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The objective of this study is to review the role of cell-derived microparticles in ischemic cerebrovascular diseases.An extensive PubMed search of literature pertaining to this study was performed in April 2009 using specific keyword search terms related to cell-derived microparticles and ischemic stroke. Some references are not cited here as it is not possible to be all inclusive or due to space limitation.Cell-derived microparticles are small membranous vesicles released from the plasma membranes of platelets, leukocytes, red cells and endothelial cells in response to diverse biochemical agents or mechanical stresses. They are the main carriers of circulating tissue factor, the principal initiator of intravascular thrombosis, and are implicated in a variety of thrombotic and inflammatory disorders. This review outlines evidence suggesting that cell-derived microparticles are involved predominantly with microvascular, as opposed to macrovascular, thrombosis. More specifically, cell-derived microparticles may substantially contribute to ischemic brain disease in several settings, as well as to neuroinflammatory conditions.If further work confirms this hypothesis, novel therapeutic strategies for minimizing cell-derived microparticles-mediated ischemia are available or can be developed, as discussed.

The spread of hepatitis C virus (HCV) infection involves a complex interplay of social risks, and molecular factors of both virus and host. Injection drug abuse is the most powerful risk factor for HCV infection, followed by sexual transmission and additional non-injection drug abuse factors such as co-infection with other viruses and barriers to treatment. It is clearly important to understand the wider context in which the factors related to HCV infection occur. This understanding is required for a comprehensive approach leading to the successful prevention, diagnosis, and treatment of HCV. An additional consideration is that current treatments and advanced molecular methods are generally unavailable to socially disadvantaged patients. Thus, the recognition of behavioral/social, viral, and host factors as components of an integrated approach to HCV is important to help this vulnerable group. Equally important, this approach is key to the development of personalized patient treatment - a significant goal in global healthcare. In this review, we discuss recent findings concerning the impact of drug abuse, epidemiology, social behavior, virology, immunopathology, and genetics on HCV infection and the course of disease.

Dementia is characterized by a decline in cognitive faculties and occurrence of behavioral abnormalities which interfere with an individual's activities of daily living. Dementing disorders usually affect elderly individuals but may occur in individuals younger than 65 years (early-onset dementia or EOD). EOD is often misdiagnosed or its diagnosis is delayed due to the fact that it has a more varied differential diagnosis than late-onset dementia. EOD affects individuals at the height of their career and productivity and produces devastating consequences and financial loss for the patient's family as well as society. EOD is not uncommon and is diagnosed in up to a third of patients presenting with dementia. Most importantly, some of the causes of EOD are curable which makes the need for a specific and timely diagnosis crucial. The present chapter presents a systematic approach to the differential diagnosis of EOD and provides readers with the clinical and neuroimaging features of these disorders as well as important considerations for their diagnostic evaluation. Specifically, the nuances of assessing the history and examination are discussed with careful attention to the various methods of cognitive and behavioral evaluation. A step-wise approach to diagnostic testing is followed by a discussion of anatomical localization, which often aids in identifying specific etiologies. Finally, in order to organize the subject for the reader, the various etiologies are grouped under the general categories of vascular, infectious, toxic-metabolic, immune-mediated, neoplastic/metastatic, and neurodegenerative.

MRI findings of primary anti-phospholipid antibody syndrome (PAPLS) are difficult to distinguish from those of multiple sclerosis (MS). Only a few previous studies have compared conventional and non-conventional MRI findings in MS and PAPLS patients. In addition, MRI differences between anti-phospholipid antibody (APLA) positive (+) and APLA negative (-) MS patients have not been reported. Therefore, the aim of this study was to investigate the differences in MRI measures among patients with PAPLS, MS and normal control (NC) subjects. We also explored non-conventional MRI measures in APLA+ and APLA- MS patients. Forty-nine (49) consecutive MS patients among whom 39 had relapsing-remitting (RR) and 10 secondary-progressive (SP) disease course, 30 patients with PAPLS and 49 NC were enrolled. Twenty-eight (28) MS patients were APLA+. MRI measures of T1- and T2-lesion volumes (LV) and brain atrophy, including fractions of whole brain (BPF), gray matter (GMF) and white matter (WMF), were evaluated. The magnetization transfer ratio (MTR) of T2- and T1-LVs and different normal-appearing brain tissue (NABT) compartments as well as diffusion-weighted imaging of whole brain mean parenchyma diffusivity (MPD) were obtained. MS patients differed significantly from NC in all MRI measures. PAPLS patients differed from NC in their T2-LV, in MTR measures and in MPD. When MS patients were compared to PAPLS patients, they showed significantly higher T2- and T1-LVs and T2-LV MTR, lower BPF and GMF and higher MPD. APLA+ RR and SPMS (all APLA+) patients showed significantly higher T2-LV, lower GMF, lower normal-appearing gray matter MTR and higher MPD when compared to APLA- patients. The results indicate that brain abnormalities can be detected in PAPLS patients with non-conventional MRI. MRI reveals more profound injury in patients with MS versus PAPLS. APLA mediates heterogeneous cerebral pathology that remains to be further investigated.

Objectives This is a critical review of anti-phospholipid antibodies (aPL). Most prior reviews focus on the aPL syndrome (APS), a thrombotic condition often marked by neurological disturbance. We bring to attention recent evidence that aPL may be equally relevant to non-thrombotic autoimmune conditions, notably, multiple sclerosis and ITP. Organization After a brief history, the recent proliferation of aPL target antigens is reviewed. The implication is that many more exist. Theories of aPL in thrombosis are then reviewed, concluding that all have merit but that aPL may have more diverse pathological consequences than now recognized. Next, conflicting results are explained by methodological differences. The lupus anticoagulant (LA) is then discussed. LA is the best predictor of thrombosis, but why this is true is not settled. Finally, aPL in non-thrombotic disorders is reviewed. Conclusion The current paradigm of aPL holds that they are important in thrombosis, but they may have much wider clinical significance, possibly of special interest in neurology.

Involvement of the gray matter (GM) in the pathology of multiple sclerosis (MS) was already recognized in the early days of MS research, but the detection of (cortical) GM lesions under the microscope and with magnetic resonance imaging (MRI) techniques was initially suboptimal and could only recently be enhanced. The visualization of GM lesions in vivo opens new doors for studies focusing on clinical, especially cognitive, effects of GM pathology, as well as for monitoring of neuroprotective treatment. However, so far little is known about what causes GM pathology. In this review, several pathogenetic mechanisms will be discussed, affecting the MS brain both from the 'outside-in' and from the 'inside-out'. Also, the use and reliability of MRI atrophy measures as a monitoring tool for GM damage in the therapeutic setting will be reviewed.

Dementia is characterized by a decline in cognitive faculties and occurrence of behavioral abnormalities which interfere with an individual's activities of daily living. Dementing disorders usually affect elderly individuals but may occur in individuals younger than 65 years (early-onset dementia or EOD). EOD is often misdiagnosed or its diagnosis is delayed due to the fact that it has a more varied differential diagnosis than late-onset dementia. EOD affects individuals at the height of their career and productivity and produces devastating consequences and financial loss for the patient's family as well as society. EOD is not uncommon and is diagnosed in up to a third of patients presenting with dementia. Most importantly, some of the causes of EOD are curable which makes the need for a specific and timely diagnosis crucial. The present chapter presents a systematic approach to the differential diagnosis of EOD and provides readers with the clinical and neuroimaging features of these disorders as well as important considerations for their diagnostic evaluation. Specifically, the nuances of assessing the history and examination are discussed with careful attention to the various methods of cognitive and behavioral evaluation. A step-wise approach to diagnostic testing is followed by a discussion of anatomical localization, which often aids in identifying specific etiologies. Finally, in order to organize the subject for the reader, the various etiologies are grouped under the general categories of vascular, infectious, toxic-metabolic, immune-mediated, neoplastic/metastatic, and neurodegenerative.

Sarcoidosis is a multisystemic granulomatous disease, which uncommonly affects nervous system. However, when present, it may affect both central and peripheral nervous systems and potentially mimics other chronic diseases of the nervous system. Pathogenesis of neurosarcoidosis remains largely unknown, and its diagnosis and management pose serious challenges to clinicians. Early diagnosis and aggressive treatment of neurosarcoidosis are necessary to produce satisfactory clinical outcomes. This review discusses clinical manifestations, current diagnostic studies, and currently available modalities for management of neurosarcoidosis.

Cortical and subcortical atrophy occurs in multiple sclerosis (MS) and relates to clinical outcomes. FreeSurfer, a voxel-based automated software for brain reconstruction was used to investigate the extent of subcortical and cortical atrophy in 71 MS and 17 clinically isolated syndrome (CIS) patients, and 38 normal controls (NC), and to relate group differences to disease type and severity. Segmentation was performed on 3D SPGR T1-weighted MRI 1.5T images. Region-specific subcortical tissue volumes were calculated in mm(3) and cortical thickness in mm. Logistic regression and general linear model analyses, adjusted for age and intracranial volume, examined differences between NC, MS and CIS patients and disease subtypes. The MS group was characterized by significantly lower volumes of thalamus (left and right p0.0001), left inferior lateral ventricle, third ventricle (p0.0001), ventral diencephalon, pallidum and putamen bilaterally, as well as of right accumbens and brainstem with corresponding bilateral increase in volumes of lateral ventricles (p0.01). Focal cortical atrophy areas in the thalamus, inferior parietal lobule of left hemisphere and in right precuneus were also significant in the MS sample. Versus CIS patients, RR or progressive MS patients showed significantly lower volumes of subcortical regions and cortical thinning. Hippocampal atrophy appeared only in advanced disease stages. Cerebellum WM volumes were significantly lower in MS and CIS patients vs. NC. Subcortical and cortical atrophy correlated with higher disability as measured by EDSS. This study confirmed selective deep gray matter atrophy (mostly thalamic), revealed cerebellum WM atrophy from the earliest clinical stages, and showed that cortical thinning advances with disease progression.

Background. In patients diagnosed with Alzheimer's disease, positron emission tomography brain scans can have characteristic hypometabolic patterns that strongly support this diagnosis, but this pattern is often subtle or absent in early stages. A sensitive and objective method for detection of positron emission tomography abnormalities may have value in early detection of Alzheimer's disease. Methods. A 2-fluoro-2-deoxy-D-glucose positron emission tomography scans from cognitively impaired patients (n = 43) were compared individually to 28 normal controls using statistical parametric mapping, hypometabolic regions visualized, and clinically correlated. The objective SPM results were compared to the official Nuclear Medicine report based upon subjective interpretation criteria. Results. A total of 22/43 had abnormalities per the Nuclear Medicine physician, while 21/43 appeared normal. The objective analysis detected abnormalities in 41/43 participants, including 19 of 21 that appeared normal. In these 19, 8 had findings consistent with early Alzheimer's disease. Conclusion. Objective analysis of positron emission tomography brain scans may extend the ability to detect early brain abnormalities in patients with cognitive decline.

The perfusion/diffusion 'mismatch model' in acute ischemic stroke provides the potential to more accurately understand the consequences of thrombolytic therapy on an individual patient basis. Few methods exist to quantify mismatch extent (ischemic penumbra) and none have shown a robust ability to predict infarcted tissue outcome. Hidden Markov random field (HMRF) approaches have been used successfully in many other applications. The aim of the study was to develop a method for rapid and reliable identification and quantification of perfusion/diffusion mismatch using an HMRF approach. An HMRF model was used in combination with automated contralateral identification to segment normal tissue from non-infarcted tissue with perfusion abnormality. The infarct was used as a seed point to initialize segmentation, along with the contralateral mirror tissue. The two seeds were then allowed to compete for ownership of all unclassified tissue. In addition, a novel method was presented for quantifying tissue salvageability by weighting the volume with the degree of hypoperfusion, allowing the penumbra voxels to contribute unequal potential damage estimates. Simulated and in vivo datasets were processed and compared with results from a conventional thresholding approach. Both simulated and in vivo experiments demonstrated a dramatic improvement in accuracy with the proposed technique. For the simulated dataset, the mean absolute error decreased from 171.9% with conventional thresholding to 2.9% for the delay-weighted HMRF approach. For the in vivo dataset, the mean absolute error decreased from 564.6% for thresholding to 34.2% for the delay-weighted HMRF approach. The described method represents a significant improvement over thresholding techniques.

(2008). Vascular neurology: a winding but illuminating road of progress. Neurological Research: Vol. 30, Vascular Neurology, pp. 773-774.

Hyperdensity in the basal cisterns on computed tomography (CT) brain scan is a diagnostic feature in subarachnoid hemorrhage. However, false enhancement of the subarachnoid space on CT scan may be seen in diffuse neurological conditions with acute presentation. This is the first reported case of a 'focal lesion' (acute cerebellar infarct) producing a 'pseudo-subarachnoid hemorrhage' secondary to increased intracranial pressure.A 42-year-old man presented with acute onset of left hemiataxia and neck pain. CT brain scan showed a left cerebellar infarct. During the admission, he had sudden onset of altered sensorium, and an emergency CT scan showed diffuse cerebral edema and hyperdensity of the basal cisterns. The patient then developed sudden cardiac arrest and all resuscitative measures failed. Autopsy showed no evidence of subarachnoid hemorrhage.Pseudo-subarachnoid hemorrhage is a rare clinical entity. It should be considered as a possibility in the evaluation and management of patients presenting acutely with CT brain scan showing hyperdensity of the basal cisterns and vascular imaging revealing absence of any aneurysm or vascular malformation.

Epigenetics studies factors related to the organism and environment that modulate inheritance from generation to generation. Molecular epigenetics examines non-coding DNA (ncdDNA) vs. coding DNA (cdDNA), and pertains to every domain of physiology, including immune and brain function. Molecular cartography, including genomics, proteomics, and interactomics, seeks to recognize and to identify the multi-faceted and intricate array of interacting genes and gene products that characterize the function and specialization of each individual cell in the context of cell-cell interaction, tissue, and organ function. Molecular cartography, epigenetics, and chromatin assembly, repair and remodeling (CARR), which, together with the RNA interfering signaling complex (RISC), is responsible for much of the control and regulation of gene expression, intersect. We describe current and ongoing studies aimed to apply these overlapping areas of research, CARR and RISC, to a novel understanding of the immuno-neuropathology of HIV-1 infection, as an example. Taken together, the arguments presented here lead to a novel working hypothesis of molecular immune epigenetics as it pertains to HIV/AIDS, and the immunopathology of HIV-1-infected CD4+ cells. Specifically, we discuss these views in the context of the structure-function relationship of chromatin, the cdDNA/ncdDNA ratio, and possible nucleotide divergence in the untranslated regions (UTRs) of mature mRNA intronic and intergenic DNA sequences, and putative catastrophic consequences for immune surveillance and the preservation of health in HIV/AIDS. Here, we discuss the immunopathology of HIV Infection, with emphasis on CARR in cellular, humoral and molecular immune epigenetics.

Isolated amyloidoma rarely involves the nervous system.We report a patient with progressively worsening triparesis and numbness in his extremities.Magnetic resonance imaging (MRI) of the brain revealed a mass lesion involving both hemispheres, which on positron emission tomography (PET) scan and magnetic resonance-spectroscopy (MR-SPECT) appeared to be a butterfly glioma. However, neuropathological examination revealed a large area with localized vascular amyloidosis.This is the first case of a localized central nervous system vascular amyloid to imitate a butterfly glioma on MRI and PET scan studies.

Disease-modifying agents (DMAs), including interferon beta (IFNbeta) and glatiramer acetate (GA), are the mainstays of long-term treatment of multiple sclerosis (MS). Other potent anti-inflammatory agents like natalizumab and different types of chemotherapeutics are increasingly being used for treatment of MS, particularly in patients with breakthrough disease activity. Brain volume (BV) loss occurs early in the disease process, accelerates over time, and may be only partially affected by DMA therapy. Low-dose, low frequency IFNbeta administered once weekly and GA appear to partially reduce BV decline over the second and third years of treatment. High dose, high frequency IFNbeta demonstrated no clear effect on BV loss during this time period. Current evidence suggests that changes in BV after immunoablation may not be due entirely to the resolution of edema but may be related to potential chemotoxicity of high dose cyclophosphamide. Natalizumab reduces the development of BV decline in the second and third years of treatment. IV immunoglobulin showed a positive effect on decelerating BV reduction in relapsing and advanced stages of MS. These differences between DMAs may be explained by the extent of their therapeutic effects on inflammation and on the balance between inhibition or promotion of remyelination and neuronal repair in the CNS. We described the mechanisms of action by which DMAs induce accelerated, non-tissue-related BV loss (pseudoatrophy) in the short term but, in the long run, may still potentially lead to permanent BV decline. The effects of corticosteroid therapy on changes in BV in patients with MS help clarify the mechanisms through which potent anti-inflammatory treatments may prevent, stabilize, or induce BV loss.

Alzheimer's disease (AD), the most common cause of dementia, has few clinical similarities to HIV-1-associated dementia (HAD). However, genes were identified related among these dementias. Discovering correlations between gene function, expression, and structure in the human genome continues to aid in understanding the similarities between pathogenesis of these two dementing disorders. The current work attempts to identify relationships between these dementias in spite of their clinical differences, based on genomic structure, function, and expression. In this comparative study, the NCBI Entrez Genome Database is used to detect these relationships. This approach serves as a model for future diagnosis and treatment in the clinical arena as well as suggesting parallel pathways of disease mechanisms. Identifying a correlation among expression, structure, and function of genes involved in pathogenesis of these dementing disorders, may assist to understand better their interaction with each other and the human genome.

We describe current research that applies epigenetics to a novel understanding of the immuno-neuropathogenesis of HIV-1 viral infection and NeuroAIDS. We propose the hypothesis that HIV-1 alters the structure-function relationship of chromatin, coding DNA and non-coding DNA, including RNA transcribed from these regions resulting in pathogenesis in AIDS, drug abuse, and NeuroAIDS. We discuss the general implications of molecular epigenetics with special emphasis on drug abuse, bar-codes, pyknons, and miRNAs for translational and clinical research. We discuss the application of the recent recursive algorithm of biology to this field and propose to synthesize the Genomic and Epigenomic views into a holistic approach of HoloGenomics.

To evaluate the efficacy, safety, and tolerability of combination therapy with intramuscular interferon beta-1a and oral doxycycline, a potent inhibitor of matrix metalloproteinases, in patients with relapsing-remitting multiple sclerosis (RRMS) having breakthrough disease activity.Open-label, 7-month trial.Louisiana State University Health Sciences Center, Shreveport.Fifteen patients with RRMS taking interferon beta-1a with breakthrough disease activity took doxycycline for 4 months. Patients underwent monthly neurologic examination, magnetic resonance imaging of the brain using triple-dose gadolinium, and safety blood work.Ongoing treatment with intramuscular interferon beta-1a plus oral doxycycline, 100 mg daily, for 4 months.The primary end point was gadolinium-enhancing lesion number change, and the secondary end points were relapse rates, safety and tolerability of the combination of interferon beta-1a and doxycycline in patients with MS, Expanded Disability Status Scale score, serum matrix metalloproteinase-9 levels, and transendothelial migration of monocytes exposed to serum from patients with RRMS.Combination of doxycycline and interferon beta-1a treatment resulted in reductions in contrast-enhancing lesion numbers and posttreatment Expanded Disability Status Scale values (P.001 for both). Only 1 patient relapsed. Multivariate analyses indicated correlations between decreased serum matrix metalloproteinase-9 levels and enhancing lesion activity reduction. Transendothelial migration of monocytes incubated with serum from patients with RRMS undergoing combination therapy was suppressed. Adverse effects were mild; no adverse synergistic effects of combination therapy or unexpected adverse events were reported.Combination of intramuscular interferon beta-1a and oral doxycycline treatment was effective, safe, and well tolerated. Controlled clinical trials in larger cohorts of patients with MS are needed to evaluate the efficacy and tolerability of this combination. Trial Registration clinicaltrials.gov Identifier: NCT00246324

Background MAdCAM-1 plays a central role in T-lymphocyte homing to the gut, but its role in chronic liver inflammation remains unknown. Therefore, this study measured MAdCAM-1 expression, regulation, and function in cultured murine hepatic endothelial cells. Methods Cultures of hepatic endothelial cells (HEC) were prepared from mice expressing a temperature-sensitive SV40 large T antigen (H-2K b -tsA58) under the control of an IFN-γ promoter. Time and dose dependent expression of MAdCAM-1 in response to TNF-α, IL-1β and IFN-γ was studied by immunoblotting. Lymphocyte adhesion was studied using α4β7integrin expressing lymphocytes (TK-1) +/- anti-MAdCAM-1 mAb. Results TNF-α induced MAdCAM-1 dose-and time-dependently with maximum expression at 20 ng/ml and at 48 hours. IL-1β also induced MAdCAM-1 to a lesser extent compared to TNF-α; IFN-γ did not induce MAdCAM-1. TNF-α significantly increased lymphocyte-endothelial adhesion (P < 0.01), which was reversed by anti-MAdCAM-1 antibody. MAdCAM-1 expression was also reduced by N-acetylcysteine and by two NO donors (SperNO, DETANO) suggesting that hepatic endothelial MAdCAM-1 is oxidant and NO regulated. Conclusion MAdCAM-1 is a major determinant of leukocyte recruitment in chronic inflammation and is expressed by HEC in response to IL-1β and TNF-α. This system may provide a useful model for studying inflammatory mechanisms in liver disease and help determine if controlled MAdCAM-1 expression might influence inflammation in liver disease.

The most important confirmed genetic factor of susceptibility to multiple sclerosis (MS) has been identified in the HLA class II region. The hypothesis that several genes, including HLA class II, may influence the prognosis of patients with MS has been proposed. In a recent study, using low intermediate resolution typing, we found that some HLA alleles may predict disease severity as assessed by magnetic resonance imaging (MRI) measures. The aim of this study was to examine the relationship between high-resolution typing of HLA alleles and disease severity as measured by brain MRI quantitative markers of demyelinating and destructive pathology in patients with MS. In 41 MS patients (27 relapsing-remitting, 7 secondary progressive, and 7 primary progressive), we performed high-resolution typing of alleles HLA-DRB1*04, -DQB1*03, -DRB1*15, -DQB1*06, and of haplotypes -DRB1*04-DQB1*03 and -DRB1*15-DQB1*06. These alleles and haplotypes were associated with higher susceptibility to MS in a recently published case-control study conducted in the Friuli-Venezia-Giulia region, Italy. Of 41 included patients, 13 were men and 28 were women. Mean age was 43.3 (SD 11.4) years, mean disease duration 10.3 (SD 7.8) years, and mean EDSS 2.3. DNA extraction and genomic typing were obtained with the sequence-specific primers method using primer pairs that amplified the HLA alleles. All patients underwent a 1.5-T MRI examination of the brain. Disease severity was assessed by clinical measures [Expanded Disability Status Scale (EDSS)] and MRI measures. T2- and T1-lesion volumes (LVs) and brain atrophy measures [fractions of brain parenchyma (BPF), gray matter (GMF), and white matter (WMF)] were calculated. We used general linear model analysis (GML), controlled for age, disease duration, and treatment status, to compare the MRI measures according to allele and haplotype status. The following significant results were found: HLA-DRB1*1501 positive patients had significantly lower GMF (0.493 vs 0.526, p0.001), lower BPF (0.784 vs 0.815, p = 0.018), and higher T1-LV (2.8 vs 0.7ml, p = 0.036); -DQB1*0301 positive patients had significantly higher T2-LV (34.1 vs 0.7 ml, p = 0.041), and showed a trend for lower BPF (0.790 vs 0.846, p = 0.064); -DQB1*0302 positive patients had significantly lower T1-LV (2.4 vs 0.9 ml, p = 0.016); and -DQB1*0602 positive patients had significantly lower GMF (0.492 vs 0.521, p = 0.007) and lower BPF (0.781 vs 0.811, p = 0.023). No differences were found in the indices of MRI disease severity according to HLA haplotype associations. Both in correlation and in regression analyses, we observed significant associations between HLA-DRB1*1501 and lower GMF and BPF and higher T1-LV, between -DQB1*0301 and higher T2-LV and disease duration, between -DQB1*0302 and lower GMF and higher T1- and T2-LV, between -DQB1*0602 and lower GMF and BPF, and between -DQB1*0603 and higher T1-LV and EDSS. High-resolution HLA genotyping analysis revealed a robust relationship between alleles HLA-DRB1*1501, -DQB1*0301, -DQB1*0302, -DQB1*0602, and -DQB1*0603, and more severe damage on inflammatory and neurodegenerative MRI measures.

Differentiation of acute and subacute ischemic stroke lesions from acute demyelinating lesions of multiple sclerosis (MS) may not be possible on conventional magnetic resonance imaging (MRI). Both lesion types enhance on T1 with gadolinium (Gd) contrast and both are hyperintense on diffusion-weighted imaging (DWI). This study is an analysis of two quantitative MR indices: (1) calculated apparent diffusion coefficients (ADCs) and (2) T2 relaxation times (T2R) as means toward differentiating acute ischemic lesions from acute demyelinating lesions. Chronic ischemic and demyelinating lesions were evaluated for comparison as well.The MRI of nine patients with both acute and chronic ischemic lesions and six patients with both acute and chronic demyelinating lesions were analyzed for ADC and T2Rs. The indices were measured by manually placing regions of interest (ROIs) at the anatomic center of the acute lesion. Acute ischemic lesions were chosen by their hyperintensity on DWI and hypointensity on ADC mapping. Acute demyelinating lesions were selected by peripheral contrast enhancement after the administration of Gd. Computation of the ADC involved the diffusion coefficient on a region by region basis as follows: D = -(b(0)/b(1000))ln(S(b1000)/S(b0)), where S(b1000) is the signal intensity on DWI and S(b0) is the signal intensity on T2 with diffusion sensitivities of b(0) and b(1000), respectively. Computation of the T2R was made as follows: T2R = (TE(T2)--TE(PD))/(ln SI(PD)--ln SI(T2)), where TE is the echo time of the different pulse sequences, SI is signal intensity on the different echo sequences, and PD represents proton density sequence.Twenty-nine acute ischemia, 27 acute demyelination, 28 chronic ischemia, and 43 chronic demyelination image sets were analyzed. The differences between ADC(acute infarct) (0.760) versus ADC(acute plaque) (1.106) were significant (p0.02). The differences between T2R(acute infarct) (235.5) versus T2R(acute plaque) (170.5) were also significant (p0.02).ADC in combination with T2R is a useful tool to differentiate acute ischemic from acute demyelinating lesions. The use of these neuroimaging indices along with magnetic resonance spectroscopy metabolite ratios is then demonstrated in elucidating the pathophysiological mechanism for a case of delayed posttraumatic bilateral internuclear ophthalmoplegia.

All blood cells and the vascular endothelium shed microparticles (MP) from their plasma membranes when suitably stimulated, and assay of MP in patient blood has found increasing application to the monitoring of disease states. In addition, mounting evidence suggests that MP are not mere epiphenomena but play significant roles in the pathophysiology of thromboses, inflammation, and cancers. This chapter endeavors to summarize the limited number of studies thus far done on MP in neurological disorders such as multiple sclerosis (MS), transient ischemic attacks, and the neurological manifestations of antiphospholipid syndrome (APS). In addition, the chapter offers some plausible hypotheses on possible roles of MP in the pathophsyiology of these disorders, chiefly, the hypothesis that MP are indeed important participants in some neuropathologies, especially those which are ischemic in nature, but probably also inflammatory ones. The chapter also goes over the history and general principles of MP studies (e.g., assay methods and pitfalls), comparison with alternative methods (e.g., soluble markers of disease states), subclasses of MP (such as exosomes), and other topics aimed at helping readers to consider MP studies in their own clinical fields. Tables include a listing of bioactive agents known to be carried on MP, many of which were heretofore considered strictly soluble, and some of which can be transferred from cell to cell via MP vectors, for example certain cytokine receptors.

Multiple sclerosis (MS) is an inflammatory disease of the human central nervous system (CNS) which develops predominantly in young adults with certain predisposing genetic characteristics, often following exposure to initiating environmental insult(s) including viral infections. The causes of MS remain elusive and no entire cure is in sight. However, it is well known that interactions between the immune system and the CNS play a central role in MS pathogenesis. Patients with MS generate CD4+ autoreactive T cells that at some point differentiate to Th1 phenotype cells, which are the major players in maintaining a continuous destructive immune response against brain and spinal cord antigens. Other significant participants in MS pathogenesis involved in the destruction of the target tissue are cerebral endothelial cells, CD8+ T cells, B cells, complement, autoantibodies, cytokines, and chemokines. The presence and interactions of all these participants further complicate the pathogenesis of MS, and make finding a cure for MS challenging. This chapter looks at the roles of these factors in the development of MS.

The introduction of immunomodulatory and immunosuppressive agents for treatment of multiple sclerosis (MS) has forever altered the natural course of this incurable and disabling neurodegenerative disorder. Despite early diagnosis of relapsing-remitting MS and early initiation of therapy, patients still experience breakthrough relapses and progression of their underlying MS pathology. The imperfect effectiveness, side effects, and toxicity of these agents, emphasize the necessity for development of more effective medications with less adverse events. This chapter presents readers with the most current information on the nature, mechanism(s) of action, and side effects of the most promising experimental agents currently under clinical trials. Some of the agents now at different stages of clinical trial have emerged as both safe and promising. The understanding of MS etiology will lead to the development of increasingly specific, safer, and effective treatments for MS by neuroscientists and neurologists.

Understanding the importance of cortical lesions in MS pathogenesis has changed. Histopathologic studies using new immunohistochemical methods show that cortical lesions can be detected more frequently than previously reported. Newer MRI sequences also detect cortical lesions more accurately. The aim of this study was to evaluate whether the effect of slice thickness (th) is an important factor for detection of cortical lesions in patients with multiple sclerosis (MS). We aimed also to investigate the relationship of cortical lesions with clinical status or other MRI variables. Forty-one patients with relapsing-remitting (RR) MS (11 males, 30 females with mean EDSS 2.3) underwent scans of Two-dimensional (2D)-fluid-attenuated inversion recovery (FLAIR) and 3D-T1-WI at 1.5-, 3-, and 5-mm slice thicknesses on 1.5-T MRI. Cortical and juxtacortical lesions were volumetrically assessed using a semiautomated method. 2D-FLAIR and 3D-T1-WI were coregistered and the matrix of the neocortical volume (NCV) segmentation mask (SIENAX-generated) was used to classify the location of the cortical-subcortical lesions. Cortical lesions fell into three classes: (1) class 1 were defined as lesions located in the NCV, (2) class 2 were juxtacortical lesions in contact with the NCV mask, and (3) class 3 were cortical-juxtacortical lesions situated in both regions. We measured NCV and normalized gray matter (GM) volume as well. We used partial correlation and multiple regressions to investigate the relationship between cortical lesions and other clinical and MRI variables. Of the total T2-lesion volume (T2-LV) measured on 1.5-mm th scans (mean 16108 mm(3)), cortical lesions represented 2.4% (276 mm(3)), juxtacortical lesions 6.1% (760 mm(3)), and cortical-juxtacortical 3.7% (491 mm(3)). Compared to 1.5-mm th scan, cortical LV was reduced by -28.3%, p0.001 on 3-mm th and by -40.78%, p0.001 on 5-mm th scans. Results for juxtacortical LV were for 3-mm th scans (-17.9%, p0.01) and for 5-mm th scans (-30.3%, p0.01). The figures for cortical-juxtacortical LV were also for 3-mm th scans (-16.2%, p0.01) and for 5-mm th scans (-26.7%, p0.01). We observed a significant correlation between T2-LV and GM atrophy in all slice thickness (r = -0.4 to -0.48, p = 0.001-0.003) and a modest relationship between cortical and cortical-juxtacortical LVs and disability, especially at 1.5-mm slice thickness (r = 0.35, p = 0.025). Use of thinner slices (1.5 mm) on 2D-FLAIR images can significantly increase the sensitivity and precision of detecting cortical and juxtracotical lesions in patients with MS. Cortical and juxtacortical lesions contribute more to disability development than total T2-LV alone.

Multiple sclerosis (MS) is an inflammatory disease of the human central nervous system (CNS) which develops predominantly in young adults with certain predisposing genetic characteristics, often following exposure to initiating environmental insult(s) including viral infections. The causes of MS remain elusive and no entire cure is in sight. However, it is well known that interactions between the immune system and the CNS play a central role in MS pathogenesis. Patients with MS generate CD4+ autoreactive T cells that at some point differentiate to Th1 phenotype cells, which are the major players in maintaining a continuous destructive immune response against brain and spinal cord antigens. Other significant participants in MS pathogenesis involved in the destruction of the target tissue are cerebral endothelial cells, CD8+ T cells, B cells, complement, autoantibodies, cytokines, and chemokines. The presence and interactions of all these participants further complicate the pathogenesis of MS, and make finding a cure for MS challenging. This chapter looks at the roles of these factors in the development of MS.

Understanding the importance of cortical lesions in MS pathogenesis has changed. Histopathologic studies using new immunohistochemical methods show that cortical lesions can be detected more frequently than previously reported. Newer MRI sequences also detect cortical lesions more accurately. The aim of this study was to evaluate whether the effect of slice thickness (th) is an important factor for detection of cortical lesions in patients with multiple sclerosis (MS). We aimed also to investigate the relationship of cortical lesions with clinical status or other MRI variables. Forty‐one patients with relapsing‐remitting (RR) MS (11 males, 30 females with mean EDSS 2.3) underwent scans of Two‐dimensional (2D)‐fluid‐attenuated inversion recovery (FLAIR) and 3D‐T1‐WI at 1.5‐, 3‐, and 5‐mm slice thicknesses on 1.5‐T MRI. Cortical and juxtacortical lesions were volumetrically assessed using a semiautomated method. 2D‐FLAIR and 3D‐T1‐WI were coregistered and the matrix of the neocortical volume (NCV) segmentation mask (SIENAX‐generated) was used to classify the location of the cortical–subcortical lesions. Cortical lesions fell into three classes: (1) class 1 were defined as lesions located in the NCV, (2) class 2 were juxtacortical lesions in contact with the NCV mask, and (3) class 3 were cortical–juxtacortical lesions situated in both regions. We measured NCV and normalized gray matter (GM) volume as well. We used partial correlation and multiple regressions to investigate the relationship between cortical lesions and other clinical and MRI variables. Of the total T2‐lesion volume (T2‐LV) measured on 1.5‐mm th scans (mean 16108 mm 3 ), cortical lesions represented 2.4% (276 mm 3 ), juxtacortical lesions 6.1% (760 mm 3 ), and cortical–juxtacortical 3.7% (491 mm 3 ). Compared to 1.5‐mm th scan, cortical LV was reduced by −28.3%, p p p p p p r = −0.4 to −0.48, p = 0.001–0.003) and a modest relationship between cortical and cortical–juxtacortical LVs and disability, especially at 1.5‐mm slice thickness ( r = 0.35, p = 0.025). Use of thinner slices (1.5 mm) on 2D‐FLAIR images can significantly increase the sensitivity and precision of detecting cortical and juxtracotical lesions in patients with MS. Cortical and juxtacortical lesions contribute more to disability development than total T2‐LV alone.

All blood cells and the vascular endothelium shed microparticles (MP) from their plasma membranes when suitably stimulated, and assay of MP in patient blood has found increasing application to the monitoring of disease states. In addition, mounting evidence suggests that MP are not mere epiphenomena but play significant roles in the pathophysiology of thromboses, inflammation, and cancers. This chapter endeavors to summarize the limited number of studies thus far done on MP in neurological disorders such as multiple sclerosis (MS), transient ischemic attacks, and the neurological manifestations of antiphospholipid syndrome (APS). In addition, the chapter offers some plausible hypotheses on possible roles of MP in the pathophsyiology of these disorders, chiefly, the hypothesis that MP are indeed important participants in some neuropathologies, especially those which are ischemic in nature, but probably also inflammatory ones. The chapter also goes over the history and general principles of MP studies (e.g., assay methods and pitfalls), comparison with alternative methods (e.g., soluble markers of disease states), subclasses of MP (such as exosomes), and other topics aimed at helping readers to consider MP studies in their own clinical fields. Tables include a listing of bioactive agents known to be carried on MP, many of which were heretofore considered strictly soluble, and some of which can be transferred from cell to cell via MP vectors, for example certain cytokine receptors.

The introduction of immunomodulatory and immunosuppressive agents for treatment of multiple sclerosis (MS) has forever altered the natural course of this incurable and disabling neurodegenerative disorder. Despite early diagnosis of relapsing‐remitting MS and early initiation of therapy, patients still experience breakthrough relapses and progression of their underlying MS pathology. The imperfect effectiveness, side effects, and toxicity of these agents, emphasize the necessity for development of more effective medications with less adverse events. This chapter presents readers with the most current information on the nature, mechanism(s) of action, and side effects of the most promising experimental agents currently under clinical trials. Some of the agents now at different stages of clinical trial have emerged as both safe and promising. The understanding of MS etiology will lead to the development of increasingly specific, safer, and effective treatments for MS by neuroscientists and neurologists.

The most important confirmed genetic factor of susceptibility to multiple sclerosis (MS) has been identified in the HLA class II region. The hypothesis that several genes, including HLA class II, may influence the prognosis of patients with MS has been proposed. In a recent study, using low intermediate resolution typing, we found that some HLA alleles may predict disease severity as assessed by magnetic resonance imaging (MRI) measures. The aim of this study was to examine the relationship between high‐resolution typing of HLA alleles and disease severity as measured by brain MRI quantitative markers of demyelinating and destructive pathology in patients with MS. In 41 MS patients (27 relapsing‐remitting, 7 secondary progressive, and 7 primary progressive), we performed high‐resolution typing of alleles HLA‐DRB1*04, ‐DQB1*03, ‐DRB1*15, ‐DQB1*06, and of haplotypes ‐DRB1*04‐DQB1*03 and ‐DRB1*15‐DQB1*06. These alleles and haplotypes were associated with higher susceptibility to MS in a recently published case‐control study conducted in the Friuli–Venezia–Giulia region, Italy. Of 41 included patients, 13 were men and 28 were women. Mean age was 43.3 (SD 11.4) years, mean disease duration 10.3 (SD 7.8) years, and mean EDSS 2.3. DNA extraction and genomic typing were obtained with the sequence‐specific primers method using primer pairs that amplified the HLA alleles. All patients underwent a 1.5‐T MRI examination of the brain. Disease severity was assessed by clinical measures [Expanded Disability Status Scale (EDSS)] and MRI measures. T2‐ and T1‐lesion volumes (LVs) and brain atrophy measures [fractions of brain parenchyma (BPF), gray matter (GMF), and white matter (WMF)] were calculated. We used general linear model analysis (GML), controlled for age, disease duration, and treatment status, to compare the MRI measures according to allele and haplotype status. The following significant results were found: HLA‐DRB1*1501 positive patients had significantly lower GMF (0.493 vs 0.526, p

Background and purpose: Differentiation of acute and subacute ischemic stroke lesions from acute demyelinating lesions of multiple sclerosis (MS) may not be possible on conventional magnetic resonance imaging (MRI). Both lesion types enhance on T1 with gadolinium (Gd) contrast and both are hyperintense on diffusion‐weighted imaging (DWI). This study is an analysis of two quantitative MR indices: (1) calculated apparent diffusion coefficients (ADCs) and (2) T2 relaxation times (T2R) as means toward differentiating acute ischemic lesions from acute demyelinating lesions. Chronic ischemic and demyelinating lesions were evaluated for comparison as well. Methods: The MRI of nine patients with both acute and chronic ischemic lesions and six patients with both acute and chronic demyelinating lesions were analyzed for ADC and T2Rs. The indices were measured by manually placing regions of interest (ROIs) at the anatomic center of the acute lesion. Acute ischemic lesions were chosen by their hyperintensity on DWI and hypointensity on ADC mapping. Acute demyelinating lesions were selected by peripheral contrast enhancement after the administration of Gd. Computation of the ADC involved the diffusion coefficient on a region by region basis as follows: D = −(b0/b1000)ln(Sb1000/Sb0), where Sb1000 is the signal intensity on DWI and Sb0 is the signal intensity on T2 with diffusion sensitivities of b0 and b1000, respectively. Computation of the T2R was made as follows: T2R = (TET2 − TEPD)/(ln SIPD − ln SIT2), where TE is the echo time of the different pulse sequences, SI is signal intensity on the different echo sequences, and PD represents proton density sequence. Results: Twenty‐nine acute ischemia, 27 acute demyelination, 28 chronic ischemia, and 43 chronic demyelination image sets were analyzed. The differences between ADCacute infarct (0.760) versus ADCacute plaque (1.106) were significant (p Conclusions: ADC in combination with T2R is a useful tool to differentiate acute ischemic from acute demyelinating lesions. The use of these neuroimaging indices along with magnetic resonance spectroscopy metabolite ratios is then demonstrated in elucidating the pathophysiological mechanism for a case of delayed posttraumatic bilateral internuclear ophthalmoplegia.

Background A correlation between plasma CD31+ endothelial microparticles (CD31+EMP) levels and clinical, as well as brain MRI activity, in multiple sclerosis (MS) patients has been previously reported. However, the effect(s) of treatment with interferon-β1a (IFN-β1a) on plasma levels of CD31+EMP has not been assessed. In a prospective study, we measured plasma CD31+EMP levels in 30 patients with relapsing-remitting MS. Methods Using flow cytometry, in a blinded study, we measured plasma CD31+EMP in 30 consecutive patients with relapsing-remitting MS (RRMS) prior to and 4, 12, 24 and 52 weeks after initiation of intramuscular therapy with interferon-β1a (IFN-β1a), 30 micrograms weekly. At each visit, clinical examination was performed and expanded disability status scale (EDSS) scores were assessed. Results Plasma levels of CD31+EMP were significantly reduced from 24 through 52 weeks following initiation of treatment with IFN-β1a. Conclusion Our data suggest that serial measurement of plasma CD31+EMP levels may be used as a surrogate marker of response to therapy with INF-β1a. In addition, the decline in plasma levels of CD31+EMP further supports the concept that IFN-β1a exerts stabilizing effect on the cerebral endothelial cells in pathogenesis of MS.

Application of magnetic resonance spectroscopy (MRS) to study the nature, pathogenesis, tissue injury and therapeutic response of MS patients has altered our view of multiple sclerosis (MS) fundamentally. By offering biochemical analysis of demyelinating lesions and axonal injury, MRS generates objective and quantifiable data on central nervous system tissue and metabolism during pathogenesis of MS. Of these biochemical markers, N-acetylaspartate, which serves as an indicator of neuronal and axonal injury and choline (Cho) peaks which demonstrate cell membrane metabolism, provide a plethora of data on the neuropathology of MS. Based on these findings, MRS provides neuroscientists with a unique diagnostic and prognostic tool to follow MS patients and assess their response to treatment with immunomodulators. MRS findings are so significant that consideration should be given to their routine inclusion as secondary outcome measures in clinical trials of MS patients.

Objective To investigate the utility of a clinical laboratory ELISA format assay that measures neural thread protein (NTP) in urine in the assessment of patients presenting with cognitive symptoms. Design A prospective blinded multicentered study. Setting Eight US specialty clinics for the evaluation of cognitive or memory disorder or dementia, including memory disorder and dementia clinics, neurology clinics, and psychiatry clinics, in 8 states. Participants Prospectively enrolled consecutive patients who were newly referred to a specialty clinic for assessment of cognitive or memory disorder symptoms or dementia to rule out or rule in Alzheimer’s disease (AD). Measurements Participants provided a first morning urine sample for UNTP measurement for testing at a central core laboratory and subsequently went through specialized diagnostic evaluations in accordance with established clinical criteria. Urine NTP measurement was compared to the diagnostic categorization of the patients as probable or possible AD (according to National Institute of Neurological Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association [NINCDS-ADRDA] criteria), mild cognitive impairment (MCI) (according to Quality Standards Subcommittee of the American Academy of Neurology [AAN] criteria) or definite non-AD. Clinical diagnoses were made without reference to UNTP measurement; the testing laboratory was blinded to both patient identity and clinical diagnoses. Results A total of 168 enrolled and consented patients provided qualifying urine samples and completed specialized diagnostic workups. There were 91.4% of subjects with probable AD, 37.7% of subjects categorized as possible AD, and 48.6% of subjects with MCI who had an elevated NTP measurement (>22 μg/mL). There were 90.7% of subjects diagnosed as definite non-AD who had a normal NTP measurement (≤22 μg/mL). Conclusion Noninvasive UNTP test results are potentially helpful as part of the workup of dementia for the nonspecialist to help in the decision as to whether referral and/or more detailed investigation is advisable.

Recognizing cognitive deficits and psychiatric disorders in patients with autosomal dominant ataxias is relatively new. At this time, the percentage of patients with these disorders who experience changes in cognition or psychiatric symptoms is unknown. Cognitive impairment, when seen, is often found on tests of executive function, probably reflecting disruption of afferent and efferent pathways of the prefrontal cortex and subcortical structures, including the cerebellum. Widespread global dysfunction does occur in some cases, especially later in the disease course. Psychiatric symptoms including depression, aggression, irritability, and psychosis have all been reported. As these behavioral changes receive further study, one hopes that guidelines for treating these symptoms will emerge. Clinicians should be mindful of the psychosocial effects that genetic testing for the hereditary ataxias may have, especially in cases of predictive testing for those who are asymptomatic but at risk because of family history. Guidelines established for genetic testing in HD may be helpful when approaching these cases.

Multiple sclerosis (MS) has been recognised as a disease since the mid-19th century. The delineation of its CNS pathology, revealing the presence of inflammatory demyelination and relative sparing of axons, was originally interpreted as evidence of infection. Despite many studies, a primary infectious aetiology of MS has not been found. However, the occurrence of acute demyelinating disease following a variety of infections and vaccinations, leading to MS in about a third of cases, provides evidence for the existence of an auto-allergic pathogenesis for the disease. Improved understanding of the role of the blood-brain barrier in protecting the CNS, and the mechanisms by which cells gain entry into the brain and spinal cord has advanced the understanding of MS. Evidence of the central role of the adhesion molecule alpha4beta1-integrin (very late activation antigen-4 [VLA-4]) for lymphocytes in endothelial transmigration into the CNS specifically, has provided a major insight into the pathogenesis of human demyelinating disease and its experimental model, experimental autoimmune encephalomyelitis (EAE). This finding has led to a new window of therapeutic opportunity in MS. Monoclonal antibodies to VLA-4 abrogate the development of EAE in sensitised animals and may actually reverse its clinical and pathological findings in manifest disease. Natalizumab, one such monoclonal antibody, which is administered intravenously, has been found to be a promising agent in the treatment of MS. Although single doses produced no improvement in the speed or quality of recovery from acute exacerbations of MS in a phase II trial, long-term administration (in phase II and phase III trials) have produced significant benefits with results showing both a marked reduction in the risk of new magnetic resonance imaging lesions and a significant reduction in the risk of exacerbations within 2 months of the initiation of therapy. Phase III double-blinded controlled trials have provided additional evidence of safety and a favourable impact on exacerbation rates over the 1 year of administration. Unfortunately, the success of natalizumab has been curtailed by three cases of progressive multifocal leukoencephalopathy, which have prompted the manufacturer to voluntary withdraw the drug from the market. An independent review board is currently investigating the safety of the drug to determine whether it should return to the market. The demonstration that selective modulation (blocking) of the adhesion molecule VLA-4 by natalizumab in MS, resembling that observed in experimental disease, represents a major advance in rational therapy.

During relapses in relapsing-remitting multiple sclerosis (RRMS), serum soluble HLA class I surface antigen (sHLA-I) levels are reported to either decrease or remain unchanged, whereas serum sHLA-II levels increase. Interferon-beta1b therapy was recently reported to increase serum sHLA-I in RRMS. In the present prospective study, solid-phase enzyme-linked immunosorbent assay was used to measure sHLA-I and sHLA-II in the sera of 21 RRMS patients during a clinical exacerbation, and then six weeks after treatment with high-dose interferon-beta1a (IFN-beta1a). Pretreatment serum sHLA-I was significantly lower in patients than in normal controls (P < 0.0005). Pretreatment sHLA-II was also significantly lower than in normal controls (P = .003) unless enhancing MRI lesions (objectified relapse) were present; then sHLA-II levels were similar to normal controls (relative increase). Six weeks after initiation of IFN-beta1a treatment, a significant increase in serum sHLA-I was observed in all 21 RRMS patients (P < .0005). Conversely, serum sHLA-II decreased significantly after treatment in the entire patient group (P < .0005). The acute effect of IFN-beta1a on serum sHLA-I and sHLA-II was observed to be the opposite of that occurring during RRMS relapses. Monitoring of both sHLA-I and sHLA-II appears necessary if these molecules are to be developed as RRMS activity markers.

Monocyte migration through the disrupted cerebral endothelial cell (EC) junctions plays an essential role in formation of multiple sclerosis (MS) demyelinating lesions. During pathogenesis of MS, activated ECs release endothelial microparticles (EMP), which possibly facilitate transendothelial migration (TEMIG) of monocytes. To assess functional roles of EMP in MS, specifically, their (i) interaction with monocytes, (ii) effect on monocyte TEMIG in an in vitro model of the brain microvascular endothelial cells (BMVEC), (iii) phenotypic profiles of EMP elicited by MS plasma and (iv) the effects of IFN-beta 1b on release of EMP and on TEMIG of monocytes (mono) and monocytes:EMP complexes (mono:EMP) through the BMVEC. The effect of IFN-beta 1b on the release of EMP and the TEMIG of mono and mono:EMP was assessed by preincubating BMVEC cultures of IFN-beta 1b prior to addition of plasma. Three EMP phenotypes, CD54, CD62E and CD31 were assayed. Plasma specimens from 20 patients with relapsing remitting MS (11 in exacerbation, MS-E, and 9 in remission, ME-R) and 10 healthy controls were studied. Incubation of BMVEC with MS-E plasma yielded elevated levels of EMPCD54, EMP62E and EMPCD31 relative to MS-R and control plasmas. MS-E but not MS-R or control plasma also augmented TEMIG of monocytes, respectively. Mono:EMP complexes further augmented TEMIG relative to mono alone, but only in the presence of MS-E plasma; there was no significant effect with MS-R or control plasmas. The presence of IFN-beta 1b inhibited TEMIG of mono and mono:EMP by 20% and 30%, respectively. MS-E but not MS-R plasma elicited release of activation-derived EMP and enhanced TEMIG of mono and mono:EMP. IFN-beta 1b inhibited TEMIG and release of EMP, suggesting a role of EMP and a novel therapeutic mechanism for IFN-beta 1b in MS.

BackgroundMeasurement of soluble HLA in body fluids has a potential role in assessing disease activity in autoimmune disorders.MethodsWe applied a solid phase, enzyme-linked immunoassay to measure soluble HLA class I (sHLA-I) and class II (sHLA-II) molecules in the saliva and cerebrospinal fluid (CSF) in 13 untreated patients with relapsing-remitting form of multiple sclerosis (MS). For comparison purposes, we also studied saliva from 53 healthy subjects.ResultsSaliva from normal controls had detectable sHLA-I levels in 41 of 53 individuals studied, with values ranging from 9–100 ng/ml (mean = 41 ± 2.8 ng/ml). sHLA-I was undetectable in the saliva in 11 of 13 MS patients, and in none of the CSF specimens. In contrast, mean sHLA-II concentration in the saliva of MS patients was significantly increased compared to controls (386 ± 52 unit/ml vs. 222 ± 18.4 unit/ml, t = 8.68, P < 0.005). The mean CSF sHLA-II level (369 ± 16 unit/ml) was equivalent to the mean sHLA-II concentration measured in saliva (mean = 386 ± 52 unit/ml) (P = 0.7). In patients with brain magnetic resonance imaging (MRI) enhancing lesions (n = 5), reflective of more active disease, CSF sHLA-II averaged 356 ± 26 unit/ml compared to 380 ± 51 in saliva. Similarly, in patients with non-enhancing lesions (n = 8), CSF sHLA-II averaged 377 ± 18 unit/ml compared to 390 ± 77 unit/ml in saliva. Thus, the mean sHLA-II concentration in saliva and CSF was essentially equivalent for MS patients with or without enhancing plaques.ConclusionOur data suggest that the measurement of soluble HLA in saliva, specifically sHLA-II, correlates with the level found in the CSF. Therefore, if sHLA correlates with disease activity in MS, as has been proposed, saliva measurements provide a noninvasive correlate of CSF measurement.

Myasthenia gravis (MS) is an immune-mediated disorder characterized by fluctuating weakness and fatigue of voluntary muscles. The muscular disorder is generalized in 85% and confined to extraocular muscles in 15% of patients. Pathophysiology of MG involves generation of antiacetylcholine receptor antibodies, which leads to a reduction of the number of acetylcholine receptors at the muscular motor endplate. This in turn results in fewer acetylcholine receptors available for stimulation, lower amplitude stimulations, less muscle fiber activation, and the eventual development of weakness in the affected muscles. The diagnostic workup for MS consists of administration of anticholinesterase agents (Tensilon test), repetitive nerve stimulation, Ach-R antibody assay, and single-fiber electromyography. Management of patients with MG includes cholinesterase inhibitors, corticosteroids, thymectomy, immunosuppressants, plasma exchange, and IVIg.

Summary: Magnetic resonance imaging (MRI) plays an ever-expanding role in the evaluation of multiple sclerosis (MS). This includes its sensitivity for the diagnosis of the disease and its role in identifying patients at high risk for conversion to MS after a first presentation with selected clinically isolated syndromes. In addition, MRI is a key tool in providing primary therapeutic outcome measures for phase I/II trials and secondary outcome measures in phase III trials. The utility of MRI stems from its sensitivity to longitudinal changes including those in overt lesions and, with advanced MRI techniques, in areas affected by diffuse occult disease (the so-called normal-appearing brain tissue). However, all current MRI methodology suffers from limited specificity for the underlying histopathology. Conventional MRI techniques, including lesion detection and measurement of atrophy from T1- or T2-weighted images, have been the mainstay for monitoring disease activity in clinical trials, in which the use of gadolinium with T1-weighted images adds additional sensitivity and specificity for areas of acute inflammation. Advanced imaging methods including magnetization transfer, fluid attenuated inversion recovery, diffusion, magnetic resonance spectroscopy, functional MRI, and nuclear imaging techniques have added to our understanding of the pathogenesis of MS and may provide methods to monitor therapies more sensitively in the future. However, these advanced methods are limited by their cost, availability, complexity, and lack of validation. In this article, we review the role of conventional and advanced imaging techniques with an emphasis on neurotherapeutics.

Mortality of obese patients with sepsis has been reported to be significantly higher than lean patients. The underlying basis for this difference is not currently known. However, it has been suggested that obesity is associated with an altered immune response to a septic or inflammatory insult. Since obesity is based on exclusion in many sepsis trials, little is known about how obesity affects mortality or whether obese individuals respond differently to therapeutic interventions. In this study, obese and non-obese mice were given intra-peritoneal injection of saline or LPS and the livers were harvested 2 hours later. RNA from these livers were subjected to DNA microarray. Analysis showed distinct differences in gene expression between lean and obese animals. The expression of one hundred and seventeen genes was found to be different among the groups. In the obese animals treated with LPS, the expression of 20 genes showed a significant change. Ontology analysis revealed increased expression of 15 genes and significant decrease in expression of 5 genes. This study shows different gene expression of liver in response to LPS in lean versus obese animals. These genes might play a role in the outcome of sepsis.