Showing papers in "Journal of Neural Transmission in 2005"

Post-translational modifications of tau protein in Alzheimer's disease.

Abstract: Microtubule-associated protein tau undergoes several post-translational modifications and aggregates into paired helical filaments (PHFs) in Alzheimer's disease (AD) and other tauopathies. These modifications of tau include hyperphosphorylation, glycosylation, ubiquitination, glycation, polyamination, nitration, and proteolysis. Hyperphosphorylation and glycosylation are crucial to the molecular pathogenesis of neurofibrillary degeneration of AD. The others appear to represent failed mechanisms for neurons to remove damaged, misfolded, and aggregated proteins. This review summarizes the abnormal post-translational modifications of tau and discusses the pathophysiological relevance of hyperphosphorylation and glycosylation of tau. Total tau and phosphorylated tau levels in cerebrospinal fluid as a diagnostic biomarkers are also reviewed. Analyses of the current advances in tau modifications suggest that intervention addressing these abnormalities may offer promising therapeutic opportunities to prevent and treat neurofibrillary degeneration of AD and other tauopathies.

Oxidative stress potentiates BACE1 gene expression and Aβ generation

Abstract: Alzheimer’s Disease (AD) is the most common neurodegenerative disorder leading to dementia and its prevalence increases with age. The pathological features of AD are characterized by the β-amyloid protein (Aβ) deposits in the core of neuritic plaques and abnormal neurofibrillary tangles in the brain of AD patients. BACE1 is the major β-secretase to cleave the β-amyloid precursor protein (APP) to generate Aβ. Oxidative stress has been shown to affect Aβ generation in the AD pathogenesis and the mechanism of such effect is unknown. In this report we generated a novel promoterless enhanced green fluorescent protein (EGFP) reporter gene cloning vector and cloned a 1.9-kb BACE1 gene promoter fragment in this vector. The BACE1 promoter fragment can efficiently activate EGFP or luciferase gene transcription. Oxidative stress induced by hydrogen peroxide resulted in significant increase in the BACE1 promoter activity. Furthermore, hydrogen peroxide treatment facilitated β-secretase activity and Aβ generation. Thus, upregulation of BACE1 transcription by oxidative stress may contribute to the pathogenesis of Alzheimer’s disease.

Combined 123I-FP-CIT and 123I-IBZM SPECT for the diagnosis of parkinsonian syndromes: study on 72 patients.

Abstract: 72 consecutive patients with suspected parkinsonian syndromes (PS) were studied by dopamine transporter (DAT) and D2 receptor SPECT in order to evaluate the accuracy of combined SPECT imaging. In the follow-up, the patients were diagnosed as having Parkinson’s disease (PD, n = 25), dementia with Lewy bodies (DLB, n = 6), multiple system atrophy (MSA, n = 13), progressive supranuclear palsy (PSP, n = 8), corticobasal degeneration (CBD, n = 9), and essential tremor (ET, n = 11). Using the iteratively estimated optimal cutoffs, DAT was reduced in 57/61 PS patients, whereas all ET patients were identified as “normal”. Reduced D2 receptor binding had 7/13 patients with MSA, 6/8 patients with PSP, 2/9 patients with CBD and no ET, PD or DLB patients. FP-CIT SPECT allows an accurate detection of nigrostriatal affection in neurodegenerative PS. IBZM SPECT is useful to approve the diagnosis of PSP and MSA although a normal finding cannot exclude an atypical PS. IBZM SPECT seems to be of restricted value in CBD.

Amygdala responsiveness is modulated by tryptophan hydroxylase-2 gene variation.

Abstract: The tryptophan hydroxylase-2 gene (TPH2) codes for the enzyme of serotonin (5-HT) synthesis in the brain and variation of TPH2 has been implicated in disorders of emotion regulation. Here, we used functional magnetic resonance imaging (fMRI) to demonstrate that a potentially functional variant of TPH2 modulates amygdala responsiveness to emotional stimuli of both negative and positive valence.

Early stages (P100) of face perception in humans as measured with event-related potentials (ERPs).

Abstract: According to current ERP literature, face specific activity is reflected by a negative component over the inferior occipito-temporal cortex between 140 and 180 ms after stimulus onset (N170). A recently published study (Liu et al., 2002) using magnetoencephalography (MEG) clearly indicated that a face-selective component can be observed at 100 ms (M100) which is about 70 ms earlier than reported in most previous studies. Here we report these early differences at 107 ms between the ERPs of faces and buildings over the occipito-temporal cortex using electroencephalography. To exclude contrast differences as the main factor for this P100 differences we replicated this study using pictures of faces and scrambled faces. Both studies indicated that face processing starts already at ∼100 ms with an initial stage which can be measured not only with MEG but also with ERPs.

High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study

Abstract: Increasing evidence has suggested that oxidative stress may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). The antioxidant vitamin E (alpha-tocopherol) has been shown to slow down the onset and progression of the paralysis in transgenic mice expressing a mutation in the superoxide dismutase gene found in certain forms of familial ALS. The current study, a double blind, placebo-controlled, randomised, stratified, parallel-group clinical trial, was designed to determine whether vitamin E (5000 mg per day) may be efficacious in slowing down disease progression when added to riluzole. Methods. 160 patients in 6 German centres with either probable or definite ALS (according to the El Escorial Criteria) and a disease duration of less than 5 years, treated with riluzole, were included in this study and were randomly assigned to receive either alpha-tocopherol (5000 mg per day) or placebo for 18 months. The Primary outcome measure was survival, calculating time to death, tracheostomy or permanent assisted ventilation, according to the WFN-Criteria of clinical trials. Secondary outcome measures were the rate of deterioration of function assessed by the modified Norris limb and bulbar scales, manual muscle testing (BMRC), spasticity scale, ventilatory function and the Sickness Impact Profile (SIP ALS/19). Patients were assessed at entry and every 4 months thereafter during the study period until month 16 and at a final visit at month 18. Vitamin E samples were taken for compliance check and Quality Control of the trial. For Safety, a physical examination was performed at baseline and then every visit until the treatment discontinuation at month 18. Height and weight were recorded at baseline and weight alone at the follow-up visits. A neurological examination as well as vital signs (heart rate and blood pressure), an ECG and VEP’s were recorded at each visit. Furthermore, spontaneously reported adverse experiences and serious adverse events were documented and standard laboratory tests including liver function tests performed. For Statistical Analysis, the population to be considered for the primary outcome measure was an “intent-to-treat” (ITT) population which included all randomised patients who had received at least one treatment dose (n = 160 patients). For the secondary outcome measures, a two way analysis of variance was performed on a patient population that included all randomised patients who had at least one assessment after inclusion. Results. Concerning the primary endpoint, no significant difference between placebo and treatment group could be detected either with the stratified Logrank or the Wilcoxon test. The functional assessments showed a marginal trend in favour of vitamin E, without reaching significance. Conclusion. Neither the primary nor the secondary outcome measures could determine whether a megadose of vitamin E is efficacious in slowing disease progression in ALS as an add-on therapy to riluzol. Larger or longer studies might be needed. However, administration of this megadose does not seem to have any significant side effects in this patient population.

Salivary cortisol and aggression in a population-based longitudinal study of adolescent males

Abstract: Chronic antisocial behaviour in youth has been associated with cortisol, a measure of stress reactivity. However, some studies have found low cortisol levels, while others have found elevated cortisol levels. The present study compared variously defined aggressive subgroups for differences in salivary cortisol. A population-based sample of boys was followed longitudinally from childhood to adolescence. Assessments of different forms of antisocial behaviour were obtained from various informants at several points in time, and cortisol was collected at age 13. Higher cortisol levels were found in boys with conduct disorder (CD) than in boys without CD. In addition, boys with an aggressive form of CD had higher cortisol levels than boys who showed a covert form of CD. Furthermore, reactive aggression was strongly correlated with elevated cortisol. Adolescent boys with chronic reactive aggression and those who scored high on aggressive CD symptoms seem to have a more active hypothalamic-pituitary-adrenal system.

Absence of α-synuclein mRNA expression in normal and multiple system atrophy oligodendroglia

Abstract: α-Synuclein is a major constituent of glial cytoplasmic inclusions (GCIs), which are pathognomic for multiple system atrophy (MSA). We have previously demonstrated that in normal human brain, α-synuclein mRNA has a restricted pattern of neuronal expression and no apparent glial expression. The current study used double-label in situ hybridization to determine if α-synuclein mRNA is expressed by oligodendroglia of MSA cases. Analysis of MSA brain tissue revealed depletion of regional signal for this transcript in many brain areas due to extensive neurodegeneration. Cellular analysis of oligodendroglia in crus cerebri, a GCI-rich region ventral to substantia nigra, revealed an absence of α-synuclein mRNA signal in control and MSA cases. However, an abundance of this transcript was detected in melanin-containing neurons of substantia nigra. Therefore, oligodendroglia do not express α-synuclein mRNA in control and MSA cases suggesting that involvement of α-synuclein in GCI pathology of MSA is due to its ectopic presence in oligodendroglia.

ERP correlates of impaired error monitoring in children with ADHD.

Abstract: Objective: The purpose of the current study was to elaborate on error monitoring in children with Attention Deficit Hyperactivity Disorder (ADHD) using the ERP methodology. Method: Children with ADHD executed a visual Go/No-Go task with 25 percent No-Go trials; and a two stimulus reaction time task wherein a neutral warning signal (S1) was presented to inform the child to prepare for an imperative stimulus (S2). Results: In both tasks, children with ADHD responded as fast as controls but made twice as many errors. In addition, they failed to adjust their speed of responding after making an error. Exploring the error-related potentials revealed that the error-related negativity (ERN) was the same for the two groups, but that children with ADHD showed a diminished error positivity (Pe). Conclusions: Based on these findings, we conclude that children with ADHD are normal in early error monitoring processes related to error detection, but show abnormal response strategy adjustments and are deviant in later error monitoring processes associated with the subjective/emotional, conscious evaluation of the error.

CNS Targets for multi-functional drugs in the treatment of Alzheimer's and Parkinson's diseases.

Abstract: Patients with mild forms of dementia and age-related memory impairment have just begun to benefit from pharmacotherapy developed over the last several years. However, current approaches do not significantly modify the course of neurodegeneration or of the aging process, and they offer limited and transient benefit to many patients. The goal of this review is to summarize new potential approaches in which molecules have been developed expressly to target multiple brain systems for the treatment of memory and cognition impairment. Some of these approaches include the development of single molecular entities that combine activity as cholinesterase inhibitors, muscarinic cholinergic M2 receptor antagonists, nicotinic acetylcholine receptor agonists, alpha(2)-adrenergic agonists, or monoamine oxidase inhibitors. Many of the bi-functional compounds discussed have improved efficacy as cognitive enhancing agents and/or they offer potential for neuroprotection and disease modification. It is likely that syndromes such as Alzheimer's disease will require multiple drug therapy to address the varied pathological aspects of the disease. Even if the strategy of combining drugs with different therapeutic targets is workable, the development of multi-functional compounds will obviate the challenge of administering multiple single drug entities with potentially different degrees of bioavailability, pharmacokinetics, and metabolism. Also, the simplification of the therapeutic regimen for individuals with AD who have difficulty with compliance is important.

Inhibition of microglial activation by the herbal flavonoid baicalein attenuates inflammation-mediated degeneration of dopaminergic neurons.

Abstract: Accumulating evidence has suggested that inflammation in the brain participates in the pathogenesis of Parkinson's disease (PD). Therefore, anti-inflammatory therapy has attracted much attention as novel interference to neurodegenerative diseases. Baicalein, a major flavonoid extracted from a traditional Chinese herb Scutellaria baicalensis Georgi (Huangqin), possesses potent anti-inflammatory and antioxidant properties. To test the potential neuroprotective effect of baicalein on dopaminergic neurons, primary midbrain neuron-glia cultures from E-14 rat embryos were used. Cultures were pretreated with baicalein for 30 min prior to stimulation with lipopolysaccharide (LPS, 10 ng/ml). LPS leads to massive activation of microglial cells revealed by OX-42 immunostaining, and produced excessive quantities of NO. Excessive elevation of superoxide level was also observed in enriched-microglia after stimulating with LPS. LPS-induced damage to dopaminergic neurons was evaluated by uptake capacity for [3H]dopamine and tyrosine hydroxylase (TH)-immunocytochemistry. Pretreatment with baicalein concentration-dependently attenuated LPS-induced decrease in [3H]dopamine uptake and loss of TH-immunoreactive (TH-ir) neurons, which the maximum protective effect was observed at the concentration of 5 microM. Post-treatment with baicalein (5 microM) was also shown to be effective even if baicalein administered up to 2 h later than LPS application. Morphological study shows that baicalein (5 microM) almost completely blocked LPS-induced activation of microglia. Excessive production of TNF(alpha) and free radicals such as NO and superoxide by LPS stimulation were also attenuated by baicalein at a concentration-dependent pattern. The present study indicates that baicalein exerts potent neuroprotective effect on LPS-induced injury of dopaminergic neurons. We hypothesize that the inhibition of LPS-induced production of NO and free radicals from microglia may underlie the mechanism of baicalein's neuroprotection.

Levodopa-induced dyskinesia in Parkinson’s disease

Abstract: Levodopa-induced dyskinesias (LID) are abnormal involuntary movements that develop progressively with repeated dopamine replacement therapy in Parkinson's disease (PD). The pathophysiology of LID comprises many functionally-related abnormalities in neurotransmission which lead to abnormalities in the rate, pattern and synchronisation of neuronal activity within and outside the basal ganglia. In this review, we discuss the significance of the problem of LID, options currently available for avoiding and treating LID, recent advances in understanding the mechanisms responsible for the generation of LID once it has been established. In particular the discussion relates to the mechanisms underlying LID seen while levodopa is exerting its peak anti-parkinsonian actions, as it is this component of LID that is best modelled in animals and, to date, best understood. We do not aim to discuss the mechanisms by which LID is established and evolves, often termed priming, with repeated treatment, though this is an important area that has also witnessed significant advances recently (for recent review, see Blanchet et al., 2004). Finally, we define, where possible, the rationale for multiple novel therapeutic approaches that might help resolve the problem of LID.

High activity of acid sphingomyelinase in major depression

Abstract: Acid sphingomyelinase (A-SMase) and its reaction product ceramide may play a role in the pathophysiology of depressive disorders and in the therapeutic action of antidepressive drugs. In a prospective case-control study, A-SMase activity was measured in peripheral blood mononuclear cells of 17 patients with a major depressive episode who were free of antidepressant drug therapy for at least 10 days and 8 healthy volunteers. In the patient group, A-SMase activity was correlated to the score (n = 17, r = 0.64, P = 0.005). The patient group exhibited higher A-SMase activity compared to healthy volunteers (T = 2.09, df = 21.33, P<0.05). In addition, we demonstrate that the antidepressants imipramine and amitriptyline induce a long-term reduction of the activity of A-SMase in cultured cells.

Olfactory bulb volumes in patients with idiopathic Parkinson's disease a pilot study.

Abstract: Olfactory loss is among early signs of idiopathic Parkinson's disease (IPD) The present pilot study aimed to investigate whether this loss would be reflected in a decreased volume of the olfactory bulb (OB) established through magnetic resonance imaging Eleven consecutive IPD patients were compared to 9 healthy, age-matched controls Results indicated that there is little or no difference between IPD patients and healthy controls in terms of OB volume Based upon the relation between loss of olfactory input to the olfactory bulb and consecutive decrease in volume, these data support the idea that olfactory loss in IPD is not a primary consequence of damage to the olfactory epithelium but rather results from central-nervous changes

Alzheimer's associated inflammation, potential drug targets and future therapies.

Abstract: Alzheimer's disease is the most common cause of dementia in the elderly population. The most widely used treatment for Alzheimer's disease at present is acetylcholinesterase inhibitors, which aim to prolong cognitive function through increased synaptic activity, without providing neuroprotection. This treatment is only symptomatic and provides modest outcomes for patients. The recent elucidation of the inflammatory pathways involved in Alzheimer's disease however, has opened doors for better treatment and prevention by identification of areas of therapeutic intervention that target the cause of the disease rather than the symptoms. This review describes the inflammatory pathways that are thought to be present in Alzheimer's disease and some of the new therapies that have shown promise, via alteration or inhibition of these pathways. Some of the therapies included in this review, which have already demonstrated beneficial effects in the treatment of Alzheimer's disease, or have the potential to do so, are nonsteroidal anti-inflammatory drugs, statins, RAGE antagonists and antioxidants.

Oxidative stress mechanisms and potential therapeutics in Alzheimer disease

Abstract: Oxidative damage of biological macromolecules is a hallmark of most neurodegenerative disorders such as Alzheimer, Parkinson and diffuse Lewy body diseases. Another important phenomenon involved in these disorders is the alteration of iron and copper homeostasis. Data from the literature support the involvement of metal homeostasis in mitochondrial dysfunction, protein alterations and nucleic acid damage which are relevant in brain function and consequently, in the development of neurodegenerative disorders. Although alterations in transition metal homeostasis, redox activity, and localization are well documented, it must be determined how alterations of specific copper- and iron-containing metalloenzymes are also involved in Alzheimer disease. The clarification of these phenomena can open a new window for understanding the mechanisms underlying neurodegeneration and, consequently, for the development of new therapeutic strategies such as gene therapy and new pharmaceutical formulations with antioxidant and chelating properties.

Neuroprotective treatment with cerebrolysin in patients with acute stroke: a randomised controlled trial.

Abstract: Background and purpose. Cerebrolysin is a compound with neurotrophic and neuroprotective activity. It is produced by enzymatic breakdown of purified brain proteins and consists of low molecular weight peptides and amino acids. Cellular and animal models of cerebral ischaemia have shown that it is a potent neuroprotective agent. We explored the safety and preliminary outcome of Cerebrolysin treatment in patients with acute stroke. Methods. Randomised, placebo-controlled, parallel group trial. Patients with acute stroke were randomised within 24 h of stroke onset to IV therapy with placebo or Cerebrolysin 50 mL/day for 21 days. Both groups received concomitant treatment with ASA 250 mg/day PO and pentoxifylline 300 mg/day IV. Clinical examinations were performed on days 1, 3, 7, 21 and 90 post baseline. Outcome measures were the Canadian Neurological Scale, the Barthel Index, the Clinical Global Impressions, the Mini-Mental State Examination, and the Syndrome Short Test. Treatment emergent adverse events, lab tests, and vital signs were recorded to assess the safety of Cerebrolysin. Results. 146 patients were enrolled in two groups: 78 Cerebrolysin and 68 placebo. At baseline, no significant group differences were observed. Patients in the Cerebrolysin group had no significant improvement in the CNS score, the Barthel Index and the Clinical Global Impressions when compared to the placebo group. A significant improvement of cognitive function of the patients on Cerebrolysin was observed in the Syndrome Short Test when compared to the placebo group. Cerebrolysin was well tolerated and safe. Adverse events occurred with a similar frequency in both groups. Conclusion. The results demonstrate that neurotrophic treatment with Cerebrolysin is safe and well tolerated by patients with acute stroke. The findings, despite the small sample size, also indicate a potential treatment effect of Cerebrolysin in acute stroke. Larger studies, however, are needed to confirm and extend these findings.

Brain-derived neurotrophic factor gene polymorphisms and Alzheimer’s disease

Abstract: Several lines of evidence have made brain-derived neurotrophic factor (BDNF) an important candidate gene conferring risk for Alzheimer’s disease (AD). Recently, three studies reported an association between two single-nucleotide polymorphisms (SNP) – i.e., C270T and G196A – in the BDNF gene and AD. This attempt to confirm these associations in a larger AD sample included examination of the linkage disequilibrium of these two SNPs. Comparison of 487 Japanese AD subjects with 471 cognitively normal elderly controls showed higher frequencies of the G allele (60.5 vs. 55.5%, p = 0.028) and of both the GG and GA genotypes (85.8 vs. 79.8%, p = 0.025) of the G196A polymorphism in AD subjects than in controls and higher frequency of the T allele of the C270T polymorphism in AD subjects who were negative for apolipotrotein E4 (2.0 vs. 4.4%, p = 0.035) or positive for AD family history (2.8 vs. 7.1%, p = 0.046). These findings suggest that BDNF gene polymorphisms play some role in the development of AD.

Inflammatory process as a determinant factor for the degeneration of substantia nigra dopaminergic neurons.

Abstract: The specific degeneration of dopaminergic neurons in the substantia nigra (SN) is a pathological hallmark of Parkinson’s disease (PD). Although the cause of chronic nigral cell death in PD and its underlying mechanisms remain elusive, substantial involvement of inflammatory events has been postulated since inflammatory features have been described in parkinsonians CNS tissue. We have developed an animal model of dopaminergic neurons degeneration by the single intranigral injection of lipopolysaccharide (LPS), an inflammatory compound. This single injection produced the induction of inflammatory process with the activation of microglia along with the specific degeneration of dopaminergic neurons in the SN without affecting neither other neurotransmitter systems nor other structures of the CNS. Dexamethasone, a potent anti-inflammatory drug preventing many of the features characterizing pro-inflammatory glial activation, prevented the loss of dopaminergic cells. We also discuss other inductors of inflammatory process in relationship to the dopaminergic degeneration in the SN.

Botulinum toxin type A in experimental neuropathic pain.

Abstract: A peripheral application of botulinum toxin type A (7 U/kg) has significantly reduced thermal and mechanical hypersensitivity in rats with the partial sciatic nerve transection as a classical model of surgical neuropathy.

Changes in vascularization in substantia nigra pars compacta of monkeys rendered parkinsonian

Abstract: The degeneration of nigral dopaminergic neurons in Parkinson's disease is believed to be associated with a glial reaction and inflammatory changes. In turn, local factors may induce changes in vascularization and contribute to neuronal vulnerability. Among these factors, Vascular Endothelial Growth Factor (VEGF) is released in adults under pathological conditions and is thought to induce angiogenesis. In order to determine whether changes in brain vasculature are observed in the affected brain regions in parkinsonism, we quantitatively analysed the VEGF-expressing cells and blood vessels in the substantia nigra of monkeys rendered parkinsonian by MPTP injection and compared the results with those obtained in control monkeys. Using stereological methods, we observed an increase in the number of VEGF-expressing neurons and an increase of the number of blood vessels and their volume occupying the substantia nigra pars compacta of monkeys rendered parkinsonian by chronic MPTP intoxication. These changes in vascularization may therefore modify the neuronal availability of blood nutrients, blood cells or toxic substances and neuronal susceptibility to parkinsonism.

Antioxidant capacity of the neurohormone melatonin.

Abstract: The aim of this study was to elucidate the antioxidant behaviour of melatonin (M) and determine its activity–structure relationship. M or 5-metoxy-N acetyltriptamine is a neurohormone secreted by the pineal gland, which plays a proven role in maintaining sleep-wake rhythms. The antioxidant capacity of M was analysed using the oxygen radical absorbance capacity (ORAC) assay. Furthermore, spectral measurements for aerobic photolytic reaction of neutral red (NR) and degree of inhibition of photolysis with M, glutathione (GSH), ascorbic acid (AA) and vitamin E analogue Trolox were studied at room temperature 25°C, using visible (VIS) and ultra-violet (UV) radiations. In the ORAC assay 2,2-azobis (2-amidino-propane)dihydrochloride (AAPH) a peroxyl radical generator, ROO°; H2O2–Cu2+, mainly a hydroxyl radical generator, °OH; and Cu2+ a transition metal were used. Although some studies indicated that M is a powerful antioxidant, no one has compared its antioxidant capacities with GSH, E-vitamin and AA, using three free radical (FR) generators in an assay which utilizes an area-under curve technique and thus combines both inhibition time and inhibition degree of FR action by an antioxidant into a single quantity. In the current study, we used ORAC assay with three FR generators. The assay is based on propensity of the fluorescence emitted by the protein β-phycoerythrin (β-PE) from porphyridium cruentum to be quenched when exposed to FR action. M in our experiments acted as a universal antioxidant against ROO° and °OH radicals. Also, M served as an antioxidant in the presence of Cu2+. M, which is a lipid-soluble compound, was a twice more powerful antioxidant than vitamin E, and four times than AA or GSH. Furthermore, M inhibited aerobic photolysis of NR photoinduced with VIS and UV rays faster and more effectively, than AA, GSH or vitamin E. AA with NR, under aerobic conditions during irradiation with VIS and UV acted as a pro-oxidant.

Efficacy and tolerability of a botulinum toxin type A free of complexing proteins (NT 201) compared with commercially available botulinum toxin type A (BOTOX) in healthy volunteers.

Abstract: Purpose: This randomized controlled trial was performed to compare the novel botulinum toxin type A free of complexing proteins (NT 201) with the marketed preparation BOTOX° regarding efficacy and tolerability. Methods: Fourteen healthy volunteers received a single intramuscular injection into the extensor digitorum brevis (EDB) muscle of either 4 units NT 201, or 4 units of BOTOX° randomised by foot. Compound muscle action potential (CMAP) measurements were recorded for up to 90 days after injection. Results: Both drugs produced a maximum decline between Day 7 and Day 14. At Day 90, administration of both drugs resulted in approximately a 40% CMAP decline as compared to baseline. Duration of paralytic effect was comparable in both groups, at all response thresholds tested. Both drugs were well tolerated. Conclusion: The effects of small amounts of NT 201 and BOTOX° injected into the EDB muscle are comparable in terms of efficacy, time to onset of action, duration of action, and tolerability.

Sexuality in multiple sclerosis

Abstract: Sexuality and partnership have an important influence on the quality of life of every person and also on people with chronic disorders such as multiple sclerosis. The findings in literature show high evidence that people with multiple sclerosis experience high levels of sexual dysfunction, most of them with hypoactive sexual behaviour often associated with dissatisfaction in relationship, and also the partners seem to show lower sexual and partnership satisfaction. The most common problems in women are lack of sexual interest and decreased libido, often with problems in orgasmic capacity, while men report erectile dysfunction and also lack of sexual interest. The impact of the level of disability and duration of the illness remains unclear. Positive familial support can often help the patient in coping with the illness, nonetheless problems with changing roles and multiple-sclerosis-minimizing can improve the need of contacts to outstanding persons.

Glia and volume transmission during physiological and pathological states.

Abstract: Extrasynaptic communication between neurons or neurons and glia is mediated by the diffusion of neuroactive substances through the extracellular space (ECS). Structural changes and amino acid release occurring under physiological and pathological conditions result in cellular (particularly glial) swelling, leading to dynamic changes in the ECS volume and geometry that in turn affect ECS diffusion. Significant changes in ECS volume and in diffusion barriers occur during development and aging. They are often the result of cell death, astrogliosis, the rearrangement of astrocytic processes and changes in extracellular matrix molecules. Plastic changes in ECS volume, geometry and anisotropy significantly affect the spatial relation of glial processes towards synapses, glutamate or GABA ‘spillover’, synaptic cross-talk and neuron-glia communication/interaction. In addition, changes occurring during pathological states can be important for diagnosis, drug delivery and treatment.

Sleep disorders in multiple system atrophy.

Abstract: Complaints about sleep disorders and excessive daytime sleepiness are common among patients with multiple system atrophy. The diffuse neurodegenerative process that encompasses the key structures involved in the regulation of the sleep/wake transition and respiratory function may account for these complaints and for the most frequent polysomnographic findings in MSA, i.e., sleep-related breathing disturbances and REM sleep behaviour disorder, which are both treatable conditions. Nocturnal stridor is an inspiratory sound produced by complex vocal cord muscle dysfunction. Often occurring with sleep apnoea, stridor is associated with decreased survival. REM sleep behaviour disorder, a parasomnia characterized by loss of normal skeletal muscle atonia during REM sleep with prominent motor activity, is detected in almost all patients. The pathophysiology of both disorders is partially elucidated but increasing evidence points to the role of basal ganglia dysfunction.

The European Multiple System Atrophy-Study Group (EMSA-SG)

Abstract: Introduction. The European Multiple System Atrophy-Study Group (EMSA-SG) is an academic network comprising 23 centers across Europe and Israel that has constituted itself already in January 1999. This international forum of established experts under the guidance of the University Hospital of Innsbruck as coordinating center is supported by the 5th framework program of the European Union since March 2001 (QLK6-CT-2000-00661). Objectives. Primary goals of the network include (1) a central Registry for European multiple system atrophy (MSA) patients, (2) a decentralized DNA Bank, (3) the development and validation of the novel Unified MSA Rating Scale (UMSARS), (4) the conduction of a Natural History Study (NHS), and (5) the planning or implementation of interventional therapeutic trials. Methods. The EMSA-SG Registry is a computerized data bank localized at the coordinating centre in Innsbruck collecting diagnostic and therapeutic data of MSA patients. Blood samples of patients and controls are recruited into the DNA Bank. The UMSARS is a novel specific rating instrument that has been developed and validated by the EMSA-SG. The NHS comprises assessments of basic anthropometric data as well as a range of scales including the UMSARS, Unified Parkinson's Disease Rating Scale (UPDRS), measures of global disability, Red Flag list, MMSE (Mini Mental State Examination), quality of live measures, i.e. EuroQoL 5D (EQ-5D) and Medical Outcome Study Short Form (SF-36) as well as the Beck Depression Inventory (BDI). In a subgroup of patients dysautonomic features are recorded in detail using the Queen Square Cardiovascular Autonomic Function Test Battery, the Composite Autonomic Symptom Scale (COMPASS) and measurements of residual urinary volume. Most of these measures are repeated at 6-monthly follow up visits for a total study period of 24 months. Surrogate markers of the disease progression are identified by the EMSA-SG using magnetic resonance and diffusion weighted imaging (MRI and DWI, respectively). Results. 412 patients have been recruited into the Registry so far. Probable MSA-P was the most common diagnosis (49% of cases). 507 patients donated DNA for research. 131 patients have been recruited into the NHS. There was a rapid deterioration of the motor disorder (in particular akinesia) by 26.1% of the UMSARS II, and - to a lesser degree - of activities of daily living by 16.8% of the UMSARS I in relation to the respective baseline scores. Motor progression was associated with low motor or global disability as well as low akinesia or cerebellar subscores at baseline. Mental function did not deteriorate during this short follow up period. Conclusion. For the first time, prospective data concerning disease progression are available. Such data about the natural history and prognosis of MSA as well as surrogate markers of disease process allow planning and implementation of multi-centre phase II/III neuroprotective intervention trials within the next years more effectively. Indeed, a trial on growth hormone in MSA has just been completed, and another on minocycline will be completed by the end of this year.

Prostaglandin-mediated control of rat brain kynurenic acid synthesis--opposite actions by COX-1 and COX-2 isoforms.

Abstract: Kynurenic acid (KYNA), an endogenous glutamate-receptor antagonist preferentially blocking NMDA-receptors, has analgesic properties and has also been implicated in the pathophysiology of schizophrenia. Recently, the non-steroid anti-inflammatory drug (NSAID) diclofenac was found to increase rat brain KYNA. Here, we analyze whether cyclooxygenase (COX)-1 or COX-2 modulate the levels of rat brain KYNA. The non-selective COX-inhibitor diclofenac (50 mg/kg, i.p.) or indomethacin (50 mg/kg, i.p.), a non-selective inhibitor with a preferential selectivity for COX-1, produced an elevation in brain KYNA. In contrast, the COX-2 selective inhibitors parecoxib (25 mg/kg, i.p.) or meloxicam (5 mg/kg, i.p.) decreased brain KYNA. Both elevation and lowering of brain KYNA by indomethacin or parecoxib, respectively, were prevented by the prostaglandin E1/E2 agonist misoprostol (1 mg/kg, s.c.). It is proposed that increased brain KYNA formation induced by NSAIDs displaying an inhibitory action on COX-1 contribute to their analgesic efficacy as well as to their psychiatric side effects.

Traumatic brain injury: cause or risk of Alzheimer's disease? A review of experimental studies.

Abstract: Traumatic Brain Injury is the leading cause of death and disability among young individuals in our society. Moreover, according to some epidemiological studies, head trauma is one of the most potent environmental risk factors for subsequent development of Alzheimer's disease. Interestingly, pathological features that are present also in Alzheimer's disease (in particular deposition of beta-amyloid protein) were observed in traumatised brains already a few hours after the initial insult. The primary objective of this review is to present methodology and results of numerous recent human and animal studies dealing with this issue. Special emphasis was placed on head trauma experiments in transgenic mouse models of Alzheimer's disease. We further evaluate the connection between traumatic brain insults and subsequent development of dementia and try to differentiate between primary and secondary pathological mechanisms.

The North American Multiple System Atrophy Study Group.

Abstract: The North American Multiple System Atrophy Study Group involves investigators in 12 US medical centers funded by a grant from the National Institutes of Health. The objectives are to examine the environmental and genetic risk factors for MSA; elucidate pathogenic mechanisms underlying the disorder; and refine evaluations used for assessment. During its first year, the group enrolled 87 patients, implemented four cores, and initiated four scientific projects. Most patients among the 87 had parkinsonian features, which frequently began asymmetrically and remained asymmetrical; one-third responded to levodopa and many developed levodopa complications; almost two-thirds of the patients had cerebellar dysfunction, of these 90% had ataxia; urinary incontinence occurred commonly, and sleep disorders affected most. The investigators studied the effects of oxidative and nitrative stress upon the formation of alpha-synuclein inclusions; generated transgenic models of alpha-synuclein accumulation that recapitulate several behavioral and neuropathological features of MSA; and compared the severity of the autonomic features of MSA, Parkinson's disease and dementia with Lewy bodies.