Application of Granger Causality Analysis of the Directed Functional Connection in Alzheimer's Disease and Mild Cognitive Impairment

Impaired functional connectivity in the Default Mode Network (DMN) may be involved in the progression of Alzheimer&#39;s Disease (AD). The Posterior ...

Zhejiang Provincial People's Hospital

The amplitude of low-frequency fluctuation (ALFF) measures low-frequency oscillations of the blood-oxygen-level-dependent signal, characterizing local spontaneous activity during the resting state. ALFF is a commonly used measure for resting-state functional magnetic resonance imaging (rs-fMRI) in numerous basic and clinical neuroscience studies. Using a test-retest rs-fMRI dataset consisting of 21 healthy subjects and three repetitive scans, we found that several key brain regions with high ALFF intensities (or magnitude) had poor reliability. Such regions included the posterior cingulate cortex, the medial prefrontal cortex in the default mode network, parts of the right and left thalami, and the primary visual and motor cortices. The above finding was robust with regard to different sample sizes (number of subjects), different scanning parameters (repetition time) and variations of test-retest intervals (i.e., intra-scan, intra-session, and inter-session reliability), as well as with different scanners. Moreover, the qualitative, map-wise results were validated further with a region-of-interest-based quantitative analysis using "canonical" coordinates as reported previously. Therefore, we suggest that the reliability assessments be incorporated in future ALFF studies, especially for the brain regions with a large ALFF magnitude as listed in our paper. Splitting single data into several segments and assessing within-scan "test-retest" reliability is an acceptable alternative if no "real" test-retest datasets are available. Such evaluations might become more necessary if the data are collected with clinical scanners whose performance is not as good as those that are used for scientific research purposes and are better maintained because the lower signal-to-noise ratio may further dampen ALFF reliability.

Low-Frequency Fluctuations of the Resting Brain: High Magnitude Does Not Equal High Reliability.

Tumor heterogeneity of high-grade glioma (HGG) is recognized by four clinically relevant subtypes based on core gene signatures. However, molecular signaling in glioma stem cells (GSCs) in individual HGG subtypes is poorly characterized. Previously we identified and characterized two mutually exclusive GSC subtypes with distinct activated signaling pathways and biological phenotypes. One GSC subtype presented with a gene signature resembling Proneural (PN) HGG, whereas the other was similar to Mesenchymal (Mes) HGG. Classical HGG-derived GSCs were sub-classified as either one of these two subtypes. Differential mRNA expression analysis of PN and Mes GSCs identified 5,796 differentially expressed genes, revealing a pronounced correlation with the corresponding PN or Mes HGGs. Mes GSCs displayed more aggressive phenotypes in vitro and as intracranial xenografts in mice. Further, Mes GSCs were markedly resistant to radiation compared with PN GSCs. Expression of ALDH1A3 - one of the most up-regulated Mes representative genes and a universal cancer stem cell marker in non-brain cancers - was associated with self-renewal and a multi-potent stem cell population in Mes but not PN samples. Moreover, inhibition of ALDH1A3 attenuated the growth of Mes but not PN GSCs in vitro. Lastly, radiation treatment of PN GSCs up-regulated Mes-associated markers and down-regulated PN-associated markers, whereas inhibition of ALDH1A3 attenuated an irradiation-induced gain of Mes identity in PN GSCs in vitro. Taken together, our data suggest that two subtypes of GSCs, harboring distinct metabolic signaling pathways, represent intertumoral glioma heterogeneity and highlight previously unidentified roles of ALDH1A3-associated signaling that promotes aberrant proliferation of Mes HGGs and GSCs. Inhibition of ALDH1A3-mediated pathways therefore might provide a promising therapeutic approach for a subset of HGGs with the Mes signature. Here, we describe the gene expression analysis, including pre-processing methods for the data published by Mao and colleagues in PNAS [1], integration of microarray data from this study with The Cancer Genome Atlas (TCGA) glioblastoma data and also with another published study.

Gene expression profiling distinguishes proneural glioma stem cells from mesenchymal glioma stem cells.

The main goal of brain tumor surgery is to maximize tumor resection while minimizing the risk of irreversible postoperative functional sequelae. Eloquent functional areas should be delineated preoperatively, particularly for patients with tumors near eloquent areas. Functional magnetic resonance imaging (fMRI) is a noninvasive technique that demonstrates great promise for presurgical planning. However, specialized data processing toolkits for presurgical planning remain lacking. Based on several functions in open-source software such as Statistical Parametric Mapping (SPM), Resting-State fMRI Data Analysis Toolkit (REST), Data Processing Assistant for Resting-State fMRI (DPARSF) and Multiple Independent Component Analysis (MICA), here, we introduce an open-source MATLAB toolbox named PreSurgMapp. This toolbox can reveal eloquent areas using comprehensive methods and various complementary fMRI modalities. For example, PreSurgMapp supports both model-based (general linear model, GLM, and seed correlation) and data-driven (independent component analysis, ICA) methods and processes both task-based and resting-state fMRI data. PreSurgMapp is designed for highly automatic and individualized functional mapping with a user-friendly graphical user interface (GUI) for time-saving pipeline processing. For example, sensorimotor and language-related components can be automatically identified without human input interference using an effective, accurate component identification algorithm using discriminability index. All the results generated can be further evaluated and compared by neuro-radiologists or neurosurgeons. This software has substantial value for clinical neuro-radiology and neuro-oncology, including application to patients with low- and high-grade brain tumors and those with epilepsy foci in the dominant language hemisphere who are planning to undergo a temporal lobectomy.

PreSurgMapp: a MATLAB Toolbox for Presurgical Mapping of Eloquent Functional Areas Based on Task-Related and Resting-State Functional MRI.

Impaired functional connectivity in the default mode network (DMN) is supposedly involved in Alzheimer's disease (AD) progression. The posterior cingulate cortex (PCC) might be an imaging marker for monitoring AD progression.

Directed functional connectivity of posterior cingulate cortex and whole brain in Alzheimer's disease and mild cognitive impairment.

Many functional magnetic resonance imaging (fMRI) studies have indicated that Granger causality analysis (GCA) is a suitable method for revealing causal effects between brain regions. The purpose of the present study was to identify neuroimaging biomarkers with a high sensitivity to amnestic mild cognitive impairment (aMCI). The resting-state fMRI data of 30 patients with Alzheimer's disease (AD), 14 patients with aMCI, and 18 healthy controls (HC) were evaluated using GCA. This study focused on the "triple networks" concept, a recently proposed higher-order functioning-related brain network model that includes the default-mode network (DMN), salience network (SN), and executive control network (ECN). As expected, GCA techniques were able to reveal differences in connectivity in the three core networks among the three patient groups. The fMRI data were pre-processed using DPARSFA v2.3 and REST v1.8. Voxel-wise GCA was performed using the REST-GCA in the REST toolbox. The directed (excitatory and inhibitory) connectivity obtained from GCA could differentiate among the AD, aMCI and HC groups. This result suggests that analysing the directed connectivity of inter-hemisphere connections represents a sensitive method for revealing connectivity changes observed in patients with aMCI. Specifically, inhibitory within-DMN connectivity from the posterior cingulate cortex (PCC) to the hippocampal formation and from the thalamus to the PCC as well as excitatory within-SN connectivity from the dorsal anterior cingulate cortex (dACC) to the striatum, from the ECN to the DMN, and from the SN to the ECN demonstrated that changes in connectivity likely reflect compensatory effects in aMCI. These findings suggest that changes observed in the triple networks may be used as sensitive neuroimaging biomarkers for the early detection of aMCI.

High-sensitivity neuroimaging biomarkers for the identification of amnestic mild cognitive impairment based on resting-state fMRI and a triple network model.

Myxopapillary ependymoma (MPE) is a rare variant of ependymoma that is most commonly located in the cauda equina and filum terminale. We present a case of 23-year-old man diagnosed with MPE in the fourth ventricle and sacral canal area with extensive disseminated lesions along the cerebrospinal ventricular system. Additionally, a molecular pathological diagnosis was performed. The patient underwent a craniotomy and a lumbar laminectomy. In the course of 18 months of follow-up, the patient have recovered very well.

Dewang Mao

Department of Radiology

Zhejiang Provincial People's Hospital

Application of Granger Causality Analysis of the Directed Functional Connection in Alzheimer's Disease and Mild Cognitive Impairment

Dewang Mao

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Radiology

Zhejiang Provincial People's Hospital

Application of Granger Causality Analysis of the Directed Functional Connection in Alzheimer's Disease and Mild Cognitive Impairment

Department of Radiology