MRAß: A multimodal MRI-derived amyloid-ß biomarker for Alzheimer's disease.

Florbetapir 18 F (AV45), a highly sensitive and specific positron emission tomographic (PET) molecular biomarker binding to the amyloid-ß of Alzheimer's disease (AD), is constrained by radiation and cost. We sought to combat it by combining multimodal magnetic resonance imaging (MRI) images and a collaborative generative adversarial networks model (CollaGAN) to develop a multimodal MRI-derived Amyloid-ß (MRAß) biomarker. We collected multimodal MRI and PET AV45 data of 380 qualified participants from the ADNI dataset and 64 subjects from OASIS3 dataset. A five-fold cross-validation CollaGAN were applied to generate MRAß. In the ADNI dataset, we found MRAß could characterize the subject-level AV45 spatial variations in both AD and mild cognitive impairment (MCI). Voxel-wise two-sample t-tests demonstrated amyloid-ß depositions identified by MRAß in AD and MCI were significantly higher than healthy controls (HCs) in widespread cortices (p < .05, corrected) and were much similar to those by AV45 (r > .92, p < .001). Moreover, a 3D ResNet classifier demonstrated that MRAß was comparable to AV45 in discriminating AD from HC in both the ADNI and OASIS3 datasets, and in discriminate MCI from HC in ADNI. Finally, we found MRAß could mimic cortical hyper-AV45 in HCs who later converted to MCI (r = .79, p < .001) and was comparable to AV45 in discriminating them from stable HC (p > .05). In summary, our work illustrates that MRAß synthesized by multimodal MRI could mimic the cerebral amyloid-ß depositions like AV45 and lends credence to the feasibility of advancing MRI toward molecular-explainable biomarkers.

Mapping cerebral atrophic trajectory from amnestic mild cognitive impairment to Alzheimer's disease.

Alzheimer's disease (AD) patients suffer progressive cerebral atrophy before dementia onset. However, the region-specific atrophic processes and the influences of age and apolipoprotein E (APOE) on atrophic trajectory are still unclear. By mapping the region-specific nonlinear atrophic trajectory of whole cerebrum from amnestic mild cognitive impairment (aMCI) to AD based on longitudinal structural magnetic resonance imaging data from Alzheimer's disease Neuroimaging Initiative (ADNI) database, we unraveled a quadratic accelerated atrophic trajectory of 68 cerebral regions from aMCI to AD, especially in the superior temporal pole, caudate, and hippocampus. Besides, interaction analyses demonstrated that APOE ε4 carriers had faster atrophic rates than noncarriers in 8 regions, including the caudate, hippocampus, insula, etc.; younger patients progressed faster than older patients in 32 regions, especially for the superior temporal pole, hippocampus, and superior temporal gyrus; and 15 regions demonstrated complex interaction among age, APOE, and disease progression, including the caudate, hippocampus, etc. (P < 0.05/68, Bonferroni correction). Finally, Cox proportional hazards regression model based on the identified region-specific biomarkers could effectively predict the time to AD conversion within 10 years. In summary, cerebral atrophic trajectory mapping could help a comprehensive understanding of AD development and offer potential biomarkers for predicting AD conversion.

A causal association of ANKRD37 with human hippocampal volume.

Human hippocampal volume has been separately associated with single nucleotide polymorphisms (SNPs), DNA methylation and gene expression, but their causal relationships remain largely unknown. Here, we aimed at identifying the causal relationships of SNPs, DNA methylation, and gene expression that are associated with hippocampal volume by integrating cross-omics analyses with genome editing, overexpression and causality inference. Based on structural neuroimaging data and blood-derived genome, transcriptome and methylome data, we prioritized a possibly causal association across multiple molecular phenotypes: rs1053218 mutation leads to cg26741686 hypermethylation, thus leads to overactivation of the associated ANKRD37 gene expression in blood, a gene involving hypoxia, which may result in the reduction of human hippocampal volume. The possibly causal relationships from rs1053218 to cg26741686 methylation to ANKRD37 expression obtained from peripheral blood were replicated in human hippocampal tissue. To confirm causality, we performed CRISPR-based genome and epigenome-editing of rs1053218 homologous alleles and cg26741686 methylation in mouse neural stem cell differentiation models, and overexpressed ANKRD37 in mouse hippocampus. These in-vitro and in-vivo experiments confirmed that rs1053218 mutation caused cg26741686 hypermethylation and ANKRD37 overexpression, and cg26741686 hypermethylation favored ANKRD37 overexpression, and ANKRD37 overexpression reduced hippocampal volume. The pairwise relationships of rs1053218 with hippocampal volume, rs1053218 with cg26741686 methylation, cg26741686 methylation with ANKRD37 expression, and ANKRD37 expression with hippocampal volume could be replicated in an independent healthy young (n = 443) dataset and observed in elderly people (n = 194), and were more significant in patients with late-onset Alzheimer's disease (n = 76). This study revealed a novel causal molecular association mechanism of ANKRD37 with human hippocampal volume, which may facilitate the design of prevention and treatment strategies for hippocampal impairment.

Sirt1 protects against hippocampal atrophy and its induced cognitive impairment in middle-aged mice.

BACKGROUND: Sirtuin 1 (Sirt1) is a recognized longevity gene and has been shown to be associated with aging and its related diseases. Hippocampal volume is considered to be the most sensitive brain imaging phenotype for cognition, but the effect of Sirt1 on hippocampal morphology during aging has not been reported. RESULTS: Herein, we investigated the effect of conditional Sirt1 knockdown on hippocampal volume in middle-aged mice, as well as its cognitive function and the underlying molecular mechanisms. Brain structural magnetic resonance imaging (MRI) showed that adeno-associated virus (AAV) mediated hippocampal Sirt1 knockdown caused hippocampal atrophy in 8-month-old mice. Open field test (OFT) and Morris Water Maze (MWM) test revealed that hippocampal Sirt1 knockdown significantly weakened spatial learning and memory of mice without effect on anxiety and exploratory behavior. Western blotting analysis showed that P-tau levels at serine 396 epitope were significantly increased with slightly decreased T-tau levels, while PSD95 and NMDAR2B levels were obviously reduced, indicating that hippocampal Sirt1 knockdown could activate tau hyperphosphorylation and synaptic damage. CONCLUSIONS: This work revealed that Sirt1 is an important protective gene against hippocampal atrophy and its induced cognitive impairment during aging, providing potential therapeutic targets for the prevention and intervention of aging-related neuropsychic diseases.

Dimethyl Fumarate is a Potential Therapeutic Option for Alzheimer's Disease.

BACKGROUND: Dimethyl fumarate (DMF) has been approved for clinical treatment of multiple sclerosis based on its antioxidant and anti-inflammatory effects by activating the Nrf2 pathway. Since both oxidative stress and inflammation are involved in Alzheimer's disease (AD), DMF is a potential therapeutic option for AD. OBJECTIVE: This study aims to test the therapeutic effects of DMF on AD model mice and to reveal its underlying molecular mechanisms. METHODS: Cell viability assay and in vitro immunofluorescence imaging were used to evaluate the antioxidant effect of DMF on embryonic mouse hippocampal neurons. Behavioral test and brain magnetic resonance imaging were used to assess the therapeutic effects of DMF on spatial learning and memory as well as hippocampal volume in AD model mice with and without Nrf2 knockdown. Western blotting was used to analyze the expression of antioxidant enzymes and molecules associated with AD-related pathological pathways. RESULTS: DMF inhibits reactive oxygen species overproduction and protects neurons without Nrf2 knockdown from death. DMF reduces amyloid-ß induced memory impairment and hippocampal atrophy in AD model mice rather than in Nrf2 knockdown AD mice. DMF delays the progression of AD by activating the Nrf2 pathway to enhance the expression of downstream antioxidant enzymes and inhibits lipid peroxidation, apoptosis, inflammation, mitochondrial dysfunction and amyloid-ß deposition. CONCLUSION: These results indicate that DMF is a potential therapeutic option for AD through its antioxidant, anti-inflammatory, anti-apoptotic, and other anti-AD effects by activating the Nrf2 pathway.

A dual-targeted multifunctional nanoformulation for potential prevention and therapy of Alzheimer's disease.

Antioxidation and adjustable treatment strategies are critical for the effective treatment of Alzheimer's disease (AD). Here, we design a dual-targeted Prussian blue nanoformulation (PTCN) that can cross the blood-brain barrier and target amyloid beta aggregates further exert antioxidant effects. An adjustable gradient dosing strategy with PTCN is used for the first time to design the preventive and therapeutic trials based on the severity of oxidative stress at different AD stages. The results show that PTCN could effectively ameliorate AD-related pathological processes, improve the cognitive decline, and rescue hippocampal atrophy of APP/PS1 mice in both preventive and therapeutic trials. Altogether, PTCN provided here is a successful combination of three traditional biomaterials with good biosafety, which has broad prospects for the early prevention, mild remission, and late treatment of AD, and is expected to be developed into personalized therapeutic drugs and healthcare products for clinical AD in the future.

A Comparative Study of Diffusion Fiber Reconstruction Models for Pyramidal Tract Branches.

Currently, comparative studies evaluating the quantification accuracy of pyramidal tracts (PT) and PT branches that were tracked based on four mainstream diffusion models are deficient. The present study aims to evaluate four mainstream models using the high-quality Human Connectome Project (HCP) dataset. Diffusion tensor imaging (DTI), diffusion spectral imaging (DSI), generalized Q-space sampling imaging (GQI), and Q-ball imaging (QBI) were used to construct the PT and PT branches in 50 healthy volunteers from the HCP. False and true PT fibers were identified based on anatomic information. One-way repeated measure analysis of variance and post hoc paired-sample t-test were performed to identify the best PT and PT branch quantification model. The number, percentage, and density of true fibers of PT obtained based on GQI and QBI were significantly larger than those based on DTI and DSI (all p < 0.0005, Bonferroni corrected), whereas false fibers yielded the opposite results (all p < 0.0005, Bonferroni corrected). More trunk branches (PTtrunk) were present in the four diffusion models compared with the upper limb (PTUlimb), lower limb (PTLlimb), and cranial (PTcranial) branches. In addition, significantly more true fibers were obtained in PTtrunk, PTUlimb, and PTLlimb based on the GQI and QBI compared with DTI and DSI (all p < 0.0005, Bonferroni corrected). Finally, GQI-based group probabilistic maps showed that the four PT branches exhibited relatively unique spatial distributions. Therefore, the GQI and QBI represent better diffusion models for the PT and PT branches. The group probabilistic maps of PT branches have been shared with the public to facilitate more precise studies on the plasticity of and the damage to the motor pathway.

Anatomical and functional coupling between the dorsal and ventral attention networks.

Studies have indicated that the dorsal attention network (DAN) and the ventral attention network (VAN) functionally interact via several fronto-parietal connector hubs. However, the anatomical connectivity profiles of these connector hubs, and the coupling between the anatomical and functional connectivities of them, are still unknown. In the present study, we found that functional connector hubs anatomically bridged the DAN and VAN based on multimodal magnetic resonance imaging data from the Human Connectome Project (HCP) Consortium and an independent Chinese cohort. The three hubs had unique anatomical connectivity patterns with the attention sub-networks. For each connector hub, the pattern of anatomical connectivity resembled the functional one. Finally, the strength of the anatomical connectivity of these connector hubs was positively associated with the functional connectivity at the group- and individual-levels. Our findings help to better understand the anatomical mechanisms underlying the functional interactions between the DAN and the VAN.

Structural connectivity profile supports laterality of the salience network.

The salience network (SN) is mainly involved in detecting and filtering multimodal salient stimuli, and mediating the switch between the default mode network and central executive network. Early studies have indicated a right-sided dominance in the functional organization of the SN; however, the anatomical basis of the functional lateralization remains unclear. Here, we hypothesized that the structural connectivity profile between the frontoinsular cortex (FIC) and dorsal anterior cingulate cortex (dACC), which are two core hubs of the SN, is also dominant in the right hemisphere. Based on diffusion and resting-state functional magnetic resonance imaging (rfMRI) of adult healthy volunteers in independent datasets, we found a stable right-sided laterality of both the FIC-dACC structural and functional connectivity in both the human connectome project cohort and a local Chinese cohort. Furthermore, a significant effect of aging on the integrity of the right FIC-dACC structural connectivity was also identified. The right-sided laterality of the structural organization of the SN may help us to better understand the functional roles of the SN in the normal human brain.

Analysis of the Three-Tiered Treatment Model for Emergency Medical Rescue Services After the Lushan Earthquake.

OBJECTIVE: To explore the 3-tiered treatment model for medical treatment after an earthquake. METHODS: Based on the practices of the national emergency medical rescue services in the Lushan earthquake zone, the 3-tiered treatment classification approach was retrospectively reviewed. RESULTS: Medical rescue teams assembled and reported quickly to the disaster areas after the earthquake. The number of injured people had reached 25,176 as of April 30; of these, 18,611 people were treated as outpatients, 6565 were hospitalized, and 977 were seriously or severely injured. CONCLUSIONS: The 3-tiered treatment model was the main approach used by rescue services after the Lushan earthquake. Primary and secondary treatments were of the highest importance and formed the basis of the Lushan model of earthquake rescue and treatment. (Disaster Med Public Health Preparedness. 2018; 12: 301-304).

Monitoring Leiomyoma Response to Uterine Artery Embolization Using Diffusion and Perfusion Indices from Diffusion-Weighted Imaging.

PURPOSE: To investigate the potential of diffusion and perfusion indices (ADC and perfusion fraction f) from DWI at 3.0 T in monitoring treatment response to uterine artery embolization (UAE) at 6-month follow-up. METHODS: Twelve female patients with uterine fibroids who underwent 3.0-T pelvic DWI before and 6 months after UAE were included. ADC and perfusion fraction f were calculated from DWI. The Wilcoxon signed-rank test and Spearman rank correlation test were used for statistics. RESULTS: Seventeen fibroids were studied. The median ADCs showed a significant increase from 1.20 × 10-3 mm2/s (range, 0.86-1.66 × 10-3 mm2/s) at baseline to 1.56 × 10-3 mm2/s (range, 1.00-1.86 × 10-3 mm2/s) at 6-month follow-up (P = 0.0003). Conversely, the median perfusion fraction f was significantly decreased after UAE (P = 0.0001), with a median pre-UAE value of 14.2% (range, 6.7%-17.6%) and a median post-UAE value of 9.2% (range, 3.2%-14.6%). Significant correlations were found between fibroid volume reduction rate and percentage changes in ADC and perfusion fraction f at 6-month follow-up relative to baseline, with ρ values of -0.50 (P = 0.04) and 0.55 (P = 0.02), respectively. CONCLUSION: ADC and perfusion fraction f obtained from DWI at 3.0 T may help to evaluate treatment response to UAE.

Characterization of breast masses as benign or malignant at 3.0T MRI with whole-lesion histogram analysis of the apparent diffusion coefficient.

PURPOSE: To investigate the utility of whole-lesion apparent diffusion coefficient (ADC) histogram analysis in capturing breast lesion heterogeneity and determine which ADC metric may help best differentiate benign from malignant breast mass lesions at 3.0T magnetic resonance imaging (MRI). MATERIALS AND METHODS: We retrospectively included 101 women with breast mass lesions (benign:malignant = 36:65) who underwent 3.0T diffusion-weighted imaging (DWI) and subsequently had histopathologic confirmation. ADC histogram parameters, including the mean, minimum, maximum, 10th/25th/50th/75th/90th percentile, skewness, kurtosis, and entropy ADCs, were derived for the whole-lesion volume in each patient. Mann-Whitney U-test, univariate and multivariate logistic regression, area under the receiver-operating characteristic curve (Az ), intraclass correlation coefficient (ICC), and Bland-Altman test were used for statistical analysis. RESULTS: Mean, minimum, maximum, and 10th/25th/50th/75th/90th percentile ADCs were significantly lower (all P < 0.0001), while skewness and entropy ADCs were significantly higher (P < 0.001 and P = 0.001, respectively) in malignant lesions compared with benign ones. The Az values of minimum and 25th percentile ADCs were significantly higher than that of mean ADC (P = 0.0194 and P = 0.0154, respectively) or that of median ADC (P = 0.0300 and P = 0.0401, respectively), indicating that minimum and 25th percentile ADCs may be more accurate for lesion discrimination. Multivariate logistic regression showed that the minimum ADC was the unique independent predictor of breast malignancy. Minimum and 25th percentile ADCs had excellent interobserver agreement (ICC = 0.943 and 0.989, respectively; narrow width of 95% limits of agreement). CONCLUSION: These results suggest that whole-lesion ADC histogram analysis may facilitate the differentiation between benign and malignant breast mass lesions.