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ObjectiveExploring the clinical characteristics and HLA associations of patients with anti-leucine–rich glioma-inactivated 1 encephalitis (LGI1E) from a large single center in IsraelBackgroundAnti-LGI1E is one of the most commonly diagnosed antibody-associated encephalitic syndromes in adults. Recent studies of various populations reveal significant associations with specific Human Leukocyte Antigen (HLA) genes. We examined the clinical characteristics and HLA associations of a cohort of Israeli patients.Design/MethodsSeventeen consecutive anti-LGI1E patients diagnosed at Tel Aviv Sourasky Medical Center between the years 2011-2018 were included. HLA typing was performed using NGS methodology at the tissue typing laboratory of Sheba Medical Center and compared to data from the "Ezer Mizion" Bone Marrow Donor Registry, containing over 1,000,000 samples.ResultsOur cohort displayed a male predominance and median age of onset in the 7th decade, as previously reported. All patients responded to immunotherapy, though residual damage was not uncommon (23% with MRS >1). HLA analysis revealed overexpression of DRB1*07:01 (OR 13, CI 0.6 p < 1.e-10) and DRB1*04:02 (OR 12, CI-0.6 p < 1.e-10), as previously reported, as well as of the DQ alleles DQB1*02:02 (OR 12, CI 0.6 p < 1.e-10), DQB1*03:03 (OR 27, CI 0.9 p < 1.e-10), previously attributed to linkage disequilibrium (LD) with the mentioned DR alleles. An additional allele overexpressed among our patients was the DQB1*03:02 allele (OR 12, CI 0.6 p < 1.e-10), which appeared in complete LD with DRB1*04:02. Linkage disequilibrium analysis performed on patients and controls suggests these DR-DQ associations are unique to anti-LGI1E patients. In silico predictions performed for the overexpressed DQ alleles reveal them to be strong binders of LGI1 derived peptides, and suggest a correlation between peptide binding sites of paired DR-DQ alleles.ConclusionsOur findings shed additional light on the complex role of immunogenetics in the pathogenesis of anti-LGI1E, implying the possible relevance of certain DQ alleles as well as DR-DQ interactions.

The interstitium-to-plasma rate constant (kep), extracted from dynamic contrast enhancement (DCE-MRI) MRI data, seems to have an important role in the assessment of patients with brain tumors. This parameter is affected by the slow behavior of the system, and thus is expected to be highly dependent on acquisition duration. The aim of this study was to optimize the scan duration and protocol of DCE-MRI for accurate estimation of the kep parameter in patients with high grade brain tumors. The effects of DCE-MRI scan duration and protocol design (continuous vs integrated scanning) on the estimated pharmacokinetic (PK) parameters and on model selection, were studied using both simulated and patient data. Scan duration varied, up to 60min for simulated data, and up to 25min in 25 MRI scans obtained from patients with high grade brain tumors, with continuous and integrated scanning protocols. Converging results were obtained from simulated and real data. Significant effect of scan duration was detected on kep. Scan duration of 9min, with integrated protocol in which the data are acquired continuously for 5min, and additional volumes at 7 and 9min, was sufficient for accurate estimation of even low kep values, with an average error of 3%. Over-estimation of the PK parameters was detected for scan duration 12min. An integrated protocol of 9min is suggested as optimal for clinical use in patients with high grade brain tumors. Lower acquisition time may result in over-estimation of kep when using ETM, and therefore care should be taken using model selection.

To study the repeatability of plasma volume (vTwenty eight healthy subjects, of which eleven scanned twice, were used to assess the repeatability of vThe threshold values for significant changes were: LDD = 0.0024 (ml/100 ml, 21%) for mean vThis study shows high repeatability of v

We present a novel method for fiber-based comparison of diffusion tensor imaging (DTI) scans of groups of subjects. The method entails initial preprocessing and fiber reconstruction by tractography of each brain in its native coordinate system. Several diffusion parameters are sampled along each fiber and used in subsequent comparisons. A spatial correspondence between subjects is established based on geometric similarity between fibers in a template set (several choices for template are explored), and fibers in all other subjects. Diffusion parameters between groups are compared statistically for each template fiber. Results are presented at single fiber resolution. As an initial exploratory step in neurological population studies this method points to the locations affected by the pathology of interest, without requiring a hypothesis. It does not make any grouping assumptions on the fibers and no manual intervention is needed. The framework was applied here to 18 healthy subjects and 23 amyotrophic lateral sclerosis (ALS) patients. The results are compatible with previous findings and with the tract based spatial statistics (TBSS) method. Hum Brain Mapp 37:477-490, 2016. © 2015 Wiley Periodicals, Inc.

Cerebral blood volume (CBV) is an important parameter for the assessment of brain tumors, usually obtained using dynamic susceptibility contrast (DSC) MRI. However, this method often suffers from low spatial resolution and high sensitivity to susceptibility artifacts and usually does not take into account the effect of tissue permeability. The plasma volume (v p) can also be extracted from dynamic contrast enhancement (DCE) MRI. The aim of this study was to investigate whether DCE can be used for the measurement of cerebral blood volume in place of DSC for the assessment of patients with brain tumors. Twenty-eight subjects (17 healthy subjects and 11 patients with glioblastoma) were scanned using DCE and DSC. v p and CBV values were measured and compared in different brain components in healthy subjects and in the tumor area in patients. Significant high correlations were detected between v p and CBV in healthy subjects in the different brain components; white matter, gray matter, and arteries, correlating with the known increased tissue vascularity, and within the tumor area in patients. This work proposes the use of DCE as an alternative method to DSC for the assessment of blood volume, given the advantages of its higher spatial resolution, its lower sensitivity to susceptibility artifacts, and its ability to provide additional information regarding tissue permeability.

a b s t r a c t Background: Lesion size in fluid attenuation inversion recovery (FLAIR) images is an important clinical parameter for patient assessment and follow-up. Although manual delineation of lesion areas consid- ered as ground truth, it is time-consuming, highly user-dependent and difficult to perform in areas of indistinct borders. In this study, an automatic methodology for FLAIR lesion segmentation is proposed, and its application in patients with brain tumors undergoing therapy; and in patients following stroke is demonstrated. Materials and methods: FLAIR lesion segmentation was performed in 57 magnetic resonance imaging (MRI) data sets obtained from 44 patients: 28 patients with primary brain tumors; 5 patients with recurrent- progressive glioblastoma (rGB) who were scanned longitudinally during anti-angiogenic therapy (18 MRI scans); and 11 patients following ischemic stroke. Results: FLAIR lesion segmentation was obtained in all patients. When compared to manual delineation, a high visual similarity was observed, with an absolute relative volume difference of 16.80% and 20.96% and a volumetric overlap error of 24.87% and 27.50% obtained for two raters: accepted values for automatic methods. Quantitative measurements of the segmented lesion volumes were in line with qualitative radiological assessment in four patients who received anti-anogiogenic drugs. In stroke patients the proposed methodology enabled identification of the ischemic lesion and differentiation from other FLAIR hyperintense areas, such as pre-existing disease. Conclusion: This study proposed a replicable methodology for FLAIR lesion detection and quantification and for discrimination between lesion of interest and pre-existing disease. Results from this study show the wide clinical applications of this methodology in research and clinical practice. © 2013 Published by Elsevier Ireland Ltd.

Current methods for evaluation of treatment response in glioblastoma are inaccurate, limited and time-consuming. This study aimed to develop a multi-modal MRI automatic classification method to improve accuracy and efficiency of treatment response assessment in patients with recurrent glioblastoma (GB).A modification of the k-Nearest-Neighbors (kNN) classification method was developed and applied to 59 longitudinal MR data sets of 13 patients with recurrent GB undergoing bevacizumab (anti-angiogenic) therapy. Changes in the enhancing tumor volume were assessed using the proposed method and compared with Macdonald's criteria and with manual volumetric measurements. The edema-like area was further subclassified into peri- and non-peri-tumoral edema, using both the kNN method and an unsupervised method, to monitor longitudinal changes.Automatic classification using the modified kNN method was applicable in all scans, even when the tumors were infiltrative with unclear borders. The enhancing tumor volume obtained using the automatic method was highly correlated with manual measurements (N=33, r=0.96, p0.0001), while standard radiographic assessment based on Macdonald's criteria matched manual delineation and automatic results in only 68% of cases. A graded pattern of tumor infiltration within the edema-like area was revealed by both automatic methods, showing high agreement. All classification results were confirmed by a senior neuro-radiologist and validated using MR spectroscopy.This study emphasizes the important role of automatic tools based on a multi-modal view of the tissue in monitoring therapy response in patients with high grade gliomas specifically under anti-angiogenic therapy.

Our objective was to quantify and better understand white matter (WM) impairment in patients with amyotrophic lateral sclerosis (ALS) and to propose a model based on diffusion tensor imaging (DTI) for diagnosing patients with suspected ALS with upper motor neuron (UMN) signs. Twenty-six ALS patients (24 with prominent UMN signs and two with an isolated lower-motor neuron (LMN) syndrome) and 22 healthy volunteers were examined using DTI. Data analysis included voxel-based WM tract-based spatial statistics (TBSS), volume-of-interest analysis of the TBSS results and stream-line tractography analysis. Converging evidence revealed WM impairment along the corticospinal tracts and in the mid-body of the corpus callosum. This was demonstrated by reduced fractional anisotropy values caused by increased radial diffusivity, without significant changes in axial diffusivity. There were no significant correlations between diffusivity indices and patients' disability or disease duration. A discriminant analysis model based on the tractography results was designed to distinguish between patients with UMN signs and controls, yielding 87.5% sensitivity and 85% specificity. In conclusion, DTI can detect WM impairment in patients with ALS in several brain regions, and might be a sensitive tool for the diagnosis of ALS in the early stages of the disease with UMN involvement.

Mental time travel allows individuals to mentally project themselves backwards and forwards in subjective time. This case report describes a young woman suddenly rendered amnesic as a result of bilateral hippocampal damage following an epileptic seizure and brain anoxia. Her neuropsychological profile was characterized by a high-average general level of cognitive functioning, selective deficit in episodic memory of past events and a significant difficulty to envisage her personal future. This case provides clinical support for the concept of mental time travel with its retrospective and prospective components and for the hippocampus being its critical neural substrate.

Magnetic resonance imaging (MRI) findings are reported from 15 individuals in an Arab-Israeli community who were diagnosed with Alzheimer's disease (AD). The quantitative parameters that were used for MRI analyses included gradings (0-3) and linear measurements of different brain structures. Generalized tissue loss was assessed by combined measurements of the ventricles (ventricular score, VS) and sulcal grading and width (SG, SW, respectively). Loss of brain tissue in specific regions of interest, eg, temporal lobes, basal ganglia, and midbrain, was evaluated by precise measurements. We observed abnormal tissue characteristics, expressed as high intensity foci in white matter on T2W sequences, as well as tissue loss, both generalized and focal. Most notable were changes involving the head of the caudate nuclei, the midbrain, and to a lesser degree, medial temporal structures.

Familial dysautonomia (FD) is an autosomal recessive disorder characterized by hereditary sensory and autonomic neuropathies. Although extremely rare in most populations, FD is common among Ashkenazi Jews (AJ), with a calculated carrier frequency of 1 in 30, based on disease prevalence. The gene for FD was recently identified as IKBKAP. One major mutation (IVS2 + 6T --C) is responsible in99.5% of cases among AJ. The purpose of this study was to determine the actual frequency of FD carriers in the AJ population in Israel and to determine whether carriers are more frequent among a subpopulation of AJ from Poland. The study group included 1267 Jews of Ashkenazi origin who were referred for routine DNA screening tests. These included 1100 individuals who were full AJ and 167 who were part AJ. None had a family history of FD. Mutation analysis for (IVS2 + 6T --C) was performed by PCR amplification followed by restriction enzyme analysis. All positive cases were confirmed by DHPLC WAVE( trade mark ). Among the 1100 full AJ tested, 34 were found to be FD carriers (1:32). The incidence of mutation carriers was significantly higher in AJ of Polish descent (1:18) compared to AJ of non-Polish descent (1:99). Among the 167 individuals who were part AJ, there were 3 carriers (1:56). The incidence of FD among AJ, particularly those of Polish background, warrants population screening. Population screening may be performed by denaturing high-performance liquid chromatography.