Brain Lesion Volume Research Articles

Pharmacological and Non-pharmacological Therapies of Cognitive Impairment in Multiple Sclerosis.

BackgroundCognitive impairment is one of the most important clinical features of neurodegenerative disorders including multiple sclerosis (MS). Conducted research shows that up to 65 percent of MS patients have cognitive deficits such as episodic memory, sustained attention, reduced verbal fluency; however, the cognitive MS domain is information processing speed. It is the first syndrome of cognitive dysfunction and the most widely affected in MS. Occasionally these impairments occur even before the appearance of physical symptoms.MethodsTherefore, this review focused on the current status of our knowledge about possible methods of treatment cognitive impairment in MS patients including novel strategies. Research and online content was performed using Medline and EMBASE databases.ResultsThe most recent research suggests that cognitive impairment is correlated with brain lesion volume and brain atrophy. The examination of the cognitive impairment is usually based on particular neuropsychological batteries. However, it can be not enough to make a precise diagnosis. This creates a demand to find markers that might be useful for identifying patients with risk of cognitive impairment at an early stage of the disease. Currently the most promising methods consist of neuroimaging indicators, such as diffusion tensor imaging, the magnetization transfer ratio, and N-acetyl aspartate levels. Diagnosis problems are strictly connected with treatment procedures. There are two main cognitive therapies: pharmacological (disease modifying drugs (DMD), symptomatic treatments) and non-pharmacological interventions that are focused on psychological and physical rehabilitation. Some trials have shown a positive association between physical activity and the cognitive function.ConclusionThis article is an overview of the current state of knowledge related to cognition impairment treatment in MS. Additionally, novel strategies for cognitive impairments such as cryostimulation and other complementary methods are presented.

20-HETE synthesis inhibition promotes cerebral protection after intracerebral hemorrhage without inhibiting angiogenesis

20-HETE, an arachidonic acid metabolite synthesized by cytochrome P450 4A, plays an important role in acute brain damage from ischemic stroke or subarachnoid hemorrhage. We tested the hypothesis that 20-HETE inhibition has a protective effect after intracerebral hemorrhage (ICH) and then investigated its effect on angiogenesis. We exposed hippocampal slice cultures to hemoglobin and induced ICH in mouse brains by intrastriatal collagenase injection to investigate the protective effect of 20-HETE synthesis inhibitor N-hydroxy-N′-(4-n-butyl-2-methylphenyl)-formamidine (HET0016). Hemoglobin-induced neuronal death was assessed by propidium iodide after 18 h in vitro. Lesion volume, neurologic deficits, cell death, reactive oxygen species (ROS), neuroinflammation, and angiogenesis were evaluated at different time points after ICH. In cultured mouse hippocampal slices, HET0016 attenuated hemoglobin-induced neuronal death and decreased levels of proinflammatory cytokines and ROS. In vivo, HET0016 reduced brain lesion volume and neurologic deficits, and decreased neuronal death, ROS production, gelatinolytic activity, and the inflammatory response at three days after ICH. However, HET0016 did not inhibit angiogenesis, as levels of CD31, VEGF, and VEGFR2 were unchanged on day 28. We conclude that 20-HETE is involved in ICH-induced brain damage. Inhibition of 20-HETE synthesis may provide a viable means to mitigate ICH injury without inhibition of angiogenesis.

Plasma citrulline levels are increased in patients with multiple sclerosis

BackgroundMultiple sclerosis is an inflammatory demyelinating disorder of the central nervous system (CNS). Myelin basic protein (MBP), which is one of the main compounds of CNS myelin, appears to be hypercitrullinated in the brain of patients with MS. We hypothesized that MS is associated with an increased release of citrulline from the brain. MethodsTwenty-five patients with MS, 25 controls without neurological disease (CwND) and 25 subjects with non-MS cerebral white matter lesions were included in this study. Groups were matched for age and gender. Clinical MS disability measures were recorded by means of Expanded Disability Status Scale (EDSS) scores and Multiple Sclerosis Severity Scores (MSSS). Citrulline was assessed in plasma obtained from an antecubital peripheral vein (PV) in all participants. Additional internal jugular vein (IJV) samples were examined in 10 patients with MS and 10 CwND. Twelve patients with MS underwent brain magnetic resonance imaging to determine total brain and T2 fluid-attenuated inversion recovery lesion volume. ResultsMedian [IQR] PV citrulline levels were increased in patients with MS (50.47 [86.61] μM), as compared to CwND (33.58 [43.65] μM, P = 0.042) and subjects with non-MS cerebral white matter lesions (32.41 [28.86] μM, P = 0.006). Citrulline IJV levels and IJV/PV ratios were comparable between patients with MS and CwND. No significant correlations were found between PV citrulline levels and any of the clinical, nor radiological, disease measures. ConclusionPV plasma levels of citrulline are elevated in patients with MS but this does not seem to result from an augmented release from the brain. Increased plasma citrulline may be a promising new biomarker in MS but the origin and significance need to be further elucidated.

Effects of progesterone on the neonatal brain following hypoxia-ischemia

Progesterone displays a strong potential for the treatment of neonatal hypoxic-ischemic encephalopathy since it has been shown to be beneficial in the treatment of the central nervous system injuries in adult animals. Here, we evaluated the effects of the administration of progesterone (10mg/kg) in seven-days-old male Wistar rats submitted to neonatal hypoxia-ischemia (HI). Progesterone was administered immediately before ischemia and/or 6 and 24h after the onset of hypoxia. The body weight of the animals, the volume of brain lesion and the expression of p-Akt and procaspase-3 in the hippocampus were evaluated. All animals submitted to HI showed a reduction in the body weight. However, this reduction was more remarkable in those animals which received progesterone before surgery. Administration of progesterone was unable to reduce the volume of brain damage caused by HI. Moreover, no significant differences were observed in the expression of p-Akt and procaspase-3 in animals submitted to HI and treated with either progesterone or vehicle. In summary, progesterone did not show a neuroprotective effect on the volume of brain lesion in neonatal rats submitted to hypoxia-ischemia. Furthermore, progesterone was unable to modulate p-Akt and procaspase-3 signaling pathways, which may explain the absence of neuroprotection. On the other hand, it seems that administration of progesterone before ischemia exerts some systemic effect, leading to a remarkable reduction in the body weight.

Sequestosome 1 Deficiency Delays, but Does Not Prevent Brain Damage Formation Following Acute Brain Injury in Adult Mice.

Neuronal degeneration following traumatic brain injury (TBI) leads to intracellular accumulation of dysfunctional proteins and organelles. Autophagy may serve to facilitate degradation to overcome protein debris load and therefore be an important pro-survival factor. On the contrary, clearing may serve as pro-death factor by removal of essential or required proteins involved in pro-survival cascades. Sequestosome 1 (SQSTM1/p62) is a main regulator of the autophagic pathway that directs ubiquinated cargoes to autophagosomes for degradation. We show that SQSTM1 protein levels are suppressed 24 h and by trend 5 days after trauma. In line with these data the expression of Sqstm1 mRNA is reduced by 30% at day 3 after and stays depressed until day 5 after injury, indicating an impaired autophagy post controlled cortical impact (CCI). To determine the potential role of SQSTM1-dependent autophagy after TBI, mice lacking SQSTM1 (SQSTM1-KO) and littermates (WT) were subjected to CCI and brain lesion volume was determined 24 h and 5 days after insult. Lesion volume is 17% smaller at 24 h and immunoblotting reveals a reduction by trend of cell death marker αII-spectrin cleavage. But there is no effect on brain damage and cell death markers 5 days after trauma in SQSTM1-KO compared with WT. In line with these data neurofunctional testing does not reveal any differences. Additionally, gene expression of inflammatory (Tnf-α, iNos, Il-6, and Il-1β) and protein degradation markers (Bag1 and Bag3) were quantified by real-time PCR. Protein levels of LC3, BAG1, and BAG3 were analyzed by immunoblotting. Real-time PCR reveals minor changes in inflammatory marker gene expression and reduced Bag3 mRNA levels 5 days after trauma. Immunoblotting of autophagy markers LC3, BAG1, and BAG3 does not show any difference between KO and WT 24 h and 5 days after TBI. In conclusion, genetic ablation of SQSTM1-dependent autophagy leads to a delay but shows no persistent effect on post-traumatic brain damage formation. SQSTM1 therefore only plays a minor role for secondary brain damage formation and autophagic clearance of debris after TBI.

Embolic protection devices for transcatheter aortic valve replacement.

Transcatheter aortic valve replacement (TAVR) is a major advancement in the treatment of severe aortic valve stenosis in elderly high-risk patients. Implementing TAVR also in younger intermediate- or low-risk patients increases interest in the possibility of further lowering the risk of perioperative cerebrovascular events. To this aim, some embolic protection devices (EPDs) have been developed, some of which have already been approved for clinical use. Nevertheless, the cause of cerebrovascular events after TAVR is multifactorial, and selection of patients who would benefit from EPD is crucial to further improve outcomes, survival rate and quality of life. We reviewed the available literature in order to assess the incidence of and the mechanisms responsible for neurological events that can occur during TAVR, and we analysed clinical results and imaging findings following EPD use. Clinical trials for Embrella, TriGuard, Sentinel and Embol-X devices were designed to test their safety and their ability to prevent neurological complications in patients having TAVR. So far, published results showed that EPD may help in reducing the volume and size of periprocedural silent ischaemic brain lesions identified on magnetic resonance images but not in reducing the incidence of new lesions and new neurological events. The clinical impact of EPD in lowering the number of transient ischaemic attacks/strokes during TAVR needs to be further investigated in randomized trials.

Evidence of progressive tissue loss in the core of chronic MS lesions: A longitudinal DTI study.

ObjectiveUsing diffusion tensor imaging (DTI), we examined chronic stable MS lesions, peri-lesional white matter (PLWM) and normal appearing white matter (NAWM) in patients with relapsing-remitting multiple sclerosis (RRMS) for evidence of progressive tissue destruction and evaluated whether diffusivity change is associated with conventional MRI parameters and clinical findings.MethodPre- and post-gadolinium T1, T2 and DTI images were acquired from 55 consecutive RRMS patients at baseline and 42.3 ± 9.7 months later. Chronic stable T2 lesions of sufficient size were identified in 43 patients (total of 134 lesions). Diffusivity parameters such as axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD) and fractional anisotropy (FA) were compared at baseline and follow-up. MRI was also performed in 20 normal subjects of similar age and gender.ResultsWithin the core of chronic MS lesions the diffusion of water molecules significantly increased over the follow-up period, while in NAWM all diffusivity indices remained stable. Since increase of AD and RD in lesional core was highly concordant, indicating isotropic nature of diffusivity change, and considering potential effect of crossing fibers on directionally-selective indices, only MD, a directionally-independent measure, was used for further analysis. The significant increase of MD in the lesion core during the follow-up period (1.29 ± 0.19 μm2/ms and 1.34 ± 0.20 μm2/ms at baseline and follow-up respectively, P < 0.0001) was independent of age or disease duration, total brain lesion volume or new lesion activity, lesion size or location and baseline tissue damage (T1 hypointensity). Change of MD in the lesion core, however, was associated with progressive brain atrophy (r = 0.47, P = 0.002). A significant gender difference was also observed: the MD change in male patients was almost twice that of female patients (0.030 ± 0.04 μm2/ms and 0.058 ± 0.03 μm2/ms in female and male respectively, P = 0.01). Sub-analysis of lesions with lesion-free surrounding revealed the largest MD increase in the lesion core, while MD progression gradually declined towards PLWM. MD in NAWM remained stable over the follow-up period.ConclusionThe significant increase of isotropic water diffusion in the core of chronic stable MS lesions likely reflects gradual, self-sustained tissue destruction in demyelinated white matter that is more aggressive in males.

Risk of leptomeningeal carcinomatosis in patients with brain metastases treated with stereotactic radiosurgery.

There is limited available literature examining factors that predispose patients to the development of LMC after stereotactic radiosurgery (SRS) for brain metastases. We sought to evaluate risk factors that may predispose patients to LMC after SRS treatment in this case-control study of patients with brain metastases who underwent single-fraction SRS between 2011 and 2016. Demographic and clinical information were collected retrospectively for 19 LMC cases and 30 controls out of 413 screened patients with brain metastases. Risk factors of interest were evaluated by univariate and multivariate logistic regression analyses and overall survival rateswere evaluated by Kaplan-Meier survival analysis. About 5% of patients with brain metastases treated with SRS developed LMC. Patients with LMC (median 154 days, 95% CI 33-203 days) demonstrated a poorer overall survival than matched controls (median 417 days, 95% CI 121-512 days, p = 0.002). The most common primary tumor histologies that lead to the development of LMC were non-small cell lung cancer (36.8%), breast cancer (26.3%), and melanoma (21.1%). No association was found between the risk of LMC and the location of the brain lesion or total volume of brain metastases. Prior surgical resection of brain metastasesbefore SRS was associated with a 6.5 times higher odds (95% CI 1.45-29.35, p = 0.01) of developing LMC post-radiosurgerycompared tothose with no prior resections of brain metastases. Additionally, adjuvant WBRT may help to reduce the risk of LMC and can be considered in decision-making for patients who have had brain metastasectomy.

Imaging outcome measures for progressive multiple sclerosis trials

Imaging markers that are reliable, reproducible and sensitive to neurodegenerative changes in progressive multiple sclerosis (MS) can enhance the development of new medications with a neuroprotective mode-of-action. Accordingly, in recent years, a considerable number of imaging biomarkers have been included in phase 2 and 3 clinical trials in primary and secondary progressive MS. Brain lesion count and volume are markers of inflammation and demyelination and are important outcomes even in progressive MS trials. Brain and, more recently, spinal cord atrophy are gaining relevance, considering their strong association with disability accrual; ongoing improvements in analysis methods will enhance their applicability in clinical trials, especially for cord atrophy. Advanced magnetic resonance imaging (MRI) techniques (e.g. magnetization transfer ratio (MTR), diffusion tensor imaging (DTI), spectroscopy) have been included in few trials so far and hold promise for the future, as they can reflect specific pathological changes targeted by neuroprotective treatments. Position emission tomography (PET) and optical coherence tomography have yet to be included. Applications, limitations and future perspectives of these techniques in clinical trials in progressive MS are discussed, with emphasis on measurement sensitivity, reliability and sample size calculation.

Neuroinflammation and its relationship to changes in brain volume and white matter lesions in multiple sclerosis.

Brain magnetic resonance imaging is an important tool in the diagnosis and monitoring of multiple sclerosis patients. However, magnetic resonance imaging alone provides limited information for predicting an individual patient's disability progression. In part, this is because magnetic resonance imaging lacks sensitivity and specificity for detecting chronic diffuse and multi-focal inflammation mediated by activated microglia/macrophages. The aim of this study was to test for an association between 18 kDa translocator protein brain positron emission tomography signal, which arises largely from microglial activation, and measures of subsequent disease progression in multiple sclerosis patients. Twenty-one patients with multiple sclerosis (seven with secondary progressive disease and 14 with a relapsing remitting disease course) underwent T1- and T2-weighted and magnetization transfer magnetic resonance imaging at baseline and after 1 year. Positron emission tomography scanning with the translocator protein radioligand 11C-PBR28 was performed at baseline. Brain tissue and lesion volumes were segmented from the T1- and T2-weighted magnetic resonance imaging and relative 11C-PBR28 uptake in the normal-appearing white matter was estimated as a distribution volume ratio with respect to a caudate pseudo-reference region. Normal-appearing white matter distribution volume ratio at baseline was correlated with enlarging T2-hyperintense lesion volumes over the subsequent year (ρ = 0.59, P = 0.01). A post hoc analysis showed that this association reflected behaviour in the subgroup of relapsing remitting patients (ρ = 0.74, P = 0.008). By contrast, in the subgroup of secondary progressive patients, microglial activation at baseline was correlated with later progression of brain atrophy (ρ = 0.86, P = 0.04). A regression model including the baseline normal-appearing white matter distribution volume ratio, T2 lesion volume and normal-appearing white matter magnetization transfer ratio for all of the patients combined explained over 90% of the variance in enlarging lesion volume over the subsequent 1 year. Glial activation in white matter assessed by translocator protein PET significantly improves predictions of white matter lesion enlargement in relapsing remitting patients and is associated with greater brain atrophy in secondary progressive disease over a period of short term follow-up.

Distinctive Roles for α7*- and α9*-Nicotinic Acetylcholine Receptors in Inflammatory and Autoimmune Responses in the Murine Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis.

Previous studies have demonstrated immunosuppressive and anti-inflammatory effects of nicotine, including in the experimental autoimmune encephalomyelitis (EAE) model in mice of some forms of multiple sclerosis (MS). Other studies using knock-out (KO) mice have implicated nicotinic acetylcholine (ACh) receptors containing α7, α9, or β2 subunits (α7*-, α9*- or β2*-nAChR) in different, disease-exacerbating or disease-ameliorating processes. These outcomes are in harmony with gene expression analyses showing nAChR subunit mRNA in many classes of immune system cell types. Consistent with influences on disease status, predictable effects of nAChR subunit (and subtype) KO, or of nicotine exposure, are seen on immune cell numbers and distribution and on cytokine levels or other markers of immunity, inflammation, demyelination, and axonal degradation. Providing support for our hypotheses about distinctive roles for nAChR subtypes in EAE, here we have used direct and adoptive EAE induction and a nAChR subunit gene double knock-out (DKO) strategy. Immune cell expression of nAChR α9 subunits as protein is demonstrated by immunostaining of isolated CD4+, CD8+, CD11b+ and CD11c+ cells from wild-type (WT) mice, but not in cells from nAChR α9 subunit KO animals. Nicotine exposure is protective against directly-induced EAE in WT or α7/α9 DKO animals relative to effects seen in WT/vehicle-treated mice, but, remarkably, EAE is exacerbated in vehicle-treated α7/α9 DKO mice. Brain lesion volume and intra-cranial inflammatory activity similarly are higher in DKO/vehicle than in WT/vehicle-treated animals, although nicotine’s protective effects are seen in each instance. By contrast, in adoptive transfer studies, disease severity is attenuated and disease onset is delayed in recipients of splenocytes from WT animals treated with nicotine rather than with vehicle. Moreover, protection as seen in nicotine-treated WT animals is the same in recipients of splenocytes from nAChR α7/α9 DKO mice irrespective of their exposure to nicotine or vehicle. When combined with previous observations, these findings are consistent with disease exacerbation (or even induction) being mediated at least in part via α9*-nAChR in peripheral immune cells. They also suggest protective roles of central nervous system (CNS) α7*-nAChR. The results suggest that both α7*- and α9*-nAChR are potential targets of therapeutic ligands to modulate inflammation and autoimmunity.

Progression of retinal ganglion cell loss in multiple sclerosis is associated with new lesions in the optic radiations.

The mechanism of retinal ganglion cell and retinal nerve fiber layer loss in multiple sclerosis (MS) remains unknown. This study aimed to investigate the association between temporal retinal nerve fiber layer (tRNFL) thinning and disease activity in the brain determined by T2 lesions on magnetic resonance imaging (MRI). Fifty-five consecutive patients with relapsing-remitting MS and 25 controls were enrolled. All patients underwent annual optical coherence tomography and high-resolution MRI scans for tRNFL thickness and brain lesion volume analysis, respectively. Significant tRNFL thickness reduction was observed over the 3-year follow-up period at a relatively constant rate (1.02 μm/year). Thinning of tRNFL fibers was more prominent in younger patients (P = 0.01). The tRNFL loss was associated with new MRI lesions in the optic radiations (ORs). There was significantly greater tRNFL thinning in patients with new lesional activity in the ORs compared with patients with new lesions outside the ORs (P = 0.009). This study supports the notion that retrograde transneuronal degeneration caused by OR lesions might play a role in progressive retinal nerve fiber layer loss. In addition, the results of the study also indicate that the disease-related neurodegenerative changes in the retina start much earlier than the clinical diagnosis of MS.

The Influence of Proinflammatory Factors on the Neuroprotective Efficiency of Multipotent Mesenchymal Stromal Cells in Traumatic Brain Injury.

We studied the neuroprotective potential of multipotent mesenchymal stromal cells in traumatic brain injury and the effect of inflammatory preconditioning on neuroprotective properties of stem cells under in vitro conditions. To this end, the effects of cell incubation with LPS or their co-culturing with leukocytes on production of cytokines IL-1α, IL-6, TNFα, and MMP-2 and MMP-9 by these cells were evaluated. Culturing under conditions simulating inflammation increased the production of all these factors by multipotent mesenchymal stromal cells. However, acquisition of the inflammatory phenotype by stromal cells did not reduce their therapeutic effectiveness in traumatic brain injury. Moreover, in some variants of inflammatory preconditioning, multipotent mesenchymal stromal cells exhibited more pronounced neuroprotective properties reducing the volume of brain lesion and promoting recovery of neurological functions after traumatic brain injury.

Neuron-specific caveolin-1 overexpression improves motor function and preserves memory in mice subjected to brain trauma.

Studies in vitro and in vivo demonstrate that membrane/lipid rafts and caveolin (Cav) organize progrowth receptors, and, when overexpressed specifically in neurons, Cav-1 augments neuronal signaling and growth and improves cognitive function in adult and aged mice; however, whether neuronal Cav-1 overexpression can preserve motor and cognitive function in the brain trauma setting is unknown. Here, we generated a neuron-targeted Cav-1-overexpressing transgenic (Tg) mouse [synapsin-driven Cav-1 (SynCav1 Tg)] and subjected it to a controlled cortical impact model of brain trauma and measured biochemical, anatomic, and behavioral changes. SynCav1 Tg mice exhibited increased hippocampal expression of Cav-1 and membrane/lipid raft localization of postsynaptic density protein 95, NMDA receptor, and tropomyosin receptor kinase B. When subjected to a controlled cortical impact, SynCav1 Tg mice demonstrated preserved hippocampus-dependent fear learning and memory, improved motor function recovery, and decreased brain lesion volume compared with wild-type controls. Neuron-targeted overexpression of Cav-1 in the adult brain prevents hippocampus-dependent learning and memory deficits, restores motor function after brain trauma, and decreases brain lesion size induced by trauma. Our findings demonstrate that neuron-targeted Cav-1 can be used as a novel therapeutic strategy to restore brain function and prevent trauma-associated maladaptive plasticity.-Egawa, J., Schilling, J. M., Cui, W., Posadas, E., Sawada, A., Alas, B., Zemljic-Harpf, A. E., Fannon-Pavlich, M. J., Mandyam, C. D., Roth, D. M., Patel, H. H., Patel, P. M., Head, B. P. Neuron-specific caveolin-1 overexpression improves motor function and preserves memory in mice subjected to brain trauma.

Analysis of brain and spinal cord lesions to occult brain damage in seropositive and seronegative neuromyelitis optica

ObjectivesAccording to aquaporin-4 antibody (AQP4-Ab), neuromyelitis optica (NMO) can be divided into seropositive and seronegative subgroups. The purpose of this study was to a) compare the distribution of spinal cord and brain magnetic resonance imaging (MRI) lesions between seropositive and seronegative NMO patients; b) explore occult brain damage in seropositive and seronegative NMO patients; and c) explore the contribution of visible lesions to occult grey and white matter damage in seropositive and seronegative NMO patients. Materials and methodsTwenty-two AQP4-Ab seropositive and 14 seronegative NMO patients and 30 healthy controls were included in the study. Two neuroradiologists independently measured the brain lesion volume (BLV) and the length of spinal cord lesion (LSCL) and recorded the region of brain lesions. The normal-appearing grey matter volume (NAGM-GMV) and white matter fractional anisotropy (NAWM-FA) were calculated for each subject to evaluate occult brain damage. ResultsThe seropositive patients displayed more extensive damage in the spinal cord than the seronegative patients, and the seronegative group had a higher proportion of patients with brainstem lesions (28.57%) than the seropositive group (4.55%, P=0.064). Both NMO subgroups exhibited reduced NAGM-GMV and NAWM-FA compared with the healthy controls. NAGM-GMV was negatively correlated with LSCL in the seropositive group (rs=−0.444, P=0.044) and with BLV in the seronegative group (rs=−0.768, P=0.002). NAWM-FA was also negatively correlated with BLV in the seropositive group (rs=−0.682, P<0.001). ConclusionOur findings suggest that the occult brain damage in these two NMO subgroups may be due to different mechanisms, which need to be further clarified.

Different patterns of longitudinal brain and spinal cord changes and their associations with disability progression in NMO and MS.

To investigate the longitudinal spinal cord and brain changes in neuromyelitis optica (NMO) and multiple sclerosis (MS) and their associations with disability progression. We recruited 28 NMO, 22 MS, and 20 healthy controls (HC), who underwent both spinal cord and brain MRI at baseline. Twenty-five NMO and 20 MS completed 1-year follow-up. Baseline spinal cord and brain lesion loads, mean upper cervical cord area (MUCCA), brain, and thalamus volume and their changes during a 1-year follow-up were measured and compared between groups. All the measurements were also compared between progressive and non-progressive groups in NMO and MS. MUCCA decreased significantly during the 1-year follow-up in NMO not in MS. Percentage brain volume changes (PBVC) and thalamus volume changes in MS were significantly higher than NMO. MUCCA changes were significantly different between progressive and non-progressive groups in NMO, while baseline brain lesion volume and PBVC were associated with disability progression in MS. MUCCA changes during 1-year follow-up showed association with clinical disability in NMO. Spinal cord atrophy changes were associated with disability progression in NMO, while baseline brain lesion load and whole brain atrophy changes were related to disability progression in MS. • Spinal cord atrophy progression was observed in NMO. • Spinal cord atrophy changes were associated with disability progression in NMO. • Brain lesion and atrophy were related to disability progression in MS.

Topical application of the hematostatic agent Surgiflo® could attenuate brain injury in experimental TBI mice

Object: The pathologies resulting from traumatic brain injury (TBI) have been thoroughly studied, but rarely have the effects of bleeding and coagulation in the early stage of TBI been considered. In this study, we investigated the effects of topical Surgiflo® application on brain injury in experimental TBI mice using S100β, MAP-2 and mNSS scores.Methods: TBI was induced by modified weight drop injury in male C57BL/6 mice. The mice were then randomly divided into (i) the sham group, (ii) TBI mice applied with saline (vehicle), and (iii) TBI mice applied with Surgiflo® in the same volume. Modified neurological severity scores (mNSS) were measured on days 0 (before surgery), 1, 3, 7, and 28 to evaluate neurologic functional deficits. At day 28, the mice were sacrificed, and the forebrains were sliced. The effects of Surgiflo® on microtubule-associated protein 2 and serum S100β protein were examined by immunohistochemistry and electro-chemiluminescence immunoassay.Results: Serum S100β protein levels were significantly elevated at different time points (24 h, 3 days, 7 days) in the TBI groups (p < 0.01) compared to normal control groups. Surgiflo® induced a lower concentration of serum S100β protein levels at day 3 (p < 0.05) and day 7 (p < 0.05) compared to the TBI group applied with saline. H&E staining showed that Surgiflo® treatment led to a 45% decrease in cortical brain lesion volume and in subcortical white matter 28 days after TBI. Compared with the saline-treated group, the number of MAP2-positive cells was significantly increased in the perilesional area of the Surgiflo®-treated group. The Surgiflo®-treated group exhibited lower mNSS scores on days 7 and 28 than did the saline-treated group.Discussion: Surgiflo® treatment produced a significant decrease in serum S100β protein levels in TBI mouse models, which may lead to an improvement in the recovery of TBI models.

What drives patient outcomes in brain metastases: Number, volume, or biology?

2071 Background: To delineate the prognostic importance of number of brain metastases (BM), lesion volume, and biology on overall survival. Methods: Patients treated for BM with whole-brain radiation therapy (WBRT), surgery, and/or stereotactic radiosurgery (SRS) at a single tertiary care institution from 1997-2015 were reviewed. The primary outcome was overall survival. Multivariable proportional hazards regression was used to adjust for confounding factors. Results: 3,955 patients with 16,189 BM were included in the analysis. There was a reduction in median survival with increasing number of lesions [1 lesion, 10.2 months; 2-4 lesions, 7.2 months, Hazard Ratio (HR) 1.36; 5-10 lesions, 5.6 months, HR: 1.69; &gt; 10 lesions, 5.5 months, HR: 1.57, p&lt; 0.001]. Among 1,651 patients (35%) who underwent SRS, there was a similar reduction in median survival with increasing lesion number [1 lesion, 12.2 months; 2-4 lesions, 10.1 months, HR 1.20; 5-10 lesions, 8.4 months, HR 1.41; &gt; 10 lesions, 6.9 months, HR 1.19], p&lt; 0.001). Among patients who underwent upfront SRS, increasing number of BM did not adversely affect survival in those with the smallest intracranial disease volume (≤0.4 cc, 10th percentile, p= 0.39), but was associated with inferior survival in patients with larger disease volumes (≤1.1 cc, 25th percentile, p= 0.05; ≤2.6 cc, 50th percentile, p= 0.005; ≤6.3 cc, 75th percentile, p= 0.006, and ≤12.2 cc, and 90th percentile, p =0.004). After partitioning the cohort into molecular subsets, patients with ALK+ disease had no difference in survival based on either lesion number or volume. Patients with EGFR+, HER2+, and luminal B disease had no difference in survival based on number of metastases, while patients with BRAF V600+and luminal A disease had no difference in survival based on intracranial disease volume. Conclusions: Number of BM closely correlates with survival in the majority of patients and intracranial disease volume impacts survival independent of number of metastases. For patients with certain tumor subtypes ( ALK+), intracranial disease burden appears to have no correlation with survival. Molecular profile characterization is important to identify patients with favorable subtypes given available treatment options.

Leptomeningeal Enhancement at 7T in Multiple Sclerosis: Frequency, Morphology, and Relationship to Cortical Volume.

Perform an investigation of the frequency and distribution of leptomeningeal enhancement on postgadolinium magnetization-prepared FLAIR (MPFLAIR) in multiple sclerosis (MS) on 7 Tesla (7T) MRI and to relate this finding to measures of brain structure and lesion volumes. Twenty-nine participants with MS underwent 7T MRI of the brain. Three healthy volunteers (HVs) were scanned for comparison. Areas of postcontrast leptomeningeal enhancement were identified. Images were segmented for brain structure and lesion volumes. The relationship between leptomeningeal enhancement and clinical and volumetric data was explored. Two patterns of enhancement were found: "nodular" (discrete, spherical nodules at the pial surface or subarachnoid space) and "spread/fill" (appearance of contrast spread through the local subarachnoid space). Twenty-six of 29 (90%) MS participants had at least one focus of leptomeningeal enhancement. Nodular foci were present in 15 of 29 (51%) MS participants. Spread/fill foci were present in 22 of 29 (76%) MS participants. Two HVs had examples of nodular foci, but none had spread/fill enhancement. MS participants with spread/fill foci were older (48.9 years [SD 8.3]) than those without (33.3 years [SD 11.5], P = .005). MS participants with spread/fill foci had reduced cortical gray matter volume compared to those without (P = .020). Leptomeningeal enhancement on postcontrast 7T MPFLAIR is more prevalent than prior reports at 3T-occurring at frequencies closer to histopathologic data. Spread/fill foci are associated with reduced cortical gray matter volumes and may represent blood-meningeal barrier breakdown near sites of meningeal inflammation, whereas nodular foci may be a normal variant.

BRAIM: A computer-aided diagnosis system for neurodegenerative diseases and brain lesion monitoring from volumetric analyses

Background and objectiveThis paper presents BRAIM, a computer-aided diagnosis (CAD) system to help clinicians in diagnosing and treatment monitoring of brain diseases from magnetic resonance image processing. BRAIM can be used for early diagnosis of neurodegenerative diseases such as Parkinson, Alzheimer or Multiple Sclerosis and also for brain lesion diagnosis and monitoring. MethodsThe developed CAD system includes different user-friendly tools for segmenting and determining whole brain and brain structure volumes in an easy and accurate way. Specifically, three types of measurements can be performed: (1) total volume of white, gray matter and cerebrospinal fluid; (2) brain structure volumes (volume of putamen, thalamus, hippocampus and caudate nucleus); and (3) brain lesion volumes. ResultsAs a proof of concept, some study cases were analyzed with the presented system achieving promising results. In addition to be used to quantify treatment effectiveness in patients with brain lesions, it was demonstrated that BRAIM is able to classify a subject according to the brain volume measurements using as reference a healthy control database created for this purpose. ConclusionsThe CAD system presented in this paper simplifies the daily work of clinicians and provides them with objective and quantitative volume data for prospective and retrospective analyses.