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2. Decreased myelin proteins in brain donors exposed to football-related repetitive head impacts

Author

Alosco, Michael L, Ly, Monica, Mosaheb, Sydney, Saltiel, Nicole, Uretsky, Madeline, Tripodis, Yorghos, Martin, Brett, Palmisano, Joseph, Delano-Wood, Lisa, Bondi, Mark W, Meng, Gaoyuan, Xia, Weiming, Daley, Sarah, Goldstein, Lee E, Katz, Douglas I, Dwyer, Brigid, Daneshvar, Daniel H, Nowinski, Christopher, Cantu, Robert C, Kowall, Neil W, Stern, Robert A, Alvarez, Victor E, Mez, Jesse, Huber, Bertrand Russell, McKee, Ann C, and Stein, Thor D

Subjects
Biological Psychology, Psychology, Acquired Cognitive Impairment, Brain Disorders, Neurodegenerative, Neurosciences, Neurological, Good Health and Well Being, myelin, cerebrovascular disease, chronic traumatic encephalopathy, repetitive head impacts, white matter, Clinical sciences, Biological psychology
Abstract

American football players and other individuals exposed to repetitive head impacts can exhibit a constellation of later-life cognitive and neuropsychiatric symptoms. While tau-based diseases such as chronic traumatic encephalopathy can underpin certain symptoms, contributions from non-tau pathologies from repetitive head impacts are increasingly recognized. We examined cross-sectional associations between myelin integrity using immunoassays for myelin-associated glycoprotein and proteolipid protein 1 with risk factors and clinical outcomes in brain donors exposed to repetitive head impacts from American football. Immunoassays for myelin-associated glycoprotein and proteolipid protein 1 were conducted on dorsolateral frontal white matter tissue samples of 205 male brain donors. Proxies of exposure to repetitive head impacts included years of exposure and age of first exposure to American football play. Informants completed the Functional Activities Questionnaire, Behavior Rating Inventory of Executive Function-Adult Version (Behavioral Regulation Index), and Barratt Impulsiveness Scale-11. Associations between myelin-associated glycoprotein and proteolipid protein 1 with exposure proxies and clinical scales were tested. Of the 205 male brain donors who played amateur and professional football, the mean age was 67.17 (SD = 16.78), and 75.9% (n = 126) were reported by informants to be functionally impaired prior to death. Myelin-associated glycoprotein and proteolipid protein 1 correlated with the ischaemic injury scale score, a global indicator of cerebrovascular disease (r = -0.23 and -0.20, respectively, Ps < 0.01). Chronic traumatic encephalopathy was the most common neurodegenerative disease (n = 151, 73.7%). Myelin-associated glycoprotein and proteolipid protein 1 were not associated with chronic traumatic encephalopathy status, but lower proteolipid protein 1 was associated with more severe chronic traumatic encephalopathy (P = 0.03). Myelin-associated glycoprotein and proteolipid protein 1 were not associated with other neurodegenerative disease pathologies. More years of football play was associated with lower proteolipid protein 1 [beta = -2.45, 95% confidence interval (CI) [-4.52, -0.38]] and compared with those who played

Published
2023

8. Prevalence of Mild Cognitive Impairment and Alzheimer’s Disease Identified in Veterans in the United States

Author

Aguilar, Byron J., primary, Jasuja, Guneet K., additional, Li, Xuyang, additional, Shishova, Ekaterina, additional, Palacios, Natalia, additional, Berlowitz, Dan, additional, Morin, Peter, additional, O’Connor, Maureen K., additional, Nguyen, Andrew, additional, Reisman, Joel, additional, Leng, Yue, additional, Zhang, Raymond, additional, Monfared, Amir Abbas Tahami, additional, Zhang, Quanwu, additional, and Xia, Weiming, additional

Published
2024
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10. β-amyloid accumulation enhances microtubule associated protein tau pathology in an APPNL-G-F/MAPTP301S mouse model of Alzheimer’s disease

Author

Jiang, Lulu, primary, Roberts, Rebecca, additional, Wong, Melissa, additional, Zhang, Lushuang, additional, Webber, Chelsea Joy, additional, Libera, Jenna, additional, Wang, Zihan, additional, Kilci, Alper, additional, Jenkins, Matthew, additional, Ortiz, Alejandro Rondón, additional, Dorrian, Luke, additional, Sun, Jingjing, additional, Sun, Guangxin, additional, Rashad, Sherif, additional, Kornbrek, Caroline, additional, Daley, Sarah Anne, additional, Dedon, Peter C., additional, Nguyen, Brian, additional, Xia, Weiming, additional, Saito, Takashi, additional, Saido, Takaomi C., additional, and Wolozin, Benjamin, additional

Published
2024
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13. A comparison between tau and amyloid-β cerebrospinal fluid biomarkers in chronic traumatic encephalopathy and Alzheimer disease

Author

Turk, Katherine W., Geada, Alexandra, Alvarez, Victor E., Xia, Weiming, Cherry, Jonathan D., Nicks, Raymond, Meng, Gaoyuan, Daley, Sarah, Tripodis, Yorghos, Huber, Bertrand R., Budson, Andrew E., Dwyer, Brigid, Kowall, Neil W., Cantu, Robert C., Goldstein, Lee E., Katz, Douglas I., Stern, Robert A., Alosco, Michael L., Mez, Jesse, McKee, Ann C., and Stein, Thor D.

Published
2022
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20. Development and validation of a natural language processing system that extracts cognitive test results from clinical notes

Author

Chen, Jinying, primary, Li, Xuyang, additional, Aguilar, Byron J., additional, Shishova, Ekaterina, additional, Morin, Peter J, additional, Berlowitz, Dan, additional, Miller, Donald R, additional, O'Connor, Maureen K., additional, Nguyen, Andrew H., additional, Zhang, Raymond, additional, Monfared, Amir Abbas Tahami, additional, Zhang, Quanwu, additional, and Xia, Weiming, additional

Published
2023
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21. Diagnosis of Severity of Alzheimer’s Disease from Clinical notes in the Veterans Affairs Healthcare System

Author

Aguilar, Byron J., primary, Shishova, Ekaterina, additional, Li, Xuyang, additional, Nguyen, Andrew H., additional, Morin, Peter J, additional, Berlowitz, Dan, additional, O'Connor, Maureen K., additional, Miller, Donald R, additional, Jasuja, Guneet, additional, Zhang, Raymond, additional, Monfared, Amir Abbas Tahami, additional, Zhang, Quanwu, additional, and Xia, Weiming, additional

Published
2023
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22. Building a neuropsychiatric testing database for veterans with mild cognitive impairment and Alzheimer’s disease with unstructured electronic health records

Author

Li, Xuyang, primary, Chen, Jinying, additional, Aguilar, Byron J., additional, Shishova, Ekaterina, additional, Morin, Peter J, additional, Berlowitz, Dan, additional, Miller, Donald R, additional, O'Connor, Maureen K., additional, Nguyen, Andrew Huy, additional, Zhang, Raymond, additional, Monfared, Amir Abbas Tahami, additional, Zhang, Quanwu, additional, and Xia, Weiming, additional

Published
2023
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23. Identification of Alzheimer’s disease in Veteran patients using clinical notes from electronic health records

Author

Miller, Donald R, primary, Aguilar, Byron J., additional, Li, Xuyang, additional, Shishova, Ekaterina, additional, Jasuja, Guneet, additional, Berlowitz, Dan, additional, Morin, Peter J, additional, O'Connor, Maureen K., additional, Nguyen, Andrew H., additional, Christiansen, Cindy, additional, Zhang, Haixin, additional, Monfared, Amir Abbas Tahami, additional, Zhang, Quanwu, additional, and Xia, Weiming, additional

Published
2023
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24. Estimating the prevalence of mild cognitive impairment from clinical notes in U.S. Veterans

Author

Jasuja, Guneet, primary, Li, Xuyang, additional, Aguilar, Byron J., additional, Shishova, Ekaterina, additional, Morin, Peter J, additional, Berlowitz, Dan, additional, Miller, Donald R, additional, O'Connor, Maureen K., additional, Nguyen, Andrew H., additional, Zhang, Raymond, additional, Monfared, Amir Abbas Tahami, additional, Zhang, Quanwu, additional, and Xia, Weiming, additional

Published
2023
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25. Comparative identification of Veterans with mild cognitive impairment or Alzheimer’s disease extracted from clinical notes and administrative data

Author

Berlowitz, Dan, primary, Aguilar, Byron J., additional, Li, Xuyang, additional, Shishova, Ekaterina, additional, Jasuja, Guneet, additional, Morin, Peter J, additional, Miller, Donald R, additional, O'Connor, Maureen K., additional, Nguyen, Andrew H., additional, Zhang, Raymond, additional, Monfared, Amir Abbas Tahami, additional, Zhang, Quanwu, additional, and Xia, Weiming, additional

Published
2023
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27. Pharmacological and Toxicological Properties of the Potent Oral γ-Secretase Modulator BPN-15606.

Author

Wagner, Steven L, Rynearson, Kevin D, Duddy, Steven K, Zhang, Can, Nguyen, Phuong D, Becker, Ann, Vo, Uyen, Masliah, Deborah, Monte, Louise, Klee, Justin B, Echmalian, Corinne M, Xia, Weiming, Quinti, Luisa, Johnson, Graham, Lin, Jiunn H, Kim, Doo Y, Mobley, William C, Rissman, Robert A, and Tanzi, Rudolph E

Subjects
Central Nervous System, Cells, Cultured, Animals, Mice, Inbred C57BL, Mice, Transgenic, Macaca fascicularis, Humans, Mice, Rats, Rats, Sprague-Dawley, Alzheimer Disease, Phenethylamines, Pyridazines, Peptide Fragments, Amyloid beta-Protein Precursor, tau Proteins, Enzyme Inhibitors, Dose-Response Relationship, Drug, Male, Amyloid Precursor Protein Secretases, Amyloid beta-Peptides, Plaque, Amyloid, Cells, Cultured, Inbred C57BL, Transgenic, Sprague-Dawley, Dose-Response Relationship, Drug, Plaque, Amyloid, Pharmacology and Pharmaceutical Sciences, Pharmacology & Pharmacy
Abstract

Alzheimer's disease (AD) is characterized neuropathologically by an abundance of 1) neuritic plaques, which are primarily composed of a fibrillar 42-amino-acid amyloid-β peptide (Aβ), as well as 2) neurofibrillary tangles composed of aggregates of hyperphosporylated tau. Elevations in the concentrations of the Aβ42 peptide in the brain, as a result of either increased production or decreased clearance, are postulated to initiate and drive the AD pathologic process. We initially introduced a novel class of bridged aromatics referred tγ-secretase modulatoro as γ-secretase modulators that inhibited the production of the Aβ42 peptide and to a lesser degree the Aβ40 peptide while concomitantly increasing the production of the carboxyl-truncated Aβ38 and Aβ37 peptides. These modulators potently lower Aβ42 levels without inhibiting the γ-secretase-mediated proteolysis of Notch or causing accumulation of carboxyl-terminal fragments of APP. In this study, we report a large number of pharmacological studies and early assessment of toxicology characterizing a highly potent γ-secretase modulator (GSM), (S)-N-(1-(4-fluorophenyl)ethyl)-6-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methylpyridazin-3-amine (BPN-15606). BPN-15606 displayed the ability to significantly lower Aβ42 levels in the central nervous system of rats and mice at doses as low as 5-10 mg/kg, significantly reduce Aβ neuritic plaque load in an AD transgenic mouse model, and significantly reduce levels of insoluble Aβ42 and pThr181 tau in a three-dimensional human neural cell culture model. Results from repeat-dose toxicity studies in rats and dose escalation/repeat-dose toxicity studies in nonhuman primates have designated this GSM for 28-day Investigational New Drug-enabling good laboratory practice studies and positioned it as a candidate for human clinical trials.

Published
2017

32. Contact sport participation and chronic traumatic encephalopathy are associated with altered severity and distribution of cerebral amyloid angiopathy

Author

Standring, Oliver J., Friedberg, Jacob, Tripodis, Yorghos, Chua, Alicia S., Cherry, Jonathan D., Alvarez, Victor E., Huber, Bertrand R., Xia, Weiming, Mez, Jesse, Alosco, Michael L., Nicks, Raymond, Mahar, Ian, Pothast, Morgan J., Gardner, Hannah M., Meng, Gaoyuan, Palmisano, Joseph N., Martin, Brett M., Dwyer, Brigid, Kowall, Neil W., Cantu, Robert C., Goldstein, Lee E., Katz, Douglas I., Stern, Robert A., McKee, Ann C., and Stein, Thor D.

Published
2019
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33. Alzheimer's Disease Stage Transitions Among United States Veterans.

Author

Morin, Peter, Aguilar, Byron J., Li, Xuyang, Chen, Jinying, Berlowitz, Dan, Zhang, Raymond, Tahami Monfared, Amir Abbas, Zhang, Quanwu, and Xia, Weiming

Subjects
ALZHEIMER'S disease, MILD cognitive impairment, MONTREAL Cognitive Assessment, DISEASE progression, MINI-Mental State Examination, APOLIPOPROTEIN E4
Abstract

Background: Alzheimer's disease (AD) and related dementias are progressive neurological disorders with stage-specific clinical features and challenges. An important knowledge gap is the "window of time" within which patients transition from mild cognitive impairment or mild AD to moderate or severe AD. Better characterization/establishment of transition times would help clinicians initiating treatments, including anti-amyloid therapy. Objective: To describe cognitive test score-based AD stage transitions in Veterans with AD in the US Veterans Affairs Healthcare System (VAHS). Methods: This retrospective analysis (2010–2019) identified Veterans with AD from the VAHS Electronic Health Record (EHR) notes. AD stage was based on Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), or Saint Louis University Mental Status (SLUMS) Examination scores in the EHR. Results: We identified 296,519 Veterans with cognitive test-based AD staging. Over the 10-year study, the proportion of veterans with MMSE scores declined from 24.9% to 9.5% while those with SLUMS rose from 9.0% to 17.8%; and MoCA rose from 5.0% to 25.4%. The average forward transition times between each stage were approximately 2–4 years, whether assessed by MMSE, MoCA, or SLUMS. Conclusion: The average transition time for cognitive test-based assessments of initial cognitive decline, early-stage AD, and moderate/severe AD in the VAHS is 2–4 years. In view of the short window for introducing disease-modifying therapy and the significant benefits of early treatment of AD, our data suggest a critical need for treatment guidelines in the management of AD. [ABSTRACT FROM AUTHOR]

Published
2024
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34. List of contributors

Author

Artukoglu, Bekir B., primary, Bachoo, Robert M., additional, Baranzini, Sergio E., additional, Benson, Merrill D., additional, Biglan, Kevin, additional, Blakeney, Iona, additional, Bloch, Michael H., additional, Brady, Melanie, additional, Brandsema, John F., additional, Broccolini, Aldobrando, additional, Brown, Robert H., additional, Cohen, Bernard, additional, Cole, Jordan J., additional, Comi, Anne M., additional, Crabbe, John C., additional, Darras, Basil T., additional, Dowling, Michael M., additional, Dunn, Walter, additional, Elroy-Stein, Orna, additional, Elsheikh, Bakri H., additional, Engel, Andrew G., additional, Fahn, Stanley, additional, Fasching, Liana, additional, Fears, Scott C., additional, Felling, Ryan J., additional, Ferner, Rosalie E., additional, Fink, John K., additional, Gillespie, Charles F., additional, Goldman, Alica M., additional, Goldman, Jill, additional, Gutmann, David H., additional, Haltia, Matti, additional, Hauser, Stephen L., additional, Hilbert, James E., additional, Iliopoulos, Othon, additional, Islam, Monica P., additional, Jenkins, Aaron K., additional, Jia, Xiaoming, additional, Jungbluth, Heinz, additional, Kayani, Saima N., additional, Khemani, Pravin, additional, Kirkham, Fenella J., additional, Kirkorian, A. Yasmine, additional, Kissel, John T., additional, Klein, Christine, additional, Kleopa, Kleopas A., additional, Kolb, Stephen J., additional, Konstantakou, Eumorphia, additional, Lambracht-Washington, Doris, additional, Lennington, Jessica B., additional, Lewis, David A., additional, Liang, Wen-Chen, additional, Lidstone, Paven A., additional, Lohmann, Katja, additional, Lombroso, Paul J., additional, Maher, Elizabeth A., additional, Marshall, Frederick, additional, McCann, Meghan, additional, McGarry, Andrew, additional, Meola, Giovanni, additional, Metelo, Ana, additional, Miller, Bruce L., additional, Mirabella, Massimiliano, additional, Mizutani, Shuki, additional, Mole, Sara E., additional, Moxley, Richard T., additional, Muntoni, Francesco, additional, Nemeroff, Charles B., additional, Nishino, Ichizo, additional, Noebels, Jeffrey L., additional, Pandolfo, Massimo, additional, Pevsner, Jonathan, additional, Ptáček, Louis, additional, Ralph, Jeffrey, additional, Renthal, William, additional, Reus, Victor I., additional, Roach, E. Steve, additional, Rosenberg, Roger N., additional, Savarese, Antonia M., additional, Sawyer, Russell P., additional, Scherer, Steven S., additional, Schiffmann, Raphael, additional, Schulz, Angela, additional, Sewry, Caroline, additional, Shakkottai, Vikram G., additional, Shinagawa, Shunichiro, additional, Singh, Pratibha, additional, Sreedharan, Jemeen, additional, Statland, Jeffrey M., additional, Szabo, Steven T., additional, Szuhay, Gabor, additional, Udd, Bjarne, additional, Vaccarino, Flora M., additional, Volk, David W., additional, Wilson, Kathleen S., additional, Xia, Weiming, additional, and Yu, Gang, additional

Published
2020
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37. Amyloid β synaptotoxicity is Wnt-PCP dependent and blocked by fasudil

Author

Sellers, Katherine J., Elliott, Christina, Jackson, Joshua, Ghosh, Anshua, Ribe, Elena, Rojo, Ana I., Jarosz-Griffiths, Heledd H., Watson, Iain A., Xia, Weiming, Semenov, Mikhail, Morin, Peter, Hooper, Nigel M., Porter, Rod, Preston, Jane, Al-Shawi, Raya, Baillie, George, Lovestone, Simon, Cuadrado, Antonio, Harte, Michael, Simons, Paul, Srivastava, Deepak P., and Killick, Richard

Published
2018
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42. Accumulation of m6A exhibits stronger correlation with MAPT than β-amyloid pathology in an APPNL-G-F /MAPTP301S mouse model of Alzheimer's disease

Author

Jiang, Lulu, primary, Roberts, Rebecca, additional, Wong, Melissa, additional, Zhang, Lushuang, additional, Webber, Chelsea Joy, additional, Kilci, Alper, additional, Jenkins, Matthew, additional, Sun, Jingjing, additional, Sun, Guangxin, additional, Rashad, Sherif, additional, Dedon, Peter C, additional, Daley, Sarah Anne, additional, Xia, Weiming, additional, Ortiz, Alejandro Rondón, additional, Dorrian, Luke, additional, Saito, Takashi, additional, Saido, Takaomi C, additional, and Wolozin, Benjamin, additional

Published
2023
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43. The epidemiology of mild cognitive impairment, Alzheimer's disease and related dementia in U.S. veterans

Author

Dinesh, Deepika, primary, Shao, Qing, additional, Palnati, Madhuri, additional, McDannold, Sarah, additional, Zhang, Quanwu, additional, Monfared, Amir Abbas Tahami, additional, Jasuja, Guneet K., additional, Davila, Heather, additional, Xia, Weiming, additional, Moo, Lauren R., additional, Miller, Donald R., additional, and Palacios, Natalia, additional

Published
2023
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44. Practice Implications of Patterns of Healthcare Utilization before and after Alzheimer’s Disease diagnosis (P2-6.005)

Author

Moo, Lauren, primary, Davila, Heather, additional, Jasuja, Guneet, additional, Palnati, Madhuri, additional, Shao, Qing, additional, Dinesh, Deepika, additional, Palacios, Natalia, additional, MacDannold, Sarah, additional, Xia, Weiming, additional, Zhang, Quanwu, additional, Monfared, Amir Abbas Tahami, additional, and Miller, Donald, additional

Published
2023
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45. Accumulation of m6A exhibits stronger correlation with MAPT than β-amyloid pathology in an APPNL-G-F/MAPTP301Smouse model of Alzheimer’s disease

Author

Jiang, Lulu, primary, Roberts, Rebecca, additional, Wong, Melissa, additional, Zhang, Lushuang, additional, Webber, Chelsea Joy, additional, Kilci, Alper, additional, Jenkins, Matthew, additional, Sun, Guangxin, additional, Rashad, Sherif, additional, Sun, Jingjing, additional, Dedon, Peter C, additional, Daley, Sarah Anne, additional, Xia, Weiming, additional, Ortiz, Alejandro Rondón, additional, Dorrian, Luke, additional, Saito, Takashi, additional, Saido, Takaomi C., additional, and Wolozin, Benjamin, additional

Published
2023
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