Exploring joint patterns of brain structure and function in inflammatory bowel diseases using multimodal data fusion.

BACKGROUND: A growing number of neuroimaging studies suggest distinct neural changes in inflammatory bowel diseases (IBDs). Whether such changes may show similar spatial patterns across distinct neural features within and between specific IBD is unclear. To address this question, we used multivariate multimodal data fusion analysis to investigate structure/function modulation in remitted patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Patients with IBD (n = 46; n = 31 with CD, n = 15 with UC) in stable remission and 17 healthy controls (HC) underwent structural magnetic resonance imaging (sMRI) and resting-state functional magnetic resonance imaging (rs-fMRI) as well as cognitive testing. Anxiety, depression, and fatigue were assessed using self-rating questionnaires. sMRI data were analyzed via voxel-based morphometry (VBM) and rs-fMRI data via amplitude of low-frequency fluctuations (ALFFs) and regional homogeneity (ReHo). Detection of cross-information between VBM, ALFF, and ReHo was conducted by means of a joint independent component analysis (jICA), followed by group-inference statistics. KEY RESULTS: Joint independent component analysis detected structural alterations in middle frontal and temporal regions (VBM), and functional changes in the superior frontal gyrus (ReHo) and the medial as well as inferior frontal, inferior temporal, rectal, and subcallosal gyrus (ALFF). One joint component of extracted features of the three modalities differed significantly between IBD patients and controls (p = 0.03), and most distinctly between HC and patients with UC. CONCLUSIONS AND INFERENCES: Using a multivariate data fusion technique, this study provides further evidence to brain alterations in IBD. The data suggest distinct neural differences between CD and UC, particularly in frontotemporal regions.

Aberrant brain structural large-scale connectome in Crohn's disease.

BACKGROUND: Disturbed brain-gut interactions and a bidirectional relationship between inflammation and psychiatric symptoms such as anxiety and depression are being discussed in patients with inflammatory bowel diseases (IBD). Alterations of brain structure and function in IBD have been reported with heterogeneous results. Whether these changes reflect independent localized deficits or rather a systematic disruption in the anatomical organization of large-scale brain networks remains unclear. The present study investigated the gray matter structural connectome in patients with Crohn's disease (CD). METHODS: Sixty participants (30 with quiescent CD and 30 matched healthy controls [HC]) underwent high-resolution brain MRI at 3 Tesla. Well-established graph theoretical metrics were analyzed at the global and regional network level and compared between groups. KEY RESULTS: The networks in both groups followed a small-world organization, that is, an architecture that is simultaneously highly segregated and integrated. However, transitivity, a measure of global network segregation, was significantly reduced in patients (P = 0.003). Regionally, patients showed a reduction of nodal betweenness centrality in the right insula and cuneus and the left superior frontal cortex and reduced nodal degree within the left-hemispheric cingulate and the left lateral and right medial orbitofrontal cortex. CONCLUSION AND INFERENCES: These findings lend support to the hypothesis that CD is accompanied by alterations in both global network organization and regional connectivity. A deeper understanding of neural central networks in IBD may facilitate the development of complementary strategies in the treatment of "extraintestinal" comorbid conditions such as depression or anxiety.

Intrinsic neural network dysfunction in quiescent Crohn's Disease.

Psychological factors and comorbidities play an important role in inflammatory bowel diseases. Such comorbidity could be associated with a specific neural phenotype. Brain regions associated with emotion regulation and self-referential processing, including areas assigned to the "default mode network" (DMN), could be promising candidates in this regard. We investigated the functional integrity of multiple intrinsic neural networks in remitted patients with Crohn's disease (CD) and sought to establish relationships between neural network connectivity and psychiatric symptoms. Fifteen CD patients in remission and 14 controls were investigated. We employed resting-state functional magnetic resonance imaging (fMRI) at 3 Tesla followed by a spatial Independent Component Analysis for fMRI data. Abnormal connectivity in CD patients was observed in DMN subsystems only (p < 0.05, cluster-corrected). Increased connectivity was found in the anterior cingulate and left superior medial frontal gyrus (aDMN) and the middle cingulate cortex (pDMN). Middle cingulate activity showed a significant association with anxiety scores in patients (p = 0.029). This study provides first evidence of selectively disrupted intrinsic neural network connectivity in CD and suggests abnormalities of self-referential neural networks. An increased sensitivity to self-related affective and somatic states in CD patients could account for these findings and explain a higher risk for anxiety symptoms.

MRI Characteristics of the Evolution of Supratentorial Recent Small Subcortical Infarcts.

OBJECTIVE: Morphological changes of recent small subcortical infarcts are not well defined. The purpose of the present study was to describe the MRI characteristics of the evolution for this stroke subtype. METHODS: We conducted a retrospective review of patients diagnosed with definite supratentorial recent small subcortical infarcts according to the ASCO classification with baseline and follow-up MRI (≥90 days of stroke onset). We investigated the incidence of cavity formation, the infarct volume change, and the positional relationship between infarct lesions and preexisting white matter hyperintensities (WMHs) of presumed vascular origin. RESULTS: We identified 62 patients with a median age of 71 years (range: 30-87). Median follow-up period was 26 months (range: 3-99). Cavity formation was observed in 38 infarct lesions (61%). Eighteen lesions (29%) were partially adjacent to WMHs and 7 (11%) were fused into WMHs. In a multiple logistic regression analysis, age [odds ratio per 5-year increase: 1.34; 95% confidence interval (CI): 1.03-1.80; p = 0.03] and baseline infarct volume (odds ratio per 1-ml increase: 4.7; 95% CI: 1.6-19.7; p = 0.003) were independent predictors of cavity formation. There was a significant volume reduction between baseline and follow-up infarct lesions (median volume reduction rate: 44%). CONCLUSION: More than one-third of recent small subcortical infarcts do not lead to cavity formation and 40% of infarct lesions overlap with WMHs. Our data indicate the continuity between recent small subcortical infarcts and WMHs.

Presumptive progressive multifocal leukoencephalopathy in multiple sclerosis after natalizumab therapy.

BACKGROUND AND PURPOSE: To describe a patient with relapsing remitting MS who was treated with natalizumab for 36 months. First symptoms of presumptive progressive multifocal leukoencephalopathy (PML) appeared 14 weeks after her last natalizumab infusion. METHODS: Neurological examination, MRI and CSF analysis were performed. RESULTS: The lack of anti-inflammatory treatment response, clinical course, and serial MRI examinations showed lesion development typical for PML on diffusion-weighted and FLAIR MRI. CSF analysis for JC virus was tested negative twice. CONCLUSIONS: This case represents a presumptive PML after discontinuation of natalizumab treatment-similar to the definition established for PML in HIV patients.

Thrombolytic stroke treatment of a 12-year-old girl with intracranial fibromuscular dysplasia.

Fibromuscular dysplasia, predominantly found in adult women, is a rare disease of small and middle-sized arteries of the kidney and brain. We present a case of a 12-year-old girl with acute ischemic stroke, due to fibromuscular dysplasia of the distal internal carotid artery and the proximal middle cerebral artery, which was successfully treated with t-PA.

Lipoaspirate-derived adult mesenchymal stem cells improve functional outcome during intracerebral hemorrhage by proliferation of endogenous progenitor cells stem cells in intracerebral hemorrhages.

Stem cell therapy seems promising in reducing deficits after focal cerebral ischemia. As stroke may result from intracerebral hemorrhage (ICH) in up to 20% we investigated whether human processed lipoaspirate mesenchymal stem cells (PLA-MSC) influence the functional outcome, migration behavior and the activation of endogenous progenitor cells. Experimental ICH was induced by stereotactic administration of collagenase in rats randomly assigned to the control or treatment group. The latter received 3 x 10(6) PLA-MSC by intravenous (i.v.) injection 24h after ICH induction. The outcome was continuously monitored using the RotaRod test over a period of 4 weeks. Morphometric analysis of ICH was performed consecutively by magnetic resonance imaging (MRI) studies and immunohistochemical analysis. The RotaRod test revealed a significant 1.5-fold improvement (p<0.005) in functional outcome for the PLA-MSC treated group after 4 weeks compared to controls. Histological and MRI assessment of lesion size showed no difference between the two groups. Although i.v. injected human cells could not be detected in the post mortem brain, evaluation of the number of endogenous progenitor cells revealed a twofold increase in the treated animals compared to controls. Treatment with PLA-MSC improved the functional outcome significantly in an experimental ICH model. This effect was achieved by stimulation of endogenous progenitor cells rather than integration and differentiation of the infused PLA-MSC.

Gadofluorine m uptake in stem cells as a new magnetic resonance imaging tracking method: an in vitro and in vivo study.

OBJECTIVES: Cell tracking using ultrasmall iron particles is well established in magnetic resonance imaging (MRI). However, in experimental models, intrinsic iron signals derived from erythrocytes mask the labeled cells. Therefore, we evaluated Gadofluorine M with other gadolinium chelates for a T1-weighted positive enhancement for cell tracking in vitro. In addition, Gadofluorine M was tested in vivo. MATERIAL AND METHODS: Gadofluorine M and other gadolinium chelates were used to label stem cells with and without uptake-mediating agents in vitro and in vivo using a 1.5 T MRI. In addition, histology and molecular modeling was investigated. RESULTS: Gadofluorine M revealed comparable properties to an uptake mediating agent in molecular modeling. Without an uptake-mediating agent Gadofluorine M-labeled cells were detected as a T1-weighted positive contrast in vitro and in vivo. Histology confirmed a 100% success rate for intracellular labeling. CONCLUSION: This study describes a novel contrast agent with the capability of intracellular accumulation without an uptake mediator providing a T1-positive MRI signal at 1.5 T and may be suitable for cell tracking in animal models with intraparenchymal hemorrhages such as stroke or malignant tumors.

Influence of neuroendocrine tumor cells on proliferation in prostatic carcinoma.

Neuroendocrine (NE) tumor cells in prostatic carcinoma (PCa) may influence tumor proliferation by a paracrine stimulus. The role of NE tumor cells is discussed controversially. This study investigates the influence of NE tumor differentiation on proliferation in PCa. Neuroendocrine differentiation, Ki-67, and Polo-like kinase 1 were studied immunohistochemically in 73 consecutive prostatectomies. Polo-like kinase 1 (PLK1) expression was also studied by Western and Northern blot analysis. Tumors were classified as high NE (HNE) and low NE differentiated (LNE), and depending on the growth pattern, with solitary and clusters of NE tumor cells. Low NE differentiated tumors were defined as less than 30 and HNE as 30 or more NE tumor cells per hot spot. Patients were followed by serum prostate-specific antigen (PSA) analysis. Neuroendocrine differentiation was present at least focally in 70% of tumors; 57% were HNE and 43% LNE. Solitary NE tumor cells were more often found in low-grade PCa, whereas clusters of NE tumor cells were more frequent in high-grade PCa. PLK1 messenger RNA and protein as well as Ki-67 were overexpressed in tumor tissue compared with tumor-free tissue. A stronger proliferation as determined by Ki-67 and PLK1 expression was present in HNE tumors compared with LNE tumors and in tumors with clusters in contrast to tumors with solitary NE tumor cells. Analysis for PSA relapse-free survival showed an earlier progression in HNE than in LNE tumors and in PCa with clusters of NE tumor cells. A significant and clustered NE differentiation in PCa may lead to an increased proliferation and earlier tumor progression, whereas few and solitary NE tumor cells have no prognostic impact.