Selective loss of noradrenaline exacerbates early cognitive dysfunction and synaptic deficits in APP/PS1 mice.

Background: Degeneration of the locus coeruleus (LC), the major noradrenergic nucleus in the brain, occurs early and is ubiquitous in Alzheimer’s disease (AD). Experimental lesions to the LC exacerbate AD-like neuropathology and cognitive deficits in several transgenic mouse models of AD. Because the LC contains multiple neuromodulators known to affect amyloid toxicity and cognitive function, the specific role of noradrenaline (NA) in AD is not well understood. Methods: To determine the consequences of selective NA deficiency in an AD mouse model, we crossed dopamine -hydroxylase (DBH) knockout mice with amyloid precursor protein (APP)/presenilin-1 (PS1) mice overexpressing mutant APP and PS1. Dopamine -hydroxylase (/) mice are unable to synthesize NA but otherwise have normal LC neurons and co-transmitters. Spatial memory, hippocampal long-term potentiation, and synaptic protein levels were assessed. Results: The modest impairments in spatial memory and hippocampal long-term potentiation displayed by young APP/PS1 or DBH (/) single mutant mice were augmented in DBH (/)/APP/PS1 double mutant mice. Deficits were associated with reduced levels of total calcium/calmodulin-dependent protein kinase II and N-methyl-D-aspartate receptor 2A and increased N-methyl-D-aspartate receptor 2B levels and were independent of amyloid accumulation. Spatial memory performance was partly improved by treatment with the NA precursor drug L-threo-dihydroxyphenylserine. Conclusions: These results indicate that early LC degeneration and subsequentNAdeficiency inADmay contribute to cognitive deficits via altered levels of calcium/calmodulin-dependent protein kinase II and N-methyl-D-aspartate receptors and suggest that NA supplementation could be beneficial in early AD

Genetic or pharmacological blockade of noradrenaline synthesis enhances the neurochemical, behavioral, and neurotoxic effects of methamphetamine

N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) lesions of the locus coeruleus, the major brain noradrenergic nucleus, exacerbate the damage to nigrostriatal dopamine (DA) terminals caused by the psychostimulant methamphetamine (METH). However, because noradrenergic terminals contain other neuromodulators and the noradrenaline (NA) transporter, which may act as a neuroprotective buffer, it was unclear whether this enhancement of METH neurotoxicity was caused by the loss of noradrenergic innervation or the loss of NA itself. We addressed the specific role of NA by comparing the effects of METH in mice with noradrenergic lesions (DSP-4) and those with intact noradrenergic terminals but specifically lacking NA (genetic or acute pharmacological blockade of the NA biosynthetic enzyme dopamine beta-hydroxylase; DBH). We found that genetic deletion of DBH (DBH-/- mice) and acute treatment of wild-type mice with a DBH inhibitor (fusaric acid) recapitulated the effects of DSP-4 lesions on METH responses. All three methods of NA depletion enhanced striatal DA release, extracellular oxidative stress (as measured by in vivo microdialysis of DA and 2,3-dihydroxybenzoic acid), and behavioral stereotypies following repeated METH administration. These effects accompanied a worsening of the striatal DA neuron terminal damage and ultrastructural changes to medium spiny neurons. We conclude that NA itself is neuroprotective and plays a fundamental role in the sensitivity of striatal DA terminals to the neurochemical, behavioral, and neurotoxic effects of METH

The frequency of transforming growth factor-TGF-B gene polymorphisms in a normal southern Iranian population

Several single nucleotide polymorphisms (SNPs) of the transforming growth factor-β1 gene (TGFB1) have been reported. Determination of TGFB1 SNPs allele frequencies in different ethnic groups is useful for both population genetic analyses and association studies with immunological diseases. In this study, five SNPs of TGFB1 were determined in 325 individuals from a normal southern Iranian population using polymerase chain reaction-restriction fragment length polymorphism method. This population was in Hardy-Weinberg equilibrium for these SNPs. Of the 12 constructed haplotypes, GTCGC and GCTGC were the most frequent in the normal southern Iranian population. Comparison of genotype and allele frequencies of TGFB SNPs between Iranian and other populations (meta-analysis) showed significant differences, and in this case the southern Iranian population seems genetically similar to Caucasoid populations. However, neighbour-joining tree using Nei's genetic distances based on TGF-β1 allele frequencies showed that southern Iranians are genetically far from people from the USA, Germany, UK, Denmark and the Czech Republic. In conclusion, this is the first report of the distribution of TGFB1 SNPs in an Iranian population and the results of this investigation may provide useful information for both population genetic and disease studies. © 2008 The Authors

Cost of managing an episode of relapse in multiple sclerosis in the United States

BACKGROUND: The purpose of this study was to determine the direct medical US cost of managing multiple sclerosis relapses. METHODS: Direct data analysis and cost modeling were employed to derive typical resource use profiles and costs in 2002 US dollars, from the perspective of a third-party payer responsible for comprehensive health-care. The location and scope of health care services provided over a 90-day period were used to define three levels of relapse management. Hospitalization and resulting subsequent care was defined as high intensity management. A medium level of intervention was defined as either use of the emergency room, an observational unit, or administration of acute treatments, such as intravenous methylprednisolone in an outpatient or home setting. The lowest intensity of care comprised physician office visits and symptom-related medications. Data were obtained from many sources including all payer inpatient, ambulatory and emergency room databases from several states, fee schedules, government reports, and literature. All charges were adjusted using cost-to-charge ratios. RESULTS: Average cost per person for high management level was $12,870, based on analysis of 4,634 hospital cases (mean age 48 years, 73$1,847 and mild episode $243. CONCLUSIONS: Management strategies leading to a reduction in the frequency and severity of a relapse, less reliance on inpatient care, or increased access to steroid infusions in the home, would have a substantial impact on the economic consequences of managing relapses

The neurotoxin DSP-4 dysregulates the locus coeruleus-norepinephrine system and recapitulates molecular and behavioral aspects of prodromal neurodegenerative disease

The noradrenergic locus coeruleus (LC) is among the earliest sites of tau and α-synuclein pathology in Alzheimer\u27s disease (AD) and Parkinson\u27s disease (PD), respectively. The onset of these pathologies coincides with loss of noradrenergic fibers in LC target regions and the emergence of prodromal symptoms including sleep disturbances and anxiety. Paradoxically, these prodromal symptoms are indicative of a noradrenergic hyperactivity phenotype, rather than the predicted loss of norepinephrine (NE) transmission following LC damage, suggesting the engagement of complex compensatory mechanisms. Because current therapeutic efforts are targeting early disease, interest in the LC has grown, and it is critical to identify the links between pathology and dysfunction. We employed the LC-specific neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), which preferentially damages LC axons, to model early changes in the LC-NE system pertinent to AD and PD in male and female mice. DSP-4 (two doses of 50 mg/kg, one week apart) induced LC axon degeneration, triggered neuroinflammation and oxidative stress, and reduced tissue NE levels. There was no LC cell death or changes to LC firing, but transcriptomics revealed reduced expression of genes that define noradrenergic identity and other changes relevant to neurodegenerative disease. Despite the dramatic loss of LC fibers, NE turnover and signaling were elevated in terminal regions and were associated with anxiogenic phenotypes in multiple behavioral tests. These results represent a comprehensive analysis of how the LC-NE system responds to axon/terminal damage reminiscent of early AD and PD at the molecular, cellular, systems, and behavioral levels, and provides potential mechanisms underlying prodromal neuropsychiatric symptoms

Widespread sex differences in gene expression and splicing in the adult human brain

There is strong evidence to show that men and women differ in terms of neurodevelopment, neurochemistry and susceptibility to neurodegenerative and neuropsychiatric disease. The molecular basis of these differences remains unclear. Progress in this field has been hampered by the lack of genome-wide information on sex differences in gene expression and in particular splicing in the human brain. Here we address this issue by using post-mortem adult human brain and spinal cord samples originating from 137 neuropathologically confirmed control individuals to study whole-genome gene expression and splicing in 12 CNS regions. We show that sex differences in gene expression and splicing are widespread in adult human brain, being detectable in all major brain regions and involving 2.5% of all expressed genes. We give examples of genes where sex-biased expression is both disease-relevant and likely to have functional consequences, and provide evidence suggesting that sex biases in expression may reflect sex-biased gene regulatory structures

Coordination of opposing sex-specific and core muscle groups regulates male tail posture during Caenorhabditis elegans male mating behavior

Background To survive and reproduce, animals must be able to modify their motor behavior in response to changes in the environment. We studied a complex behavior of Caenorhabditis elegans, male mating behavior, which provided a model for understanding motor behaviors at the genetic, molecular as well as circuit level. C. elegans male mating behavior consists of a series of six sub-steps: response to contact, backing, turning, vulva location, spicule insertion, and sperm transfer. The male tail contains most of the sensory structures required for mating, in addition to the copulatory structures, and thus to carry out the steps of mating behavior, the male must keep his tail in contact with the hermaphrodite. However, because the hermaphrodite does not play an active role in mating and continues moving, the male must modify his tail posture to maintain contact. We provide a better understanding of the molecular and neuro-muscular pathways that regulate male tail posture during mating. Results Genetic and laser ablation analysis, in conjunction with behavioral assays were used to determine neurotransmitters, receptors, neurons and muscles required for the regulation of male tail posture. We showed that proper male tail posture is maintained by the coordinated activity of opposing muscle groups that curl the tail ventrally and dorsally. Specifically, acetylcholine regulates both ventral and dorsal curling of the male tail, partially through anthelmintic levamisole-sensitive, nicotinic receptor subunits. Male-specific muscles are required for acetylcholine-driven ventral curling of the male tail but dorsal curling requires the dorsal body wall muscles shared by males and hermaphrodites. Gamma-aminobutyric acid activity is required for both dorsal and ventral acetylcholine-induced curling of the male tail and an inhibitory gamma-aminobutyric acid receptor, UNC-49, prevents over-curling of the male tail during mating, suggesting that cross-inhibition of muscle groups helps maintain proper tail posture. Conclusion Our results demonstrated that coordination of opposing sex-specific and core muscle groups, through the activity of multiple neurotransmitters, is required for regulation of male tail posture during mating. We have provided a simple model for regulation of male tail posture that provides a foundation for studies of how genes, molecular pathways, and neural circuits contribute to sensory regulation of this motor behavior

Preferential Gs protein coupling of the galanin Gal1 receptor in the μ-opioid-Gal1 receptor heterotetramer

Recent studies have proposed that heteromers of μ-opioid receptors (MORs) and galanin Gal1 receptors (Gal1Rs) localized in the mesencephalon mediate the dopaminergic effects of opioids. The present study reports converging evidence, using a peptide-interfering approach combined with biophysical and biochemical techniques, including total internal reflection fluorescence microscopy, for a predominant homodimeric structure of MOR and Gal1R when expressed individually, and for their preference to form functional heterotetramers when co-expressed. Results show that a heteromerization-dependent change in the Gal1R homodimeric interface leads to a switch in G-protein coupling from inhibitory Gi to stimulatory Gs proteins. The MOR-Gal1R heterotetramer, which is thus bound to Gs via the Gal1R homodimer and Gi via the MOR homodimer, provides the framework for a canonical Gs-Gi antagonist interaction at the adenylyl cyclase level. These novel results shed light on the intense debate about the oligomeric quaternary structure of G protein-coupled receptors, their predilection for heteromer formation, and the resulting functional significance

Placebo-controlled study in neuromyelitis optica : ethical and design considerations

BACKGROUND: To date, no treatment for neuromyelitis optica (NMO) has been granted regulatory approval, and no controlled clinical studies have been reported. OBJECTIVE: To design a placebo-controlled study in NMO that appropriately balances patient safety and clinical-scientific integrity. METHODS: We assessed the "standard of care" for NMO to establish the ethical framework for a placebo-controlled trial. We implemented measures that balance the need for scientific robustness while mitigating the risks associated with a placebo-controlled study. The medical or scientific community, patient organizations, and regulatory authorities were engaged early in discussions on this placebo-controlled study, and their input contributed to the final study design. RESULTS: The N-MOmentum study (NCT02200770) is a clinical trial that randomizes NMO patients to receive MEDI-551, a monoclonal antibody that depletes CD19+ B-cells, or placebo. The study design has received regulatory, ethical, clinical, and patient approval in over 100 clinical sites in more than 20 countries worldwide. CONCLUSION: The approach we took in the design of the N-MOmentum trial might serve as a roadmap for other rare severe diseases when there is no proven therapy and no established clinical development path

Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria

New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis. The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan. These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use. Ann Neurol 201