Your search for: 'author:("Hyman, Bradley T.")' has returned 13 results. (0.023s) Save search

Authors: Skoch, Jesse | Hyman, Bradley T. | Bacskai, Brian J.

Article Type: Research Article

Abstract: Multiphoton microscopy is an optical imaging technique that allows high resolution detection of fluorescence in thick, scattering tissues. The technique has been used for trans-cranial imaging of the brains of living transgenic mouse models of Alzheimer's disease. Direct detection of senile plaques in these mice has allowed the characterization of the natural history of individual senile plaques, the evaluation of plaque clearance during immunotherapy, and the characterization of the kinetics and biodistribution of the PET ligand, PIB. With the expanding repertoire of structural and functional fluorescent probes, and the preclinical characterization of new contrast agents for complementary imaging modalities like …MRI, PET, SPECT, and NIRS, multiphoton microscopy will continue to be a powerful tool in understanding and combating Alzheimer's disease. Show more

DOI: 10.3233/JAD-2006-9S345

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 401-407, 2006

Authors: Macklin, Eric A. | Blacker, Deborah | Hyman, Bradley T. | Betensky, Rebecca A.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) trials initiated during or before the prodrome are costly and lengthy because patients are enrolled long before clinical symptoms are apparent, when disease progression is slow. We hypothesized that design of such trials could be improved by: 1) selecting individuals at moderate near-term risk of progression to AD dementia (the current clinical standard) and 2) by using short-term surrogate endpoints that predict progression to AD dementia. We used a longitudinal cohort of older, initially non-demented, community-dwelling participants (n = 358) to derive selection criteria and surrogate endpoints and tested them in an independent national data set (n …= 6,243). To identify a “mid-risk” subgroup, we applied conditional tree-based survival models to Clinical Dementia Rating (CDR) scale scores and common neuropsychological tests. In the validation cohort, a time-to-AD dementia trial applying these mid-risk selection criteria to a pool of all non-demented individuals could achieve equivalent power with 47% fewer participants than enrolling at random from that pool. We evaluated surrogate endpoints measureable over two years of follow-up based on cross-validated concordance between predictions from Cox models and observed time to AD dementia. The best performing surrogate, rate of change in CDR sum-of-boxes, did not reduce the trial duration required for equivalent power using estimates from the validation cohort, but alternative surrogates with better ability to predict time to AD dementia should be able to do so. The approach tested here might improve efficiency of prodromal AD trials using other potential measures and could be generalized to other diseases with long prodromal phases. Show more

Keywords: Alzheimer's disease, clinical trials as topic, National Alzheimer's Coordinating Center Uniform Data Set, surrogate endpoint, survival analysis

DOI: 10.3233/JAD-122212

Citation: Journal of Alzheimer's Disease, vol. 36, no. 3, pp. 475-486, 2013

Authors: Saidi, Laiq-Jan | Polydoro, Manuela | Kay, Kevin R. | Sanchez, Laura | Mandelkow, Eva-Maria | Hyman, Bradley T. | Spires-Jones, Tara L.

Article Type: Research Article

Abstract: One of the hallmarks of Alzheimer's disease is the formation of neurofibrillary tangles, intracellular aggregates of hyperphosphorylated, mislocalized tau protein, which are associated with neuronal loss. Changes in tau are known to impair cellular transport (including that of mitochondria) and are associated with cell death in cell culture and mouse models of tauopathy. Thus clearing pathological forms of tau from cells is a key therapeutic strategy. One critical modulator in the degradation and clearance of misfolded proteins is the co-chaperone CHIP (Carboxy terminus Hsp70 interacting Protein), which is known to play a role in refolding and clearance of hyperphosphorylated tau. …Here, we tested the hypothesis that CHIP could ameliorate pathological changes associated with tau. We find that co-expressing CHIP with full-length tau, tau truncated at D421 mimicking caspase cleavage, or the short tauRD ΔK280 tau construct containing only the tau repeat domain with a tauopathy mutation, decreases tau protein levels in human H4 neuroglioma cells in a manner dependent on the Hsp70-binding TPR domain of CHIP. The observed reduction in tau levels by CHIP is associated with a decrease of tau phosphorylation and reduced levels of cleaved Caspase 3 indicating that CHIP plays an important role in preventing tau-induced pathological changes. Furthermore, tau-associated mitochondrial transport deficits are rescued by CHIP co-expression in H4 cells. Together, these data suggest that the co-chaperone CHIP can rescue the pathological effects of tau, and indicate that other diseases of protein misfolding and accumulation may also benefit from CHIP upregulation. Show more

Keywords: Alzheimer's disease, caspase, CHIP, mitochondrial transport, tau protein

DOI: 10.3233/JAD-142094

Citation: Journal of Alzheimer's Disease, vol. 44, no. 3, pp. 937-947, 2015

Authors: Noori, Ayush | Jayakumar, Rojashree | Moturi, Vaishnavi | Li, Zhaozhi | Liu, Rongxin | Serrano-Pozo, Alberto | Hyman, Bradley T. | Das, Sudeshna

Article Type: Research Article

Abstract: Background: Recent Alzheimer’s disease (AD) discoveries are increasingly based on studies from a variety of omics technologies on large cohorts. Currently, there is no easily accessible resource for neuroscientists to browse, query, and visualize these complex datasets in a harmonized manner. Objective: Create an online portal of public omics datasets for AD research. Methods: We developed Alzheimer DataLENS, a web-based portal, using the R Shiny platform to query and visualize publicly available transcriptomics and genetics studies of AD on human cohorts. To ensure consistent representation of AD findings, all datasets were processed through a uniform bioinformatics pipeline. Results: Alzheimer DataLENS …currently houses 2 single-nucleus RNA sequencing datasets, over 30 bulk RNA sequencing datasets from 19 brain regions and 3 cohorts, and 2 genome-wide association studies (GWAS). Available visualizations for single-nucleus data include bubble plots, heatmaps, and UMAP plots; for bulk expression data include box plots and heatmaps; for pathways include protein-protein interaction network plots; and for GWAS results include Manhattan plots. Alzheimer DataLENS also links to two other knowledge resources: the AD Progression Atlas and the Astrocyte Atlas. Conclusions: Alzheimer DataLENS is a valuable resource for investigators to quickly and systematically explore omics datasets and is freely accessible at https://alzdatalens.partners.org . Show more

Keywords: Alzheimer’s disease, database, genetics, multiomics, single-cell RNA-seq, transcriptomics

DOI: 10.3233/JAD-230884

Citation: Journal of Alzheimer's Disease, vol. 99, no. s2, pp. S397-S407, 2024

Authors: Mezlini, Aziz M. | Magdamo, Colin | Merrill, Emily | Chibnik, Lori B. | Blacker, Deborah L. | Hyman, Bradley T. | Das, Sudeshna

Article Type: Research Article

Abstract: Background: The APOE ɛ 4 allele is the largest genetic risk factor for late-onset Alzheimer’s disease (AD). Recent literature suggested that the contribution of APOE ɛ 4 to AD risk could be population-specific, with ɛ 4 conferring a lower risk to Blacks or African Americans. Objective: To investigate the effect of APOE haplotypes on AD risk in individuals with European ancestry (EU) and Blacks or African Americans (AA). Methods: We selected data from 1) the National Alzheimer’s Coordinating Center: a total of 3,486 AD cases and 4,511 controls (N = 7,997, 60% female) with genotypes from the Alzheimer’s Disease Genetics Consortium (ADGC), …and 2) the Rush University Religious Orders Study and Memory and Aging Project (ROSMAP) cohort with 578 AD and 670 controls (N = 1,248, 60% female). Using ɛ 3 homozygotes as the reference, we compared the association of various APOE haplotypes with the clinical and neuropathological correlates of dementia in AA and EU. Results: In both cohorts, we find no difference in the odds or age of onset of AD among the ɛ 4-linked haplotypes defined by rs769449 within either AA or EU. Additionally, while APOE ɛ 4 was associated with a faster rate of decline, no differences were found in rate of decline, clinical or neuropathological features among the ɛ 4-linked haplotypes. Further analysis with other variants near the APOE locus failed to identify any effect modification. Conclusion: Our study finds similar effects of the ɛ 4-linked haplotypes defined by rs769449 on AD as compared to ɛ 3 in both AA and EU. Future studies are required to understand the heterogeneity of APOE conferred risk of AD among various genotypes and populations. Show more

Keywords: African Americans, APOE, clinicopathological features, Europeans, genotype

DOI: 10.3233/JAD-200228

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 467-477, 2020

Authors: Etiene, Dannie | Kraft, Joanny | Ganju, Neema | Gomez-Isla, Teresa | Gemelli, Brad | Hyman, Bradley T. | Hedley-Whyte, E. Tessa | Wands, Jack R. | de la Monte, Suzanne M.

Article Type: Research Article

Abstract: Heterogeneous pathology in Alzheimer's Disease (AD) is due to variability in the nature and severity of lesions, overlap with other neurodegenerative diseases such as Parkinson's disease, or the co-existence of cerebrovascular disease. In the MGH-ADRC autopsy archives, remote cerebral infarcts (CVA) were reported in 30% of the otherwise uncomplicated AD cases. To determine the potential significance of cerebrovascular lesions in relation to AD, the relative densities (CERAD grading criteria) of Bielschowsky-stained AD lesions and Ab-amyloid immunoreactive plaques were compared among cases of AD+CVA (N = 52), AD (N = 48), aged controls (NC; N = 9), and aged controls with AD lesions (ADC; N = 8). The prevalence …of the ApoE e4 allele was also determined for each group. This study demonstrated: 1) higher densities of Bielschowsky-stained plaques in AD, AD+CVA, and ADC than in NC (P < 0.0001); 2) more abundant neurofibrillary tangles in AD relative to all other groups (P < 0.0005), and in AD+CVA and ADC relative to NC (P < 0.05); and 3) increased densities of Aβ-amyloid-immunoreactive plaques in AD relative to AD+CVA (P = 0.0003). In AD+CVA, cerebral vascular lesions consisting of remote microscopic cortical and subcortical white matter infarcts, ischemic lesions, and leukoaraiosis were consistently distributed in structures typically damaged by AD neurodegeneration, as well as in the basal ganglia. The ApoE ε4 allele was more prevalent in the AD+CVA (70%) than in the AD (58%) group (P = 0.05). Since the AD and AD+CVA groups had similar degrees of dementia, the results suggest that cerebral vascular lesions in regions typically destroyed by AD may contribute to the clinical manifestations of AD. Show more

Keywords: Alzheimer's disease, cerebral infarction, multi-infarct dementia, Aβ-amyloid, Apolipoprotein E

DOI: 10.3233/JAD-1998-1205

Citation: Journal of Alzheimer's Disease, vol. 1, no. 2, pp. 119-134, 1998

Authors: Marshall, Gad A. | Lorius, Natacha | Locascio, Joseph J. | Hyman, Bradley T. | Rentz, Dorene M. | Johnson, Keith A. | Sperling, Reisa A. | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Impairment in instrumental activities of daily living (IADL) heralds the transition from mild cognitive impairment (MCI) to dementia and is a major source of burden for both the patient and caregiver. Objective: To investigate the relationship between IADL and regional cortical thinning and cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers cross-sectionally and longitudinally in clinically normal (CN) elderly, MCI, and mild AD dementia subjects. Methods: Two hundred and twenty nine CN, 395 MCI, and 188 AD dementia subjects participating in the Alzheimer’s Disease Neuroimaging Initiative underwent baseline magnetic resonance imaging, baseline lumbar puncture, and clinical assessments, including the Functional …Activities Questionnaire used to measure IADL, every 6 to 12 months up to 3 years. General linear regression and mixed effects models were employed. Results: IADL impairment was associated with the interactions between lower inferior temporal cortical thickness and diagnosis (p < 0.0001), greater lateral occipital cortical thickness and diagnosis (p < 0.0001), and greater amyloid-β 1-42 (Aβ1-42 ) and diagnosis (p = 0.0002) at baseline (driven by AD dementia). Lower baseline supramarginal (p = 0.02) and inferior temporal (p = 0.05) cortical thickness, lower Aβ1-42 (p < 0.0001), and greater total tau (t-tau) (p = 0.02) were associated with greater rate of IADL impairment over time. Conclusions: Temporal atrophy is associated with IADL impairment in mild AD dementia at baseline, while baseline parietal and temporal atrophy, lower CSF Aβ1-42 , and greater t-tau predict worsening IADL impairment over time across the AD spectrum. These results emphasize the importance of assessing IADL at the stage of MCI and even at the transition from CN to MCI. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, instrumental activities of daily living, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-132768

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 719-728, 2014

Authors: Okereke, Olivia I. | Xia, Weiming | Irizarry, Michael C. | Sun, Xiaoyan | Qiu, Wei Q. | Fagan, Anne M. | Mehta, Pankaj D. | Hyman, Bradley T. | Selkoe, Dennis J. | Grodstein, Francine

Article Type: Research Article

Abstract: Identifying biomarkers of Alzheimer's disease (AD) risk will be critical to effective AD prevention. Levels of circulating amyloid-β (Aβ) 40 and 42 may be candidate biomarkers. However, properties of plasma Aβ assays must be established. Using five different protocols, blinded samples were used to assess: intra-assay reproducibility; impact of EDTA vs. heparin anticoagulant tubes; and effect of time-to-blood processing. In addition, percent recovery of known Aβ concentrations in spiked samples was assessed. Median intra-assay coefficients of variation for the assay protocols ranged from 6–24% for Aβ40 , and 8–14% for Aβ42 . There were no systematic differences in reproducibility by …collection method. Plasma concentrations of Aβ (particularly Aβ42 ) appeared stable in whole blood kept in ice packs and processed as long as 24 hours after collection. Recovery of expected concentrations was modest, ranging from −24% to 44% recovery of Aβ40 , and 17% to 61% of Aβ42 . In conclusion, across five protocols, plasma Aβ40 and Aβ42 levels were measured with generally low error, and measurements appeared similar in blood collected in EDTA versus heparin. While these preliminary findings suggest that measuring plasma Aβ40 and Aβ42 may be feasible in varied research settings, additional work in this area is necessary. Show more

Keywords: Alzheimer's disease, amyloid, assay reliability, biomarker, quality control

DOI: 10.3233/JAD-2009-0948

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 277-285, 2009

Authors: Ren, Yan | Lin, Wen-Lang | Sanchez, Laura | Ceballos, Carolina | Polydoro, Manuela | Spires-Jones, Tara L. | Hyman, Bradley T. | Dickson, Dennis W. | Sahara, Naruhiko

Article Type: Research Article

Abstract: Tau belongs to the microtubule-associated family of proteins that maintain cytoskeletal structure by regulating microtubule dynamics. In certain neurodegenerative diseases termed tauopathies, tau is abnormally phosphorylated and accumulates as filamentous inclusions. Transgenic mouse models that overexpress human tau have been widely used to investigate tau pathogenesis. Although many studies have attempted to elucidate the pathological function of transgenic human tau, it remains unknown whether endogenous mouse tau is involved in disease progression. Here we generated an mTau antibody that selectively recognizes mouse and rat tau, but not human tau. In rTg4510 tau transgenic mice, we identified a higher molecular weight …mouse tau (~60-kDa) in sarkosyl-insoluble fractions. mTau antibody started to recognize intracellular aggregates and thread-like structures in 4- to 6-month-old rTg4510 mice. Tau inclusions appeared earlier, being detected in 2.5-month-old rTg4510 mice with MC1 antibody. Immunoelectron microscopy confirmed the presence of filamentous aggregates of mouse tau, which were abundant in oligodendrocytes but rare in neurons. Mouse tau inclusions in oligodendrocytes were confirmed by double-labeling with an oligodendrocyte marker. Our data indicate that mouse tau has potential aggregation properties in neurons and non-neurons. The mTau antibody will be useful for investigating the role of mouse tau in mouse models of tauopathy. Show more

Keywords: Antibody, mouse tau, oligodendrocytes, tau protein, tauopathy, transgenic mice

DOI: 10.3233/JAD-130986

Citation: Journal of Alzheimer's Disease, vol. 38, no. 3, pp. 589-600, 2014

Authors: Bakshi, Rachit | Macklin, Eric A. | Hung, Albert Y. | Hayes, Michael T. | Hyman, Bradley T. | Wills, Anne-Marie | Gomperts, Stephen N. | Growdon, John H. | Ascherio, Alberto | Scherzer, Clemens R. | Schwarzschild, Michael A.

Article Type: Short Communication

Abstract: Two purines, caffeine and urate, have been associated with a reduced risk of idiopathic Parkinson’s disease (PD) in multiple cohorts and populations. The Harvard Biomarkers Study (HBS) is a longitudinal study designed to accelerate the discovery and validation of molecular diagnostic and progression markers of early-stage PD. To investigate whether these ‘reduced risk’ factors are associated with PD within this cohort, we conducted a cross-sectional, case-control study in 566 subjects consisting of idiopathic PD patients and healthy controls. Caffeine intake as assessed by a validated questionnaire was significantly lower in idiopathic PD patients compared to healthy controls in males (mean …difference –125 mg/day, p  < 0.001) but not in females (mean difference –30 mg/day, p  = 0.29). A strong inverse association was also observed with plasma urate levels both in males (mean difference –0.46 mg/dL, p  = 0.017) and females (mean difference –0.45 mg/dL, p  = 0.001). Both analyses stratified for sex and adjusted for age, body mass index, and either urate level or caffeine consumption, respectively. These results highlight the robustness of caffeine intake and urate as factors inversely associated with idiopathic PD. Show more

Keywords: Caffeine, uric acid, biomarker, Parkinson’s disease

DOI: 10.3233/JPD-191882

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 505-510, 2020