Central Nervous Disorders Research Articles

Wissenschaftliche Neurobildgebung in der Medizin

Neuroimaging has in recent years greatly contributed to our understanding of a wide range of aspects of central neurological diseases. These include the classification and localization of disease (e.g., in headache), the understanding of pathology (e.g., in Parkinson's disease), mechanisms of reorganization (e.g., in stroke), and the subclinical progress of disease (e.g., in degenerative diseases). Apart form presurgical mapping, clinical applications of fMRI are limited. However, functional imaging enables the formulation of neurobiological hypotheses that can be tested clinically and is suited to test classical clinical hypotheses about how the brain works. Understanding the mechanisms and the site of pathology, e.g., in cluster headaches, will lead and has led to new therapeutic strategies. New methodological developments for neuroscientific applications are aimed at the integration of functional and morphological connectivity through a combination of magnetic resonance techniques (fMRI, DTI) and electrophysiological (EEG, MEG) recordings. In addition to stimulus-dependent activations, resting state activity has found increasing interest, for example, in sleep research and various psychiatric diseases (e.g., schizophrenia, borderline).

Novel plasminogen activator inhibitor-1-derived peptide protects against impairment of cerebrovasodilation after photothrombosis through inhibition of JNK MAPK

The sole FDA-approved treatment for acute stroke is recombinant tissue-type plasminogen activator (rtPA). However, rtPA aggravates the impairment of cerebrovasodilation induced by global hypoxia/ischemia; this impairment is attenuated by the preinjury treatment with the plasminogen activator inhibitor derivative EEIIMD. MAPK (a family of kinases, p38, and JNK) is upregulated after cerebral ischemia. In this study, we determined whether the novel plasminogen activator inhibitor-derived peptide, Ac-RMAPEEIIMDRPFLYVVR-amide, (PAI-1-DP) given 30 min before or 2 h after, focal central nervous system injury induced by photothrombosis would preserve responses to cerebrovasodilators and the role of p38 and JNK MAPK in such effects. Cerebrospinal fluid JNK and p38 levels were elevated by photothrombotic injury, an effect potentiated by rtPA. Cerebrovasodilation was blunted by photothrombosis and reversed to vasoconstriction by rtPA but restored to dilation by PAI-1-DP pre- and posttreatment. PAI-1-DP blocked JNK, but preserved p38 MAPK upregulation after photothrombosis. The JNK MAPK antagonist SP600125 prevented, and the p38 antagonist SB203580 potentiated, impaired cerebrovasodilation after photothrombosis. These data indicate that rtPA impairs cerebrovasodilation after injury by activating JNK, while p38 MAPK is protective, and that the novel peptide PAI-1-DP protects by inhibiting activation of JNK by rtPA. JNK MAPK inhibitors, including PAI-1-DP, may offer a novel approach to increase the benefit-to-risk ratio of thrombolytic therapy and enable its use in central nervous system ischemic disorders.

Differentiation of cryopreserved human umbilical cord blood-derived stromal cells into cells with an oligodendrocyte phenotype

In this study, we examined the phenotypic characteristics of human umbilical cord blood-derived mesenchymal stromal cells (UCB-derived MSCs) differentiated along an oligodendrocyte pathway. We induced human UCB-derived MSCs to form floating neurospheres, and these neurospheres were then induced to differentiate into oligodendrocyte progenitor-like cells using multiple induction factors. Differentiated UCB-derived MSCs showed morphologic characteristics of an oligodendrocyte phenotype. The expression of cell surface markers characteristic of oligodendrocyte progenitor cells or oligodendrocytes was determined by immunocytochemical staining. These results suggest that human UCB-derived MSCs can be induced to differentiate into cells with an oligodendrocyte phenotype and that these cells may have potential in the future cellular therapy of central neurological disorders.

Neuropilin-1 is important for proper suppression of inflammation and autoreactivity (143.23)

Abstract The surface molecule Neuropilin-1 (Nrp1), was originally identified for its role in neuronal development. Recently, Nrp1 has been implicated in several aspects of immune function, including maintenance of the immune synapse and development of regulatory T cells (Treg). We provide the first evidence for a role of Nrp1 in the pathogenesis of an immune mediated disease, experimental autoimmune encephalomyelitis (EAE), which serves as an animal model for the central nervous system inflammatory disorder multiple sclerosis (MS). Using a mouse cell type specific deletion system, we observed that the lack of Nrp1 on CD4+ T cells results in increased EAE disease severity. These Nrp1 conditional knockout mice exhibit preferential Th17 lineage commitment. Further, CD4+ T cells expressing Nrp1 can suppress Th17 cell expansion and cytokine production both in vitro and in vivo. These findings suggest that Nrp1 is essential for proper maintenance of peripheral tolerance and its absence can result in unchecked autoreactive responses.

Isolated Epstein-Barr Virus-Induced Central Nervous System Post-Transplantation Lymphoproliferative Disorder Despite Negative Serum PCR

Isolated Epstein-Barr Virus-Induced Central Nervous System Post-Transplantation Lymphoproliferative Disorder Despite Negative Serum PCR

Impact of low intensity millimetre waves on cell functions

Investigations on the biological impact of low levels of millimetre-wave energy date back to the first experiments on the generation and detection of these high-frequency signals by Sir Jagadis Chunder Bose at the end of the 19th century. Slightly more than a hundred years later, millimetre-wave transmission has become a ubiquitous commercial reality. Despite the widespread use of millimetre-wave transmitters for communications, radar and even non-lethal weapons systems, only a handful of researchers have funded programmes focusing on millimetre-wave interactions with biological systems. As such, there is a growing need for a better understanding of the mechanisms of these interactions and their possible adverse and therapeutic implications. Independent of the health impact of long-term exposure to high doses of millimetre-wave energy on whole organisms, there exists the potential for subtle effects on specific tissues or organs which can best be quantified in studies which examine real-time changes in cellular function as energy is applied. In this Letter, a series of experiments are presented which show changes in cell membrane potential and the action potential firing rate of cortical neurons under short (1 min) exposures to continuous-wave 60 GHz radiation at µW/cm2 power levels, more than 1000 times below the US government maximum permissible exposure. The findings have implications for non-contact stimulation and control of neurologic function, and might prove useful in a variety of health applications from suppression of peripheral neuropathic pain to the treatment of central neurological disorders.

Effectiveness of Non-Surgical Management Strategies for Constipation in Adults with Stroke: A Systematic Review

Effectiveness of Non-Surgical Management Strategies for Constipation in Adults with Stroke: A Systematic Review

High prevalence of multidrug-resistant Pneumococcal molecular epidemiology network clones among Streptococcus pneumoniae isolates from adult patients with community-acquired pneumonia in Japan

A total of 141 Streptococcus pneumoniae isolates from patients with community-acquired pneumonia were collected from May 2003 through October 2004. The strains were tested for antimicrobial agent susceptibility, serotype and genotype by multilocus sequence typing (MLST) and the presence of the pilus rlrA islet. MLST analysis identified 49 sequence types (STs), of which 19 were novel. eBURST analysis using the MLST database (3773 STs) grouped the isolates into 27 clonal complexes and three singletons. A total of 92 (65.2%) isolates were related to ten of the 43 international Pneumococcal Molecular Epidemiology Network (PMEN) clones; major clones found were multidrug-resistant Netherlands3-31 [clonal complex (CC) 180], Taiwan19F-14 (CC271), Taiwan23F-15 (CC242), and Colombia23F-26 (CC138) (the latter new to Asia). We adopted univariate and multiple logistic regression models to identify factors associated with PMEN CCs. Multivariate analysis showed that multidrug resistance (OR 6.3; 95% CI 2.0–22.9), carriage serogroups (OR 7.2; 95% CI 2.5–23.7), prevalence of rlrA (OR 12.6; 95% CI 3.6–59.7) and central nervous system-related disorders (OR 7.7; 95% CI 1.8–48.4) were independently associated with PMEN CCs. Our data indicate that multidrug-resistant PMEN clones are highly prevalent, contributing to the high frequency of resistance to antimicrobial agents in Japan, and suggest that certain predisposing factors in patients contribute to the high frequency of these clones.

Neuroprotective effect of 4-hydroxybenzyl alcohol against transient focal cerebral ischemia via anti-apoptosis in rats

4-hydroxybenzyl alcohol (4-HBA), one of the major active phenolic constituents of Gastrodia elata Blume, a very important traditional Chinese medicinal herb, has been shown to be an effective agent against the central and peripheral nervous disorders. In this study, we attempted to explore the possible mechanisms underlying the neuroprotection against transient focal cerebral ischemia by 4-HBA.4-HBA (25, 50 mg/kg) was given 30 min before focal ischemia in rats caused by middle cerebral artery occlusion (1 h of occlusion, 24 h of reperfusion). Under the treatment of 50 mg/kg 4-HBA, total (100.76±2.90 mm3), cortical (64.91±1.46 mm3), and sub-cortical (38.77±2.78 mm3) infarct volumes were significantly decreased in comparison to ischemia-reperfusion values. Neurological evaluation and Nissl-staining of the 4-HBA group were improved significantly compared to the untreated ischemia group. TUNEL-positive cells were reduced significantly in 4-HBA treated group. Results of immunofluorescence staining analysis and Western immunoblot indicated that 4-HBA increased the expression of Bcl-2 and inhibited the activation of caspase-3 ultimately inhibiting apoptosis. These results suggested that 4-HBA ameliorated ischemic injury induced by transient focal cerebral ischemia in rats, and this neuroprotective effect may be partly related to attenuate apoptosis pathway.

Paradoxical Vocal Cord Motion-Haloperidol Usage in Acute Attack Treatment

Paradoxical vocal cord motion (PVCM) is an uncommon disease characterized by vocal cord adduction during inspiration and/or expiration. It can create shortness of breath, wheezing, respiratory stridor, or breathy dysphonia. Possible etiological factors include asthma, underlying psychologic condition, gastroesophageal acid reflux disease, respiratory irritants exposure, central neurologic diseases, viral upper airway infections, and postsurgical procedures. Many treatment modalities were performed for acute attack of PVCM, including reassurance and onsite maneuvers, benzodiazepines, heliox, and so forth. We report a patient with PVCM who had stridor and dyspnea for 10 days and responded to intravenous haloperidol treatment.

Synthesis and in vitro evaluation of 2,4-diamino-1,3,5-triazine derivatives as neuronal voltage-gated sodium channel blockers

Neuronal sodium channels blockers interfere with ion flux and have been used for managing neuropathic pain, epilepsy, and cerebral ischemic disorders. In the current study, four groups of 2,4-diamino-1,3,5-triazine derivatives were synthesized and investigated for their neuronal sodium channels binding activity. 5-Aryl-1,3,5-triazaspiro[5.5]undeca-1,3-diene-2,4-diamines ( 4a– 4j) were found to have the best neuronal sodium binding activity among the four groups of triazines evaluated. Derivatives 4a– 4j blocked the sodium channels with IC 50 values ranged from 4.0 to 14.7 μM. The result from this study showed that analogues of 2,4-diamino-1,3,5-triazines could be used as leads for the discovery of neuronal sodium channels blockers for managing central nervous system related disorders.

Neurogenic colorectal and pelvic floor dysfunction

Constipation and faecal incontinence are common symptoms among patients with spinal cord injury (SCI), myelomeningocoele (MMC), multiple sclerosis (MS), Parkinson's disease (PD) and stroke. Faecal incontinence in SCI, MMC and MS is mainly due to abnormal rectosigmoid compliance and rectoanal reflexes, loss of rectoanal sensibility and loss of voluntary control of the external anal sphincter. Constipation in SCI, MMC and MS is probably due to immobilisation, abnormal colonic contractility, tone and rectoanal reflexes or side effects from medication. In PD, dystonia of the external anal sphincter causes difficult rectal evacuation and the loss of dopaminergic neurons in the enteric nervous system probably causes slow-transit constipation. Changes after stroke remain to be studied. Though dietary adjustments, oral laxatives, suppositories and other conservative treatment modalities are commonly used, evidence for their use in patients with central neurological disorders is scarce. For patients with severe symptoms trans-anal irrigation, the Malone appendicostomy or a colostomy can be recommended.

NRXN3 Is a Novel Locus for Waist Circumference: A Genome-Wide Association Study from the CHARGE Consortium

Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4×10−7)]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3×10−8 for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4×10−6, 0.024 z-score units (0.10 kg/m2) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07–1.19; p = 3.2×10−5 per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.

Hyaluronic acid hydrogel loaded with genetically-engineered brain-derived neurotrophic factor as a neural cell carrier

Cell transplantation is a potential therapy for central nervous disorders such as Parkinson's disease. However, the therapeutic effect is limited by the low viability of transplanted cells. To solve this problem, we synthesized hyaluronic acid (HAc)-based hydrogel to be used as a carrier for neural cells. Another feature of the hydrogel synthesized here is to incorporate brain-derived neurotrophic factor (BDNF) for enhancing cell survival in the hydrogel. The cross-linking of HAc and the incorporation of BDNF were both achieved by employing the ability of a hexahistidine peptide to form stable chelate with metal ions. HAc was reacted with N-(5-amino-1-carboxypentyl) iminodiacetic acid and chelated with Zn(II) ions. An alpha-helical peptide of 70 amino acid residues carrying a hexahistidine peptide (His) at the both termini and BDNF carrying a His at the C-terminus were synthesized by recombinant DNA technology. These polypeptides were coordinated with the Zn(II) ions chelated to HAc chains for both the cross-linking of HAc and the tethering of BDNF. Viscosity measurements revealed that intermolecular cross-links were introduced in the Zn(II)–chelated HAc chains upon mixing with the His-containing helical peptide. It was shown by release tests that the coordinated BDNF was firmly bound to the Zn(II)-chelated HAc for more than 12 days. The results of cell culture experiments combined with live/dead assays demonstrated that a significantly higher fraction of neural cells survived 3 days post-seeding in the HAc-based hydrogel incorporating BDNF than in the control hydrogel lacking BDNF. These results suggest that the HAc-based hydrogel developed here has potential to improve survival of transplanted neural cells.

Imagerie par résonance magnétique de l’inflammation du système nerveux central

Magnetic resonance imaging (MRI) is widely used to explore central nervous system inflammatory disorders, especially multiple sclerosis (MS). Advanced MRI methods are bringing more sensitive and specific tools for each step of the inflammatory process. In this review, we discuss the different MRI approaches for inflammatory disorders exploration, especially MS. We give particular emphasize on sensibility and specificity of each MRI approach and we also discuss the current knowledge concerning biological and histopathological substratum that could explain MRI signal with each modality.

Isolated Central Nervous System Posttransplant Lymphoproliferative Disorder Treated with High-Dose Intravenous Methotrexate

Posttransplant lymphoproliferative disorder (PTLD) is an uncommon neoplastic complication of kidney trans- plantation, affecting about 1% of recipients. It is generally associated with Epstein–Barr virus (EBV) infection of B-lineage lymphocytes. Central nervous system (CNS) involvement is rare. There is little clinical experience with treatment of CNS PTLD due to the relative rarity of the disease other than reduction or withdrawal of immunosuppression, but it is usually fatal. We describe six patients with renal allografts and histologically proven isolated CNS PTLD. Tissue analysis from the biopsy specimens was positive for EBV material infive of the six patients. All six patients were treated with high-dose intravenous methotrexate (HD IV MTX). Methotrexate was initiated at 8 g/m2, with later adjustments for creatinine clearance. With MTX therapy, four patients have had a sustained complete response, and two had progressive disease and were referred for radiation therapy. This finding suggests a subgroup of patients may benefit from MTX but our case series is inadequate to describe overall efficacy. No unexpected toxicities were encountered in 37 courses of treatment. HD IV MTX chemotherapy should be considered as an alternative for treatment of CNS PTLD.

Neuropilin-1 is important for proper suppression of inflammation and autoreactivity (99.6)

Abstract Neuropilin-1(Nrp1) is a surface molecule originally identified for its role in neuronal development. Recently, Nrp1 has been implicated in several aspects of immune function including maintenance of the immune synapse and development of regulatory T cells (Treg). In this study we provide the first evidence for a role of Nrp1 in the pathogenesis of an immune mediated disease, experimental autoimmune encephalomyelitis (EAE), which is an animal model for the central nervous system inflammatory disorder multiple sclerosis (MS). Using a cell type specific deletion system, we observed that the lack of Nrp1 on CD4+ T cells results in increased EAE disease severity. These conditional knockout mice exhibit preferential Th17 lineage commitment and decreased Treg numbers and functionality. Conversely, mice receiving CD4 T cells that were retrovirally transduced with Nrp1 and immunized for EAE developed only mild EAE compared to controls. This suggests that Nrp1 is essential for proper maintenance of peripheral tolerance and its absence can result in unchecked autoreactive responses leading to diseases like EAE and MS. This work was supported by National Institutes of Health Grants AI 57854 and AI 072434 (to MSB).

Post‐natal investigations: management and prognosis for fetuses with CNS anomalies identified in utero excluding neurosurgical problems

The suspicion of an abnormality of the central nervous (CNS) system raises difficult questions for the clinician and the family and will inevitably lead to considerable anxiety. These questions include what it means for the child's future, whether it can be treated and whether it will happen again in subsequent pregnancies. For many disorders accurate prenatal diagnosis remains elusive, as even with fetal magnetic resonance imaging (MRI), early recognition and characterisation are simply not possible because of the immature state of brain development at that stage of pregnancy. The natural history of many prenatally diagnosed CNS disorders remains to be elucidated which means that an accurate prognosis cannot be given in all cases. We review the current state of knowledge regarding the investigation, management and prognosis of the most common and important CNS malformations. We also discuss the post-natal management of these conditions both in the neonate and subsequent pregnancies for the families.

Multivalent-Based Drug Design Applied to Serotonin 5-HT4 Receptor Oligomers

Historically treated as monomeric polypeptides, G protein-coupled receptors (GPCRs) have been shown to exist and function as constitutively formed dimers or oligomers. The quaternary structure of GPCRs may modulate ligand binding properties through allosteric mechanisms offering new opportunities for drug design by exploiting multivalency. In this context, multivalent ligands versus bivalent-ligands, possessing two binding motifs connected by a linker, have been investigated and have revealed striking differences in their functional properties compared to their monovalent counterparts. These bi-functional drugs, which are able to activate the two protomers in a dimer simultaneously, emerge as novel and promising drugs for a variety of multi-factorial diseases. In this review, key requirements for the successful design and synthesis of GPCR multivalent ligands composed of pharmacophores and a linker will be discussed. We will then focus on the 5-HT(4) receptor (5-HT(4)R), whose ligands emerged as promising drugs for a variety of central nervous disorders. Upon description of biochemical and biophysical evidences of 5-HT(4)R dimerization, we will present the multivalent ligand approach, which was assisted by molecular docking experiments on the 5-HT(4)R dimer model.

Characterization of a Degenerative Cardiomyopathy Associated with Domoic Acid Toxicity in California Sea Lions (Zalophus californianus)

Domoic acid, produced by marine algae, can cause acute and chronic neurologic sequela in California sea lions (Zalophus californianus) from acute toxicity or sublethal exposure. Eight sea lions, representing acute and chronic cases, both sexes, and all age classes, were selected to demonstrate a concurrent degenerative cardiomyopathy. Critical aspects of characterizing the cardiomyopathy by lesion distribution and morphology were the development of a heart dissection and tissue-trimming protocol and the delineation of the cardiac conducting system by histomorphology and immunohistochemistry for neuron-specific protein gene product 9.5. Histopathologic features and progression of the cardiomyopathy are described, varying from acute to chronic active and mild to severe. The cardiomyopathy is distinguished from other heart lesions in pinnipeds. Based on histopathologic features, immunopositive staining for cleaved caspase-3, and comparison with known, similar-appearing cardiomyopathies, the proposed pathogenesis for the degenerative cardiomyopathy is the primary or at least initial direct interaction of domoic acid with receptors that are suspected to exist in the heart. l-Carnitine, measured in the heart and skeletal muscle, and troponin-I, measured in serum collected at the time of death from additional animals (n = 58), were not predictive of the domoic acid-associated cardiomyopathy. This degenerative cardiomyopathy in California sea lions represents another syndrome beyond central neurologic disease associated with exposure to domoic acid and may contribute to morbidity and mortality.