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1. Feasibility of assessing cognitive impairment via distributed camera network and privacy-preserving edge computing

Author

Hegde, Chaitra, Kiarashi, Yashar, Levey, Allan I, Rodriguez, Amy D, Kwon, Hyeokhyen, and Clifford, Gari D

Subjects
Computer Science - Artificial Intelligence, Computer Science - Computer Vision and Pattern Recognition
Abstract

INTRODUCTION: Mild cognitive impairment (MCI) is characterized by a decline in cognitive functions beyond typical age and education-related expectations. Since, MCI has been linked to reduced social interactions and increased aimless movements, we aimed to automate the capture of these behaviors to enhance longitudinal monitoring. METHODS: Using a privacy-preserving distributed camera network, we collected movement and social interaction data from groups of individuals with MCI undergoing therapy within a 1700$m^2$ space. We developed movement and social interaction features, which were then used to train a series of machine learning algorithms to distinguish between higher and lower cognitive functioning MCI groups. RESULTS: A Wilcoxon rank-sum test revealed statistically significant differences between high and low-functioning cohorts in features such as linear path length, walking speed, change in direction while walking, entropy of velocity and direction change, and number of group formations in the indoor space. Despite lacking individual identifiers to associate with specific levels of MCI, a machine learning approach using the most significant features provided a 71% accuracy. DISCUSSION: We provide evidence to show that a privacy-preserving low-cost camera network using edge computing framework has the potential to distinguish between different levels of cognitive impairment from the movements and social interactions captured during group activities.

Published
2024

2. Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease

Author

Western, Daniel, Timsina, Jigyasha, Wang, Lihua, Wang, Ciyang, Yang, Chengran, Phillips, Bridget, Wang, Yueyao, Liu, Menghan, Ali, Muhammad, Beric, Aleksandra, Gorijala, Priyanka, Kohlfeld, Pat, Budde, John, Levey, Allan I., Morris, John C., Perrin, Richard J., Ruiz, Agustin, Marquié, Marta, Boada, Mercè, de Rojas, Itziar, Rutledge, Jarod, Oh, Hamilton, Wilson, Edward N., Le Guen, Yann, Reus, Lianne M., Tijms, Betty, Visser, Pieter Jelle, van der Lee, Sven J., Pijnenburg, Yolande A. L., Teunissen, Charlotte E., del Campo Milan, Marta, Alvarez, Ignacio, Aguilar, Miquel, Greicius, Michael D., Pastor, Pau, Pulford, David J., Ibanez, Laura, Wyss-Coray, Tony, Sung, Yun Ju, and Cruchaga, Carlos

Published
2024
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3. Serum proteomics reveal APOE-ε4-dependent and APOE-ε4-independent protein signatures in Alzheimer’s disease

Author

Frick, Elisabet A., Emilsson, Valur, Jonmundsson, Thorarinn, Steindorsdottir, Anna E., Johnson, Erik C. B., Puerta, Raquel, Dammer, Eric B., Shantaraman, Anantharaman, Cano, Amanda, Boada, Mercè, Valero, Sergi, García-González, Pablo, Gudmundsson, Elias F., Gudjonsson, Alexander, Pitts, Rebecca, Qiu, Xiazi, Finkel, Nancy, Loureiro, Joseph J., Orth, Anthony P., Seyfried, Nicholas T., Levey, Allan I., Ruiz, Agustin, Aspelund, Thor, Jennings, Lori L., Launer, Lenore J., Gudmundsdottir, Valborg, and Gudnason, Vilmundur

Published
2024
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4. Using a standalone ear-EEG device for focal-onset seizure detection

Author

Joyner, McGregor, Hsu, Sheng-Hsiou, Martin, Stephanie, Dwyer, Jennifer, Chen, Denise Fay, Sameni, Reza, Waters, Samuel H, Borodin, Konstantin, Clifford, Gari D, Levey, Allan I, Hixson, John, Winkel, Daniel, and Berent, Jonathan

Subjects
Biomedical and Clinical Sciences, Engineering, Biomedical Engineering, Brain Disorders, Epilepsy, Clinical Research, Neurodegenerative, Neurosciences, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Neurological, Ear-EEG, Focal epilepsy, Long-term EEG, Seizure detection, Temporal lobe, Wearable technologies
Abstract

BackgroundSeizure detection is challenging outside the clinical environment due to the lack of comfortable, reliable, and practical long-term neurophysiological monitoring devices. We developed a novel, discreet, unobstructive in-ear sensing system that enables long-term electroencephalography (EEG) recording. This is the first study we are aware of that systematically compares the seizure detection utility of in-ear EEG with that of simultaneously recorded intracranial EEG. In addition, we present a similar comparison between simultaneously recorded in-ear EEG and scalp EEG.MethodsIn this foundational research, we conducted a clinical feasibility study and validated the ability of the ear-EEG system to capture focal-onset seizures against 1255 hrs of simultaneous ear-EEG data along with scalp or intracranial EEG in 20 patients with refractory focal epilepsy (11 with scalp EEG, 8 with intracranial EEG, and 1 with both).ResultsIn a blinded, independent review of the ear-EEG signals, two epileptologists were able to detect 86.4% of the seizures that were subsequently identified using the clinical gold standard EEG modalities, with a false detection rate of 0.1 per day, well below what has been reported for ambulatory monitoring. The few seizures not detected on the ear-EEG signals emanated from deep within the mesial temporal lobe or extra-temporally and remained very focal, without significant propagation. Following multiple sessions of recording for a median continuous wear time of 13 hrs, patients reported a high degree of tolerance for the device, with only minor adverse events reported by the scalp EEG cohort.ConclusionsThese preliminary results demonstrate the potential of using ear-EEG to enable routine collection of complementary, prolonged, and remote neurophysiological evidence, which may permit real-time detection of paroxysmal events such as seizures and epileptiform discharges. This study suggests that the ear-EEG device may assist clinicians in making an epilepsy diagnosis, assessing treatment efficacy, and optimizing medication titration.

Published
2024

9. LATE-NC risk alleles (in TMEM106B, GRN, and ABCC9 genes) among persons with African ancestry.

Author

Katsumata, Yuriko, Fardo, David W, Shade, Lincoln MP, Bowen, James D, Crane, Paul K, Jarvik, Gail P, Keene, C Dirk, Larson, Eric B, McCormick, Wayne C, McCurry, Susan M, Mukherjee, Shubhabrata, Kowall, Neil W, McKee, Ann C, Honig, Robert A, Lawrence, S, Vonsattel, Jean Paul, Williamson, Jennifer, Small, Scott, Burke, James R, Hulette, Christine M, Welsh-Bohmer, Kathleen A, Gearing, Marla, Lah, James J, Levey, Allan I, Wingo, Thomas S, Apostolova, Liana G, Farlow, Martin R, Ghetti, Bernardino, Saykin, Andrew J, Spina, Salvatore, Albert, Marilyn S, Lyketsos, Constantine G, Troncoso, Juan C, Frosch, Matthew P, Green, Robert C, Growdon, John H, Hyman, Bradley T, Tanzi, Rudolph E, Potter, Huntington, Dickson, Dennis W, Ertekin-Taner, Nilufer, Graff-Radford, Neill R, Parisi, Joseph E, Petersen, Ronald C, Duara, Ranjan, Buxbaum, Joseph D, Goate, Alison M, Sano, Mary, Masurkar, Arjun V, Wisniewski, Thomas, Bigio, Eileen H, Mesulam, Marsel, Weintraub, Sandra, Vassar, Robert, Kaye, Jeffrey A, Quinn, Joseph F, Woltjer, Randall L, Barnes, Lisa L, Bennett, David A, Schneider, Julie A, Yu, Lei, Henderson, Victor, Fallon, Kenneth B, Harrell, Lindy E, Marson, Daniel C, Roberson, Erik D, DeCarli, Charles, Jin, Lee-Way, Olichney, John M, Kim, Ronald, LaFerla, Frank M, Monuki, Edwin, Head, Elizabeth, Sultzer, David, Geschwind, Daniel H, Vinters, Harry V, Chesselet, Marie-Francoise, Galasko, Douglas R, Brewer, James B, Boxer, Adam, Karydas, Anna, Kramer, Joel H, Miller, Bruce L, Rosen, Howard J, Seeley, William W, Burns, Jeffrey M, Swerdlow, Russell H, Abner, Erin, Van Eldik, Linda J, Albin, Roger L, Lieberman, Andrew P, Paulson, Henry L, Arnold, Steven E, Trojanowski, John Q, Van Deerlin, Vivianna M, Hamilton, Ronald L, Kamboh, M Ilyas, Lopez, Oscar L, and Becker, James T

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Brain Disorders, Neurodegenerative, Alzheimer's Disease, Acquired Cognitive Impairment, Prevention, Aging, Minority Health, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Health Disparities, Genetics, 2.1 Biological and endogenous factors, Aetiology, Humans, Alleles, Polymorphism, Single Nucleotide, Alzheimer Disease, TDP-43 Proteinopathies, Progranulins, Membrane Proteins, Nerve Tissue Proteins, Sulfonylurea Receptors, Alzheimer’s Disease Genetics Consortium, KCNMB2, Diversity, Epidemiology, FTLD, Genome-Wide Association Studies, KATP, Neurology & Neurosurgery, Clinical sciences
Abstract

Limbic-predominant age-related TDP-43 encephalopathy (LATE) affects approximately one-third of older individuals and is associated with cognitive impairment. However, there is a highly incomplete understanding of the genetic determinants of LATE neuropathologic changes (LATE-NC) in diverse populations. The defining neuropathologic feature of LATE-NC is TDP-43 proteinopathy, often with comorbid hippocampal sclerosis (HS). In terms of genetic risk factors, LATE-NC and/or HS are associated with single nucleotide variants (SNVs) in 3 genes-TMEM106B (rs1990622), GRN (rs5848), and ABCC9 (rs1914361 and rs701478). We evaluated these 3 genes in convenience samples of individuals of African ancestry. The allele frequencies of the LATE-associated alleles were significantly different between persons of primarily African (versus European) ancestry: In persons of African ancestry, the risk-associated alleles for TMEM106B and ABCC9 were less frequent, whereas the risk allele in GRN was more frequent. We performed an exploratory analysis of data from African-American subjects processed by the Alzheimer's Disease Genomics Consortium, with a subset of African-American participants (n = 166) having corroborating neuropathologic data through the National Alzheimer's Coordinating Center (NACC). In this limited-size sample, the ABCC9/rs1914361 SNV was associated with HS pathology. More work is required concerning the genetic factors influencing non-Alzheimer disease pathology such as LATE-NC in diverse cohorts.

Published
2023

10. Author Correction: Serum proteomics reveal APOE-ε4-dependent and APOE-ε4-independent protein signatures in Alzheimer’s disease

Author

Frick, Elisabet A., Emilsson, Valur, Jonmundsson, Thorarinn, Steindorsdottir, Anna E., Johnson, Erik C. B., Puerta, Raquel, Dammer, Eric B., Shantaraman, Anantharaman, Cano, Amanda, Boada, Mercè, Valero, Sergi, García-González, Pablo, Gudmundsson, Elias F., Gudjonsson, Alexander, Pitts, Rebecca, Qiu, Xiazi, Finkel, Nancy, Loureiro, Joseph J., Orth, Anthony P., Seyfried, Nicholas T., Levey, Allan I., Ruiz, Agustin, Aspelund, Thor, Jennings, Lori L., Launer, Lenore J., Gudmundsdottir, Valborg, and Gudnason, Vilmundur

Published
2024
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11. Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART

Author

Ehrenberg, Alexander J, Kelberman, Michael A, Liu, Kathy Y, Dahl, Martin J, Weinshenker, David, Falgàs, Neus, Dutt, Shubir, Mather, Mara, Ludwig, Mareike, Betts, Matthew J, Winer, Joseph R, Teipel, Stefan, Weigand, Alexandra J, Eschenko, Oxana, Hämmerer, Dorothea, Leiman, Marina, Counts, Scott E, Shine, James M, Robertson, Ian H, Levey, Allan I, Lancini, Elisa, Son, Gowoon, Schneider, Christoph, Van Egroo, Maxime, Liguori, Claudio, Wang, Qin, Vazey, Elena M, Rodriguez‐Porcel, Federico, Haag, Lena, Bondi, Mark W, Vanneste, Sven, Freeze, Whitney M, Yi, Yeo‐Jin, Maldinov, Mihovil, Gatchel, Jennifer, Satpati, Abhijit, Babiloni, Claudio, Kremen, William S, Howard, Robert, Jacobs, Heidi IL, and Grinberg, Lea T

Subjects
Neurosciences, Dementia, Acquired Cognitive Impairment, Alzheimer's Disease, Aging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Neurological, Humans, Alzheimer Disease, Brain, Biomarkers, Disease Progression, Clinical Sciences, Geriatrics
Abstract

The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here, the NSS Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment highlights knowledge gaps about NSS within AD and provides recommendations for priorities specific to clinical research, biomarker development, modeling, and intervention. HIGHLIGHTS: Neuromodulatory nuclei degenerate in early Alzheimer's disease pathological stages. Alzheimer's pathophysiology is exacerbated by neuromodulatory nuclei degeneration. Neuromodulatory nuclei degeneration drives neuropsychiatric symptoms in dementia. Biomarkers of neuromodulatory integrity would be value-creating for dementia care. Neuromodulatory nuclei present strategic prospects for disease-modifying therapies.

Published
2023

12. CSF proteomics identifies early changes in autosomal dominant Alzheimer’s disease

Author

Noble, James M., Day, Gregory S., Graff-Radford, Neill R., Voglein, Jonathan, Allegri, Ricardo, Mendez, Patricio Chrem, Surace, Ezequiel, Berman, Sarah B., Ikonomovic, Snezana, Nadkarni, Neelesh, Lopera, Francisco, Ramirez, Laura, Aguillon, David, Leon, Yudy, Ramos, Claudia, Alzate, Diana, Baena, Ana, Londono, Natalia, Mathias Jucker, Sonia Moreno, Laske, Christoph, Kuder-Buletta, Elke, Graber-Sultan, Susanne, Preische, Oliver, Hofmann, Anna, Ikeuchi, Takeshi, Kasuga, Kensaku, Niimi, Yoshiki, Ishii, Kenji, Senda, Michio, Sanchez-Valle, Raquel, Rosa-Neto, Pedro, Fox, Nick, Cash, Dave, Lee, Jae-Hong, Roh, Jee Hoon, Riddle, Meghan, Menard, William, Bodge, Courtney, Surti, Mustafa, Takada, Leonel Tadao, Farlow, Martin, Chhatwal, Jasmeer P., Sanchez-Gonzalez, V.J., Orozco-Barajas, Maribel, Goate, Alison, Renton, Alan, Esposito, Bianca, Karch, Celeste M., Marsh, Jacob, Cruchaga, Carlos, Fernandez, Victoria, Gordon, Brian A., Fagan, Anne M., Jerome, Gina, Herries, Elizabeth, Llibre-Guerra, Jorge, Levey, Allan I., Johnson, Erik C.B., Seyfried, Nicholas T., Schofield, Peter R., Brooks, William, Bechara, Jacob, Bateman, Randall J., McDade, Eric, Hassenstab, Jason, Perrin, Richard J., Franklin, Erin, Benzinger, Tammie L.S., Chen, Allison, Chen, Charles, Flores, Shaney, Friedrichsen, Nelly, Hantler, Nancy, Hornbeck, Russ, Jarman, Steve, Keefe, Sarah, Koudelis, Deborah, Massoumzadeh, Parinaz, McCullough, Austin, McKay, Nicole, Nicklaus, Joyce, Pulizos, Christine, Wang, Qing, Mishall, Sheetal, Sabaredzovic, Edita, Deng, Emily, Candela, Madison, Smith, Hunter, Hobbs, Diana, Scott, Jalen, Levin, Johannes, Xiong, Chengjie, Wang, Peter, Xu, Xiong, Li, Yan, Gremminger, Emily, Ma, Yinjiao, Bui, Ryan, Lu, Ruijin, Martins, Ralph, Sosa Ortiz, Ana Luisa, Daniels, Alisha, Courtney, Laura, Mori, Hiroshi, Supnet-Bell, Charlene, Xu, Jinbin, Ringman, John, Shen, Yuanyuan, Timsina, Jigyasha, Heo, Gyujin, Beric, Aleksandra, Ali, Muhammad, Wang, Ciyang, Yang, Chengran, Wang, Yueyao, Western, Daniel, Liu, Menghan, Gorijala, Priyanka, Budde, John, Do, Anh, Liu, Haiyan, Gordon, Brian, Llibre-Guerra, Jorge J., Joseph-Mathurin, Nelly, Maschi, Dario, Wyss-Coray, Tony, Pastor, Pau, Renton, Alan E., Surace, Ezequiel I., Alvarez, Ignacio, Ringman, John M., Allegri, Ricardo Francisco, Seyfried, Nicholas, Day, Gregg S., Wu, Qisi, Fernández, M. Victoria, Tarawneh, Rawan, Morris, John C., Ibanez, Laura, and Sung, Yun Ju

Published
2024
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14. γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS)

Author

Aguillon, David, Allegri, Ricardo F., Aschenbrenner, Andrew J., Baker, Bryce, Barthelemy, Nicolas, Bechara, Jacob A., Berman, Sarah B., Brooks, William S., Cash, David M., Chen, Allison, Chrem Mendez, Patricio, Courtney, Laura, Cruchaga, Carlos, Daniels, Alisha J., Fagan, Anne M., Flores, Shaney, Fox, Nick C., Franklin, Erin, Goate, Alison M., Graber-Sultan, Susanne, Graff-Radford, Neill R., Gremminger, Emily, Herries, Elizabeth, Hofmann, Anna, Holtzman, David M., Hornbeck, Russ, Huey, Edward D., Ibanez, Laura, Ikeuchi, Takeshi, Ikonomovic, Snezana, Jackson, Kelley, Jarman, Steve, Jerome, Gina, Johnson, Erik C.B, Kasuga, Kensaku, Keefe, Sarah, Koudelis, Deborah, Kuder-Buletta, Elke, Laske, Christoph, Leon, Yudy Milena, Levey, Allan I., Li, Yan, Llibre-Guerra, Jorge J., Lopera, Francisco, Lu, Ruijin, Marsh, Jacob, Martins, Ralph, Massoumzadeh, Parinaz, Masters, Colin, McCullough, Austin, McKay, Nicole, Minton, Matthew, Mori, Hiroshi, Morris, John C., Nadkarni, Neelesh K., Nicklaus, Joyce, Niimi, Yoshiki, Noble, James M., Obermueller, Ulrike, Picarello, Danielle M., Pulizos, Christine, Ramirez, Laura, Renton, Alan E., Ringman, John, Rizzo, Jacqueline, Roedenbeck, Yvonne, Roh, Jee Hoon, Rosa-Neto, Pedro, Ryan, Natalie S., Sabaredzovic, Edita, Salloway, Stephen, Sanchez-Valle, Raquel, Scott, Jalen, Seyfried, Nicholas T., Simmons, Ashlee, Smith, Jennifer, Smith, Hunter, Stauber, Jennifer, Stout, Sarah, Supnet-Bell, Charlene, Surace, Ezequiel, Vazquez, Silvia, Vöglein, Jonathan, Wang, Guoqiao, Wang, Qing, Xu, Xiong, Xu, Jinbin, Schultz, Stephanie A, Liu, Lei, Schultz, Aaron P, Fitzpatrick, Colleen D, Levin, Raina, Bellier, Jean-Pierre, Shirzadi, Zahra, Joseph-Mathurin, Nelly, Chen, Charles D, Benzinger, Tammie L S, Day, Gregory S, Farlow, Martin R, Gordon, Brian A, Hassenstab, Jason J, Jack, Clifford R, Jr, Jucker, Mathias, Karch, Celeste M, Lee, Jae-Hong, Levin, Johannes, Perrin, Richard J, Schofield, Peter R, Xiong, Chengjie, Johnson, Keith A, McDade, Eric, Bateman, Randall J, Sperling, Reisa A, Selkoe, Dennis J, and Chhatwal, Jasmeer P

Published
2024
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15. Sex differences in brain protein expression and disease

Author

Wingo, Aliza P., Liu, Yue, Gerasimov, Ekaterina S., Vattathil, Selina M., Liu, Jiaqi, Cutler, David J., Epstein, Michael P., Blokland, Gabriëlla A. M., Thambisetty, Madhav, Troncoso, Juan C., Duong, Duc M., Bennett, David A., Levey, Allan I., Seyfried, Nicholas T., and Wingo, Thomas S.

Published
2023
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16. Integrating human brain proteomes with genome-wide association data implicates novel proteins in post-traumatic stress disorder

Author

Wingo, Thomas S, Gerasimov, Ekaterina S, Liu, Yue, Duong, Duc M, Vattathil, Selina M, Lori, Adriana, Gockley, Jake, Breen, Michael S, Maihofer, Adam X, Nievergelt, Caroline M, Koenen, Karestan C, Levey, Daniel F, Gelernter, Joel, Stein, Murray B, Ressler, Kerry J, Bennett, David A, Levey, Allan I, Seyfried, Nicholas T, and Wingo, Aliza P

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical and Health Psychology, Clinical Sciences, Psychology, Anxiety Disorders, Neurosciences, Brain Disorders, Post-Traumatic Stress Disorder (PTSD), Mental Illness, Mental Health, Genetics, Human Genome, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Neurological, Mental health, Brain, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Proteome, Stress Disorders, Post-Traumatic, Transcriptome, Veterans, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract

Genome-wide association studies (GWAS) have identified several risk loci for post-traumatic stress disorder (PTSD); however, how they confer PTSD risk remains unclear. We aimed to identify genes that confer PTSD risk through their effects on brain protein abundance to provide new insights into PTSD pathogenesis. To that end, we integrated human brain proteomes with PTSD GWAS results to perform a proteome-wide association study (PWAS) of PTSD, followed by Mendelian randomization, using a discovery and confirmatory study design. Brain proteomes (N = 525) were profiled from the dorsolateral prefrontal cortex using mass spectrometry. The Million Veteran Program (MVP) PTSD GWAS (n = 186,689) was used for the discovery PWAS, and the Psychiatric Genomics Consortium PTSD GWAS (n = 174,659) was used for the confirmatory PWAS. To understand whether genes identified at the protein-level were also evident at the transcript-level, we performed a transcriptome-wide association study (TWAS) using human brain transcriptomes (N = 888) and the MVP PTSD GWAS results. We identified 11 genes that contribute to PTSD pathogenesis via their respective cis-regulated brain protein abundance. Seven of 11 genes (64%) replicated in the confirmatory PWAS and 4 of 11 also had their cis-regulated brain mRNA levels associated with PTSD. High confidence level was assigned to 9 of 11 genes after considering evidence from the confirmatory PWAS and TWAS. Most of the identified genes are expressed in other PTSD-relevant brain regions and several are preferentially expressed in excitatory neurons, astrocytes, and oligodendrocyte precursor cells. These genes are novel, promising targets for mechanistic and therapeutic studies to find new treatments for PTSD.

Published
2022

17. Integrative proteomics identifies a conserved Aβ amyloid responsome, novel plaque proteins, and pathology modifiers in Alzheimer’s disease

Author

Levites, Yona, Dammer, Eric B., Ran, Yong, Tsering, Wangchen, Duong, Duc, Abreha, Measho, Gadhavi, Joshna, Lolo, Kiara, Trejo-Lopez, Jorge, Phillips, Jennifer, Iturbe, Andrea, Erquizi, Aya, Moore, Brenda D., Ryu, Danny, Natu, Aditya, Dillon, Kristy, Torrellas, Jose, Moran, Corey, Ladd, Thomas, Afroz, Farhana, Islam, Tariful, Jagirdar, Jaishree, Funk, Cory C., Robinson, Max, Rangaraju, Srikant, Borchelt, David R., Ertekin-Taner, Nilüfer, Kelly, Jeffrey W., Heppner, Frank L., Johnson, Erik C.B., McFarland, Karen, Levey, Allan I., Prokop, Stefan, Seyfried, Nicholas T., and Golde, Todd E.

Published
2024
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20. Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer’s disease

Author

Johnson, Erik C. B., Bian, Shijia, Haque, Rafi U., Carter, E. Kathleen, Watson, Caroline M., Gordon, Brian A., Ping, Lingyan, Duong, Duc M., Epstein, Michael P., McDade, Eric, Barthélemy, Nicolas R., Karch, Celeste M., Xiong, Chengjie, Cruchaga, Carlos, Perrin, Richard J., Wingo, Aliza P., Wingo, Thomas S., Chhatwal, Jasmeer P., Day, Gregory S., Noble, James M., Berman, Sarah B., Martins, Ralph, Graff-Radford, Neill R., Schofield, Peter R., Ikeuchi, Takeshi, Mori, Hiroshi, Levin, Johannes, Farlow, Martin, Lah, James J., Haass, Christian, Jucker, Mathias, Morris, John C., Benzinger, Tammie L. S., Roberts, Blaine R., Bateman, Randall J., Fagan, Anne M., Seyfried, Nicholas T., and Levey, Allan I.

Published
2023
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21. Comparison of tau spread in people with Down syndrome versus autosomal-dominant Alzheimer's disease: a cross-sectional study

Author

Aizenstein, Howard J., Andrews, Howard F., Bell, Karen, Birn, Rasmus M., Bulova, Peter, Cheema, Amrita, Chen, Kewei, Clare, Isabel, Clark, Lorraine, Cohen, Ann D., Constantino, John N., Doran, Eric W., Feingold, Eleanor, Foroud, Tatiana M., Hartley, Sigan L., Hom, Christy, Honig, Lawrence, Ikonomovic, Milos D., Johnson, Sterling C., Jordan, Courtney, Kamboh, M. Ilyas, Keator, David, Klunk, William E., Kofler, Julia K., Kreisl, William C., Krinsky-McHale, Sharon J., Lao, Patrick, Laymon, Charles, Lott, Ira T., Lupson, Victoria, Mathis, Chester A., Minhas, Davneet S., Nadkarni, Neelesh, Pang, Deborah, Petersen, Melissa, Price, Julie C., Pulsifer, Margaret, Reiman, Eric, Rizvi, Batool, Sabbagh, Marwan N., Schupf, Nicole, Tudorascu, Dana L., Tumuluru, Rameshwari, Tycko, Benjamin, Varadarajan, Badri, White, Desiree A., Yassa, Michael A., Zaman, Shahid, Zhang, Fan, Bateman, Randall, Daniels, Alisha J., Courtney, Laura, McDade, Eric, Llibre-Guerra, Jorge J., Supnet-Bell, Charlene, Xiong, Chengie, Xu, Xiong, Lu, Ruijin, Wang, Guoqiao, Li, Yan, Gremminger, Emily, Perrin, Richard J., Franklin, Erin, Ibanez, Laura, Jerome, Gina, Herries, Elizabeth, Stauber, Jennifer, Baker, Bryce, Minton, Matthew, Cruchaga, Carlos, Goate, Alison M., Renton, Alan E., Picarello, Danielle M., Benzinger, Tammie, Gordon, Brian A., Hornbeck, Russall, Hassenstab, Jason, Smith, Jennifer, Stout, Sarah, Aschenbrenner, Andrew J., Karch, Celeste M., Marsh, Jacob, Morris, John C., Holtzman, David M., Barthelemy, Nicolas, Xu, Jinbin, Noble, James M., Berman, Sarah B., Ikonomovic, Snezana, Nadkarni, Neelesh K., Day, Gregory, Graff-Radford, Neill R., Farlow, Martin, Chhatwal, Jasmeer P., Ikeuchi, Takeshi, Kasuga, Kensaku, Niimi, Yoshiki, Huey, Edward D., Salloway, Stephen, Schofield, Peter R., Brooks, William S., Bechara, Jacob A., Martins, Ralph, Fox, Nick C., Cash, David M., Ryan, Natalie S., Jucker, Mathias, Laske, Christoph, Hofmann, Anna, Kuder-Buletta, Elke, Graber-Sultan, Susanne, Obermueller, Ulrike, Levin, Johannes, Roedenbeck, Yvonne, Vöglein, Jonathan, Lee, Jae-Hong, Roh, Jee Hoon, Sanchez-Valle, Raquel, Rosa-Neto, Pedro, Allegri, Ricardo F., Chrem Mendez, Patricio, Surace, Ezequiel, Vazquez, Silvia, Lopera, Francisco, Leon, Yudy Milena, Ramirez, Laura, Aguillon, David, Levey, Allan I., Johnson, Erik C.B, Seyfried, Nicholas T., Ringman, John, Mori, Hiroshi, Wisch, Julie K, McKay, Nicole S, Boerwinkle, Anna H, Kennedy, James, Flores, Shaney, Handen, Benjamin L, Christian, Bradley T, Head, Elizabeth, Mapstone, Mark, Rafii, Michael S, O’Bryant, Sid E, Price, Julie C, Laymon, Charles M, Krinsky-McHale, Sharon J, Lai, Florence, Rosas, H Diana, Hartley, Sigan L, Lott, Ira T, Tudorascu, Dana, Zammit, Matthew, Brickman, Adam M, Lee, Joseph H, Bird, Thomas D, Cohen, Annie, Chrem, Patricio, Daniels, Alisha, Chhatwal, Jasmeer P, Karch, Celeste M, Day, Gregory S, Llibre-Guerra, Jorge, Ringman, John M, van Dyck, Christopher H, Xiong, Chengjie, Morris, John C, Bateman, Randall J, Benzinger, Tammie L S, Gordon, Brian A, and Ances, Beau M

Published
2024
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22. Deconstructing pathological tau by biological process in early stages of Alzheimer disease: a method for quantifying tau spatial spread in neuroimaging

Author

Noble, James M., Day, Gregory S., Graff-Radford, Neill R., Voglein, Jonathan, Levin, Johannes, Allegri, Ricardo F., Mendez, Patricio Chrem, Surace, Ezequiel, Berman, Sarah B., Ikonomovic, Snezana, Nadkarni, Neelesh K., Lopera, Francisco, Ramirez, Laura, Aguillon, David, Leon, Yudy, Ramos, Claudia, Alzate, Diana, Baena, Ana, Londono, Natalia, Moreno, Sonia, Jucker, Mathias, Laske, Christoph, Kuder-Buletta, Elke, Graber-Sultan, Susanne, Preische, Oliver, Hofmann, Anna, Ikeuchi, Takeshi, Kasuga, Kensaku, Niimi, Yoshiki, Ishii, Kenji, Senda, Michio, Sanchez-Valle, Raquel, Rosa-Neto, Pedro, Fox, Nick C., Cash, Dave, Lee, Jae-Hong, Roh, Jee Hoon, Salloway, Stephen, Riddle, Meghan C., Menard, William, Bodge, Courtney, Surti, Mustafa, Takada, Leonel Tadao, Farlow, Martin, Chhatwal, Jasmeer P., Sanchez-Gonzalez, V.J., Orozco-Barajas, Maribel, Goate, Alison M., Renton, Alan E., Esposito, Bianca T., Karch, Celeste M., Marsh, Jacob, Cruchaga, Carlos, Fernanadez, Victoria, Gordon, Brian A., Fagan, Anne M., Jerome, Gina, Herries, Elizabeth, Llibre-Guerra, Jorge, Levey, Allan I., Johnson, Erik C.B., Seyfried, Nicholas T., Schofield, Peter R., Brooks, William S., Bechara, Jacob A., Bateman, Randall, McDade, Eric, Hassenstab, Jason, Perrin, Richard J., Franklin, Erin E., Benzinger, Tammie, Chen, Allison, Chen, Charles, Flores, Shaney, Friedrichsen, Nelly, Gordon, Brian, Hantler, Nancy, Hornbeck, Russ, Jarman, Steve, Keefe, Sarah, Koudelis, Deborah, Massoumzadeh, Parinaz, McCullough, Austin, McKay, Nicole, Nicklaus, Joyce, Pulizos, Christine, Wang, Qing, Mishall, Sheetal, Sabaredzovic, Edita, Deng, Emily, Candela, Madison, Smith, Hunter, Hobbs, Diana, Scott, Jalen, Xiong, Chengjie, Wang, Peter, Xu, Xiong, Li, Yan, Gremminger, Emily, Ma, Yinjiao, Bui, Ryan, Lu, Ruijin, Martins, Ralph, Sosa Ortiz, Ana Luisa, Daniels, Alisha, Courtney, Laura, Mori, Hiroshi, Supnet-Bell, Charlene, Xu, Jinbin, Ringman, John, Barthelemy, Nicolas, Morris, John, Smith, Jennifer, Doering, Stephanie, Chen, Charles D., Jarman, Stephen, Jackson, Kelley, Hornbeck, Russ C., Ances, Beau M., Aschenbrenner, Andrew J., Bateman, Randall J., Morris, John C., and Benzinger, Tammie L.S.

Published
2024
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23. Association of plasma and CSF cytochrome P450, soluble epoxide hydrolase, and ethanolamide metabolism with Alzheimer’s disease

Author

Borkowski, Kamil, Pedersen, Theresa L, Seyfried, Nicholas T, Lah, James J, Levey, Allan I, Hales, Chadwick M, Dammer, Eric B, Blach, Colette, Louie, Gregory, Kaddurah-Daouk, Rima, and Newman, John W

Subjects
Medical Biochemistry and Metabolomics, Biomedical and Clinical Sciences, Aging, Acquired Cognitive Impairment, Alzheimer's Disease, Brain Disorders, Dementia, Neurosciences, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aetiology, 2.1 Biological and endogenous factors, Neurological, Alzheimer Disease, Cytochrome P-450 Enzyme System, Epoxide Hydrolases, Fatty Acids, Humans, Oxylipins, Alzheimer's disease, Lipid mediators, Endocannabinoids, Cognition, Alzheimer’s Disease Metabolomics Consortium, Alzheimer’s disease, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundAlzheimer's disease, cardiovascular disease, and other cardiometabolic disorders may share inflammatory origins. Lipid mediators, including oxylipins, endocannabinoids, bile acids, and steroids, regulate inflammation, energy metabolism, and cell proliferation with well-established involvement in cardiometabolic diseases. However, their role in Alzheimer's disease is poorly understood. Here, we describe the analysis of plasma and cerebrospinal fluid lipid mediators in a case-control comparison of ~150 individuals with Alzheimer's disease and ~135 healthy controls, to investigate this knowledge gap.MethodsLipid mediators were measured using targeted quantitative mass spectrometry. Data were analyzed using the analysis of covariates, adjusting for sex, age, and ethnicity. Partial least square discriminant analysis identified plasma and cerebrospinal fluid lipid mediator discriminates of Alzheimer's disease. Alzheimer's disease predictive models were constructed using machine learning combined with stepwise logistic regression.ResultsIn both plasma and cerebrospinal fluid, individuals with Alzheimer's disease had elevated cytochrome P450/soluble epoxide hydrolase pathway components and decreased fatty acid ethanolamides compared to healthy controls. Circulating metabolites of soluble epoxide hydrolase and ethanolamides provide Alzheimer's disease predictors with areas under receiver operator characteristic curves ranging from 0.82 to 0.92 for cerebrospinal fluid and plasma metabolites, respectively.ConclusionsPrevious studies report Alzheimer's disease-associated soluble epoxide hydrolase upregulation in the brain and that endocannabinoid metabolism provides an adaptive response to neuroinflammation. This study supports the involvement of P450-dependent and endocannabinoid metabolism in Alzheimer's disease. The results further suggest that combined pharmacological intervention targeting both metabolic pathways may have therapeutic benefits for Alzheimer's disease.

Published
2021

24. Discovery of FERM domain protein–protein interaction inhibitors for MSN and CD44 as a potential therapeutic approach for Alzheimer’s disease

Author

Du, Yuhong, Bradshaw, William J., Leisner, Tina M., Annor-Gyamfi, Joel K., Qian, Kun, Bashore, Frances M., Sikdar, Arunima, Nwogbo, Felix O., Ivanov, Andrey A., Frye, Stephen V., Gileadi, Opher, Brennan, Paul E., Levey, Allan I., Axtman, Alison D., Pearce, Kenneth H., Fu, Haian, and Katis, Vittorio L.

Published
2023
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26. Unique molecular characteristics and microglial origin of Kv1.3 channel–positive brain myeloid cells in Alzheimer’s disease

Author

Ramesha, Supriya, Rayaprolu, Sruti, Bowen, Christine A, Giver, Cynthia R, Bitarafan, Sara, Nguyen, Hai M, Gao, Tianwen, Chen, Michael J, Nwabueze, Ngozi, Dammer, Eric B, Engstrom, Amanda K, Xiao, Hailian, Pennati, Andrea, Seyfried, Nicholas T, Katz, David J, Galipeau, Jacques, Wulff, Heike, Waller, Edmund K, Wood, Levi B, Levey, Allan I, and Rangaraju, Srikant

Subjects
Biomedical and Clinical Sciences, Immunology, Neurosciences, Neurodegenerative, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease, Acquired Cognitive Impairment, Aging, Dementia, 2.1 Biological and endogenous factors, Aetiology, Neurological, Alzheimer Disease, Amyloid beta-Peptides, Animals, Brain, Disease Models, Animal, Female, Humans, Kv1.3 Potassium Channel, Male, Mice, Microglia, Myeloid Cells, microglia, Alzheimer's disease, neurodegeneration, euroinflammation, potassium channel, Alzheimer’s disease, neuroinflammation
Abstract

Kv1.3 potassium channels, expressed by proinflammatory central nervous system mononuclear phagocytes (CNS-MPs), are promising therapeutic targets for modulating neuroinflammation in Alzheimer's disease (AD). The molecular characteristics of Kv1.3-high CNS-MPs and their cellular origin from microglia or CNS-infiltrating monocytes are unclear. While Kv1.3 blockade reduces amyloid beta (Aβ) burden in mouse models, the downstream immune effects on molecular profiles of CNS-MPs remain unknown. We show that functional Kv1.3 channels are selectively expressed by a subset of CD11b+CD45+ CNS-MPs acutely isolated from an Aβ mouse model (5xFAD) as well as fresh postmortem human AD brain. Transcriptomic profiling of purified CD11b+Kv1.3+ CNS-MPs, CD11b+CD45int Kv1.3neg microglia, and peripheral monocytes from 5xFAD mice revealed that Kv1.3-high CNS-MPs highly express canonical microglial markers (Tmem119, P2ry12) and are distinct from peripheral Ly6chigh/Ly6clow monocytes. Unlike homeostatic microglia, Kv1.3-high CNS-MPs express relatively lower levels of homeostatic genes, higher levels of CD11c, and increased levels of glutamatergic transcripts, potentially representing phagocytic uptake of neuronal elements. Using irradiation bone marrow CD45.1/CD45.2 chimerism in 5xFAD mice, we show that Kv1.3+ CNS-MPs originate from microglia and not blood-derived monocytes. We show that Kv1.3 channels regulate membrane potential and early signaling events in microglia. Finally, in vivo blockade of Kv1.3 channels in 5xFAD mice by ShK-223 reduced Aβ burden, increased CD11c+ CNS-MPs, and expression of phagocytic genes while suppressing proinflammatory genes (IL1b). Our results confirm the microglial origin and identify unique molecular features of Kv1.3-expressing CNS-MPs. In addition, we provide evidence for CNS immunomodulation by Kv1.3 blockers in AD mouse models resulting in a prophagocytic phenotype.

Published
2021

27. 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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29. Identification of Conserved Proteomic Networks in Neurodegenerative Dementia

Author

Swarup, Vivek, Chang, Timothy S, Duong, Duc M, Dammer, Eric B, Dai, Jingting, Lah, James J, Johnson, Erik CB, Seyfried, Nicholas T, Levey, Allan I, and Geschwind, Daniel H

Subjects
Acquired Cognitive Impairment, Human Genome, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Genetics, Biotechnology, Aging, Brain Disorders, Alzheimer's Disease, Neurosciences, Dementia, Aetiology, 2.1 Biological and endogenous factors, Neurological, Good Health and Well Being, Alzheimer Disease, Genetic Predisposition to Disease, Humans, Nerve Degeneration, Proteome, Proteomics, Risk Factors, Transcriptome, Alzheimer’s disease, gene networks, genetics, genomics, neurodegenerative diseases, progressive supranuclear palsy, proteomics, systems biology, transcriptomics, Biochemistry and Cell Biology, Medical Physiology
Abstract

Data-driven analyses are increasingly valued in modern medicine. We integrate quantitative proteomics and transcriptomics from over 1,000 post-mortem brains from six cohorts representing Alzheimer's disease (AD), asymptomatic AD, progressive supranuclear palsy (PSP), and control patients from the Accelerating Medicines Partnership - Alzheimer's Disease consortium. We define robust co-expression trajectories related to disease progression, including early neuronal, microglial, astrocyte, and immune response modules, and later mRNA splicing and mitochondrial modules. The majority of, but not all, modules are conserved at the transcriptomic level, including module C3, which is only observed in proteome networks and enriched in mitogen-activated protein kinase (MAPK) signaling. Genetic risk enriches in modules changing early in disease and indicates that AD and PSP have distinct causal biological drivers at the pathway level, despite aspects of similar pathology, including synaptic loss and glial inflammatory changes. The conserved, high-confidence proteomic changes enriched in genetic risk represent targets for drug discovery.

Published
2020

30. CSF proteome profiling across the Alzheimer’s disease spectrum reflects the multifactorial nature of the disease and identifies specific biomarker panels

Author

del Campo, Marta, Peeters, Carel F. W., Johnson, Erik C. B., Vermunt, Lisa, Hok-A-Hin, Yanaika S., van Nee, Mirrelijn, Chen-Plotkin, Alice, Irwin, David J., Hu, William T., Lah, James J., Seyfried, Nicholas T., Dammer, Eric B., Herradon, Gonzalo, Meeter, Lieke H., van Swieten, John, Alcolea, Daniel, Lleó, Alberto, Levey, Allan I., Lemstra, Afina W., Pijnenburg, Yolande A. L., Visser, Pieter J., Tijms, Betty M., van der Flier, Wiesje M., and Teunissen, Charlotte E.

Published
2022
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31. Reply: LATE to the PART-y

Author

Nelson, Peter T, Dickson, Dennis W, Trojanowski, John Q, Jack, Clifford R, Boyle, Patricia A, Arfanakis, Konstantinos, Rademakers, Rosa, Alafuzoff, Irina, Attems, Johannes, Brayne, Carol, Coyle-Gilchrist, Ian TS, Fardo, David W, Flanagan, Margaret E, Halliday, Glenda, Hunter, Sally, Jicha, Gregory A, Katsumata, Yuriko, Kawas, Claudia H, Keene, C Dirk, Kovacs, Gabor G, Kukull, Walter A, Levey, Allan I, Makkinejad, Nazanin, Montine, Thomas J, Murray, Melissa E, Nag, Sukriti, Seeley, William W, Sperling, Reisa A, White, Charles L, and Schneider, Julie A

Subjects
Biomedical and Clinical Sciences, Health Sciences, Psychology, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences
Published
2019

32. Erratum

Author

Nelson, Peter T, Dickson, Dennis W, Trojanowski, John Q, Jack, Clifford R Jr, Boyle, Patricia A, Arfanakis, Konstantinos, Rademakers, Rosa, Alafuzoff, Irina, Attems, Johannes, Brayne, Carol, Coyle-Gilchrist, Ian TS, Chui, Helena C, Fardo, David W, Flanagan, Margaret E, Halliday, Glenda, Hokkanen, Suvi RK, Hunter, Sally, Jicha, Gregory A, Katsumata, Yuriko, Kawas, Claudia H, Keene, C Dirk, Kovacs, Gabor G, Kukull, Walter A, Levey, Allan I, Makkinejad, Nazanin, Montine, Thomas J, Murayama, Shigeo, Murray, Melissa E, Nag, Sukriti, Rissman, Robert A, Seeley, William W, Sperling, Reisa A, White, Charles LIII, Yu, Lei, and Schneider, Julie A

Subjects
Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

The publisher apologizes for erroneously omitting part of the footnote for Table 2. This has now been corrected both online and in print.

Published
2019

33. Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report.

Author

Nelson, Peter T, Dickson, Dennis W, Trojanowski, John Q, Jack, Clifford R, Boyle, Patricia A, Arfanakis, Konstantinos, Rademakers, Rosa, Alafuzoff, Irina, Attems, Johannes, Brayne, Carol, Coyle-Gilchrist, Ian TS, Chui, Helena C, Fardo, David W, Flanagan, Margaret E, Halliday, Glenda, Hokkanen, Suvi RK, Hunter, Sally, Jicha, Gregory A, Katsumata, Yuriko, Kawas, Claudia H, Keene, C Dirk, Kovacs, Gabor G, Kukull, Walter A, Levey, Allan I, Makkinejad, Nazanin, Montine, Thomas J, Murayama, Shigeo, Murray, Melissa E, Nag, Sukriti, Rissman, Robert A, Seeley, William W, Sperling, Reisa A, White Iii, Charles L, Yu, Lei, and Schneider, Julie A

Subjects
Brain, Humans, Brain Diseases, Alzheimer Disease, Retrospective Studies, Aged, Aged, 80 and over, Middle Aged, Female, Male, Frontotemporal Lobar Degeneration, TDP-43 Proteinopathies, Frontotemporal Dementia, Neuroimaging, FTLD, MRI, PET, SNAP, epidemiology, and over, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer's-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-β plaques and tauopathy. Given that the 'oldest-old' are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer's disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.

Published
2019

34. Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia

Author

Swarup, Vivek, Hinz, Flora I, Rexach, Jessica E, Noguchi, Ken-ichi, Toyoshiba, Hiroyoshi, Oda, Akira, Hirai, Keisuke, Sarkar, Arjun, Seyfried, Nicholas T, Cheng, Chialin, Haggarty, Stephen J, Grossman, Murray, Van Deerlin, Vivianna M, Trojanowski, John Q, Lah, James J, Levey, Allan I, Kondou, Shinichi, and Geschwind, Daniel H

Subjects
Biomedical and Clinical Sciences, Health Sciences, Frontotemporal Dementia (FTD), Neurodegenerative, Genetics, Dementia, Alzheimer's Disease, Rare Diseases, Aging, Brain Disorders, Neurosciences, Orphan Drug, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Human Genome, Acquired Cognitive Impairment, Biotechnology, 2.1 Biological and endogenous factors, Aetiology, Neurological, Animals, Cell Death, Disease Models, Animal, Evolution, Molecular, Frontotemporal Dementia, Gene Expression Regulation, Gene Regulatory Networks, Genetic Predisposition to Disease, Genetic Vectors, Humans, Mice, Inbred C57BL, Mice, Transgenic, MicroRNAs, Neurodegenerative Diseases, Proteomics, RNA, Messenger, Reproducibility of Results, Transcriptome, tau Proteins, International Frontotemporal Dementia Genomics Consortium, Medical and Health Sciences, Immunology, Biomedical and clinical sciences, Health sciences
Abstract

Identifying the mechanisms through which genetic risk causes dementia is an imperative for new therapeutic development. Here, we apply a multistage, systems biology approach to elucidate the disease mechanisms in frontotemporal dementia. We identify two gene coexpression modules that are preserved in mice harboring mutations in MAPT, GRN and other dementia mutations on diverse genetic backgrounds. We bridge the species divide via integration with proteomic and transcriptomic data from the human brain to identify evolutionarily conserved, disease-relevant networks. We find that overexpression of miR-203, a hub of a putative regulatory microRNA (miRNA) module, recapitulates mRNA coexpression patterns associated with disease state and induces neuronal cell death, establishing this miRNA as a regulator of neurodegeneration. Using a database of drug-mediated gene expression changes, we identify small molecules that can normalize the disease-associated modules and validate this experimentally. Our results highlight the utility of an integrative, cross-species network approach to drug discovery.

Published
2019

39. CT1812 biomarker signature from a meta‐analysis of CSF proteomic findings from two Phase 2 clinical trials in Alzheimer's disease.

Author

Lizama, Britney N., Williams, Claire, North, Hilary A., Pandey, Kiran, Duong, Duc, Di Caro, Valentina, Mecca, Adam P., Blennow, Kaj, Zetterberg, Henrik, Levey, Allan I., Grundman, Michael, van Dyck, Christopher H., Caggiano, Anthony O., Seyfried, Nicholas T., and Hamby, Mary E.

Abstract

INTRODUCTION: CT1812 is in clinical development for the treatment of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) exploratory proteomics was employed to identify pharmacodynamic biomarkers of CT1812 in mild to moderate AD from two independent clinical trials. METHODS: Unbiased analysis of tandem‐mass tag mass spectrometry (TMT‐MS) quantitative proteomics, pathway analysis and correlation analyses with volumetric magnetic resonance imaging (vMRI) were performed for the SPARC cohort (NCT03493282). Comparative analyses and a meta‐analysis with the interim SHINE cohort (NCT03507790; SHINE‐A) followed by network analysis (weighted gene co‐expression network analysis [WGCNA]) were used to understand the biological impact of CT1812. RESULTS: CT1812 pharmacodynamic biomarkers and biological pathways were identified that replicate across two clinical cohorts. The meta‐analysis revealed novel candidate biomarkers linked to S2R biology and AD, and network analysis revealed treatment‐associated networks driven by S2R. DISCUSSION: Early clinical validation of CT1812 candidate biomarkers replicating in independent cohorts strengthens the understanding of the biological impact of CT1812 in patients with AD, and supports CT1812's synaptoprotective mechanism of action and its continued clinical development. Highlights: This exploratory proteomics study identified candidate biomarkers of CT1812 in SPARC (NCT03493282)Comparative analyses identified biomarkers replicating across trials/cohortsTwo independent Ph2 trial cohorts (SPARC and interim SHINE [NCT03507790; SHINE‐A]) were used in a meta‐analysisAmyloid beta (Aβ) & synaptic biology impacted by CT1812 and volumetric magnetic resonance imaging (vMRI) treatment‐related correlates emergeNetwork analyses revealed sigma‐2 receptor (S2R)‐interacting proteins that may be "drivers" of changes [ABSTRACT FROM AUTHOR]

Published
2024
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40. Lower Prevalence of Asymptomatic Alzheimer's Disease Among Healthy African Americans.

Author

Lah, James J., Tian, Ganzhong, Risk, Benjamin B., Hanfelt, John J., Wang, Liangkang, Zhao, Liping, Hales, Chadwick M., Johnson, Erik C.B., Elmor, Morgan B., Malakauskas, Sarah J., Heilman, Craig, Wingo, Thomas S., Dorbin, Cornelya D., Davis, Crystal P., Thomas, Tiffany I., Hajjar, Ihab M., Levey, Allan I., and Parker, Monica W.

Subjects
ALZHEIMER'S disease, GAUSSIAN mixture models, CEREBROSPINAL fluid, DISEASE risk factors, AFRICAN Americans
Abstract

Objective: Alzheimer's disease (AD) is believed to be more common in African Americans (AA), but biomarker studies in AA populations are limited. This report represents the largest study to date examining cerebrospinal fluid AD biomarkers in AA individuals. Methods: We analyzed 3,006 cerebrospinal fluid samples from controls, AD cases, and non‐AD cases, including 495 (16.5%) self‐identified black/AA and 2,456 (81.7%) white/European individuals using cutoffs derived from the Alzheimer's Disease Neuroimaging Initiative, and using a data‐driven multivariate Gaussian mixture of regressions. Results: Distinct effects of race were found in different groups. Total Tauand phospho181‐Tau were lower among AA individuals in all groups (p < 0.0001), and Aβ42 was markedly lower in AA controls compared with white controls (p < 0.0001). Gaussian mixture of regressions modeling of cerebrospinal fluid distributions incorporating adjustments for covariates revealed coefficient estimates for AA race comparable with 2‐decade change in age. Using Alzheimer's Disease Neuroimaging Initiative cutoffs, fewer AA controls were classified as biomarker‐positive asymptomatic AD (8.0% vs 13.4%). After adjusting for covariates, our Gaussian mixture of regressions model reduced this difference, but continued to predict lower prevalence of asymptomatic AD among AA controls (9.3% vs 13.5%). Interpretation: Although the risk of dementia is higher, data‐driven modeling indicates lower frequency of asymptomatic AD in AA controls, suggesting that dementia among AA populations may not be driven by higher rates of AD. ANN NEUROL 2024;96:463–475 [ABSTRACT FROM AUTHOR]

Published
2024
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41. Cerebral Aβ deposition in an Aβ-precursor protein-transgenic rhesus monkey

Author

Chan, Anthony W.S., Cho, In Ki, Li, Chun-Xia, Zhang, Xiaodong, Patel, Sudeep, Rusnak, Rebecca, Raper, Jessica, Bachevalier, Jocelyne, Moran, Sean P., Chi, Tim, Cannon, Katherine H., Hunter, Carissa E., Martin, Ryan C., Xiao, Hailian, Yang, Shang-Hsun, Gumber, Sanjeev, Herndon, James G., Rosen, Rebecca F., Hu, William T., Lah, James J., Levey, Allan I., Smith, Yoland, and Walker, Lary C.

Published
2022
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42. Large-scale deep multi-layer analysis of Alzheimer’s disease brain reveals strong proteomic disease-related changes not observed at the RNA level

Author

Johnson, Erik C. B., Carter, E. Kathleen, Dammer, Eric B., Duong, Duc M., Gerasimov, Ekaterina S., Liu, Yue, Liu, Jiaqi, Betarbet, Ranjita, Ping, Lingyan, Yin, Luming, Serrano, Geidy E., Beach, Thomas G., Peng, Junmin, De Jager, Philip L., Haroutunian, Vahram, Zhang, Bin, Gaiteri, Chris, Bennett, David A., Gearing, Marla, Wingo, Thomas S., Wingo, Aliza P., Lah, James J., Levey, Allan I., and Seyfried, Nicholas T.

Published
2022
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43. Analysis of shared heritability in common disorders of the brain

Author

Consortium, The Brainstorm, Anttila, Verneri, Bulik-Sullivan, Brendan, Finucane, Hilary K, Walters, Raymond K, Bras, Jose, Duncan, Laramie, Escott-Price, Valentina, Falcone, Guido J, Gormley, Padhraig, Malik, Rainer, Patsopoulos, Nikolaos A, Ripke, Stephan, Wei, Zhi, Yu, Dongmei, Lee, Phil H, Turley, Patrick, Grenier-Boley, Benjamin, Chouraki, Vincent, Kamatani, Yoichiro, Berr, Claudine, Letenneur, Luc, Hannequin, Didier, Amouyel, Philippe, Boland, Anne, Deleuze, Jean-François, Duron, Emmanuelle, Vardarajan, Badri N, Reitz, Christiane, Goate, Alison M, Huentelman, Matthew J, Kamboh, M Ilyas, Larson, Eric B, Rogaeva, Ekaterina, St George-Hyslop, Peter, Hakonarson, Hakon, Kukull, Walter A, Farrer, Lindsay A, Barnes, Lisa L, Beach, Thomas G, Demirci, F Yesim, Head, Elizabeth, Hulette, Christine M, Jicha, Gregory A, Kauwe, John SK, Kaye, Jeffrey A, Leverenz, James B, Levey, Allan I, Lieberman, Andrew P, Pankratz, Vernon S, Poon, Wayne W, Quinn, Joseph F, Saykin, Andrew J, Schneider, Lon S, Smith, Amanda G, Sonnen, Joshua A, Stern, Robert A, Van Deerlin, Vivianna M, Van Eldik, Linda J, Harold, Denise, Russo, Giancarlo, Rubinsztein, David C, Bayer, Anthony, Tsolaki, Magda, Proitsi, Petra, Fox, Nick C, Hampel, Harald, Owen, Michael J, Mead, Simon, Passmore, Peter, Morgan, Kevin, Nöthen, Markus M, Schott, Jonathan M, Rossor, Martin, Lupton, Michelle K, Hoffmann, Per, Kornhuber, Johannes, Lawlor, Brian, McQuillin, Andrew, Al-Chalabi, Ammar, Bis, Joshua C, Ruiz, Agustin, Boada, Mercè, Seshadri, Sudha, Beiser, Alexa, Rice, Kenneth, van der Lee, Sven J, De Jager, Philip L, Geschwind, Daniel H, Riemenschneider, Matthias, Riedel-Heller, Steffi, Rotter, Jerome I, Ransmayr, Gerhard, Hyman, Bradley T, Cruchaga, Carlos, Alegret, Montserrat, Winsvold, Bendik, Palta, Priit, Farh, Kai-How, and Cuenca-Leon, Ester

Subjects
Biological Sciences, Genetics, Biological Psychology, Health Sciences, Psychology, Clinical Research, Mental Health, Human Genome, Brain Disorders, Neurosciences, Mental Illness, 2.1 Biological and endogenous factors, Neurological, Mental health, Brain Diseases, Genetic Variation, Genome-Wide Association Study, Humans, Mental Disorders, Phenotype, Quantitative Trait, Heritable, Risk Factors, Brainstorm Consortium, General Science & Technology
Abstract

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Published
2018

44. Analysis of shared heritability in common disorders of the brain.

Author

Brainstorm Consortium, Anttila, Verneri, Bulik-Sullivan, Brendan, Finucane, Hilary K, Walters, Raymond K, Bras, Jose, Duncan, Laramie, Escott-Price, Valentina, Falcone, Guido J, Gormley, Padhraig, Malik, Rainer, Patsopoulos, Nikolaos A, Ripke, Stephan, Wei, Zhi, Yu, Dongmei, Lee, Phil H, Turley, Patrick, Grenier-Boley, Benjamin, Chouraki, Vincent, Kamatani, Yoichiro, Berr, Claudine, Letenneur, Luc, Hannequin, Didier, Amouyel, Philippe, Boland, Anne, Deleuze, Jean-François, Duron, Emmanuelle, Vardarajan, Badri N, Reitz, Christiane, Goate, Alison M, Huentelman, Matthew J, Kamboh, M Ilyas, Larson, Eric B, Rogaeva, Ekaterina, St George-Hyslop, Peter, Hakonarson, Hakon, Kukull, Walter A, Farrer, Lindsay A, Barnes, Lisa L, Beach, Thomas G, Demirci, F Yesim, Head, Elizabeth, Hulette, Christine M, Jicha, Gregory A, Kauwe, John SK, Kaye, Jeffrey A, Leverenz, James B, Levey, Allan I, Lieberman, Andrew P, Pankratz, Vernon S, Poon, Wayne W, Quinn, Joseph F, Saykin, Andrew J, Schneider, Lon S, Smith, Amanda G, Sonnen, Joshua A, Stern, Robert A, Van Deerlin, Vivianna M, Van Eldik, Linda J, Harold, Denise, Russo, Giancarlo, Rubinsztein, David C, Bayer, Anthony, Tsolaki, Magda, Proitsi, Petra, Fox, Nick C, Hampel, Harald, Owen, Michael J, Mead, Simon, Passmore, Peter, Morgan, Kevin, Nöthen, Markus M, Rossor, Martin, Lupton, Michelle K, Hoffmann, Per, Kornhuber, Johannes, Lawlor, Brian, McQuillin, Andrew, Al-Chalabi, Ammar, Bis, Joshua C, Ruiz, Agustin, Boada, Mercè, Seshadri, Sudha, Beiser, Alexa, Rice, Kenneth, van der Lee, Sven J, De Jager, Philip L, Geschwind, Daniel H, Riemenschneider, Matthias, Riedel-Heller, Steffi, Rotter, Jerome I, Ransmayr, Gerhard, Hyman, Bradley T, Cruchaga, Carlos, Alegret, Montserrat, Winsvold, Bendik, Palta, Priit, Farh, Kai-How, Cuenca-Leon, Ester, and Furlotte, Nicholas

Subjects
Brainstorm Consortium, Humans, Brain Diseases, Risk Factors, Mental Disorders, Quantitative Trait, Heritable, Phenotype, Genetic Variation, Genome-Wide Association Study, Clinical Research, Neurosciences, Rare Diseases, Human Genome, Brain Disorders, Genetics, Mental Health, 2.1 Biological and endogenous factors, Mental health, Neurological, General Science & Technology
Abstract

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Published
2018

45. Conserved brain myelination networks are altered in Alzheimer's and other neurodegenerative diseases

Author

Allen, Mariet, Wang, Xue, Burgess, Jeremy D, Watzlawik, Jens, Serie, Daniel J, Younkin, Curtis S, Nguyen, Thuy, Malphrus, Kimberly G, Lincoln, Sarah, Carrasquillo, Minerva M, Ho, Charlotte, Chakrabarty, Paramita, Strickland, Samantha, Murray, Melissa E, Swarup, Vivek, Geschwind, Daniel H, Seyfried, Nicholas T, Dammer, Eric B, Lah, James J, Levey, Allan I, Golde, Todd E, Funk, Cory, Li, Hongdong, Price, Nathan D, Petersen, Ronald C, Graff‐Radford, Neill R, Younkin, Steven G, Dickson, Dennis W, Crook, Julia R, Asmann, Yan W, and Ertekin‐Taner, Nilüfer

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Aging, Acquired Cognitive Impairment, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Neurodegenerative, Alzheimer's Disease, 2.1 Biological and endogenous factors, Aetiology, 1.1 Normal biological development and functioning, Underpinning research, Neurological, Alzheimer Disease, Brain, Cohort Studies, Computational Biology, Female, Gene Expression Regulation, Genetic Predisposition to Disease, Humans, Male, Myelin Sheath, Neurons, Supranuclear Palsy, Progressive, Transcriptome, Proteinopathies, Alzheimer's disease, Progressive supranuclear palsy, Myelination, Coexpression networks, Temporal cortex, Cerebellum, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionComparative transcriptome analyses in Alzheimer's disease (AD) and other neurodegenerative proteinopathies can uncover both shared and distinct disease pathways.MethodsWe analyzed 940 brain transcriptomes including patients with AD, progressive supranuclear palsy (PSP; a primary tauopathy), and control subjects.ResultsWe identified transcriptional coexpression networks implicated in myelination, which were lower in PSP temporal cortex (TCX) compared with AD. Some of these associations were retained even after adjustments for brain cell population changes. These TCX myelination network structures were preserved in cerebellum but they were not differentially expressed in cerebellum between AD and PSP. Myelination networks were downregulated in both AD and PSP, when compared with control TCX samples.DiscussionDownregulation of myelination networks may underlie both PSP and AD pathophysiology, but may be more pronounced in PSP. These data also highlight conservation of transcriptional networks across brain regions and the influence of cell type changes on these networks.

Published
2018

46. Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer’s disease pathogenesis

Author

Zhou, Xiaopu, Chen, Yu, Mok, Kin Y, Zhao, Qianhua, Chen, Keliang, Chen, Yuewen, Hardy, John, Li, Yun, Fu, Amy KY, Guo, Qihao, Ip, Nancy Y, Saykin, Andrew J, Toga, Arthur W, Borowski, Bret, Ward, Chad, DeCarli, Charles, Mathis, Chet, Jack, Clifford R, Harvey, Danielle, Holtzman, David, Jones, David, Gessert, Devon, Lilly, Eli, Reiman, Eric M, Franklin, Erin, Hefti, Franz, Sorensen, Greg, Jimenez, Gustavo, Fillit, Howard, Gunter, Jeff, Salazar, Jennifer, Hsiao, John, Morris, John, Trojanowki, John Q, Neu, Karen Crawford Scott, Kantarci, Kejal, Faber, Kelley, Harless, Kelly, Chen, Kewei, Nho, Kwangsik, Beckett, Laurel, Thal, Lean, Thal, Leon, Shaw, Leslie M, Kuller, Lew, Shen, Li, Hergesheimer, Lindsey, Taylor-Reinwald, Lisa, Mesulam, M Marcel, Korecka, Magdalena, Raichle, Marc, Carrillo, Maria, Albert, Marilyn, Senjem, Matt, Bernstein, Matthew, Donohue, Michael, Weiner, Michael, Figurski, Michal, Buckholtz, Neil, Fox, Nick, Cairns, Nigel J, Schuff, Norbert, Foster, Norm, Aisen, Paul, Thompson, Paul, Davies, Peter, Snyder, Peter J, Snyder, Peter, Vemuri, Prashanthi, Frank, Richard, Koeppe, Robert A, Green, Robert C, Petersen, Ronald, Walter, Sarah, Paul, Steven, Potkin, Steven, Kim, Sungeun, Foroud, Tatiana M, Montine, Tom, Lee, Virginia, Jagust, William, Potter, William, Cabrera, Yuliana, Khachaturian, Zaven, Fleisher, Adam, Pierce, Aimee, Mintz, Akiva, Lerner, Alan, Norbash, Alexander, Levey, Allan I, Rosen, Allyson, Smith, Amanda, Ulysse, Anaztasia, Budson, Andrew E, Kertesz, Andrew, Oliver, Angela, Hake, Ann Marie, Burke, Anna, Sarrael, Antero, and Porsteinsson, Anton P

Subjects
Biological Sciences, Genetics, Dementia, Acquired Cognitive Impairment, Prevention, Brain Disorders, Aging, Human Genome, Neurosciences, Alzheimer's Disease, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), 2.1 Biological and endogenous factors, Aetiology, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Good Health and Well Being, Age of Onset, Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Asian People, China, Cohort Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Immune System, Male, Middle Aged, Potassium Channels, Inwardly Rectifying, Risk Factors, Alzheimer’s Disease Neuroimaging Initiative, Alzheimer’s disease, GWAS, immune, risk variant, whole-genome sequencing
Abstract

Alzheimer's disease (AD) is a leading cause of mortality among the elderly. We performed a whole-genome sequencing study of AD in the Chinese population. In addition to the variants identified in or around the APOE locus (sentinel variant rs73052335, P = 1.44 × 10-14), two common variants, GCH1 (rs72713460, P = 4.36 × 10-5) and KCNJ15 (rs928771, P = 3.60 × 10-6), were identified and further verified for their possible risk effects for AD in three small non-Asian AD cohorts. Genotype-phenotype analysis showed that KCNJ15 variant rs928771 affects the onset age of AD, with earlier disease onset in minor allele carriers. In addition, altered expression level of the KCNJ15 transcript can be observed in the blood of AD subjects. Moreover, the risk variants of GCH1 and KCNJ15 are associated with changes in their transcript levels in specific tissues, as well as changes of plasma biomarkers levels in AD subjects. Importantly, network analysis of hippocampus and blood transcriptome datasets suggests that the risk variants in the APOE, GCH1, and KCNJ15 loci might exert their functions through their regulatory effects on immune-related pathways. Taking these data together, we identified common variants of GCH1 and KCNJ15 in the Chinese population that contribute to AD risk. These variants may exert their functional effects through the immune system.

Published
2018

47. Kv1.3 inhibition as a potential microglia-targeted therapy for Alzheimer’s disease: preclinical proof of concept

Author

Maezawa, Izumi, Nguyen, Hai M, Di Lucente, Jacopo, Jenkins, David Paul, Singh, Vikrant, Hilt, Silvia, Kim, Kyoungmi, Rangaraju, Srikant, Levey, Allan I, Wulff, Heike, and Jin, Lee-Way

Subjects
Biomedical and Clinical Sciences, Brain Disorders, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Acquired Cognitive Impairment, Neurosciences, Neurodegenerative, Biotechnology, Dementia, Aetiology, 2.1 Biological and endogenous factors, Neurological, Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Animals, Newborn, Avoidance Learning, Cells, Cultured, Disease Models, Animal, Exploratory Behavior, Ficusin, Gene Expression Regulation, Kv1.3 Potassium Channel, Membrane Potentials, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microglia, Mutation, Peptide Fragments, Potassium Channel Blockers, Presenilin-1, Shab Potassium Channels, potassium channel, microglia, Alzheimer's disease, neuroinflammation, amyloid-beta, Alzheimer’s disease, amyloid-β, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

Microglia significantly contribute to the pathophysiology of Alzheimer's disease but an effective microglia-targeted therapeutic approach is not yet available clinically. The potassium channels Kv1.3 and Kir2.1 play important roles in regulating immune cell functions and have been implicated by in vitro studies in the 'M1-like pro-inflammatory' or 'M2-like anti-inflammatory' state of microglia, respectively. We here found that amyloid-β oligomer-induced expression of Kv1.3 and Kir2.1 in cultured primary microglia. Likewise, ex vivo microglia acutely isolated from the Alzheimer's model 5xFAD mice co-expressed Kv1.3 and Kir2.1 as well as markers traditionally associated with M1 and M2 activation suggesting that amyloid-β oligomer induces a microglial activation state that is more complex than previously thought. Using the orally available, brain penetrant small molecule Kv1.3 blocker PAP-1 as a tool, we showed that pro-inflammatory and neurotoxic microglial responses induced by amyloid-β oligomer required Kv1.3 activity in vitro and in hippocampal slices. Since we further observed that Kv1.3 was highly expressed in microglia of transgenic Alzheimer's mouse models and human Alzheimer's disease brains, we hypothesized that pharmacological Kv1.3 inhibition could mitigate the pathology induced by amyloid-β aggregates. Indeed, treating APP/PS1 transgenic mice with a 5-month oral regimen of PAP-1, starting at 9 months of age, when the animals already manifest cognitive deficits and amyloid pathology, reduced neuroinflammation, decreased cerebral amyloid load, enhanced hippocampal neuronal plasticity, and improved behavioural deficits. The observed decrease in cerebral amyloid deposition was consistent with the in vitro finding that PAP-1 enhanced amyloid-β uptake by microglia. Collectively, these results provide proof-of-concept data to advance Kv1.3 blockers to Alzheimer's disease clinical trials.

Published
2018

48. Proteomic changes in the human cerebrovasculature in Alzheimer's disease and related tauopathies linked to peripheral biomarkers in plasma and cerebrospinal fluid

Author

Wojtas, Aleksandra M., primary, Dammer, Eric B., additional, Guo, Qi, additional, Ping, Lingyan, additional, Shantaraman, Ananth, additional, Duong, Duc M., additional, Yin, Luming, additional, Fox, Edward J., additional, Seifar, Fatemeh, additional, Lee, Edward B., additional, Johnson, Erik C. B., additional, Lah, James J., additional, Levey, Allan I., additional, Levites, Yona, additional, Rangaraju, Srikant, additional, Golde, Todd E., additional, and Seyfried, Nicholas T., additional

Published
2024
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49. Deconstructing pathological tau by biological process in early stages of Alzheimer disease: a method for quantifying tau spatial spread in neuroimaging

Author

Doering, Stephanie, primary, McCullough, Austin, additional, Gordon, Brian A., additional, Chen, Charles D., additional, McKay, Nicole, additional, Hobbs, Diana, additional, Keefe, Sarah, additional, Flores, Shaney, additional, Scott, Jalen, additional, Smith, Hunter, additional, Jarman, Stephen, additional, Jackson, Kelley, additional, Hornbeck, Russ C., additional, Ances, Beau M., additional, Xiong, Chengjie, additional, Aschenbrenner, Andrew J., additional, Hassenstab, Jason, additional, Cruchaga, Carlos, additional, Daniels, Alisha, additional, Bateman, Randall J., additional, Noble, James M., additional, Day, Gregory S., additional, Graff-Radford, Neill R., additional, Voglein, Jonathan, additional, Levin, Johannes, additional, Allegri, Ricardo F., additional, Mendez, Patricio Chrem, additional, Surace, Ezequiel, additional, Berman, Sarah B., additional, Ikonomovic, Snezana, additional, Nadkarni, Neelesh K., additional, Lopera, Francisco, additional, Ramirez, Laura, additional, Aguillon, David, additional, Leon, Yudy, additional, Ramos, Claudia, additional, Alzate, Diana, additional, Baena, Ana, additional, Londono, Natalia, additional, Moreno, Sonia, additional, Jucker, Mathias, additional, Laske, Christoph, additional, Kuder-Buletta, Elke, additional, Graber-Sultan, Susanne, additional, Preische, Oliver, additional, Hofmann, Anna, additional, Ikeuchi, Takeshi, additional, Kasuga, Kensaku, additional, Niimi, Yoshiki, additional, Ishii, Kenji, additional, Senda, Michio, additional, Sanchez-Valle, Raquel, additional, Rosa-Neto, Pedro, additional, Fox, Nick C., additional, Cash, Dave, additional, Lee, Jae-Hong, additional, Roh, Jee Hoon, additional, Salloway, Stephen, additional, Riddle, Meghan C., additional, Menard, William, additional, Bodge, Courtney, additional, Surti, Mustafa, additional, Takada, Leonel Tadao, additional, Farlow, Martin, additional, Chhatwal, Jasmeer P., additional, Sanchez-Gonzalez, V.J., additional, Orozco-Barajas, Maribel, additional, Goate, Alison M., additional, Renton, Alan E., additional, Esposito, Bianca T., additional, Karch, Celeste M., additional, Marsh, Jacob, additional, Fernanadez, Victoria, additional, Fagan, Anne M., additional, Jerome, Gina, additional, Herries, Elizabeth, additional, Llibre-Guerra, Jorge, additional, Levey, Allan I., additional, Johnson, Erik C.B., additional, Seyfried, Nicholas T., additional, Schofield, Peter R., additional, Brooks, William S., additional, Bechara, Jacob A., additional, Bateman, Randall, additional, McDade, Eric, additional, Perrin, Richard J., additional, Franklin, Erin E., additional, Benzinger, Tammie, additional, Chen, Allison, additional, Chen, Charles, additional, Friedrichsen, Nelly, additional, Gordon, Brian, additional, Hantler, Nancy, additional, Hornbeck, Russ, additional, Jarman, Steve, additional, Koudelis, Deborah, additional, Massoumzadeh, Parinaz, additional, Nicklaus, Joyce, additional, Pulizos, Christine, additional, Wang, Qing, additional, Mishall, Sheetal, additional, Sabaredzovic, Edita, additional, Deng, Emily, additional, Candela, Madison, additional, Wang, Peter, additional, Xu, Xiong, additional, Li, Yan, additional, Gremminger, Emily, additional, Ma, Yinjiao, additional, Bui, Ryan, additional, Lu, Ruijin, additional, Martins, Ralph, additional, Sosa Ortiz, Ana Luisa, additional, Courtney, Laura, additional, Mori, Hiroshi, additional, Supnet-Bell, Charlene, additional, Xu, Jinbin, additional, Ringman, John, additional, Barthelemy, Nicolas, additional, Morris, John, additional, Smith, Jennifer, additional, Morris, John C., additional, and Benzinger, Tammie L.S., additional

Published
2024
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50. Large- Scale Deep Proteomic Analysis in Alzheimer's Disease Brain Regions Across Race and Ethnicity

Author

Seifar, Fatemeh, primary, Fox, Edward J., additional, Shantaraman, Ananth, additional, Liu, Yue, additional, Dammer, Eric B., additional, Modeste, Erica, additional, Duong, Duc M., additional, Yin, Luming, additional, Trautwig, Adam N., additional, Guo, Qi, additional, Xu, Kaiming, additional, Ping, Lingyan, additional, Reddy, Joseph S., additional, Allen, Mariet, additional, Quicksall, Zachary, additional, Heath, Laura, additional, Scanlan, Jo, additional, Wang, Erming, additional, Wang, Minghui, additional, Vander Linden, Abby, additional, Poehlman, William, additional, Chen, Xianfeng, additional, Baheti, Saurabh, additional, Ho, Charlotte, additional, Nguyen, Thuy, additional, Yepez, Geovanna, additional, Mitchell, Adriana O., additional, Oatman, Stephanie R., additional, Wang, Xue, additional, Carrasquillo, Minerva M., additional, Runnels, Alexi, additional, Beach, Thomas, additional, Serrano, Geidy E., additional, Dickson, Dennis W., additional, Lee, Edward B., additional, Golde, Todd E., additional, Prokop, Stefan, additional, Barnes, Lisa L., additional, Zhang, Bin, additional, Haroutunian, Varham, additional, Gearing, Marla, additional, Lah, James J., additional, De Jager, Philip, additional, Bennett, David A., additional, Greenwood, Anna, additional, Ertekin-Taner, Nil fer, additional, Levey, Allan I., additional, Wingo, Aliza, additional, Wingo, Thomas, additional, and Seyfried, Nicholas T., additional

Published
2024
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