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Showing papers in "Journal of Neural Transmission in 2010"


Journal ArticleDOI
TL;DR: Evidence is provided that bonafide exosomes, constitutively released by Glioblastoma cells and Astrocytes, can carry mtDNA, which can be transferred between cells, which may help the understanding of some diseases due to mitochondrial alterations.
Abstract: Cells can exchange information not only by means of chemical and/or electrical signals, but also via microvesicles released into the intercellular space. The present paper, for the first time, provides evidence that Glioblastoma and Astrocyte cells release microvesicles, which carry mitochondrial DNA (mtDNA). These microvesicles have been characterised as exosomes in view of the presence of some protein markers of exosomes, such as Tsg101, CD9 and Alix. Thus, the important finding has been obtained that bonafide exosomes, constitutively released by Glioblastoma cells and Astrocytes, can carry mtDNA, which can be, therefore, transferred between cells. This datum may help the understanding of some diseases due to mitochondrial alterations.

550 citations


Journal ArticleDOI
TL;DR: The mechanisms that microglia utilize to clear Aβ and the effectors that modulate the processes are explored.
Abstract: Alzheimer’s disease (AD), the most prominent cause of senile dementia, is clinically characterized by the extracellular deposition of β-amyloid (Aβ) and the intracellular neurofibrillary tangles. It has been well accepted that AD pathogenesis arises from perturbation in the homeostasis of Aβ in the brain. Aβ is normally produced at high levels in the brain and cleared in an equivalent rate. Thus, even a moderate decrease in the clearance leads to the accumulation of Aβ and subsequent amyloid deposition. Microglia are the tissue macrophages in the central nervous system (CNS) and have been shown to play major roles in internalization and degradation of Aβ. Aβ exists in the brain both in soluble and in fibrillar forms. Microglia interact with these two forms of Aβ in different ways. They take up soluble forms of Aβ through macropinocytosis and LDL receptor-related proteins (LRPs) mediated pathway. Fibrillar forms of Aβ interact with the cell surface innate immune receptor complex, initiating intracellular signaling cascades that stimulate phagocytosis. Inflammatory responses influence the activation status of microglia and subsequently regulate their ability to take up and degrade Aβ. ApoE and its receptors have been shown to play critical roles in these processes. In this review, we will explore the mechanisms that microglia utilize to clear Aβ and the effectors that modulate the processes.

531 citations


Journal ArticleDOI
TL;DR: Non-steroidal anti-inflammatory drugs have been shown to reduce the risk and delay the onset to develop AD and a number of possible mechanisms including cyclooxygenase 2 or γ-secretase inhibition and activation of the peroxisome proliferator activated receptor γ may alone or in concert account for the epidemiologically observed protection.
Abstract: Generation of neurotoxic amyloid β peptides and their deposition along with neurofibrillary tangle formation represent key pathological hallmarks in Alzheimer’s disease (AD). Recent evidence suggests that inflammation may be a third important component which, once initiated in response to neurodegeneration or dysfunction, may actively contribute to disease progression and chronicity. Various neuroinflammatory mediators including complement activators and inhibitors, chemokines, cytokines, radical oxygen species and inflammatory enzyme systems are expressed and released by microglia, astrocytes and neurons in the AD brain. Degeneration of aminergic brain stem nuclei including the locus ceruleus and the nucleus basalis of Meynert may facilitate the occurrence of inflammation in their projection areas given the antiinflammatory and neuroprotective action of their key transmitters norepinephrine and acetylcholine. While inflammation has been thought to arise secondary to degeneration, recent experiments demonstrated that inflammatory mediators may stimulate amyloid precursor protein processing by various means and therefore can establish a vicious cycle. Despite the fact that some aspects of inflammation may even be protective for bystander neurons, antiinflammatory treatment strategies should therefore be considered. Non-steroidal anti-inflammatory drugs have been shown to reduce the risk and delay the onset to develop AD. While, the precise molecular mechanism underlying this effect is still unknown, a number of possible mechanisms including cyclooxygenase 2 or γ-secretase inhibition and activation of the peroxisome proliferator activated receptor γ may alone or, more likely, in concert account for the epidemiologically observed protection.

381 citations


Journal ArticleDOI
TL;DR: A systematic review of HF-rTMS studies stimulating over the prefrontal cortex of patients suffering from psychiatric/neurological diseases or healthy volunteers, where the effects on cognitive functions were measured found selective cognitive improvement after high-frequency stimulation specifically over the left dorsolateral prefrontal cortex (DLPFC).
Abstract: Transcranial magnetic stimulation (TMS) was introduced as a non-invasive tool for the investigation of the motor cortex. The repetitive application (rTMS), causing longer lasting effects, was used to study the influence on a variety of cerebral functions. High-frequency (>1 Hz) rTMS is known to depolarize neurons under the stimulating coil and to indirectly affect areas being connected and related to emotion and behavior. Researchers found selective cognitive improvement after high-frequency (HF) stimulation specifically over the left dorsolateral prefrontal cortex (DLPFC). This article provides a systematic review of HF-rTMS studies (1999–2009) stimulating over the prefrontal cortex of patients suffering from psychiatric/neurological diseases or healthy volunteers, where the effects on cognitive functions were measured. The cognitive effect was analyzed with regard to the impact of clinical status (patients/healthy volunteers) and stimulation type (verum/sham). RTMS at 10, 15 or 20 Hz, applied over the left DLPFC, within a range of 10–15 successive sessions and an individual motor threshold of 80–110%, is most likely to cause significant cognitive improvement. In comparison, patients tend to reach a greater improvement than healthy participants. Limitations concern the absence of healthy groups in clinical studies and partly the absence of sham groups. Thus, future investigations are needed to assess cognitive rTMS effects in different psychiatric disorders versus healthy subjects using an extended standardized neuropsychological test battery. Since the pathophysiological and neurobiological basis of cognitive improvement with rTMS remains unclear, additional studies including genetics, experimental neurophysiology and functional brain imaging are necessary to explore stimulation-related functional changes in the brain.

290 citations


Journal ArticleDOI
TL;DR: A new chaos–wavelet approach is presented for electroencephalogram (EEG)-based diagnosis of Alzheimer’s disease (AD) employing a recently developed concept in graph theory, visibility graph (VG), with a high diagnostic accuracy.
Abstract: A new chaos-wavelet approach is presented for electroencephalogram (EEG)-based diagnosis of Alzheimer's disease (AD) employing a recently developed concept in graph theory, visibility graph (VG). The approach is based on the research ideology that nonlinear features may not reveal differences between AD and control group in the band-limited EEG, but may represent noticeable differences in certain sub-bands. Hence, complexity of EEGs is computed using the VGs of EEGs and EEG sub-bands produced by wavelet decomposition. Two methods are employed for computation of complexity of the VGs: one based on the power of scale-freeness of a graph structure and the other based on the maximum eigenvalue of the adjacency matrix of a graph. Analysis of variation is used for feature selection. Two classifiers are applied to the selected features to distinguish AD and control EEGs: a Radial Basis Function Neural Network (RBFNN) and a two-stage classifier consisting of Principal Component Analysis (PCA) and the RBFNN. After comprehensive statistical studies, effective classification features and mathematical markers were discovered. Finally, using the discovered features and a two-stage classifier (PCA-RBFNN), a high diagnostic accuracy of 97.7% was obtained.

281 citations


Journal ArticleDOI
TL;DR: This review paper focuses on the understanding of the inflammatory etiology of PD, as well as the molecular signaling involved in this inflammatory response, with the aim of providing more effective treatments to slow down or halt the progression of chronic inflammation-induced CNS disorders, such as PD.
Abstract: Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra and depletion of dopamine in the striatum, which lead to pathological and clinical abnormalities. Increasing evidence has demonstrated that inflammation is the fundamental process contributing to neuron death in PD. Neuroinflammation, which is characterized by activated microglia and infiltrating T cells at sites of neuronal injury, is a prominent contributor to the pathogenesis of progressive PD. Microglia play a critical role in forming a self-propelling cycle leading to sustained chronic neuroinflammation and driving the progressive neurodegeneration in PD. This activation depends heavily on the respiratory burst within the microglia, which in turn regulates a number of downstream pro-inflammatory activities. On the other hand, the adaptive immune responses, most notably T cells, are now emerging as important components of the inflammatory response that contribute to the pathogenesis of PD. This review paper focus on the understanding of the inflammatory etiology of PD, as well as the molecular signaling involved in this inflammatory response, with the aim to provide more effective treatments to slow down or halt the progression of chronic inflammation-induced CNS disorders, such as PD.

275 citations


Journal ArticleDOI
TL;DR: This review will try to shed some light on the current state of research in this area and provide an outlook on potential future developments.
Abstract: Huntington's disease (HD) is a monogenic neurodegenerative disease characterized by abnormal motor movements, personality changes and early death. In contrast to other neurodegenerative diseases, very little is known about the role of neuroinflammation in HD. While the current data clearly demonstrate the existence of inflammatory processes in HD pathophysiology, the question of whether neuroinflammation is purely reactive or might actively participate in disease pathogenesis is currently a matter of ongoing research and debate. This review will try to shed some light on the current state of research in this area and provide an outlook on potential future developments.

172 citations


Journal ArticleDOI
TL;DR: The extant findings from this review suggest loss of white matter network connectivity as a possible phenomenon associated with bipolar disorder, involving prefrontal and frontal regions, projection, associative and commissural fibres, with sparse and less consistent evidence implicating the subcortical and non-frontal lobes of the brain.
Abstract: Diffusion tensor imaging (DTI) is a neuroimaging technique with the potential to elucidate white matter abnormalities. Recently, it has been applied to help in better understanding of the pathophysiology of bipolar disorder (BD). This review sought to synthesise existing literature on DTI studies in BD, summarise current findings and highlight brain regions that have consistently been implicated in BD, as well as posit possible future directions for DTI research in BD. The extant findings from this review suggest loss of white matter network connectivity as a possible phenomenon associated with bipolar disorder, involving prefrontal and frontal regions, projection, associative and commissural fibres, with sparse and less consistent evidence implicating the subcortical and non-frontal lobes of the brain. There are some differences in the direction of changes observed in white matter indices, and these may be attributed to factors including sample heterogeneity and limitations of DTI techniques. The possible roles of the parietal, temporal and occipital lobes and subcortical regions in BD await further investigation. Studies of bipolar disorder using DTI lag behind other neuropsychiatric diseases such as schizophrenia, but DTI research in BD is fast gaining pace. The emerging trends from these DTI findings underscore the importance of further research to unravel the underlying neural mechanisms and clinico-anatomical correlations involving white matter in BD.

139 citations


Journal ArticleDOI
TL;DR: Results indicated significant beneficial effect of short-term levodopa administration or long-term dopaminergic medication on different dimensions of speech in PD patients, as some improvement of vowel articulation was seen in individual patients.
Abstract: While the beneficial effect of levodopa on motor impairment in Parkinson's disease (PD) has been well documented, its effect on speech has rarely been examined and the respective literature is inconclusive. The aim of our study was to analyze the effect of short-term levodopa admission and long-term dopaminergic treatment on speech in PD patients in early stages of the disease. Motor examination according to UPDRS III and speech testing were performed in 23 PD patients (9 males; median age 68, 42-78 years) in the early morning after having abstained from dopaminergic medication overnight ("off" state, t0) after administration of 200 mg of soluble levodopa (t1), and at follow-up after 12-14 weeks under stable dopaminergic medication (t2). Speech examination comprised the perceptual rating of global speech performance and an acoustical analysis based upon a standardized reading task. While UPDRS III showed a significant amelioration after L: -dopa application, none of the parameters of phonation, intonation, articulation and speech velocity improved significantly in the "on" state, neither under short-term levodopa administration (t1) nor on stable dopaminergic treatment (t2). However, there was a positive effect of dopaminergic stimulation on vowel articulation in individual patients. Results indicated significant beneficial effect of short-term levodopa administration or long-term dopaminergic medication on different dimensions of speech in PD patients. As some improvement of vowel articulation was seen in individual patients, the pre-existing pattern of speech impairment might be responsible for the different response to pharmacological treatment.

116 citations


Journal ArticleDOI
TL;DR: Two novel monoclonal antibodies were generated which were characterized as highly specific for AβpE3 peptides and used to analyze plaque deposition in APP/PS1KI mice, an AD model with severe neuron loss and learning deficits and was compared with the plaque pattern present in brain tissue from sporadic and familial AD cases.
Abstract: The presence of AβpE3 (N-terminal truncated Aβ starting with pyroglutamate) in Alzheimer’s disease (AD) has received considerable attention since the discovery that this peptide represents a dominant fraction of Aβ peptides in senile plaques of AD brains. This was later confirmed by other reports investigating AD and Down’s syndrome postmortem brain tissue. Importantly, AβpE3 has a higher aggregation propensity, and stability, and shows an increased toxicity compared to full-length Aβ. We have recently shown that intraneuronal accumulation of AβpE3 peptides induces a severe neuron loss and an associated neurological phenotype in the TBA2 mouse model for AD. Given the increasing interest in AβpE3, we have generated two novel monoclonal antibodies which were characterized as highly specific for AβpE3 peptides and herein used to analyze plaque deposition in APP/PS1KI mice, an AD model with severe neuron loss and learning deficits. This was compared with the plaque pattern present in brain tissue from sporadic and familial AD cases. Abundant plaques positive for AβpE3 were present in patients with sporadic AD and familial AD including those carrying mutations in APP (arctic and Swedish) and PS1. Interestingly, in APP/PS1KI mice we observed a continuous increase in AβpE3 plaque load with increasing age, while the density for Aβ1-x plaques declined with aging. We therefore assume that, in particular, the peptides starting with position 1 of Aβ are N-truncated as disease progresses, and that, AβpE3 positive plaques are resistant to age-dependent degradation likely due to their high stability and propensity to aggregate.

108 citations


Journal ArticleDOI
TL;DR: This review begins with a historical perspective of peripheral mononuclear phagocytes in AD, and moves on to critically consider the controversy surrounding their identity as distinct from brain-resident microglia and their potential impact on AD pathology.
Abstract: Alzheimer’s disease (AD) is a progressive and incurable neurodegenerative disorder clinically characterized by cognitive decline involving loss of memory, reasoning and linguistic ability. The amyloid cascade hypothesis holds that mismetabolism and aggregation of neurotoxic amyloid-β (Aβ) peptides, which are deposited as amyloid plaques, are the central etiological events in AD. Recent evidence from AD mouse models suggests that blood-borne mononuclear phagocytes are capable of infiltrating the brain and restricting β-amyloid plaques, thereby limiting disease progression. These observations raise at least three key questions: (1) what is the cell of origin for macrophages in the AD brain, (2) do blood-borne macrophages impact the pathophysiology of AD and (3) could these enigmatic cells be therapeutically targeted to curb cerebral amyloidosis and thereby slow disease progression? This review begins with a historical perspective of peripheral mononuclear phagocytes in AD, and moves on to critically consider the controversy surrounding their identity as distinct from brain-resident microglia and their potential impact on AD pathology.

Journal ArticleDOI
TL;DR: Blockade of P2X7 receptors may represent a novel protective strategy for striatal DA terminals in Parkinson’s disease and warrants further future investigation.
Abstract: The role of the ATP-gated receptor, P2X7, has been evaluated in the unilateral 6-OHDA rat model of Parkinson’s disease using the P2X7 competitive antagonist A-438079. Nigral P2X7 immunoreactivity was mainly located in microglia but also in astroglia. A-438079 partially but significantly prevented the 6-OHDA-induced depletion of striatal DA stores. However, this was not associated with a reduction of DA cell loss. Blockade of P2X7 receptors may represent a novel protective strategy for striatal DA terminals in Parkinson’s disease and warrants further future investigation.

Journal ArticleDOI
TL;DR: In the present study on a subset of 33 brains, SN echogenicity was found to be correlated with microglia activation and this findings strengthen the hypothesis of a close pathophysiological connection between SN hyperechogensicity and PD pathology.
Abstract: Hyperechogenicity of the substantia nigra (SN) is a sensitive marker for Parkinson’s disease (PD). Previously, a relation between SN echogenicity and iron as well as neuromelanin content could be described in 60 human brains. In the present study on a subset of 33 brains, SN echogenicity was found to be correlated with microglia activation (ρ = 0.46, p = 0.008) after correction for iron and neuromelanin content. These findings strengthen the hypothesis of a close pathophysiological connection between SN hyperechogenicity and PD pathology.

Journal ArticleDOI
TL;DR: The premonitory urge can be measured reliably and the PUTS is a useful instrument for measuring this important phenomena, which seems to be related to obsessions, compulsions, and depression in older children and this may have implications for the developmental psychopatholgy of these symptoms.
Abstract: The aims of this study were to examine a non-English (Hebrew) version of a scale that measures the premonitory urge in children suffering from tic disorder, as well as examine the correlations of the urge with demographic and clinical aspects of Tourette Syndrome. Forty children and adolescents, suffering from tics participated in this study. They were assessed with the Premonitory Urge for Tics Scale (PUTS); the Yale Global Tic Severity Scale (YGTSS); the Childhood Version of the Yale Brown Obsessive Compulsive Scale (CYBOCS); the ADHD Rating Scale IV (Conners) Scale; the Screen for Child Anxiety Related Emotional Disorders (SCARED); and the Child Depression Inventory (CDI). The mean PUTS score was 20.15 (SD = 5.89). For the entire sample the PUTS was found to be internally consistent at a = 0.79. Youths older than 10 years had higher consistency (a = 0.83) than youths younger than 10 (a = 0.69). Premonitory urge was not correlated with tic severity in the entire sample. In youths older than 10, as opposed to youths younger than 10, premonitory urge did correlate with obsessions, compulsions and depression, but not with anxiety or with ADHD. The premonitory urge can be measured reliably and the PUTS is a useful instrument for measuring this important phenomena. Premonitory urges seems to be related to obsessions, compulsions, and depression in older children and this may have implications for the developmental psychopatholgy of these symptoms.

Journal ArticleDOI
TL;DR: DNA methylation of the 5′ promoter of the POMC gene that is embedded in a CpG island using bisulfite sequencing in 145 alcohol-dependent patients and 37 healthy controls taken from the Franconian Alcoholism Research Studies implicate that epigenetic changes possibly due to alcohol intake may contribute to craving via promoting HPA-axis dysfunction.
Abstract: Hypothalamic–pituitary–adrenal (HPA) axis dysfunction has been implicated in the pathogenesis of addictive behaviour and especially in alcohol craving. The pro-opiomelanocortin gene (POMC), encoding a 241 amino acids stretching polypeptide hormone precursor, plays an important role in the regulation of the HPA, and is prone to epigenetic regulation due to promoter-related DNA methylation. Aim of the present study therefore was to investigate possible differences in promoter-related DNA methylation in patients suffering from alcohol dependence compared to healthy controls. We analysed the DNA methylation of the 5′ promoter of the POMC gene that is embedded in a CpG island using bisulfite sequencing in 145 alcohol-dependent patients and 37 healthy controls taken from the Franconian Alcoholism Research Studies. We found only marginal, hence significant differences at single CpG sites between patients and controls. We identified a cluster of CpGs showing a significant association with alcohol craving in the patients group. These results implicate that epigenetic changes possibly due to alcohol intake may contribute to craving via promoting HPA-axis dysfunction. Further studies should more closely investigate the impact of these changes on the several derivatives of the POMC gene.

Journal ArticleDOI
TL;DR: The hypothesis is that the deficits in dendritic arborization observed in the principal neurons of DS patients and Ts65Dn mice may be mediated to some extent by changes in their inhibitory inputs, and Different types of interneurons control different types of inhibition.
Abstract: Down’s syndrome (DS), with an incidence of one in 800 live births, is the most common genetic disorder associated with mental retardation. This trisomy on chromosome 21 induces a variable phenotype in which the only common feature is the presence of mental retardation. The neural mechanisms underlying mental retardation might include defects in the formation of neuronal networks and neural plasticity. DS patients have alterations in the morphology, the density and the distribution of dendritic spines in the pyramidal neurons of the cortex. Our hypothesis is that the deficits in dendritic arborization observed in the principal neurons of DS patients and Ts65Dn mice (a model for DS that mimics most of the structural alterations observed in humans) may be mediated to some extent by changes in their inhibitory inputs. Different types of interneurons control different types of inhibition. Therefore, to understand well the changes in inhibition in DS, it is necessary to study the different types of interneurons separately. We have studied the expression of synaptophysin, Glutamic acid decarboxylase-67 (GAD-67) and calcium-binding protein-expressing cells in the primary somatosensory cortex of 4–5 month old Ts65Dn mice. We have observed an increment of GAD67 immunoreactivity that is related mainly to an increment of calretinin-immunoreactive cells and among them the ones with bipolar morphology. Since there is a propensity for epilepsy in DS patients, this increase in interneurons might reflect an attempt by the system to block overexcitation rather than an increment in total inhibition and could explain the deficit in interneurons and principal cells observed in elderly DS patients.

Journal ArticleDOI
TL;DR: Interestingly, chronic administration of harmine at the higher doses, but not imipramine, increased BDNF protein levels in rat hippocampus, which further support the hypothesis that harmine could bring about behavior and molecular effects, similar to antidepressants drugs.
Abstract: A growing body of evidence has pointed to the β-carboline harmine as a potential therapeutic target for the treatment of major depression. The present study was aimed to evaluate behavioural and molecular effects of the chronic treatment with harmine and imipramine in rats. To this aim, rats were treated for 14 days once a day with harmine (5, 10 and 15 mg/kg) and imipramine (10, 20 and 30 mg/kg) and then subjected to the forced swimming and open-field tests. Harmine and imipramine, at all doses tested, reduced immobility time of rats compared with the saline group. Imipramine increased the swimming time at 20 and 30 mg/kg and harmine increased swimming time at all doses. The climbing time increased in rats treated with imipramine (10 and 30 mg/kg) and harmine (5 and 10 mg/kg), without affecting spontaneous locomotor activity. Brain-derived neurotrophic factor (BDNF) hippocampal levels were assessed in imipramine and harmine-treated rats by ELISA sandwich assay. Interestingly, chronic administration of harmine at the higher doses (10 and 15 mg/kg), but not imipramine, increased BDNF protein levels in rat hippocampus. Finally, these findings further support the hypothesis that harmine could bring about behavior and molecular effects, similar to antidepressants drugs.

Journal ArticleDOI
TL;DR: The plasma levels of VEGF and FGF-2, important factors for regulation of neuroplasticity such as neurogenesis, in patients in remission from major depressive disorders (MDD) showed significantly higher values than in matched control subjects.
Abstract: We investigated the plasma levels of VEGF and FGF-2, important factors for regulation of neuroplasticity such as neurogenesis, in patients in remission from major depressive disorders (MDD). The plasma VEGF levels were significantly higher in the MDD patients than in the matched control subjects, while no significant difference in plasma FGF-2 levels was found. In particular, the MDD patients with family history of psychiatric disorders, but not patients without such a family history, showed significantly higher values of plasma VEGF than the controls. Although this is a preliminary study, altered VEGF levels might be involved in the pathophysiology of MDD.

Journal ArticleDOI
TL;DR: The data suggest that deficits in different cognitive domains are persistent across the lifespan, albeit less pronounced in adolescents with ADHD, as well as in adults with ADHD.
Abstract: Attention-deficit/hyperactivity disorder (ADHD) often persists into adulthood, albeit with changes in clinical symptoms throughout the life span. Although effect sizes of neuropsychological deficits in ADHD are well established, developmental approaches have rarely been explored and little is yet known about age-dependent changes in cognitive dysfunction from childhood to adulthood. In this cross-sectional study, 20 male children (8–12 years), 20 adolescents (13–16 years), and 20 adults (18–40 years) with ADHD and a matched control group were investigated using six experimental paradigms tapping into different domains of cognitive dysfunction. Subjects with ADHD were more delay-aversive and showed deficits in time discrimination and time reproduction, but they were not impaired in working memory, interference control or time production. Independent of age, the most robust group differences were observed with respect to delay aversion and time reproduction, pointing to persistent dysfunction in the mesolimbic reward circuitry and in the frontal-striatal-cerebellar timing system in subjects with ADHD. Across all tasks, effect sizes were lowest for adolescents with ADHD compared to age-matched controls. Developmental dissociations were found only for simple stimuli comparison, which was particularly impaired in ADHD children. Thus, in line with current multiple-pathway approaches to ADHD, our data suggest that deficits in different cognitive domains are persistent across the lifespan, albeit less pronounced in adolescents with ADHD.

Journal ArticleDOI
TL;DR: Preliminary evidence is provided that the RAGE G82S variant is involved in genetic susceptibility to AD, and plasma sRAGE levels were lower in AD than in normal elderly controls, and the presence of the risk allele was associated with further plasma s RAGE reduction and a fast cognitive deterioration.
Abstract: The receptor for advanced glycation end products (RAGE) is associated with several pathological states including Alzheimer’s disease (AD) pathology, while its soluble form (sRAGE) acts as a decoy receptor. We have tested for association of AD with a functional single-nucleotide polymorphism (SNP) in the RAGE gene (G82S; rs2070600), a SNP associated with increased ligand affinity of RAGE. Analysis of a Chinese cohort (276 cases; 254 controls) showed a higher prevalence of the RAGE 82S allele and GS + SS genotype in the patients [82S vs. 82G: P = 0.017, odds ratio (OR) = 1.431; GS + SS vs. GG: P = 0.025, OR = 1.490]. Further stratification analysis revealed that the association of the RAGE G82S polymorphism with AD was significant in early onset AD stratum. Moreover, plasma sRAGE levels were lower in AD than in normal elderly controls, and the presence of the risk allele was associated with further plasma sRAGE reduction and a fast cognitive deterioration. The present study provides preliminary evidence that the RAGE G82S variant is involved in genetic susceptibility to AD.

Journal ArticleDOI
TL;DR: The data implicate that the HPA axis is not only relevant to the expression of aggressive behavior in clinical groups, but also to a large extent in healthy ones.
Abstract: The hypothalamic–pituitary–adrenal (HPA) axis seems to play a major role in the development, elicitation, and enhancement of aggressive behavior in animals. Increasing evidence suggests that this is also true for humans. However, most human research on the role of the HPA axis in aggression has been focusing on highly aggressive children and adolescent clinical samples. Here, we report on a study of the role of basal and acute HPA axis activity in a sample of 20 healthy male and female adults. We used the Taylor Aggression Paradigm to induce and measure aggression. We assessed the cortisol awakening response as a trait measure of basal HPA axis activity. Salivary free cortisol measures for the cortisol awakening response were obtained on three consecutive weekdays immediately following awakening and 30, 45, and 60 min after. Half of the subjects were provoked with the Taylor Aggression Paradigm to behave aggressively; the other half was not provoked. Acute HPA axis activity was measured four times, once before and three times after the induction of aggression. Basal cortisol levels were significantly and negatively related to aggressive behavior in the provoked group and explained 67% of the behavioral variance. Cortisol levels following the induction of aggression were significantly higher in the provoked group when baseline levels were taken into account. The data implicate that the HPA axis is not only relevant to the expression of aggressive behavior in clinical groups, but also to a large extent in healthy ones.

Journal ArticleDOI
TL;DR: The result suggests that the association between cortisol levels and aggression in adolescents is mediated rather by impulsivity than by unemotional or psychopathic traits.
Abstract: In this study, the association of aggressive behavior and personality traits with plasma cortisol levels was investigated in a high-risk community sample of adolescents. Plasma cortisol levels were collected in 245 fifteen-year-olds (118 males, 127 females) from an epidemiological cohort study of children at risk for psychopathology. Additionally, measures of reactive and proactive aggression, externalizing behavior and callous-unemotional together with impulsive personality features were assessed. Both subtypes of aggression as well as delinquent behavior and impulsive personality traits showed significant negative correlations with plasma cortisol levels. This association was observed in males, but not in females. In both gender groups, callous-unemotional traits were unrelated to plasma cortisol levels. This result suggests that the association between cortisol levels and aggression in adolescents is mediated rather by impulsivity than by unemotional or psychopathic traits.

Journal ArticleDOI
TL;DR: The hypothesis of a fundamental impairment of vocal pace performance in parkinsonian patients based on a syllable repetition paradigm is tested and the pattern of pace disturbance shows similarities with the finding of speech acceleration and rhythm irregularity in the course of reading or more complex conversational speech and therefore might share the same pathophysiology.
Abstract: Alterations of speech rate and rhythm are well-known features in parkinsonian patients suffering from hypokinetic dysarthria and are thought to be induced by complex dysfunction of planning, preparing and executing of motor speech sequences. Since speech can be subdivided down to the level of single utterances, the aim of our study was to test the hypothesis of a fundamental impairment of vocal pace performance in parkinsonian patients based on a syllable repetition paradigm. Furthermore, the overall integrity of acoustical feedback mechanisms was surveyed by testing the ability to correctly identify pace and steadiness of the presented audio examples. N = 73 patients with Parkinson’s disease (PD) and n = 43 age-matched healthy controls were tested. Participants had to repeat the syllable/pa/at least 30 times at a “comfortable” self-chosen steady (isochronous) pace. Percent coefficient of variance (COV) of interval length and the change in interval length with successive utterances were measured for the description of pace stability throughout the performance. Then, participants had to identify irregularities of 30 played-back audio tests. The number of incorrect classification was defined as the error rate (ER). Patients with PD showed significant difficulties in steadily executing a syllable repetition task with a significant elevation of COV and showed a clear tendency to pace acceleration in the course of the performance. However, we found no differences in the correct auditory identification of rhythm irregularities between the PD group and controls. As compared to healthy controls, the PD group features disabilities in performing a steady sequence of utterances, which cannot be explained solely by impaired acoustical feedback mechanisms. The pattern of pace disturbance shows similarities with the finding of speech acceleration and rhythm irregularity in the course of reading or more complex conversational speech and therefore might share the same pathophysiology. Further studies are necessary to reveal the correlations between speech rhythm and motor performance to identify the underlying mechanisms that lead to “dysrhythmia” in PD.

Journal ArticleDOI
TL;DR: The occurrence of ultrastructural cell pathology reminiscent of neuronal degeneration in HD, suggests the use of human peripheral cells as a tool to investigate the pathogenic cascade subsequent to huntingtin dysregulation.
Abstract: We investigated the genotype-dependency of morphological abnormalities in peripheral cells from Huntington disease (HD) patients. Cell cultures derived from skin and muscle biopsies showed a different set of abnormalities depending on the genotype (i.e. heterozygous and homozygous for CAG mutations) and the tissue (i.e. fibroblasts and myoblasts). In general, homozygotes’ cell lines showed massive ultrastructural damage of specific cell organelles compared with age matched control. These consist of vacuolization, deranged crests and matrix found within giant mitochondria. In addition, enlarged endoplasmic reticulum and the occurrence of numerous autophagic vacuoles, which were similar to those occurring in neurons within affected brain areas, were described. Despite a comparable dose-dependency on mitochondrial changes, this kind of alterations differ in fibroblasts compared with myoblasts. In fact, the internal mitochondrial structure was merely lost in myoblasts, while it shows pathological re-organization within fibroblasts, where altered crests appear as multilamellar circles. These data indicate that ultrastructural abnormalities from peripheral tissues of HD patients can be used as potential disease markers which are easier to get than autoptic brains. Moreover, the occurrence of ultrastructural cell pathology reminiscent of neuronal degeneration in HD, suggests the use of human peripheral cells as a tool to investigate the pathogenic cascade subsequent to huntingtin dysregulation.

Journal ArticleDOI
TL;DR: Results suggest that prolongation of life span may be associated with slow rate of KYN formation from TRY, and eye-color mutants, white (w1118) and vermilion (v48a and v2) (deficient TDO activity), were compared with wild-type Oregon-R (Ore-R) strain of Drosophila melanogaster.
Abstract: Animal and human studies suggest that aging is associated with increased formation of kynurenine (KYN) from tryptophan (TRY). The rate-limiting factors of TRY–KYN metabolism are transmembrane transport of TRY, and activity of enzyme, TRY 2,3-dioxygenase (TDO2). Eye-color mutants, white (w1118) (impaired TRY transport) and vermilion (v48a and v2) (deficient TDO activity), were compared with wild-type Oregon-R (Ore-R) strain of Drosophila melanogaster. Female 1-day-old adult flies maintained on a standard medium, and acclimatized to 12-h light:12-h dark cycle were collected, and then regularly transferred to fresh medium every 3–4 days. The number of dead flies was recorded at the time of transfer. Forty flies were studied in each experimental group. The life span of w1118 (mean = 45.5 days), and v48a (mean = 47.6 days) and v2 (mean = 43.8 days), were significantly longer than of wild-type Ore-R flies (27.1 days) (p < 0.001, Logrank test). There were no differences in life span between w1118 and v48a and v2 mutants. Present results suggest that prolongation of life span may be associated with slow rate of KYN formation from TRY.

Journal ArticleDOI
TL;DR: It is concluded that in ADHD some time-processing deficits are still present in adults, but may take on age-related different forms.
Abstract: A time-processing deficit has been proposed as a neuropsychological candidate endophenotype for Attention Deficit Hyperactivity Disorder (ADHD), but its developmental trajectory still needs to be explored. In the present study, children (N = 33) and adults (N = 22) with ADHD were compared to normal controls on two time-processing tasks. For time reproduction, ADHD-related impairment was found in the full group, but not when adults were analyzed separately. For the discrimination of brief intervals, children and adults with ADHD showed different patterns of deficit. We conclude that in ADHD some time-processing deficits are still present in adults, but may take on age-related different forms.

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TL;DR: In this article, the authors performed transcript profiling via quantitative RT-PCR in RNA originating from peripheral blood samples and achieved a sensitivity and specificity of more than 80% using these four biomarkers for PD diagnosis.
Abstract: The need for an early and differential diagnosis of Parkinson’s disease (PD) is undoubtedly one of the main quests of the century. An early biomarker would enable therapy to begin sooner and would, hopefully, slow or better prevent progression of the disease. We performed transcript profiling via quantitative RT-PCR in RNA originating from peripheral blood samples. The groups were de novo (n = 11) and medicated PD (n = 94) subjects and healthy controls (n = 34), while for negative control Alzheimer’s disease (AD; n = 14) subjects were recruited as an additional neurodegenerative disease. The results were retested on a second recruitment consisting 22 medicated PD subjects versus 33 controls and 12 AD. Twelve transcripts were chosen as candidate genes, according to previous postmortem brain profiling. Multiple analyses resulted in four significant genes: proteasome (prosome, macropain) subunit-alpha type-2 (PSMA2; p = 0.0002, OR = 1.15 95% CI 1.07–1.24), laminin, beta-2 (laminin S) (LAMB2; p = 0.0078, OR = 2.26 95% CI 1.24–4.14), aldehyde dehydrogenase 1 family-member A1 (ALDH1A1; p = 0.016, OR = 1.05 95% CI 1.01–1.1), and histone cluster-1 H3e (HIST1H3E; p = 0.03, OR = 0.975 95% CI 0.953–0.998) differentiating between medicated PD subjects versus controls. Using these four biomarkers for PD diagnosis, we achieved sensitivity and specificity of more than 80%. These biomarkers might be specific for PD diagnosis, since in AD subjects no significant results were observed. In the second validation, three genes (PSMA2, LAMB2 and ALDH1A1) demonstrated high reproducibility. This result supports previous studies of gene expression profiling and may facilitate the development of biomarkers for early diagnosis of PD.

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TL;DR: An overview of current concepts regarding perinatal brain damage and the role of inflammation in the disease pathomechanism is provided.
Abstract: Once viewed as an isolated, immune-privileged organ, the central nervous system has undergone a conceptual change. Neuroinflammation has moved into the focus of research work regarding pathomechanisms underlying perinatal brain damage. In this review, we provide an overview of current concepts regarding perinatal brain damage and the role of inflammation in the disease pathomechanism.

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TL;DR: Rotigotine treatment was considered feasible by patients, their anesthesiologists and neurologists with good control of PD symptoms and easy switching and re-switching of PD medication.
Abstract: Continuous delivery of antiparkinsonian medication during a perioperative period is desirable to avoid ‘off’-symptom complications in surgical patients with concomitant Parkinson’s disease (PD) Fourteen PD patients undergoing surgery under general anesthesia were switched from oral dopaminergic medication to transdermally delivered 24-h rotigotine (median dose 12 mg/24 h) for the perioperative period Rotigotine treatment was considered feasible by patients, their anesthesiologists and neurologists with good control of PD symptoms and easy switching and re-switching of PD medication

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TL;DR: The hypothesis that central mechanisms of pain processing in the frontal cortex and cingulate cortex may play an important role in patients with FMS is supported.
Abstract: Studies with functional neuroimaging support the hypothesis of central pain augmentation in fibromyalgia syndrome (FMS) with functional differences in areas of the medial pain system. To clarify whether these findings are unique to patients with FMS, BOLD-signal patterns during and before tonic experimental pain were compared to healthy controls and patients with rheumatoid arthritis (RA) as a chronic pain disorder of somatic origin. We expected different BOLD-signal patterns in areas of the medial pain system that were most pronounced in patients with FMS. An fMRI-block design before, during and after an incision was performed in patients with FMS (n = 17), RA (n = 16) and in healthy controls (n = 17). A 2-factorial model of BOLD-signal changes was designed to explore significant differences of brain activation between the groups during the pain stimulus. Additionally, the correlation of brain activity during the anticipation of pain with the amount of the impending pain was determined. We observed a FMS-unique temporal brain activation of the frontal cortex in patients with FMS. Moreover, areas of the motor cortex and the cingulate cortex presented a FMS-specific relation between brain activity during pain anticipation and the magnitude of the subsequent pain experience. Our results support the hypothesis that central mechanisms of pain processing in the frontal cortex and cingulate cortex may play an important role in patients with FMS.