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1. The effects of mosaicism on biological and clinical markers of Alzheimer's disease in adults with Down syndrome

Author

Xicota, Laura, Dang, Lam-Ha T, Lee, Alice, Krinsky-McHale, Sharon, Pang, Deborah, Melilli, Lisa, O'Bryant, Sid, Henson, Rachel L, Laymon, Charles, Lai, Florence, Rosas, H Diana, Ances, Beau, Lott, Ira, Hom, Christy, Christian, Bradley, Hartley, Sigan, Zaman, Shahid, Head, Elizabeth, Mapstone, Mark, Jin, Zhezhen, Silverman, Wayne, Schupf, Nicole, Handen, Benjamin, Lee, Joseph H, Syndrome, Alzheimer's Biomarker Consortium–Down, Aizenstein, Howard J, Ances, Beau M, Andrews, Howard F, Bell, Karen, Birn, Rasmus, Brickman, Adam M, Bulova, Peter, Cheema, Amrita, Chen, Kewei, Christian, Bradley T, Clare, Isabel, Clark, Lorraine, Cohen, Ann D, Constantino, John N, Doran, Eric W, Fagan, Anne, Feingold, Eleanor, Foroud, Tatiana M, Handen, Benjamin L, Harp, Jordan, Hartley, Sigan L, Henson, Rachel, Honig, Lawrence, Ikonomovic, Milos D, Johnson, Sterling C, Jordan, Courtney, Kamboh, M Ilyas, Keator, David, Klunk, William E, Kofler, Julia K, Kreisl, William Charles, Krinsky-McHale, Sharon J, Lao, Patrick, Lott, Ira T, Lupson, Victoria, Mathis, Chester A, Minhas, Davneet Singh, Nadkarni, Neelesh, O’Bryant, Sid, Parisi, Melisa, Pettersen, Melissa, Price, Julie C, Pulsifer, Margaret, Rafii, Michael S, Reiman, Eric, Rizvi, Batool, Ryan, Laurie, Schmitt, Frederick, Silverman, Wayne P, Tudorascu, Dana L, Tumuluru, Rameshwari, Tycko, Benjamin, Varadarajan, Badri, White, Desiree A, Yassa, Michael A, and Zhang, Fan

Subjects
Epidemiology, Health Sciences, Alzheimer's Disease, Clinical Research, Down Syndrome, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Acquired Cognitive Impairment, Aging, Neurosciences, Dementia, Prevention, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, 2.1 Biological and endogenous factors, 4.2 Evaluation of markers and technologies, Neurological, Congenital, Down syndrome, Mosaicism, Alzheimer's disease, Plasma biomarkers, CSF, PET, Alzheimer's Biomarker Consortium – Down Syndrome, mosaicism, Alzheimer&#x27, s disease, plasma biomarkers, Clinical Sciences, Public Health and Health Services, Clinical sciences
Abstract

BackgroundIndividuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21.MethodsWe examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium-Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma AD biomarkers (Aβ40, Aβ42, tau, and NfL) and longitudinal cognitive measures. A subset had cerebrospinal fluid biomarkers (Aβ40, Aβ42, tau, ptau181, and NfL) and amyloid and tau PET data.FindingsFor both cohorts, the prevalence of mosaicism was

Published
2024

2. Cerebrovascular disease is associated with Alzheimer’s plasma biomarker concentrations in adults with Down syndrome

Author

Edwards, Natalie C, Lao, Patrick J, Alshikho, Mohamad J, Ericsson, Olivia M, Rizvi, Batool, Petersen, Melissa E, O’Bryant, Sid, Aguilar, Lisi Flores, Simoes, Sabrina, Mapstone, Mark, Tudorascu, Dana L, Janelidze, Shorena, Hansson, Oskar, Handen, Benjamin L, Christian, Bradley T, Lee, Joseph H, Lai, Florence, Rosas, H Diana, Zaman, Shahid, Lott, Ira T, Yassa, Michael A, Aizenstein, Howard J, Ances, Beau M, Andrews, Howard F, Bell, Karen, Birn, Rasmus M, Brickman, Adam M, Bulova, Peter, Cheema, Amrita, Chen, Kewei, Clare, Isabel, Cohen, Ann D, Constantino, John N, Doran, Eric W, Fagan, Anne, Feingold, Eleanor, Foroud, Tatiana M, Harp, Jordan, Hartley, Sigan L, Head, Elizabeth, Henson, Rachel, 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 Charles, Krinsky-McHale, Sharon J, Lao, Patrick, Laymon, Charles, Lupson, Victoria, Mathis, Chester A, Minhas, Davneet Singh, Nadkarni, Neelesh, Parisi, Melissa, Pang, Deborah, Petersen, Melissa, Price, Julie C, Pulsifer, Margaret, Rafii, Michael S, Reiman, Eric, Rosas, Herminia Diana, Ryan, Laurie, Schmitt, Frederick, Schupf, Nicole, Silverman, Wayne P, Tumuluru, Rameshwari, Tycko, Benjamin, Varadarajan, Badri, White, Desiree A, Zhang, Fan, Gutierrez, José, and Wilcock, Donna M

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Dementia, Neurodegenerative, Brain Disorders, Vascular Cognitive Impairment/Dementia, Acquired Cognitive Impairment, Alzheimer's Disease, Aging, Alzheimer's Disease Related Dementias (ADRD), Biomedical Imaging, Cerebrovascular, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Prevention, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Neurological, Alzheimer's disease, Down syndrome, cerebrovascular disease, magnetic resonance imaging, biomarkers, Alzheimer’s Biomarkers Consortium–Down Syndrome (ABC-DS) Investigators, Alzheimer’s disease, Clinical sciences, Biological psychology
Abstract

By age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome.

Published
2024

3. Multi-analyte proteomic analysis identifies blood-based neuroinflammation, cerebrovascular and synaptic biomarkers in preclinical Alzheimer’s disease

Author

Zeng, Xuemei, Lafferty, Tara K., Sehrawat, Anuradha, Chen, Yijun, Ferreira, Pamela C. L., Bellaver, Bruna, Povala, Guilherme, Kamboh, M. Ilyas, Klunk, William E., Cohen, Ann D., Lopez, Oscar L., Ikonomovic, Milos D., Pascoal, Tharick A., Ganguli, Mary, Villemagne, Victor L., Snitz, Beth E., and Karikari, Thomas K.

Published
2024
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4. Alzheimer blood biomarkers: practical guidelines for study design, sample collection, processing, biobanking, measurement and result reporting

Author

Zeng, Xuemei, Chen, Yijun, Sehrawat, Anuradha, Lee, Jihui, Lafferty, Tara K., Kofler, Julia, Berman, Sarah B., Sweet, Robert A., Tudorascu, Dana L., Klunk, William E., Ikonomovic, Milos D., Pfister, Anna, Zetterberg, Henrik, Snitz, Beth E., Cohen, Anne D., Villemagne, Victor L., Pascoal, Tharick A., Kamboh, M. llyas, Lopez, Oscar I., Blennow, Kaj, and Karikari, Thomas K.

Published
2024
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5. Comparison of amyloid burden in individuals with Down syndrome versus autosomal dominant Alzheimer's disease: a cross-sectional study

Author

Boerwinkle, Anna H, Gordon, Brian A, Wisch, Julie, Flores, Shaney, Henson, Rachel L, Butt, Omar H, McKay, Nicole, Chen, Charles D, Benzinger, Tammie LS, Fagan, Anne M, Handen, Benjamin L, Christian, Bradley T, Head, Elizabeth, Mapstone, Mark, Rafii, Michael S, O'Bryant, Sid, Lai, Florence, Rosas, H Diana, Lee, Joseph H, Silverman, Wayne, Brickman, Adam M, Chhatwal, Jasmeer P, Cruchaga, Carlos, Perrin, Richard J, Xiong, Chengjie, Hassenstab, Jason, McDade, Eric, Bateman, Randall J, Ances, Beau M, Syndrome, Alzheimer's Biomarker Consortium-Down, 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, McHale, Sharon J Krinsky-, 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, Network, Dominantly Inherited Alzheimer, Adams, Sarah, Allegri, Ricardo, Araki, Aki, Barthelemy, Nicolas, Bechara, Jacob, Berman, Sarah, Bodge, Courtney, Brandon, Susan, Brooks, William, Brosch, Jared, Buck, Jill, Buckles, Virginia, Carter, Kathleen, Cash, Lisa, Mendez, Patricio C, Chua, Jasmin, Chui, Helena, Courtney, Laura, Day, Gregory, and DeLaCruz, Chrismary

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Biomedical Imaging, Aging, Alzheimer's Disease, Clinical Research, Neurodegenerative, Brain Disorders, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Intellectual and Developmental Disabilities (IDD), Genetics, Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adult, Aged, Humans, Middle Aged, Alzheimer Disease, Amyloid beta-Peptides, Apolipoproteins E, Biomarkers, Cross-Sectional Studies, Down Syndrome, Positron-Emission Tomography, Cerebral Cortex, Alzheimer's Biomarker Consortium-Down Syndrome, Dominantly Inherited Alzheimer Network, Neurology & Neurosurgery, Clinical sciences
Abstract

BackgroundImportant insights into the early pathogenesis of Alzheimer's disease can be provided by studies of autosomal dominant Alzheimer's disease and Down syndrome. However, it is unclear whether the timing and spatial distribution of amyloid accumulation differs between people with autosomal dominant Alzheimer's disease and those with Down syndrome. We aimed to directly compare amyloid changes between these two groups of people.MethodsIn this cross-sectional study, we included participants (aged ≥25 years) with Down syndrome and sibling controls who had MRI and amyloid PET scans in the first data release (January, 2020) of the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study. We also included carriers of autosomal dominant Alzheimer's disease genetic mutations and non-carrier familial controls who were within a similar age range to ABC-DS participants (25-73 years) and had MRI and amyloid PET scans at the time of a data freeze (December, 2020) of the Dominantly Inherited Alzheimer Network (DIAN) study. Controls from the two studies were combined into a single group. All DIAN study participants had genetic testing to determine PSEN1, PSEN2, or APP mutation status. APOE genotype was determined from blood samples. CSF samples were collected in a subset of ABC-DS and DIAN participants and the ratio of amyloid β42 (Aβ42) to Aβ40 (Aβ42/40) was measured to evaluate its Spearman's correlation with amyloid PET. Global PET amyloid burden was compared with regards to cognitive status, APOE ɛ4 status, sex, age, and estimated years to symptom onset. We further analysed amyloid PET deposition by autosomal dominant mutation type. We also assessed regional patterns of amyloid accumulation by estimated number of years to symptom onset. Within a subset of participants the relationship between amyloid PET and CSF Aβ42/40 was evaluated.Findings192 individuals with Down syndrome and 33 sibling controls from the ABC-DS study and 265 carriers of autosomal dominant Alzheimer's disease mutations and 169 non-carrier familial controls from the DIAN study were included in our analyses. PET amyloid centiloid and CSF Aβ42/40 were negatively correlated in carriers of autosomal dominant Alzheimer's disease mutations (n=216; r=-0·565; p

Published
2023

6. The effects of mosaicism on biological and clinical markers of Alzheimer's disease in adults with Down syndrome

Author

Aizenstein, Howard J., Ances, Beau M., Andrews, Howard F., Bell, Karen, Birn, Rasmus, Brickman, Adam M., Bulova, Peter, Cheema, Amrita, Chen, Kewei, Christian, Bradley T., Clare, Isabel, Clark, Lorraine, Cohen, Ann D., Constantino, John N., Doran, Eric W., Fagan, Anne, Feingold, Eleanor, Foroud, Tatiana M., Handen, Benjamin L., Harp, Jordan, Hartley, Sigan L., Head, Elizabeth, Henson, Rachel, 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 Charles, Krinsky-McHale, Sharon J., Lai, Florence, Lao, Patrick, Laymon, Charles, Lee, Joseph H., Lott, Ira T., Lupson, Victoria, Mapstone, Mark, Mathis, Chester A., Minhas, Davneet Singh, Nadkarni, Neelesh, O’Bryant, Sid, Parisi, Melisa, Pang, Deborah, Pettersen, Melissa, Price, Julie C., Pulsifer, Margaret, Rafii, Michael S., Reiman, Eric, Rizvi, Batool, Rosas, H. Diana, Ryan, Laurie, Schmitt, Frederick, Schupf, Nicole, Silverman, Wayne P., Tudorascu, Dana L., Tumuluru, Rameshwari, Tycko, Benjamin, Varadarajan, Badri, White, Desiree A., Yassa, Michael A., Zaman, Shahid, Zhang, Fan, Xicota, Laura, Dang, Lam-Ha T., Lee, Alice, Krinsky-McHale, Sharon, Melilli, Lisa, O'Bryant, Sid, Henson, Rachel L., Ances, Beau, Lott, Ira, Christian, Bradley, Hartley, Sigan, Jin, Zhezhen, Silverman, Wayne, and Handen, Benjamin

Published
2024
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7. Astrocyte reactivity influences amyloid-β effects on tau pathology in preclinical Alzheimer’s disease

Author

Bellaver, Bruna, Povala, Guilherme, Ferreira, Pamela C. L., Ferrari-Souza, João Pedro, Leffa, Douglas T., Lussier, Firoza Z., Benedet, Andréa L., Ashton, Nicholas J., Triana-Baltzer, Gallen, Kolb, Hartmuth C., Tissot, Cécile, Therriault, Joseph, Servaes, Stijn, Stevenson, Jenna, Rahmouni, Nesrine, Lopez, Oscar L., Tudorascu, Dana L., Villemagne, Victor L., Ikonomovic, Milos D., Gauthier, Serge, Zimmer, Eduardo R., Zetterberg, Henrik, Blennow, Kaj, Aizenstein, Howard J., Klunk, William E., Snitz, Beth E., Maki, Pauline, Thurston, Rebecca C., Cohen, Ann D., Ganguli, Mary, Karikari, Thomas K., Rosa-Neto, Pedro, and Pascoal, Tharick A.

Published
2023
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8. 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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9. Joint‐label fusion brain atlases for dementia research in Down syndrome

Author

Queder, Nazek, Phelan, Michael J, Taylor, Lisa, Tustison, Nicholas, Doran, Eric, Hom, Christy, Nguyen, Dana, Lai, Florence, Pulsifer, Margaret, Price, Julie, Kreisl, William C, Rosas, Herminia D, Krinsky‐McHale, Sharon, Brickman, Adam M, Yassa, Michael A, Schupf, Nicole, Silverman, Wayne, Lott, Ira T, Head, Elizabeth, Mapstone, Mark, Keator, David B, Aizenstein, Howard J, Ances, Beau M, Andrews, Howard F, Bell, Karen, Birn, Rasmus M, Bulova, Peter, Cheema, Amrita, Chen, Kewei, Christian, Bradley T, Clare, Isabel, Clark, Lorraine, Cohen, Ann D, Constantino, John N, Doran, Eric W, Fagan, Anne, Feingold, Eleanor, Foroud, Tatiana M, Handen, Benjamin L, Hartley, Sigan L, Henson, Rachel, Honig, Lawrence, Ikonomovic, Milos D, Johnson, Sterling C, Jordan, Courtney, Kamboh, M Ilyas, Keator, David, Klunk, William E, Kofler, Julia K, Kreisl, William Charles, Krinsky‐McHale, Sharon J, Lao, Patrick, Laymon, Charles, Lee, Joseph Hyungwoo, Lupson, Victoria, Mathis, Chester A, Minhas, Davneet Singh, Nadkarni, Neelesh, O'Bryant, Sid, Pang, Deborah, Petersen, Melissa, Price, Julie C, Reiman, Eric, Rizvi, Batool, Rosas, Herminia Diana, Silverman, Wayne P, Tudorascu, Dana L, Tumuluru, Rameshwari, Tycko, Benjamin, Varadarajan, Badri, White, Desiree A, Zaman, Shahid, and Zhang, Fan

Subjects
Biological Psychology, Psychology, Alzheimer's Disease, Intellectual and Developmental Disabilities (IDD), Acquired Cognitive Impairment, Neurosciences, Biomedical Imaging, Aging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Neurodegenerative, Down Syndrome, Mental Health, Dementia, Neurological, Alzheimer's disease, amyloid, dementia, Down syndrome, group atlas, joint label fusion, neurotypical, Alzheimer's Biomarkers Consortium, Genetics, Biological psychology
Abstract

Research suggests a link between Alzheimer's Disease in Down Syndrome (DS) and the overproduction of amyloid plaques. Using Positron Emission Tomography (PET) we can assess the in-vivo regional amyloid load using several available ligands. To measure amyloid distributions in specific brain regions, a brain atlas is used. A popular method of creating a brain atlas is to segment a participant's structural Magnetic Resonance Imaging (MRI) scan. Acquiring an MRI is often challenging in intellectually-imparied populations because of contraindications or data exclusion due to significant motion artifacts or incomplete sequences related to general discomfort. When an MRI cannot be acquired, it is typically replaced with a standardized brain atlas derived from neurotypical populations (i.e. healthy individuals without DS) which may be inappropriate for use in DS. In this project, we create a series of disease and diagnosis-specific (cognitively stable (CS-DS), mild cognitive impairment (MCI-DS), and dementia (DEM-DS)) probabilistic group atlases of participants with DS and evaluate their accuracy of quantifying regional amyloid load compared to the individually-based MRI segmentations. Further, we compare the diagnostic-specific atlases with a probabilistic atlas constructed from similar-aged cognitively-stable neurotypical participants. We hypothesized that regional PET signals will best match the individually-based MRI segmentations by using DS group atlases that aligns with a participant's disorder and disease status (e.g. DS and MCI-DS). Our results vary by brain region but generally show that using a disorder-specific atlas in DS better matches the individually-based MRI segmentations than using an atlas constructed from cognitively-stable neurotypical participants. We found no additional benefit of using diagnose-specific atlases matching disease status. All atlases are made publicly available for the research community.HighlightDown syndrome (DS) joint-label-fusion atlases provide accurate positron emission tomography (PET) amyloid measurements.A disorder-specific DS atlas is better than a neurotypical atlas for PET quantification.It is not necessary to use a disease-state-specific atlas for quantification in aged DS.Dorsal striatum results vary, possibly due to this region and dementia progression.

Published
2022

10. Traits and Trammels of Tau Tracer Imaging

Author

Villemagne, Victor L., Lopresti, Brian J., Doré, Vincent, Minhas, Davneet, Gogola, Alexandra, Nadkarni, Neelesh, Mason, N. Scott, Bourgeat, Pierrick, Lopez, Oscar, Ikonomovic, Milos D., Cohen, Ann D., Cross, Donna J., editor, Mosci, Karina, editor, and Minoshima, Satoshi, editor

Published
2023
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11. Postmortem Neocortical 3H-PiB Binding and Levels of Unmodified and Pyroglutamate Aβ in Down Syndrome and Sporadic Alzheimer’s Disease

Author

Pivtoraiko, Violetta N, Racic, Tamara, Abrahamson, Eric E, Villemagne, Victor L, Handen, Benjamin L, Lott, Ira T, Head, Elizabeth, and Ikonomovic, Milos D

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Aging, Acquired Cognitive Impairment, Dementia, Down Syndrome, Alzheimer's Disease, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Neurological, Alzheimer’s disease, Down syndrome, Pittsburgh Compound-B, amyloid, cerebral amyloid angiopathy, default mode network, pyroglutamate, Biochemistry and Cell Biology, Cognitive Sciences, Biological psychology
Abstract

Individuals with Down syndrome (DS) have a genetic predisposition for amyloid-β (Aβ) overproduction and earlier onset of Aβ deposits compared to patients with sporadic late-onset Alzheimer's disease (AD). Positron emission tomography (PET) with Pittsburgh Compound-B (PiB) detects fibrillar Aβ pathology in living people with DS and AD, but its relationship with heterogeneous Aβ forms aggregated within amyloid deposits is not well understood. We performed quantitative in vitro 3H-PiB binding assays and enzyme-linked immunosorbent assays of fibrillar (insoluble) unmodified Aβ40 and Aβ42 forms and N-terminus truncated and pyroglutamate-modified AβNpE3-40 and AβNpE3-42 forms in postmortem frontal cortex and precuneus samples from 18 DS cases aged 43-63 years and 17 late-onset AD cases aged 62-99 years. Both diagnostic groups had frequent neocortical neuritic plaques, while the DS group had more severe vascular amyloid pathology (cerebral amyloid angiopathy, CAA). Compared to the AD group, the DS group had higher levels of Aβ40 and AβNpE3-40, while the two groups did not differ by Aβ42 and AβNpE3-42 levels. This resulted in lower ratios of Aβ42/Aβ40 and AβNpE3-42/AβNpE3-40 in the DS group compared to the AD group. Correlations of Aβ42/Aβ40 and AβNpE3-42/AβNpE3-40 ratios with CAA severity were strong in DS cases and weak in AD cases. Pyroglutamate-modified Aβ levels were lower than unmodified Aβ levels in both diagnostic groups, but within group proportions of both pyroglutamate-modified Aβ forms relative to both unmodified Aβ forms were lower in the DS group but not in the AD group. The two diagnostic groups did not differ by 3H-PiB binding levels. These results demonstrate that compared to late-onset AD cases, adult DS individuals with similar severity of neocortical neuritic plaques and greater CAA pathology have a preponderance of both pyroglutamate-modified AβNpE3-40 and unmodified Aβ40 forms. Despite the distinct molecular profile of Aβ forms and greater vascular amyloidosis in DS cases, cortical 3H-PiB binding does not distinguish between diagnostic groups that are at an advanced level of amyloid plaque pathology. This underscores the need for the development of CAA-selective PET radiopharmaceuticals to detect and track the progression of cerebral vascular amyloid deposits in relation to Aβ plaques in individuals with DS.

Published
2021

12. Comparison of amyloid burden in individuals 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 MD, 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, Adams, Sarah, Allegri, Ricardo, Araki, Aki, Barthelemy, Nicolas, Bechara, Jacob, Berman, Sarah, Bodge, Courtney, Brandon, Susan, Brooks, William, Brosch, Jared, Buck, Jill, Buckles, Virginia, Carter, Kathleen, Cash, Lisa, Mendez, Patricio C, Chua, Jasmin, Chui, Helena, Courtney, Laura, Day, Gregory, DeLaCruz, Chrismary, Denner, Darcy, Diffenbacher, Anna, Dincer, Aylin, Donahue, Tamara, Douglas, Jane, Duong, Duc, Egido, Noelia, Esposito, Bianca, Farlow, Marty, Feldman, Becca, Fitzpatrick, Colleen, Fox, Nick, Franklin, Erin, Joseph-Mathurin, Nelly, Fujii, Hisako, Gardener, Samantha, Ghetti, Bernardino, Goate, Alison, Goldberg, Sarah, Goldman, Jill, Gonzalez, Alyssa, Gräber-Sultan, Susanne, Graff-Radford, Neill, Graham, Morgan, Gray, Julia, Gremminger, Emily, Grilo, Miguel, Groves, Alex, Haass, Christian, Häslerc, Lisa, Hellm, Cortaiga, Herries, Elizabeth, Hoechst-Swisher, Laura, Hofmann, Anna, Holtzman, David, Hornbeck, Russ, Igor, Yakushev, Ihara, Ryoko, Ikeuchi, Takeshi, Ikonomovic, Snezana, Ishii, Kenji, Jack, Clifford, Jerome, Gina, Johnson, Erik, Jucker, Mathias, Karch, Celeste, Käser, Stephan, Kasuga, Kensaku, Keefe, Sarah, Klunk, William, Koeppe, Robert, Koudelis, Deb, Kuder-Buletta, Elke, Laske, Christoph, Levey, Allan, Levin, Johannes, Li, Yan, Lopez, Oscar, Marsh, Jacob, Martins, Ralph, Mason, Neal S, Masters, Colin, Mawuenyega, Kwasi, McCullough, Austin, Mejia, Arlene, Morenas-Rodriguez, Estrella, Morris, John C, Mountz, James, Mummery, Catherine, Nagamatsu, Akemi, Neimeyer, Katie, Niimi, Yoshiki, Noble, James, Norton, Joanne, Nuscher, Brigitte, Obermüller, Ulricke, O'Connor, Antoinette, Patira, Riddhi, Ping, Lingyan, Preische, Oliver, Renton, Alan, Ringman, John, Salloway, Stephen, Schofield, Peter, Senda, Michio, Seyfried, Nicholas T, Shady, Kristine, Shimada, Hiroyuki, Sigurdson, Wendy, Smith, Jennifer, Smith, Lori, Snitz, Beth, Sohrabi, Hamid, Stephens, Sochenda, Taddei, Kevin, Thompson, Sarah, Vöglein, Jonathan, Wang, Peter, Wang, Qing, Weamer, Elise, Xu, Jinbin, Xu, Xiong, Boerwinkle, Anna H, Gordon, Brian A, Wisch, Julie, Flores, Shaney, Henson, Rachel L, Butt, Omar H, McKay, Nicole, Chen, Charles D, Benzinger, Tammie L S, Fagan, Anne M, Handen, Benjamin L, Christian, Bradley T, Head, Elizabeth, Mapstone, Mark, Rafii, Michael S, O'Bryant, Sid, Lai, Florence, Rosas, H Diana, Lee, Joseph H, Silverman, Wayne, Brickman, Adam M, Chhatwal, Jasmeer P, Cruchaga, Carlos, Perrin, Richard J, Xiong, Chengjie, Hassenstab, Jason, McDade, Eric, Bateman, Randall J, and Ances, Beau M

Published
2023
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13. Neuropathological correlates of amyloid PET imaging in Down syndrome

Author

Abrahamson, Eric E, Head, Elizabeth, Lott, Ira T, Handen, Benjamin L, Mufson, Elliott J, Christian, Bradley T, Klunk, William E, and Ikonomovic, Milos D

Subjects
Biomedical and Clinical Sciences, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Biomedical Imaging, Acquired Cognitive Impairment, Dementia, Brain Disorders, Down Syndrome, Alzheimer's Disease, Intellectual and Developmental Disabilities (IDD), Neurodegenerative, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Aetiology, 2.1 Biological and endogenous factors, 4.2 Evaluation of markers and technologies, Neurological, Amyloid beta-Peptides, Animals, Brain, Humans, Positron-Emission Tomography, Alzheimer's disease, Down syndrome, amyloid, neuropathology, positron emission tomography, striatum, Medical Physiology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Down syndrome (DS) results in an overproduction of amyloid-β (Aβ) peptide associated with early onset of Alzheimer's disease (AD). DS cases have Aβ deposits detectable histologically as young as 12-30 years of age, primarily in the form of diffuse plaques, the type of early amyloid pathology also seen at pre-clinical (i.e., pathological aging) and prodromal stages of sporadic late onset AD. In DS subjects aged >40 years, levels of cortical Aβ deposition are similar to those observed in late onset AD and in addition to diffuse plaques involve cored plaques associated with dystrophic neurites (neuritic plaques), which are of neuropathological diagnostic significance in AD. The purpose of this review is to summarize and discuss findings from amyloid PET imaging studies of DS in reference to postmortem amyloid-based neuropathology. PET neuroimaging applied to subjects with DS has the potential to (a) track the natural progression of brain pathology, including the earliest stages of amyloid accumulation, and (b) determine whether amyloid PET biomarkers predict the onset of dementia. In addition, the question that is still incompletely understood and relevant to both applications is the ability of amyloid PET to detect Aβ deposits in their earliest form.

Published
2019

14. Multisite study of the relationships between antemortem [11C]PIB‐PET Centiloid values and postmortem measures of Alzheimer's disease neuropathology

Author

La Joie, Renaud, Ayakta, Nagehan, Seeley, William W, Borys, Ewa, Boxer, Adam L, DeCarli, Charles, Doré, Vincent, Grinberg, Lea T, Huang, Eric, Hwang, Ji‐Hye, Ikonomovic, Milos D, Jack, Clifford, Jagust, William J, Jin, Lee‐Way, Klunk, William E, Kofler, Julia, Lesman‐Segev, Orit H, Lockhart, Samuel N, Lowe, Val J, Masters, Colin L, Mathis, Chester A, McLean, Catriona L, Miller, Bruce L, Mungas, Daniel, O'Neil, James P, Olichney, John M, Parisi, Joseph E, Petersen, Ronald C, Rosen, Howard J, Rowe, Christopher C, Spina, Salvatore, Vemuri, Prashanthi, Villemagne, Victor L, Murray, Melissa E, and Rabinovici, Gil D

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Neurosciences, Dementia, Bioengineering, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Brain Disorders, Biomedical Imaging, Acquired Cognitive Impairment, Aging, Alzheimer's Disease, Aged, Alzheimer Disease, Aniline Compounds, Autopsy, Female, Humans, Male, Neuropathology, Plaque, Amyloid, Positron-Emission Tomography, Retrospective Studies, Thiazoles, beta-amyloid, Positron emission tomography, Centiloid, CERAD, Thal, Alzheimer's disease neuropathologic changes, Harmonization, Threshold, Pittsburgh compound-B, β-amyloid, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionWe sought to establish the relationships between standard postmortem measures of AD neuropathology and antemortem [11C]PIB-positron emission tomography ([11C]PIB-PET) analyzed with the Centiloid (CL) method, a standardized scale for Aβ-PET quantification.MethodsFour centers contributed 179 participants encompassing a broad range of clinical diagnoses, PET data, and autopsy findings.ResultsCL values increased with each CERAD neuritic plaque score increment (median -3 CL for no plaques and 92 CL for frequent plaques) and nonlinearly with Thal Aβ phases (increases were detected starting at phase 2) with overlap between scores/phases. PET-pathology associations were comparable across sites and unchanged when restricting the analyses to the 56 patients who died within 2 years of PET. A threshold of 12.2 CL detected CERAD moderate-to-frequent neuritic plaques (area under the curve = 0.910, sensitivity = 89.2%, specificity = 86.4%), whereas 24.4 CL identified intermediate-to-high AD neuropathological changes (area under the curve = 0.894, sensitivity = 84.1%, specificity = 87.9%).DiscussionOur study demonstrated the robustness of a multisite Centiloid [11C]PIB-PET study and established a range of pathology-based CL thresholds.

Published
2019

17. Preclinical modelling of militarily relevant traumatic brain injuries: Challenges and recommendations for future directions

Author

Cernak, Ibolja, Stein, Donald G, Elder, Gregory A, Ahlers, Stephn, Curley, Kenneth, DePalma, Ralph G, Duda, John, Ikonomovic, Milos, Iverson, Grant L, Kobeissy, Firas, Koliatsos, Vassilis E, Leggieri, Michael J, Pacifico, Anthony M, Smith, Douglas H, Swanson, Raymond, Thompson, Floyd J, and Tortella, Frank C

Subjects
Clinical and Health Psychology, Psychology, Physical Injury - Accidents and Adverse Effects, Animals, Blast Injuries, Brain Injuries, Traumatic, Disease Models, Animal, Forecasting, Humans, Military Personnel, United States, United States Department of Veterans Affairs, conference, traumatic brain injury, blast-induced neurotrauma, preclinical research, experimental models, Medical and Health Sciences, Psychology and Cognitive Sciences, Rehabilitation, Clinical sciences, Allied health and rehabilitation science, Clinical and health psychology
Abstract

As a follow-up to the 2008 state-of-the-art (SOTA) conference on traumatic brain injuries (TBIs), the 2015 event organized by the United States Department of Veterans Affairs (VA) Office of Research and Development (ORD) analysed the knowledge gained over the last 7 years as it relates to basic scientific methods, experimental findings, diagnosis, therapy, and rehabilitation of TBIs and blast-induced neurotraumas (BINTs). The current article summarizes the discussions and recommendations of the scientific panel attending the Preclinical Modeling and Therapeutic Development Workshop of the conference, with special emphasis on factors slowing research progress and recommendations for ways of addressing the most significant pitfalls.

Published
2017

19. Implementation and Assessment of Tau Thresholds in Non-Demented Individuals as Predictors of Cognitive Decline in Tau Imaging Studies.

Author

Gogola, Alexandra, Cohen, Ann D., Snitz, Beth, Minhas, Davneet, Tudorascu, Dana, Ikonomovic, Milos D., Shaaban, C. Elizabeth, Doré, Vincent, Matan, Cristy, Bourgeat, Pierrick, Mason, N. Scott, Leuzy, Antoine, Aizenstein, Howard, Mathis, Chester A., Lopez, Oscar L., Lopresti, Brian J., and Villemagne, Victor L.

Subjects
ALZHEIMER'S disease, TEMPORAL lobe, COGNITION disorders, DISEASE progression, TAU proteins
Abstract

Background: Tau accumulation in Alzheimer's disease is associated with short term clinical progression and faster rates of cognitive decline in individuals with high amyloid-β deposition. Defining an optimal threshold of tau accumulation predictive of cognitive decline remains a challenge. Objective: We tested the ability of regional tau PET sensitivity and specificity thresholds to predict longitudinal cognitive decline. We also tested the predictive performance of thresholds in the proposed new NIA-AA biological staging for Alzheimer's disease where multiple levels of tau positivity are used to stage participants. Methods: 18F-flortaucipir scans from 301 non-demented participants were processed and sampled. Four cognitive measures were assessed longitudinally. Regional standardized uptake value ratios were split into infra- and suprathreshold groups at baseline using previously derived thresholds. Survival analysis, log rank testing, and Generalized Estimation Equations assessed the relationship between the application of regional sensitivity/specificity thresholds and change in cognitive measures as well as tau threshold performance in predicting cognitive decline within the new NIA-AA biological staging. Results: The meta temporal region was best for predicting risk of short-term cognitive decline in suprathreshold, as compared to infrathreshold participants. When applying multiple levels of tau positivity, each subsequent level of tau identified cognitive decline at earlier timepoints. Conclusions: When using 18F-flortaucipir, meta temporal suprathreshold classification was associated with increased risk of cognitive decline, suggesting that abnormal tau deposition in the cortex predicts decline. Likewise, the application of multiple levels of tau clearly predicts the distinctive cognitive trajectories in the new NIA-AA biological staging framework. [ABSTRACT FROM AUTHOR]

Published
2024
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23. Association Between β-Amyloid Accumulation and Incident Dementia in Individuals 80 Years or Older Without Dementia

Author

Lopez, Oscar L., primary, Villemagne, Victor L., additional, Chang, Yue-Fang, additional, Cohen, Ann D., additional, Klunk, William E., additional, Mathis, Chester A., additional, Pascoal, Tharick, additional, Ikonomovic, Milos D., additional, Rowe, Christopher, additional, Dore, Vincent, additional, Snitz, Beth E., additional, Lopresti, Brian J., additional, Kamboh, M. Ilyas, additional, Aizenstein, Howard J., additional, and Kuller, Lewis H., additional

Published
2024
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26. Distinct cytokine profiles in human brains resilient to Alzheimer's pathology

Author

Barroeta-Espar, Isabel, Weinstock, Laura D., Perez-Nievas, Beatriz G., Meltzer, Avery C., Siao Tick Chong, Michael, Amaral, Ana C., Murray, Melissa E., Moulder, Krista L., Morris, John C., Cairns, Nigel J., Parisi, Joseph E., Lowe, Val J., Petersen, Ronald C., Kofler, Julia, Ikonomovic, Milos D., López, Oscar, Klunk, William E., Mayeux, Richard P., Frosch, Matthew P., Wood, Levi B., and Gomez-Isla, Teresa

Published
2019
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27. Novel ultrasensitive immunoassay for the selective quantification of tau oligomers and related soluble aggregates.

Author

Islam, Tohidul, Kvartsberg, Hlin, Sehrawat, Anuradha, Kac, Przemysław R., Becker, Bruno, Olsson, Maria, Abrahamson, Eric E., Zetterberg, Henrik, Ikonomovic, Milos D., Blennow, Kaj, and Karikari, Thomas K.

Abstract

INTRODUCTION: Tau aggregation into paired helical filaments and neurofibrillary tangles is characteristic of Alzheimer's disease (AD) and related disorders. However, biochemical assays for the quantification of soluble, earlier‐stage tau aggregates are lacking. We describe an immunoassay that is selective for tau oligomers and related soluble aggregates over monomers. METHODS: A homogeneous (single‐antibody) immunoassay was developed using a novel anti‐tau monoclonal antibody and validated with recombinant and brain tissue–derived tau. RESULTS: The assay signals were concentration dependent for recombinant tau aggregates in solution but not monomers, and recognized peptides within, but not outside, the aggregation‐prone microtubule binding region. The signals in inferior and middle frontal cortical tissue homogenates increased with neuropathologically determined Braak staging, and were higher in insoluble than soluble homogenized brain fractions. Autopsy‐verified AD gave stronger signals than other neurodegenerative diseases. DISCUSSION: The quantitative oligomer/soluble aggregate‐specific assay can identify soluble tau aggregates, including oligomers, from monomers in human and in vitro biospecimens. Highlights: The aggregation of tau to form fibrils and neurofibrillary tangles is a key feature of Alzheimer's disease.However, biochemical assays for the quantification of oligomers/soluble aggregated forms of tau are lacking.We developed a new assay that preferentially binds to soluble tau aggregates, including oligomers and fibrils, versus monomers.The assay signal increased corresponding to the total protein content, Braak staging, and insolubility of the sequentially homogenized brain tissue fractions in an autopsy‐verified cohort.The assay recognized tau peptides containing the microtubule binding region but not those covering the N‐ or C‐terminal regions only. [ABSTRACT FROM AUTHOR]

Published
2024
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28. Amyloid β‐dependent tau phosphorylation is triggered by reactive astrocytes in preclinical Alzheimer’s disease

Author

Bellaver, Bruna, primary, Povala, Guilherme, additional, Ferreira, Pamela C.L., additional, Ferrari‐Souza, João Pedro, additional, Leffa, Douglas Teixeira, additional, Lussier, Firoza Z, additional, Benedet, Andrea Lessa, additional, Ashton, Nicholas J., additional, Tissot, Cécile, additional, Therriault, Joseph, additional, Servaes, Stijn, additional, Stevenson, Jenna, additional, Rahmouni, Nesrine, additional, Lopez, Oscar L., additional, Tudorascu, Dana, additional, Villemagne, Victor L, additional, Ikonomovic, Milos D, additional, Gauthier, Serge, additional, Zimmer, Eduardo R, additional, Zetterberg, Henrik, additional, Blennow, Kaj, additional, Aizenstein, Howard J, additional, Klunk, William E, additional, Snitz, Beth E., additional, Maki, Pauline M, additional, Thurston, Rebecca C, additional, Cohen, Ann D., additional, Ganguli, Mary, additional, Karikari, Thomas K, additional, Rosa‐Neto, Pedro, additional, and Pascoal, Tharick Ali, additional

Published
2023
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30. Astrocyte reactivity potentiates longitudinal tau tangle accumulation in cognitively unimpaired individuals

Author

Bellaver, Bruna, primary, Povala, Guilherme, additional, Ferreira, Pamela C.L., additional, Ferrari‐Souza, João Pedro, additional, Leffa, Douglas Teixeira, additional, Lussier, Firoza Z, additional, Zalzale, Hussein, additional, Soares, Carolina, additional, Aguzzoli, Cristiano Schaffer, additional, Rohden, Francieli, additional, Abbas, Sarah, additional, Ashton, Nicholas J., additional, Tissot, Cécile, additional, Therriault, Joseph, additional, Servaes, Stijn, additional, Stevenson, Jenna, additional, Rahmouni, Nesrine, additional, Lopez, Oscar L., additional, Tudorascu, Dana, additional, Villemagne, Victor L, additional, Ikonomovic, Milos D, additional, Klunk, William E, additional, Cohen, Ann D., additional, Gauthier, Serge, additional, Zimmer, Eduardo R., additional, Zetterberg, Henrik, additional, Blennow, Kaj, additional, Karikari, Thomas K, additional, Rosa‐Neto, Pedro, additional, and Pascoal, Tharick A., additional

Published
2023
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38. Performance of [18F]flutemetamol amyloid imaging against the neuritic plaque component of CERAD and the current (2012) NIA-AA recommendations for the neuropathologic diagnosis of Alzheimer's disease

Author

Salloway, Stephen, Gamez, Jose E., Singh, Upinder, Sadowsky, Carl H., Villena, Teresa, Sabbagh, Marwan N., Beach, Thomas G., Duara, Ranjan, Fleisher, Adam S., Frey, Kirk A., Walker, Zuzana, Hunjan, Arvinder, Escovar, Yavir M., Agronin, Marc E., Ross, Joel, Bozoki, Andrea, Akinola, Mary, Shi, Jiong, Vandenberghe, Rik, Ikonomovic, Milos D., Sherwin, Paul F., Farrar, Gill, Smith, Adrian P.L., Buckley, Christopher J., Thal, Dietmar Rudolf, Zanette, Michelle, and Curtis, Craig

Published
2017
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40. The cell‐specific roles of Nrf2 in acute and chronic phases of ischemic stroke.

Author

Fadoul, George, Ikonomovic, Milos, Zhang, Feng, and Yang, Tuo

Subjects
*NUCLEAR factor E2 related factor, *ISCHEMIC stroke, *TRANSCRIPTION factors
Abstract

Ischemic stroke refers to the sudden loss of blood flow in a specific area of the brain. It is the fifth leading cause of mortality and the leading cause of permanent disability. The transcription factor nuclear factor erythroid 2‐related factor 2 (Nrf2) controls the production of several antioxidants and protective proteins and it has been investigated as a possible pharmaceutical target for reducing harmful oxidative events in brain ischemia. Each cell type exhibits different roles and behaviors in different phases post‐stroke, which is comprehensive yet important to understand to optimize management strategies and goals for care for stroke patients. In this review, we comprehensively summarize the protective effects of Nrf2 in experimental ischemic stroke, emphasizing the role of Nrf2 in different cell types including neurons, astrocytes, oligodendrocytes, microglia, and endothelial cells during acute and chronic phases of stroke and providing insights on the neuroprotective role of Nrf2 on each cell type throughout the long term of stroke care. We also highlight the importance of targeting Nrf2 in clinical settings while considering a variety of important factors such as age, drug dosage, delivery route, and time of administration. [ABSTRACT FROM AUTHOR]

Published
2024
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41. Vesicular Glutamate Transporter Changes in the Cortical Default Mode Network During the Clinical and Pathological Progression of Alzheimer’s Disease

Author

Mi, Zhiping, primary, Abrahamson, Eric E., additional, Ryu, Angela Y., additional, Malek-Ahmadi, Michael, additional, Kofler, Julia K., additional, Fish, Kenneth N., additional, Sweet, Robert A., additional, Villemagne, Victor L., additional, Schneider, Julie A., additional, Mufson, Elliott J., additional, and Ikonomovic, Milos D., additional

Published
2023
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44. Apolipoprotein E*4 (APOE*4) Genotype Is Associated with Altered Levels of Glutamate Signaling Proteins and Synaptic Coexpression Networks in the Prefrontal Cortex in Mild to Moderate Alzheimer Disease

Author

Sweet, Robert A., MacDonald, Matthew L., Kirkwood, Caitlin M., Ding, Ying, Schempf, Tadhg, Jones-Laughner, Jackie, Kofler, Julia, Ikonomovic, Milos D., Lopez, Oscar L., Garver, Megan E., Fitz, Nicholas F., Koldamova, Radosveta, and Yates, Nathan A.

Published
2016
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47. Astrocyte reactivity influences the association of amyloid-β and tau biomarkers in preclinical Alzheimer’s disease

Author

Pascoal, Tharick, primary, Bellaver, Bruna, additional, Povala, Guilherme, additional, Ferreira, Pamela, additional, Ferrari-Souza, João Pedro, additional, Leffa, Douglas, additional, Lussier, Firoza, additional, Benedet, Andrea, additional, Ashton, Nicholas, additional, Triana-Baltzerz, Gallen, additional, Kolbzh, Hartmuth, additional, Tissot, Cécile, additional, Therriault, Joseph, additional, Servaes, Stijn, additional, Stevenson, Jenna, additional, Rahmouni, Nesrine, additional, Lopez, Oscar, additional, Tudorascu, Dana, additional, Villemagne, Victor, additional, Ikonomovic, Milos, additional, Gauthier, Serge, additional, Zimmer, Eduardo, additional, Zetterberg, Henrik, additional, Blennow, Kaj, additional, Aizenstein, Howard, additional, Klunk, William, additional, Snitz, Beth, additional, Maki, Pauline, additional, Thurston, Rebecca, additional, Cohen, Ann, additional, Ganguli, Mary, additional, Karikari, Thomas, additional, and Rosa-Neto, Pedro, additional

Published
2023
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