239 results on '"Stern, Yaakov"'
Search Results
2. Understanding Barriers Along the Patient Journey in Alzheimer’s Disease Using Social Media Data
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Tahami Monfared, Amir Abbas, Stern, Yaakov, Doogan, Stephen, Irizarry, Michael, and Zhang, Quanwu
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- 2023
- Full Text
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3. Clinical diagnosis of Alzheimer's disease: recommendations of the International Working Group
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Dubois, Bruno, Villain, Nicolas, Frisoni, Giovanni B, Rabinovici, Gil D, Sabbagh, Marwan, Cappa, Stefano, Bejanin, Alexandre, Bombois, Stéphanie, Epelbaum, Stéphane, Teichmann, Marc, Habert, Marie-Odile, Nordberg, Agneta, Blennow, Kaj, Galasko, Douglas, Stern, Yaakov, Rowe, Christopher C, Salloway, Stephen, Schneider, Lon S, Cummings, Jeffrey L, and Feldman, Howard H
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Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Dementia ,Acquired Cognitive Impairment ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Alzheimer's Disease ,Aging ,Brain Disorders ,Neurodegenerative ,Clinical Research ,Prevention ,4.1 Discovery and preclinical testing of markers and technologies ,4.2 Evaluation of markers and technologies ,Detection ,screening and diagnosis ,Neurological ,Good Health and Well Being ,Alzheimer Disease ,Amyloid beta-Peptides ,Biomarkers ,Cognitive Dysfunction ,Disease Progression ,Humans ,Phenotype ,tau Proteins ,Neurology & Neurosurgery ,Clinical sciences - Abstract
In 2018, the US National Institute on Aging and the Alzheimer's Association proposed a purely biological definition of Alzheimer's disease that relies on biomarkers. Although the intended use of this framework was for research purposes, it has engendered debate and challenges regarding its use in everyday clinical practice. For instance, cognitively unimpaired individuals can have biomarker evidence of both amyloid β and tau pathology but will often not develop clinical manifestations in their lifetime. Furthermore, a positive Alzheimer's disease pattern of biomarkers can be observed in other brain diseases in which Alzheimer's disease pathology is present as a comorbidity. In this Personal View, the International Working Group presents what we consider to be the current limitations of biomarkers in the diagnosis of Alzheimer's disease and, on the basis of this evidence, we propose recommendations for how biomarkers should and should not be used for diagnosing Alzheimer's disease in a clinical setting. We recommend that Alzheimer's disease diagnosis be restricted to people who have positive biomarkers together with specific Alzheimer's disease phenotypes, whereas biomarker-positive cognitively unimpaired individuals should be considered only at-risk for progression to Alzheimer's disease.
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- 2021
4. Race/Ethnic Disparities in Mild Cognitive Impairment and Dementia: The Northern Manhattan Study
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Wright, Clinton B, DeRosa, Janet T, Moon, Michelle P, Strobino, Kevin, DeCarli, Charles, Cheung, Ying Kuen, Assuras, Stephanie, Levin, Bonnie, Stern, Yaakov, Sun, Xiaoyan, Rundek, Tatjana, Elkind, Mitchell SV, and Sacco, Ralph L
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Biomedical and Clinical Sciences ,Biological Psychology ,Clinical Sciences ,Neurosciences ,Psychology ,Alzheimer's Disease ,Vascular Cognitive Impairment/Dementia ,Aging ,Acquired Cognitive Impairment ,Prevention ,Clinical Research ,Neurodegenerative ,Behavioral and Social Science ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Brain Disorders ,Dementia ,Neurological ,Mental health ,Aged ,Aged ,80 and over ,Cognitive Dysfunction ,Cohort Studies ,Cross-Sectional Studies ,Ethnicity ,Female ,Humans ,Male ,Middle Aged ,New York City ,Prevalence ,African American ,cohort studies ,dementia ,Hispanic American ,mild cognitive impairment ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences ,Biological psychology - Abstract
BackgroundVariability in dementia rates across racial and ethnic groups has been estimated at 60%. Studies suggest disparities in Caribbean Hispanic and Black populations, but community-based data are limited.ObjectiveEstimate the prevalence of mild cognitive impairment (MCI) and dementia in the racially and ethnically diverse community-based Northern Manhattan Study cohort and examine sociodemographic, vascular risk factor, and brain imaging correlates.MethodsCases of MCI and dementia were adjudicated by a team of neuropsychologists and neurologists and prevalence was estimated across race/ethnic groups. Ordinal proportional odds models were used to estimate race/ethnic differences in the prevalence of MCI or dementia adjusting for sociodemographic variables (model 1), model 1 plus potentially modifiable vascular risk factors (model 2), and model 1 plus structural imaging markers of brain integrity (model 3).ResultsThere were 989 participants with cognitive outcome determinations (mean age 69±9 years; 68% Hispanic, 16% Black, 14% White; 62% women; mean (±SD) follow-up five (±0.6) years). Hispanic and Black participants had greater likelihood of MCI (20%) and dementia (5%) than White participants accounting for age and education differences. Hispanic participants had greater odds of MCI or dementia than both White and Black participants adjusting for sociodemographic variables, vascular risk factors, and brain imaging factors. White matter hyperintensity burden was significantly associated with greater odds of MCI or dementia (OR = 1.3, 1.1 to 1.6), but there was no significant interaction by race/ethnicity.ConclusionIn this diverse community-based cohort, cross-sectional data revealed significant race/ethnic disparities in the prevalence of MCI and dementia. Longer follow-up and incidence data are needed to further clarify these relationships.
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- 2021
5. Women can bear a bigger burden: ante- and post-mortem evidence for reserve in the face of tau
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Digma, Leonardino A, Madsen, John R, Rissman, Robert A, Jacobs, Diane M, Brewer, James B, Banks, Sarah J, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jack, Clifford R, Jagust, William, Trojanowki, John Q, Toga, Arthur W, Beckett, Laurel, Green, Robert C, Saykin, Andrew J, Morris, John, Shaw, Leslie M, Liu, Enchi, Montine, Tom, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Jiminez, Gus, Harvey, Danielle, Bernstein, Matthew, Fox, Nick, Thompson, Paul, Schuff, Norbert, DeCArli, Charles, Borowski, Bret, Gunter, Jeff, Senjem, Matt, Vemuri, Prashanthi, Jones, David, Kantarci, Kejal, Ward, Chad, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Landau, Susan, Cairns, Nigel J, Householder, Erin, Reinwald, Lisa Taylor, Lee, Virginia, Korecka, Magdalena, Figurski, Michal, Crawford, Karen, Neu, Scott, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kelley, Faber, Kim, Sungeun, Nho, Kwangsik, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Carter, Raina, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Beccera, Mauricio, Teodoro, Liberty, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Fleisher, Adam, Heidebrink, Judith L, Lord, Joanne L, Mason, Sara S, Albers, Colleen S, Knopman, David, Johnson, Kris, Doody, Rachelle S, Meyer, Javier Villanueva, Chowdhury, Munir, Rountree, Susan, Dang, Mimi, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Ances, Beau, Morris, John C, Carroll, Maria, Leon, Sue, Mintun, Mark A, Schneider, Stacy, and Oliver, Angela
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Biological Psychology ,Psychology ,Brain Disorders ,Neurodegenerative ,Alzheimer's Disease ,Neurosciences ,Acquired Cognitive Impairment ,Women's Health ,Aging ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Dementia ,Clinical Research ,tau ,verbal memory ,sex differences ,Alzheimer's disease ,Alzheimer’s Disease Neuroimaging Initiative ,Alzheimer’s disease ,Clinical sciences ,Biological psychology - Abstract
In this study, we aimed to assess whether women are able to withstand more tau before exhibiting verbal memory impairment. Using data from 121 amyloid-β-positive Alzheimer's Disease Neuroimaging Initiative participants, we fit a linear model with Rey Auditory Verbal Learning Test score as the response variable and tau-PET standard uptake value ratio as the predictor and took the residuals as an estimate of verbal memory reserve for each subject. Women demonstrated higher reserve (i.e. residuals), whether the Learning (t = 2.78, P = 0.006) or Delay (t = 2.14, P = 0.03) score from the Rey Auditory Verbal Learning Test was used as a measure of verbal memory ability. To validate these findings, we examined 662 National Alzheimer's Coordinating Center participants with a C2/C3 score (Consortium to Establish a Registry for Alzheimer's Disease) at autopsy. We stratified our National Alzheimer's Coordinating Center sample into Braak 1/2, Braak 3/4 and Braak 5/6 subgroups. Within each subgroup, we compared Logical Memory scores between men and women. Men had worse verbal memory scores within the Braak 1/2 (Logical Memory Immediate: β = -5.960 ± 1.517, P
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- 2020
6. Perspectives on ethnic and racial disparities in Alzheimer's disease and related dementias: Update and areas of immediate need.
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Babulal, Ganesh M, Quiroz, Yakeel T, Albensi, Benedict C, Arenaza-Urquijo, Eider, Astell, Arlene J, Babiloni, Claudio, Bahar-Fuchs, Alex, Bell, Joanne, Bowman, Gene L, Brickman, Adam M, Chételat, Gaël, Ciro, Carrie, Cohen, Ann D, Dilworth-Anderson, Peggye, Dodge, Hiroko H, Dreux, Simone, Edland, Steven, Esbensen, Anna, Evered, Lisbeth, Ewers, Michael, Fargo, Keith N, Fortea, Juan, Gonzalez, Hector, Gustafson, Deborah R, Head, Elizabeth, Hendrix, James A, Hofer, Scott M, Johnson, Leigh A, Jutten, Roos, Kilborn, Kerry, Lanctôt, Krista L, Manly, Jennifer J, Martins, Ralph N, Mielke, Michelle M, Morris, Martha Clare, Murray, Melissa E, Oh, Esther S, Parra, Mario A, Rissman, Robert A, Roe, Catherine M, Santos, Octavio A, Scarmeas, Nikolaos, Schneider, Lon S, Schupf, Nicole, Sikkes, Sietske, Snyder, Heather M, Sohrabi, Hamid R, Stern, Yaakov, Strydom, Andre, Tang, Yi, Terrera, Graciela Muniz, Teunissen, Charlotte, Melo van Lent, Debora, Weinborn, Michael, Wesselman, Linda, Wilcock, Donna M, Zetterberg, Henrik, O'Bryant, Sid E, and International Society to Advance Alzheimer's Research and Treatment, Alzheimer's Association
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International Society to Advance Alzheimer's Research and Treatment ,Alzheimer's Association ,Humans ,Alzheimer Disease ,Biomedical Research ,Aged ,Continental Population Groups ,Ethnic Groups ,Healthcare Disparities ,Biomarkers ,Alzheimer's disease ,Alzheimer's related dementias ,Diversity ,Ethnicity ,Ethnoracial ,Translational ,Underserved ,Geriatrics ,Clinical Sciences ,Neurosciences - Abstract
Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; alz.org/ISTAART) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross-PIA white paper that provides both a concise "state-of-the-science" report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.
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- 2019
7. Blood Pressure Control in Aging Predicts Cerebral Atrophy Related to Small-Vessel White Matter Lesions
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Kern, Kyle C, Wright, Clinton B, Bergfield, Kaitlin L, Fitzhugh, Megan C, Chen, Kewei, Moeller, James R, Nabizadeh, Nooshin, Elkind, Mitchell SV, Sacco, Ralph L, Stern, Yaakov, DeCarli, Charles S, and Alexander, Gene E
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Biological Psychology ,Biomedical and Clinical Sciences ,Psychology ,Biomedical Imaging ,Alzheimer's Disease Related Dementias (ADRD) ,Aging ,Neurosciences ,Neurodegenerative ,Cerebrovascular ,Cardiovascular ,Dementia ,Hypertension ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Behavioral and Social Science ,Basic Behavioral and Social Science ,Brain Disorders ,Vascular Cognitive Impairment/Dementia ,Alzheimer's Disease ,Acquired Cognitive Impairment ,Neurological ,white matter hyperintensities ,brain atrophy ,hypertension ,cerebrovascular disease ,cognition ,aging ,scaled subprofile model ,voxel-based morphometry ,Biochemistry and Cell Biology ,Cognitive Sciences ,Biological psychology - Abstract
Cerebral small-vessel damage manifests as white matter hyperintensities and cerebral atrophy on brain MRI and is associated with aging, cognitive decline and dementia. We sought to examine the interrelationship of these imaging biomarkers and the influence of hypertension in older individuals. We used a multivariate spatial covariance neuroimaging technique to localize the effects of white matter lesion load on regional gray matter volume and assessed the role of blood pressure control, age and education on this relationship. Using a case-control design matching for age, gender, and educational attainment we selected 64 participants with normal blood pressure, controlled hypertension or uncontrolled hypertension from the Northern Manhattan Study cohort. We applied gray matter voxel-based morphometry with the scaled subprofile model to (1) identify regional covariance patterns of gray matter volume differences associated with white matter lesion load, (2) compare this relationship across blood pressure groups, and (3) relate it to cognitive performance. In this group of participants aged 60-86 years, we identified a pattern of reduced gray matter volume associated with white matter lesion load in bilateral temporal-parietal regions with relative preservation of volume in the basal forebrain, thalami and cingulate cortex. This pattern was expressed most in the uncontrolled hypertension group and least in the normotensives, but was also more evident in older and more educated individuals. Expression of this pattern was associated with worse performance in executive function and memory. In summary, white matter lesions from small-vessel disease are associated with a regional pattern of gray matter atrophy that is mitigated by blood pressure control, exacerbated by aging, and associated with cognitive performance.
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- 2017
8. Accelerating rates of cognitive decline and imaging markers associated with &bgr;-amyloid pathology
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Insel, Philip S, Mattsson, Niklas, Mackin, R Scott, Schöll, Michael, Nosheny, Rachel L, Tosun, Duygu, Donohue, Michael C, Aisen, Paul S, Jagust, William J, Weiner, Michael W, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jack, Clifford R, Jagust, William, Trojanowki, John Q, Toga, Arthur W, Beckett, Laurel, Green, Robert C, Saykin, Andrew J, Morris, John, Liu, Enchi, Montine, Tom, Gamst, Anthony, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Harvey, Danielle, Kornak, John, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Bandy, Dan, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Cairns, Nigel J, Taylor-Reinwald, Lisa, Trojanowki, JQ, Shaw, Les, Lee, Virginia MY, Korecka, Magdalena, Crawford, Karen, Neu, Scott, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Morris, John C, Ances, Beau, Carroll, Maria, Leon, Sue, Mintun, Mark A, Schneider, Stacy, Marson, Daniel, and Griffith, Randall
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Biomedical and Clinical Sciences ,Clinical Sciences ,Acquired Cognitive Impairment ,Dementia ,Neurodegenerative ,Biomedical Imaging ,Brain Disorders ,Aging ,Alzheimer's Disease ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Neurosciences ,Neurological ,Aged ,Amyloid beta-Peptides ,Aniline Compounds ,Atrophy ,Biomarkers ,Brain ,Cognition ,Cognitive Dysfunction ,Disease Progression ,Ethylene Glycols ,Female ,Fluorodeoxyglucose F18 ,Humans ,Longitudinal Studies ,Magnetic Resonance Imaging ,Male ,Mental Status Schedule ,Neuropsychological Tests ,Peptide Fragments ,Positron-Emission Tomography ,Radiopharmaceuticals ,Regression Analysis ,Alzheimer's Disease Neuroimaging Initiative ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences - Abstract
ObjectiveTo estimate points along the spectrum of β-amyloid pathology at which rates of change of several measures of neuronal injury and cognitive decline begin to accelerate.MethodsIn 460 patients with mild cognitive impairment (MCI), we estimated the points at which rates of florbetapir PET, fluorodeoxyglucose (FDG) PET, MRI, and cognitive and functional decline begin to accelerate with respect to baseline CSF Aβ42. Points of initial acceleration in rates of decline were estimated using mixed-effects regression.ResultsRates of neuronal injury and cognitive and even functional decline accelerate substantially before the conventional threshold for amyloid positivity, with rates of florbetapir PET and FDG PET accelerating early. Temporal lobe atrophy rates also accelerate prior to the threshold, but not before the acceleration of cognitive and functional decline.ConclusionsA considerable proportion of patients with MCI would not meet inclusion criteria for a trial using the current threshold for amyloid positivity, even though on average, they are experiencing cognitive/functional decline associated with prethreshold levels of CSF Aβ42. Future trials in early Alzheimer disease might consider revising the criteria regarding β-amyloid thresholds to include the range of amyloid associated with the first signs of accelerating rates of decline.
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- 2016
9. Better verbal memory in women than men in MCI despite similar levels of hippocampal atrophy
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Sundermann, Erin E, Biegon, Anat, Rubin, Leah H, Lipton, Richard B, Mowrey, Wenzhu, Landau, Susan, Maki, Pauline M, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jack, Clifford R, Jagust, William, Trojanowki, John Q, Toga, Arthur W, Beckett, Laurel, Green, Robert C, Saykin, Andrew J, Morris, John, Liu, Enchi, Montine, Tom, Gamst, Anthony, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Harvey, Danielle, Kornak, John, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Bandy, Dan, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Cairns, Nigel J, Taylor-Reinwald, Lisa, Trojanowki, JQ, Shaw, Les, Lee, Virginia MY, Korecka, Magdalena, Crawford, Karen, Neu, Scott, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Morris, John C, Ances, Beau, Carroll, Maria, Leon, Sue, Mintun, Mark A, Schneider, Stacy, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, and Mitsis, Effie
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Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Prevention ,Aging ,Behavioral and Social Science ,Clinical Research ,Alzheimer's Disease ,Brain Disorders ,Acquired Cognitive Impairment ,Neurodegenerative ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Clinical Trials and Supportive Activities ,Dementia ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Aged ,Aged ,80 and over ,Atrophy ,Cognitive Dysfunction ,Cross-Sectional Studies ,Female ,Hippocampus ,Humans ,Magnetic Resonance Imaging ,Male ,Memory ,Middle Aged ,Sex Characteristics ,Verbal Learning ,Alzheimer's Disease Neuroimaging Initiative ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences - Abstract
ObjectiveTo examine sex differences in the relationship between clinical symptoms related to Alzheimer disease (AD) (verbal memory deficits) and neurodegeneration (hippocampal volume/intracranial volume ratio [HpVR]) across AD stages.MethodsThe sample included 379 healthy participants, 694 participants with amnestic mild cognitive impairment (aMCI), and 235 participants with AD and dementia from the Alzheimer's Disease Neuroimaging Initiative who completed the Rey Auditory Verbal Learning Test (RAVLT). Cross-sectional analyses were conducted using linear regression to examine the interaction between sex and HpVR on RAVLT across and within diagnostic groups adjusting for age, education, and APOE ε4 status.ResultsAcross groups, there were significant sex × HpVR interactions for immediate and delayed recall (p < 0.01). Women outperformed men among individuals with moderate to larger HpVR, but not among individuals with smaller HpVR. In diagnosis-stratified analyses, the HpVR × sex interaction was significant in the aMCI group, but not in the control or AD dementia groups, for immediate and delayed recall (p < 0.01). Among controls, women outperformed men on both outcomes irrespective of HpVR (p < 0.001). In AD dementia, better RAVLT performance was independently associated with female sex (immediate, p = 0.04) and larger HpVR (delayed, p = 0.001).ConclusionWomen showed an advantage in verbal memory despite evidence of moderate hippocampal atrophy. This advantage may represent a sex-specific form of cognitive reserve delaying verbal memory decline until more advanced disease stages.
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- 2016
10. Periventricular hyperintensities are associated with elevated cerebral amyloid
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Marnane, Michael, Al-Jawadi, Osama O, Mortazavi, Shervin, Pogorzelec, Kathleen J, Wang, Bing Wei, Feldman, Howard H, Hsiung, Ging-Yuek R, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jack, Clifford R, Jagust, William, Trojanowki, John Q, Toga, Arthur W, Beckett, Laurel, Green, Robert C, Saykin, Andrew J, Morris, John, Liu, Enchi, Montine, Tom, Gamst, Anthony, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Harvey, Danielle, Kornak, John, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Bandy, Dan, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Cairns, Nigel J, Taylor-Reinwald, Lisa, Trojanowki, JQ, Shaw, Les, Lee, Virginia MY, Korecka, Magdalena, Crawford, Karen, Neu, Scott, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Morris, John C, Ances, Beau, Carroll, Maria, Leon, Sue, Mintun, Mark A, Schneider, Stacy, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, and Mitsis, Effie
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Biomedical and Clinical Sciences ,Clinical Sciences ,Prevention ,Aging ,Clinical Research ,Alzheimer's Disease ,Neurosciences ,Brain Disorders ,Acquired Cognitive Impairment ,Neurodegenerative ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Dementia ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Adult ,Aged ,Aged ,80 and over ,Amyloid beta-Peptides ,Biomarkers ,Cerebral Ventricles ,Cognitive Dysfunction ,Female ,Humans ,Magnetic Resonance Imaging ,Male ,Middle Aged ,Positron-Emission Tomography ,Prospective Studies ,Alzheimer's Disease Neuroimaging Initiative ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences - Abstract
ObjectiveTo investigate the association between periventricular white mater hyperintensities (PVWMH) and biomarkers of elevated cerebral β-amyloid (Aβ) in the Alzheimer's Disease Neuroimaging Initiative, a large prospective multicenter observational study.MethodsThe burden of frontal, parietal, and occipital PVWMH on 3T fluid-attenuated inversion recovery MRI was evaluated in 698 cognitively normal participants and participants with mild cognitive impairment (MCI) using a novel semiquantitative visual rating scale. Results were correlated with CSF-Aβ, florbetapir-PET, and fluorodeoxyglucose (FDG)-PET.ResultsIncreased burden of parietal, occipital, and frontal PVWMH was associated with elevated cerebral amyloid evidenced by high florbetapir-PET signal (p < 0.01) and low CSF-Aβ (p < 0.01). In logistic regression models, including PVWMH, age, sex, APOE status, vascular risk factors, pulse pressure, vascular secondary prevention medications, education, ethnicity, and race, parietal, occipital, and frontal PVWMH burden was independently associated with high florbetapir-PET uptake (p < 0.05). In a similar logistic regression model, parietal and occipital (p < 0.05) but not frontal (p = 0.05) PVWMH were independently associated with CSF-Aβ. Weaker associations were found between parieto-occipital PVWMH and elevated CSF-tau (p < 0.05) and occipital PVWMH and elevated CSF-phospho-tau (p < 0.05). PVWMH were associated with cerebral hypometabolism on FDG-PET independent of CSF-Aβ levels (p < 0.05). Absolute and consistency of agreement intraclass correlation coefficients were, respectively, 0.83 and 0.83 for frontal, 0.78 and 0.8 for parietal, and 0.45 and 0.75 for occipital PVWMH measurements.ConclusionsIncreased PVWMH were associated with elevated cerebral amyloid independent of potential confounders such as age, APOE genotype, and vascular risk factors. The mechanisms underlying the association between PVWMH and cerebral amyloid remain to be clarified.
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- 2016
11. Memory, executive, and multidomain subtle cognitive impairment
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Toledo, Jon B, Bjerke, Maria, Chen, Kewei, Rozycki, Martin, Jack, Clifford R, Weiner, Michael W, Arnold, Steven E, Reiman, Eric M, Davatzikos, Christos, Shaw, Leslie M, Trojanowski, John Q, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jagust, William, Trojanowki, John Q, Toga, Arthur W, Beckett, Laurel, Green, Robert C, Saykin, Andrew J, Morris, John, Liu, Enchi, Montine, Tom, Gamst, Anthony, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Harvey, Danielle, Kornak, John, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Bandy, Dan, Koeppe, Robert A, Foster, Norm, Mathis, Chet, Cairns, Nigel J, Taylor-Reinwald, Lisa, Trojanowki, JQ, Shaw, Les, Lee, Virginia MY, Korecka, Magdalena, Crawford, Karen, Neu, Scott, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Morris, John C, Ances, Beau, Leon, Sue, Schneider, Stacy, Marson, Daniel, Griffith, Randall, and Clark, David
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Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Biomedical Imaging ,Aging ,Behavioral and Social Science ,Clinical Research ,Alzheimer's Disease ,Acquired Cognitive Impairment ,Brain Disorders ,Neurodegenerative ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Dementia ,Detection ,screening and diagnosis ,4.1 Discovery and preclinical testing of markers and technologies ,Neurological ,Mental health ,Aged ,Aged ,80 and over ,Alzheimer Disease ,Biomarkers ,Brain ,Cognition Disorders ,Cognitive Dysfunction ,Disease Progression ,Executive Function ,Female ,Humans ,Magnetic Resonance Imaging ,Male ,Memory Disorders ,Multimodal Imaging ,Positron-Emission Tomography ,Alzheimer's Disease Neuroimaging Initiative ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences - Abstract
ObjectiveWe studied the biomarker signatures and prognoses of 3 different subtle cognitive impairment (SCI) groups (executive, memory, and multidomain) as well as the subjective memory complaints (SMC) group.MethodsWe studied 522 healthy controls in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cutoffs for executive, memory, and multidomain SCI were defined using participants who remained cognitively normal (CN) for 7 years. CSF Alzheimer disease (AD) biomarkers, composite and region-of-interest (ROI) MRI, and fluorodeoxyglucose-PET measures were compared in these participants.ResultsUsing a stringent cutoff (fifth percentile), 27.6% of the ADNI participants were classified as SCI. Most single ROI or global-based measures were not sensitive to detect differences between groups. Only MRI-SPARE-AD (Spatial Pattern of Abnormalities for Recognition of Early AD), a quantitative MRI pattern-based global index, showed differences between all groups, excluding the executive SCI group. Atrophy patterns differed in memory SCI and SMC. The CN and the SMC groups presented a similar distribution of preclinical dementia stages. Fifty percent of the participants with executive, memory, and multidomain SCI progressed to mild cognitive impairment or dementia at 7, 5, and 2 years, respectively.ConclusionsOur results indicate that (1) the different SCI categories have different clinical prognoses and biomarker signatures, (2) longitudinally followed CN subjects are needed to establish clinical cutoffs, (3) subjects with SMC show a frontal pattern of brain atrophy, and (4) pattern-based analyses outperform commonly used single ROI-based neuroimaging biomarkers and are needed to detect initial stages of cognitive impairment.
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- 2015
12. Brain structure and function as mediators of the effects of amyloid on memory
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Mattsson, Niklas, Insel, Philip S, Aisen, Paul S, Jagust, William, Mackin, Scott, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jack, Clifford R, Trojanowki, John Q, Toga, Arthur W, Beckett, Laurel, Green, Robert C, Saykin, Andrew J, Morris, John, Liu, Enchi, Montine, Tom, Gamst, Anthony, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Harvey, Danielle, Kornak, John, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Bandy, Dan, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Cairns, Nigel J, Taylor-Reinwald, Lisa, Trojanowki, JQ, Shaw, Les, Lee, Virginia MY, Korecka, Magdalena, Crawford, Karen, Neu, Scott, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Morris, John C, Ances, Beau, Carroll, Maria, Leon, Sue, Mintun, Mark A, Schneider, Stacy, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, Mitsis, Effie, and Romirowsky, Aliza
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Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Biomedical Imaging ,Aging ,Alzheimer's Disease ,Acquired Cognitive Impairment ,Brain Disorders ,Neurodegenerative ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Dementia ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Mental health ,Aged ,Aged ,80 and over ,Amyloid beta-Peptides ,Brain ,Cohort Studies ,Female ,Follow-Up Studies ,Humans ,Male ,Memory ,Episodic ,Middle Aged ,Prospective Studies ,Radionuclide Imaging ,Alzheimer's Disease Neuroimaging Initiative ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences - Abstract
ObjectiveThe objective of this study was to test whether effects of β-amyloid (Aβ) pathology on episodic memory were mediated by metabolism and gray matter volume in the early stages of Alzheimer disease.MethodsThis was a prospective cohort study. We measured baseline Aβ (using florbetapir-PET), brain function (using fluorodeoxyglucose-PET), and brain structure (using MRI). A mediation analysis was performed to test whether statistical effects of Aβ positivity on cross-sectional and longitudinal episodic memory were mediated by hypometabolism or regional gray matter volume in cognitively healthy controls (CN, n = 280) and mild cognitive impairment (MCI, n = 463).ResultsLower memory scores were associated with Aβ positivity (CN, mildly; MCI, strongly), smaller gray matter volumes (CN, few regions, including hippocampus; MCI, widespread), and hypometabolism. Smaller volumes and hypometabolism mediated effects of Aβ in MCI but not in CN. The strongest individual regions mediated up to approximately 25%. A combination of brain structure and function mediated up to approximately 40%. In several regions, gray matter atrophy and hypometabolism predicted episodic memory without being associated (at p < 0.05) with Aβ positivity.ConclusionsChanges in brain structure and function appear to be, in part, downstream events from Aβ pathology, ultimately resulting in episodic memory deficits. However, Aβ pathology is also strongly related to memory deficits through mechanisms that are not quantified by these imaging measurements, and episodic memory decline is partly caused by Alzheimer disease-like brain changes independently of Aβ pathology.
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- 2015
13. Brain amyloidosis ascertainment from cognitive, imaging, and peripheral blood protein measures
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Apostolova, Liana G, Hwang, Kristy S, Avila, David, Elashoff, David, Kohannim, Omid, Teng, Edmond, Sokolow, Sophie, Jack, Clifford R, Jagust, William J, Shaw, Leslie, Trojanowski, John Q, Weiner, Michael W, Thompson, Paul M, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jagust, Wiliam, Trojanowki, JQ, Toga, Arthur W, Beckett, Laurel, Green, Robert C, Gamst, Anthony, Sakin, Andrew J, Morris, John, Potter, William Z, Montine, Tom, Donohue, Michael, Walter, Sarah, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Bandy, Dan, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Cairns, Nigel J, Taylor-Reinwald, Lisa, Shaw, Lee, Lee, Virginia M-Y, Korecka, Magdalena, Crawford, Karen, Neu, Scott, Harvey, Danielle, Kornak, John, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Dolen, Sara, Quinn, Joseph, Schneider, Lon, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Mintun, Mark A, Schneider, Stacy, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, Tang, Cheuk, Marzloff, George, deToledo-Morrell, Leyla, Shah, Raj C, Duara, Ranjan, Varon, Daniel, Robers, Peggy, Albert, Marilyn S, Kozauer, Nicholas, Zerrate, Maria, Rusinek, Henry, de Leon, Mony J, De Santi, Susan M, Doraiswamy, P Murali, Petrella, Jeffrey R, Aiello, Marilyn, Arnold, Steve, and Karlawish, Jason H
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Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Biomedical Imaging ,Aging ,Behavioral and Social Science ,Clinical Research ,Alzheimer's Disease ,Acquired Cognitive Impairment ,Brain Disorders ,Neurodegenerative ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Dementia ,4.2 Evaluation of markers and technologies ,4.1 Discovery and preclinical testing of markers and technologies ,Detection ,screening and diagnosis ,Neurological ,Aged ,Algorithms ,Alzheimer Disease ,Amyloid beta-Peptides ,Amyloidosis ,Aniline Compounds ,Biomarkers ,Brain ,Cognition ,Cognitive Dysfunction ,Cohort Studies ,Databases ,Factual ,Disease Progression ,Female ,Humans ,Male ,Neuropsychological Tests ,Pattern Recognition ,Automated ,Peptide Fragments ,Positron-Emission Tomography ,Sensitivity and Specificity ,Thiazoles ,Alzheimer's Disease Neuroimaging Initiative ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences - Abstract
BackgroundThe goal of this study was to identify a clinical biomarker signature of brain amyloidosis in the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) mild cognitive impairment (MCI) cohort.MethodsWe developed a multimodal biomarker classifier for predicting brain amyloidosis using cognitive, imaging, and peripheral blood protein ADNI1 MCI data. We used CSF β-amyloid 1-42 (Aβ42) ≤ 192 pg/mL as proxy measure for Pittsburgh compound B (PiB)-PET standard uptake value ratio ≥ 1.5. We trained our classifier in the subcohort with CSF Aβ42 but no PiB-PET data and tested its performance in the subcohort with PiB-PET but no CSF Aβ42 data. We also examined the utility of our biomarker signature for predicting disease progression from MCI to Alzheimer dementia.ResultsThe CSF training classifier selected Mini-Mental State Examination, Trails B, Auditory Verbal Learning Test delayed recall, education, APOE genotype, interleukin 6 receptor, clusterin, and ApoE protein, and achieved leave-one-out accuracy of 85% (area under the curve [AUC] = 0.8). The PiB testing classifier achieved an AUC of 0.72, and when classifier self-tuning was allowed, AUC = 0.74. The 36-month disease-progression classifier achieved AUC = 0.75 and accuracy = 71%.ConclusionsAutomated classifiers based on cognitive and peripheral blood protein variables can identify the presence of brain amyloidosis with a modest level of accuracy. Such methods could have implications for clinical trial design and enrollment in the near future.Classification of evidenceThis study provides Class II evidence that a classification algorithm based on cognitive, imaging, and peripheral blood protein measures identifies patients with brain amyloid on PiB-PET with moderate accuracy (sensitivity 68%, specificity 78%).
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- 2015
14. Mild cognitive impairment with suspected nonamyloid pathology (SNAP)
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Caroli, Anna, Prestia, Annapaola, Galluzzi, Samantha, Ferrari, Clarissa, van der Flier, Wiesje M, Ossenkoppele, Rik, Van Berckel, Bart, Barkhof, Frederik, Teunissen, Charlotte, Wall, Anders E, Carter, Stephen F, Schöll, Michael, Choo, Il Han, Grimmer, Timo, Redolfi, Alberto, Nordberg, Agneta, Scheltens, Philip, Drzezga, Alexander, Frisoni, Giovanni B, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jack, Clifford R, Jagust, William, Trojanowki, JQ, Toga, Arthur W, Beckett, Laurel, Green, Robert C, Gamst, Anthony, Saykin, Andrew J, Morris, John, Potter, William Z, Montine, Tom, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Bandy, Dan, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Cairns, Nigel J, Taylor-Reinwald, Lisa, Shaw, Les, Lee, Virginia M-Y, Korecka, Magdalena, Crawford, Karen, Neu, Scott, Harvey, Danielle, Kornak, John, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Dolen, Sara, Quinn, Joseph, Schneider, Lon, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Morris, John C, and Mintun, Mark A
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Biomedical and Clinical Sciences ,Clinical Sciences ,Aging ,Alzheimer's Disease ,Neurosciences ,Brain Disorders ,Acquired Cognitive Impairment ,Neurodegenerative ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Dementia ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Aged ,Aged ,80 and over ,Cognitive Dysfunction ,Databases ,Factual ,Disease Progression ,Female ,Follow-Up Studies ,Humans ,Male ,Middle Aged ,Neurodegenerative Diseases ,Plaque ,Amyloid ,Predictive Value of Tests ,Alzheimer's Disease Neuroimaging Initiative ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences - Abstract
ObjectivesThe aim of this study was to investigate predictors of progressive cognitive deterioration in patients with suspected non-Alzheimer disease pathology (SNAP) and mild cognitive impairment (MCI).MethodsWe measured markers of amyloid pathology (CSF β-amyloid 42) and neurodegeneration (hippocampal volume on MRI and cortical metabolism on [(18)F]-fluorodeoxyglucose-PET) in 201 patients with MCI clinically followed for up to 6 years to detect progressive cognitive deterioration. We categorized patients with MCI as A+/A- and N+/N- based on presence/absence of amyloid pathology and neurodegeneration. SNAPs were A-N+ cases.ResultsThe proportion of progressors was 11% (8/41), 34% (14/41), 56% (19/34), and 71% (60/85) in A-N-, A+N-, SNAP, and A+N+, respectively; the proportion of APOE ε4 carriers was 29%, 70%, 31%, and 71%, respectively, with the SNAP group featuring a significantly different proportion than both A+N- and A+N+ groups (p ≤ 0.005). Hypometabolism in SNAP patients was comparable to A+N+ patients (p = 0.154), while hippocampal atrophy was more severe in SNAP patients (p = 0.002). Compared with A-N-, SNAP and A+N+ patients had significant risk of progressive cognitive deterioration (hazard ratio = 2.7 and 3.8, p = 0.016 and p < 0.001), while A+N- patients did not (hazard ratio = 1.13, p = 0.771). In A+N- and A+N+ groups, none of the biomarkers predicted time to progression. In the SNAP group, lower time to progression was correlated with greater hypometabolism (r = 0.42, p = 0.073).ConclusionsOur findings support the notion that patients with SNAP MCI feature a specific risk progression profile.
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- 2015
15. Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria
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Dubois, Bruno, Feldman, Howard H, Jacova, Claudia, Hampel, Harald, Molinuevo, José Luis, Blennow, Kaj, DeKosky, Steven T, Gauthier, Serge, Selkoe, Dennis, Bateman, Randall, Cappa, Stefano, Crutch, Sebastian, Engelborghs, Sebastiaan, Frisoni, Giovanni B, Fox, Nick C, Galasko, Douglas, Habert, Marie-Odile, Jicha, Gregory A, Nordberg, Agneta, Pasquier, Florence, Rabinovici, Gil, Robert, Philippe, Rowe, Christopher, Salloway, Stephen, Sarazin, Marie, Epelbaum, Stéphane, de Souza, Leonardo C, Vellas, Bruno, Visser, Pieter J, Schneider, Lon, Stern, Yaakov, Scheltens, Philip, and Cummings, Jeffrey L
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Neurodegenerative ,Brain Disorders ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Acquired Cognitive Impairment ,Aging ,Neurosciences ,Dementia ,Alzheimer's Disease ,4.1 Discovery and preclinical testing of markers and technologies ,Detection ,screening and diagnosis ,Neurological ,Alzheimer Disease ,Biomarkers ,Humans ,International Cooperation ,Phenotype ,Practice Guidelines as Topic ,Societies ,Medical ,Clinical Sciences ,Neurology & Neurosurgery - Abstract
In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging-Alzheimer's Association have contributed criteria for the diagnosis of Alzheimer's disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimer's pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD.
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- 2014
16. Remote Associations Between Tau and Cortical Amyloid-β Are Stage-Dependent.
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Hojjati, Seyed Hani, Chiang, Gloria C., Butler, Tracy A., de Leon, Mony, Gupta, Ajay, Li, Yi, Sabuncu, Mert R., Feiz, Farnia, Nayak, Siddharth, Shteingart, Jacob, Ozoria, Sindy, Gholipour Picha, Saman, Stern, Yaakov, Luchsinger, José A., Devanand, Davangere P., and Razlighi, Qolamreza R.
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TAU proteins ,POSITRON emission tomography ,ENTORHINAL cortex ,ALZHEIMER'S disease ,TEMPORAL lobe - Abstract
Background: Histopathologic studies of Alzheimer's disease (AD) suggest that extracellular amyloid-β (Aβ) plaques promote the spread of neurofibrillary tau tangles. However, these two proteinopathies initiate in spatially distinct brain regions, so how they interact during AD progression is unclear. Objective: In this study, we utilized Aβ and tau positron emission tomography (PET) scans from 572 older subjects (476 healthy controls (HC), 14 with mild cognitive impairment (MCI), 82 with mild AD), at varying stages of the disease, to investigate to what degree tau is associated with cortical Aβ deposition. Methods: Using multiple linear regression models and a pseudo-longitudinal ordering technique, we investigated remote tau-Aβ associations in four pathologic phases of AD progression based on tau spread: 1) no-tau, 2) pre-acceleration, 3) acceleration, and 4) post-acceleration. Results: No significant tau-Aβ association was detected in the no-tau phase. In the pre-acceleration phase, the earliest stage of tau deposition, associations emerged between regional tau in medial temporal lobe (MTL) (i.e., entorhinal cortex, parahippocampal gyrus) and cortical Aβ in lateral temporal lobe regions. The strongest tau-Aβ associations were found in the acceleration phase, in which tau in MTL regions was strongly associated with cortical Aβ (i.e., temporal and frontal lobes regions). Strikingly, in the post-acceleration phase, including 96% of symptomatic subjects, tau-Aβ associations were no longer significant. Conclusions: The results indicate that associations between tau and Aβ are stage-dependent, which could have important implications for understanding the interplay between these two proteinopathies during the progressive stages of AD. [ABSTRACT FROM AUTHOR]
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- 2024
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17. Microglia measured by TSPO PET are associated with Alzheimer's disease pathology and mediate key steps in a disease progression model.
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Rossano, Samantha M., Johnson, Aubrey S., Smith, Anna, Ziaggi, Galen, Roetman, Andrew, Guzman, Diana, Okafor, Amarachukwu, Klein, Julia, Tomljanovic, Zeljko, Stern, Yaakov, Brickman, Adam M., Lee, Seonjoo, Kreisl, William C., and Lao, Patrick
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INTRODUCTION: Evidence suggests microglial activation precedes regional tau and neurodegeneration in Alzheimer's disease (AD). We characterized microglia with translocator protein (TSPO) positron emission tomography (PET) within an AD progression model where global amyloid beta (Aβ) precedes local tau and neurodegeneration, resulting in cognitive impairment. METHODS: Florbetaben, PBR28, and MK‐6240 PET, T1 magnetic resonance imaging, and cognitive measures were performed in 19 cognitively unimpaired older adults and 22 patients with mild cognitive impairment or mild AD to examine associations among microglia activation, Aβ, tau, and cognition, adjusting for neurodegeneration. Mediation analyses evaluated the possible role of microglial activation along the AD progression model. RESULTS: Higher PBR28 uptake was associated with higher Aβ, higher tau, and lower MMSE score, independent of neurodegeneration. PBR28 mediated associations between tau in early and middle Braak stages, between tau and neurodegeneration, and between neurodegeneration and cognition. DISCUSSION: Microglia are associated with AD pathology and cognition and may mediate relationships between subsequent steps in AD progression. [ABSTRACT FROM AUTHOR]
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- 2024
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18. Cognitive reserve associated with FDG-PET in preclinical Alzheimer disease
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Ewers, Michael, Insel, Philip S, Stern, Yaakov, and Weiner, Michael W
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Biomedical and Clinical Sciences ,Clinical Sciences ,Aging ,Biomedical Imaging ,Dementia ,Brain Disorders ,Clinical Research ,Alzheimer's Disease ,Neurosciences ,Neurodegenerative ,Prevention ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Acquired Cognitive Impairment ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Brain Stem ,Cognition ,Cognition Disorders ,Humans ,Locus Coeruleus ,Neurons ,Alzheimer's Disease Neuroimaging Initiative ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences - Abstract
ObjectiveTo examine the effect of education (a surrogate measure of cognitive reserve) on FDG-PET brain metabolism in elderly cognitively healthy (HC) subjects with preclinical Alzheimer disease (AD).MethodsFifty-two HC subjects (mean age 75 years) with FDG-PET and CSF measurement of Aβ1-42 were included from the prospective Alzheimer's Disease Neuroimaging Initiative biomarker study. HC subjects received a research classification of preclinical AD if CSF Aβ1-42 was
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- 2013
19. Vascular burden and Alzheimer disease pathologic progression
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Lo, Raymond Y, Jagust, William J, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jack, Clifford R, Jagust, William, Trojanowki, John Q, Toga, Arthur W, Beckett, Laurel, Green, Robert C, Saykin, Andrew J, Morris, John, Liu, Enchi, Montine, Tom, Gamst, Anthony, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Harvey, Danielle, Kornak, John, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Bandy, Dan, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Cairns, Nigel J, Taylor-Reinwald, Lisa, Trojanowki, JQ, Shaw, Les, Lee, Virginia MY, Korecka, Magdalena, Crawford, Karen, Neu, Scott, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Morris, John C, Ances, Beau, Carroll, Maria, Leon, Sue, Mintun, Mark A, Schneider, Stacy, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, Mitsis, Effie, Romirowsky, Aliza, deToledo-Morrell, Leyla, Shah, Raj C, Duara, Ranjan, and Varon, Daniel
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Biomedical and Clinical Sciences ,Clinical Sciences ,Aging ,Biomedical Imaging ,Dementia ,Brain Disorders ,Clinical Research ,Vascular Cognitive Impairment/Dementia ,Alzheimer's Disease ,Neurosciences ,Neurodegenerative ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Acquired Cognitive Impairment ,4.1 Discovery and preclinical testing of markers and technologies ,Detection ,screening and diagnosis ,Neurological ,Cardiovascular ,Aged ,Alzheimer Disease ,Atrophy ,Brain ,Cognitive Dysfunction ,Disease Progression ,Female ,Genotype ,Humans ,Leukoencephalopathies ,Longitudinal Studies ,Magnetic Resonance Imaging ,Male ,Positron-Emission Tomography ,Alzheimer's Disease Neuroimaging Initiative ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences - Abstract
ObjectiveTo investigate the vascular contribution to longitudinal changes in Alzheimer disease (AD) biomarkers.MethodsThe Alzheimer's Disease Neuroimaging Initiative is a clinic based, longitudinal study with CSF, PET, and MRI biomarkers repeatedly measured in participants with normal cognition (NC), mild cognitive impairment (MCI), and mild AD. Participants with severe cerebrovascular risks were excluded. Cardiovascular risk scores and MRI white matter hyperintensities (WMHs) were treated as surrogate markers for vascular burden. Generalized estimating equations were applied, and both vascular burden and its interaction with time (vascular burden × time) or time-varying WMHs were entered into regression models to assess whether biomarker rates of change were modified by vascular burden.ResultsCardiovascular risk profiles were not predictive of progression in CSF β₄₂-amyloid, [¹⁸F]fluorodeoxyglucose (FDG) PET uptake, and MRI hippocampal atrophy. Greater baseline cardiovascular risks or WMHs were generally associated with cognitive impairment, particularly poor executive function. WMHs increased over time with a faster rate in MCI and AD than in NC. Increased time-varying WMH was associated with faster decline in executive function and lower FDG uptake in NC. Otherwise, WMH was not associated with CSF and MRI biomarkers in the 3 groups. These findings remained unchanged after accounting for APOE4.ConclusionIncreased WMHs are associated with aging, decreased glucose metabolism, and decline in executive function but do not affect AD-specific pathologic progression, suggesting that the vascular contribution to dementia is probably additive although not necessarily independent of the amyloid pathway.
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- 2012
20. Advancing Alzheimer's disease diagnosis, treatment, and care: Recommendations from the Ware Invitational Summit
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Naylor, Mary D, Karlawish, Jason H, Arnold, Steven E, Khachaturian, Ara S, Khachaturian, Zaven S, Lee, Virginia M‐Y, Baumgart, Matthew, Banerjee, Sube, Beck, Cornelia, Blennow, Kaj, Brookmeyer, Ron, Brunden, Kurt R, Buckwalter, Kathleen C, Comer, Meryl, Covinsky, Kenneth, Feinberg, Lynn Friss, Frisoni, Giovanni, Green, Colin, Guimaraes, Renato Maia, Gwyther, Lisa P, Hefti, Franz F, Hutton, Michael, Kawas, Claudia, Kent, David M, Kuller, Lewis, Langa, Kenneth M, Mahley, Robert W, Maslow, Katie, Masters, Colin L, Meier, Diane E, Neumann, Peter J, Paul, Steven M, Petersen, Ronald C, Sager, Mark A, Sano, Mary, Schenk, Dale, Soares, Holly, Sperling, Reisa A, Stahl, Sidney M, van Deerlin, Vivianna, Stern, Yaakov, Weir, David, Wolk, David A, and Trojanowski, John Q
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Biomedical and Clinical Sciences ,Biological Psychology ,Clinical Sciences ,Neurosciences ,Psychology ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Neurodegenerative ,Alzheimer's Disease ,Acquired Cognitive Impairment ,Aging ,Prevention ,Dementia ,Brain Disorders ,Neurological ,Good Health and Well Being ,Alzheimer Disease ,Cost-Benefit Analysis ,Female ,Health Policy ,Health Services Research ,Humans ,Male ,United States ,Alzheimer's disease ,Neurodegenerative disorders ,Research priorities ,Policy priorities ,Health policy recommendations ,Geriatrics ,Clinical sciences ,Biological psychology - Abstract
To address the pending public health crisis due to Alzheimer's disease (AD) and related neurodegenerative disorders, the Marian S. Ware Alzheimer Program at the University of Pennsylvania held a meeting entitled "State of the Science Conference on the Advancement of Alzheimer's Diagnosis, Treatment and Care," on June 21-22, 2012. The meeting comprised four workgroups focusing on Biomarkers; Clinical Care and Health Services Research; Drug Development; and Health Economics, Policy, and Ethics. The workgroups shared, discussed, and compiled an integrated set of priorities, recommendations, and action plans, which are presented in this article.
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- 2012
21. Racial/Ethnic Disparities in Misidentification of Dementia in Medicare Claims: Results from the Washington Heights-Inwood Columbia Aging Project.
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Zhu, Carolyn W., Gu, Yian, Cosentino, Stephanie, Kociolek, Anton J., Hernandez, Michelle, and Stern, Yaakov
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MEDICARE ,COGNITIVE aging ,RACE ,DEMENTIA ,AGING ,VASCULAR dementia - Abstract
Background: Misidentification of dementia in Medicare claims is quite common. Objective: We examined potential race/ethnic disparities in misidentification of dementia in Medicare claims in a diverse cohort of older adults who underwent careful clinical assessment. Methods: Participants were enrolled in the Washington Heights-Inwood Columbia Aging Project (WHICAP), a multiethnic, population-based, prospective study of cognitive aging in which dementia status was assessed using a rigorous clinical protocol. ICD-9-CM and ICD-10-CM diagnosis codes in all available Medicare claims (1999–2019) were compared to clinical dementia diagnosis and categorized into three mutually exclusive groups: 1) congruent-, 2) over-, and 3) under- identification during the study period. Multinomial logistic regression model was used to examine the relationship between race (White, African American/Black, other) and ethnicity (Hispanic/Latinx, non-Hispanic/Latinx) and congruency of dementia identification after controlling for clinical (cognition, function, comorbidities) and demographic characteristics (age, sex, education), and inpatient and outpatient utilization. Results: Across all person-years, 88.4% had congruent identification of dementia compared to clinical diagnosis, in 4.1% of the times participants were over-identified with dementia, and 7.5% of the times the participants were under-identified. Rates of misidentification was higher in minority participants than in White, non-Hispanic participants. Multivariable estimation results showed that the probability of over-identification with dementia was 2.2% higher for African American/Black than White (p = 0.05) and 2.7% higher for Hispanic participants than non-Hispanics (p = 0.03) participants. Differences in under-identification by race/ethnicity were not statistically significant. Conclusions: African American/Black and Hispanic participants were more likely over-identified with dementia in Medicare claims. [ABSTRACT FROM AUTHOR]
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- 2023
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22. Overview of the Reserve Concept in the Context of Cognitive Aging
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Sunderaraman, Preeti, Stern, Yaakov, Alosco, Michael L., book editor, and Stern, Robert A., book editor
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- 2019
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23. Translational research on reserve against neurodegenerative disease: consensus report of the International Conference on Cognitive Reserve in the Dementias and the Alzheimer’s Association Reserve, Resilience and Protective Factors Professional Interest Area working groups
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Perneczky, Robert, Kempermann, Gerd, Korczyn, Amos D., Matthews, Fiona E., Ikram, M. Arfan, Scarmeas, Nikolaos, Chetelat, Gael, Stern, Yaakov, and Ewers, Michael
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- 2019
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24. Longitudinal decline in semantic versus letter fluency, but not their ratio, marks incident Alzheimer's disease in Latinx Spanish-speaking older individuals.
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Fernández, Kayri K., Kociolek, Anton J., Lao, Patrick J., Stern, Yaakov, Manly, Jennifer J., and Vonk, Jet M. J.
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ALZHEIMER'S disease ,OLDER people - Abstract
Objective: To compare longitudinal verbal fluency performance among Latinx Spanish speakers who develop Alzheimer's disease to those who do not develop dementia in absolute number of words produced on each task and their ratio to combine both scores. Method: Participants included 833 Latinx Spanish-speaking older adults from a community-based prospective cohort in Manhattan. We performed growth curve modeling to investigate the trajectories of letter and semantic fluency, and their ratio (i.e., 'semantic index'), between individuals who developed Alzheimer's disease and those who did not (i.e., controls). The semantic index quantifies the proportion of words generated for semantic fluency in relation to the total verbal fluency performance. Results: Letter fluency performance did not decline in controls; we observed a linear decline in those who developed Alzheimer's disease. Semantic fluency declined in both groups and showed an increased rate of change over time in the incident Alzheimer's disease group; in comparison, the control group had a linear and slower decline. There were no group differences in the longitudinal trajectory (intercept and slope) of the semantic index. Conclusion: A decline in letter fluency and a more rapid and accelerating decline over time in semantic fluency distinguished people who developed Alzheimer's disease from controls. Using the semantic index was not a superior marker of incident Alzheimer's disease compared to examining the two fluency scores individually. Results suggest the differential decline in verbal fluency tasks, when evaluated appropriately, may be useful for early identification of Alzheimer's disease in Latinx Spanish speakers, a historically understudied population. [ABSTRACT FROM AUTHOR]
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- 2023
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25. Validation of a Multivariate Prediction Model of the Clinical Progression of Alzheimer's Disease in a Community-Dwelling Multiethnic Cohort.
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Stallard, Eric, Kociolek, Anton, Jin, Zhezhen, Ryu, Hyunnam, Lee, Seonjoo, Cosentino, Stephanie, Zhu, Carolyn, Gu, Yian, Fernandez, Kayri, Hernandez, Michelle, Kinosian, Bruce, and Stern, Yaakov
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ALZHEIMER'S disease ,DISEASE progression ,APOLIPOPROTEIN E4 ,PREDICTION models ,MILD cognitive impairment ,OLDER people - Abstract
Background: The major aims of the three Predictors Studies have been to further our understanding of Alzheimer's disease (AD) progression sufficiently to predict the length of time from disease onset to major disease outcomes in individual patients with AD. Objectives: To validate a longitudinal Grade of Membership (L-GoM) prediction algorithm developed using clinic-based, mainly white patients from the Predictors 2 Study in a statistically representative community-based sample of Hispanic (N = 211) and non-Hispanic (N = 62) older adults (with 60 males and 213 females) from the Predictors 3 Study and extend the algorithm to mild cognitive impairment (MCI). Methods: The L-GoM model was applied to data collected at the initial Predictors 3 visit for 150 subjects with AD and 123 with MCI. Participants were followed annually for up to seven years. Observed rates of survival and need for full-time care (FTC) were compared to those predicted by the algorithm. Results: Initial MCI/AD severity in Predictors 3 was substantially higher than among clinic-based AD patients enrolled at the specialized Alzheimer's centers in Predictors 2. The observed survival and need for FTC followed the L-GoM model trajectories in individuals with MCI or AD, except for N = 32 subjects who were initially diagnosed with AD but reverted to a non-AD diagnosis on follow-up. Conclusion: These findings indicate that the L-GoM model is applicable to community-dwelling, multiethnic older adults with AD. They extend the use of the model to the prediction of outcomes for MCI. They also justify release of our L-GoM calculator at this time. [ABSTRACT FROM AUTHOR]
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- 2023
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26. Development, initial validation, and application of a visual read method for [ 18 F]MK‐6240 tau PET
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Shuping, Joanna L, Matthews, Dawn C, Adamczuk, Katarzyna, Scott, David, Rowe, Christopher C, Kreisl, William C, Johnson, Sterling C, Lukic, Ana S, Johnson, Keith A, Rosa-Neto, Pedro, Andrews, Randolph D, Van Laere, Koen, Cordes, Lindsay, Ward, Larry, Wilde, Claire L, Barakos, Jerome, Purcell, Derk D, Devanand, Davangere P, Stern, Yaakov, Luchsinger, Jose A, Sur, Cyrille, Price, Julie C, Brickman, Adam M, Klunk, William E, Boxer, Adam L, Mathotaarachchi, Sulantha S, Lao, Patrick J, and Evelhoch, Jeffrey L
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Science & Technology ,positron emission tomography ,Clinical Neurology ,Neurosciences ,visual read ,ASSOCIATION ,Alzheimer's disease ,florquinitau ,tracer ,[F-18]MK-6240 ,PATHOLOGY ,VARIABILITY ,Psychiatry and Mental health ,POSITRON-EMISSION-TOMOGRAPHY ,AGE ,neurofibrillary tangles ,Neurosciences & Neurology ,tau ,Neurology (clinical) ,Life Sciences & Biomedicine ,MK-6240 ,ALZHEIMER-DISEASE - Abstract
BACKGROUND: The positron emission tomography (PET) radiotracer [18F]MK-6240 exhibits high specificity for neurofibrillary tangles (NFTs) of tau protein in Alzheimer's disease (AD), high sensitivity to medial temporal and neocortical NFTs, and low within-brain background. Objectives were to develop and validate a reproducible, clinically relevant visual read method supporting [18F]MK-6240 use to identify and stage AD subjects versus non-AD and controls. METHODS: Five expert readers used their own methods to assess 30 scans of mixed diagnosis (47% cognitively normal, 23% mild cognitive impairment, 20% AD, 10% traumatic brain injury) and provided input regarding regional and global positivity, features influencing assessment, confidence, practicality, and clinical relevance. Inter-reader agreement and concordance with quantitative values were evaluated to confirm that regions could be read reliably. Guided by input regarding clinical applicability and practicality, read classifications were defined. The readers read the scans using the new classifications, establishing by majority agreement a gold standard read for those scans. Two naïve readers were trained and read the 30-scan set, providing initial validation. Inter-rater agreement was further tested by two trained independent readers in 131 scans. One of these readers used the same method to read a full, diverse database of 1842 scans; relationships between read classification, clinical diagnosis, and amyloid status as available were assessed. RESULTS: Four visual read classifications were determined: no uptake, medial temporal lobe (MTL) only, MTL and neocortical uptake, and uptake outside MTL. Inter-rater kappas were 1.0 for the naïve readers gold standard scans read and 0.98 for the independent readers 131-scan read. All scans in the full database could be classified; classification frequencies were concordant with NFT histopathology literature. DISCUSSION: This four-class [18F]MK-6240 visual read method captures the presence of medial temporal signal, neocortical expansion associated with disease progression, and atypical distributions that may reflect different phenotypes. The method demonstrates excellent trainability, reproducibility, and clinical relevance supporting clinical use. HIGHLIGHTS: A visual read method has been developed for [18F]MK-6240 tau positron emission tomography.The method is readily trainable and reproducible, with inter-rater kappas of 0.98.The read method has been applied to a diverse set of 1842 [18F]MK-6240 scans.All scans from a spectrum of disease states and acquisitions could be classified.Read classifications are consistent with histopathological neurofibrillary tangle staging literature. ispartof: ALZHEIMERS & DEMENTIA-TRANSLATIONAL RESEARCH & CLINICAL INTERVENTIONS vol:9 issue:1 ispartof: location:United States status: published
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- 2023
27. The (in)visible Brazilians: A perspective review on the need for brain health and dementia research with Brazilian immigrants in the United States.
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Simon, Sharon Sanz, Brucki, Sonia Maria Dozzi, Fonseca, Luciana Mascarenhas, Becker, Jacqueline, Cappi, Carolina, Marques, Andrea Horvath, Heyn, Patricia C., Gonçalves, Priscila Dib, Martins, Silvia S., Busatto, Geraldo, Suemoto, Claudia Kimie, Nitrini, Ricardo, Caramelli, Paulo, Yassuda, Monica Sanches, Miotto, Eliane Correa, Grinberg, Lea Tenenholz, Arce Renteria, Miguel, Alegria, Margarita, Stern, Yaakov, and Rivera‐Mindt, Monica
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ALZHEIMER'S disease ,HEALTH services accessibility ,PUBLIC health research ,SCIENTIFIC literature ,BRAZILIANS ,EMIGRATION & immigration - Abstract
Introduction: The Brazilian population in the United States (U.S.), a Latinx subgroup, is rapidly growing and aging but remains underrepresented in U.S. health research. In addition to group‐specific genetic and environmental risks, Brazilian immigrants and their offspring in the U.S. likely have cumulative risks for health inequities. It is estimated that 71% of Brazilian immigrants in the U.S. are undocumented, which may limit healthcare access/utilization. Furthermore, mental health is reported as a health priority by Brazilian immigrants in the U.S., and there is a lack of research on Alzheimer's disease and related dementia (AD/ADRD) in this population. Methods: We reviewed the scientific literature using traditional (e.g., PubMed) sources and databases generated by U.S. and Brazilian governments, as well as international organizations, and press articles. Results: This perspective review lists recommendations for researchers, health providers, and policymakers to promote greater inclusion of U.S. Brazilian populations in health research and care. The review identifies research areas in need of attention to address health inequities and promote mental/brain health in Brazilian immigrants and their offspring living in the U.S. These research areas are: 1) epidemiological studies to map the prevalence and incidence of mental/brain health conditions; 2) research on aging and AD/ADRD risk factors among Brazilian populations in the U.S.; and 3) the need for greater representation of U.S‐residing Brazilian population in other relevant research areas involving genetics, neuropathology, and clinical trials. Conclusions: The recommendation and research efforts proposed should help to pave the way for the development of community‐engagement research and to promote mental/brain health education, improvement of mental/brain health and AD/ADRD services, and the development of culturally‐informed intervention to the U.S.‐residing Brazilian communities. HIGHLIGHTS: The Brazilian population in the United States is growing but is underrepresented in U.S. health research.Approximately 71% of Brazilian immigrants in the United States are undocumented, with an increased risk for health inequities.Mental health is reported as a central health priority by Brazilian immigrants in the United States.There is a lack of research on Alzheimer's disease and other dementias (ADRD) in Brazilian immigrants in the United States.Epidemiological research is needed to map the prevalence/incidence of mental health conditions and ADRD risk factors among Brazilian immigrants in the United States. [ABSTRACT FROM AUTHOR]
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- 2023
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28. Late-life memory trajectories in relation to incident dementia and regional brain atrophy
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Zahodne, Laura B., Wall, Melanie M., Schupf, Nicole, Mayeux, Richard, Manly, Jennifer J., Stern, Yaakov, and Brickman, Adam M.
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- 2015
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29. Costs During the Last Five Years of Life for Patients with Clinical and Pathological Confirmed Diagnosis of Lewy Body Dementia and Alzheimer's Disease.
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Zhu, Carolyn W., Gu, Yian, Kociolek, Anton J., Fernandez, Kayri K., Cosentino, Stephanie, and Stern, Yaakov
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LEWY body dementia ,ALZHEIMER'S disease ,DIAGNOSIS ,CLINICAL pathology ,MEDICAL care costs ,VASCULAR dementia ,APOLIPOPROTEIN E4 - Abstract
Background: Little is known regarding healthcare expenditures for patients with dementia with Lewy bodies (DLB) during the end of life. Objective: This study estimated Medicare expenditures during the last 5 years of life in a decedent sample of patients who were clinically diagnosed with Alzheimer's disease (AD) or DLB and had autopsy confirmed diagnosis. Methods: The study included 58 participants clinically diagnosed with mild dementia at study entry (AD: n = 44, DLB: n = 14) and also had autopsy-confirmed diagnoses of pure AD (n = 32), mixed AD+Lewy body (LB) (n = 5), or pure LB (n = 11). Total Medicare expenditures were compared by clinical and pathology confirmed diagnosis, adjusting for sex, age at death, and patient's cognition, function, comorbidities, and psychiatric and extrapyramidal symptoms. Results: When pathology diagnoses were not considered, predicted annualized total Medicare expenditures during the last 5 years of life were similar between clinically diagnosed AD ($7,465±1,098) and DLB ($7,783±1,803). When clinical diagnoses were not considered, predicted expenditures were substantially higher in patients with pathology confirmed mixed AD+LB ($12,005±2,455) than either pure AD ($6,173±941) or pure LB ($4,629±1,968) cases. Considering clinical and pathology diagnosis together, expenditures for patients with clinical DLB and pathology mixed AD+LB ($23,592±3,679) dwarfed other groups. Conclusion: Medicare expenditures during the last 5 years of life were substantially higher in patients with mixed AD+LB pathology compared to those with pure-AD and pure-LB pathologies, particularly in those clinically diagnosed with DLB. Results highlight the importance of having both clinical and pathology diagnoses in examining healthcare costs. [ABSTRACT FROM AUTHOR]
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- 2023
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30. Development, initial validation, and application of a visual read method for [18F]MK‐6240 tau PET.
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Shuping, Joanna L., Matthews, Dawn C., Adamczuk, Katarzyna, Scott, David, Rowe, Christopher C., Kreisl, William C., Johnson, Sterling C., Lukic, Ana S., Johnson, Keith A., Rosa‐Neto, Pedro, Andrews, Randolph D., Van Laere, Koen, Cordes, Lindsay, Ward, Larry, Wilde, Claire L., Barakos, Jerome, Purcell, Derk D., Devanand, Davangere P., Stern, Yaakov, and Luchsinger, Jose A.
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POSITRON emission tomography ,NEUROFIBRILLARY tangles ,TAU proteins ,ALZHEIMER'S disease ,BRAIN injuries - Abstract
Background: The positron emission tomography (PET) radiotracer [18F]MK‐6240 exhibits high specificity for neurofibrillary tangles (NFTs) of tau protein in Alzheimer's disease (AD), high sensitivity to medial temporal and neocortical NFTs, and low within‐brain background. Objectives were to develop and validate a reproducible, clinically relevant visual read method supporting [18F]MK‐6240 use to identify and stage AD subjects versus non‐AD and controls. Methods: Five expert readers used their own methods to assess 30 scans of mixed diagnosis (47% cognitively normal, 23% mild cognitive impairment, 20% AD, 10% traumatic brain injury) and provided input regarding regional and global positivity, features influencing assessment, confidence, practicality, and clinical relevance. Inter‐reader agreement and concordance with quantitative values were evaluated to confirm that regions could be read reliably. Guided by input regarding clinical applicability and practicality, read classifications were defined. The readers read the scans using the new classifications, establishing by majority agreement a gold standard read for those scans. Two naïve readers were trained and read the 30‐scan set, providing initial validation. Inter‐rater agreement was further tested by two trained independent readers in 131 scans. One of these readers used the same method to read a full, diverse database of 1842 scans; relationships between read classification, clinical diagnosis, and amyloid status as available were assessed. Results: Four visual read classifications were determined: no uptake, medial temporal lobe (MTL) only, MTL and neocortical uptake, and uptake outside MTL. Inter‐rater kappas were 1.0 for the naïve readers gold standard scans read and 0.98 for the independent readers 131‐scan read. All scans in the full database could be classified; classification frequencies were concordant with NFT histopathology literature. Discussion: This four‐class [18F]MK‐6240 visual read method captures the presence of medial temporal signal, neocortical expansion associated with disease progression, and atypical distributions that may reflect different phenotypes. The method demonstrates excellent trainability, reproducibility, and clinical relevance supporting clinical use. Highlights: A visual read method has been developed for [18F]MK‐6240 tau positron emission tomography.The method is readily trainable and reproducible, with inter‐rater kappas of 0.98.The read method has been applied to a diverse set of 1842 [18F]MK‐6240 scans.All scans from a spectrum of disease states and acquisitions could be classified.Read classifications are consistent with histopathological neurofibrillary tangle staging literature. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
31. KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer’s disease
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Neitzel, Julia, Franzmeier, Nicolai, Petersen, Ronald, Clark, David, Geldmacher, David, Brockington, John, Roberson, Erik, Grossman, Hillel, Mitsis, Effie, deToledo-Morrell, Leyla, Shah, Raj C, Duara, Ranjan, Varon, Daniel, Jack, Clifford R, Greig, Maria T, Roberts, Peggy, Albert, Marilyn, Onyike, Chiadi, D'Agostino, Daniel, Kielb, Stephanie, Galvin, James E, Pogorelec, Dana M, Cerbone, Brittany, Michel, Christina A, Jagust, William, Rusinek, Henry, de Leon, Mony J, Glodzik, Lidia, De Santi, Susan, Doraiswamy, P Murali, Petrella, Jeffrey R, Wong, Terence Z, Arnold, Steven E, Karlawish, Jason H, Wolk, David, Trojanowki, John Q, Smith, Charles D, Jicha, Greg, Hardy, Peter, Sinha, Partha, Oates, Elizabeth, Conrad, Gary, Lopez, Oscar L, Oakley, MaryAnn, Simpson, Donna M, Porsteinsson, Anton P, Toga, Arthur W, Goldstein, Bonnie S, Martin, Kim, Makino, Kelly M, Ismail, Muhammad, Brand, Connie, Mulnard, Ruth A, Thai, Gaby, Mc Adams Ortiz, Catherine, Womack, Kyle, Mathews, Dana, Beckett, Laurel, Quiceno, Mary, Arrastia, Ramon Diaz, King, Richard, Weiner, Myron, Cook, Kristen Martin, DeVous, Michael, Levey, Allan I, Lah, James J, Cellar, Janet S, Burns, Jeffrey M, Green, Robert C, Anderson, Heather S, Swerdlow, Russell H, Apostolova, Liana, Tingus, Kathleen, Woo, Ellen, Silverman, Daniel H S, Lu, Po H, Bartzokis, George, Radford, Neill R Graff, ParfittH, Francine, Saykin, Andrew J, Kendall, Tracy, Johnson, Heather, Farlow, Martin R, Hake, Ann Marie, Matthews, Brandy R, Herring, Scott, Hunt, Cynthia, van Dyck, Christopher H, Carson, Richard E, MacAvoy, Martha G, Morris, John, Chertkow, Howard, Bergman, Howard, Hosein, Chris, Black, Sandra, Stefanovic, Bojana, Caldwell, Curtis, Hsiung, Ging Yuek Robin, Feldman, Howard, Mudge, Benita, Past, Michele Assaly, Shaw, Leslie, Kertesz, Andrew, Rogers, John, Trost, Dick, Bernick, Charles, Munic, Donna, Kerwin, Diana, Mesulam, Marek Marsel, Lipowski, Kristine, Wu, Chuang Kuo, Johnson, Nancy, Rubinski, Anna, Liu, Enchi, Sadowsky, Carl, Martinez, Walter, Villena, Teresa, Turner, Raymond Scott, Johnson, Kathleen, Reynolds, Brigid, Sperling, Reisa A, Johnson, Keith A, Marshall, Gad, Frey, Meghan, Montine, Tom, Yesavage, Jerome, Taylor, Joy L, Lane, Barton, Rosen, Allyson, Tinklenberg, Jared, Sabbagh, Marwan N, Belden, Christine M, Jacobson, Sandra A, Sirrel, Sherye A, Kowall, Neil, Thomas, Ronald G, Killiany, Ronald, Budson, Andrew E, Norbash, Alexander, Johnson, Patricia Lynn, Obisesan, Thomas O, Wolday, Saba, Allard, Joanne, Lerner, Alan, Ogrocki, Paula, Hudson, Leon, Donohue, Michael, Fletcher, Evan, Carmichael, Owen, Olichney, John, DeCarli, Charles, Kittur, Smita, Borrie, Michael, Lee, T. Y., Bartha, Rob, Johnson, Sterling, Asthana, Sanjay, Walter, Sarah, Carlsson, Cynthia M, Potkin, Steven G, Preda, Adrian, Nguyen, Dana, Tariot, Pierre, Reeder, Stephanie, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Scharre, Douglas W, Gessert, Devon, Kataki, Maria, Adeli, Anahita, Zimmerman, Earl A, Celmins, Dzintra, Brown, Alice D, Pearlson, Godfrey D, Blank, Karen, Anderson, Karen, Santulli, Robert B, Kitzmiller, Tamar J, Sather, Tamie, Schwartz, Eben S, SinkS, Kaycee M, Williamson, Jeff D, Garg, Pradeep, Watkins, Franklin, Ott, Brian R, Querfurth, Henry, Tremont, Geoffrey, Salloway, Stephen, Malloy, Paul, Jiminez, Gus, Correia, Stephen, Rosen, Howard J, Miller, Bruce L, Mintzer, Jacobo, Spicer, Kenneth, Bachman, David, Finger, Elizabether, Pasternak, Stephen, Rachinsky, Irina, Drost, Dick, Harvey, Danielle, Pomara, Nunzio, Hernando, Raymundo, Sarrael, Antero, Schultz, Susan K, Ponto, Laura L Boles, Shim, Hyungsub, Smith, Karen Elizabeth, Relkin, Norman, Chaing, Gloria, Raudin, Lisa, Bernstein, Matthew, Smith, Amanda, Fargher, Kristin, Raj, Balebail Ashok, Dichgans, Martin, Fox, Nick, Thompson, Paul, Schuff, Norbert, DeCArli, Charles, Borowski, Bret, Gunter, Jeff, Senjem, Matt, Vemuri, Prashanthi, Jones, David, Kantarci, Kejal, Brendel, Matthias, Ward, Chad, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Landau, Susan, Cairns, Nigel J, Householder, Erin, Reinwald, Lisa Taylor, Initiative, Alzheimer’s Disease Neuroimaging, Lee, Virginia, Korecka, Magdalena, Figurski, Michal, Crawford, Karen, Neu, Scott, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kelley, Faber, Kim, Sungeun, Malik, Rainer, Nho, Kwangsik, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Carter, Raina, Dolen, Sara, Ewers, Michael, Schneider, Lon S, Pawluczyk, Sonia, Beccera, Mauricio, Teodoro, Liberty, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Fleisher, Adam, Heidebrink, Judith L, Lord, Joanne L, Weiner, Michael, Mason, Sara S, Albers, Colleen S, Knopman, David S, Johnson, Kris, Doody, Rachelle S, Meyer, Javier Villanueva, Chowdhury, Munir, Rountree, Susan, Dang, Mimi, Stern, Yaakov, Aisen, Paul, Honig, Lawrence S, Bell, Karen L, Ances, Beau, Morris, John C, Carroll, Maria, Leon, Sue, Mintun, Mark A, Schneider, Stacy, OliverNG, Angela, Griffith, Randall, Radiology & Nuclear Medicine, and Epidemiology
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Male ,Heterozygote ,metabolism [Amyloid beta-Peptides] ,Molecular imaging ,Gene Expression ,genetics [Alzheimer Disease] ,klotho protein ,tau Proteins ,Polymorphism, Single Nucleotide ,Article ,metabolism [Apolipoproteins E] ,Apolipoproteins E ,genetics [Memory Disorders] ,Alzheimer Disease ,mental disorders ,Humans ,metabolism [Glucuronidase] ,diagnostic imaging [Brain] ,Klotho Proteins ,Aged ,Glucuronidase ,Memory Disorders ,Amyloid beta-Peptides ,genetics [Glucuronidase] ,methods [Positron-Emission Tomography] ,metabolism [Memory Disorders] ,Brain ,Alzheimer's disease ,Middle Aged ,metabolism [tau Proteins] ,Haplotypes ,metabolism [Brain] ,Positron-Emission Tomography ,genetics [Apolipoproteins E] ,Dementia ,Female ,ddc:500 ,metabolism [Alzheimer Disease] ,Protein Binding - Abstract
Klotho-VS heterozygosity (KL-VShet) is associated with reduced risk of Alzheimer’s disease (AD). However, whether KL-VShet is associated with lower levels of pathologic tau, i.e., the key AD pathology driving neurodegeneration and cognitive decline, is unknown. Here, we assessed the interaction between KL-VShet and levels of beta-amyloid, a key driver of tau pathology, on the levels of PET-assessed neurofibrillary tau in 551 controls and patients across the AD continuum. KL-VShet showed lower cross-sectional and longitudinal increase in tau-PET per unit increase in amyloid-PET when compared to that of non-carriers. This association of KL-VShet on tau-PET was stronger in Klotho mRNA-expressing brain regions mapped onto a gene expression atlas. KL-VShet was related to better memory functions in amyloid-positive participants and this association was mediated by lower tau-PET. Amyloid-PET levels did not differ between KL-VShet carriers versus non-carriers. Together, our findings provide evidence to suggest a protective role of KL-VShet against amyloid-related tau pathology and tau-related memory impairments in elderly humans at risk of AD dementia., The KL-VS haplotype of the Klotho gene has been associated with reduced risk of Alzheimer’s disease and dementia. Here the authors show an association between the KL-VS haplotype and amyloid-dependent tau accumulation using PET data.
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- 2021
32. Stakeholder Insights in Alzheimer's Disease: Natural Language Processing of Social Media Conversations.
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Tahami Monfared, Amir Abbas, Stern, Yaakov, Doogan, Stephen, Irizarry, Michael, and Zhang, Quanwu
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ALZHEIMER'S disease , *SOCIAL media , *NATURAL language processing , *COMMUNICATION , *ANXIETY - Abstract
Background: Social media data may be especially effective for studying diseases associated with high stigma, such as Alzheimer's disease (AD).Objective: We primarily aimed to identify issues/challenges experienced by patients with AD using natural language processing (NLP) of social media posts.Methods: We searched 130 public social media sources between January 1998 and December 2021 for AD stakeholder social media posts using NLP to identify issues/challenges experienced by patients with AD. Issues/challenges identified by ≥10% of any AD stakeholder type were described. Illustrative posts were selected for qualitative review. Secondarily, issues/challenges were organized into a conceptual AD identification framework (ADIF) and representation of ADIF categories within clinical instruments was assessed.Results: We analyzed 1,859,077 social media posts from 30,341 AD stakeholders (21,011 caregivers; 7,440 clinicians; 1,890 patients). The most common issues/challenges were Worry/anxiety (34.2%), Pain (33%), Malaise (28.7%), Confusional state (27.1%), and Falls (23.9%). Patients reported a markedly higher volume of issues/challenges than other stakeholders. Patient posts reflected the broader scope of patient burden, caregiver posts captured both patient and caregiver burden, and clinician posts tended to be targeted. Less than 5% of the high frequency issues/challenges were in the "function and independence" and "social and relational well-being" categories of the ADIF, suggesting these issues/challenges may be difficult to capture. No single clinical instrument covered all ADIF categories; "social and relational well-being" was least represented.Conclusion: NLP of AD stakeholder social media data revealed a broad spectrum of real-world insights regarding patient burden. [ABSTRACT FROM AUTHOR]- Published
- 2022
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33. Multivariate Data Analysis for Neuroimaging Data: Overview and Application to Alzheimer’s Disease
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Habeck, Christian, Stern, Yaakov, and the Alzheimer’s Disease Neuroimaging Initiative
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- 2010
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34. Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer’s disease
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Lee, Joseph H., Barral, Sandra, Cheng, Rong, Chacon, Inara, Santana, Vincent, Williamson, Jennifer, Lantigua, Rafael, Medrano, Martin, Jimenez-Velazquez, Ivonne Z., Stern, Yaakov, Tycko, Benjamin, Rogaeva, Ekaterina, Wakutani, Yosuke, Kawarai, Toshitaka, St George-Hyslop, Peter, and Mayeux, Richard
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- 2008
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35. Whitepaper : Defining and investigating cognitive reserve, brain reserve, and brain maintenance
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Reserve Resilience Protective Fact, Stern, Yaakov, Arenaza-Urquijo, Eider M., Bartres-Faz, David, Vuoksimaa, Eero, Cognitive and Brain Aging, Institute for Molecular Medicine Finland, and University of Helsinki
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Cognition ,Epidemiology ,3112 Neurosciences ,Structural imaging ,Alzheimer's disease ,Functional imaging ,3124 Neurology and psychiatry - Abstract
Several concepts, which in the aggregate get might be used to account for "resilience" against age- and disease-related changes, have been the subject of much research. These include brain reserve, cognitive reserve, and brain maintenance. However, different investigators have use these terms in different ways, and there has never been an attempt to arrive at consensus on the definition of these concepts. Furthermore, there has been confusion regarding the measurement of these constructs and the appropriate ways to apply them to research. Therefore the reserve, resilience, and protective factors professional interest area, established under the auspices of the Alzheimer's Association, established a whitepaper workgroup to develop consensus definitions for cognitive reserve, brain reserve, and brain maintenance. The workgroup also evaluated measures that have been used to implement these concepts in research settings and developed guidelines for research that explores or utilizes these concepts. The workgroup hopes that this whitepaper will form a reference point for researchers in this area and facilitate research by supplying a common language.
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- 2020
36. Dietary fatty acids and risk of Alzheimer's disease and related dementias: Observations from the Washington Heights‐Hamilton Heights‐Inwood Columbia Aging Project (WHICAP)
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Gustafson, Deborah R., Bäckman, K., Scarmeas, Nikolaos, Stern, Yaakov, Manly, Jennifer J., Mayeux, Richard Paul, and Gu, Yian
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Unsaturated fatty acids ,Alzheimer's disease - Abstract
Introduction: High dietary intake of long chain, polyunsaturated fatty acids is associated with lower Alzheimer's disease (AD) risk. Methods: Washington Heights‐Hamilton Heights‐Inwood Columbia Aging Project is a multiethnic, prospective observational study of aging and dementia among elderly (≥ 65 years). Dietary intake was measured using a food frequency questionnaire. Dietary short‐, medium‐, and long‐chain fatty acid intakes were categorized by number of carbons and double bonds. Consensus AD diagnoses were made. Associations between AD risk and dietary fatty acid and cholesterol intakes were estimated using multivariable Cox proportional hazards regression models. Results: Of 2612 multiethnic women (67%) and men (baseline age 76.3 [6.4] years), 380 developed AD over an average 4.5 years follow‐up. Lower risk of AD was associated with increasing intakes of docosahexaenoic acid (DHA; hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.57 to 0.95, P = 0.018) and eicosapentaenoic acid (EPA; HR = 0.74, 95% CI: 0.57 to 0.95, P = 0.021), and longer AD‐free survival (P < 0.05). Discussion: Higher intake of DHA and EPA are protective for AD.
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- 2020
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37. Higher CSF sTREM2 attenuates ApoE4-related risk for cognitive decline and neurodegeneration
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Franzmeier, Nicolai, Suárez-Calvet, M., Kleinberger, Gernot, Doraiswamy, P Murali, Petrella, Jeffrey R, Arnold, Steven E, Karlawish, Jason H, Wolk, David, Smith, Charles D, Jicha, Greg, Hardy, Peter, Lopez, Oscar L, Oakley, Mary Ann, Haass, Christian, Simpson, Donna M, Ismail, M Saleem, Brand, Connie, Mulnard, Ruth A, Thai, Gaby, Mc-Adams-Ortiz, Catherine, Diaz-Arrastia, Ramon, Martin-Cook, Kristen, DeVous, Michael, Levey, Allan I, Ewers, Michael, Lah, James J, Cellar, Janet S, Burns, Jeffrey M, Anderson, Heather S, Swerdlow, Russell H, Bartzokis, George, Silverman, Daniel H S, Lu, Po H, Apostolova, Liana, Graff-Radford, Neill R, Initiative, Alzheimer’s Disease Neuroimaging, Parfitt, Francine, Johnson, Heather, Farlow, Martin, Herring, Scott, Hake, Ann M, van Dyck, Christopher H, Carson, Richard E, MacAvoy, Martha G, Chertkow, Howard, Bergman, Howard, Weiner, Michael, Hosein, Chris, Black, Sandra, Stefanovic, Bojana, Caldwell, Curtis, Hsiung, Ging-Yuek Robin, Feldman, Howard, Assaly, Michele, Kertesz, Andrew, Rogers, John, Trost, Dick, Aisen, Paul, Bernick, Charles, Munic, Donna, Wu, Chuang-Kuo, Johnson, Nancy, Mesulam, Marsel, Sadowsky, Carl, Martinez, Walter, Villena, Teresa, Turner, Raymond Scott, Johnson, Kathleen, Novak, Gerald, Reynolds, Brigid, Sperling, Reisa A, Frey, Meghan, Johnson, Keith A, Rosen, Allyson, Tinklenberg, Jared, Ashford, Wes, Sabbagh, Marwan, Belden, Christine, Jacobson, Sandra, Green, Robert C, Killiany, Ronald, Norbash, Alexander, Nair, Anil, Obisesan, Thomas O, Wolday, Saba, Bwayo, Salome K, Lerner, Alan, Hudson, Leon, Ogrocki, Paula, Fletcher, Evan, Montine, Tom, Carmichael, Owen, Kittur, Smita, Borrie, Michael, Lee, T-Y, Bartha, Rob, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M, Potkin, Steven G, Preda, Adrian, Petersen, Ronald, Nguyen, Dana, Tariot, Pierre, Fleisher, Adam, Reeder, Stephanie, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Hendin, Barry A, Scharre, Douglas W, Kataki, Maria, Frontzkowski, Lukas, Gamst, Anthony, Zimmerman, Earl A, Celmins, Dzintra, Brown, Alice D, Hosp, Hartford, Pearlson, Godfrey D, Blank, Karen, Anderson, Karen, Santulli, Robert B, Schwartz, Eben S, Williamson, Jeff D, Thomas, Ronald G, Sink, Kaycee M, Watkins, Franklin, Ott, Brian R, Querfurth, Henry, Tremont, Geoffrey, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Rosen, Howard J, Miller, Bruce L, Donohue, Michael, Mintzer, Jacobo, Longmire, Crystal Flynn, Spicer, Kenneth, Walter, Sarah, Gessert, Devon, Sather, Tamie, Beckett, Laurel, Harvey, Danielle, Kornak, John, Jack, Clifford R, Moore, Annah, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Jagust, William, Bandy, Dan, Hohman, Timothy J, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Morris, John, Cairns, Nigel J, Taylor-Reinwald, Lisa, Trojanowki, J. Q., Shaw, Les, Morenas-Rodriguez, Estrella, Lee, Virginia M Y, Korecka, Magdalena, Toga, Arthur W, Crawford, Karen, Neu, Scott, Saykin, Andrew J, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Nuscher, Brigitte, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Dolen, Sara, Quinn, Joseph, Schneider, Lon S, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Shaw, Leslie, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Trojanowski, John Q, Morris, John C, Mintun, Mark A, Schneider, Stacy, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, Mitsis, Effie, Romirowsky, Aliza, deToledo-Morrell, Leyla, Dichgans, Martin, Shah, Raj C, Duara, Ranjan, Varon, Daniel, Roberts, Peggy, Albert, Marilyn, Onyike, Chiadi, Kielb, Stephanie, Rusinek, Henry, de Leon, Mony J, and Glodzik, Lidia
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Male ,Aging ,pathology [Cognitive Dysfunction] ,Apolipoprotein E4 ,Cognitive decline ,genetics [Alzheimer Disease] ,Neurodegenerative ,lcsh:Geriatrics ,Alzheimer's Disease ,lcsh:RC346-429 ,pathology [Alzheimer Disease] ,Immunologic ,Receptors ,80 and over ,2.1 Biological and endogenous factors ,sTREM2 ,Microglial activation ,Aetiology ,Receptors, Immunologic ,genetics [Apolipoprotein E4] ,Aged, 80 and over ,Membrane Glycoproteins ,pathology [Nerve Degeneration] ,cerebrospinal fluid [Alzheimer Disease] ,cerebrospinal fluid [Cognitive Dysfunction] ,Neurological ,Female ,cerebrospinal fluid [Membrane Glycoproteins] ,Alzheimer’s disease ,Research Article ,Clinical Sciences ,ApoE4 ,Clinical Research ,Alzheimer Disease ,ddc:570 ,Acquired Cognitive Impairment ,Genetics ,Humans ,Cognitive Dysfunction ,Genetic Predisposition to Disease ,Neurodegeneration ,lcsh:Neurology. Diseases of the nervous system ,Aged ,Neurology & Neurosurgery ,Neurosciences ,genetics [Cognitive Dysfunction] ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Alzheimer’s Disease Neuroimaging Initiative ,Brain Disorders ,lcsh:RC952-954.6 ,Nerve Degeneration ,Dementia - Abstract
Background The Apolipoprotein E ε4 allele (i.e. ApoE4) is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD). TREM2 (i.e. Triggering receptor expressed on myeloid cells 2) is a microglial transmembrane protein brain that plays a central role in microglia activation in response to AD brain pathologies. Whether higher TREM2-related microglia activity modulates the risk to develop clinical AD is an open question. Thus, the aim of the current study was to assess whether higher sTREM2 attenuates the effects of ApoE4-effects on future cognitive decline and neurodegeneration. Methods We included 708 subjects ranging from cognitively normal (CN, n = 221) to mild cognitive impairment (MCI, n = 414) and AD dementia (n = 73) from the Alzheimer’s disease Neuroimaging Initiative. We used linear regression to test the interaction between ApoE4-carriage by CSF-assessed sTREM2 levels as a predictor of longitudinally assessed cognitive decline and MRI-assessed changes in hippocampal volume changes (mean follow-up of 4 years, range of 1.7-7 years). Results Across the entire sample, we found that higher CSF sTREM2 at baseline was associated with attenuated effects of ApoE4-carriage (i.e. sTREM2 x ApoE4 interaction) on longitudinal global cognitive (p = 0.001, Cohen’s f 2 = 0.137) and memory decline (p = 0.006, Cohen’s f 2 = 0.104) as well as longitudinally assessed hippocampal atrophy (p = 0.046, Cohen’s f 2 = 0.089), independent of CSF markers of primary AD pathology (i.e. Aβ1–42, p-tau181). While overall effects of sTREM2 were small, exploratory subanalyses stratified by diagnostic groups showed that beneficial effects of sTREM2 were pronounced in the MCI group. Conclusion Our results suggest that a higher CSF sTREM2 levels are associated with attenuated ApoE4-related risk for future cognitive decline and AD-typical neurodegeneration. These findings provide further evidence that TREM2 may be protective against the development of AD.
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- 2020
38. Dependence clusters in Alzheimer’s disease and Medicare expenditures: A longitudinal analysis from the Predictors Study: Health services research/Cost of care
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Zhu, Carolyn W., Lee, Seonjoo, Ornstein, Katherine A., Cosentino, Stephanie, Gu, Yian, Andrews, Howard F., and Stern, Yaakov
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Medical care, Cost of--Evaluation ,Dementia--Patients--Care ,Alzheimer's disease ,Medicare - Abstract
Background: Dependence has been proposed as a holistic, transparent, and meaningful representation of dementia disease severity to quantify and stage disease progression. Modeling clusters in dependence trajectories can help understand changes over time in the course of dementia and related cost of care. Method: 199 initially community‐living patients with probable AD in early stages of the disease were recruited to the Predictors 2 Study from three academic medical centers in the US. Patients were followed for up to 10 years and had at least two Dependence Scale (DS) recorded. Non‐parametric K‐means cluster analysis for longitudinal data (KmL) was used to identify dependence clusters. Medicare expenditures (1999‐2010) were compared between clusters at 6‐month intervals and cumulatively over 5 years. Result: KmL identified two distinct DS clusters: (A) high initial dependence, faster decline, and (B) low initial dependence, slower decline. At baseline, DS score in cluster A was on average 2.25 points higher than in cluster B (p
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- 2020
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39. Neuropathologic features associated with basal forebrain atrophy in Alzheimer disease
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Teipel, Stefan J, Fritz, H-Christian, Toga, Arthur W., Roberts, Peggy, Albert, Marilyn, Onyike, Chiadi, Kielb, Stephanie, Rusinek, Henry, de Leon, Mony J, Glodzik, Lidia, De Santi, Susan, Doraiswamy, P. Murali, Petrella, Jeffrey R., Beckett, Laurel, Coleman, R. Edward, Arnold, Steven E., Karlawish, Jason H., Wolk, David, Smith, Charles D., Jicha, Greg, Hardy, Peter, Lopez, Oscar L., Oakley, MaryAnn, Simpson, Donna M., Green, Robert C., Porsteinsson, Anton P., Goldstein, Bonnie S., Martin, Kim, Makino, Kelly M., Ismail, M. Saleem, Brand, Connie, Mulnard, Ruth A., Thai, Gaby, Mc-Adams-Ortiz, Catherine, Womack, Kyle, Saykin, Andrew J., Mathews, Dana, Quiceno, Mary, Diaz-Arrastia, Ramon, King, Richard, Weiner, Myron, Martin-Cook, Kristen, DeVous, Michael, Levey, Allan I., Lah, James J., Cellar, Janet S., Morris, John, Burns, Jeffrey M., Anderson, Heather S., Swerdlow, Russell H., Apostolova, Liana, Lu, Po H., Bartzokis, George, Silverman, Daniel H. S., Graff-Radford, Neill R, Parfitt, Francine, Johnson, Heather, Liu, Enchi, Farlow, Martin R., Hake, Ann Marie, Matthews, Brandy R., Herring, Scott, van Dyck, Christopher H., Carson, Richard E., MacAvoy, Martha G., Chertkow, Howard, Bergman, Howard, Hosein, Chris, Black, Sandra, Stefanovic, Bojana, Caldwell, Curtis, Hsiung, Ging-Yuek Robin, Feldman, Howard, Mudge, Benita, Assaly, Michele, Kertesz, Andrew, Rogers, John, Trost, Dick, Montine, Tom, Bernick, Charles, Munic, Donna, Kerwin, Diana, Mesulam, Marek-Marsel, Lipowski, Kristina, Wu, Chuang-Kuo, Johnson, Nancy, Sadowsky, Carl, Martinez, Walter, Villena, Teresa, Petersen, Ronald, Scott Turner, Raymond, Johnson, Kathleen, Reynolds, Brigid, Sperling, Reisa A., Johnson, Keith A., Marshall, Gad, Frey, Meghan, Yesavage, Jerome, Taylor, Joy L., Lane, Barton, Aisen, Paul, Rosen, Allyson, Tinklenberg, Jared, Sabbagh, Marwan, Belden, Christine, Jacobson, Sandra, Kowall, Neil, Killiany, Ronald, Budson, Andrew E., Norbash, Alexander, Johnson, Patricia Lynn, Grothe, Michel, Gamst, Anthony, Obisesan, Thomas O., Wolday, Saba, Bwayo, Salome K., Lerner, Alan, Hudson, Leon, Ogrocki, Paula, Fletcher, Evan, Carmichael, Owen, Olichney, John, DeCarli, Charles, Thomas, Ronald G., Kittur, Smita, Borrie, Michael, Lee, T-Y, Bartha, Rob, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M., Potkin, Steven G., Preda, Adrian, Nguyen, Dana, Donohue, Michael, Tariot, Pierre, Fleisher, Adam, Reeder, Stephanie, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Scharre, Douglas W., Kataki, Maria, Zimmerman, Earl A., Celmins, Dzintra, Walter, Sarah, Brown, Alice D., Pearlson, Godfrey D., Blank, Karen, Anderson, Karen, Santulli, Robert B., Schwartz, Eben S., Sink, Kaycee M., Williamson, Jeff D., Garg, Pradeep, Gessert, Devon, Watkins, Franklin, Ott, Brian R., Querfurth, Henry, Tremont, Geoffrey, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Rosen, Howard J., Miller, Bruce L., Mintzer, Jacobo, Sather, Tamie, Longmire, Crystal Flynn, Spicer, Kenneth, Finger, Elizabether, Rachinsky, Irina, Drost, Dick, Pomara, Nunzio, Hernando, Raymundo, Sarrael, Antero, Schultz, Susan K., Boles Ponto, Laura L., Shim, Hyungsub, Smith, Karen Elizabeth, Relkin, Norman, Chaing, Gloria, Raudin, Lisa, Smith, Amanda, Fargher, Kristin, Raj, Balebail Ashok, Harvey, Danielle, Initiative, Alzheimer's Disease Neuroimaging, Kornak, John, Jack, Clifford R., Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, Weiner, Michael, Jagust, William, Bandy, Dan, Koeppe, Robert A., Foster, Norm, Reiman, Eric M., Chen, Kewei, Mathis, Chet, Cairns, Nigel J., Taylor-Reinwald, Lisa, Trojanowki, J. Q., Shaw, Les, Lee, Virginia M Y, Korecka, Magdalena, Crawford, Karen, Neu, Scott, Foroud, Tatiana M., Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J., Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Dolen, Sara, Schneider, Lon S., Pawluczyk, Sonia, Spann, Bryan M., Brewer, James, Vanderswag, Helen, Heidebrink, Judith L., Lord, Joanne L., Johnson, Kris, Doody, Rachelle S., Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S., Bell, Karen L., Morris, John C., Ances, Beau, Carroll, Maria, Leon, Sue, Mintun, Mark A., Schneider, Stacy, Trojanowki, John Q., Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, Mitsis, Effie, Romirowsky, Aliza, deToledo-Morrell, Leyla, Shah, Raj C., Duara, Ranjan, Varon, Daniel, Instituto de Salud Carlos III, European Commission, and Ministerio de Ciencia, Innovación y Universidades (España)
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0301 basic medicine ,Male ,medicine.medical_specialty ,Multivariate analysis ,diagnostic imaging [Basal Forebrain] ,Basal Forebrain ,pathology [Basal Forebrain] ,Logistic regression ,Article ,03 medical and health sciences ,pathology [Alzheimer Disease] ,0302 clinical medicine ,Atrophy ,Alzheimer Disease ,Internal medicine ,Ischaemic stroke ,Medicine ,Humans ,ddc:610 ,Stroke ,Cost implications ,Aged ,Aged, 80 and over ,pathology [Atrophy] ,business.industry ,medicine.disease ,Magnetic Resonance Imaging ,030104 developmental biology ,Charlson comorbidity index ,Female ,Neurology (clinical) ,Alzheimer's disease ,business ,diagnostic imaging [Alzheimer Disease] ,030217 neurology & neurosurgery - Abstract
Alzheimer's Disease Neuroimaging Initiative., [Objective] To study the neuropathologic correlates of cholinergic basal forebrain (BF) atrophy as determined using antemortem MRI in the Alzheimer disease (AD) spectrum., [Methods] We determined associations between BF volume from antemortem MRI brain scans and postmortem assessment of neuropathologic features, including neuritic plaques, neurofibrillary tangles (NFTs), Lewy body (LB) pathology, and TDP-43, in 64 cases of the Alzheimer's Disease Neuroimaging Initiative cohort. For comparison, we assessed neuropathologic features associated with hippocampal and parahippocampal gyrus atrophy. In addition to region of interest–based analysis, we determined the association of neuropathologic features with whole brain gray matter volume using regionally unbiased voxel-based volumetry., [Results] BF atrophy was associated with Thal amyloid phases (95% confidence interval [CI] −0.49 to −0.01, p = 0.049) and presence of LB pathology (95% CI −0.54 to −0.06, p = 0.015), as well as with the degree of LB pathology within the nucleus basalis Meynert (95% CI −0.54 to −0.07, p = 0.025). These effects were no longer significant after false discovery rate (FDR) correction. Hippocampal atrophy was significantly associated with the presence of TDP-43 pathology (95% CI −0.61 to −0.17, p = 0.003; surviving FDR correction), in addition to dentate gyrus NFT load (95% CI −0.49 to −0.01, p = 0.044; uncorrected). Voxel-based analysis confirmed spatially restricted effects of Thal phases and presence of LB pathology on BF volume., [Conclusions] These findings indicate that neuropathologic correlates of regional atrophy differ substantially between different brain regions that are typically involved in AD-related neurodegeneration, including different susceptibilities to common comorbid pathologies., M.J.G. is supported by the “Miguel Servet” program [CP19/00031] of the Spanish Instituto de Salud Carlos III (ISCIII-FEDER).
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- 2020
40. Whitepaper: Defining and investigating cognitive reserve, brain reserve, and brain maintenance
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Stern, Yaakov, Arenaza‐Urquijo, Eider M., Bartrés‐Faz, David, Belleville, Sylvie, Cantilon, Marc, Chetelat, Gael, Ewers, Michael, Franzmeier, Nicolai, Kempermann, Gerd, Kremen, William S., Okonkwo, Ozioma, Scarmeas, Nikolaos, Soldan, Anja, Udeh‐Momoh, Chinedu, Valenzuela, Michael, Vemuri, Prashanthi, Vuoksimaa, Eero, and Reserve, Resilience
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Cognition ,Epidemiology ,Alzheimer's disease - Abstract
Several concepts, which in the aggregate get might be used to account for “resilience” against age‐ and disease‐related changes, have been the subject of much research. These include brain reserve, cognitive reserve, and brain maintenance. However, different investigators have use these terms in different ways, and there has never been an attempt to arrive at consensus on the definition of these concepts. Furthermore, there has been confusion regarding the measurement of these constructs and the appropriate ways to apply them to research. Therefore the reserve, resilience, and protective factors professional interest area, established under the auspices of the Alzheimer's Association, established a whitepaper workgroup to develop consensus definitions for cognitive reserve, brain reserve, and brain maintenance. The workgroup also evaluated measures that have been used to implement these concepts in research settings and developed guidelines for research that explores or utilizes these concepts. The workgroup hopes that this whitepaper will form a reference point for researchers in this area and facilitate research by supplying a common language.
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- 2020
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41. Relative contribution of white matter hyperintensity to amyloid and neurodegeneration in cognitive decline over time or clinical diagnoses in a diverse, community‐based cohort of older adults
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Lao, Patrick J., Chesebro, Anthony G., Beato, Juliet M., Amarante, Erica, Igwe, Kay C., Maas, Benjamin J., Boehme, Amelia K., Gu, Yian, Stern, Yaakov, Schupf, Nicole, Manly, Jennifer J., Mayeux, Richard Paul, and Brickman, Adam M.
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Cognition ,mental disorders ,White matter ,Alzheimer's disease - Abstract
Background: The 2018 NIA‐AA Alzheimer’s disease (AD) research framework moves towards a multiple biomarker approach to explain AD development and progression more fully. This research framework has the flexibility to incorporate various biomarkers into a full or partial amyloid‐tau‐neurodegeneration (A/T/N) profile. The objective of this study was to determine the relative contribution of white matter hyperintensities (WMH) to amyloid and neurodegeneration on cognition in a diverse, community‐based cohort of older adults. Method: A subset of cognitively healthy participants (n=155; age=69‐99yrs; 65% women, 30%/44%/26% Non‐Hispanic White/Non‐Hispanic Black/Hispanic) from the Washington Heights‐Inwood Columbia Aging Project underwent baseline Florbetaben PET (amyloid SUVR), T1‐weighted (cortical thickness[mm]) and T2‐weighted FLAIR MRI (WMH volume[cm3]), as well as subsequent neuropsychological assessments and consensus diagnoses every 1.5 years (up to 6 visits). Linear mixed effects models were used to test for change over time in language, memory, executive function, and visuospatial ability, while cox proportional hazard models were used to test for risk of developing MCI or AD. Biomarkers of interest included amyloid, cortical thickness, and WMH, adjusted for demographics (sex/gender, race/ethnicity, education). Interactions between biomarkers and time (e.g., slope differences) were evaluated as significant below 0.1. Result: In A/N/V models, higher amyloid was associated with faster rates of decline in language (B [95%CI]: ‐0.08 [‐0.13, ‐0.02]), memory (‐0.13 [‐0.21, ‐0.05]), and visuospatial ability (‐0.05 [‐0.12, 0.01]), higher WMH was associated with faster rates of decline in executive function (‐0.05 [‐0.11, 0.009]) and visuospatial ability (‐0.02 [‐0.05, 0.005]), and lower cortical thickness was associated with lower executive function scores (1.6 [0.10, 3.0]). Individuals were more likely to develop MCI or AD with higher amyloid (Hazard Ratio=4.2, [1.1, 15.9]), but not with higher WMH (1.2 [0.83, 1.7]) or lower cortical thickness (0.03 [4E‐4, 2]). Conclusion: In this imaging subsample of older community‐dwelling adults, cognitive decline is differentially associated by domain with amyloid or vascular burden, while broader, multi‐domain cognitive impairment necessary for MCI or AD diagnoses is associated with amyloid, one of the hallmark AD pathologies. Results support the use of complementary information from biomarker profiles, including traditional AD, vascular, and neurodegenerative biomarkers, to investigate AD and related dementias.
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- 2020
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42. Patterns of tau pathology identified with 18F‐MK‐6240 PET imaging.
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Kreisl, William Charles, Lao, Patrick J., Johnson, Aubrey, Tomljanovic, Zeljko, Klein, Julia, Polly, Krista, Maas, Benjamin, Laing, Krystal K., Chesebro, Anthony G., Igwe, Kay, Razlighi, Qolamreza R., Honig, Lawrence S., Yan, Xinyu, Lee, Seonjoo, Mintz, Akiva, Luchsinger, José A., Stern, Yaakov, Devanand, D. P., and Brickman, Adam M.
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Introduction: Positron emission tomography (PET) imaging for neurofibrillary tau allows investigation of the in vivo spatiotemporal progression of Alzheimer's disease (AD) pathology. We evaluated the suitability of 18F‐MK‐6240 in a clinical sample and determined the relationships among 18F‐MK‐6240 binding, age, cognition, and cerebrospinal fluid (CSF)‐based AD biomarkers. Methods: Participants (n = 101, 72 ± 9 years, 52% women) underwent amyloid PET, tau PET, structural T1‐weighted magnetic resonance imaging, and neuropsychological evaluation. Twenty‐one participants had lumbar puncture for CSF measurement of amyloid beta (Aβ)42, tau, and phosphorylated tau (p‐tau). Results: 18F‐MK‐6240 recapitulated Braak staging and correlated with CSF tau and p‐tau, normalized to Aβ42. 18F‐MK‐6240 negatively correlated with age across Braak regions in amyloid‐positive participants, consistent with greater tau pathology in earlier onset AD. Domain‐specific, regional patterns of 18F‐MK‐6240 binding were associated with reduced memory, executive, and language performance, but only in amyloid‐positive participants. Discussion: 18F‐MK‐6240 can approximate Braak staging across the AD continuum and provide region‐dependent insights into biomarker‐based AD models. [ABSTRACT FROM AUTHOR]
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- 2022
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43. When time's arrow doesn't bend: APOE-ε4 influences episodic memory before old age
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Eich, Teal S., Tsapanou, Angeliki, and Stern, Yaakov
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Cognition ,Apolipoprotein E gene ,Episodic memory ,Semantic memory ,Alzheimer's disease - Abstract
Episodic memory impairment is the hallmark symptom of Alzheimer's Disease (AD). However, episodic memory has also been shown to decline across the lifespan. Here, we investigated whether episodic memory is differentially affected relative to other cognitive abilities before old age, and whether being an Apolipoprotein E (APOE) ε4 carrier –a genetic risk factor for developing AD—exacerbates any such impairments. We used general linear models to test for performance differences within 4 composite measures of cognition - episodic memory, semantic memory, speed of processing, and fluid reasoning-- as a function of age group (young, M age = 30.21 vs. middle-aged, M age = 50.84) and APOE-ε4 genotype status (ε4+ vs. ε4-). We replicated findings of age-related reductions in episodic memory, speed of processing, and fluid reasoning, and age-related increases in semantic memory. However, we also found that APOE genotype status moderated the age-related declines in episodic memory: APOE-ε4+ middle-aged adults exhibited impairments relative to both APOE-ε4- middle-aged participants, and APOE-ε4+ younger adults. These results suggest specific and dynamic alterations to episodic memory as a function of APOE allelic variation and age.
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- 2019
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44. the neuroethics of cognitive reserve
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Samet, Jerry, Stern, Yaakov, Illes, Judy, book editor, and Sahakian, Barbara J., book editor
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- 2011
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45. Neuropsychological Predictors of Severe Functional Dependency in a Multiethnic Community Cohort of Individuals with Alzheimer's Disease.
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Cárcamo, Jasmine, Kociolek, Anton J., Fernández, Kayri K., Gu, Yian, Zhu, Carolyn W., Stern, Yaakov, and Cosentino, Stephanie
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ALZHEIMER'S disease ,PROPORTIONAL hazards models ,DEPENDENCY (Psychology) ,NEUROPSYCHOLOGICAL tests ,SEMANTIC memory ,MEMORY testing ,DEMENTIA - Abstract
To assess the predictive value of neuropsychological tests for severe dependency in Alzheimer's disease as defined by the Equivalent Institutional Care Rating Scale, in a multiethnic, community cohort. The sample included 146 elders from the Predictors 3 cohort. Cox proportional hazard models tested the predictive value of each neuropsychological test at baseline on relative risk of meeting severe dependency. Higher semantic processing and memory test scores at baseline were associated with lower risk of meeting severe dependency in the adjusted Cox models. The integrity of semantic processing and memory abilities in dementia appears to predict time to severe functional dependency. [ABSTRACT FROM AUTHOR]
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- 2021
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46. Extrapyramidal signs and Alzheimer's disease prognosis in a multiethnic, community‐based sample of demented elders.
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Kociolek, Anton J., Fernandez, Kayri K., Jin, Zhezhen, Cosentino, Stephanie, Zhu, Carolyn W., Gu, Yian, and Stern, Yaakov
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Introduction: Extrapyramidal signs (EPS) are a common feature of Alzheimer's disease associated with worse outcomes in observational studies of dementia. Less research has been conducted on ethnic minority and non‐clinic‐based populations. Methods: One hundred and forty‐two multiethnic community‐dwelling participants with dementia were selected. Adjusted Cox models were fitted for mortality, cognitive (Mini Mental State Examination ≤10), functional (Blessed Dementia Rating Scale ≥10), and dependency (needs full‐time care) endpoints with baseline EPS as predictor. Results: Thirty‐seven participants (26.06%) had EPS at baseline. EPS predicted more rapid time to death (hazard ratio [HR] = 2.76, 95% confidence interval [CI] = 1.49, 5.42), and functional endpoint (HR = 3.88, 95% CI = 1.75, 8.62) but not cognitive and dependency endpoints. No evidence of interaction by ethnicity, age, sex, education, or apolipoprotein E ε4 polymorphism was found. Discussion: Our results partially confirm previous studies on predominantly White, clinic‐based samples. Further research is needed to better understand the etiological role of EPS in AD. [ABSTRACT FROM AUTHOR]
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- 2021
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47. Plasma p‐tau181, p‐tau217, and other blood‐based Alzheimer's disease biomarkers in a multi‐ethnic, community study.
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Brickman, Adam M., Manly, Jennifer J., Honig, Lawrence S., Sanchez, Danurys, Reyes‐Dumeyer, Dolly, Lantigua, Rafael A., Lao, Patrick J., Stern, Yaakov, Vonsattel, Jean Paul, Teich, Andrew F., Airey, David C., Proctor, Nicholas Kyle, Dage, Jeffrey L., and Mayeux, Richard
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Introduction: Blood‐based Alzheimer's disease (AD) biomarkers provide opportunities for community studies and across ethnic groups. We investigated blood biomarker concentrations in the Washington Heights‐Inwood Columbia Aging Project (WHICAP), a multi‐ethnic community study of aging and dementia. Methods: We measured plasma amyloid beta (Aβ)40, Aβ42, total tau (t‐tau), phosphorylated tau (p‐tau)181, and p‐tau217, and neurofilament light chain (NfL) in 113 autopsied participants (29% with high AD neuropathological changes) and in 300 clinically evaluated individuals (42% with clinical AD). Receiver operating characteristics were used to evaluate each biomarker. We also investigated biomarkers as predictors of incident clinical AD. Results: P‐tau181, p‐tau217, and NfL concentrations were elevated in pathologically and clinically diagnosed AD. Decreased Aβ42/Aβ40 ratio and increased p‐tau217 and p‐tau181 were associated with subsequent AD diagnosis. Discussion: Blood‐based AD biomarker concentrations are associated with pathological and clinical diagnoses and can predict future development of clinical AD, providing evidence that they can be incorporated into multi‐ethnic, community‐based studies. [ABSTRACT FROM AUTHOR]
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- 2021
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48. Association Between Early Psychotic Symptoms and Alzheimer's Disease Prognosis in a Community-Based Cohort.
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Gottesman, Reena T., Kociolek, Anton, Fernandez, Kayri, Cosentino, Stephanie, Devanand, D.P., Stern, Yaakov, and Gu, Yian
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ALZHEIMER'S disease ,PROGNOSIS ,PSYCHOLOGICAL manifestations of general diseases ,OPTICAL illusions ,SYMPTOMS ,DISEASE progression ,RESEARCH ,PSYCHOSES ,RESEARCH methodology ,DISEASE incidence ,MEDICAL cooperation ,EVALUATION research ,NEUROPSYCHOLOGICAL tests ,COMPARATIVE studies - Abstract
Background: Psychotic symptoms are an important and increasingly recognized aspect of Alzheimer's disease (AD). They have been shown to contribute to faster disease progression in clinic-based, demographically homogenous samples with high educational attainment.Objective: We studied the association between baseline psychotic symptoms and disease progression among individuals with incident AD or 'at risk' of developing AD, from a demographically heterogenous, community-based cohort with minimal educational attainment.Methods: 212 participants received the Columbia University Scale of Psychopathology in Alzheimer's Disease scale. Participants had psychotic symptoms with any of: visual illusions, delusions, hallucinations, or agitation/aggression. Disease progression was measured yearly and defined by meeting cognitive (≤10 on the Folstein MMSE) or functional endpoints (≥10 on the Blessed Dementia Rating Scale or ≥4 on the Dependence Scale).Results: The mean age was 85 years old. The cohort was 78.3% female, 75.9% Hispanic, and had a mean 6.96 years of education. Within the follow-up period (mean: 3.69 years), 24 met the cognitive endpoint, 59 met the functional endpoint, and 132 met the cutoff for dependence. The presence of at least one psychotic symptom was initially associated with an increased risk of reaching the functional endpoint (HR 3.12, 95% CI 1.67-5.86, p < 0.001) and the endpoint of dependence (HR = 1.498, 95% CI 1.05-2.13, p = 0.03). However, these associations were attenuated and non-significant when adjusted for baseline functional status. Psychotic symptoms were not associated with the cognitive endpoint.Conclusion: Psychotic symptoms may predict functional decline in patients of non-Caucasian ethnicity and with lower educational attainment. [ABSTRACT FROM AUTHOR]- Published
- 2021
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49. Olfactory Impairment Is Related to Tau Pathology and Neuroinflammation in Alzheimer's Disease.
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Klein, Julia, Yan, Xinyu, Johnson, Aubrey, Tomljanovic, Zeljko, Zou, James, Polly, Krista, Honig, Lawrence S., Brickman, Adam M., Stern, Yaakov, Devanand, D.P., Lee, Seonjoo, and Kreisl, William C.
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TAU proteins ,ALZHEIMER'S disease ,NEUROINFLAMMATION ,SMELL ,PATHOLOGY ,PATHOLOGICAL physiology ,BRAIN ,RESEARCH ,NERVE tissue proteins ,RESEARCH methodology ,MEDICAL cooperation ,EVALUATION research ,COMPARATIVE studies ,SMELL disorders ,PEPTIDES ,DISEASE complications - Abstract
Background: Olfactory impairment is evident in Alzheimer's disease (AD); however, its precise relationships with clinical biomarker measures of tau pathology and neuroinflammation are not well understood.Objective: To determine if odor identification performance measured with the University of Pennsylvania Smell Identification Test (UPSIT) is related to in vivo measures of tau pathology and neuroinflammation.Methods: Cognitively normal and cognitively impaired participants were selected from an established research cohort of adults aged 50 and older who underwent neuropsychological testing, brain MRI, and amyloid PET. Fifty-four participants were administered the UPSIT. Forty-one underwent 18F-MK-6240 PET (measuring tau pathology) and fifty-three underwent 11C-PBR28 PET (measuring TSPO, present in activated microglia). Twenty-three participants had lumbar puncture to measure CSF concentrations of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-β (Aβ42).Results: Low UPSIT performance was associated with greater18F-MK-6240 binding in medial temporal cortex, hippocampus, middle/inferior temporal gyri, inferior parietal cortex, and posterior cingulate cortex (p < 0.05). Similar relationships were seen for 11C-PBR28. These relationships were primarily driven by amyloid-positive participants. Lower UPSIT performance was associated with greater CSF concentrations of t-tau and p-tau (p < 0.05). Amyloid status and cognitive status exhibited independent effects on UPSIT performance (p < 0.01).Conclusion: Olfactory identification deficits are related to extent of tau pathology and neuroinflammation, particularly in those with amyloid pathophysiology. The independent association of amyloid-positivity and cognitive impairment with odor identification suggests that low UPSIT performance may be a marker for AD pathophysiology in cognitive normal individuals, although impaired odor identification is associated with both AD and non-AD related neurodegeneration.NCT Registration Numbers: NCT03373604; NCT02831283. [ABSTRACT FROM AUTHOR]- Published
- 2021
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50. Benfotiamine and Cognitive Decline in Alzheimer's Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial.
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Gibson, Gary E., Luchsinger, José A., Cirio, Rosanna, Chen, Huanlian, Franchino-Elder, Jessica, Hirsch, Joseph A., Bettendorff, Lucien, Chen, Zhengming, Flowers, Sarah A., Gerber, Linda M., Grandville, Thomas, Schupf, Nicole, Xu, Hui, Stern, Yaakov, Habeck, Christian, Jordan, Barry, Fonzetti, Pasquale, Flowers, Sarah, and Gerber, Linda
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ALZHEIMER'S disease ,ADVANCED glycation end-products ,AMNESTIC mild cognitive impairment ,POSITRON emission tomography ,CLINICAL trials ,BRAIN ,DISEASE progression ,ETHYLENE glycols ,AMINES ,TREATMENT effectiveness ,COMPARATIVE studies ,RANDOMIZED controlled trials ,RADIOPHARMACEUTICALS ,APOLIPOPROTEINS ,RESEARCH funding ,VITAMIN B1 ,DEOXY sugars ,STATISTICAL sampling - Abstract
Background: In preclinical models, benfotiamine efficiently ameliorates the clinical and biological pathologies that define Alzheimer's disease (AD) including impaired cognition, amyloid-β plaques, neurofibrillary tangles, diminished glucose metabolism, oxidative stress, increased advanced glycation end products (AGE), and inflammation.Objective: To collect preliminary data on feasibility, safety, and efficacy in individuals with amnestic mild cognitive impairment (aMCI) or mild dementia due to AD in a placebo-controlled trial of benfotiamine.Methods: A twelve-month treatment with benfotiamine tested whether clinical decline would be delayed in the benfotiamine group compared to the placebo group. The primary clinical outcome was the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Secondary outcomes were the clinical dementia rating (CDR) score and fluorodeoxyglucose (FDG) uptake, measured with brain positron emission tomography (PET). Blood AGE were examined as an exploratory outcome.Results: Participants were treated with benfotiamine (34) or placebo (36). Benfotiamine treatment was safe. The increase in ADAS-Cog was 43% lower in the benfotiamine group than in the placebo group, indicating less cognitive decline, and this effect was nearly statistically significant (p = 0.125). Worsening in CDR was 77% lower (p = 0.034) in the benfotiamine group compared to the placebo group, and this effect was stronger in the APOEɛ4 non-carriers. Benfotiamine significantly reduced increases in AGE (p = 0.044), and this effect was stronger in the APOEɛ4 non-carriers. Exploratory analysis derivation of an FDG PET pattern score showed a treatment effect at one year (p = 0.002).Conclusion: Oral benfotiamine is safe and potentially efficacious in improving cognitive outcomes among persons with MCI and mild AD. [ABSTRACT FROM AUTHOR]- Published
- 2020
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