Wenzhen Zhu

Diffusion kurtosis imaging can efficiently assess the glioma grade and cellular proliferation

Conventional diffusion imaging techniques are not sufficiently accurate for evaluating glioma grade and cellular proliferation, which are critical for guiding glioma treatment. Diffusion kurtosis imaging (DKI), an advanced non-Gaussian diffusion imaging technique, has shown potential in grading glioma; however, its applications in this tumor have not been fully elucidated. In this study, DKI and diffusion weighted imaging (DWI) were performed on 74 consecutive patients with histopathologically confirmed glioma. The kurtosis and conventional diffusion metric values of the tumor were semi-automatically obtained. The relationships of these metrics with the glioma grade and Ki-67 expression were evaluated. The diagnostic efficiency of these metrics in grading was further compared. It was demonstrated that compared with the conventional diffusion metrics, the kurtosis metrics were more promising imaging markers in distinguishing high-grade from low-grade gliomas and distinguishing among grade II, III and IV gliomas; the kurtosis metrics also showed great potential in the prediction of Ki-67 expression. To our best knowledge, we are the first to reveal the ability of DKI to assess the cellular proliferation of gliomas, and to employ the semi-automatic method for the accurate measurement of gliomas. These results could have a significant impact on the diagnosis and subsequent therapy of glioma.

Investigation on positive correlation of increased brain iron deposition with cognitive impairment in Alzheimer disease by using quantitative MR R2′ mapping

Brain iron deposition has been proposed to play an important role in the pathophysiology of Alzheimer disease (AD). The aim of this study was to investigate the correlation of brain iron accumulation with the severity of cognitive impairment in patients with AD by using quantitative MR relaxation rate R2′ measurements. Fifteen patients with AD, 15 age- and sex-matched healthy controls, and 30 healthy volunteers underwent 1.5T MR multi-echo T2 mapping and T2* mapping for the measurement of transverse relaxation rate R2′ (R2′=R2*−R2). We statistically analyzed the R2′ and iron concentrations of bilateral hippocampus (HP), parietal cortex (PC), frontal white matter (FWM), putamen (PU), caudate nucleus (CN), thalamus (TH), red nucleus (RN), substantia nigra (SN), and dentate nucleus (DN) of the cerebellum for the correlation with the severity of dementia. Two-tailed t-test, Student-Newman-Keuls test (ANOVA) and linear correlation test were used for statistical analysis. In 30 healthy volunteers, the R2′ values of bilateral SN, RN, PU, CN, globus pallidus (GP), TH, and FWM were measured. The correlation with the postmortem iron concentration in normal adults was analyzed in order to establish a formula on the relationship between regional R2′ and brain iron concentration. The iron concentration of regions of interest (ROI) in AD patients and controls was calculated by this formula and its correlation with the severity of AD was analyzed. Regional R2′ was positively correlated with regional brain iron concentration in normal adults (r=0.977, P<0.01). Iron concentrations in bilateral HP, PC, PU, CN, and DN of patients with AD were significantly higher than those of the controls (P<0.05); Moreover, the brain iron concentrations, especially in parietal cortex and hippocampus at the early stage of AD, were positively correlated with the severity of patients’ cognitive impairment (P<0.05). The higher the R2′ and iron concentrations were, the more severe the cognitive impairment was. Regional R2′ and iron concentration in parietal cortex and hippocampus were positively correlated with the severity of AD patients’ cognitive impairment, indicating that it may be used as a biomarker to evaluate the progression of AD.SummaryBrain iron deposition has been proposed to play an important role in the pathophysiology of Alzheimer disease (AD). The aim of this study was to investigate the correlation of brain iron accumulation with the severity of cognitive impairment in patients with AD by using quantitative MR relaxation rate R2′ measurements. Fifteen patients with AD, 15 age- and sex-matched healthy controls, and 30 healthy volunteers underwent 1.5T MR multi-echo T2 mapping and T2* mapping for the measurement of transverse relaxation rate R2′ (R2′=R2*−R2). We statistically analyzed the R2′ and iron concentrations of bilateral hippocampus (HP), parietal cortex (PC), frontal white matter (FWM), putamen (PU), caudate nucleus (CN), thalamus (TH), red nucleus (RN), substantia nigra (SN), and dentate nucleus (DN) of the cerebellum for the correlation with the severity of dementia. Two-tailed t-test, Student-Newman-Keuls test (ANOVA) and linear correlation test were used for statistical analysis. In 30 healthy volunteers, the R2′ values of bilateral SN, RN, PU, CN, globus pallidus (GP), TH, and FWM were measured. The correlation with the postmortem iron concentration in normal adults was analyzed in order to establish a formula on the relationship between regional R2′ and brain iron concentration. The iron concentration of regions of interest (ROI) in AD patients and controls was calculated by this formula and its correlation with the severity of AD was analyzed. Regional R2′ was positively correlated with regional brain iron concentration in normal adults (r=0.977, P<0.01). Iron concentrations in bilateral HP, PC, PU, CN, and DN of patients with AD were significantly higher than those of the controls (P<0.05); Moreover, the brain iron concentrations, especially in parietal cortex and hippocampus at the early stage of AD, were positively correlated with the severity of patients’ cognitive impairment (P<0.05). The higher the R2′ and iron concentrations were, the more severe the cognitive impairment was. Regional R2′ and iron concentration in parietal cortex and hippocampus were positively correlated with the severity of AD patients’ cognitive impairment, indicating that it may be used as a biomarker to evaluate the progression of AD.

Intravoxel incoherent motion diffusion-weighted imaging analysis of diffusion and microperfusion in grading gliomas and comparison with arterial spin labeling for evaluation of tumor perfusion.

To determine the utility of intravoxel incoherent motion (IVIM) imaging in grading gliomas and compare IVIM perfusion metrics with arterial spin labeling (ASL)‐derived cerebral blood flow (CBF).

Voxel-Based Diffusion Tensor Imaging of an APP/PS1 Mouse Model of Alzheimer's Disease

Increasing evidence has demonstrated that white matter (WM) disruptions, due to the injury of the axon and myelin, play an important role in the pathogenesis of Alzheimer’s disease (AD). Diffusion tensor imaging (DTI) is a sensitive modality to evaluate the WM integrity in both AD patients and animal models. In this study, an advanced DTI modality, employing a 7.0-T magnetic resonance imaging system, was used to analyze WM changes across the whole brain of an amyloid precursor protein/presenilin 1 (APP/PS1) mouse model. A voxel-based analysis was used to compare the quantitative DTI parameters automatically in both APP/PS1 mice (n = 9) and wild-type (WT) controls (n = 9). After DTI examination, the ultrastructure analysis was compared with DTI findings. Compared with WT controls, gray matter (GM) areas in APP/PS1 mice such as the cingulate cortex and the striatum showed significant fractional anisotropy (FA) and axial diffusivity (DA) increase, while the thalamus only showed a significant FA increase (p < 0.01). Similarly, a significant mean diffusivity, DA, and radial diffusivity increase was observed in the bilateral neocortex (p < 0.01). The left hippocampus only showed significant FA increase in APP/PS1 mice (p < 0.01). The changes in WM regions were detected in the forceps minor of the corpus callosum, the anterior part of the anterior commissure, and the internal capsule, with a significant FA or DA increase (p < 0.01). Abnormalities derived from diffusion measurements were in-line with the ultrastructure findings, including extensive pathological damage of the neurons, neutrophils, and vessels. In conclusion, voxel-based diffusion tensor imaging can detect diffusion alterations not only in GM but also in WM areas in AD models, reflecting the extensive pathological changes of AD.

Superparamagnetic Iron Oxide Labeling of Neural Stem Cells and 4.7T MRI Tracking in vivo and in vitro

Neural stem cells were labeled with superparamagnetic iron oxide (SPIO) and tracked by MRI in vitro and in vivo after implantation. Rat neural stem cells were labeled with SPIO combined with PLL by the means of receptor-mediated endocytosis. Prussian blue staining and electron microscopy were conducted to identify the iron particles in these neural stem cells. SPIO-labeled cells were tracked by 4.7T MRI in vivo and in vitro after implantation. The subjects were divided into 5 groups, including 5 × 105 labeled cells cultured for one day after labeling, 5 × 105 same phase unlabeled cells, cell culture medium with 25 μg Fe/mL SPIO, cell culture medium without SPIO and distilled water. MRI scanning sequences included T1WI, T2WI and T2*WI. R2 and R2* of labeled cells were calculated. The results showed: (1) Neural stem cells could be labeled with SPIO and labeling efficiency was 100%. Prussian blue staining showed numerous blue-stained iron particles in the cytoplasm; (2) The average percentage change of signal intensity of labeled cells on T1WI in 4.7T MRI was 24.06%, T2WI 50.66% and T2*WI 53.70% respectively; (3) T2 of labeled cells and unlabeled cells in 4.7T MRI was 516 ms and 77 ms respectively, R2 was 1.94 s−1 and 12.98 s−1 respectively, and T2* was 109 ms and 22.9 ms, R2* was 9.17 s−1 and 43.67 s−1 respectively; (4) Remarkable low signal area on T2WI and T2*WI could exist for nearly 7 weeks and then disappeared gradually in the left brain transplanted with labeled cells, however no signal change in the right brain implanted with unlabeled cells. It was concluded that neural stem cells could be labeled effectively with SPIO. R2 and R2* of labeled cells were increased obviously. MRI can be used to track labeled cells in vitro and in vivo.

Experimental Study of Cell Migration and Functional Differentiation of Transplanted Neural Stem Cells Co-labeled with Superparamagnetic Iron Oxide and Brdu in an Ischemic Rat Model

OBJECTIVE To explore the migration of transplanted neural stem cells co-labeled with superparamagnetic iron oxide (SPIO) and bromodeoxyuridine (Brdu) using the 4.7T MR system and to study the cell differentiation with immuno-histochemical method in ischemic rats. METHODS Rat neural stem cells (NSCs) co-labelled with SPIO mediated by poly-L-lysine and bromodeoxyuridine (BrdU) were transplanted into the unaffected side of rat brain with middle cerebral artery occlusion (MCAO). At weeks 1, 2, 3, 4, 5, and 6 after MCAO, migration of the labelled cells was monitored by MRI. At week 6, the rats were killed and their brain tissue was cut according to the migration site of transplanted cells indicated by MRI and subjected to Prussian blue staining and immunohistochemical staining to observe the migration and differentiation of the transplanted NSCs. RESULTS Three weeks after transplantation, the linear hypointensity area derived from the migration of labelled NSCs was observed by MRI in the corpus callosum adjacent to the injection site. Six weeks after the transplantation, the linear hypointensity area was moved toward the midline along the corpus callosum. MRI findings were confirmed by Prussian blue staining and immunohistochemical staining of the specimen at week 6 after the transplantation. Flourescence co-labelled immunohistochemical methods demonstrated that the transplanted NSCs could differentiate into astrocytes and neurons. CONCLUSION MRI can monitor the migration of SPIO-labelled NSCs after transplantation in a dynamical and non-invasive manner. NSCs transplanted into ischemic rats can differentiate into astrocytes and neurons during the process of migration.

Quantitative Measurement of Cerebral Perfusion with Intravoxel Incoherent Motion in Acute Ischemia Stroke: Initial Clinical Experience

Background:Intravoxel incoherent motion (IVIM) has the potential to provide both diffusion and perfusion information without an exogenous contrast agent, its application for the brain is promising, however, feasibility studies on this are relatively scarce. The aim of this study is to assess the feasibility of IVIM perfusion in patients with acute ischemic stroke (AIS). Methods:Patients with suspected AIS were examined by magnetic resonance imaging within 24 h of symptom onset. Fifteen patients (mean age was 68.7 ± 8.0 years) who underwent arterial spin labeling (ASL) and diffusion-weighted imaging (DWI) were identified as having AIS with ischemic penumbra were enrolled, where ischemic penumbra referred to the mismatch areas of ASL and DWI. Eleven different b-values were applied in the biexponential model. Regions of interest were selected in ischemic penumbras and contralateral normal brain regions. Fast apparent diffusion coefficients (ADCs) and ASL cerebral blood flow (CBF) were measured. The paired t-test was applied to compare ASL CBF, fast ADC, and slow ADC measurements between ischemic penumbras and contralateral normal brain regions. Linear regression and Pearsons correlation were used to evaluate the correlations among quantitative results. Results:The fast ADCs and ASL CBFs of ischemic penumbras were significantly lower than those of the contralateral normal brain regions (1.93 ± 0.78 &mgr;m2/ms vs. 3.97 ± 2.49 &mgr;m2/ms, P = 0.007; 13.5 ± 4.5 ml·100 g-1·min-1 vs. 29.1 ± 12.7 ml·100 g-1·min-1, P < 0.001, respectively). No significant difference was observed in slow ADCs between ischemic penumbras and contralateral normal brain regions (0.203 ± 0.090 &mgr;m2/ms vs. 0.198 ± 0.100 &agr;&mgr;m2/ms, P = 0.451). Compared with contralateral normal brain regions, both CBFs and fast ADCs decreased in ischemic penumbras while slow ADCs remained the same. A significant correlation was detected between fast ADCs and ASL CBFs (r = 0.416, P < 0.05). No statistically significant correlation was observed between ASL CBFs and slow ADCs, or between fast ADCs and slow ADCs (r = 0.111, P = 0.558; r = 0.200, P = 0.289, respectively). Conclusions:The decrease in cerebral blood perfusion primarily results in the decrease in fast ADC in ischemic penumbras; therefore, fast ADC can reflect the perfusion situation in cerebral tissues.

Altered Intranetwork and Internetwork Functional Connectivity in Type 2 Diabetes Mellitus With and Without Cognitive Impairment

Type 2 diabetes mellitus (T2DM) is associated with cognitive impairment. We investigated whether alterations of intranetwork and internetwork functional connectivity with T2DM progression exist, by using resting-state functional MRI. MRI data were analysed from 19 T2DM patients with normal cognition (DMCN) and 19 T2DM patients with cognitive impairment (DMCI), 19 healthy controls (HC). Functional connectivity among 36 previously well-defined brain regions which consisted of 5 resting-state network (RSN) systems [default mode network (DMN), dorsal attention network (DAN), control network (CON), salience network (SAL) and sensorimotor network (SMN)] was investigated at 3 levels (integrity, network and connectivity). Impaired intranetwork and internetwork connectivity were found in T2DM, especially in DMCI, on the basis of the three levels of analysis. The bilateral posterior cerebellum, the right insula, the DMN and the CON were mainly involved in these changes. The functional connectivity strength of specific brain architectures in T2DM was found to be associated with haemoglobin A1c (HbA1c), cognitive score and illness duration. These network alterations in intergroup differences, which were associated with brain functional impairment due to T2DM, indicate that network organizations might be potential biomarkers for predicting the clinical progression, evaluating the cognitive impairment, and further understanding the pathophysiology of T2DM.

Brain white matter plasticity and functional reorganization underlying the central pathogenesis of trigeminal neuralgia

Peripheral nerve damage does not fully explain the pathogenesis of trigeminal neuralgia (TN). Central nervous system changes can follow trigeminal nerve dysfunction. We hypothesized that brain white matter and functional connectivity changes in TN patients were involved in pain perception, modulation, the cognitive-affective system, and motor function; moreover, changes in functional reorganization were correlated with white matter alterations. Twenty left TN patients and twenty-two healthy controls were studied. Diffusion kurtosis imaging was analyzed to extract diffusion and kurtosis parameters, and functional connectivity density (FCD) mapping was used to explore the functional reorganization in the brain. In the patient group, we found lower axial kurtosis and higher axial diffusivity in tracts participated in sensory, cognitive-affective, and modulatory aspects of pain, such as the corticospinal tract, superior longitudinal fasciculus, anterior thalamic radiation, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, cingulated gyrus, forceps major and uncinate fasciculus. Patients exhibited complex FCD reorganization of hippocampus, striatum, thalamus, precentral gyrus, precuneus, prefrontal cortex and inferior parietal lobule in multiple modulatory networks that played crucial roles in pain perception, modulation, cognitive-affective system, and motor function. Further, the correlated structural-functional changes may be responsible for the persistence of long-term recurrent pain and sensory-related dysfunction in TN.

The temporal evolution of diffusional kurtosis imaging in an experimental middle cerebral artery occlusion (MCAO) model.

PURPOSE Diffusional kurtosis imaging (DKI), as a non-Gaussian diffusion model, has been applied in human and animal studies of ischemic stroke. This study aimed to intensively characterize the temporal evolution of DKI-derived variables in an experimental middle cerebral artery occlusion (MCAO) model, and to explore its potential application in ischemic stroke. MATERIALS AND METHODS Eleven MCAO rats and ten control rats underwent DKI and diffusion weighted imaging (DWI) scans, at different time points of 0.5, 2, 6, 12, 24 and 72h after operation respectively. The infarct area in DKI- and DWI-derived variables was compared among different time points, and between different groups [INFARCTION, MIRROR, CONTROL-R (right side of the control group, the same side as in the infarction group), CONTROL-L (left side of the control group)] using repeated measures analysis of variance (ANOVA). The percent changes from normal to that in ischemic tissues and histology were also evaluated. RESULTS In the infarct region, from 0.5 to 72h, MK, K∥, K⊥ demonstrated irregular high signal, whereas relative homogeneous low signals were revealed by MD, D∥, D⊥ and ADC. Compared with the MIRROR and CONTROL-R group, MK, K∥, K⊥ in the infarcted area increased aggressively which peaked at 12h and gradually decreased; MD, D∥, D⊥ and ADC decreased gradually until 12h and then began to increase gradually; FA decreased rapidly from 0.5 to 72h. MD, D∥ and ADC were significantly different between Mirror and CONTROL-L group (P<0.05). CONCLUSION DKI can provide more detailed information to describe ischemic lesion, and has great potential application in ischemic stroke.