Multiple sclerosis plasma IgG aggregates induce complement-dependent neuronal apoptosis.

Grey matter pathology is central to the progression of multiple sclerosis (MS). We discovered that MS plasma immunoglobulin G (IgG) antibodies, mainly IgG1, form large aggregates (>100 nm) which are retained in the flow-through after binding to Protein A. Utilizing an annexin V live-cell apoptosis detection assay, we demonstrated six times higher levels of neuronal apoptosis induced by MS plasma IgG aggregates (n = 190, from two cohorts) compared to other neurological disorders (n = 116) and healthy donors (n = 44). MS IgG aggregate-mediated, complement-dependent neuronal apoptosis was evaluated in multiple model systems including primary human neurons, primary human astrocytes, neuroblastoma SH-SY5Y cells, and newborn mouse brain slices. Immunocytochemistry revealed the co-deposition of IgG, early and late complement activation products (C1q, C3b, and membrane attack complex C5b9), as well as active caspase 3 in treated neuronal cells. Furthermore, we found that MS plasma cytotoxic antibodies are not present in Protein G flow-through, nor in the paired plasma. The neuronal apoptosis can be inhibited by IgG depletion, disruption of IgG aggregates, pan-caspase inhibitor, and is completely abolished by digestion with IgG-cleaving enzyme IdeS. Transmission electron microscopy and nanoparticle tracking analysis revealed the sizes of MS IgG aggregates are greater than 100 nm. Our data support the pathological role of MS IgG antibodies and corroborate their connection to complement activation and axonal damage, suggesting that apoptosis may be a mechanism of neurodegeneration in MS.

Caregiver survey in glioblastoma focused on cognitive dysfunction: development and results from a multicenter study.

Aim: To develop a cognitive dysfunction (CD) focused questionnaire to evaluate caregiver burden in glioblastoma. Materials & methods: The survey was developed from stakeholder consultations and a pilot study, and disseminated at eight US academic cancer centers. Caregivers self-reported caring for an adult with glioblastoma and CD. Results: The 89-item survey covered demographics, CD symptoms and caregiver burden domains. Among 185 caregivers, most were white, educated females and reported memory problems as the most common CD symptom. An exposure-effect was observed, with increase in number of CD symptoms significantly associated with greater caregiver burden. Conclusion: This questionnaire could guide caregiver interventions and be adapted for use longitudinally, in community cancer settings, and in patients with brain metastases.

Glioblastoma (GBM) is a very aggressive brain cancer. People who have GBM have trouble remembering things and are unable to do things they used to do. These changes can be very hard. Researchers are trying to better understand what it is like for people who take care of people with GBM (or caregivers). In this study, researchers created a new survey for caregivers. The survey included questions about what caregivers see happening in their loved one with GBM. Caregivers said that memory problems were common. Also, when the patient had more problems the caregiver had a harder time, too. Researchers hope to improve the survey and use it in the future for more studies.

Short-term Topiramate treatment prevents radiation-induced cytotoxic edema in preclinical models of breast-cancer brain metastasis.

Background: Brain edema is a common complication of brain metastases (BM) and associated treatment. The extent to which cytotoxic edema, the first step in the sequence that leads to ionic edema, vasogenic edema and brain swelling, contributes to radiation-induced brain edema during BM remains unknown. This study aimed to determine whether radiation-associated treatment of BM induces cytotoxic edema and the consequences of blocking the edema in pre-clinical models of breast cancer brain metastases (BCBM). Methods: Using in vitro and in vivo models, we measured astrocytic swelling, trans-electric resistance (TEER) and aquaporin 4 (AQP4) expression following radiation. Genetic and pharmacological inhibition of AQP4 in astrocytes and cancer cells was used to assess the role of AQP4 in astrocytic swelling and brain water intake. An anti-epileptic drug that blocks AQP4 function (topiramate) was used to prevent cytotoxic edema in models of BM. Results: Radiation-induced astrocytic swelling and transient upregulation of AQP4 within the first 24 hours following radiation. Topiramate decreased radiation-induced astrocytic swelling, loss of TEER in astrocytes in vitro , and acute short term treatment (but not continuous administration), prevented radiation-induced increase in brain water content without pro-tumorigenic effects in multiple pre-clinical models of BCBM. AQP4 was expressed in clinical BM and breast cancer cell lines, but AQP4 targeting had limited direct pro-tumorigenic or radioprotective effects in cancer cells that could impact its clinical translation. Conclusions: Patients with BM could find additional benefits from acute and temporary preventive treatment of radiation-induced cytotoxic edema using anti-epileptic drugs able to block AQP4 function. Key points: Radiation induces cytotoxic edema via acute dysregulation of AQP4 in astrocytes in preclinical models of BM. Pharmacologic blockage of AQP4 function prevents water intake, astrocytic swelling and restores TEER in vitro. Pre-treatment with single-dose Topiramate prevents brain radiation-induced brain edema without direct tumor effects in pre-clinical models of BCBM. IMPORTANCE OF THE STUDY: In this study we describe a novel role for astrocytic swelling and cytotoxic edema in the progression of radiation-induced brain edema during BM treatment. While radiation-induced edema has been fully attributed to the disruption of the blood-brain barrier (BBB) and ensuing vasogenic effects, our results suggest that cytotoxic edema affecting astrocytes in the acute setting plays an important role in the progression of brain edema during BM standard of care. Current standard of care for brain edema involves pre-treatment with steroids and the use of bevacizumab only after clinically significant edema develops. Both interventions are presumed to target vasogenic edema. This study suggests that patients with BM could find additional benefits from acute and temporary preventive treatment of radiation-induced cytotoxic edema using an already FDA-approved anti-epileptic drug. Such early prevention strategy can be easily clinically implemented with the goal of minimizing treatment-related toxicities.

Retrospective analysis of hemispheric structural network change as a function of location and size of glioma.

Gliomas are neoplasms that arise from glial cell origin and represent the largest fraction of primary malignant brain tumours (77%). These highly infiltrative malignant cell clusters modify brain structure and function through expansion, invasion and intratumoral modification. Depending on the growth rate of the tumour, location and degree of expansion, functional reorganization may not lead to overt changes in behaviour despite significant cerebral adaptation. Studies in simulated lesion models and in patients with stroke reveal both local and distal functional disturbances, using measures of anatomical brain networks. Investigations over the last two decades have sought to use diffusion tensor imaging tractography data in the context of intracranial tumours to improve surgical planning, intraoperative functional localization, and post-operative interpretation of functional change. In this study, we used diffusion tensor imaging tractography to assess the impact of tumour location on the white matter structural network. To better understand how various lobe localized gliomas impact the topology underlying efficiency of information transfer between brain regions, we identified the major alterations in brain network connectivity patterns between the ipsilesional versus contralesional hemispheres in patients with gliomas localized to the frontal, parietal or temporal lobe. Results were indicative of altered network efficiency and the role of specific brain regions unique to different lobe localized gliomas. This work draws attention to connections and brain regions which have shared structural susceptibility in frontal, parietal and temporal lobe glioma cases. This study also provides a preliminary anatomical basis for understanding which affected white matter pathways may contribute to preoperative patient symptomology.

Global and Targeted Pathway Impact of Gliomas on White Matter Integrity Based on Lobar Localization.

Primary brain tumors comprise 28% of all tumors and 80% of malignant tumors. Pathophysiology of high-grade gliomas includes significant distortion of white matter architecture, necrosis, the breakdown of the blood brain barrier, and increased intracranial pressure. Diffusion tensor imaging (DTI), a diffusion weighted imaging technique, can be used to assess white matter architecture. Use of DTI as a non-invasive pathophysiological tool to analyze glioma impact on white matter microstructure has yet to be fully explored. Preliminary assessment of DTI tractography was done as a measure of intracranial tumor impact on white matter architecture. Specifically, we addressed three questions: 1) whether glioma differentially affects local white matter structure compared to metastasis, 2) whether glioma affects tract integrity of major white matter bundles, 3) whether glioma lobe localization affects tract integrity of different white matter bundles. In this study, we retrospectively investigated preoperative DTI scans from 24 patients undergoing tumor resection. Fiber tractography was estimated using a deterministic fiber tracking algorithm in DSI (diffusion spectrum imaging) Studio. The automatic anatomical labeling (AAL) atlas was used to define the left and right (L/R) hemisphere regions of interest (ROI). In addition, the John Hopkins University (JHU) White Matter Atlas was used to auto-segment major white matter bundle ROIs. For all tracts derived from ROI seed targets, we computed the following parameters: tract number, tract length, fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD). The DTI tractography analysis revealed that white matter integrity in the hemisphere ipsilateral to intracranial tumor was significantly compromised compared to the control contralateral hemisphere. No differences were observed between high vs low-grade gliomas, however, gliomas induced significantly greater white matter degradation than metastases. In addition, targeted analysis of major white matter bundles important for sensory/motor function (i.e., corticospinal tract and superior longitudinal fasciculus) revealed tract-parameter specific susceptibility due to the presence of the tumor. Finally, major tract bundles were differentially affected based on lobar localization of the glioma. These DTI-based tractographic analyses complement findings from gross histopathological examination of glioma impact on neural tissue. Global and focal white matter architecture, ipsilateral to glioma, shows higher rates of degradation or edema - based on DTI tractographic metrics - in comparison to normal brain or metastases. Gliomas, which arise in the parietal lobe, also have a higher negative impact (potentially due to increased edema) on white matter integrity of the superior longitudinal fasciculus(SLF) than those which arise in the frontal lobe. Future studies will focus on using preoperative and postoperative tractography to predict functional deficits following resective surgery.

Third Ventricular Cerebrospinal Fluid Cysts of Thalamic Origin: Review of Embryologic Origin, Presentation, and Management Strategies with a Case Series.

OBJECTIVE: Third ventricular cerebrospinal fluid (CSF) cysts of thalamic origin are rare. The objective of this study is to review their possible pathogenesis, clinical presentation, and management strategies with a case series describing management via an endoscopic approach with fenestration using a single burr-hole technique. METHODS: A systematic literature review of reported cases of thalamic cysts was conducted with further meta-analysis of CSF cysts that involve the third ventricle. The mode of presentation, pathologic analysis, surgical management, and outcomes were analyzed. RESULTS: Twenty-two studies reported between 1990 and 2013 described 42 cases of thalamic cyst. Of those cases, 13 were consistent with CSF cyst that originated in the thalamus and involved the third ventricle. Eight cases (61.5%) were treated via endoscopic fenestration, 2 cases (15.4%) were surgically drained, 2 cases (15.4%) were stereotactically aspirated, and 1 case (7.69%) was observed. The most common presenting symptoms were gait disturbance (26.3%) and headaches (26.3%) followed by tremors (15.8%) and weakness (15.8%). In our series, a single burr-hole technique was a successful definitive treatment, with an average period of 23 months. CONCLUSIONS: Third ventricular CSF cysts of thalamic origin most commonly present with hydrocephalus. They can be safely definitively treated via endoscopic fenestration to the CSF circulation using a single burr-hole technique. Long-term follow-up shows lasting improvement in symptoms without reaccumulation of the cyst.

Uncommon presentation of an intradiploic orbital epidermoid tumor: case report.

PURPOSE: Epidermoid tumors are uncommon entities that usually occur intradurally in the cerebellopontine angle and parasellar cisterns. The few cases that have been reported to occur in the intraorbital location involve patients in the first four decades of life. To our knowledge, an elderly person presenting with an orbital epidermoid tumor has never been reported. METHODS: A 67-year-old man presented with left-sided headache and eye pain. He was found to have a hemorrhagic lesion eroding bone of the greater and lesser wings of the sphenoid that was compressing the frontal and temporal lobes and displacing the globe. Significant edema of the frontal lobe was noted. RESULTS: Aggressive surgical excision was performed with cranioplasty and orbital reconstruction. Near resolution of the patient's proptosis and eye pain was achieved. Histologic analysis revealed the lesion to be an epidermoid tumor. CONCLUSIONS: Hemorrhage into a growing intradiploic orbital epidermoid and surrounding frontal lobe edema created an unusual presentation of this rarely occurring entity in an elderly man. Surgical excision allowed appropriate histologic diagnosis and resolution of symptoms. Epidermoid tumor is a rare but possible entity in the differential diagnosis of elderly patients presenting with acute ocular pain and proptosis.

Washing methanogenic cells with the liquid fraction from a Mars soil simulant and water mixture.

Certain methanogens have been shown to grow on a Mars soil simulant following a washing procedure using a carbonate buffer. In experiments where liquid fractions from the soil simulant and water mixtures were used in place of the buffer, two out of three of the species demonstrated significantly greater methane production compared to the buffer.