Showing papers in "Journal of Neural Transmission in 2014"

Glutamate as a neurotransmitter in the healthy brain.

Abstract: Glutamate is the most abundant free amino acid in the brain and is at the crossroad between multiple metabolic pathways. Considering this, it was a surprise to discover that glutamate has excitatory effects on nerve cells, and that it can excite cells to their death in a process now referred to as “excitotoxicity”. This effect is due to glutamate receptors present on the surface of brain cells. Powerful uptake systems (glutamate transporters) prevent excessive activation of these receptors by continuously removing glutamate from the extracellular fluid in the brain. Further, the blood–brain barrier shields the brain from glutamate in the blood. The highest concentrations of glutamate are found in synaptic vesicles in nerve terminals from where it can be released by exocytosis. In fact, glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. It took, however, a long time to realize that. The present review provides a brief historical description, gives a short overview of glutamate as a transmitter in the healthy brain, and comments on the so-called glutamate–glutamine cycle. The glutamate transporters responsible for the glutamate removal are described in some detail.

A further update on the role of excitotoxicity in the pathogenesis of Parkinson’s disease

Abstract: Increased levels of extracellular glutamate and hyperactivation of glutamatergic receptors in the basal ganglia trigger a critical cascade of events involving both intracellular pathways and cell-to-cell interactions that affect cell viability and promote neuronal death. The ensemble of these glutamate-triggered events is responsible for excitotoxicity, a phenomenon involved in several pathological conditions affecting the central nervous system, including a neurodegenerative disease such as Parkinson’s disease (PD). PD is an age-related disorder caused by the degeneration of dopaminergic neurons within the substantia nigra pars compacta, with a miscellaneous pathogenic background. Glutamate-mediated excitotoxicity may be involved in a lethal vicious cycle, which critically contributes to the exacerbation of nigrostriatal degeneration in PD. Since excitotoxicity is a glutamate-receptor-mediated phenomenon, growing interest and work have been dedicated to the research for modulators of glutamate neurotransmission that might enable new therapeutic interventions to slow down the neurodegenerative process and ameliorate PD motor symptoms.

The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment

Abstract: Glutamate is the major excitatory neurotransmitter in the brain and may be a key neurotransmitter involved in autism. Literature pertaining to glutamate and autism or related disorders (e.g., Fragile X syndrome) is reviewed in this article. Interest in glutamatergic dysfunction in autism is high due to increasing convergent evidence implicating the system in the disorder from peripheral biomarkers, neuroimaging, protein expression, genetics and animal models. Currently, there are no pharmaceutical interventions approved for autism that address glutamate deficits in the disorder. New treatments related to glutamatergic neurotransmission, however, are emerging. In addition, older glutamate-modulating medications with approved indications for use in other disorders are being investigated for re-tasking as treatments for autism. This review presents evidence in support of glutamate abnormalities in autism and the potential for translation into new treatments for the disorder.

Glutamate and its receptors in cancer

Abstract: Glutamate, a nonessential amino acid, is a major bioenergetic substrate for proliferating normal and neoplastic cells on one hand and an excitatory neurotransmitter that is actively involved in biosynthetic, bioenergetic, metabolic, and oncogenic signaling pathways on the other. It exerts its action through a family of receptors consisting of metabotropic glutamate receptors (mGluRs) and ionotropic glutamate receptors (iGluRs), both of which have been implicated previously in a broad spectrum of acute and chronic neurodegenerative diseases. In this review, we discuss existing data on the role of glutamate as a growth factor for neoplastic cells, the expression of glutamate receptors in various types of benign and malignant neoplasms, and the potential roles that GluRs play in cancer development and progression along with their clinical significance. We conclude that glutamate-related receptors and their signaling pathways may provide novel therapeutic opportunities for a variety of malignant human diseases.

Glutamate and its receptors in the pathophysiology and treatment of major depressive disorder

Abstract: Monoaminergic neurotransmitter (serotonin, norepinephrine and dopamine) mechanisms of disease dominated the research landscape in the pathophysiology and treatment of major depressive disorder (MDD) for more than 50 years and still dominate available treatment options. However, the sum of all brain neurons that use monoamines as their primary neurotransmitter is <20%. In addition, most patients treated with monoaminergic antidepressants are left with significant residual symptoms and psychosocial disability not to mention side effects, e.g., sexual dysfunction. In the past several decades, there has been greater focus on the major excitatory neurotransmitter in the human brain, glutamate, in the pathophysiology and treatment of MDD. Although several preclinical and human magnetic resonance spectroscopy studies had already implicated glutamatergic abnormalities in the human brain, it was rocketed by the discovery that the N-methyl-D-aspartate receptor antagonist ketamine has rapid and potent antidepressant effects in even the most treatment-resistant MDD patients, including those who failed to respond to electroconvulsive therapy and who have active suicidal ideation. In this review, we will first provide a brief introduction to glutamate and its receptors in the mammalian brain. We will then review the clinical evidence for glutamatergic dysfunction in MDD, the discovery and progress-to-date with ketamine as a rapidly acting antidepressant, and other glutamate receptor modulators (including proprietary medications) for treatment-resistant depression. We will finally conclude by offering potential future directions necessary to realize the enormous therapeutic promise of glutamatergic antidepressants.

Complex molecular regulation of tyrosine hydroxylase

Abstract: Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, is strictly controlled by several interrelated regulatory mechanisms. Enzyme synthesis is controlled by epigenetic factors, transcription factors, and mRNA levels. Enzyme activity is regulated by end-product feedback inhibition. Phosphorylation of the enzyme is catalyzed by several protein kinases and dephosphorylation is mediated by two protein phosphatases that establish a sensitive process for regulating enzyme activity on a minute-to-minute basis. Interactions between tyrosine hydroxylase and other proteins introduce additional layers to the already tightly controlled production of catecholamines. Tyrosine hydroxylase degradation by the ubiquitin–proteasome coupled pathway represents yet another mechanism of regulation. Here, we revisit the myriad mechanisms that regulate tyrosine hydroxylase expression and activity and highlight their physiological importance in the control of catecholamine biosynthesis.

Is there a role for glutamate-mediated excitotoxicity in inflammation-induced depression?

Abstract: Chronic inflammation in physically ill patients is often associated with the development of symptoms of depression. The mechanisms that are responsible for inflammation-associated depression have been elucidated over the last few years. Kynurenine produced from tryptophan in a reaction catabolized by indoleamine 2,3 dioxygenase is transported into the brain where it is metabolized by microglial enzymes into a number of neurotropic compounds including quinolinic acid, an agonist of N-methyl-D-aspartate receptors. Quinolinic acid can synergize with glutamate released by activated microglia. This chain of events opens the possibility to treat inflammation-induced depression using therapies that target the transport of kynurenine through the blood-brain barrier, the production of quinolinic acid and glutamate by activated microglia, or the efflux of glutamate from the brain to the blood.

The role of glutamate and its receptors in the proliferation, migration, differentiation and survival of neural progenitor cells

Abstract: The mammalian central nervous system derives from multipotent neural progenitor cells (NPCs) of the developing brain. During development the progenitor cells have enormous potential. They proliferate actively and differentiate into all the three main cell types, i.e., neurons, astrocytes and oligodendrocytes, of the adult brain through a tightly regulated process that coordinates cell proliferation, survival, migration, differentiation and apoptosis. This process is regulated by multiple extracellular signals including neurotrophic factors, chemoattractants and neurotransmitters in a coordinated manner. The main excitatory neurotransmitter glutamate is involved in promoting and/or inhibiting the proliferation, survival, migration and differentiation of NPCs acting via ionotropic or metabotropic receptors. The role of glutamate in the regulation of cortical NPCs has been most extensively studied. Glutamate appears to have a similar role in hippocampal, striatal as well as adult neural progenitors. Ionotropic α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate (KA) receptors and metabotropic glutamate receptor 5 (mGluR5) are expressed early during embryonic development as well as in the neurogenic zones of the adult brain. Ca(2+)-permeable AMPA/KA receptors are initially of importance for cell proliferation and neuronal motility. At later stages of development N-methyl-D-aspartate (NMDA) receptors have a more prominent role. MGluR5, which is the main metabotropic glutamate receptor during early development, is expressed in early progenitors and radial glial cells. Activation of this receptor promotes the proliferation and survival of NPCs. MGluR5 is involved in the extension of radial glial processes and in regulation of the migration of early cortical neurons.

The prevalence and incidence of Parkinson’s disease in China: a systematic review and meta-analysis

Abstract: Parkinson’s disease (PD) is a chronic neurodegenerative disorder affecting older individuals. There is inconsistent evidence about the prevalence and incidence of PD in China at present. The aim of the meta-analysis was to estimate the prevalence and incidence of PD and its relation to age, gender, and stage in China. The literature search was conducted using PubMed, EMBASE, Chinese Biological Medical Literature database (CBM), Chinese National Knowledge Infrastructure database (CNKI), Chinese Wanfang and Chongqing VIP database for studies investigating the prevalence and incidence of PD in China from the commencement of the database until August 2012; both English and Chinese publications were included. We estimated the prevalence and incidence of PD using meta-analysis. Thirteen eligible articles were collected. The results showed that the pooled prevalence and incidence of PD were 2 per 100,000 population and 797 per 100,000 person-years. A higher prevalence of PD was found in males than in females (OR 1.29, 95 % CI 1.05–1.57). The prevalence of PD increased with age: the highest was 1,663 per 100,000 in those aged 80 and older. The overall prevalence of PD is lower in China than in developed countries, but the incidence is higher than in some developed countries. Overall, the prevalence of PD appears to increase with age and there are sex differences evident in Chinese individuals.

The neurotransmitter glutamate and human T cells: glutamate receptors and glutamate-induced direct and potent effects on normal human T cells, cancerous human leukemia and lymphoma T cells, and autoimmune human T cells

Abstract: Glutamate is the most important excitatory neurotransmitter of the nervous system, critically needed for the brain’s development and function. Glutamate has also a signaling role in peripheral organs. Herein, we discuss glutamate receptors (GluRs) and glutamate-induced direct effects on human T cells. T cells are the most important cells of the adaptive immune system, crucially needed for eradication of all infectious organisms and cancer. Normal, cancer and autoimmune human T cells express functional ionotropic and metabotropic GluRs. Different GluR subtypes are expressed in different T cell subtypes, and in resting vs. activated T cells. Glutamate by itself, at low physiological 10−8M to 10−5M concentrations and via its several types of GluRs, activates many key T cell functions in normal human T cells, among them adhesion, migration, proliferation, intracellular Ca2+ fluxes, outward K+ currents and more. Glutamate also protects activated T cells from antigen-induced apoptotic cell death. By doing all that, glutamate can improve substantially the function and survival of resting and activated human T cells. Yet, glutamate’s direct effects on T cells depend dramatically on its concentration and might be inhibitory at excess pathological 10−3M glutamate concentrations. The effects of glutamate on T cells also depend on the specific GluRs types expressed on the target T cells, the T cell’s type and subtype, the T cell’s resting or activated state, and the presence or absence of other simultaneous stimuli besides glutamate. Glutamate also seems to play an active role in T cell diseases. For example, glutamate at several concentrations induces or enhances significantly very important functions of human T-leukemia and T-lymphoma cells, among them adhesion to the extracellular matrix, migration, in vivo engraftment into solid organs, and the production and secretion of the cancer-associated matrix metalloproteinase MMP-9 and its inducer CD147. Glutamate induces all these effects via activation of GluRs highly expressed in human T-leukemia and T-lymphoma cells. Glutamate also affects T cell-mediated autoimmune diseases. With regards to multiple sclerosis (MS), GluR3 is highly expressed in T cells of MS patients, and upregulated significantly during relapse and when there is neurological evidence of disease activity. Moreover, glutamate or AMPA (10−8M to 10−5M) enhances the proliferation of autoreactive T cells of MS patients in response to myelin proteins. Thus, glutamate may play an active role in MS. Glutamate and its receptors also seem to be involved in autoimmune rheumatoid arthritis and systemic lupus erythematosus. Finally, T cells can produce and release glutamate that in turn affects other cells, and during the contact between T cells and dendritic cells, the latter cells release glutamate that has potent effects on the T cells. Together, these evidences show that glutamate has very potent effects on normal, and also on cancer and autoimmune pathological T cells. Moreover, these evidences suggest that glutamate and glutamate-receptor agonists might be used for inducing and boosting beneficial T cell functions, for example, T cell activity against cancer and infectious organisms, and that glutamate-receptor antagonists might be used for preventing glutamate-induced activating effects on detrimental autoimmune and cancerous T cells.

Cerebellar and parkinsonian phenotypes in multiple system atrophy: similarities, differences and survival

Abstract: Multiple system atrophy (MSA) is a neurodegenerative disease with two motor phenotypes: parkinsonian (MSA-P) and cerebellar (MSA-C). To elucidate whether in addition to the motor abnormalities there are other significant differences between these phenotypes, we performed a retrospective review of 100 patients (61 males, 39 females) with a diagnosis of possible (12 %), or probable (88 %) MSA. Four patients eventually had post-mortem confirmation (i.e., definite MSA). Sixty percent were classified as having MSA-P and 40 % as MSA-C. MSA-C and MSA-P patients had similar male prevalence (60 %), age of onset (56 ± 9 years), and frequency of OH (69 %). Brain MRI abnormalities were more frequent in MSA-C patients (p < 0.001). Mean survival was 8 ± 3 years for MSA-C and 9 ± 4 years for MSA-P patients (p = 0.22). Disease onset before 55 years predicted longer survival in both phenotypes. Initial autonomic involvement did not influence survival. We conclude that patients with both motor phenotypes have mostly similar survivals and demographic distributions. The differences here identified could help counseling of patients with MSA.

The role of glutamate and its receptors in multiple sclerosis

Abstract: Glutamate is an excitatory neurotransmitter of the central nervous system, which has a central role in a complex communication network established between neurons, astrocytes, oligodendrocytes, and microglia. Multiple abnormal triggers such as energy deficiency, oxidative stress, mitochondrial dysfunction, and calcium overload can lead to abnormalities in glutamate signaling. Thus, the disturbance of glutamate homeostasis could affect practically all physiological functions and interactions of brain cells, leading to excitotoxicity. Excitotoxicity is the pathological process by which nerve cells are damaged or killed by excessive stimulation by glutamate. Although neuron degeneration and death are the ultimate consequences of multiple sclerosis (MS), it is now widely accepted that alterations in the function of surrounding glial cells are key features in the progression of the disease. The present knowledge raise the possibility that the modulation of glutamate release and transport, as well as receptors blockade or glutamate metabolism modulation, might be relevant targets for the development of future therapeutic interventions in MS.

The diagnostic utility of EEG in early-onset dementia: a systematic review of the literature with narrative analysis

Abstract: Early-onset dementia (EOD) is characterized by functionally impairing deterioration in memory, language, personality or visuospatial skills emerging under the age of 65. Cerebral functioning can be assessed by visual electroencephalography (EEG) interpretation. The aim of this systematic review is to evaluate the diagnostic utility of visual EEG in EOD focusing on Alzheimer’s disease (AD), vascular dementia (VAD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). Medline, Embase, Scopus, Web of Knowledge, and Google Scholar were systematically searched for studies where EEGs were included in the diagnostic evaluation of patients with dementia under the age of 65. Each paper was quality assessed and the results grouped according to dementia cause with a narrative summary. 4,157 papers were screened, 12 studies met the eligibility criteria with a total of 965 patients. An abnormal EEG was common to all causes of EOD. EEG abnormalities are more severe in early-onset AD patients. EEG severity grade is independent of disease duration. Slow wave activity is common to all dementias, but is most prominent in DLB. Frontal intermittent rhythmic delta activity could be considered as supportive for the diagnosis of DLB as can a Grand Total EEG score of over 9.5. EEG is usually normal in FTD. Focal changes can be seen in advanced VAD. Studies employed small patient groups, varying diagnostic criteria, and only a minority of patient diagnoses was pathologically confirmed. EEG may be useful as an adjunct in the diagnosis of DLB and AD. Further prospective well-powered studies are required to investigate diagnostic utility more robustly.

Retinal single-layer analysis in Parkinsonian syndromes: an optical coherence tomography study

Abstract: We report a newly developed analysis algorithm for optical coherence tomography (OCT) that makes a retinal single-layer analysis with calculation of the average thickness of retinal layers possible. The aim of the study was to examine specific patterns of retinal layer pathology as a potential marker of neurodegeneration in Parkinson's disease (PD), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA). Spectral domain OCT with a semiautomatic algorithm to calculate the average thickness of single retinal layers was applied to foveal scans of 65 PD, 16 PSP, and 12 MSA patients as well as 41 matched controls. Demographic and clinical data were collected for correlation analysis. Only PSP and MSA showed a significant reduction of retinal layers in comparison to controls. In PD, there were no significant findings in single retinal layer measurement. Most remarkably, the thickening of the outer nuclear layer in PSP and the outer plexiform layer in MSA was highly specific for these disease entities and allowed differentiating PSP from MSA with high sensitivity and specificity. With this analysis algorithm of OCT data, disease-specific retinal layer changes could be observed. Despite a general tendency to whole retinal and single retinal layer thinning that may reflect neurodegeneration in all Parkinsonian syndromes, the specific findings in MSA and PSP may serve as a highly sensitive and specific differential diagnostic tool and as a progression marker in these disease entities. Upcoming studies with a longitudinal setting will have to prove this assumption.

The effect of age, diagnosis, and their interaction on vertex-based measures of cortical thickness and surface area in autism spectrum disorder.

Abstract: Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition that is accompanied by an atypical development of brain maturation. So far, brain development has mainly been studied during early childhood in ASD, and using measures of total or lobular brain volume. However, cortical volumetric measures are a product of two distinct biological neuroanatomical features, cortical thickness, and surface area, which most likely also have different neurodevelopmental trajectories in ASD. Here, we therefore examined age-related differences in cortical thickness and surface area in a cross-sectional sample of 77 male individuals with ASD ranging from 7 to 25 years of age, and 77 male neurotypical controls matched for age and FSIQ. Surface-based measures were analyzed using a general linear model (GLM) including linear, quadratic, and cubic age terms, as well as their interactions with the main effect of group. When controlling for the effects of age, individuals with ASD had spatially distributed reductions in cortical thickness relative to controls, particularly in fronto-temporal regions, and also showed significantly reduced surface area in the prefrontal cortex and the anterior temporal lobe. We also observed significant group × age interactions for both measures. However, while cortical thickness was best predicted by a quadratic age term, the neurodevelopmental trajectory for measures of surface area was mostly linear. Our findings suggest that ASD is accompanied by age-related and region-specific reductions in cortical thickness and surface area during childhood and early adulthood. Thus, differences in the neurodevelopmental trajectory of maturation for both measures need to be taken into account when interpreting between-group differences overall.

Altered peripheral BDNF mRNA expression and BDNF protein concentrations in blood of children and adolescents with autism spectrum disorder

Abstract: Findings from molecular genetic studies and analyses of postmortem and peripheral tissue led to the hypothesis that neurotrophins—as crucial moderators of neuroplasticity—impact on the pathophysiology of autism spectrum disorder (ASD). The study projects aimed to complement former results on the role of brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family with fundamental impact on brain development and function. The purpose of this work was to investigate peripheral BDNF mRNA expression and BDNF protein concentrations in ASD as potential surrogates for the effects observed in the central nervous system. In a BDNF protein quantification study, serum concentrations were analyzed using Enzyme-Linked Immunosorbent Assays in 24 male patients with ASD, all with an IQ > 70 (age 13.9 ± 3.0 years) and 20 age- and gender-matched healthy control subjects (age 14.4 ± 2.1 years; p = 0.522). In a further independent project, a BDNF mRNA expression analysis, mRNA levels from total blood were assessed by quantitative real-time polymerase chain reaction in a sample of 16 male ASD patients (age 10.8 ± 2.2), 15 age- and gender-matched healthy controls (age 12.1 ± 2.2) and 15 patients with attention deficit hyperactivity disorder as a clinical control group (age 11.8 ± 2.2; p = 0.207). In the protein quantification project, significantly decreased BDNF serum concentrations were found in ASD cases compared to healthy control children (t = −2.123, df = 42, p < 0.05). Analysis of covariance (ANCOVA) revealed this result in accordance with significant reductions in BDNF mRNA expression in ASD, observed in the mRNA expression study (F = 3.65; df = 2.43; p < 0.05); neither age nor IQ confounded the result, as indicated by ANCOVA (F = 3.961; df = 2.41; p < 0.05, η2 = 0.162). Our study projects supported the notion that neurotrophins are involved in the pathophysiology of ASD. Further studies may eventually contribute to the identification of distinct peripheral mRNA expression and protein concentration patterns possibly supporting diagnostic and therapeutic processes.

Evidence for metaplasticity in the human visual cortex

Abstract: The threshold and direction of excitability changes induced by low- and high-frequency repetitive transcranial magnetic stimulation (rTMS) in the primary motor cortex can be effectively reverted by a preceding session of transcranial direct current stimulation (tDCS), a phenomenon referred to as “metaplasticity”. Here, we used a combined tDCS–rTMS protocol and visual evoked potentials (VEPs) in healthy subjects to provide direct electrophysiological evidence for metaplasticity in the human visual cortex. Specifically, we evaluated changes in VEPs at two different contrasts (90 and 20 %) before and at different time points after the application of anodal or cathodal tDCS to occipital cortex (i.e., priming), followed by an additional conditioning with low- or high-frequency rTMS. Anodal tDCS increased the amplitude of VEPs and this effect was paradoxically reverted by applying high-frequency (5 Hz), conventionally excitatory rTMS (p 0.5), confirming the spatial selectivity of our conditioning protocol. Our findings show that preconditioning primary visual area excitability with tDCS can modulate the direction and strength of plasticity induced by subsequent application of 1 or 5 Hz rTMS. These data indicate the presence of mechanisms of metaplasticity that keep synaptic strengths within a functional dynamic range in the human visual cortex.

Emerging issues on selection criteria of levodopa carbidopa infusion therapy: considerations on outcome of 28 consecutive patients

Abstract: Many studies confirmed the efficacy and safety of continuous infusion of intrajejunal levodopa/carbidopa gel (CIILG) for advanced Parkinson's disease (PD). Although this treatment is widely used, definite inclusion/exclusion criteria do not exist. In this prospective open-label study, we evaluated the long-term outcome in 28 consecutive patients and sought to detect any predictive factor to identify the best candidates for CIILG therapy. The assessment was carried out routinely at baseline, after 6 months and every year with UPDRS III-IV, FOG Questionnaire, non-motor symptoms scale, PD questionnaire (PDQ-8), cognitive and psychiatric status evaluation (MMSE, FAB, NPI) and caregiver's quality of life. 17/28 patients reached the 24-month follow-up. A statistically significant beneficial effect was shown on motor complications in short- and long-term follow-up, also on axial symptoms like gait disturbances. A concomitant improvement in PDQ8 score was observed, with a parallel mild amelioration, but not significant, on Caregivers QoL. When classified according to their outcome on QoL, the only predictive positive factor was less severe at Neuropsychiatric Inventory (NPI) score at baseline. Considering the improvement in motor scores (duration of "off" period), the more advanced age was associated with a poorer outcome. Our results confirmed a sustained efficacy and safety in long-term follow-up and suggest that younger age at operation and absence or mild presence of psychiatric/behavioural symptoms could be considered valid predicting factors in selecting the best candidates for this efficacious therapy.

Taste performance in Parkinson’s disease

Abstract: While olfactory deficit is already known to be associated with early-stage Parkinson’s disease (PD), taste perception has not fully clarified so far. In this study, we investigated the taste performance in 61 patients with PD and 66 healthy controls (HC) using the Whole Mouth (WMT) and Taste Strip Tests (TST). In addition, we evaluated their olfactory function by means of the Sniffin’ Sticks Test (SST). TST score was significantly lower in PD patients than in HC (TST score 11.0 ± 2.8 vs. 12.2 ± 2.1; p<0.018) while WMT showed no difference. The olfactory evaluation confirmed the results reported in the literature with a significant reduction of the SST score in PD patients than in HC (SST score 7.0 ± 2.8 vs. 11.3 ± 2.8; p<0.0001). The conflicting results revealed by TST and WMT could rely on a taste impairment not detectable at supra-threshold concentration of tastes, typical of the daily life. Possible biological correlates of taste impairment in PD are discussed.

Quadruple deep brain stimulation in Huntington's disease, targeting pallidum and subthalamic nucleus: case report and review of the literature.

Abstract: Deep brain stimulation (DBS) represents an established treatment option in a growing number of movement disorders. Recent case reports suggest beneficial effect of globus pallidus internus (GPi)-DBS in selected patients suffering from Huntington’s disease with marked disabling chorea. We present a 41-year-old man with genetically confirmed HD following quadruple GPi- and subthalamic nucleus (STN)-DBS. Motor function was assessed by Abnormal Involuntary Movement Scale (AIMS) and by Unified Huntington Disease Rating Scale (UHDRS) presurgery and postsurgery for up to 4 years. Furthermore, cognitive, neuropsychiatric state and quality of life (QoL) including life satisfaction (QLS) were annually evaluated. Chorea assessed by AIMS and UHDRS subscores improved by 52 and 55 %, 45 and 60 %, 35 and 45 % and 55–66 % at 1–4 years, respectively, compared to presurgical state following GPi–STN-DBS. During these time periods bradykinesia did not increase following separate STN- and combined GPi–STN-DBS compared to presurgical state. Mood, QoL and QLS were ameliorated. However, dysexecutive symptoms increased at 4 years postsurgery. The present case report suggests that bilateral GPi- and STN-DBS may represent a new treatment avenue in selected HD patients. Clinically, GPi-DBS attenuated chorea and was associated with a larger effect–adverse effect window compared to STN-DBS. However, GPi-DBS-induced bradykinesia may emerge as one main limitation of GPi-DBS in HD. Thus, quadruple GPi–STN-DBS may be indicated, if separate GPi-DBS does not result in sufficient control of motor symptoms. Future controlled studies need to confirm if the present anecdotal observation of additive beneficial effects of GPi- and STN-DBS in a HD patient with severe generalized chorea and relatively intact cognitive and affective functions indeed represents a new therapeutic option.

Hypercholesterolemia induces short-term spatial memory impairments in mice: up-regulation of acetylcholinesterase activity as an early and causal event?

Abstract: Epidemiological studies have indicated hypercholesterolemia in midlife as a risk factor for dementia in later life, bringing cholesterol to the forefront of Alzheimer’s disease research. Herein, we modeled mild hypercholesterolemia in mice to evaluate biochemical and behavioral alterations linked to hypercholesterolemia. Swiss mice were fed a high fat/cholesterol diet (20 % fat and 1.25 % cholesterol) for an 8-week period (from 12 to 18 weeks old) and were tested on the object location, forced swimming and elevated plus-maze tasks. We also investigated hypercholesterolemia-induced changes on acetylcholinesterase (AChE) activity, oxidative damage, amyloid precursor protein (APP) processing and blood brain barrier (BBB) integrity within the prefrontal cortex and hippocampus. It was found that increased AChE activity within the prefrontal cortex and hippocampus is an early event associated with hypercholesterolemia-induced short-term memory impairments. We observed no signs of antioxidant imbalance and/or oxidative damage or changes in cortical and hippocampal densities of beta-site amyloid precursor protein-cleaving enzyme 1 and aquaporin-4, biomarkers of APP processing and BBB integrity, respectively. In addition, we treated SH-SY5Y human neuroblastoma cells with low-density lipoprotein (LDL) cholesterol in an attempt to manipulate cell cholesterol content. Notably, LDL cholesterol increased in a dose-dependent manner the activity of AChE in SH-SY5Y cells. The present findings provide new evidence that increased AChE activity within the prefrontal cortex and hippocampus is an early event associated with hypercholesterolemia-induced cognitive impairments.

Salubrinal, ER stress inhibitor, attenuates kainic acid-induced hippocampal cell death.

Abstract: Kainic acid (KA)-induced neuronal death is closely linked to endoplasmic reticulum (ER) and mitochondrial dysfunction. Parkin is an ubiquitin E3 ligase that mediates the ubiquitination of the Bcl-2 family of proteins and its mutations are associated with neuronal apoptosis in neurodegenerative diseases. We investigated the effect of salubrinal, an ER stress inhibitor, on the regulation of ER stress and mitochondrial apoptosis induced by KA, in particular, by controlling parkin expression. We showed that salubrinal significantly reduced seizure activity and increased survival rates of mice with KA-induced seizures. We found that salubrinal protected neurons against apoptotic death by reducing expression of mitochondrial apoptotic factors and elF2α–ATF4–CHOP signaling proteins. Interestingly, we showed that salubrinal decreased the KA-induced parkin expression and inhibited parkin translocation to mitochondria, which suggests that parkin may regulate a cross-talk between ER and mitochondria. Collectively, inhibition of ER stress attenuates mitochondrial apoptotic and ER stress pathways and controls parkin-mediated neuronal death following KA-induced seizures.

Brain to blood glutamate scavenging as a novel therapeutic modality: a review

Abstract: It is well known that abnormally elevated glutamate levels in the brain are associated with secondary brain injury following acute and chronic brain insults. As such, a tight regulation of brain glutamate concentrations is of utmost importance in preventing the neurodegenerative effects of excess glutamate. There has been much effort in recent years to better understand the mechanisms by which glutamate is reduced in the brain to non-toxic concentrations, and in how to safely accelerate these mechanisms. Blood glutamate scavengers such as oxaloacetate, pyruvate, glutamate-oxaloacetate transaminase, and glutamate-pyruvate transaminase have been shown to reduce blood glutamate concentrations, thereby increasing the driving force of the brain to blood glutamate efflux and subsequently reducing brain glutamate levels. In the past decade, blood glutamate scavengers have gained increasing international interest, and its uses have been applied to a wide range of experimental contexts in animal models of traumatic brain injury, ischemic stroke, subarachnoid hemorrhage, epilepsy, migraine, and malignant gliomas. Although glutamate scavengers have not yet been used in humans, there is increasing evidence that their use may provide effective and exciting new therapeutic modalities. Here, we review the laboratory evidence for the use of blood glutamate scavengers. Other experimental neuroprotective treatments thought to scavenge blood glutamate, including estrogen and progesterone, beta-adrenergic activation, hypothermia, insulin and glucagon, and hemodialysis and peritoneal dialysis are also discussed. The evidence reviewed here will hopefully pave the way for future clinical trials.

Impaired motor speech performance in Huntington's disease.

Abstract: Dysarthria is a common symptom of Huntington's disease and has been reported, besides other features, to be characterized by alterations of speech rate and regularity. However, data on the specific pattern of motor speech impairment and their relationship to other motor and neuropsychological symptoms are sparse. Therefore, the aim of the present study was to describe and objectively analyse different speech parameters with special emphasis on the aspect of speech timing of connected speech and non-speech verbal utterances. 21 patients with manifest Huntington's disease and 21 age- and gender-matched healthy controls had to perform a reading task and several syllable repetition tasks. Computerized acoustic analysis of different variables for the measurement of speech rate and regularity generated a typical pattern of impaired motor speech performance with a reduction of speech rate, an increase of pauses and a marked disability to steadily repeat single syllables. Abnormalities of speech parameters were more pronounced in the subgroup of patients with Huntington's disease receiving antidopaminergic medication, but were also present in the drug-naive patients. Speech rate related to connected speech and parameters of syllable repetition showed correlations to overall motor impairment, capacity of tapping in a quantitative motor assessment and some score of cognitive function. After these preliminary data, further investigations on patients in different stages of disease are warranted to survey if the analysis of speech and non-speech verbal utterances might be a helpful additional tool for the monitoring of functional disability in Huntington's disease.

Botulinum toxin therapy of cervical dystonia: comparing onabotulinumtoxinA (Botox®) and incobotulinumtoxinA (Xeomin®)

Abstract: Several botulinum toxin (BT) drugs are licensed for the treatment of cervical dystonia (CD). We wanted to compare the efficacy and the potency labelling of incobotulinumtoxinA (Xeomin®) and onabotulinumtoxinA (Botox®) by analysing the duration of their therapeutic effect in a cross-over study. For this we studied 40 CD patients (26 females, 14 males, age at therapy onset 52.6 ± 12.0 years, duration of dystonia at therapy onset 10.0 ± 9.2 years, Tsui score 9.1 ± 3.9) who first received Botox® and then Xeomin® for at least 4 injection series each. BT doses were exchanged based on a 1:1 conversion ratio. Altogether 1,101 treatment cycles were evaluated. For each patient 27.5 ± 13.1 treatment cycles were recorded. Patients received 18.4 ± 12.4 treatment cycles with Botox® and 9.2 ± 4.5 with Xeomin®. The treatment duration (TD) throughout the treatment course was 11.3 ± 1.0 weeks (Botox® 11.2 ± 1.1 weeks, Xeomin® 11.4 ± 1.3 weeks). The interinjection interval (II) throughout the treatment course was 14.8 ± 1.9 weeks (Botox® 14.7 ± 1.6 weeks, Xeomin® 15.0 ± 2.2 weeks). The mean difference between Botox® and Xeomin® was 0.3 weeks for TD (two-sided 95 % confidence interval [−0.3; 0.9]) and 0.5 weeks for II (two-sided 95 % confidence intervals [−0.4; 1.4]). The confidence intervals of both parameters were within the predefined therapeutic equivalence range set to ±1.5 weeks, thus indicating similar efficacy of both BT drugs. Having based the exchange of Botox® and Xeomin® on a conversion factor of 1:1 our data confirm previous findings of an identical potency labelling of both products, thus allowing comparisons of efficacy, adverse effects and costs.

A quantitative study of α-synuclein pathology in fifteen cases of dementia associated with Parkinson disease

Abstract: The α-synuclein-immunoreactive pathology of dementia associated with Parkinson disease (DPD) comprises Lewy bodies (LB), Lewy neurites (LN), and Lewy grains (LG). The densities of LB, LN, LG together with vacuoles, neurons, abnormally enlarged neurons (EN), and glial cell nuclei were measured in fifteen cases of DPD. Densities of LN and LG were up to 19 and 70 times those of LB, respectively, depending on region. Densities were significantly greater in amygdala, entorhinal cortex (EC), and sectors CA2/CA3 of the hippocampus, whereas middle frontal gyrus, sector CA1, and dentate gyrus were least affected. Low densities of vacuoles and EN were recorded in most regions. There were differences in the numerical density of neurons between regions, but no statistical difference between patients and controls. In the cortex, the density of LB and vacuoles was similar in upper and lower laminae, while the densities of LN and LG were greater in upper cortex. The densities of LB, LN, and LG were positively correlated. Principal components analysis suggested that DPD cases were heterogeneous with pathology primarily affecting either hippocampus or cortex. The data suggest in DPD: (1) ratio of LN and LG to LB varies between regions, (2) low densities of vacuoles and EN are present in most brain regions, (3) degeneration occurs across cortical laminae, upper laminae being particularly affected, (4) LB, LN and LG may represent degeneration of the same neurons, and (5) disease heterogeneity may result from variation in anatomical pathway affected by cell-to-cell transfer of α-synuclein.

Characteristics and occurrence of speech impairment in Huntington’s disease: possible influence of antipsychotic medication

Abstract: Although motor speech impairment is a common manifestation of Huntington’s disease (HD), its description remains limited. The aim of the current study was therefore to estimate the occurrence and characteristics of speech disorder in HD and to explore the influence of antipsychotic medication on speech performance. Speech samples, including reading passage and monologue, were acquired from 40 individuals diagnosed with HD and 40 age- and sex-matched healthy controls. Objective acoustic analyses were used to evaluate key aspects of speech including vowel articulation, intensity, pitch and timing. A predictive model was constructed to detect the occurrence and most prominent patterns of speech dysfunction in HD. We revealed that 93 % of HD patients manifest some degree of speech impairment. Decreased number of pauses, slower articulation rate, imprecise vowel articulation and excess intensity variations were found to be the most salient patterns of speech dysfunction in HD. We further demonstrated that antipsychotic medication may induce excessive loudness and pitch variations perceptually resembling excess patterns of word stress, and may also accentuate general problems with speech timing. Additionally, antipsychotics induced a slight improvement of vowel articulation. Specific speech alterations observed in HD patients indicate that speech production may reflect the pathophysiology of the disease as well as treatment effects, and may therefore be considered a valuable marker of functional disability in HD.

Plasma BDNF levels are correlated with aggressiveness in patients with amnestic mild cognitive impairment or Alzheimer disease

Abstract: In the present study, we examined whether neuropsychiatric symptoms were correlated with plasma brain-derived neurotrophic factor (BDNF) levels as a state marker or were associated with the BDNF polymorphism Val66Met in patients with amnestic mild cognitive impairment (A-MCI) or Alzheimer disease (AD). One hundred and seventy-six outpatients with AD (n = 129) or A-MCI (n = 47) were selected and their plasma BDNF concentrations measured. Next, we investigated the correlation between the plasma BDNF level and the Behavioral Pathology in Alzheimer Disease (Behave-AD) subscale scores, which reflect neuropsychiatric symptoms. We also compared the plasma BDNF level and the Behave-AD subscale scores among the BDNF Val66Met genotypic groups. Among the seven Behave-AD subscale scores, aggressiveness was positively correlated with the plasma BDNF level (ρ = 0.237, P < 0.005), but did not differ significantly among the three BDNF Val66Met genotypic groups. The Behave-AD total and other subscale scores did not differ significantly among the BDNF Val66Met genotypic groups and were not associated with the plasma BDNF level. Moreover, the plasma BDNF level did not differ significantly among the three BDNF Val66Met genotypic groups or between patients with A-MCI and those with AD. The plasma BDNF level was robustly correlated with aggressiveness, implying that the plasma BDNF level might be useful as a behavioral state marker in patients with AD or A-MCI.

Striatal volume is related to phonemic verbal fluency but not to semantic or alternating verbal fluency in early Parkinson’s disease

Abstract: Verbal fluency impairments are frequent in Parkinson’s disease (PD) and they may be present already at early stages. Semantic fluency impairment is associated with Parkinson’s disease dementia and temporal, frontal and cerebellar cortical changes. Few studies have addressed cerebral structural correlates of different verbal fluency tasks in early stage PD. We therefore studied gray matter volumes of T1-weighted MRI images using voxel-based morphometry in relation to semantic, phonemic, and alternating verbal fluency in younger (mean age <65 years), early stage (mean disease duration <3 years), non-demented PD patients (n = 28) and healthy controls (n = 27). We found a significant association between worse phonemic fluency and smaller striatal, namely right caudate gray matter volume in the PD group only (family-wise error corrected p = 0.007). Reduced semantic fluency was associated with smaller gray matter volumes in left parietal cortex (p = 0.037) and at trend level with smaller bilateral cerebellum gray matter volume across groups (p = 0.062), but not in the separate PD or control groups. There were no significant relationships between alternating fluency and gray matter volumes in the whole sample or in the groups separately. The fact that phonemic fluency, but not semantic or alternating fluency, was associated with caudate gray matter volume at early stage PD suggests that different fluency tasks rely on different neural substrates, and that language networks supporting semantic search and verbal-semantic switching are unrelated to brain gray matter volume at early disease stages in PD.

Acute and chronic dose–response effect of methylphenidate on ventral tegmental area neurons correlated with animal behavior

Abstract: Methylphenidate (MPD) is used to treat ADHD and as a cognitive enhancement and recreationally. MPD's effects are not fully understood. One of the sites of psychostimulant action is the ventral tegmental area (VTA). The VTA neuronal activity was recorded from freely behaving rats using a wireless system. 51 animals were divided into groups: saline, 0.6, 2.5, and 10.0 mg/kg MPD. The same repetitive MPD dose can elicit either behavioral sensitization or tolerance; thus the evaluation of the VTA neuronal activity was based on the animals' behavioral response to chronic MPD exposure: animals exhibiting behavioral tolerance or sensitization. Acute MPD elicits dose-related increases in behavioral activity. About half of the animals exhibited behavioral sensitization or tolerance to each of the MPD doses. 361 units were recorded from the VTA and exhibited similar spike shape on experimental day 1 (ED1) and on ED10. 71, 84, and 79 % of VTA units responded to acute 0.6, 2.5, and 10.0 mg/kg MPD, respectively. The neuronal baseline activity at ED10 was significantly modified in 94, 95, and 100 % of VTA units following 0.6, 2.5 and 10.0 mg/kg MPD, respectively. Following chronic MPD exposure, 91, 98, and 100 % exhibit either electrophysiological tolerance or sensitization of 0.6, 2.6, or 10.0 mg/kg MPD, respectively. In conclusion, the chronic administration of the same dose of MPD caused some animals to exhibit behavioral sensitization and other animals to exhibit tolerance. The VTA units recorded from animals exhibiting behavioral sensitization responded significantly differently to MPD from animals that exhibited behavioral tolerance.