecka, M., Crawford, K., Neu, S., Foroud, T. M., Potkin, S., Shen, L., Khachaturian, Z., Frank, R., Snyder, P. J., Molchan, S., Kaye, J., Quinn, J., Lind, B., Dolen, S., Schneider, L. S., Pawluczyk, S., Spann, B. M., Brewer, J., Vanderswag, H., Heidebrink, J. L., Lord, J. L., Johnson, K., Doody, R. S., Villanueva-Meyer, J., Chowdhury, M., Stern, Yaakov, Honig, L. S., Bell, K. L., Morris, J. C., Ances, B., Carroll, M., Leon, S., Mintun, M. A., Schneider, S., Marson, D., Griffith, R., Clark, D., Grossman, H., Mitsis, E., Romirowsky, A., deToledo-Morrell, L., Shah, R. C., Duara, R., Varon, D., Roberts, P., Albert, M., Onyike, C., Kielb, S., Rusinek, H., de Leon, M. J., Glodzik, L., De Santi, S., Doraiswamy, P. M., Petrella, J. R., Coleman, R. E., Arnold, S. E., Karlawish, J. H., Wolk, D., Smith, C. D., Jicha, G., Hardy, P., Lopez, O. L., Oakley, M., Simpson, D. M., Porsteinsson, A. P., Goldstein, B. S., Martin, K., Makino, K. M., Ismail, M. S., Brand, C., Mulnard, R. A., Thai, G., Mc-Adams-Ortiz, C., Womack, K., Mathews, D., Quiceno, M., Diaz-Arrastia, R., King, R., Martin-Cook, K., DeVous, M., Levey, A. I., Lah, J. J., Cellar, J. S., Burns, J. M., Anderson, H. S., Swerdlow, R. H., Apostolova, L., Lu, P. H., Bartzokis, G., Silverman, D. H. S., Graff-Radford, N. R., Parfitt, F., Johnson, H., Farlow, M. R., Hake, A. M., Matthews, B. R., Herring, S., van Dyck, C. H., Carson, R. E., MacAvoy, M. G., Chertkow, H., Bergman, H., Hosein, C., Black, S., Stefanovic, B., Caldwell, C., Hsiung, G.-Y. R., Feldman, H., Mudge, B., Assaly, M., Kertesz, A., Rogers, J., Trost, D., Bernick, C., Munic, D., Kerwin, D., Mesulam, M.-M., Lipowski, K., Wu, C.-K., Johnson, N., Sadowsky, C., Martinez, W., Villena, T., Turner, R. S., Reynolds, B., Sperling, R. A., Johnson, K. A., Marshall, G., Frey, M., Yesavage, J., Taylor, J. L., Lane, B., Rosen, A., Tinklenberg, J., Sabbagh, M., Belden, C., Jacobson, S., Kowall, N., Killiany, R., Budson, A. E., Norbash, A., Johnson, P. L., Obisesan, T. O., Wolday, S., Bwayo, S. K., Lerner, A., Hudson, L., Ogrocki, P., Fletcher, E., Carmichael, O., Olichney, J., Kittur, S., Borrie, M., Lee, T.- Y., Bartha, R., Johnson, S., Asthana, S., Carlsson, C. M., Potkin, S. G., Preda, A., Nguyen, D., Tariot, P., Fleisher, A., Reeder, S., Bates, V., Capote, H., Rainka, M., Scharre, D. W., Kataki, M., Zimmerman, E. A., Celmins, D., Brown, A. D., Pearlson, G. D., Blank, K., Anderson, K., Santulli, R. B., Schwartz, E. S., Sink, K. M., Williamson, J. D., Garg, P., Watkins, F., Ott, B. R., Querfurth, H., Tremont, G., Salloway, S., Malloy, P., Correia, S., Rosen, H. J., Miller, B. L., Mintzer, J., Longmire, C. F., Spicer, K., Finger, E., Rachinsky, I., and Drost, D.

Published
2013
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17. Apolipoprotein E (APOE) genotype has dissociable effects on memory and attentional-executive network function in Alzheimer's disease

Author

Wolk, D. A., Dickerson, B. C., the Alzheimer's Disease Neuroimaging Initiative, Weiner, M., Aiello, M., Aisen, P., Albert, M. S., Alexander, G., Anderson, H. S., Anderson, K., Apostolova, L., Arnold, S., Ashford, W., Assaly, M., Asthana, S., Bandy, D., Bartha, R., Bates, V., Beckett, L., Bell, K. L., Benincasa, A. L., Bergman, H., Bernick, C., Bernstein, M., Black, S., Blank, K., Borrie, M., Brand, C., Brewer, J., Brown, A. D., Burns, J. M., Cairns, N. J., Caldwell, C., Capote, H., Carlsson, C. M., Carmichael, O., Cellar, J. S., Celmins, D., Chen, K., Chertkow, H., Chowdhury, M., Clark, D., Connor, D., Correia, S., Crawford, K., Dale, A., de Leon, M. J., De Santi, S. M., DeCarli, C., deToledo-Morrell, L., DeVous, M., Diaz-Arrastia, R., Dolen, S., Donohue, M., Doody, R. S., Doraiswamy, P. M., Duara, R., Englert, J., Farlow, M., Feldman, H., Felmlee, J., Fleisher, A., Fletcher, E., Foroud, T. M., Foster, N., Fox, N., Frank, R., Gamst, A., Given, C. A., Graff-Radford, N. R., Green, R. C., Griffith, R., Grossman, H., Hake, A. M., Hardy, P., Harvey, D., Heidebrink, J. L., Hendin, B. A., Herring, S., Honig, L. S., Hosein, C., Robin Hsiung, G.-Y., Hudson, L., Ismail, M. S., Jack, C. R., Jacobson, S., Jagust, W., Jayam-Trouth, A., Johnson, K., Johnson, H., Johnson, N., Johnson, K. A., Johnson, S., Kachaturian, Z., Karlawish, J. H., Kataki, M., Kaye, J., Kertesz, A., Killiany, R., Kittur, S., Koeppe, R. A., Korecka, M., Kornak, J., Kozauer, N., Lah, J. J., Laubinger, M. M., Lee, V. M.- Y., Lee, T.- Y., Lerner, A., Levey, A. I., Longmire, C. F., Lopez, O. L., Lord, J. L., Lu, P. H., MacAvoy, M. G., Malloy, P., Marson, D., Martin-Cook, K., Martinez, W., Marzloff, G., Mathis, C., Mc-Adams-Ortiz, C., Mesulam, M., Miller, B. L., Mintun, M. A., Mintzer, J., Molchan, S., Montine, T., Morris, J., Mulnard, R. A., Munic, D., Nair, A., Neu, S., Nguyen, D., Norbash, A., Oakley, M., Obisesan, T. O., Ogrocki, P., Ott, B. R., Parfitt, F., Pawluczyk, S., Pearlson, G., Petersen, R., Petrella, J. R., Potkin, S., Potter, W. Z., Preda, A., Quinn, J., Rainka, M., Reeder, S., Reiman, E. M., Rentz, D. M., Reynolds, B., Richard, J., Roberts, P., Rogers, J., Rosen, A., Rosen, H. J., Rusinek, H., Sabbagh, M., Sadowsky, C., Salloway, S., Santulli, R. B., Saykin, A. J., Scharre, D. W., Schneider, L., Schneider, S., Schuff, N., Shah, R. C., Shaw, L., Shen, L., Silverman, D. H. S., Simpson, D. M., Sink, K. M., Smith, C. D., Snyder, P. J., Spann, B. M., Sperling, R. A., Spicer, K., Stefanovic, B., Stern, Yaakov, Stopa, E., Tang, C., Tariot, P., Taylor-Reinwald, L., Thai, G., Thomas, R. G., Thompson, P., Tinklenberg, J., Toga, A. W., Tremont, G., Trojanowki, J. Q., Trost, D., Turner, R. S., van Dyck, C. H., Vanderswag, H., Varon, D., Villanueva-Meyer, J., Villena, T., Walter, S., Wang, P., Watkins, F., Williamson, J. D., Wolk, D., Wu, C.-K., Zerrate, M., and Zimmerman., E. A.

Published
2010
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18. A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly

Author

Ho, A. J., Stein, J. L., Hua, X., Lee, S., Hibar, D. P., Leow, A. D., Dinov, I. D., Toga, A. W., Saykin, A. J., Shen, L., Foroud, T., Pankratz, N., Huentelman, M. J., Craig, D. W., Gerber, J. D., Allen, A. N., Corneveaux, J. J., Stephan, D. A., DeCarli, C. S., DeChairo, B. M., Potkin, S. G., Jack, C. R., Weiner, M. W., Raji, C. A., Lopez, O. L., Becker, J. T., Carmichael, O. T., Thompson, P. M., the Alzheimer's Disease Neuroimaging Initiative, Weiner, M., Thal, L., Petersen, R., Jagust, W., Trojanowki, J., Beckett, L., Green, R. C., Gamst, A., Potter, W. Z., Montine, T., Anders, D., Bernstein, M., Felmlee, J., Fox, N., Thompson, P., Schuff, N., Alexander, G., Bandy, D., Koeppe, R. A., Foster, N., Reiman, E. M., Chen, K., Shaw, L., Lee, V. M.- Y., Korecka, M., Crawford, K., Neu, S., Harvey, D., Kornak, J., Kachaturian, Z., Frank, R., Snyder, P. J., Molchan, S., Kaye, J., Vorobik, R., Quinn, J., Schneider, L., Pawluczyk, S., Spann, B., Fleisher, A. S., Vanderswag, H., Heidebrink, J. L., Lord, J. L., Johnson, K., Doody, R. S., Villanueva-Meyer, J., Chowdhury, M., Stern, Yaakov, Honig, L. S., Bell, K. L., Morris, J. C., Mintun, M. A., Schneider, S., Marson, D., Griffith, R., Badger, B., Grossman, H., Tang, C., Stern, J., deToledo-Morrell, L., Shah, R. C., Bach, J., Duara, R., Isaacson, R., Strauman, S., Albert, M. S., Pedroso, J., Toroney, J., Rusinek, H., de Leon, M. J., De Santi, S. M., Doraiswamy, P. M., Petrella, J. R., Aiello, M., Clark, C. M., Pham, C., Nunez, J., Smith, C. D., Given II, C. A., Hardy, P., DeKosky, S. T., Oakley, M., Simpson, D. M., Ismail, M. S., Porsteinsson, A., McCallum, C., Cramer, S. C., Mulnard, R. A., McAdams-Ortiz, C., Diaz-Arrastia, R., Martin-Cook, K., DeVous, M., Levey, A. I., Lah, J. J., Cellar, J. S., Burns, J. M., Anderson, H. S., Laubinger, M. M., Bartzokis, G., Silverman, D. H. S., Lu, P. H., Fletcher, R., Parfitt, F., Johnson, H., Farlow, M., Herring, S., Hake, A. M., van Dyck, C. H., MacAvoy, M. G., Bifano, L. A., Chertkow, H., Bergman, H., Hosein, C., Black, S., Graham, S., Caldwell, C., Feldman, H., Assaly, M., Hsiung, G.-Y. R., Kertesz, A., Rogers, J., Trost, D., Bernick, C., Gitelman, D., Johnson, N., Mesulam, M., Sadowsky, C., Villena, T., Mesner, S., Aisen, P. S., Johnson, K. B., Behan, K. E., Sperling, R. A., Rentz, D. M., Johnson, K. A., Rosen, A., Tinklenberg, J., Ashford, W., Sabbagh, M., Connor, D., Obradov, S., Killiany, R., Norbash, A., Obisesan, T. O., Jayam-Trouth, A., Wang, P., Auchus, A. P., Huang, J., Friedland, R. P., DeCarli, C., Fletcher, E., Carmichael, O., Kittur, S., Mirje, S., Johnson, S. C., Borrie, M., Lee, T.-Y., Asthana, S., Carlsson, C. M., Highum, D., Preda, A., Nguyen, D., Tariot, P. N., Hendin, B. A., Scharre, D. W., Kataki, M., Beversdorf, D. Q., Zimmerman, E. A., Celmins, D., Brown, A. D., Gandy, S., Marenberg, M. E., Rovner, B. W., Pearlson, G., Blank, K., Anderson, K., Santulli, R. B., Pare, N., Williamson, J. D., Sink, K. M., Potter, H., Ashok Raj, B., Giordano, A., Ott, B. R., Wu, C.-K., Cohen, R., and Wilks, K. L.

Published
2010
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27. Cardiac resynchronisation therapy response predicts occurrence of atrial fibrillation in non-ischaemic dilated cardiomyopathy.

Author

D'Ascia, S. L., D'Ascia, C., Marino, V., Lombardi, A., Santulli, R., Chiariello, M., and Santulli, G.

Abstract

Summary Aim: The aim of this study was to determine whether or not cardiac resynchronization therapy (CRT) has a favourable effect on the incidence of new-onset atrial fibrillation (AF) in a homogeneous population of patients with non-ischaemic idiopathic-dilated cardiomyopathy and severe heart failure. Methods: We designed a single-centre prospective study and enrolled 58 patients AF naïve when received CRT. After 1 year of follow-up our population was subdivided into responders (72.4%) and non-responders (27.6%), so as to compare the incidence of AF after 1, 2 and 3 years of follow-up in these two groups. Results: Already after 1 year, there was a significant (p < 0.05) difference in new-onset AF in non-responder patients with respect to responders (18.2% vs. 3.3%). These data were confirmed at 2 years (33.3% vs. 12.2%) and 3 years (50.0% vs. 15.0%) follow-up. In particular, 3 years after device implantation non-responders had an increased risk to develop new-onset AF (OR = 5.67). Conclusions: This is the first study analysing long-term effects of CRT in a homogeneous population of patients with non-ischaemic dilated cardiomyopathy, indicating the favourable role of this non-pharmacological therapy on the prevention of AF. [ABSTRACT FROM AUTHOR]

Published
2011
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28. The Effect of Ovarian Steroidogenesis on Ovulation and Fertilizability in the in Vitro Perfused Rabbit Ovary1

Author

Yoshimura, Y., Hosoi, Y., Atlas, S. J., Bongiovanni, A. M., Santulli, R., and Wallach, E. E.

Abstract

The effects of aminoglutethimide phosphate (AGP) on ovulation, ovum maturation, fertilizability, and steroid production were studied with the use of an isolated perfused rabbit ovary preparation. AGP (10−3or 10−4M) was added to the perfusate of one ovary. The contralateral control ovary was perfused in medium alone. Thirty minutes later human chorionic gonadotropin (hCG) (50 IU) was added to the perfusate of all ovaries. No difference was observed in time of ovulation or ovulatory efficiency between controls and AGP-treated ovaries. The degree of ovum maturity and degeneration was also comparable in the two groups. Progesterone and estradiol production were significantly reduced by AGP treatment.A second experiment examined fertilizability of ova ovulated in vitro after perfusion with 10−3M AGP. AGP significantly reduced the rate of normal fertilization as observed 12 h after insemination. The percentage of inseminated ova with evidence of degeneration was greater in ova from AGP-treated ovaries than in those from controls, however, this difference was not significant.The study indicates that AGP affects neither hCG-induced ovulation nor meiotic resumption; however, fertilizability of ova from ovaries treated with AGP is impaired. These data suggest that the intrafollicular steroid environment may participate in cytoplasmic maturation of ovulated ova.

Published
1986
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29. Cardiovascular responses mediated by protease-activated receptor-2 (PAR-2) and thrombin receptor (PAR-1) are distinguished in mice deficient in PAR-2 or PAR-1.

Author

P, Damiano B, M, Cheung W, J, Santulli R, P, Fung-Leung W, K, Ngo, D, Ye R, L, Darrow A, K, Derian C, L, de Garavilla, and P, Andrade-Gordon

Abstract

We developed mice deficient in protease-activated receptor-2 (PAR-2) or PAR-1 to explore the pathophysiological functions of these receptors. In this report, we evaluated mean arterial pressure and heart rate (HR) changes in response to PAR-1 or PAR-2 activation in anesthetized wild-type (WT), PAR-1-deficient (PAR-1(-/-)), and PAR-2-deficient (PAR-2(-/-)) mice. In WT mice, TFLLRNPNDK, a PAR-1 selective activating peptide, caused hypotension and HR decreases at 1 micromol/kg. TFLLRNPNDK also caused secondary hypertension following L-NAME pretreatment. These responses were absent in PAR-1(-/-) mice. In WT mice, SLIGRL, a PAR-2 selective activating peptide, caused hypotension without changing HR at 0.3 micromol/kg. SLIGRL did not induce hypertension following Nomega-nitrol-arginine-methyl ester-HCl (L-NAME). The response to SLIGRL was absent in PAR-2(-/-) mice. SFLLRN, a nonselective receptor activating peptide caused hypotension and HR decreases in WT mice at 0.3 micromol/kg, as well as secondary hypertension following L-NAME. SFLLRN still induced hypotension in PAR-1(-/-) mice, but HR decrease and secondary hypertension following L-NAME were absent. The hypotensive and bradycardic responses to SFLLRN and TFLLRNPNDK in PAR-2(-/-) mice were accentuated compared with WT mice. By using mouse strains deficient in either PAR-1 or PAR-2, we confirmed the in vivo specificity of TFLLRNPNDK and SLIGRL as respective activating peptides for PAR-1 and PAR-2, and the distinct hemodynamic responses mediated by activation of PAR-1 or PAR-2. Moreover, the accentuated response to PAR-1 activation in PAR-2-deficient mice suggests a compensatory response and potential receptor cross-talk.

Published
1999

31. The effect of adrenergic agents on the ovulatory process in the in vitro perfused rabbit ovary

Author

Kobayashi, Y., Sjöberg, N.O., Walles, B., Owman, Ch., Wright, K.H., Santulli, R., and Wallach, E.E.

Abstract

The presence of adrenergic nerves and smooth muscle in the mammalian ovary has prompted an investigation of the role of this neuromuscular complex in the ovulatory process. The in vitro perfused rabbit ovary preparation was used to study the effects of adrenergic agents on ovulation. Ovaries were exposed to norepinephrine (NE) at four dose levels (6 × 10−6M, 10−7M, 10−8M, and 10−9M). Ovulation occurred in a dose-dependent fashion with 10−6M NE resulting in the greatest ovulatory efficiency (64.7%). Addition of NE to ovaries treated with the minimal effective dose of human chorionic gonadotropin (hCG) (5 IU) led to an increase (59.9%) in ovulatory efficiency when compared to that of the ovaries treated with hCG alone (25.9%) but was not associated with an increase when compared to that of the ovaries treated with NE alone at the same dose level. Phenoxybenzamine (PBZ), an irreversible α-receptor antagonist, or phentolamine (POA), a competitive α-adrenergic inhibitor, was added to perfused ovaries to determine if either agent could block hCG- or NE-induced ovulation. Neither PBZ (10−6M) nor POA (10−5M) had any effect on NE (10−8M)-induced ovulation. The addition to the perfusate of either PBZ or POA significantly reduced ovulatory efficiency associated with hCG stimulation (p < 0.02) but did not completely block ovulation. Determination of the stage of maturity of ovulated ova and follicular oocytes demonstrated that more than 85% of ova exposed to NE remained in the germinal vesicle stage. Only those ova exposed to hCG consistently achieved metaphase I or II. A high percentage of degenerated ova was observed in both ovulated ova and follicular oocytes exposed to POA. A positive correlation was observed between ovarian edema and ovulatory efficiency (p < 0.005). These experiments indicate that adrenergic receptors can contribute to follicle rupture. However, the failure of PBZ and POA to inhibit NE- or hCG-induced ovulation indicates that adrenergic receptors are not essential mediators of the ovulatory process.

Published
1983
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39. Exploring the intersection of e-commerce and context in family business in China: the effects on organisational form and identity

Author

Yong Wang, Rong Pei, Donella Caspersz, Salvatore Tomaselli, D'Allura G M, Colli A, Goel S., Agrò G, Bannò M, Calabrò A, Carreri A, Caspersz D, Colli A, Craig J.B, D'Allura G.M, Dawson A, De Massis A, Della Piana B, Faraci R, Fazio G, Feninger M, Ferlito R, Fricano S, Gallucci C, Gimenez D, Goel S, Haddad C, Kammerlander N, Labaki R, Lumpkin G.T, Meyer M, Rong P, Santulli R, Tomaselli S, Trento S, Varum C, Wang Y, Donella Caspersz, Yong Wang, Salvatore Tomaselli, and Rong Pei

Subjects
Settore SECS-P/07 - Economia Aziendale, Intersection, Family business, business.industry, Media studies, Identity (social science), Context (language use), e-commerce, innovation strategy, family business, China, institutional theory, institutional context, external context, internal context, Sociology, E-commerce, China, business
Abstract

This chapter melds these interests of understanding how the context of e-Commerce and family business affects organisational form and subsequently organisational identity by integrating a narrative about the development of family business and e-Commerce in China with an exploratory analysis of two Chinese family businesses. Institutional theory informs this discussion (Scott, 2008: Suddaby, Elsbach, Greenwood, Meyer and Zilber, 2010). After describing why businesses adopt e-Commerce, and illustrating the contextual conditions in China that foster the development of private enterprises such as family businesses, and the adoption of e-Commerce, the chapter subsequently explores the question “given the context of “newness” of both private enterprises such as family businesses and e-Commerce in China, how is the organisational form of family businesses in China affected by the adoption of e-Commerce?” The chapter thus makes a contribution to the edited collection by providing some insights about how institutional contexts create both opportunity and challenges for the sustainability of the family business model in the digital economy

Published
2019
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40. Adapting the Serious Illness Conversation Guide for Dementia Care.

Author

Berry CE, Montgomery SH, Santulli R, and Cullinan A

Subjects
Humans, Male, Female, Aged, Aged, 80 and over, Middle Aged, Interviews as Topic, Dementia therapy, Advance Care Planning organization & administration, Caregivers psychology, Communication
Abstract

Introduction: Advance care planning (ACP), a critical component of quality dementia care, is underutilized due to lack of clinician comfort and the challenging nature of ACP in this context. The Serious Illness Conversation Guide (SICG) is a well-validated clinician-facing tool, developed with patient and clinician input, to facilitate ACP. The aim of this project was to adapt the SICG for dementia for the first time to promote high-quality ACP. Methods: This study uses a mixed-methods approach to adapt the SICG tool for use in dementia care. Experts with relevant clinical, ethical, and topical knowledge were interviewed to develop alterations to the SICG for dementia care. Patients and caregivers were shown a mock interview of the adapted SICG for dementia (SICG-D) to elicit feedback. Results: 8 relevant experts were interviewed. Adaptations included topical alterations to make the conversation more applicable to dementia as well as alterations to the structure of the conversation to accommodate the patient-caregiver dyad. Twenty interviews were conducted with 14 patients and 18 caregivers (either together or separately). A thematic content analysis of interview transcripts demonstrated positive impressions of the tool. In anonymous survey results, 94% reported a positive impression of the conversation and 89% endorsed incorporation of the adapted guide into dementia healthcare. Conclusion: This paper presents the SICG-D, an adapted version of the SICG for use in dementia care. This guide leverages the strengths of the SICG to promote values-based ACP conversations and has been adapted to better facilitate patient-caregiver-clinician triadic communication., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Published
2024
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41. Discovery of potent and orally bioavailable indazole-based glucagon receptor antagonists for the treatment of type 2 diabetes.

Author

Xu G, Gaul MD, Song F, Du F, Liang Y, DesJarlais RL, DiLoreto K, Shook B, Rentzeperis D, Santulli R, Eckardt A, and Demarest K

Subjects
Amino Acid Sequence, Animals, Blood Glucose drug effects, Carbohydrate Metabolism, Dogs, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Humans, Hypoglycemic Agents pharmacokinetics, Liver metabolism, Mice, Models, Molecular, Molecular Structure, Protein Binding, Rats, Structure-Activity Relationship, beta-Alanine pharmacokinetics, Diabetes Mellitus, Type 2 drug therapy, Hypoglycemic Agents chemical synthesis, Indazoles chemistry, Receptors, Glucagon antagonists & inhibitors, beta-Alanine chemical synthesis
Abstract

Type 2 diabetes mellitus (T2DM) is characterized by chronically elevated plasma glucose levels. The inhibition of glucagon-induced hepatic glucose output via antagonism of the glucagon receptor (GCGR) using a small-molecule antagonist is a promising mechanism for improving glycemic control in the diabetic state. The present work discloses the discovery of indazole-based β-alanine derivatives as potent GCGR antagonists through an efficient enantioselective synthesis and structure-activity relationship (SAR) exploration and optimization. Compounds within this class exhibited excellent pharmacokinetic properties in multiple preclinical species. In an acute dog glucagon challenge test, compound 13K significantly inhibited glucagon-mediated blood glucose increase when dosed orally at 10 mg/kg., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Published
2019
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42. Design, synthesis and structure activity relationships of indazole and indole derivatives as potent glucagon receptor antagonists.

Author

Song F, Xu G, Gaul MD, Zhao B, Lu T, Zhang R, DesJarlais RL, DiLoreto K, Huebert N, Shook B, Rentzeperis D, Santulli R, Eckardt A, and Demarest K

Subjects
Humans, Molecular Structure, Structure-Activity Relationship, Indazoles chemistry, Receptors, Glucagon antagonists & inhibitors
Abstract

A novel series of indazole/indole derivatives were discovered as glucagon receptor (GCGR) antagonists through scaffold hopping based on two literature leads: MK-0893 and LY-2409021. Further structure-activity relationship (SAR) exploration and optimization led to the discovery of multiple potent GCGR antagonists with excellent pharmacokinetic properties in mice and rats, including low systemic clearance, long elimination half-life, and good oral bioavailability. These potent GCGR antagonists could be used for potential treatment of type II diabetes., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Published
2019
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43. Arginine-specific protease from Porphyromonas gingivalis activates protease-activated receptors on human oral epithelial cells and induces interleukin-6 secretion.

Author

Lourbakos A, Potempa J, Travis J, D'Andrea MR, Andrade-Gordon P, Santulli R, Mackie EJ, and Pike RN

Subjects
Adhesins, Bacterial, Animals, CHO Cells, Calcium metabolism, Cell Line, Cricetinae, Epithelial Cells cytology, Epithelial Cells metabolism, Gene Expression, Gingipain Cysteine Endopeptidases, Gingiva cytology, Gingiva metabolism, Humans, Mouth Mucosa cytology, Mouth Mucosa metabolism, Receptor, PAR-1, Receptor, PAR-2, Receptors, Thrombin genetics, Cysteine Endopeptidases metabolism, Endopeptidases metabolism, Hemagglutinins metabolism, Interleukin-6 metabolism, Porphyromonas gingivalis enzymology, Receptors, Thrombin metabolism
Abstract

Periodontitis is a chronic inflammatory disease affecting oral tissues. Oral epithelial cells represent the primary barrier against bacteria causing the disease. We examined the responses of such cells to an arginine-specific cysteine proteinase (RgpB) produced by a causative agent of periodontal disease, Porphyromonas gingivalis. This protease caused an intracellular calcium transient in an oral epithelial cell line (KB), which was dependent on its enzymatic activity. Since protease-activated receptors (PARs) might mediate such signaling, reverse transcription-PCR was used to characterize the range of these receptors expressed in the KB cells. The cells were found to express PAR-1, PAR-2, and PAR-3, but not PAR-4. In immunohistochemical studies, human gingival epithelial cells were found to express PAR-1, PAR-2, and PAR-3 on their surface, but not PAR-4, indicating that the cell line was an effective model for the in vivo situation. PAR-1 and PAR-2 expression was confirmed in intracellular calcium mobilization assays by treatment of the cells with the relevant receptor agonist peptides. Desensitization experiments strongly indicated that signaling of the effects of RgpB was occurring through PAR-1 and PAR-2. Studies with cells individually transfected with each of these two receptors confirmed that they were both activated by RgpB. Finally, it was shown that, in the oral epithelial cell line, PAR activation by the bacterial protease-stimulated secretion of interleukin-6. This induction of a powerful proinflammatory cytokine suggests a mechanism whereby cysteine proteases from P. gingivalis might mediate inflammatory events associated with periodontal disease on first contact with a primary barrier of cells.

Published
2001
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44. Activation of protease-activated receptors by gingipains from Porphyromonas gingivalis leads to platelet aggregation: a new trait in microbial pathogenicity.

Author

Lourbakos A, Yuan YP, Jenkins AL, Travis J, Andrade-Gordon P, Santulli R, Potempa J, and Pike RN

Subjects
Adhesins, Bacterial, Animals, Blood Platelets cytology, Blood Platelets metabolism, Calcium metabolism, Cardiovascular Diseases etiology, Cell Line, Transformed, Cysteine Endopeptidases isolation & purification, Cysteine Endopeptidases metabolism, Gingipain Cysteine Endopeptidases, Hemagglutinins isolation & purification, Hemagglutinins metabolism, Humans, Mice, Periodontitis complications, Periodontitis microbiology, Protein Binding, Receptor, PAR-1, Receptor, PAR-2, Receptors, Thrombin agonists, Transfection, Bacteroidaceae Infections, Cysteine Endopeptidases pharmacology, Hemagglutinins pharmacology, Platelet Aggregation drug effects, Porphyromonas gingivalis enzymology, Receptors, Thrombin metabolism
Abstract

The bacterium Porphyromonas gingivalis is a major etiologic agent in the pathogenesis of adult periodontitis in humans. Cysteine proteinases produced by this pathogen, termed gingipains, are considered to be important virulence factors. Among many other potentially deleterious activities, arginine-specific gingipains-R (RgpB and HRgpA) efficiently activate coagulation factors. To further expand knowledge of the interaction between gingipains and the clotting cascade, this study examined their effects on cellular components of the coagulation system. The enzymes induced an increase in intracellular calcium in human platelets at nanomolar concentrations and caused platelet aggregation with efficiency comparable to thrombin. Both effects were dependent on the proteolytic activity of the enzymes. Based on desensitization studies carried out with thrombin and peptide receptor agonists, and immunoinhibition experiments, gingipains-R appeared to be activating the protease-activated receptors, (PAR)-1 and -4, expressed on the surface of platelets. This was confirmed by the finding that HRgpA and RgpB potently activated PAR-1 and PAR-4 in transfected cells stably expressing these receptors. Cumulatively, the results indicate the existence of a novel pathway of host cell activation by bacterial proteinases through PAR cleavage. This mechanism not only represents a new trait in bacterial pathogenicity, but may also explain an emerging link between periodontitis and cardiovascular disease. (Blood. 2001;97:3790-3797)

Published
2001
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45. Differential expression of protease-activated receptors-1 and -2 in stromal fibroblasts of normal, benign, and malignant human tissues.

Author

D'Andrea MR, Derian CK, Santulli RJ, and Andrade-Gordon P

Subjects
Actins analysis, Breast Neoplasms genetics, Breast Neoplasms metabolism, Carcinoma genetics, Carcinoma metabolism, Cell Division, Cells, Cultured, Female, Fibroblasts cytology, Humans, Immunohistochemistry, In Situ Hybridization, Neoplasms genetics, RNA, Messenger biosynthesis, RNA, Neoplasm biosynthesis, Receptor, PAR-1, Receptor, PAR-2, Receptors, Thrombin genetics, Fibroblasts metabolism, Neoplasms metabolism, Receptors, Thrombin biosynthesis, Stromal Cells metabolism
Abstract

The serine proteases thrombin and trypsin are among many factors that malignant cells secrete into the extracellular space to mediate metastatic processes such as cellular invasion, extracellular matrix degradation, angiogenesis, and tissue remodeling. The degree of protease secretion from malignant cells has been correlated to their metastatic potential. Protease activated receptors (PAR)-1 and -2, which are activated by thrombin and trypsin respectively, have not been extensively characterized in human tumors in situ. We investigated the presence of PAR-1 and PAR-2 in human normal, benign and malignant tissues using immunohistochemistry and in situ hybridization. Our results demonstrate PAR-1 and PAR-2 expression in the tumor cells, mast cells, macrophages, endothelial cells, and vascular smooth muscle cells of the metastatic tumor microenvironment. Most notably, an up-regulation of PAR-1 and PAR-2 observed in proliferating, smooth muscle actin (SMA)-positive stromal fibroblasts surrounding the carcinoma cells was not observed in normal or benign conditions. Furthermore, in vitro studies using proliferating, SMA-positive, human dermal fibroblasts, and scrape-wounded human dermal fibroblasts demonstrated the presence of PAR-1 and PAR-2 not detected in quiescent, SMA-negative cultures. PAR-1 and PAR-2 in the cells forming the tumor microenvironment suggest that these receptors mediate the signaling of secreted thrombin and trypsin in the processes of cellular metastasis.

Published
2001
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46. Protease-activated receptor-2 (PAR-2): structure-function study of receptor activation by diverse peptides related to tethered-ligand epitopes.

Author

Maryanoff BE, Santulli RJ, McComsey DF, Hoekstra WJ, Hoey K, Smith CE, Addo M, Darrow AL, and Andrade-Gordon P

Subjects
Amino Acid Motifs, Amino Acid Sequence, Amino Acid Substitution, Animals, Blood Platelets drug effects, Blood Platelets metabolism, Blood Platelets physiology, Calcium metabolism, Calcium Signaling drug effects, Cell Line, Directed Molecular Evolution, Dose-Response Relationship, Drug, Drug Design, Humans, Ligands, Mice, Peptide Library, Peptides genetics, Peptides metabolism, Platelet Aggregation drug effects, Rats, Receptor, PAR-1, Receptor, PAR-2, Receptors, Thrombin chemistry, Receptors, Thrombin genetics, Structure-Activity Relationship, Peptides chemistry, Peptides pharmacology, Receptors, Thrombin agonists, Receptors, Thrombin metabolism
Abstract

Protease-activated receptor-2 (PAR-2) is a tethered-ligand, G-protein-coupled receptor that is activated by proteolytic cleavage or by small peptides derived from its cleaved N-terminal sequence, such as SLIGRL-NH2. To assess specific PAR activity, we developed an immortalized murine PAR-1 (-/-) cell line transfected with either human PAR-2 or PAR-1. A "directed" library of more than 100 PAR agonist peptide analogues was synthesized and evaluated for PAR-2 and PAR-1 activity to establish an in-depth structure-function profile for specific action on PAR-2. The most potent agonist peptides (EC50 = 2-4 microM) had Lys at position 6, Ala at position 4, and pFPhe at position 2; however, these also exhibited potent PAR-1 activity (EC50 = 0.05-0.35 microM). We identified SLIARK-NH2 and SL-Cha-ARL-NH2 as relatively potent, highly selective PAR-2 agonists with EC50 values of 4 microM. Position 1 did not tolerate basic, acidic, or large hydrophobic amino acids. N-Terminal capping by acetyl eliminated PAR-2 activity, although removal of the amino group reduced potency by just 4-fold. At position 2, substitution of Leu by Cha or Phe gave equivalent PAR-2 potency, but this modification also activated PAR-1, whereas Ala, Asp, Lys, or Gln abolished PAR-2 activity; at position 3, Ile and Cha were optimal, although various amino acids were tolerated; at position 4, Ala or Cha increased PAR-2 potency 2-fold, although Cha introduced PAR-1 activity; at position 5, Arg or Lys could be replaced successfully by large hydrophobic amino acids. These results with hexapeptide C-terminal amides that mimic the native PAR-2 ligand indicate structural modes for obtaining optimal PAR-2 activity, which could be useful for the design of PAR-2 antagonists.

Published
2001
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47. The relationship between fMRI activation and cerebral atrophy: comparison of normal aging and alzheimer disease.

Author

Johnson SC, Saykin AJ, Baxter LC, Flashman LA, Santulli RB, McAllister TW, and Mamourian AC

Subjects
Adult, Aged, Aging, Atrophy, Female, Humans, Male, Middle Aged, Reference Values, Regression Analysis, Alzheimer Disease pathology, Brain growth & development, Brain pathology, Magnetic Resonance Imaging
Abstract

Functional MRI has recently been used to examine activation associated with aging and dementia, yet little is known regarding the effect of cerebral atrophy on fMRI signal. The purpose of this study was to examine the relationship between measures of global and regionally specific atrophy and fMRI activation in normal aging and in Alzheimer disease (AD). Two groups of subjects were studied with echoplanar imaging and quantitative structural volumetry: healthy controls spanning a broad age and atrophy range (n = 16) and patients with mild AD (n = 8). Results from a semantic task previously found to activate left inferior frontal (LIFG) and left superior temporal (LSTG) gyri were analyzed. The correlations between clusters of activation in the LIFG and LSTG and measures of local atrophy in the LIFG and LSTG regions were evaluated. For control subjects, there was no significant correlation between activation and regional or total brain atrophy (for LIFG r = -0.03, NS; for LSTG r = 0.20, NS). In contrast, for AD patients, there was a significant positive correlation between atrophy and activation in LIFG (r = 0.70, P = 0.05) but not LSTG (r = 0.00, NS). These results suggest that activation of language regions and atrophy within those regions may be independent among healthy adults spanning a broad age and atrophy range. However, in AD, a relationship exists in the LIFG that may reflect compensatory recruitment of cortical units or disease-specific changes in the hemodynamic response., (Copyright 2000 Academic Press.)

Published
2000
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48. Design, synthesis, and biological characterization of a peptide-mimetic antagonist for a tethered-ligand receptor.

Author

Andrade-Gordon P, Maryanoff BE, Derian CK, Zhang HC, Addo MF, Darrow AL, Eckardt AJ, Hoekstra WJ, McComsey DF, Oksenberg D, Reynolds EE, Santulli RJ, Scarborough RM, Smith CE, and White KB

Subjects
Base Sequence, Cell Line, DNA Primers, Humans, Peptides metabolism, Peptides pharmacology, Platelet Aggregation Inhibitors chemical synthesis, Platelet Aggregation Inhibitors metabolism, Platelet Aggregation Inhibitors pharmacology, Radioligand Assay, Receptor, PAR-1, Receptors, Thrombin metabolism, Molecular Mimicry, Peptides chemical synthesis, Receptors, Thrombin antagonists & inhibitors
Abstract

Protease-activated receptors (PARs) represent a unique family of seven-transmembrane G protein-coupled receptors, which are enzymatically cleaved to expose a truncated extracellular N terminus that acts as a tethered activating ligand. PAR-1 is cleaved and activated by the serine protease alpha-thrombin, is expressed in various tissues (e.g., platelets and vascular cells), and is involved in cellular responses associated with hemostasis, proliferation, and tissue injury. We have discovered a series of potent peptide-mimetic antagonists of PAR-1, exemplified by RWJ-56110. Spatial relationships between important functional groups of the PAR-1 agonist peptide epitope SFLLRN were employed to design and synthesize candidate ligands with appropriate groups attached to a rigid molecular scaffold. Prototype RWJ-53052 was identified and optimized via solid-phase parallel synthesis of chemical libraries. RWJ-56110 emerged as a potent, selective PAR-1 antagonist, devoid of PAR-1 agonist and thrombin inhibitory activity. It binds to PAR-1, interferes with PAR-1 calcium mobilization and cellular function (platelet aggregation; cell proliferation), and has no effect on PAR-2, PAR-3, or PAR-4. By flow cytometry, RWJ-56110 was confirmed as a direct inhibitor of PAR-1 activation and internalization, without affecting N-terminal cleavage. At high concentrations of alpha-thrombin, RWJ-56110 fully blocked activation responses in human vascular cells, albeit not in human platelets; whereas, at high concentrations of SFLLRN-NH(2), RWJ-56110 blocked activation responses in both cell types. Thus, thrombin activates human platelets independently of PAR-1, i.e., through PAR-4, which we confirmed by PCR analysis. Selective PAR-1 antagonists, such as RWJ-56110, should serve as useful tools to study PARs and may have therapeutic potential for treating thrombosis and restenosis.

Published
1999
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49. Neuroanatomic substrates of semantic memory impairment in Alzheimer's disease: patterns of functional MRI activation.

Author

Saykin AJ, Flashman LA, Frutiger SA, Johnson SC, Mamourian AC, Moritz CH, O'Jile JR, Riordan HJ, Santulli RB, Smith CA, and Weaver JB

Subjects
Aged, Cognition Disorders diagnosis, Female, Humans, Magnetic Resonance Imaging, Male, Memory Disorders diagnosis, Neuropsychological Tests, Phonetics, Alzheimer Disease, Brain Diseases complications, Brain Diseases pathology, Memory Disorders etiology, Semantics
Abstract

Impairment in semantic processing occurs early in Alzheimer's disease (AD) and differential impact on subtypes of semantic relations have been reported, yet there is little data on the neuroanatomic basis of these deficits. Patients with mild AD and healthy controls underwent 3 functional MRI auditory stimulation tasks requiring semantic or phonological decisions (match-mismatch) about word pairs (category-exemplar, category-function, pseudoword). Patients showed a significant performance deficit only on the exemplar task. On voxel-based fMRI activation analyses, controls showed a clear activation focus in the left superior temporal gyrus for the phonological task; patients showed additional foci in the left dorsolateral prefrontal and bilateral cingulate areas. On the semantic tasks, predominant activation foci were seen in the inferior and middle frontal gyrus (left greater than right) in both groups but patients showed additional activation suggesting compensatory recruitment of locally expanded foci and remote regions, for example, right frontal activation during the exemplar task. Covariance analyses indicated that exemplar task performance was strongly related to signal increase in bilateral medial prefrontal cortex. The authors conclude that fMRI can reveal similarities and differences in functional neuroanatomical processing of semantic and phonological information in mild AD compared to healthy elderly, and can help to bridge cognitive and neural investigations of the integrity of semantic networks in AD.

Published
1999
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50. Cardiovascular responses mediated by protease-activated receptor-2 (PAR-2) and thrombin receptor (PAR-1) are distinguished in mice deficient in PAR-2 or PAR-1.

Author

Damiano BP, Cheung WM, Santulli RJ, Fung-Leung WP, Ngo K, Ye RD, Darrow AL, Derian CK, de Garavilla L, and Andrade-Gordon P

Subjects
Animals, Blood Pressure drug effects, Female, Heart Rate drug effects, Male, Mice, Oligopeptides pharmacology, Receptor, PAR-2, Receptors, Thrombin deficiency, Receptors, Thrombin drug effects, Substrate Specificity, Blood Pressure physiology, Heart Rate physiology, Receptors, Thrombin physiology
Abstract

We developed mice deficient in protease-activated receptor-2 (PAR-2) or PAR-1 to explore the pathophysiological functions of these receptors. In this report, we evaluated mean arterial pressure and heart rate (HR) changes in response to PAR-1 or PAR-2 activation in anesthetized wild-type (WT), PAR-1-deficient (PAR-1(-/-)), and PAR-2-deficient (PAR-2(-/-)) mice. In WT mice, TFLLRNPNDK, a PAR-1 selective activating peptide, caused hypotension and HR decreases at 1 micromol/kg. TFLLRNPNDK also caused secondary hypertension following L-NAME pretreatment. These responses were absent in PAR-1(-/-) mice. In WT mice, SLIGRL, a PAR-2 selective activating peptide, caused hypotension without changing HR at 0.3 micromol/kg. SLIGRL did not induce hypertension following Nomega-nitrol-arginine-methyl ester-HCl (L-NAME). The response to SLIGRL was absent in PAR-2(-/-) mice. SFLLRN, a nonselective receptor activating peptide caused hypotension and HR decreases in WT mice at 0.3 micromol/kg, as well as secondary hypertension following L-NAME. SFLLRN still induced hypotension in PAR-1(-/-) mice, but HR decrease and secondary hypertension following L-NAME were absent. The hypotensive and bradycardic responses to SFLLRN and TFLLRNPNDK in PAR-2(-/-) mice were accentuated compared with WT mice. By using mouse strains deficient in either PAR-1 or PAR-2, we confirmed the in vivo specificity of TFLLRNPNDK and SLIGRL as respective activating peptides for PAR-1 and PAR-2, and the distinct hemodynamic responses mediated by activation of PAR-1 or PAR-2. Moreover, the accentuated response to PAR-1 activation in PAR-2-deficient mice suggests a compensatory response and potential receptor cross-talk.

Published
1999

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