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Authors: Spencer, Barbara E. | Jennings, Robin G. | Brewer, James B. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Biomarkers may soon be used to predict decline in older individuals. Extended follow-up studies are needed to determine the stability of such biomarker-based predictions. Objective: To examine the long-term performance of baseline cognitive, neuroimaging, and cerebrospinal fluid (CSF) biomarker-assisted prognoses in patients with mild cognitive impairment. Methods: Established, biomarker-defined cohorts of subjects with mild cognitive impairment were examined for progression to dementia. Subjects with a baseline volumetric magnetic resonance imaging, lumbar puncture, and Rey Auditory Verbal Learning Test were included. Dementia-free survival time in each biomarker-defined risk group was determined with Kaplan-Meier survival curves. The influence of each risk …factor or combination of factors on dementia-free survival was examined with Cox proportional hazard analyses. Results: 185 subjects were followed longitudinally for a mean (SD) 4.3 (2.8) years. 59% of participants converted within the follow-up period and the median dementia-free survival time was 2.8 years. Each individual risk factor predicted conversion to dementia (HR 1.9–3.7). The joint presence of any two risk factors increased risk for conversion (HR 7.1–11.0), with the presence of medial temporal atrophy and memory impairment showing the greatest risk for decline. Concordant atrophy, memory impairment, and abnormal CSF amyloid and tau was associated with the highest risk for conversion (HR 15.1). The presence of medial temporal atrophy was associated with the shortest dementia-free survival time, both alone and in combination with memory impairment, abnormal CSF amyloid and tau, or both. Conclusion: These results suggest that baseline biomarker-assisted predictions of decline to dementia are stable over the long term, and that combinations of complementary biomarkers can improve the accuracy of these predictions. Show more

Keywords: Biomarkers, cerebrospinal fluid, dementia, magnetic resonance imaging, mild cognitive impairment, prognosis, rey auditory verbal learning test

DOI: 10.3233/JAD-181243

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1549-1559, 2019

Authors: Fleisher, Adam S. | Donohue, Michael | Chen, Kewei | Brewer, James B. | Aisen, Paul S. | the Alzheimer's Disease Neuroimaging Initiative,

Article Type: Research Article

Abstract: Critical to development of new therapies for Alzheimer's disease (AD) is the ability to detect clinical or pathological change over time. Clinical outcome measures typically used in therapeutic trials have unfortunately proven to be relatively variable and somewhat insensitive to change in this slowly progressive disease. For this reason, development of surrogate biomarkers that identify significant disease-associated brain changes are necessary to expedite treatment development in AD. Since AD pathology is present in the brain many years prior to clinical manifestation, ideally we want to develop biomarkers of disease that identify abnormal brain structure or function even prior to cognitive …decline. Magnetic resonance imaging, fluorodeoxyglucose positron emission tomography, new amyloid imaging techniques, and spinal fluid markers of AD all have great potential to provide surrogate endpoint measures for AD pathology. The Alzheimer's disease neuroimaging initiative (ADNI) was developed for the distinct purpose of evaluating surrogate biomarkers for drug development in AD. Recent evidence from ADNI demonstrates that imaging may provide more sensitive, and earlier, measures of disease progression than traditional clinical measures for powering clinical drug trials in Alzheimer's disease. This review discusses recently presented data from the ADNI dataset, and the importance of imaging in the future of drug development in AD. Show more

DOI: 10.3233/BEN-2009-0241

Citation: Behavioural Neurology, vol. 21, no. 1-2, pp. 129-136, 2009

Authors: Andrews, Murray | Ross, Ryan | Malhotra, Atul | Ancoli-Israel, Sonia | Brewer, James B. | Banks, Sarah J. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The increasing prevalence of Alzheimer’s disease (AD) and lack of effective medications has led to a need to identify modifiable risk factors as targets for interventions. Objective: In this cross-sectional study, we sought to determine whether worse sleep quality is associated with increased pathological tau, and whether this relationship is affected by amyloid pathology. Methods: 66 male participants underwent Florbetapir (AV45) positron emission tomography (PET) and Flortaucipir (FTP) PET and completed the Pittsburgh Sleep Quality Index questionnaire (PSQI) as part of the Department of Defense Alzheimer’s Disease Neuroimaging Initiative, a multicenter study collecting data from Vietnam War veterans, some …of whom have a history of post-traumatic stress disorder, or non-penetrating traumatic brain injury. AV45 PET was used to determine the presence of significant amyloid pathology. We used regression models to determine the effects of amyloid pathology and PSQI on tau deposition in brain regions associated with Braak stages. Results: Among the 66 participants, 14 individuals were amyloid positive (21%) and 52 were amyloid negative (79%). In regions associated with Braak stages III-IV, there was a significant interaction of amyloid status on PSQI (β= 0.04, p  = 0.003) with higher PSQI correlating with higher FTP SUVr in amyloid-positive individuals only (β= 0.031, p  = 0.005). Conclusion: Our study found that an AD profile of tau deposition was associated with an interaction between self-reported sleep quality and amyloid pathology such that worse self-reported sleep was related to higher tau in regions usually associated with AD progression, but only in individuals with high cerebral amyloid deposition. Show more

Keywords: Amyloid, mild cognitive impairment, positron emission tomography, preclinical AD, sleep, tau

DOI: 10.3233/ADR-200245

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 41-48, 2021

Authors: Soria, Jose A. | Huisa, Branko N. | Edland, Steven D. | Litvan, Irene | Peavy, Guerry M. | Salmon, David P. | Hansen, Lawrence A. | Galasko, Douglas R. | Brewer, James B. | González, Hector M. | Rissman, Robert A.

Article Type: Research Article

Abstract: Clinical, neuropsychological, and neurological procedures used to diagnose Alzheimer’s disease (AD) and related dementias were largely developed and validated in well-educated, non-Latino, English-speaking populations. Sociocultural and genetic differences in Latinos might influence the accuracy of clinical diagnosis of AD and other dementias. We aim to compare the accuracy of the clinical diagnosis of AD and related dementias in Latinos with the corresponding neuropathological diagnosis. From the UCSD Alzheimer’s Disease Research Center longitudinal cohort, we selected all Latino participants who had autopsy neuropathological studies from 1991 to 2017. Participants underwent annual neurological clinical evaluations, standard neuropsychological tests, neuroimaging, and genotyping of …Apolipoprotein E. We calculated the sensitivity and specificity of the clinical diagnosis of AD against the primary pathological diagnosis. Of the 34 participants with a primary neuropathological diagnosis of AD, 33 (97.1%) were correctly clinically diagnosed as having AD at the last clinical evaluation, and 1 was incorrectly diagnosed with dementia with Lewy bodies. Of the 19 participants without a primary neuropathological diagnosis of AD, 8 were incorrectly clinically diagnosed with probable AD at the last clinic evaluation. The clinical diagnosis of AD at the last clinical evaluation had 97.1% sensitivity and 57.9% specificity for autopsy-verified AD. In this Latino cohort, clinicians predicted AD pathological findings with high sensitivity but moderate specificity. Tangle-only dementia was the most common misdiagnosis. Our study suggests that current procedures and instruments to clinically determine AD in Latinos have high sensitivity compared with neuropathology, but specificity needs to be improved. Show more

Keywords: Alzheimer’s disease, dementia, Latino, Lewy bodies, neuropathology

DOI: 10.3233/JAD-180789

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1539-1548, 2018

Authors: Reas, Emilie T. | Hagler Jr. , Donald J. | Kuperman, Joshua M. | Wierenga, Christina E. | Galasko, Douglas | White, Nathan S. | Dale, Anders M. | Banks, Sarah J. | McEvoy, Linda K. | Brewer, James B.

Article Type: Research Article

Abstract: Background: Although amyloid-β (Aβ) and microstructural brain changes are both effective biomarkers of Alzheimer’s disease, their independent or synergistic effects on cognitive decline are unclear. Objective: To examine associations of Aβ and brain microstructure with cognitive decline in amnestic mild cognitive impairment and dementia. Methods: Restriction spectrum imaging, cerebrospinal fluid Aβ, and longitudinal cognitive data were collected on 23 healthy controls and 13 individuals with mild cognitive impairment or mild to moderate Alzheimer’s disease. Neurite density (ND) and isotropic free water diffusion (IF) were computed in fiber tracts and cortical regions of interest. We examined associations of Aβ with regional …and whole-brain microstructure, and assessed whether microstructure mediates effects of Aβ on cognitive decline. Results: Lower ND in limbic and association fibers and higher medial temporal lobe IF predicted baseline impairment and longitudinal decline across multiple cognitive domains. ND and IF predicted cognitive outcomes after adjustment for Aβ or whole-brain microstructure. Correlations between microstructure and cognition were present for both amyloid-positive and amyloid-negative individuals. Aβ correlated with whole-brain, rather than regional, ND and IF. Conclusion: Aβ correlates with widespread microstructural brain changes, whereas regional microstructure correlates with cognitive decline. Microstructural abnormalities predict cognitive decline regardless of amyloid, and may inform about neural injury leading to cognitive decline beyond that attributable to amyloid. Show more

Keywords: Aging, Alzheimer’s disease, amyloid, cognitive decline, dementia, diffusion imaging, magnetic resonance imaging, memory, mild cognitive impairment

DOI: 10.3233/JAD-190871

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 347-357, 2020

Authors: Rafii, Michael S. | Lukic, Ana S. | Andrews, Randolph D. | Brewer, James | Rissman, Robert A. | Strother, Stephen C. | Wernick, Miles N. | Pennington, Craig | Mobley, William C. | Ness, Seth | Matthews, Dawn C. | for the Down Syndrome Biomarker Initiative and the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Adults with Down syndrome (DS) represent an enriched population for the development of Alzheimer’s disease (AD), which could aid the study of therapeutic interventions, and in turn, could benefit from discoveries made in other AD populations. Objectives: 1) Understand the relationship between tau pathology and age, amyloid deposition, neurodegeneration (MRI and FDG PET), and cognitive and functional performance; 2) detect and differentiate AD-specific changes from DS-specific brain changes in longitudinal MRI. Methods: Twelve non-demented adults, ages 30 to 60, with DS were enrolled in the Down Syndrome Biomarker Initiative (DSBI), a 3-year, observational, cohort study to demonstrate the feasibility …of conducting AD intervention/prevention trials in adults with DS. We collected imaging data with 18 F-AV-1451 tau PET, AV-45 amyloid PET, FDG PET, and volumetric MRI, as well as cognitive and functional measures and additional laboratory measures. Results: All amyloid negative subjects imaged were tau-negative. Among the amyloid positive subjects, three had tau in regions associated with Braak stage VI, two at stage V, and one at stage II. Amyloid and tau burden correlated with age. The MRI analysis produced two distinct volumetric patterns. The first differentiated DS from normal (NL) and AD, did not correlate with age or amyloid, and was longitudinally stable. The second pattern reflected AD-like atrophy and differentiated NL from AD. Tau PET and MRI atrophy correlated with several cognitive and functional measures. Conclusions: Tau accumulation is associated with amyloid positivity and age, as well as with progressive neurodegeneration measurable using FDG and MRI. Tau correlates with cognitive decline, as do AD-specific hypometabolism and atrophy. Show more

Keywords: Alzheimer’s disease, biomarkers, dementia, Down syndrome, Tau PET, volumetric MRI

DOI: 10.3233/JAD-170390

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 439-450, 2017