Focal Inflammatory Lesions Research Articles

Retigabine, a potassium channel opener, restores thalamocortical neuron functionality in a murine model of autoimmune encephalomyelitis

BackgroundMultiple Sclerosis (MS) is an autoimmune neurodegenerative disease, whose primary hallmark is the occurrence of inflammatory lesions in white and grey matter structures. Increasing evidence in MS patients and respective murine models reported an impaired ionic homeostasis driven by inflammatory-demyelination, thereby profoundly affecting signal propagation. However, the impact of a focal inflammatory lesion on single-cell and network functionality has hitherto not been fully elucidated. ObjectivesIn this study, we sought to determine the consequences of a localized cortical inflammatory lesion on the excitability and firing pattern of thalamic neurons in the auditory system. Moreover, we tested the neuroprotective effect of Retigabine (RTG), a specific Kv7 channel opener, on disease outcome. MethodsTo resemble the human disease, we focally administered pro-inflammatory cytokines, TNF-α and IFN-γ, in the primary auditory cortex (A1) of MOG35-55 immunized mice. Thereafter, we investigated the impact of the induced inflammatory milieu on afferent thalamocortical (TC) neurons, by performing ex vivo recordings. Moreover, we explored the effect of Kv7 channel modulation with RTG on auditory information processing, using in vivo electrophysiological approaches. ResultsOur results revealed that a cortical inflammatory lesion profoundly affected the excitability and firing pattern of neighboring TC neurons. Noteworthy, RTG restored control-like values and TC tonotopic mapping. ConclusionOur results suggest that RTG treatment might robustly mitigate inflammation-induced altered excitability and preserve ascending information processing.

Use of gadolinium-based contrast agents in multiple sclerosis: a review by the ESMRMB-GREC and ESNR Multiple Sclerosis Working Group.

Magnetic resonance imaging (MRI) is the most sensitive technique for detecting inflammatory demyelinating lesions in multiple sclerosis (MS) and plays a crucial role in diagnosis and monitoring treatment effectiveness, and for predicting the disease course. In clinical practice, detection of MS lesions is mainly based on T2-weighted and contrast-enhanced T1-weighted sequences. Contrast-enhancing lesions (CEL) on T1-weighted sequences are related to (sub)acute inflammation, while new or enlarging T2 lesions reflect the permanent footprint from a previous acute inflammatory demyelinating event. These two types of MRI features provide redundant information, at least in regular monitoring of the disease. Due to the concern of gadolinium deposition after repetitive injections of gadolinium-based contrast agents (GBCAs), scientific organizations and regulatory agencies in Europe and North America have proposed that these contrast agents should be administered only if clinically necessary. In this article, we provide data on the mode of action of GBCAs in MS, the indications of the use of these agents in clinical practice, their value in MS for diagnostic, prognostic, and monitoring purposes, and their use in specific populations (children, pregnant women, and breast-feeders). We discuss imaging strategies that achieve the highest sensitivity for detecting CELs in compliance with the safety regulations established by different regulatory agencies. Finally, we will briefly discuss some alternatives to the use of GBCA for detecting blood-brain barrier disruption in MS lesions. CLINICAL RELEVANCE STATEMENT: Although use of GBCA at diagnostic workup of suspected MS is highly valuable for diagnostic and prognostic purposes, their use in routine monitoring is not mandatory and must be reduced, as detection of disease activity can be based on the identification of new or enlarging lesions on T2-weighted images. KEY POINTS: • Both the EMA and the FDA state that the use of GBCA in medicine should be restricted to clinical scenarios in which the additional information offered by the contrast agent is required. • The use of GBCA is generally recommended in the diagnostic workup in subjects with suspected MS and is generally not necessary for routine monitoring in clinical practice. • Alternative MRI-based approaches for detecting acute focal inflammatory MS lesions are not yet ready to be used in clinical practice.

In vivo MRI is sensitive to remyelination in a nonhuman primate model of multiple sclerosis.

Remyelination is crucial to recover from inflammatory demyelination in multiple sclerosis (MS). Investigating remyelination in vivo using magnetic resonance imaging (MRI) is difficult in MS, where collecting serial short-interval scans is challenging. Using experimental autoimmune encephalomyelitis (EAE) in common marmosets, a model of MS that recapitulates focal cerebral inflammatory demyelinating lesions, we investigated whether MRI is sensitive to, and can characterize, remyelination. In six animals followed with multisequence 7 T MRI, 31 focal lesions, predicted to be demyelinated or remyelinated based on signal intensity on proton density-weighted images, were subsequently assessed with histopathology. Remyelination occurred in four of six marmosets and 45% of lesions. Radiological-pathological comparison showed that MRI had high statistical sensitivity (100%) and specificity (90%) for detecting remyelination. This study demonstrates the prevalence of spontaneous remyelination in marmoset EAE and the ability of in vivo MRI to detect it, with implications for preclinical testing of pro-remyelinating agents.

Whole-lesion histogram analysis of multiple diffusion metrics for differentiating lung cancer from inflammatory lesions.

Whole-lesion histogram analysis can provide comprehensive assessment of tissues by calculating additional quantitative metrics such as skewness and kurtosis; however, few studies have evaluated its value in the differential diagnosis of lung lesions. To compare the diagnostic performance of conventional diffusion-weighted imaging (DWI), intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) and diffusion kurtosis imaging (DKI) in differentiating lung cancer from focal inflammatory lesions, based on whole-lesion volume histogram analysis. Fifty-nine patients with solitary pulmonary lesions underwent multiple b-values DWIs, which were then postprocessed using mono-exponential, bi-exponential and DKI models. Histogram parameters of the apparent diffusion coefficient (ADC), true diffusivity (D), pseudo-diffusion coefficient (D*), and perfusion fraction (f), apparent diffusional kurtosis (Kapp) and kurtosis-corrected diffusion coefficient (Dapp) were calculated and compared between the lung cancer and inflammatory lesion groups. Receiver operating characteristic (ROC) curves were constructed to evaluate the diagnostic performance. The ADCmean, ADCmedian, D mean and D median values of lung cancer were significantly lower than those of inflammatory lesions, while the ADCskewness, Kapp mean, Kapp median, Kapp SD, Kapp kurtosis and Dapp skewness values of lung cancer were significantly higher than those of inflammatory lesions (all p < 0.05). ADCskewness (p = 0.019) and D median (p = 0.031) were identified as independent predictors of lung cancer. D median showed the best performance for differentiating lung cancer from inflammatory lesions, with an area under the ROC curve of 0.777. Using a D median of 1.091 × 10-3 mm2/s as the optimal cut-off value, the sensitivity, specificity, positive predictive value and negative predictive value were 69.23%, 85.00%, 90.00% and 58.62%, respectively. Whole-lesion histogram analysis of DWI, IVIM and DKI parameters is a promising approach for differentiating lung cancer from inflammatory lesions, and D median shows the best performance in the differential diagnosis of solitary pulmonary lesions.

Selective PDE4 subtype inhibition provides new opportunities to intervene in neuroinflammatory versus myelin damaging hallmarks of multiple sclerosis

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by focal inflammatory lesions and prominent demyelination. Even though the currently available therapies are effective in treating the initial stages of disease, they are unable to halt or reverse disease progression into the chronic progressive stage. Thus far, no repair-inducing treatments are available for progressive MS patients. Hence, there is an urgent need for the development of new therapeutic strategies either targeting the destructive immunological demyelination or boosting endogenous repair mechanisms. Using in vitro, ex vivo, and in vivo models, we demonstrate that selective inhibition of phosphodiesterase 4 (PDE4), a family of enzymes that hydrolyzes and inactivates cyclic adenosine monophosphate (cAMP), reduces inflammation and promotes myelin repair. More specifically, we segregated the myelination-promoting and anti-inflammatory effects into a PDE4D- and PDE4B-dependent process respectively. We show that inhibition of PDE4D boosts oligodendrocyte progenitor cells (OPC) differentiation and enhances (re)myelination of both murine OPCs and human iPSC-derived OPCs. In addition, PDE4D inhibition promotes in vivo remyelination in the cuprizone model, which is accompanied by improved spatial memory and reduced visual evoked potential latency times. We further identified that PDE4B-specific inhibition exerts anti-inflammatory effects since it lowers in vitro monocytic nitric oxide (NO) production and improves in vivo neurological scores during the early phase of experimental autoimmune encephalomyelitis (EAE). In contrast to the pan PDE4 inhibitor roflumilast, the therapeutic dose of both the PDE4B-specific inhibitor A33 and the PDE4D-specific inhibitor Gebr32a did not trigger emesis-like side effects in rodents. Finally, we report distinct PDE4D isoform expression patterns in human area postrema neurons and human oligodendroglia lineage cells. Using the CRISPR-Cas9 system, we confirmed that pde4d1/2 and pde4d6 are the key targets to induce OPC differentiation. Collectively, these data demonstrate that gene specific PDE4 inhibitors have potential as novel therapeutic agents for targeting the distinct disease processes of MS.

Epidemiology and Pathophysiology of Multiple Sclerosis.

This article provides an overview of genetic, environmental, and lifestyle risk factors affecting the disease course of multiple sclerosis (MS) and reviews the pathophysiologic characteristics of both relapsing and progressive MS. The prevalence of MS has increased in recent decades, and costs of care for patients with MS have risen dramatically. Black, Asian, and Hispanic individuals may be at risk for more severe MS-related disability. Multiple genetic MS risk factors have been identified. Factors such as low vitamin D levels and a history of Epstein-Barr virus, smoking, and obesity, especially during childhood, also influence MS risk. Traditionally thought to be a T-cell-mediated disease, recent research has highlighted the additional roles of B cells and microglia in both relapsing and progressive MS. Complex interactions between genetic, environmental, and lifestyle factors affect the risk for MS as well as the disease course. People of color have historically been underrepresented in both MS clinical trials and literature, but current research is attempting to better clarify unique considerations in these groups. MS pathology consists of the focal inflammatory lesions that have been well characterized in relapsing MS, as well as a more widespread neurodegenerative component that is posited to drive progressive disease. Recent advances in characterization of both the inflammatory and neurodegenerative aspects of MS pathophysiology have yielded potential targets for future therapeutic options.

Combined model of radiomics, clinical, and imaging features for differentiating focal pneumonia-like lung cancer from pulmonary inflammatory lesions: an exploratory study

BackgroundOnly few studies have focused on differentiating focal pneumonia-like lung cancer (F-PLC) from focal pulmonary inflammatory lesion (F-PIL). This exploratory study aimed to evaluate the clinical value of a combined model incorporating computed tomography (CT)-based radiomics signatures, clinical factors, and CT morphological features for distinguishing F-PLC and F-PIL.MethodsIn total, 396 patients pathologically diagnosed with F-PLC and F-PIL from two medical institutions between January 2015 and May 2021 were retrospectively analyzed. Patients from center 1 were included in the training (n = 242) and internal validation (n = 104) cohorts. Moreover, patients from center 2 were classified under the external validation cohort (n = 50). The clinical and CT morphological characteristics of both groups were compared first. And then, a clinical model incorporating clinical and CT morphological features, a radiomics model reflecting the radiomics signature of lung lesions, and a combined model were developed and validated, respectively.ResultsAge, gender, smoking history, respiratory symptoms, air bronchogram, necrosis, and pleural attachment differed significantly between the F-PLC and F-PIL groups (all P < 0.05). For the clinical model, age, necrosis, and pleural attachment were the most effective factors to differentiate F-PIL from F-PLC, with the area under the curves (AUCs) of 0.838, 0.819, and 0.717 in the training and internal and external validation cohorts, respectively. For the radiomics model, five radiomics features were found to be significantly related to the identification of F-PLC and F-PIL (all P < 0.001), with the AUCs of 0.804, 0.877, and 0.734 in the training and internal and external validation cohorts, respectively. For the combined model, five radiomics features, age, necrosis, and pleural attachment were independent predictors for distinguishing between F-PLC and F-PIL, with the AUCs of 0.915, 0.899, and 0.805 in the training and internal and external validation cohorts, respectively. The combined model exhibited a better performance than had the clinical and radiomics models.ConclusionsThe combined model, which incorporates CT-based radiomics signatures, clinical factors, and CT morphological characteristics, is effective in differentiating F-PLC from F-PIL.

Patterns of Cerebrospinal Fluid Biomarkers and Amyloid Positron Emission Tomography in a Patient with Cerebral Amyloid Angiopathy-Related Inflammation

Cerebral amyloid angiopathy-related inflammation (CAA-RI) is a distinct subset of cerebral amyloid angiopathy characterized by the auto-inflammatory response to amyloid-laden small arteries of cerebral cortex and leptomeninges. Clinical features include cognitive-behavioral change, headache, focal neurologic deficits and seizure. Because anti-inflammatory treatments can rapidly relieve neurologic symptoms, early diagnosis is critical. Herein, we report a CAA-RI case with distinct laboratory findings of a decreased cerebrospinal fluid amyloid beta 1-42 level and relatively reduced florbetaben uptake in the focal inflammatory lesion during the acute phase of CAA-RI.

Contrast-enhanced ultrasound of transplant organs — liver and kidney — in children

Ultrasound (US) is the first-line imaging tool for evaluating liver and kidney transplants during and after the surgical procedures. In most patients after organ transplantation, gray-scale US coupled with color/power and spectral Doppler techniques is used to evaluate the transplant organs, assess the patency of vascular structures, and identify potential complications. In technically difficult or inconclusive cases, however, contrast-enhanced ultrasound (CEUS) can provide prompt and accurate diagnostic information that is essential for management decisions. CEUS is indicated to evaluate for vascular complications including vascular stenosis or thrombosis, active bleeding, pseudoaneurysms and arteriovenous fistulas. Parenchymal indications for CEUS include evaluation for perfusion defects and focal inflammatory and non-inflammatory lesions. When transplant rejection is suspected, CEUS can assist with prompt intervention by excluding potential underlying causes for organ dysfunction. Intracavitary CEUS applications can evaluate the biliary tract of a liver transplant (e.g., for biliary strictures, bile leak or intraductal stones) or the urinary tract of a renal transplant (e.g., for urinary obstruction, urine leak or vesicoureteral reflux) as well as the position and patency of hepatic, biliary and renal drains and catheters. The aim of this review is to present current experience regarding the use of CEUS to evaluate liver and renal transplants, focusing on the examination technique and interpretation of the main imaging findings, predominantly those related to vascular complications.

Metal Imbalance in Neurodegenerative Diseases with a Specific Concern to the Brain of Multiple Sclerosis Patients.

There is increasing evidence that deregulation of metals contributes to a vast range of neurodegenerative diseases including multiple sclerosis (MS). MS is a chronic inflammatory disease of the central nervous system (CNS) manifesting disability and neurological symptoms. The precise origin of MS is unknown, but the disease is characterized by focal inflammatory lesions in the CNS associated with an autoimmune reaction against myelin. The treatment of this disease has mainly been based on the prescription of immunosuppressive and immune-modulating agents. However, the rate of progressive disability and early mortality is still worrisome. Metals may represent new diagnostic and predictive markers of severity and disability as well as innovative candidate drug targets for future therapies. In this review, we describe the recent advances in our understanding on the role of metals in brain disorders of neurodegenerative diseases and MS patients.

DIFFERENTIAL RESPONSE TO GLUCOCORTICOID IMMUNOSUPPRESSION OF TWO DISTINCT INFLAMMATORY SIGNS ASSOCIATED WITH PUNCTATE INNER CHOROIDOPATHY

To describe the differential response of two distinct inflammatory signs occurring in eyes with punctate inner choroidopathy. Retrospective, observational case series using multimodal imaging. Four eyes of 4 myopic female patients (mean age of 35 years, range 31-42 years) presenting with retinal manifestations of punctate inner choroidopathy. All study eyes had 2 distinct signs of active disease: 1) acute focal hyperreflective lesions splitting the retinal pigment epithelium/Bruch membrane complex on optical coherence tomography which appeared hypoautofluorescent on fundus autofluorescence and 2) more diffuse areas of outer retinal disruption limited to the ellipsoid zone and interdigitation zone on optical coherence tomography and corresponding to hyperautofluorescence on fundus autofluorescence. All patients were treated with oral prednisone and demonstrated prompt regression of the retinal pigment epithelium/Bruch membrane complex lesions with a concurrent, paradoxical centrifugal expansion of outer retinal disruption. The outer retinal disruption eventually resolved in all eyes (mean time of 6 weeks, range 4-10 weeks). In patients with punctate inner choroidopathy, two distinct inflammatory signs observed with multimodal imaging display a differential response to systemic corticosteroids. Although focal inflammatory lesions splitting the retinal pigment epithelium/Bruch membrane complex seem to respond rapidly, the more diffuse, transient outer retinal disruption shows little response. This difference in treatment response may reflect different immunological phenomena with independent natural history.

Evaluation of lung damage in pneumonia, from chest magnetic resonance imaging, in primary diagnosis and in the follow-up of treatment

Purpose of the study. To evaluate the practical significance of MRI in the primary diagnosis of inflammatory lung diseases, as well as in follow-up control of treatment, also in comparison with the results of CT of the chest.Material and Methods. In 25 patients with acute pneumonia, six of them with acute myocardial infarction developed as complication of it, the MRI of the chest organs was performed in T1 - and T2-weighted (-w.) modes, also with fat signal suppression, with slice thickness of 2.5 to 5 mm, in a matrix of 256 × 256 or 256 ×392 pixels, with a scanning field of view as large as 40 x 40 cm. In T1-w. mode TR = 390–650 ms, TE = 10–15 ms. When T2-w. scanning, respectively, TR = 2900 -4000 ms, TE = 20–25 ms. Paramagnetic contrast enhancement was also carried out in 16 of 24 patients, at a dosage of 0.1 mmol/kg of body weight. Post-contrast images were acquired 12-17 minutes after the introduction of paramagnetic agent. In 17 out of 25 of our patients, chest CT was also performed.Results. The minimal cross-dimension of focal inflammatory lesions for community-acquired pneumonia, imaged with MRI chest scanning was as little as 9 х 21 mm. The dimensions of lung lesion obtained from the MRI scanning did correlate significantly with results of the CT (r = 0.96, p &lt; 0.001). Also MRI of the lung did prove the successful cure of pneumonia. Also in six cases the MRI verified the acute myocardial infarction occurred as complication of severe pneumonia. Based on the results of MRI of the lungs and chest, the treatment strategy was supplemented in 16 cases and significantly changed in 9 cases.Conclusion. MRI of the lungs employing the T1- and T2-weighted protocols with fat suppression, diffusionweighted imaging and use of contrast enhancement delivers highly efficient technique of imaging of nodal, segment and lobe inflammation. MRI of the chest should be reasonably employed for diagnosis and follow-up of treatment in hospitals and diagnostic units possessing high- and middle-field MRI scanners able toacquire the images in breath-synchronised mode.

Gadolinium enhancement on cranial MRI in multiple sclerosis is age dependent.

Epidemiological, pathological and radiological studies suggest that inflammatory demyelination in MS is an age-dependent process, and that the formation of focal inflammatory demyelinating lesions decreases with age. Gadolinium-enhancing lesions are a biomarker of inflammatory disease activity in MS, but little is known about the relation of age and gadolinium enhancement on cranial MRI scans in people with MS. In this study, we investigated the association of age and other risk factors with gadolinium enhancement on cranial MRI in a retrospective cross-sectional clinical MS cohort. In a cohort including 1543 people with CIS and MS, we investigated the association of the risk factors age, sex, disease course, immunomodulatory drug (IMD) treatment, and disability with gadolinium enhancement on cranial MRI scans using a binary logistic regression model. Age was the most important factor associated with gadolinium enhancement, with the odds of gadolinium enhancement decreasing with advancing age. Participants with CIS had lower odds of gadolinium enhancement (odds ratio of 0.42, 95% confidence interval of 0.24-0.72 compared to RRMS). Sex, disease course and IMD treatment were not significantly associated with gadolinium enhancement in our cohort. Our investigation shows that gadolinium enhancement is strongly associated with age. Since gadolinium enhancement is a marker of inflammatory disease activity, our findings suggest that inflammatory disease activity declines with age, and that IMD treatment may be more beneficial in younger and less useful in older people with MS.

Folate Receptor β-Targeted PET Imaging of Macrophages in Autoimmune Myocarditis.

Currently available imaging techniques have limited specificity for the detection of active myocardial inflammation. Aluminum 18F-labeled 1,4,7-triazacyclononane-N,N',N″-triacetic acid conjugated folate (18F-FOL) is a PET tracer targeting folate receptor β (FR-β), which is expressed on activated macrophages at sites of inflammation. We evaluated 18F-FOL PET for the detection of myocardial inflammation in rats with autoimmune myocarditis and studied the expression of FR-β in human cardiac sarcoidosis specimens. Methods: Myocarditis was induced by immunizing rats (n = 18) with porcine cardiac myosin in complete Freund adjuvant. Control rats (n = 6) were injected with Freund adjuvant alone. 18F-FOL was intravenously injected, followed by imaging with a small-animal PET/CT scanner and autoradiography. Contrast-enhanced high-resolution CT or 18F-FDG PET images were used for coregistration. Rat tissue sections and myocardial autopsy samples from 6 patients with cardiac sarcoidosis were studied for macrophages and FR-β. Results: The myocardium of 10 of 18 immunized rats showed focal macrophage-rich inflammatory lesions, with FR-β expression occurring mainly in M1-polarized macrophages. PET images showed focal myocardial 18F-FOL uptake colocalizing with inflammatory lesions (SUVmean, 2.1 ± 1.1), whereas uptake in the remote myocardium of immunized rats and controls was low (SUVmean, 0.4 ± 0.2 and 0.4 ± 0.1, respectively; P < 0.01). Ex vivo autoradiography of tissue sections confirmed uptake of 18F-FOL in myocardial inflammatory lesions. Uptake of 18F-FOL in inflamed myocardium was efficiently blocked by a nonlabeled FR-β ligand folate glucosamine in vivo. The myocardium of patients with cardiac sarcoidosis showed many FR-β-positive macrophages in inflammatory lesions. Conclusion: In a rat model of autoimmune myocarditis, 18F-FOL shows specific uptake in inflamed myocardium containing macrophages expressing FR-β, which were also present in human cardiac sarcoid lesions. Imaging of FR-β expression is a potential approach for the detection of active myocardial inflammation.

Current questions of multiple sclerosis: the secunder progressive form of the disease

Recent data suggest that long-term worsening is common in relapsing-remitting multiple sclerosis patients and is largely independent of relapses or new lesion formation on brain MRI. The current definition of secunder progressive multiple sclerosis is worsening of disability independent of relapses over at least 6-month interval. Early focal inflammatory disease activity and spinal cord lesion are predictors of very-long term disease outcomes in relapse - onset multiple sclerosis. The potential of PET imaging to visualize hidden inflammation in MS brain in vivo is an important contribution for better understanding the progression of the disease. Therefore, PET imaging is a promising tool in detecting the conversion from relapsing remitting multiple sclerosis to secunder progressive form of multiple sclerosis. Furthermore, neuro-axonal damage is the pathological substrate of permanent disability in different neurological disorders including multiple sclerosis. The neurofilament proteins have promise in this context because their levels rise upon neuro-axonal damage not only in the cerebrospinal fluid but also in blood. Patients with increased serum levels of neurofilament at baseline, independent of other clinical and MRI variables, experience significantly more brain and spinal cord volume loss over 2 years and 5 years of follow-up. The kynurenine-pathway abnormalities may be associated with the swich from early-mild stage multiple sclerosis to debilitating progressive forms of the disease. Analysis of these metabolites in serum may have application as multiple sclerosis disease biomarkers. Free radical action has been suggested as a causal factor in the illness. Increased free radical production and consumption of the scavenger molecules were found during the active phase of the disease. Based on the clinical findings (EXPAND Study) and pathomechanism of the disease siponimod is approved by the US Food and Drug Administration for the treatment of relapsing remitting forms of multiple sclerosis, to include secunder progressive multiple sclerosis with active disease, relapsing-remitting multiple sclerosis and clinically isolated syndrome.

Nuclear Medicine Image Interpretation Progress in the Assessment of Cardiac Sarcoidosis: July &lt;b&gt;2019&lt;/b&gt; ASNC/JSNC Joint Session

Sarcoidosis is a significant disease affecting the heart. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is a well-validated method for identifying significant focal inflammatory sarcoid lesions. The recent progress in image interpretation in nuclear medicine improves the diagnosis and the risk stratification in patients with cardiac sarcoidosis. Especially, metabolic activity, texture analysis, phase analysis, right ventricle assessment, and digital PET/CT are promising methods to assess cardiac sarcoidosis. This review focuses on the latest data analyses and image interpretation used in nuclear medicine to assess cardiac sarcoidosis.

Laquinimod ameliorates secondary brain inflammation

Accumulating evidence suggests that a degenerative processes within the brain can trigger the formation of new, focal inflammatory lesions in Multiple Sclerosis (MS). Here, we used a novel pre-clinical MS animal model to test whether the amelioration of degenerative brain events reduces the secondary recruitment of peripheral immune cells and, in consequence, inflammatory lesion development.Neural degeneration was induced by a 3 weeks cuprizone intoxication period. To mitigate the cuprizone-induced pathology, animals were treated with Laquinimod (25 mg/kg) during the cuprizone-intoxication period. At the beginning of week 6, encephalitogenic T cell development in peripheral lymphoid organs was induced by the immunization with myelin oligodendrocyte glycoprotein 35–55 peptide (i.e., Cup/EAE). Demyelination, axonal injury and reactive gliosis were determined by immunohistochemistry. Positron emission tomography (PET) imaging was performed to analyze glia activation in vivo.Vehicle-treated cuprizone mice displayed extensive callosal demyelination, glia activation and enhanced TSPO-ligand binding. This cuprizone-induced pathology was profoundly ameliorated in mice treated with Laquinimod. In vehicle-treated Cup/EAE mice, the cuprizone-induced pathology triggered massive peripheral immune cell recruitment into the forebrain, evidenced by multifocal perivascular inflammation, glia activation and neuro-axonal injury. While anti myelin oligodendrocyte glycoprotein 35–55 peptide immune responses were comparable in vehicle- and Laquinimod-treated Cup/EAE mice, the cuprizone-triggered immune cell recruitment was ameliorated by the Laquinimod treatment.This study clearly illustrates that amelioration of a primary brain-intrinsic degenerative process secondary halts peripheral immune cell recruitment and, in consequence, inflammatory lesion development. These findings have important consequences for the interpretation of the results of clinical studies.

Early imaging predictors of long-term outcomes in relapse-onset multiple sclerosis.

The clinical course of relapse-onset multiple sclerosis is highly variable. Demographic factors, clinical features and global brain T2 lesion load have limited value in counselling individual patients. We investigated early MRI predictors of key long-term outcomes including secondary progressive multiple sclerosis, physical disability and cognitive performance, 15 years after a clinically isolated syndrome. A cohort of patients with clinically isolated syndrome (n = 178) was prospectively recruited within 3 months of clinical disease onset and studied with MRI scans of the brain and spinal cord at study entry (baseline) and after 1 and 3 years. MRI measures at each time point included: supratentorial, infratentorial, spinal cord and gadolinium-enhancing lesion number, brain and spinal cord volumetric measures. The patients were followed-up clinically after ∼15 years to determine disease course, and disability was assessed using the Expanded Disability Status Scale, Paced Auditory Serial Addition Test and Symbol Digit Modalities Test. Multivariable logistic regression and multivariable linear regression models identified independent MRI predictors of secondary progressive multiple sclerosis and Expanded Disability Status Scale, Paced Auditory Serial Addition Test and Symbol Digit Modalities Test, respectively. After 15 years, 166 (93%) patients were assessed clinically: 119 (72%) had multiple sclerosis [94 (57%) relapsing-remitting, 25 (15%) secondary progressive], 45 (27%) remained clinically isolated syndrome and two (1%) developed other disorders. Physical disability was overall low in the multiple sclerosis patients (median Expanded Disability Status Scale 2, range 0-10); 71% were untreated. Baseline gadolinium-enhancing (odds ratio 3.16, P < 0.01) and spinal cord lesions (odds ratio 4.71, P < 0.01) were independently associated with secondary progressive multiple sclerosis at 15 years. When considering 1- and 3-year MRI variables, baseline gadolinium-enhancing lesions remained significant and new spinal cord lesions over time were associated with secondary progressive multiple sclerosis. Baseline gadolinium-enhancing (β = 1.32, P < 0.01) and spinal cord lesions (β = 1.53, P < 0.01) showed a consistent association with Expanded Disability Status Scale at 15 years. Baseline gadolinium-enhancing lesions was also associated with performance on the Paced Auditory Serial Addition Test (β = - 0.79, P < 0.01) and Symbol Digit Modalities Test (β = -0.70, P = 0.02) at 15 years. Our findings suggest that early focal inflammatory disease activity and spinal cord lesions are predictors of very long-term disease outcomes in relapse-onset multiple sclerosis. Established MRI measures, available in routine clinical practice, may be useful in counselling patients with early multiple sclerosis about long-term prognosis, and personalizing treatment plans.

Investigation of activin A in inflammatory responses of the testis and its role in the development of testicular fibrosis.

Does activin A contribute to testicular fibrosis under inflammatory conditions? Our results show that activin A and key fibrotic proteins are increased in human testicular biopsies with leukocytic infiltrates and impaired spermatogenesis and in murine experimental autoimmune orchitis (EAO) and that activin A stimulates fibrotic responses in peritubular cells (PTCs) and NIH 3T3 fibroblasts. Fibrosis is a feature of EAO. Activin A, a regulator of fibrosis, was increased in testes of mice with EAO and its expression correlated with severity of the disease. This is a cross-sectional and longitudinal study of adult mice immunized with testicular homogenate (TH) in adjuvant to induce EAO, collected at 30 (n= 6), 50 (n= 6) and 80 (n= 5) days after first immunization. Age-matched mice injected with adjuvant alone (n= 14) and untreated mice (n= 15) were included as controls. TH-immunized mice with elevated endogenous follistatin, injected with a non-replicative recombinant adeno-associated viral vector carrying a gene cassette of follistatin (rAAV-FST315; n= 3) or vector with an empty cassette (empty vector controls; n= 2) 30days prior to the first immunization, as well as appropriate adjuvant (n= 2) and untreated (n = 2) controls, were also examined.Human testicular biopsies showing focal inflammatory lesions associated with impaired spermatogenesis (n= 7) were included. Biopsies showing intact spermatogenesis without inflammation, from obstructive azoospermia patients, served as controls (n= 7).Mouse primary PTC and NIH 3T3 fibroblasts were stimulated with activin A and follistatin 288 (FST288) to investigate the effect of activin A on the expression of fibrotic markers. Production of activin A by mouse primary Sertoli cells (SCs) was also investigated. Testicular RNA and protein extracts collected from mice at days 30, 50 and 80 after first immunization were used for analysis of fibrotic marker genes and proteins, respectively. Total collagen was assessed by hydroxyproline assay and fibronectin; collagen I, III and IV, α-smooth muscle actin (α-SMA) expression and phosphorylation of suppressor of mothers against decapentaplegic (SMAD) family member 2 were measured by western blot. Immunofluorescence was used to detect fibronectin. Fibronectin (Fn), αSMA (Acta2), collagen I (Col1a2), III (Col3a1) and IV (Col4a1) mRNA in PTC and NIH 3T3 cells treated with activin A and/or FST288 were measured by quantitative RT-PCR (qRT-PCR). Activin A in SC following tumour necrosis factor (TNF) or FST288 stimulation was measured by ELISA. Human testicular biopsies were analysed by qRT-PCR for PTPRC (CD45) and activin A (INHBA), hydroxyproline assay and immunofluorescence. Production of activin A by SC was stimulated by 25 and 50ng/ml TNF (P< 0.01, P< 0.001, respectively) as compared to untreated cells. INHBA mRNA was increased in human testicular biopsies with leukocytic infiltrates and impaired spermatogenesis, compared with control biopsies (P< 0.05), accompanied by increased total collagen (P< 0.01) and fibronectin deposition. Total testicular collagen (P< 0.0001) and fibronectin protein expression (P< 0.05) were also increased in EAO, and fibronectin expression was correlated with the severity of the disease (r= 0.9028). In animals pre-treated with rAAV-FST315 prior to immunization with TH, protein expression of fibronectin was comparable to control. Stimulation of PTC and NIH 3T3 cells with activin A increased fibronectin mRNA (P< 0.05) and the production of collagen I (P< 0.001; P< 0.01) and fibronectin (P< 0.05). Moreover, activin A also increased collagen IV mRNA (P< 0.05) in PTC, while αSMA mRNA (P< 0.01) and protein (P< 0.0001) were significantly increased by activin A in NIH 3T3 cells. N/A. A limited number of human testicular specimens was available for the study. Part of the study was performed in vitro, including NIH 3T3 cells as a surrogate for testicular fibroblasts. Resident fibroblasts and PTC may contribute to the progression of testicular fibrosis following inflammation, and activin A is implicated as a key mediator of this process. This work was supported by the National Health and Medical Research Council of Australia, the Victorian Government's Operational Infrastructure Support Program and the International Research Training Group between Justus Liebig University (Giessen) and Monash University (Melbourne) (GRK 1871/1-2) on `Molecular pathogenesis on male reproductive disorders' funded by the Deutsche Forschungsgemeinschaft and Monash University. The authors declare no competing financial interests.

Effects of Optic Neuritis, T2 Lesions, and Microstructural Diffusion Integrity in the Visual Pathway on Cortical Thickness in Pediatric-Onset Multiple Sclerosis.

Pediatric-onset multiple sclerosis (POMS) is associated with focal inflammatory lesions and the loss of cortical and deep gray matter. Optic neuritis (ON) and white matter (WM) lesions in the visual pathway can directly contribute to visual cortical mantle thinning. We determine the relative contributions of MS insult on anterior and posterior visual pathway integrity. High- and low-contrast visual acuity, optical coherence tomography (OCT), and 3T MRI scans were obtained from 20 POMS patients (10 with remote ON) and 22 age- and sex-matched healthy controls. Cortical mantle thickness was measured using FreeSurfer. Fractional anisotropy (FA) and mean diffusivity were calculated for postchiasmal optic radiations (with and without WM lesions). Groups were compared using Student's t-test (adjusted for multiple comparisons), and simple linear regression was used to investigate interrelationships between measures. Mean cortical thickness of the whole brain was reduced in patients (2.49mm) versus controls (2.58mm,P = .0432) and in the visual cortex (2.07mm vs. 2.17mm,P = .0059), although the foveal confluence was spared. Mean FA of the optic radiations was reduced in POMS (.40) versus controls (.43,P = .0042) and correlated with visual cortical mantle thickness in POMS (P = .017). Visual acuity, OCT measures, and lesion volumes in the optic radiations were not associated with cortical mantle thickness. POMS negatively impacts the integrity of the anterior visual pathway, but it is the loss of WM integrity that drives anterograde loss of the cortical mantle. Preserved visual acuity and foveal sparing imply some degree of functional and structural resilience.