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2. Robust, fully-automated assessment of cerebral perivascular spaces and white matter lesions: a multicentre MRI longitudinal study of their evolution and association with risk of dementia and accelerated brain atrophy

Author

Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jack, Clifford R., Jagust, William, Trojanowki, John Q., Toga, Arthur W., Beckett, Laurel, Green, Robert C., Saykin, Andrew J., Morris, John, Shaw, Leslie M., Liu, Enchi, Montine, Tom, Thomas, Ronald G., Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Jiminez, Gus, Harvey, Danielle, Bernstein, Matthew, Fox, Nick, Thompson, Paul, Schuff, Norbert, DeCarli, Charles, Borowski, Bret, Gunter, Jeff, Senjem, Matt, Vemuri, Prashanthi, Jones, David, Kantarci, Kejal, Ward, Chad, Koeppe, Robert A., Foster, Norm, Reiman, Eric M., Chen, Kewei, Mathis, Chet, Landau, Susan, Cairns, Nigel J., Householder, Erin, Reinwald, Lisa Taylor, Lee, Virginia, Korecka, Magdalena, Figurski, Michal, Crawford, Karen, Neu, Scott, Foroud, Tatiana M., Potkin, Steven, Shen, Li, Kelley, Faber, Kim, Sungeun, Nho, Kwangsik, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J., Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Carter, Raina, Dolen, Sara, Schneider, Lon S., Pawluczyk, Sonia, Beccera, Mauricio, Teodoro, Liberty, Spann, Bryan M., Brewer, James, Vanderswag, Helen, Fleisher, Adam, Heidebrink, Judith L., Lord, Joanne L., Mason, Sara S., Albers, Colleen S., Knopman, David, Johnson, Kris, Doody, Rachelle S., Meyer, Javier Villanueva, Chowdhury, Munir, Rountree, Susan, Dang, Mimi, Stern, Yaakov, Honig, Lawrence S., Bell, Karen L., Ances, Beau, Morris, John C., Carroll, Maria, Leon, Sue, Mintun, Mark A., Schneider, Stacy, Oliver, Angela, Marson, Daniel, Griffith, Randall, Clark, David, Geld-macher, David, Brockington, John, Roberson, Erik, Grossman, Hillel, Mitsis, Effie, Leyla deToledo-Morrell, Shah, Raj C., Duara, Ranjan, Varon, Daniel, Greig, Maria T., Roberts, Peggy, Albert, Marilyn, Onyike, Chiadi, D’Agostino, Daniel, Kielb, Stephanie, Galvin, James E., Pogorelec, Dana M., Cerbone, Brittany, Michel, Christina A., Rusinek, Henry, de Leon, Mony J., Glodzik, Lidia, De Santi, Susan, Doraiswamy, P. Murali, Petrella, Jeffrey R., Wong, Terence Z., Arnold, Steven E., Karlawish, Jason H., Wolk, David, Smith, Charles D., Jicha, Greg, Hardy, Peter, Sinha, Partha, Oates, Elizabeth, Conrad, Gary, Lopez, Oscar L., Oakley, MaryAnn, Simpson, Donna M., Porsteinsson, Anton P., Goldstein, Bonnie S., Martin, Kim, Makino, Kelly M., Ismail, M. Saleem, Brand, Connie, Mulnard, Ruth A., Thai, Gaby, Adams Ortiz, Catherine Mc, Womack, Kyle, Mathews, Dana, Quiceno, Mary, Arrastia, Ramon Diaz, King, Richard, Weiner, Myron, Cook, Kristen Martin, DeVous, Michael, Levey, Allan I., Lah, James J., Cellar, Janet S., Burns, Jeffrey M., Anderson, Heather S., Swerdlow, Russell H., Apostolova, Liana, Tingus, Kathleen, Woo, Ellen, Silverman, Daniel H.S., Lu, Po H., Bartzokis, George, Graff Radford, Neill R., Parfitt, Francine, Kendall, Tracy, Johnson, Heather, Farlow, Martin R., Hake, AnnMarie, Matthews, Brandy R., Herring, Scott, Hunt, Cynthia, van Dyck, Christopher H., Carson, Richard E., MacAvoy, Martha G., Chertkow, Howard, Bergman, Howard, Hosein, Chris, Black, Sandra, Stefanovic, Bojana, Caldwell, Curtis, Robin Hsiung, Ging-Yuek, Feldman, Howard, Mudge, Benita, Assaly, Michele, Kertesz, Andrew, Rogers, John, Trost, Dick, Bernick, Charles, Munic, Donna, Kerwin, Diana, Mesulam, Marek Marsel, Lipowski, Kristine, Wu, Chuang Kuo, Johnson, Nancy, Sadowsky, Carl, Martinez, Walter, Villena, Teresa, Turner, Raymond Scott, Johnson, Kathleen, Reynolds, Brigid, Sperling, Reisa A., Johnson, Keith A., Marshall, Gad, Frey, Meghan, Yesavage, Jerome, Taylor, Joy L., Lane, Barton, Rosen, Allyson, Tinklenberg, Jared, Sabbagh, Marwan N., Belden, Christine M., Jacobson, Sandra A., Sirrel, Sherye A., Kowall, Neil, Killiany, Ronald, Budson, Andrew E., Norbash, Alexander, Johnson, Patricia Lynn, Obisesan, Thomas O., Wolday, Saba, Allard, Joanne, Lerner, Alan, Ogrocki, Paula, Hudson, Leon, Fletcher, Evan, Carmichael, Owen, Olichney, John, Kittur, Smita, Borrie, Michael, Lee, T.Y., Bartha, Rob, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M., Potkin, Steven G., Preda, Adrian, Nguyen, Dana, Tariot, Pierre, Reeder, Stephanie, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Scharre, Douglas W., Kataki, Maria, Adeli, Anahita, Zimmerman, Earl A., Celmins, Dzintra, Brown, Alice D., Pearlson, Godfrey D., Blank, Karen, Anderson, Karen, Santulli, Robert B., Kitzmiller, Tamar J., Schwartz, Eben S., Sink, Kaycee M., Williamson, Jeff D., Garg, Pradeep, Watkins, Franklin, Ott, Brian R., Querfurth, Henry, Tremont, Geoffrey, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Rosen, Howard J., Miller, Bruce L., Mintzer, Jacobo, Spicer, Kenneth, Bachman, David, Finger, Elizabeth, Pasternak, Stephen, Rachinsky, Irina, Drost, Dick, Pomara, Nunzio, Hernando, Raymundo, Sarrael, Antero, Schultz, Susan K., Boles Ponto, Laura L., Shim, Hyungsub, Smith, Karen Elizabeth, Relkin, Norman, Chaing, Gloria, Raudin, Lisa, Smith, Amanda, Fargher, Kristin, Raj, Balebail Ashok, Barisano, Giuseppe, Iv, Michael, Choupan, Jeiran, and Hayden-Gephart, Melanie

Published
2025
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5. Neuroimaging of tissue microstructure as a marker of neurodegeneration in the AT(N) framework: defining abnormal neurodegeneration and improving prediction of clinical status

Author

Gallagher, Rigina L., Koscik, Rebecca Langhough, Moody, Jason F., Vogt, Nicholas M., Adluru, Nagesh, Kecskemeti, Steven R., Van Hulle, Carol A., Chin, Nathaniel A., Asthana, Sanjay, Kollmorgen, Gwendlyn, Suridjan, Ivonne, Carlsson, Cynthia M., Johnson, Sterling C., Dean, III, Douglas C., Zetterberg, Henrik, Blennow, Kaj, Alexander, Andrew L., and Bendlin, Barbara B.

Published
2023
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6. Associations between recall of proper names in story recall and CSF amyloid and tau in adults without cognitive impairment

Author

Hale, Madeline R., Langhough, Rebecca, Du, Lianlian, Hermann, Bruce P., Van Hulle, Carol A., Carboni, Margherita, Kollmorgen, Gwendlyn, Basche, Kristin E., Bruno, Davide, Sanson-Miles, Leah, Jonaitis, Erin M., Chin, Nathaniel A., Okonkwo, Ozioma C., Bendlin, Barbara B., Carlsson, Cynthia M., Zetterberg, Henrik, Blennow, Kaj, Betthauser, Tobey J., Johnson, Sterling C., and Mueller, Kimberly D.

Published
2024
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8. Circular-SWAT for deep learning based diagnostic classification of Alzheimer's disease: application to metabolome data

Author

Kaddurah-Daouk, Rima, Kueider-Paisley, Alexandra, Doraiswamy, P. Murali, Blach, Colette, Moseley, Arthur, Thompson, Will, St John-Williams, Lisa, Mahmoudiandehkhordi, Siamak, Tenenbaum, Jessica, Welsh-Balmer, Kathleen, Plassman, Brenda, Saykin, Andrew J., Nho, Kwangsik, Risacher, Shannon L., Kastenmüller, Gabi, Arnold, Matthias, Han, Xianlin, Baillie, Rebecca, Knight, Rob, Dorrestein, Pieter, Brewer, James, Mayer, Emeran, Labus, Jennifer, Baldi, Pierre, Gupta, Arpana, Fiehn, Oliver, Barupal, Dinesh, Meikle, Peter, Mazmanian, Sarkis, Rader, Dan, Kling, Mitchel, Shaw, Leslie, Trojanowski, John, van Duijin, Cornelia, Nevado-Holgado, Alejo, Bennett, David, Krishnan, Ranga, Keshavarzian, Ali, Vogt, Robin, Ikram, Arfan, Hankemeier, Thomas, Thiele, Ines, Price, Nathan, Funk, Cory, Baloni, Priyanka, Jia, Wei, Wishart, David, Brinton, Roberta, Chang, Rui, Farrer, Lindsay, Au, Rhoda, Qiu, Wendy, Würtz, Peter, Koal, Therese, Mangravite, Lara, Krumsiek, Jan, Suhre, Karsten, Newman, John, Moreno, Herman, Foroud, Tatania, Sacks, Frank, Jansson, Janet, Weiner, Michael W., Aisen, Paul, Petersen, Ronald, Jack, Clifford R., Jr., Jagust, William, Trojanowki, John Q., Toga, Arthur W., Beckett, Laurel, Green, Robert C., Morris, John C., Perrin, Richard J., Shaw, Leslie M., Khachaturian, Zaven, Carrillo, Maria, Potter, William, Barnes, Lisa, Bernard, Marie, Gonzalez, Hector, Ho, Carole, Hsiao, John K., Jackson, Jonathan, Masliah, Eliezer, Masterman, Donna, Okonkwo, Ozioma, Perrin, Richard, Ryan, Laurie, Silverberg, Nina, Fleisher, Adam, Sacrey, Diana Truran, Fockler, Juliet, Conti, Cat, Veitch, Dallas, Neuhaus, John, Jin, Chengshi, Nosheny, Rachel, Ashford, Miriam, Flenniken, Derek, Kormos, Adrienne, Montine, Tom, Rafii, Michael, Raman, Rema, Jimenez, Gustavo, Donohue, Michael, Gessert, Devon, Salazar, Jennifer, Zimmerman, Caileigh, Cabrera, Yuliana, Walter, Sarah, Miller, Garrett, Coker, Godfrey, Clanton, Taylor, Hergesheimer, Lindsey, Smith, Stephanie, Adegoke, Olusegun, Mahboubi, Payam, Moore, Shelley, Pizzola, Jeremy, Shaffer, Elizabeth, Sloan, Brittany, Harvey, Danielle, Forghanian-Arani, Arvin, Borowski, Bret, Ward, Chad, Schwarz, Christopher, Jones, David, Gunter, Jeff, Kantarci, Kejal, Senjem, Matthew, Vemuri, Prashanthi, Reid, Robert, Fox, Nick C., Malone, Ian, Thompson, Paul, Thomopoulos, Sophia I., Nir, Talia M., Jahanshad, Neda, DeCarli, Charles, Knaack, Alexander, Fletcher, Evan, Tosun-Turgut, Duygu, Chen, Stephanie Rossi, Choe, Mark, Crawford, Karen, Yushkevich, Paul A., Das, Sandhitsu, Koeppe, Robert A., Reiman, Eric M., Chen, Kewei, Mathis, Chet, Landau, Susan, Cairns, Nigel J., Householder, Erin, Franklin, Erin, Bernhardt, Haley, Taylor-Reinwald, Lisa, Korecka, Magdalena, Figurski, Michal, Neu, Scott, Apostolova, Liana G., Shen, Li, Foroud, Tatiana M., Nudelman, Kelly, Faber, Kelley, Wilmes, Kristi, Thal, Leon, Silbert, Lisa C., Lind, Betty, Crissey, Rachel, Kaye, Jeffrey A., Carter, Raina, Dolen, Sara, Quinn, Joseph, Schneider, Lon S., Pawluczyk, Sonia, Becerra, Mauricio, Teodoro, Liberty, Dagerman, Karen, Spann, Bryan M., Vanderswag, Helen, Ziolkowski, Jaimie, Heidebrink, Judith L., Zbizek-Nulph, Lisa, Lord, Joanne L., Mason, Sara S., Albers, Colleen S., Knopman, David, Johnson, Kris, Villanueva-Meyer, Javier, Pavlik, Valory, Pacini, Nathaniel, Lamb, Ashley, Kass, Joseph S., Doody, Rachelle S., Shibley, Victoria, Chowdhury, Munir, Rountree, Susan, Dang, Mimi, Stern, Yaakov, Honig, Lawrence S., Mintz, Akiva, Ances, Beau, Winkfield, David, Carroll, Maria, Stobbs-Cucchi, Georgia, Oliver, Angela, Creech, Mary L., Mintun, Mark A., Schneider, Stacy, Geldmacher, David, Love, Marissa Natelson, Griffith, Randall, Clark, David, Brockington, John, Marson, Daniel, Grossman, Hillel, Goldstein, Martin A., Greenberg, Jonathan, Mitsis, Effie, Shah, Raj C., Lamar, Melissa, Samuels, Patricia, Duara, Ranjan, Greig-Custo, Maria T., Rodriguez, Rosemarie, Albert, Marilyn, Onyike, Chiadi, Farrington, Leonie, Rudow, Scott, Brichko, Rottislav, Kielb, Stephanie, Smith, Amanda, Raj, Balebail Ashok, Fargher, Kristin, Sadowski, Martin, Wisniewski, Thomas, Shulman, Melanie, Faustin, Arline, Rao, Julia, Castro, Karen M., Ulysse, Anaztasia, Chen, Shannon, Sheikh, Mohammed O., Singleton-Garvin, Jamika, Petrella, JeffreyR., James, Olga, Wong, Terence Z., Borges-Neto, Salvador, Karlawish, Jason H., Wolk, David A., Vaishnavi, Sanjeev, Clark, Christopher M., Arnold, Steven E., Smith, Charles D., Jicha, Gregory A., Raslau, Flavius D., Lopez, Oscar L., Oakley, MaryAnn, Simpson, Donna M., Porsteinsson, Anton P., Martin, Kim, Kowalski, Nancy, Keltz, Melanie, Goldstein, Bonnie S., Makino, Kelly M., Ismail, M. Saleem, Brand, Connie, Thai, Gaby, Pierce, Aimee, Yanez, Beatriz, Sosa, Elizabeth, Witbracht, Megan, Kelley, Brendan, Nguyen, Trung, Womack, Kyle, Mathews, Dana, Quiceno, Mary, Levey, Allan I., Lah, James J., Hajjar, Ihab, Cellar, Janet S., Burns, Jeffrey M., Swerdlow, Russell H., Brooks, William M., Silverman, Daniel H.S., Kremen, Sarah, Apostolova, Liana, Tingus, Kathleen, Lu, Po H., Bartzokis, George, Woo, Ellen, Teng, Edmond, Graff-Radford, Neill R., Parfitt, Francine, Poki-Walker, Kim, Farlow, Martin R., Hake, Ann Marie, Matthews, Brandy R., Brosch, Jared R., Herring, Scott, van, Christopher H., Mecca, Adam P., Good, Susan P., MacAvoy, Martha G., Carson, Richard E., Varma, Pradeep, Chertkow, Howard, Vaitekunis, Susan, Hosein, Chris, Black, Sandra, Stefanovic, Bojana, Heyn, Chris (Chinthaka), Robin Hsiung, Ging-Yuek, Kim, Ellen, Mudge, Benita, Sossi, Vesna, Feldman, Howard, Assaly, Michele, Finger, Elizabeth, Pasternak, Stephen, Rachinsky, Irina, Kertesz, Andrew, Drost, Dick, Rogers, John, Grant, Ian, Muse, Brittanie, Rogalski, Emily, Robson, Jordan, Mesulam, M.-Marsel, Kerwin, Diana, Wu, Chuang-Kuo, Johnson, Nancy, Lipowski, Kristine, Weintraub, Sandra, Bonakdarpour, Borna, Pomara, Nunzio, Hernando, Raymundo, Sarrael, Antero, Rosen, Howard J., Miller, Bruce L., Perry, David, Turner, Raymond Scott, Johnson, Kathleen, Reynolds, Brigid, MCCann, Kelly, Poe, Jessica, Sperling, Reisa A., Johnson, Keith A., Marshall, Gad A., Yesavage, Jerome, Taylor, Joy L., Chao, Steven, Coleman, Jaila, White, Jessica D., Lane, Barton, Rosen, Allyson, Tinklenberg, Jared, Belden, Christine M., Atri, Alireza, Clark, Kelly A., Zamrini, Edward, Sabbagh, Marwan, Killiany, Ronald, Stern, Robert, Mez, Jesse, Kowall, Neil, Budson, Andrew E., Obisesan, Thomas O., Ntekim, Oyonumo E., Wolday, Saba, Khan, Javed I., Nwulia, Evaristus, Nadarajah, Sheeba, Lerner, Alan, Ogrocki, Paula, Tatsuoka, Curtis, Fatica, Parianne, Maillard, Pauline, Olichney, John, Carmichael, Owen, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Borrie, Michael, Lee, T.-Y., Bartha, Dr Rob, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M., Perrin, Allison, Burke, Anna, Scharre, Douglas W., Kataki, Maria, Tarawneh, Rawan, Hart, David, Zimmerman, Earl A., Celmins, Dzintra, Miller, Delwyn D., BolesPonto, Laura L., Smith, Karen Ekstam, Koleva, Hristina, Shim, Hyungsub, Nam, Ki Won, Schultz, Susan K., Williamson, Jeff D., Craft, Suzanne, Cleveland, Jo, Yang, Mia, Sink, Kaycee M., Ott, Brian R., Drake, Jonathan, Tremont, Geoffrey, Daiello, Lori A., Drake, Jonathan D., Ritter, Aaron, Bernick, Charles, Munic, Donna, O'Connelll, Abigail, Mintzer, Jacobo, Wiliams, Arthur, Masdeu, Joseph, Shi, Jiong, Garcia, Angelica, Newhouse, Paul, Potkin, Steven, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Kittur, Smita, Pearlson, Godfrey D., Blank, Karen, Anderson, Karen, Flashman, Laura A., Seltzer, Marc, Hynes, Mary L., Santulli, Robert B., Relkin, Norman, Chiang, Gloria, Lee, Athena, Lin, Michael, Ravdin, Lisa, Petersen, Ron, Neylan, Thomas, Grafman, Jordan, Danowski, Sarah, Nguyen-Barrera, Catherine, Hayes, Jacqueline, Finley, Shannon, Bernstein, Matthew, Senjem, Matt, Foster, Norm, Kim, Sungeun, Sood, Ajay, Blanchard, Kimberly S., Fleischman, Debra, Arfanakis, Konstantinos, Varon, Daniel, Greig, Maria T., Petrella, Jeffrey R., Goldstein, Bonnie, Martin, Kimberly S., Reist, Christopher, Sadowsky, Carl, Martinez, Walter, Villena, Teresa, Rosen, Howard, Marshall, Gad, Peskind, Elaine R., Petrie, Eric C., Li, Gail, Mackin, Scott, Jimenez-Maggiora, Gustavo, Drake, Erin, Donohue, Mike, Nelson, Craig, Bickford, David, Butters, Meryl, Zmuda, Michelle, Reyes, Denise, Faber, Kelley M., Nudelman, Kelly N., Au, Yiu Ho, Scherer, Kelly, Catalinotto, Daniel, Stark, Samuel, Ong, Elise, Fernandez, Dariella, Jo, Taeho, Kim, Junpyo, Bice, Paula, Huynh, Kevin, Wang, Tingting, Meikle, Peter J., and Giles, Corey

Published
2023
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12. Association between remote Traumatic Brain Injury and AD pathology, vascular injury, and cognitive decline among Veterans and non‐Veterans.

Author

Van Hulle, Carol A., Zylstra, Hanna, Betthauser, Tobey J., Du, Lianlian, Cole, Aleshia, Cronin, Katherine, Rivera‐Rivera, Leonardo A., Gleason, Carey E., Johnson, Sterling C., Zetterberg, Henrik, and Carlsson, Cynthia M.

Abstract

Background: Each year, millions of Americans experience mild traumatic brain injury (mTBI). Current research on the long‐term effects of mTBI vary considerably. Several mechanisms linking mTBI to dementia have been proposed including amyloid plaque formation and cerebrovascular injury following mTBI. Veterans have higher rates of mTBI than non‐Veterans. As efforts to increase Veteran enrollment in clinical trials and studies related to Alzheimer disease expand, it is critical to understand the potential impact of mTBI on cognitive ability and factors related to risk for AD. This study leveraged two cohorts to examine the association between history of mTBI and white matter hyperintensity lesion volume (WMLV), CSF pTau181, total tau, and Aβ42, and cognitive ability. Method: The sample comprises, N = 131 VA eligible Veterans without memory impairment enrolled in the Brain Amyloid and Vascular Effects of Eicosapentaenoic Acid (BRAVE) clinical trial (NCT02719327) and N = 320 participants in the Wisconsin ADRC clinical core, including n = 36 identified as Veterans. BRAVE participants reported if they had experienced symptoms of mTBI (e.g. loss of consciousness, dizziness, headache). ADRC participants indicated if they had a recent or remote mTBI; participants with a recent mTBI were excluded (n = 6). CSF samples were assayed using elecsys® beta‐Amyloid(1_42) CSF II, phopho‐Tau (181P), and Total tau assays (Roche Diagnostics International, Switzerland) and log‐transfomed prior to analyses. WMHLV adjusted for TIV was binarized to WMH presence or absence. Separate Preclinical Alzheimer's Cognitive Composite scores were created for BRAVE and were analyzed separately. Regression models included gender, age at study visit, clinical status and education level (PACC only) as covariates. Result: Demographics and study outcomes stratified by cohort and Veteran status are shown in Table 1 and 2. Veterans had higher rates of mTBI than non‐Veterans. History of mild TBI status was unrelated to study outcomes (see Figure 1; WMH presence: p =.06; CSF biomarkers: ps =.50 to.88; BRAVE‐PACC: p =.15, ADRC‐PACC, p =.48). Conclusion: History of mild TBI had no long‐term impact on cerebrovascular dysfunction, AD biomarkers or baseline cognitive performance. Further analyses will explore severity of TBI (with or without loss of consciousness) on study outcomes as well asexamine the impact of mTBIon change in cognitive performance and biomarkers of neuroinflammation. [ABSTRACT FROM AUTHOR]

Published
2024
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13. Amyloid-β positivity is less prevalent in cognitively unimpaired KLOTHO KL-VS heterozygotes.

Author

Cook, Noah, Driscoll, Ira, Gaitán, Julian M, Glittenberg, Matthew, Betthauser, Tobey J, Carlsson, Cynthia M, Johnson, Sterling C, Asthana, Sanjay, Zetterberg, Henrik, Blennow, Kaj, Kollmorgen, Gwendlyn, Quijano-Rubio, Clara, Dubal, Dena B, and Okonkwo, Ozioma C

Subjects
POSITRON emission tomography, ALZHEIMER'S disease, BLOOD proteins, CEREBROSPINAL fluid, TAU proteins
Abstract

Background: Klotho, encoded by the KLOTHO gene, is an anti-aging and neuroprotective protein. KLOTHO KL-VS heterozygosity (KL-VSHET) is hypothesized to be protective against the accumulation of Alzheimer's disease (AD) neuropathological hallmarks (amyloid-β (Aβ) and tau). Objective: We examine whether being positive for Aβ (A+) or tau (T+), or A/T joint status [positive for Aβ (A + T-), tau (A-T+), both (A + T+) or neither (A-T-)] vary by KL-VS and whether serum klotho protein levels vary based on A+, T+, or A/T status in a cohort enriched for AD risk. Methods: The sample consisted of 704 cognitively unimpaired, late middle-aged, and older adults; MeanAge(SD) = 64.9(8.3). Serum klotho was available for a sub-sample of 396 participants; MeanAge(SD) = 66.8(7.4). Covariate-adjusted logistic regression examined whether A + or T+, and multinomial regression examined whether A/T status, vary by KL-VS genotype. Covariate-adjusted linear regression examined whether serum klotho levels differ based on A+, T+, or A/T status. Results: A+ prevalence was lower in KL-VSHET (p = 0.05), with no differences in T + prevalence (p = 0.52). KL-VSHET also had marginally lower odds of being A + T- (p = 0.07). Serum klotho levels did not differ based on A+, T+, or A/T status (all ps ≥ 0.40). Conclusions: KL-VSHET is associated with lower odds of being positive for Aβ, regardless of whether one is also positive for tau. Conversely, the likelihood of being tau positive did not differ based on KL-VS genotype. Our findings add to the growing KLOTHO literature and suggests the need for further research focused on understanding the mechanisms underlying KL-VS-related putative resilience to AD. [ABSTRACT FROM AUTHOR]

Published
2024
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17. Fitness, independent of physical activity is associated with cerebral blood flow in adults at risk for Alzheimer’s disease

Author

Dougherty, Ryan J., Boots, Elizabeth A., Lindheimer, Jacob B., Stegner, Aaron J., Van Riper, Stephanie, Edwards, Dorothy F., Gallagher, Catherine L., Carlsson, Cynthia M., Rowley, Howard A., Bendlin, Barbara B., Asthana, Sanjay, Hermann, Bruce P., Sager, Mark A., Johnson, Sterling C., Okonkwo, Ozioma C., and Cook, Dane B.

Published
2020
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19. Measuring longitudinal cognition: Individual tests versus composites

Author

Jonaitis, Erin M., Koscik, Rebecca L., Clark, Lindsay R., Ma, Yue, Betthauser, Tobey J., Berman, Sara E., Allison, Samantha L., Mueller, Kimberly D., Hermann, Bruce P., Van Hulle, Carol A., Christian, Bradley T., Bendlin, Barbara B., Blennow, Kaj, Zetterberg, Henrik, Carlsson, Cynthia M., Asthana, Sanjay, and Johnson, Sterling C.

Published
2019
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20. Association between enrollment factors and incident cognitive impairment in Blacks and Whites: Data from the Alzheimer's Disease Center

Author

Gleason, Carey E., Norton, Derek, Zuelsdorff, Megan, Benton, Susan F., Wyman, Mary F., Nystrom, Naomi, Lambrou, Nickolas, Salazar, Hector, Koscik, Rebecca L., Jonaitis, Erin, Carter, Fabu, Harris, Brieanna, Gee, Alexander, Chin, Nathaniel, Ketchum, Frederick, Johnson, Sterling C., Edwards, Dorothy F., Carlsson, Cynthia M., Kukull, Walter, and Asthana, Sanjay

Published
2019
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22. Post‐GWAS multiomic functional investigation of the TNIP1 locus in Alzheimer's disease highlights a potential role for GPX3.

Author

Panyard, Daniel J., Reus, Lianne M., Ali, Muhammad, Liu, Jihua, Deming, Yuetiva K., Lu, Qiongshi, Kollmorgen, Gwendlyn, Carboni, Margherita, Wild, Norbert, Visser, Pieter J., Bertram, Lars, Zetterberg, Henrik, Blennow, Kaj, Gobom, Johan, Western, Dan, Sung, Yun Ju, Carlsson, Cynthia M., Johnson, Sterling C., Asthana, Sanjay, and Cruchaga, Carlos

Abstract

INTRODUCTION: Recent genome‐wide association studies (GWAS) have reported a genetic association with Alzheimer's disease (AD) at the TNIP1/GPX3 locus, but the mechanism is unclear. METHODS: We used cerebrospinal fluid (CSF) proteomics data to test (n = 137) and replicate (n = 446) the association of glutathione peroxidase 3 (GPX3) with CSF biomarkers (including amyloid and tau) and the GWAS‐implicated variants (rs34294852 and rs871269). RESULTS: CSF GPX3 levels decreased with amyloid and tau positivity (analysis of variance P = 1.5 × 10−5) and higher CSF phosphorylated tau (p‐tau) levels (P = 9.28 × 10−7). The rs34294852 minor allele was associated with decreased GPX3 (P = 0.041). The replication cohort found associations of GPX3 with amyloid and tau positivity (P = 2.56 × 10−6) and CSF p‐tau levels (P = 4.38 × 10−9). DISCUSSION: These results suggest variants in the TNIP1 locus may affect the oxidative stress response in AD via altered GPX3 levels. Highlights: Cerebrospinal fluid (CSF) glutathione peroxidase 3 (GPX3) levels decreased with amyloid and tau positivity and higher CSF phosphorylated tau.The minor allele of rs34294852 was associated with lower CSF GPX3. levels when also controlling for amyloid and tau category.GPX3 transcript levels in the prefrontal cortex were lower in Alzheimer's disease than controls.rs34294852 is an expression quantitative trait locus for GPX3 in blood, neutrophils, and microglia. [ABSTRACT FROM AUTHOR]

Published
2024
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23. Older adults at greater risk for Alzheimer's disease show stronger associations between sleep apnea severity in REM sleep and verbal memory.

Author

Lui, Kitty K., Dave, Abhishek, Sprecher, Kate E., Chappel-Farley, Miranda G., Riedner, Brady A., Heston, Margo B., Taylor, Chase E., Carlsson, Cynthia M., Okonkwo, Ozioma C., Asthana, Sanjay, Johnson, Sterling C., Bendlin, Barbara B., Mander, Bryce A., and Benca, Ruth M.

Subjects
DISEASE risk factors, RAPID eye movement sleep, OLDER people, SLEEP apnea syndromes, MIDDLE-aged persons
Abstract

Background: Obstructive sleep apnea (OSA) increases risk for cognitive decline and Alzheimer's disease (AD). While the underlying mechanisms remain unclear, hypoxemia during OSA has been implicated in cognitive impairment. OSA during rapid eye movement (REM) sleep is usually more severe than in non-rapid eye movement (NREM) sleep, but the relative effect of oxyhemoglobin desaturation during REM versus NREM sleep on memory is not completely characterized. Here, we examined the impact of OSA, as well as the moderating effects of AD risk factors, on verbal memory in a sample of middle-aged and older adults with heightened AD risk. Methods: Eighty-one adults (mean age:61.7 ± 6.0 years, 62% females, 32% apolipoprotein E ε4 allele (APOE4) carriers, and 70% with parental history of AD) underwent clinical polysomnography including assessment of OSA. OSA features were derived in total, NREM, and REM sleep. REM-NREM ratios of OSA features were also calculated. Verbal memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT). Multiple regression models evaluated the relationships between OSA features and RAVLT scores while adjusting for sex, age, time between assessments, education years, body mass index (BMI), and APOE4 status or parental history of AD. The significant main effects of OSA features on RAVLT performance and the moderating effects of AD risk factors (i.e., sex, age, APOE4 status, and parental history of AD) were examined. Results: Apnea–hypopnea index (AHI), respiratory disturbance index (RDI), and oxyhemoglobin desaturation index (ODI) during REM sleep were negatively associated with RAVLT total learning and long-delay recall. Further, greater REM-NREM ratios of AHI, RDI, and ODI (i.e., more events in REM than NREM) were related to worse total learning and recall. We found specifically that the negative association between REM ODI and total learning was driven by adults 60 + years old. In addition, the negative relationships between REM-NREM ODI ratio and total learning, and REM-NREM RDI ratio and long-delay recall were driven by APOE4 carriers. Conclusion: Greater OSA severity, particularly during REM sleep, negatively affects verbal memory, especially for people with greater AD risk. These findings underscore the potential importance of proactive screening and treatment of REM OSA even if overall AHI appears low. [ABSTRACT FROM AUTHOR]

Published
2024
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27. Association of longitudinal white matter degeneration and cerebrospinal fluid biomarkers of neurodegeneration, inflammation and Alzheimer’s disease in late-middle-aged adults

Author

Racine, Annie M., Merluzzi, Andrew P., Adluru, Nagesh, Norton, Derek, Koscik, Rebecca L., Clark, Lindsay R., Berman, Sara E., Nicholas, Christopher R., Asthana, Sanjay, Alexander, Andrew L., Blennow, Kaj, Zetterberg, Henrik, Kim, Won Hwa, Singh, Vikas, Carlsson, Cynthia M., Bendlin, Barbara B., and Johnson, Sterling C.

Published
2019
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31. Transethnic genome-wide scan identifies novel Alzheimer's disease loci

Author

Adams, Perrie M., Albert, Marilyn S., Albin, Roger L., Apostolova, Liana G., Arnold, Steven E., Asthana, Sanjay, Atwood, Craig S., Barmada, Michjael M., Barnes, Lisa L., Beach, Thomas G., Becker, James T., Bigio, Eileen H., Bird, Thomas D., Blacker, Deborah, Boeve, Bradley F., Bowen, James D., Boxer, Adam, Burke, James R., Cairns, Nigel J., Cao, Chuanhai, Carlson, Chris S., Carlsson, Cynthia M., Carney, Regina M., Carrasquillo, Minerva M., Carroll, Steven L., Chui, Helena C., Clark, David G., Corneveaux, Jason, Cribbs, David H., Crocco, Elizabeth A., Cruchaga, Carlos, De Jager, Philip L., DeCarli, Charles, DeKosky, Steven T., Demirci, F. Yesim, Dick, Malcolm, Dickson, Dennis W., Doody, Rachelle S., Duara, Ranjan, Ertekin-Taner, Nilufer, Faber, Kelley M., Fairchild, Thomas J., Fallon, Kenneth B., Farlow, Martin R., Ferris, Steven, Frosch, Matthew P., Galasko, Douglas R., Gearing, Marla, Geschwind, Daniel H., Ghetti, Bernardino, Gilbert, John R., Glass, Jonathan D., Graff-Radford, Neill R., Green, Robert C., Growdon, John H., Hakonarson, Hakon, Hamilton, Ronald L., Hardy, John, Harrell, Lindy E., Head, Elizabeth, Honig, Lawrence S., Huebinger, Ryan M., Huentelman, Matthew J., Hulette, Christine M., Hyman, Bradley T., Jarvik, Gail P., Jicha, Gregory A., Jin, Lee-Way, Karydas, Anna, Kauwe, John S.K., 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., 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., Mukherjee, Shubhabrata, Murrell, Jill R., Myers, Amanda J., O'Bryant, Sid, Olichney, John M., Pankratz, Vernon S., Parisi, Joseph E., Partch, Amanda, Paulson, Henry L., Perry, William, Peskind, Elaine, Petersen, Ronald C., Pierce, Aimee, Poon, Wayne W., Potter, Huntington, Quinn, Joseph F., Raj, Ashok, Raskind, Murray, Reisberg, Barry, Reisch, Joan S., Reitz, Christiane, Ringman, John M., Roberson, Erik D., Rogaeva, Ekaterina, Rosen, Howard J., Rosenberg, Roger N., Royall, Donald R., Sager, Mark A., 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., Wu, Chuang-Kuo, Yu, Chang-En, Yu, Lei, Zhang, Xiaoling, Jun, Gyungah R., Chung, Jaeyoon, Mez, Jesse, Barber, Robert, Beecham, Gary W., Bennett, David A., Buxbaum, Joseph D., Byrd, Goldie S., Crane, Paul K., De Jager, Philip, Evans, Denis, Fallin, M. Danielle, Foroud, Tatiana M., Friedland, Robert P., Goate, Alison M., Hendrie, Hugh, Hall, Kathleen S., Hamilton-Nelson, Kara L., Inzelberg, Rivka, Kamboh, M. Ilyas, Kukull, Walter A., Kunkle, Brian W., Kuwano, Ryozo, Larson, Eric B., Logue, Mark W., Manly, Jennifer J., Martin, Eden R., Montine, Thomas J., Naj, Adam, Reiman, Eric M., Sherva, Richard, St. George-Hyslop, Peter H., Thornton, Timothy, Younkin, Steven G., Wang, Li-San, Wendlund, Jens R., Winslow, Ashley R., Haines, Jonathan, Mayeux, Richard, Pericak-Vance, Margaret A., Schellenberg, Gerard, Lunetta, Kathryn L., and Farrer, Lindsay A.

Published
2017
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32. Circulating Klotho Is Higher in Cerebrospinal Fluid than Serum and Elevated Among KLOTHO Heterozygotes in a Cohort with Risk for Alzheimer’s Disease

Author

Gaitán, Julian M., Asthana, Sanjay, Carlsson, Cynthia M., Engelman, Corinne D., Johnson, Sterling C., Sager, Mark A., Wang, Dan, Dubal, Dena B., and Okonkwo, Ozioma C.

Subjects
Male, Heterozygote, Aging, Clinical Sciences, Article, Klotho, cerebrospinal fluid, Alzheimer Disease, Genetics, Acquired Cognitive Impairment, Humans, Glucuronidase, Neurology & Neurosurgery, Prevention, General Neuroscience, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative Diseases, General Medicine, Alzheimer's disease, Hormones, Brain Disorders, Psychiatry and Mental health, Clinical Psychology, KL-VS, Neurological, Female, Cognitive Sciences, Geriatrics and Gerontology, Alzheimer’s disease, serum
Abstract

Background: Klotho is a longevity and neuroprotective hormone encoded by the KLOTHO gene, and heterozygosity for the KL-VS variant confers a protective effect against neurodegenerative disease. Objective: Test whether klotho concentrations in serum or cerebrospinal fluid (CSF) vary as a function of KLOTHO KL-VS genotype, determine whether circulating klotho concentrations from serum and CSF differ from one another, and evaluate whether klotho levels are associated with Alzheimer’s disease risk factors. Methods: Circulating klotho was measured in serum (n = 1,116) and CSF (n = 183) of cognitively intact participants (aged 62.4 ± 6.5 years; 69.5% female). KLOTHO KL-VS zygosity (non-carrier; heterozygote; homozygote) was also determined. Linear regression was used to test whether klotho hormone concentration varied as a function of KL-VS genotype, specimen source, and demographic and clinical characteristics. Results: Serum and CSF klotho were higher in KL-VS carriers than non-carriers. Klotho concentration was higher in CSF than in serum. Females had higher serum and CSF klotho, while younger age was associated with higher klotho in CSF. Conclusion: In a cohort enriched for risk for Alzheimer’s disease, heterozygotic and homozygotic carriers of the KL-VS allele, females, and younger individuals have higher circulating klotho. Fluid source, KL-VS genotype, age, and sex should be considered in analyses of circulating klotho on brain health.

Published
2022
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34. Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology.

Author

Ashton, Nicholas J., Brum, Wagner S., Di Molfetta, Guglielmo, Benedet, Andrea L., Arslan, Burak, Jonaitis, Erin, Langhough, Rebecca E., Cody, Karly, Wilson, Rachael, Carlsson, Cynthia M., Vanmechelen, Eugeen, Montoliu-Gaya, Laia, Lantero-Rodriguez, Juan, Rahmouni, Nesrine, Tissot, Cecile, Stevenson, Jenna, Servaes, Stijn, Therriault, Joseph, Pascoal, Tharick, and Lleó, Alberto

Published
2024
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37. Cerebrospinal fluid ratios with Aβ42 predict preclinical brain β-amyloid accumulation

Author

Racine, Annie M., Koscik, Rebecca L., Nicholas, Christopher R., Clark, Lindsay R., Okonkwo, Ozioma C., Oh, Jennifer M., Hillmer, Ansel T., Murali, Dhanabalan, Barnhart, Todd E., Betthauser, Tobey J., Gallagher, Catherine L., Rowley, Howard A., Dowling, N. Maritza, Asthana, Sanjay, Bendlin, Barbara B., Blennow, Kaj, Zetterberg, Henrik, Carlsson, Cynthia M., Christian, Bradley T., and Johnson, Sterling C.

Published
2016
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38. Associations of sleep duration and daytime sleepiness with plasma amyloid beta and cognitive performance in cognitively unimpaired, middle-aged and older African Americans.

Author

Cook, Jesse D, Malik, Ammara, Plante, David T, Norton, Derek, Koscik, Rebecca Langhough, Du, Lianlian, Bendlin, Barbara B, Kirmess, Kris M, Holubasch, Mary S, Meyer, Matthew R, Venkatesh, Venky, West, Tim, Verghese, Philip B, Yarasheski, Kevin E, Thomas, Kevin V, Carlsson, Cynthia M, Asthana, Sanjay, Johnson, Sterling C, Gleason, Carey E, and Zuelsdorff, Megan

Published
2024
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39. CSF SNAP‐25 Correlations with Synaptic Density by [11C]‐UCB‐J‐PET Imaging and AD Biomarkers.

Author

Wilson, Rachael E, Jonaitis, Erin M., Langhough, Rebecca E, Betthauser, Tobey J, DiFilippo, Alexandra H, Christian, Bradley T., Okonkwo, Ozioma, Bendlin, Barbara B, Chin, Nathaniel A., Carlsson, Cynthia M, Asthana, Sanjay, Johnson, Sterling C, and Zetterberg, Henrik

Abstract

Background: Synaptic dysfunction occurs prior to neuronal loss in the early stages of AD. A biomarker reflective of these changes could indicate AD before clinical manifestations. SNAP‐25 is a potential candidate, but the relationship between SNAP‐25 and established AD biomarkers is unclear. Further investigation is needed to determine the utility of this biomarker during the pre‐clinical phase. Method: SNAP‐25 was measured using the Quanterix Single molecule array platform. A partial validation was conducted to evaluate assay performance in CSF and EDTA plasma. A cross‐sectional pilot study was then performed by measuring SNAP‐25 in CSF from 54 participants in the Wisconsin Registry for Alzheimer's Prevention (WRAP) and Wisconsin Alzheimer's Disease Research Center (WI‐ADRC) cohorts. SV2A synaptic density was measured in each participant using [11C]‐UCB‐J‐PET. Amyloid and tau status was determined in a subset of the group using [11C]‐PiB (N = 52) and [18F]‐MK6240‐PET (N = 44), respectively. Additional CSF biomarkers (Aß42, pTau‐181, and tTau) were measured using the Roche Cobas e601 Elecsys platform. A confirmatory study was performed with 80 additional WRAP and WI‐ADRC participants (53A+, 27 A‐). These participants did not have [11C]‐UCB‐J‐PET imaging. Result: The SNAP‐25 assay demonstrated excellent precision (<5% CV), recovery (96‐101%), and linearity in CSF. Plasma SNAP‐25 levels were detectable but inconsistent, suggesting matrix interference. In the pilot study, SNAP‐25 was highly correlated with CSF pTau‐181 and tTau (Figures 1A, 1B). SNAP‐25 was not correlated with CSF Aß42 (Figure 1C). A modest but significant correlation was observed with amyloid PET in the pilot study (Figure 2A) but not in the confirmatory study (Figure 3). SNAP‐25 did not correlate with SV2A density (Figure 2B) or fibrillary tau (Figure 2A). Mean SNAP‐25 levels were significantly different between amyloid‐ and tau‐positive groups compared to biomarker negative controls (p < 0.001 for amyloid, p < 0.05 for tau). Similar trends were observed in the confirmatory study (Figure 3). Conclusion: These results demonstrate a close relationship between SNAP‐25 and soluble tau in CSF, suggesting that CSF SNAP‐25 reflects early Aß‐induced neuronal impairment in a way that correlates with tau pathophysiology. This indicates that SNAP‐25 could be a useful biomarker of early neurodegeneration in pre‐clinical AD. [ABSTRACT FROM AUTHOR]

Published
2023
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40. An Update on the Building Bridges Study: Examining the effects of two interventions on trust in medical researchers and research attitudes among African American participants.

Author

Bouges, Shenikqua, Noell, Debra, Osman, Fauzia, Oby, Alayna, Benton, Susan Flowers, Clipps, Antwon D, Fischer, Barbara L., Gooding, Diane C., Anthony, Ruben L, Carter, Fabu P., Salazar, Hector, Simó, Carola A. Ferrer, Ennis, Gilda E., Van Hulle, Carol A., Zuelsdorff, Megan, Wyman, Mary F., Johnson, Adrienne L., Lambrou, Nickolas H., James, Taryn T., and Carlsson, Cynthia M.

Abstract

Background: Data suggest that establishing trust supports willingness to participate in research studies; yet there is a shortage of standardized systematic studies testing the effectiveness of various methods of building trust. The Building Bridges pilot study examined ways of establishing trust in communities of color comparing two different interventions. Method: Using African American community leaders' input, we conducted a mixed method study to investigate participants' 1) preferred format for community‐based interventions, 2) comfort with discussing dementia with researchers/healthcare providers, and 3) attitudes of trust about research and researchers. African American subjects (age ≥ 45 years) without self‐reported cognitive impairment completed research attitudes (RAQ) and trust in medical researcher questionnaires, pre‐ and post‐intervention; individual medication reviews (n = 48) and/or public community talks (n = 49). Quantitatively, we compared pre‐ and post‐ intervention outcomes with paired Wilcoxon non‐parametric sign rank tests; all qualitative themes were analyzed using Nvivo QSR 12. Result: Participants' mean age was 64 (SD = 9.9). See Table 1 for demographics. Quantitatively, there was greater change in research attitudes and trust following a medication review intervention compared to experiencing a community talk (Figure 1); e.g., participants expressed "positive views about medical research in general" on questionnaires following medication reviews (p = 0.007). Qualitatively, we found a similar trend during our focus group discussions. Focus group members expressed more comfort with the medication review than the community talk resulting from "positive bedside manners, positive feedback, personal 1‐on‐1 interactions and race concordance." Focus group participants noted a willingness to participate in future studies because of trust built from their Building Bridges team interactions. "Commonality, better connection, relatability, affinity and cultural similarities" all influenced trust and willingness to participate in future studies. Factors found to reduce trust included: "negative feedback, stereotypes, predominantly white practitioners in medicine and research, clinician unskillfulness, and not feeling seen as a "whole person" by providers" (Figure 2). Conclusion: Findings continue to support our hypothesis that more personalized community engagement approaches have a greater influence on participants' research attitudes and build interest in research. Additional studies of person‐centered recruitment strategies are essential to understanding how to improve trust and positive research attitudes among communities of color. [ABSTRACT FROM AUTHOR]

Published
2023
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41. Recruitment of Underrepresented Groups into the AHEAD Study: Strategic plan of Action.

Author

James, Taryn T., Gleason, Carey E., Gee, Alexander, Gooding, Diane C., Lofton, Brenda Caroll, Carter, Fabu P., Green‐Harris, Gina, Norris, Nia, Lawrence, Sacheen L., King, Margaret F, Salazar, Hector, Cardenas, Cecilia, Cole, Aleshia, Cronin, Katherine, Carlsson, Cynthia M, and Bouges, Shenikqua

Abstract

Background: To ensure that therapies are applicable for all groups, ethnic/racial diversity in Alzheimer's disease (AD) clinical trials is an ethical imperative. Toward this goal, we developed a recruitment model founded on 1) building trust by providing accurate and transparent information, and 2) using culturally sensitive approaches to address legitimate concerns. Our ultimate goal is to empower individuals from under‐represented groups (URG) to participate in AD research. Method: Our group focuses on recruitment of racialized groups. Using a multistep approach (figure1), we established partnerships and created community advisory boards (CABs) comprised of leaders who effectively advocate for community needs. Research projects are presented to the CABs to determine alignment with community needs. Assessments with community leaders and advisory networks help identify opportunities to fulfill community needs. Recruitment of African Americans (AA) into the AHEAD study, a study assessing the recently approved monoclonal antibody, lecanemab in participants with preclinical AD, began by presenting the project to the Black Leaders of Brain Health (BLBH) CAB. Incorporating their input into our approach, we will structure community talks and events in a culturally appropriate manner in discussions with the larger AA community. Example, we utilized a questionnaire at an event to introduce AA participants in a biomarker study to the AHEAD study (figures 2 & 3). Result: Feedback received from BLBH includes advocating to funders, including the NIH to fund research that reflects inclusivity and diversity. BLBH recommended building URG voices into study design by having a diverse scientific team and hiring community members to collect data. Additionally, rather than excessive compensation, researchers should speak to the study benefits both for the individual's and the community's health. Finally, BLBH members emphasized the need to include hopeful messages and advice to improve health, rather than merely pointing out that AA are most likely among racial groups to have the disease. Conclusion: Recruitment models involving trust building and partnerships with groups consisting of community members of URG will be mutually beneficial for both the health researcher and the communities that they serve. This may serve as a means to tip the scale toward increased participation by URG in biomedical research. [ABSTRACT FROM AUTHOR]

Published
2023
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42. Memory Screening in the Community: Increasing access to early detection, diagnosis, and care.

Author

Yang, Kao Lee, Kelble, Laura M., Felten, Kristen, Carlsson, Cynthia M, and Clark, Lindsay R.

Abstract

Community‐based memory screening may reduce barriers and increase access to earlier diagnosis and care of Alzheimer's disease and related dementias (ADRDs). The Memory Screening in the Community program was developed to provide cognitive screens for community members ("customers") through Aging & Disability Resource Centers (ADRCs) across the state of Wisconsin. We evaluated program results for screens completed between 2/2022‐12/2022. Trained ADRC staff administered a Memory Screening survey to customers during memory screening events, walk‐ins, or scheduled appointments. The Memory Screening survey collected site information, appointment type, demographics, living arrangements, and reasons for screen. Staff administered the Mini‐cog, Animal Naming, and/or AD8 instruments. Upon screen completion, staff indicated whether they recommended customers seek follow‐up evaluation with their primary care providers (PCPs) and provided education. After 6‐9 months, staff followed up with customers who received referrals over telephone to gather post‐screening and outcomes information. 647 surveys were completed across 39 counties and 5 tribal communities in Wisconsin (Figure 1). Most (∼52%) evaluations were conducted during a memory screening event and 37.4% of screens were completed due to customer memory concerns. Most customers were White (93.7%), women (70.2%), and between 70‐79 years old (31.7%; see Table). Screen results from 214 customers suggested potential cognitive impairment and they were recommended to follow‐up with their PCPs. Most memory screens included discussions about brain health, potential causes of symptoms, dementia warning signs, and importance of early detection (Figure 2). Of customers who were referred to PCPs and agreed to follow‐up calls (n = 166), 20 have completed follow‐up calls (data collection ongoing). Of these 20, 60% (n = 12) met with their PCPs, and 42% (n = 5) received a dementia diagnosis. The Memory Screening in the Community program is feasible and has potential to provide access for cognitive screening and dementia education, especially among rural communities. In addition, roughly 1/3 of all customers screened were referred to a provider. Preliminary follow‐up data suggests community‐screening programs could facilitate diagnostic evaluation and results will be updated with a larger follow‐up sample. Overall, this evaluation demonstrates that community memory screening programs may be an effective first‐line approach in addressing ADRD‐related concerns in the community. [ABSTRACT FROM AUTHOR]

Published
2023
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43. Two novel cerebrospinal fluid markers for vascular injury are associated with CSF markers of AD, neurodegeneration, and gliosis.

Author

Van Hulle, Carol A., Ince, Selvi, Jonaitis, Erin M., Betthauser, Tobey J, Kollmorgen, Gwendlyn, Wild, Norbert, Bendlin, Barbara B, Love, Seth, Asthana, Sanjay, Johnson, Sterling C, Carlsson, Cynthia M, Blennow, Kaj, Zetterberg, Henrik, and Miners, James Scott

Abstract

Background: Vascular dysfunction often occurs concurrently with Alzheimer's disease (AD). Breakdown of the blood–brain barrier (BBB) and vascular injury may be related to amyloid and tau pathology. In preliminary analyses, we examined the relationship between cerebrospinal fluid (CSF) biomarkers of AD, neurodegeneration, and glial activation, and two novel CSF markers of vascular dysfunction: soluble platelet‐derived growth factor receptor beta (sPDGFRβ) a marker of BBB integrity, and angiopoietin‐2 (Ang2), a marker of vascular injury. Method: CSF samples from participants enrolled in the Wisconsin Registry for Alzheimer's Prevention (WRAP) or the Wisconsin Alzheimer's Disease Research Center (WADRC) studies were assayed for markers of AD, neurodegeneration, and gliosis, using Roche NeuroToolKit® immunoassays (Roche Diagnostics International Ltd, Switzerland). A subset of serially sampled participants (N = 209, Nobs = 531) who spanned the AD clinical spectrum (cognitively unimpaired, MCI, dementia) underwent sPDGFRβ measurement (ELISA); a sample of N = 121 (Nobs= 276) was also assayed for Ang2 (ELISA) (Table 1). Pearson correlations were calculated for all CSF biomarkers. Linear mixed‐effects models with random intercepts, age‐at‐lumbar‐puncture as the measure of time, and CSF vascular biomarker as the outcome were used to test associations with tau positivity (>24.8 pg/mL), and cognitive status. Result: sPDGFRβ correlated with all CSF biomarkers (rs range.18 to.45, ps<.001, Figure 1A) except AB42/40. Ang2 correlated with all CSF biomarkers (rs range.21 to.45 ps <.001, Figure 1B) except AB42/40, and S100B. sPDGFRβ and Ang2 correlated most strongly with Aβ40 and biomarkers of synaptic function (neurogranin and α‐synuclein). Tau positivity was associated with sPDGFRβ in the whole sample (estimate = 64.5, p<.001) and excluding participants with MCI/dementia (estimate = 77.7, p<.001). Tau positivity was associated with Ang2 (estimate = 18.1, p =.007), however the association was not significant after excluding participants with MCI/dementia. There was no difference in sPDGFRβ across the AD clinical spectrum. Ang2 was higher among participants with MCI than cognitively unimpaired participants (estimate = 21.0, p =.037, Figure 2). Conclusion: CSF markers of vascular injury were elevated in MCI and were moderately related to tau pathology and markers of neuronal injury and neuroinflammation, but not amyloid pathology, providing insight into the association of of vascular injury to AD related disease [ABSTRACT FROM AUTHOR]

Published
2023
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44. Gut microbiome moderates the association between metabolic syndrome and the cerebrospinal fluid concentration of YKL‐40 in a cognitively unimpaired cohort.

Author

Peter, Darby, Heston, Margo B., Ennis, Gilda E., Knight, Rob, Kaddurah‐Daouk, Rima F., Johnson, Sterling C, Asthana, Sanjay, Carlsson, Cynthia M., Chin, Nathaniel A., Kollmorgen, Gwendlyn, Carboni, Margherita, Blennow, Kaj, Zetterberg, Henrik, Ulland, Tyler K., Rey, Federico E., and Bendlin, Barbara B

Abstract

Background: Type 2 diabetes (T2D) and metabolic syndrome (MetS) are associated with increased risk of dementia, as well as altered gut microbiome composition (Ott et al., 1999; Ley et al., 2006). However, the extent to which gut microbiome alterations moderate brain pathology in these conditions remains unclear. Here, we examined the extent to which MetS associates with altered cerebrospinal fluid (CSF) biomarkers of Alzheimer's Disease (AD), glial activation, and neurodegeneration, and whether MetS interacts with gut microbiome composition to impact brain pathology. Method: Cognitively unimpaired adults (n = 88, Wisconsin Registry for Alzheimer's Prevention and Wisconsin Alzheimer's Disease Research Center; Table 1) underwent fasting blood collection and lumbar puncture, and provided a stool sample. Twenty‐six percent (n = 23) of participants met MetS criteria. Fecal microbiota composition was characterized using 16S rRNA sequencing. QIIME2 was used to denoise and classify features, followed by Phyloseq to filter rare taxa, agglomerate taxa at the phylum rank, and compute relative abundances. Analyses centered on Firmicutes:Bacteroidetes, given its previously observed alterations in T2D and MetS (Stadlbauer et al., 2015). CSF biomarkers were quantified using a robust prototype assay as part of the Roche NeuroToolKit research platform. Multiple regression models were used to determine associations between MetS and CSF biomarkers in addition to Firmicutes:Bacteroidetes, and any MetS by Firmicutes:Bacteroidetes effects on CSF biomarkers. Results are reported as significant when p < 0.05, uncorrected. Result: A significant negative association between MetS and CSF YKL‐40 was observed (Figs. 1a, 1b), but no significant association between MetS and Firmicutes:Bacteroidetes (Fig 1c), nor associations with other CSF biomarkers (Table 2). MetS showed a significant interaction with Firmicutes:Bacteroidetes on YKL‐40 (Fig. 1d), as control participants with a higher ratio showed increased YKL‐40. Conclusion: In a cognitively unimpaired cohort, MetS was associated with lower CSF YKL‐40 (a marker of astrocytic activation) and moderated the relationship between Firmicutes:Bacteroidetes and CSF YKL‐40. While the direction of the findings was unexpected, T2D is associated with inhibition of astrocyte activation (Jing et al., 2013), and astroglial function is modulated by gut microbiota. Follow‐up studies are currently testing how gut microbiome modulates neuroimmune function in the context of AD. [ABSTRACT FROM AUTHOR]

Published
2023
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45. Large‐scale proteome and metabolome analysis of CSF implicates altered glucose and carbon metabolism and succinylcarnitine in Alzheimer's disease.

Author

Panyard, Daniel J., McKetney, Justin, Deming, Yuetiva K., Morrow, Autumn R., Ennis, Gilda E., Jonaitis, Erin M., Van Hulle, Carol A., Yang, Chengran, Sung, Yun Ju, Ali, Muhammad, Kollmorgen, Gwendlyn, Suridjan, Ivonne, Bayfield, Anna, Bendlin, Barbara B., Zetterberg, Henrik, Blennow, Kaj, Cruchaga, Carlos, Carlsson, Cynthia M., Johnson, Sterling C., and Asthana, Sanjay

Abstract

INTRODUCTION: A hallmark of Alzheimer's disease (AD) is the aggregation of proteins (amyloid beta [A] and hyperphosphorylated tau [T]) in the brain, making cerebrospinal fluid (CSF) proteins of particular interest. METHODS: We conducted a CSF proteome‐wide analysis among participants of varying AT pathology (n = 137 participants; 915 proteins) with nine CSF biomarkers of neurodegeneration and neuroinflammation. RESULTS: We identified 61 proteins significantly associated with the AT category (P < 5.46 × 10−5) and 636 significant protein‐biomarker associations (P < 6.07 × 10−6). Proteins from glucose and carbon metabolism pathways were enriched among amyloid‐ and tau‐associated proteins, including malate dehydrogenase and aldolase A, whose associations with tau were replicated in an independent cohort (n = 717). CSF metabolomics identified and replicated an association of succinylcarnitine with phosphorylated tau and other biomarkers. DISCUSSION: These results implicate glucose and carbon metabolic dysregulation and increased CSF succinylcarnitine levels with amyloid and tau pathology in AD. Highlights: Cerebrospinal fluid (CSF) proteome enriched for extracellular, neuronal, immune, and protein processing.Glucose/carbon metabolic pathways enriched among amyloid/tau‐associated proteins.Key glucose/carbon metabolism protein associations independently replicated.CSF proteome outperformed other omics data in predicting amyloid/tau positivity.CSF metabolomics identified and replicated a succinylcarnitine–phosphorylated tau association. [ABSTRACT FROM AUTHOR]

Published
2023
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47. Amyloid burden, cortical thickness, and cognitive function in the Wisconsin Registry for Alzheimer's Prevention

Author

Doherty, Benjamin M., Schultz, Stephanie A., Oh, Jennifer M., Koscik, Rebecca L., Dowling, N. Maritza, Barnhart, Todd E., Murali, Dhanabalan, Gallagher, Catherine L., Carlsson, Cynthia M., Bendlin, Barbara B., LaRue, Asenath, Hermann, Bruce P., Rowley, Howard A., Asthana, Sanjay, Sager, Mark A., Christian, Brad T., Johnson, Sterling C., and Okonkwo, Ozioma C.

Published
2015
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50. Amyloid burden and neural function in people at risk for Alzheimer's Disease

Author

Johnson, Sterling C., Christian, Bradley T., Okonkwo, Ozioma C., Oh, Jennifer M., Harding, Sandra, Xu, Guofan, Hillmer, Ansel T., Wooten, Dustin W., Murali, Dhanabalan, Barnhart, Todd E., Hall, Lance T., Racine, Annie M., Klunk, William E., Mathis, Chester A., Bendlin, Barbara B., Gallagher, Catherine L., Carlsson, Cynthia M., Rowley, Howard A., Hermann, Bruce P., Dowling, N. Maritza, Asthana, Sanjay, and Sager, Mark A.

Published
2014
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