The Distributional Characteristics of Multiple Sclerosis Lesions on Quantitative Susceptibility Mapping and Their Correlation With Clinical Severity.

Background: Multiple sclerosis (MS) patients have a wide spectrum of severity and responses to therapy; the personalization of treatment relies on sensitive and specific biomarkers. Previous studies have suggested that susceptibility contrast in demyelinated plaques is associated with iron-related pathology in multiple sclerosis which may indicate clinical severity. The aims of this study were to characterize the spatial distribution of MS lesions with different iron patterns by using quantitative susceptibility mapping and to explore neuroradiological findings that correlate with poor clinical outcome. Methods: Twenty-six patients with relapsing-remitting MS [14 men, 12 women; mean age, 29 ± 8 (standard deviation) years; age range, 21-52 years] were included in this study. Differences in lesion number, T2 volume, and susceptibility were compared among lesions subcategorized by location and by the presence or absence of a hyperintense rim on quantitative susceptibility mapping. Associations between these imaging features and clinical outcomes including Expanded Disability Status Scale scores and annual relapse rates were investigated. Results: A total of 811 unifocal MS lesions were included, and their QSM patterns were nodular hyperintensity with no rim (rim-, 540, 67%) or with a hyperintense rim on the edge (rim+, 172, 21%) and nodular isointensity (99, 12%). Rim+ lesions had significantly larger volume (115 ± 142 vs. 166 ± 185 mm3, p < 0.001) and lower susceptibility (4 ± 15 vs. 8 ± 16 ppb, p < 0.05) than rim- lesions. More rim+ lesions were found in periventricular areas [median, 45%; interquartile range (IQR), 36%], whereas a larger proportion of rim- lesions were distributed in juxtacortical (median, 32%; IQR, 21%) and deep white matter (median, 38%; IQR, 22%) areas. The annual relapse rate was positively correlated with the proportion of periventricular rim+ lesions (p < 0.001, r = 0.65) and the proportion of subtentorial rim+ lesions (p < 0.05, r = 0.40). Additionally, a significant association was found between the burden of periventricular rim+ lesions (ß = 0.64, p < 0.001) and the burden of subtentorial rim- lesions (ß = 0.36, p < 0.05). Conclusions: A high number or lesion burden of periventricular rim+ lesions or subtentorial lesions is associated with frequent clinical relapses.

A Case Report of Parry-Romberg Syndrome Misdiagnosed as Multiple Sclerosis.

Background: Parry-Romberg syndrome (PRS) is a rare disease that causes hemiatrophy of the face. The pathophysiological mechanisms involved in its etiology are unknown, but several previous reports suggest the involvement of autoimmune factors. Herein we describe the case of a patient with PRS who was initially misdiagnosed as having multiple sclerosis (MS). The relevant literature is briefly reviewed, and some previous reports suggesting associations between PRS and autoimmunity are discussed. Case Presentation: A 34-year-old man presented with recurrent paroxysmal weakness of the right hand, a 3-years history of unilateral tinnitus, and headache for 6 months. MS was initially diagnosed but the patient was subsequently diagnosed as having PRS on the basis of clinical manifestations and radiological findings. Conclusions: PRS may be associated with autoimmune pathogenesis, but the present case does not support that theory.

CLCN2-related leukoencephalopathy: a case report and review of the literature.

BACKGROUND: Loss-of-function mutations in the CLCN2 gene were recently discovered to be a cause of a type of leukodystrophy named CLCN2-related leukoencephalopathy (CC2L), which is characterized by intramyelinic edema. Herein, we report a novel mutation in CLCN2 in an individual with leukodystrophy. CASE PRESENTATION: A 38-year-old woman presented with mild hand tremor, scanning speech, nystagmus, cerebellar ataxia in the upper limbs, memory decline, tinnitus, and dizziness. An ophthalmologic examination indicated macular atrophy, pigment epithelium atrophy and choroidal capillary atrophy. Brain magnetic resonance imaging (MRI) showed the diffuse white matter involvement of specific white matter tracts. Decreased diffusion anisotropy was detected in various brain regions of the patient. Diffusion tensor tractography (DTT) showed obviously thinner tracts of interest than in the controls, with a decreased fiber number (FN), increased radial diffusivity (RD) and unchanged axial diffusivity (AD). A novel homozygous c.2257C > T (p.Arg753Ter) mutation in exon 20 of the CLCN2 gene was identified. CONCLUSION: CC2L is a rare condition characterized by diffuse edema involving specific fiber tracts that pass through the brainstem. The distinct MRI patterns could be a strong indication for CLCN2 gene analysis. The findings of our study may facilitate the understanding of the pathophysiology and clinical symptoms of this disease.

Susceptibility-weighted imaging in the differential diagnosis of autoimmune central nervous system vasculitis and multiple sclerosis.

OBJECTIVES: To determine the differentiating features of autoimmune central nervous system (CNS) vasculitis and multiple sclerosis (MS) on susceptibility-weighted imaging (SWI). METHODS: Seventy-three patients (27 with autoimmune CNS vasculitis and 46 with MS) who underwent magnetic resonance imaging with SWI sequence were included. The features of lesions and distinct SWI findings were investigated in both diseases. RESULTS: On SWI, autoimmune CNS vasculitis presented with a higher prevalence of multiple microbleeds (48.1%), cortical superficial siderosis (70.4%), and tortuosity of the vascular route (59.3%) than were found in MS (p < 0.001, p < 0.001, and p = 0.001, respectively). Multivariable logistic analysis showed that multiple microbleeds and cortical superficial siderosis were associated with a much higher probability of a diagnosis of autoimmune CNS vasculitis than of MS (OR 19.09, 95% CI 1.13-321.18, p = 0.041; and OR 13.20, 95% CI 2.22-78.30, p = 0.005, respectively). The presence of more than eleven lesions was associated with a lower probability of a diagnosis of autoimmune CNS vasculitis than of MS (OR 0.14, 95% CI 0.03-0.73, p = 0.020). CONCLUSIONS: SWI may be a useful adjunct in distinguishing autoimmune CNS vasculitis from MS. The identification of multiple microbleeds and cortical superficial siderosis can point to a diagnosis of autoimmune CNS vasculitis.

In Vivo Assessment of Neurodegeneration in Type C Niemann-Pick Disease by IDEAL-IQ.

Objective: To noninvasively assess the neurodegenerative changes in the brain of patients with Niemann-Pick type C (NPC) disease by measuring the lesion tissue with the iterative decomposition of water and fat with echo asymmetry and least square estimation-iron quantification (IDEAL-IQ). Materials and Methods: Routine brain MRI, IDEAL-IQ and 1H-proton magnetic resonance spectroscopy (1H-MRS, served as control) were performed on 12 patients with type C Niemann-Pick disease (4 males and 8 females; age range, 15-61 years; mean age, 36 years) and 20 healthy subjects (10 males and 10 females; age range, 20-65 years; mean age, 38 years). The regions with lesion and the normal appearing regions (NARs) of patients were measured and analyzed based on the fat/water signal intensity on IDEAL-IQ and the lipid peak on 1H-MRS. Results: Niemann-Pick type C patients showed a higher fat/water signal intensity ratio with IDEAL-IQ on T2 hyperintensity lesions and NARs (3.7-4.9%, p < 0.05 and 1.8-3.0%, p < 0.05, respectively), as compared to healthy controls (HCs) (1.2-2.3%). After treatment, the fat/water signal intensity ratio decreased (2.2-3.4%), but remained higher than in the HCs (p < 0.05). The results of the 1H-MRS measurements showed increased lipid peaks in the same lesion regions, and the micro-lipid storage disorder of NARs in NPC patients was detectable by IDEAL-IQ instead of 1H-MRS. Conclusion: The findings of this study suggested that IDEAL-IQ may be useful as a noninvasive and objective method in the evaluation of patients with NPC; additionally, IDEAL-IQ can be used to quantitatively measure the brain parenchymal adipose content and monitor patient follow-up after treatment of NPC.

Brain MRI findings in acute hepatic encephalopathy in liver transplant recipients.

Acute hepatic encephalopathy has significant morbidity and mortality in liver transplant recipients unless it is promptly treated. We evaluated the brain magnetic resonance (MR) imaging findings associated with acute hepatic encephalopathy in transplant recipients. We retrospectively reviewed the clinical and imaging data and outcomes of twenty-five liver transplant patients (16 male; mean age, 49.3 years) with clinically diagnosed acute hepatic encephalopathy and forty liver transplant patients (20 males; mean age, 45.5 years) without neurological symptoms suggestive of hepatic encephalopathy at our institution. Bilateral symmetric hyperintensities of the insular cortex and cingulate gyrus were observed in twenty-one patients (84.00%), bilateral symmetric extensive increased cortical signal intensity (involving two or more regions) was observed in 72.00% of the patients, leptomeningeal enhancement in 73.68%, and visualization of prominent venules in 52.00%. The most common symptom at diagnosis was rigidity (n = 14), and the plasma ammonia levels ranged from 68.63 to 192.16 µmol/L. After active treatment, 17 patients gradually recovered, four patients suffered from mild or moderate neurologic deficits, and four patients with widespread brain edema died. The specific brain MR imaging features were bilateral symmetric increased cortical signal intensity, especially in the insular cortex and cingulate gyrus, leptomeningeal enhancement, visualization of the prominent venules, and widespread brain edema. These features may indicate poor prognosis and should alert radiologists to the possibility of acute hepatic encephalopathy in liver transplant recipients and encourage clinicians to prepare appropriate treatment in advance.

Evidence of cortical reorganization of language networks after stroke with subacute Broca's aphasia: a blood oxygenation level dependent-functional magnetic resonance imaging study.

Aphasia is an acquired language disorder that is a common consequence of stroke. The pathogenesis of the disease is not fully understood, and as a result, current treatment options are not satisfactory. Here, we used blood oxygenation level-dependent functional magnetic resonance imaging to evaluate the activation of bilateral cortices in patients with Broca's aphasia 1 to 3 months after stroke. Our results showed that language expression was associated with multiple brain regions in which the right hemisphere participated in the generation of language. The activation areas in the left hemisphere of aphasia patients were significantly smaller compared with those in healthy adults. The activation frequency, volumes, and intensity in the regions related to language, such as the left inferior frontal gyrus (Broca's area), the left superior temporal gyrus, and the right inferior frontal gyrus (the mirror region of Broca's area), were lower in patients compared with healthy adults. In contrast, activation in the right superior temporal gyrus, the bilateral superior parietal lobule, and the left inferior temporal gyrus was stronger in patients compared with healthy controls. These results suggest that the right inferior frontal gyrus plays a role in the recovery of language function in the subacute stage of stroke-related aphasia by increasing the engagement of related brain areas.

The anti-inflammatory effect of donepezil on experimental autoimmune encephalomyelitis in C57 BL/6 mice.

Donepezil is a potent and selective acetylcholinesterase inhibitor. It has been reported to restore cognitive performance in multiple sclerosis (MS) patients and experimental autoimmune encephalomyelitis (EAE) mice, an established model of MS. However, there are no reports about the anti-inflammatory effects of donepezil on EAE. In this study, the donepezil treatments on EAE mice were initiated at day 7 post immunization (7 p.i., subclinical periods, early donepezil treatment) and day 13 p.i. (clinical periods, late donepezil treatment) with the dosage of 1, 2 and 4 mg/kg/d respectively and the treatments persisted throughout the experiments. Blood-brain barrier (BBB) permeability was detected by Evan's blue content, the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9, Akt and phosphorylated Akt (p-Akt) as well as nerve growth factor (NGF) and its precursor form (proNGF) in the brains of EAE mice were detected by Western blot, and the levels of interferon-γ and interleukin-4 in the splenocytes culture supernatants and brains of EAE mice were evaluated by ELISA. The results showed that the 2 mg/kg/d late donepezil treatment was the optimal dosage and could ameliorate clinical and pathological parameters, improve magnetic resonance imaging outcomes, reduce the permeability of BBB, inhibit the production of MMP-2 and MMP-9, modulate the expression of NGF and proNGF, increase Th2 bias and the phosphorylation of Akt in the brains of EAE mice. Our data suggested that the anti-inflammatory effects of donepezil may be a novel mechanism on treating EAE and provided further insights to understand the donepezil's neuroprotective activities in MS.

The protective effect of berberine against neuronal damage by inhibiting matrix metalloproteinase-9 and laminin degradation in experimental autoimmune encephalomyelitis.

OBJECTIVE: This study aims to assess the protective effect of berberine against neuronal damage in the brain parenchyma of mice with experimental autoimmune encephalomyelitis (EAE). METHODS: EAE was induced in female C57 BL/6 mice with myelin oligodendrocyte glycoprotein 35-55 amino acid peptide. The berberine treatment was initiated on the day of disease onset and administered daily until the mice were sacrificed. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay, gelatin gel, and gelatin in situ zymography were analysed in this study. RESULTS: Berberine reduced the TUNEL-positive neuronal cells of EAE mice. Gelatin gel and gelatin in situ zymography showed up-regulation of gelatinase activity, which was mainly located in neurons and colocalized with remarkable laminin degradation in EAE mice. Berberine significantly inhibited gelatinase activity and reduced the laminin degradation in EAE mice. DISCUSSION: Our data suggest that berberine could provide protection against neuronal damage in EAE by inhibiting gelatinase activity and reducing laminin degradation. These findings provide further support that berberine can be a potential therapeutic agent for multiple sclerosis.

Minocycline reduces oxygen-glucose deprivation-induced PC12 cell cytotoxicity via matrix metalloproteinase-9, integrin ß1 and phosphorylated Akt modulation.

Minocycline has shown anti-inflammatory, anti-apoptotic, and antioxidative activities in many models of cerebral ischemia and human acute ischemic stroke. However, the cellular and molecular bases for its neuroprotective effects have not been fully elucidated. In this study, we investigated whether pre-treatment with minocycline could attenuate oxygen-glucose deprivation-induced PC12 cytotoxicity. The activity of matrix metalloproteinase-9 was detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis zymography. And the expressions of integrin ß1, Akt and phosphorylated Akt were analyzed by Western blot. Our results showed that minocycline could ameliorate oxygen-glucose deprivation-induced PC12 cell cytotoxicity at concentrations of 20 nM-20 µM, down-regulate the production and activity of matrix metalloproteinase-9, inhibit the degradation of integrin ß1, and up-regulate Akt phosphorylation at optimal concentration of 200 nM. The results may provide a new area for minocycline's therapeutic intervention for improving the outcomes of cerebral ischemia.

Minocycline up-regulates the expression of brain-derived neurotrophic factor and nerve growth factor in experimental autoimmune encephalomyelitis.

Previous evidence demonstrated that minocycline could ameliorate clinical severity of experimental autoimmune encephalomyelitis and exhibit several anti-inflammatory and neuroprotective activities. However, few studies have been carried out to assess its effects on the expression of neurotrophins in experimental autoimmune encephalomyelitis or multiple sclerosis. Here we investigated the alteration of brain-derived neurotrophic factor and nerve growth factor in the sera, cerebral cortex, and lumbar spinal cord of experimental autoimmune encephalomyelitis C57 BL/6 mice in vivo as well as the splenocytes culture supernatants in vitro after minocycline administration. Our results demonstrated that minocycline could up-regulate the expression of brain-derived neurotrophic factor and nerve growth factor both in peripheral (sera and splenocytes culture supernatants) and target organs (cerebral cortex and lumber spinal cord) of mice with experimental autoimmune encephalomyelitis. These data suggest that up-regulation of neurotrophins in experimental autoimmune encephalomyelitis may be a novel neuroprotective mechanism of minocycline.

Imaging changes in neural circuits in patients with depression using (1)H-magnetic resonance spectroscopy and diffusion tensor imaging.

(1)H-magnetic resonance spectroscopy imaging and diffusion tensor imaging were performed in 19 patients with mild depression and in 13 controls. The mean age of the patients was 31 years. The mean Hamilton depression score of the patients was 22.5 ± 13.2. N-acetylaspartate, choline and creatine concentrations and the average diffusion coefficient and fractional anisotropy values were measured in the bilateral hippocampus, striatum, thalamus and prefrontal deep white matter. Compared with the control group, the mild depressed patients had: (1) a higher choline/creatine ratio and a negative correlation between the choline/creatine ratio and the average diffusion coefficient in the hippocampus; (2) a lower choline/creatine ratio and a higher fractional anisotropy in the striatum; (3) a lower fractional anisotropy and a positive correlation between the fractional anisotropy and the choline/creatine ratio in the prefrontal deep white matter; and (4) a higher average diffusion coefficient and a positive correlation between the choline/creatine ratio and the N-acetylaspartate/creatine ratio in the thalamus, as well as positive correlation between the choline/creatine ratio and Hamilton depression scores. These data suggest evidence of abnormal connectivity in neurofibrotic microstructures and abnormal metabolic alterations in the limbic-cortical-striatal-pallidal-thalamic neural circuit in patients with mild depression.

[Magnetic resonance imaging findings of lesions in limbic system related structures in general paresis of insane].

OBJECTIVE: To analyze the magnetic resonance imaging (MRI) findings of lesions in the limbic system related structures in general paresis of insane (GPI) patients so as to explore its pathogenesis and provide a new MRI diagnostic method. METHODS: The clinical data and MRI findings of lesions in the limbic system related structures were retrospectively analyzed for a total of 31 GPI patients. The parameters were volume and signal abnormality. RESULTS: On MRI, structural abnormalities were found in amygdaloid body (n = 29), hippocampus (n = 28), insular lobe (n = 24), parahippocampal gyrus (n = 23), lenticular nucleus (n = 23), corpus callosum (n = 20), caudate nucleus (n = 11), hypothalamus (n = 10), anterior nucleus of thalamus (n = 10), cingulate gyrus (n = 8) and thalamus (n = 2). The frequent manifestations were atrophy, swelling, T2 hyperintensity in various structures and T2 hypointensity in lenticular nucleus. CONCLUSION: A frequent involvement of limbic system structures in GPI patients may be related with dementia and other psychiatric symptoms. Swelling and T2 hyperintensity of involved structures may be the characteristic MRI manifestations of GPI.

MRI findings of cerebral cryptococcosis in immunocompetent patients.

Worldwide, cerebral cryptococcal infections caused by cryptococcus neoformans are mostly found in immunocompromised patients, but less found in immunocompetent patients with fewer related imaging reports in literatures. This pictorial essay describes some important MR imaging features in arriving at diagnosis for cerebral cryptococcosis in immunocompetent patients by way of five illustrative cases with intact MRI data.

Wnt 10b activates the CCN2 promoter in NIH 3T3 fibroblasts through the Smad response element.

Wnt proteins elevate expression of the CCN family. For example, Wnt10b induces the fibrogenic pro-adhesive molecule connective tissue growth factor (CTGF, CCN2) in NIH 3T3 fibroblasts. Wnt10b activates the CCN2 minimal promoter. In this report, we map the Wnt10b response element in the CCN2 minimal promoter to the previously identified Smad response element. These results suggest that Wnts may cross-talk with the Smad signaling pathway to induce fibrotic responses in fibroblasts.

Regulation of CCN2 mRNA expression and promoter activity in activated hepatic stellate cells.

The matricellular protein connective tissue growth factor (CCN2) is considered a faithful marker of fibroblast activation in wound healing and in fibrosis. CCN2 is induced during activation of hepatic stellate cells (HSC). Here, we investigate the molecular basis of CCN2 gene expression in HSC. Fluoroscence activated cell sorting was used to investigate CCN2 expression in HSC in vivo in mice treated with CCl(4). CCN2 and TGF-beta mRNA expression were assessed by polymerase chain reaction as a function of culture-induced activation of HSC. CCN2 promoter/reporter constructs were used to map cis-acting elements required for basal and TGFbeta-induced CCN2 promoter activity. Real-time polymerase chain reaction analysis was used to further clarify signaling pathways required for CCN2 expression in HSC. CCl(4) administration in vivo increased CCN2 production by HSC. In vitro, expression of CCN2 and TGF-beta mRNA were concommitantly increased in mouse HSC between days 0 and 14 of culture. TGFbeta-induced CCN2 promoter activity required the Smad and Ets-1 elements in the CCN2 promoter and was reduced by TGFbeta type I receptor (ALK4/5/7) inhibition. CCN2 overexpression in activated HSC was ALK4/5/7-dependent. As CCN2 overexpression is a faithful marker of fibrogenesis, our data are consistent with the notion that signaling through TGFbeta type I receptors such as ALK5 contributes to the activation of HSC and hence ALK4/5/7 inhibition would be expected to be an appropriate treatment for liver fibrosis.

Diffusion tensor imaging of the brain in patients with Alzheimer's disease and cerebrovascular lesions.

BACKGROUND: Recent autopsy study showed a high incidence of cerebrovascular lesions in Alzheimer's disease (AD). To assess the impact of cerebrovascular pathology in AD, we used diffusion tensor imaging (DTI) to study AD patients with and without cerebrovascular lesions. MATERIALS AND METHODS: Conventional and DTI scans were obtained from 10 patients with probable AD, 10 AD/V patients (probable AD with cerebrovascular lesions) and ten normal controls. Mean diffusivity (D) and fractional anisotropy (FA) values of some structures involved with AD pathology were measured. RESULTS: D value was higher in AD patients than in controls in hippocampus and the cingulate gyrus. In AD/V patients, increased D value was found in the same structures and also in the thalamus and basal ganglia compared to controls. There was a significant difference of D value between AD and AD/V patients. FA value reduced in the white matter of left inferior temporal gyrus and in the bilateral middle cingulate gyrus in patients with AD/V compared with controls. The MMSE (mini-mental state examination) score significantly correlated with FA value in the right hippocampus (r=0.639, P<0.019), in the right anterior cingulate gyrus (r=0.587, P<0.035) and in left parahippocampal gyrus (r=0.559, P<0.047). CONCLUSION: Cerebrovascular pathology had stronger impact on the D value than the AD pathology alone did. Elevated D value in thalamic and basal ganglia may contribute to cognitive decline in AD/V patients. Reduced FA values in AD/V patients may indicate that cerebrovascular pathology induced more severe white matter damage than the AD pathology alone did.

NF-kappaB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF.

Advanced breast cancers frequently metastasize to bone, resulting in osteolytic lesions, yet the underlying mechanisms are poorly understood. Here we report that nuclear factor-kappaB (NF-kappaB) plays a crucial role in the osteolytic bone metastasis of breast cancer by stimulating osteoclastogenesis. Using an in vivo bone metastasis model, we found that constitutive NF-kappaB activity in breast cancer cells is crucial for the bone resorption characteristic of osteolytic bone metastasis. We identified the gene encoding granulocyte macrophage-colony stimulating factor (GM-CSF) as a key target of NF-kappaB and found that it mediates osteolytic bone metastasis of breast cancer by stimulating osteoclast development. Moreover, we observed that the expression of GM-CSF correlated with NF-kappaB activation in bone-metastatic tumor tissues from individuals with breast cancer. These results uncover a new and specific role of NF-kappaB in osteolytic bone metastasis through GM-CSF induction, suggesting that NF-kappaB is a potential target for the treatment of breast cancer and the prevention of skeletal metastasis.