Faculty Bibliography
Searched for:
in-biosketch:true
person:sadowm01
Total Results:
160
New Perspective for Non-invasive Brain Stimulation Site Selection in Mild Cognitive Impairment: Based on Meta- and Functional Connectivity Analyses
BACKGROUND:Non-invasive brain stimulation (NIBS) has been widely used to treat mild cognitive impairment (MCI). However, there exists no consensus on the best stimulation sites. OBJECTIVE:To explore potential stimulation locations for NIBS treatment in patients with MCI, combining meta- and resting state functional connectivity (rsFC) analyses. METHODS:The meta-analysis was conducted to identify brain regions associated with MCI. Regions of interest (ROIs) were extracted based on this meta-analysis. The rsFC analysis was applied to 45 MCI patients to determine brain surface regions that are functionally connected with the above ROIs. RESULTS:We found that the dorsolateral prefrontal cortex (DLPFC) and inferior frontal gyrus (IFG) were the overlapping brain regions between our results and those of previous studies. In addition, we recommend that the temporoparietal junction (including the angular gyrus), which was found in both the meta- and rsFC analysis, should be considered in NIBS treatment of MCI. Furthermore, the bilateral orbital prefrontal gyrus, inferior temporal gyrus, medial superior frontal gyrus, and right inferior occipital gyrus may be potential brain stimulation sites for NIBS treatment of MCI. CONCLUSION/CONCLUSIONS:Our results provide several potential sites for NIBS, such as the DLFPC and IFG, and may shed light on the locations of NIBS sites in the treatment of patients with MCI.
PMCID:6736566
PMID: 31551754
ISSN: 1663-4365
CID: 5864662
18F-florbetapir Positron Emission Tomography-determined Cerebral beta-Amyloid Deposition and Neurocognitive Performance after Cardiac Surgery
BACKGROUND:Amyloid deposition is a potential contributor to postoperative cognitive dysfunction. The authors hypothesized that 6-week global cortical amyloid burden, determined by F-florbetapir positron emission tomography, would be greater in those patients manifesting cognitive dysfunction at 6 weeks postoperatively. METHODS:Amyloid deposition was evaluated in cardiac surgical patients at 6 weeks (n = 40) and 1 yr (n = 12); neurocognitive function was assessed at baseline (n = 40), 6 weeks (n = 37), 1 yr (n = 13), and 3 yr (n = 9). The association of 6-week amyloid deposition with cognitive dysfunction was assessed by multivariable regression, accounting for age, years of education, and baseline cognition. Differences between the surgical cohort with cognitive deficit and the Alzheimer's Disease Neuroimaging Initiative cohorts (normal and early/late mild cognitive impairment) was assessed, adjusting for age, education, and apolipoprotein E4 genotype. RESULTS:The authors found that 6-week abnormal global cortical amyloid deposition was not associated with cognitive dysfunction (13 of 37, 35%) at 6 weeks postoperatively (median standard uptake value ratio [interquartile range]: cognitive dysfunction 0.92 [0.89 to 1.07] vs. 0.98 [0.93 to 1.05]; P = 0.455). In post hoc analyses, global cortical amyloid was also not associated with cognitive dysfunction at 1 or 3 yr postoperatively. Amyloid deposition at 6 weeks in the surgical cohort was not different from that in normal Alzheimer's Disease Neuroimaging Initiative subjects, but increased over 1 yr in many areas at a rate greater than in controls. CONCLUSIONS:In this study, postoperative cognitive dysfunction was not associated with 6-week cortical amyloid deposition. The relationship between cognitive dysfunction and regional amyloid burden and the rate of postoperative amyloid deposition merit further investigation.
PMCID:5849499
PMID: 29389750
ISSN: 1528-1175
CID: 2994312
Biomarker pattern of ARIA-E participants in phase 3 randomized clinical trials with bapineuzumab
OBJECTIVE:To evaluate whether amyloid-related imaging abnormalities with edema/effusion (ARIA-E) observed in bapineuzumab clinical trials was associated with specific biomarker patterns. METHODS:Bapineuzumab, an anti-β-amyloid monoclonal antibody, was evaluated in patients with mild to moderate Alzheimer disease. Amyloid PET imaging, CSF biomarkers, or volumetric MRI (vMRI) were assessed. RESULTS:. CONCLUSIONS:Baseline biomarkers largely do not predict risk for developing ARIA-E. ARIA-E was associated with significant longitudinal changes in several biomarkers, with larger reductions in amyloid PET and CSF p-tau and t-tau concentrations, and paradoxically greater hippocampal volume reduction and ventricular enlargement, suggesting that ARIA-E in bapineuzumab-treated cases may be related to increased Aβ efflux from the brain and affecting downstream pathogenic processes.
PMID: 29429971
ISSN: 1526-632x
CID: 3256922
Proceedings of the National Academy of Sciences of the United States of America (PNAS). 2018:115(8):1697-1706.DOI: 10.1073/pnas.1715554115
Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer's disease pathogenesis
Alzheimer's disease (AD) is a leading cause of mortality among the elderly. We performed a whole-genome sequencing study of AD in the Chinese population. In addition to the variants identified in or around the APOE locus (sentinel variant rs73052335, P = 1.44 × 10-14), two common variants, GCH1 (rs72713460, P = 4.36 × 10-5) and KCNJ15 (rs928771, P = 3.60 × 10-6), were identified and further verified for their possible risk effects for AD in three small non-Asian AD cohorts. Genotype-phenotype analysis showed that KCNJ15 variant rs928771 affects the onset age of AD, with earlier disease onset in minor allele carriers. In addition, altered expression level of the KCNJ15 transcript can be observed in the blood of AD subjects. Moreover, the risk variants of GCH1 and KCNJ15 are associated with changes in their transcript levels in specific tissues, as well as changes of plasma biomarkers levels in AD subjects. Importantly, network analysis of hippocampus and blood transcriptome datasets suggests that the risk variants in the APOE, GCH1, and KCNJ15 loci might exert their functions through their regulatory effects on immune-related pathways. Taking these data together, we identified common variants of GCH1 and KCNJ15 in the Chinese population that contribute to AD risk. These variants may exert their functional effects through the immune system.
PMID: 29432188
ISSN: 1091-6490
CID: 5864612
Proceedings of the National Academy of Sciences of the United States of America (PNAS). 2018:115(7):1481-1486.DOI: 10.1073/pnas.1719747115
Statistical tests and identifiability conditions for pooling and analyzing multisite datasets
When sample sizes are small, the ability to identify weak (but scientifically interesting) associations between a set of predictors and a response may be enhanced by pooling existing datasets. However, variations in acquisition methods and the distribution of participants or observations between datasets, especially due to the distributional shifts in some predictors, may obfuscate real effects when datasets are combined. We present a rigorous statistical treatment of this problem and identify conditions where we can correct the distributional shift. We also provide an algorithm for the situation where the correction is identifiable. We analyze various properties of the framework for testing model fit, constructing confidence intervals, and evaluating consistency characteristics. Our technical development is motivated by Alzheimer's disease (AD) studies, and we present empirical results showing that our framework enables harmonizing of protein biomarkers, even when the assays across sites differ. Our contribution may, in part, mitigate a bottleneck that researchers face in clinical research when pooling smaller sized datasets and may offer benefits when the subjects of interest are difficult to recruit or when resources prohibit large single-site studies.
PMCID:5816202
PMID: 29386387
ISSN: 1091-6490
CID: 3257392
Dual-Model Radiomic Biomarkers Predict Development of Mild Cognitive Impairment Progression to Alzheimer's Disease
Predicting progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD) is clinically important. In this study, we propose a dual-model radiomic analysis with multivariate Cox proportional hazards regression models to investigate promising risk factors associated with MCI conversion to AD. T1 structural magnetic resonance imaging (MRI) and 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) data, from the AD Neuroimaging Initiative database, were collected from 131 patients with MCI who converted to AD within 3 years and 132 patients with MCI without conversion within 3 years. These subjects were randomly partition into 70% training dataset and 30% test dataset with multiple times. We fused MRI and PET images by wavelet method. In a subset of subjects, a group comparison was performed using a two-sample t-test to determine regions of interest (ROIs) associated with MCI conversion. 172 radiomic features from ROIs for each individual were established using a published radiomics tool. Finally, L1-penalized Cox model was constructed and Harrell's C index (C-index) was used to evaluate prediction accuracy of the model. To evaluate the efficacy of our proposed method, we used a same analysis framework to evaluate MRI and PET data separately. We constructed prognostic Cox models with: clinical data, MRI images, PET images, fused MRI/PET images, and clinical variables and fused MRI/PET images in combination. The experimental results showed that captured ROIs significantly associated with conversion to AD, such as gray matter atrophy in the bilateral hippocampus and hypometabolism in the temporoparietal cortex. Imaging model (MRI/PET/fused) provided significant enhancement in prediction of conversion compared to clinical models, especially the fused-modality Cox model. Moreover, the combination of fused-modality imaging and clinical variables resulted in the greatest accuracy of prediction. The average C-index for the clinical/MRI/PET/fused/combined model in the test dataset was 0.69, 0.73, 0.73 and 0.75, and 0.78, respectively. These results suggested that a combination of radiomic analysis and Cox model analyses could be used successfully in survival analysis and may be powerful tools for personalized precision medicine patients with potential to undergo conversion from MCI to AD.
PMCID:6338093
PMID: 30686995
ISSN: 1662-4548
CID: 5134342
Pattern Discovery in Brain Imaging Genetics via SCCA Modeling with a Generic Non-convex Penalty
Brain imaging genetics intends to uncover associations between genetic markers and neuroimaging quantitative traits. Sparse canonical correlation analysis (SCCA) can discover bi-multivariate associations and select relevant features, and is becoming popular in imaging genetic studies. The L1-norm function is not only convex, but also singular at the origin, which is a necessary condition for sparsity. Thus most SCCA methods impose [Formula: see text]-norm onto the individual feature or the structure level of features to pursuit corresponding sparsity. However, the [Formula: see text]-norm penalty over-penalizes large coefficients and may incurs estimation bias. A number of non-convex penalties are proposed to reduce the estimation bias in regression tasks. But using them in SCCA remains largely unexplored. In this paper, we design a unified non-convex SCCA model, based on seven non-convex functions, for unbiased estimation and stable feature selection simultaneously. We also propose an efficient optimization algorithm. The proposed method obtains both higher correlation coefficients and better canonical loading patterns. Specifically, these SCCA methods with non-convex penalties discover a strong association between the APOE e4 rs429358 SNP and the hippocampus region of the brain. They both are Alzheimer's disease related biomarkers, indicating the potential and power of the non-convex methods in brain imaging genetics.
PMCID:5656688
PMID: 29070790
ISSN: 2045-2322
CID: 3257412
Translational Control of APP Expression for Alzheimer Disease Therapy [Editorial]
ORIGINAL:0012875
ISSN: 2573-6051
CID: 3257472
APOE genotype and Alzheimer's immunotherapy [Editorial]
PMCID:5522246
PMID: 28537920
ISSN: 1949-2553
CID: 2574812
A phase 3 trial of IV immunoglobulin for Alzheimer disease
OBJECTIVE:We tested biweekly infusions of IV immunoglobulin (IVIg) as a possible treatment for mild to moderate Alzheimer disease (AD) dementia. METHODS:In a phase 3, double-blind, placebo-controlled trial, we randomly assigned 390 participants with mild to moderate AD to receive placebo (low-dose albumin) or IVIg (Gammagard Liquid; Baxalta, Bannockburn, IL) administered IV at doses of 0.2 or 0.4 g/kg every 2 weeks for 18 months. The primary cognitive outcome was change from baseline to 18 months on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale; the primary functional outcome was 18-month change on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory. Safety and tolerability data, as well as serial MRIs and plasma samples, were collected throughout the study from all enrolled participants. RESULTS:No beneficial effects were observed in the dual primary outcome measures for the 2 IVIg doses tested. Significant decreases in plasma Aβ42 (but not Aβ40) levels were observed in IVIg-treated participants. Analysis of safety data showed no difference between IVIg and placebo in terms of the rate of occurrence of amyloid-related imaging abnormalities (brain edema or microhemorrhage). IVIg-treated participants had more systemic reactions (chills, rashes) but fewer respiratory infections than participants receiving placebo. CONCLUSIONS:Participants with mild to moderate AD showed good tolerability of treatment with low-dose human IVIg for 18 months but did not show beneficial effects on cognition or function relative to participants who received placebo. CLINICALTRIALSGOV IDENTIFIER/UNASSIGNED:NCT00818662. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class II evidence that IVIg infusions performed every 2 weeks do not improve cognition or function at 18 months in patients with mild to moderate AD.
PMCID:5409846
PMID: 28381506
ISSN: 1526-632x
CID: 3257462
