Showing papers in "Journal of Neural Transmission in 2012"
TL;DR: There is developing interest in the role of the kynurenines in the immune function and the anti-inflammatory effect of kynurenic acid provides a further feedback mechanism in modulating the immune responses.
Abstract: There is developing interest in the role of the kynurenines in the immune function. A considerable amount of evidence has accumulated as concerns interactions between the kynurenine pathway, cytokines and the nervous system. Indoleamine 2,3-dioxygenase (IDO) occupies a key position connecting the immune system and the kynurenine pathway. There are evidences of the immunosuppressive effect of IDO. Following the interferon (IFN)-mediated activation of antigen presenting cells, the induction of IDO and the kynurenine system exerts a counter-regulating effect, maintaining the homeostasis. Inhibition of T cell functions, activation of the regulatory T cells, and the inhibition of Natural Killer cells are among the important factors in the immunosuppressive effects of IDO and kynurenines. There is a close connection between cytokines (IFN-α, IFN-γ, TNF-α, TGF-β, IL-4 and IL-23) and the kynurenine system, and an imbalance in the TH1/TH2 cytokine profile may possibly lead to neurologic or psychiatric disorders. As the tryptophan metabolic pathway is activated by pro-inflammatory stimuli, the anti-inflammatory effect of kynurenic acid provides a further feedback mechanism in modulating the immune responses.
327 citations
TL;DR: The authors review the influence of shift work as a form of systematic desynchronization of inner clock systems on the endocrine, the physical, and the mental level and the significance of the findings is discussed.
Abstract: Occupational engagement is a pre-requisite for continuous income opportunities. Among the changing social circumstances work-related conditions play an increasingly eminent role in psychological and mental well-being. The public discusses the question of a possible association between the demands of modern work life and the increases of psychological, psychosomatic and cardiovascular disorders. Given the socioeconomic implications of psychiatric and psychosomatic suffering in the general population, there is a need to further elucidate the causes of their increasing incidence. From a medical point of view, any organization of work disrupting the phased circadian rhythms for bio-psycho-social processes and functioning of the individual are interesting against the background of clock genes and certain biological functions that are organized in a circadian fashion. The authors review the influence of shift work as a form of systematic desynchronization of inner clock systems on the endocrine, the physical, and the mental level. The significance of the findings in the field is discussed along with future directions of conclusive research.
164 citations
TL;DR: The evidence for possible mechanistic explanations for involvement of free radicals in the pathogenesis of neurodegenerative diseases is put forth.
Abstract: The continuous production and efflux of reactive oxygen/nitrogen species from endogenous and exogenous sources can damage biological molecules and initiate a cascade of events. Mitochondria are pivotal in controlling cell survival and death. Cumulative oxidative stress, disrupted mitochondrial respiration, and mitochondrial damage are related with various neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and others. Biochemical cascades of apoptosis are mediated in signaling molecules, including protein kinases and transcription factors. The expressions in the pro-apoptotic signal transduction networks may indeed promote cell death and degeneration in brain cells. The regulation of that protein phosphorylation by kinases and phosphatases is emerging as a prerequisite mechanism in the control of the apoptotic cell death program. In this review, we attempt to put forth the evidence for possible mechanistic explanations for involvement of free radicals in the pathogenesis of neurodegenerative diseases.
162 citations
TL;DR: KYNA has receptors in the nervous and the immune systems and may play interesting regulatory roles in cell function and by interacting with GPR35, KYNA may also reduce glutamate release in brain and pro-inflammatory cytokines release in cell lines.
Abstract: It is usually assumed that kynurenic acid (KYNA) modifies neuronal function because it antagonizes the glycine site of the NMDA receptors and/or the neuronal cholinergic α7 nicotine receptors. It is not clear, however, whether the basal levels of KYNA found in brain extracellular spaces are sufficient to interact with these targets. Another reported target for KYNA is GPR35, an orphan receptor negatively coupled to Gi proteins. GPR35 is expressed both in neurons and other cells (including glia, macrophages and monocytes). KYNA affinity for GPR35 in native systems has not been clarified and the low-affinity data widely reported in the literature for the interaction between KYNA and human or rat GPR35 have been obtained in modified expression systems. Possibly by interacting with GPR35, KYNA may also reduce glutamate release in brain and pro-inflammatory cytokines release in cell lines. The inhibition of inflammatory mediator release from both glia and macrophages may explain why KYNA has analgesic effects in inflammatory models. Furthermore, it may also explain why, KYNA administration (200 mg/kg ip × 3 times) to mice treated with lethal doses of LPS, significantly reduces the number of deaths. Finally, KYNA has been reported as an agonist of aryl hydrocarbon receptor (AHR), a nuclear protein involved in the regulation of gene transcription and able to cause immunosuppression after binding with dioxin. Thus, KYNA has receptors in the nervous and the immune systems and may play interesting regulatory roles in cell function.
155 citations
TL;DR: The presence of αvβ3 reactive vessels in PD and its syndromes is indicative of newly created vessels that have not likely developed the restrictive properties of the blood brain barrier and could contribute to neuroinflammation by failing to protect the parenchyma from peripheral immune cells and inflammatory or toxic factors in the peripheral circulation.
Abstract: Angiogenesis has not been extensively studied in Parkinson’s disease (PD) despite being associated with other neurodegenerative disorders. Post-mortem human brain tissues were obtained from subjects with pathologically confirmed Parkinson’s disease (PD) and progressive supranuclear palsy (PSP), a rapidly progressing Parkinsonian-like disorder. Tissues were also obtained from subjects with incidental Lewy body disease (iLBD) who had Lewy bodies in the substantia nigra pars compacta (SNpc) but had not been diagnosed with PD, and age-matched controls without Lewy body pathology. The SNpc, putamen, locus ceruleus (LC) and midfrontal cortex were examined for integrin αvβ3, a marker for angiogenesis, along with vessel number and activated microglia. All parkinsonian syndromes had greater αvβ3 in the LC and the SNpc, while only PD and PSP subjects had elevated αvβ3 in the putamen compared to controls. PD and PSP subjects also had increases in microglia number and activation in the SNpc suggesting a link between inflammation and clinical disease. Microglia activation in iLBD subjects was limited to the LC, an area involved at an early stage of PD. Likewise, iLBD subjects did not differ from controls in αvβ3 staining in the putamen, a late area of involvement in PD. The presence of αvβ3 reactive vessels in PD and its syndromes is indicative of newly created vessels that have not likely developed the restrictive properties of the blood brain barrier. Such angiogenic vessels could contribute to neuroinflammation by failing to protect the parenchyma from peripheral immune cells and inflammatory or toxic factors in the peripheral circulation.
105 citations
TL;DR: This review aims to address the limitations and clinical relevance of transgenic rodent models in AD, and to highlight the potential for O. degu as a natural model for the study of AD neuropathology.
Abstract: Alzheimer’s disease (AD) is the most common origin of dementia in the elderly. Although the cause of AD remains unknown, several factors have been identified that appear to play a critical role in the development of this debilitating disorder. In particular, amyloid precursor protein (APP), tau hyperphosphorylation, and the secretase enzymes, have become the focal point of recent research. Over the last two decades, several transgenic and non-transgenic animal models have been developed to elucidate the mechanistic aspects of AD and to validate potential therapeutic targets. Transgenic rodent models over-expressing human β-amyloid precursor protein (β-APP) and mutant forms of tau have become precious tools to study and understand the pathogenesis of AD at the molecular, cellular and behavioural levels, and to test new therapeutic agents. Nevertheless, none of the transgenic models of AD recapitulate fully all of the pathological features of the disease. Octodon degu, a South American rodent has been recently found to spontaneously develop neuropathological signs of AD in old age. This review aims to address the limitations and clinical relevance of transgenic rodent models in AD, and to highlight the potential for O. degu as a natural model for the study of AD neuropathology.
105 citations
TL;DR: It is argued that an understanding of the mechanistic overlap between SCRD and schizophrenia will ultimately lead to novel treatment approaches, which will not only ameliorate SCRD in schizophrenia patients, but also will improve their broader health problems and overall quality of life.
Abstract: Sleep and circadian rhythm disruption (SCRD) and schizophrenia are often co-morbid. Here, we propose that the co-morbidity of these disorders stems from the involvement of common brain mechanisms. We summarise recent clinical evidence that supports this hypothesis, including the observation that the treatment of SCRD leads to improvements in both the sleep quality and psychiatric symptoms of schizophrenia patients. Moreover, many SCRD-associated pathologies, such as impaired cognitive performance, are routinely observed in schizophrenia. We suggest that these associations can be explored at a mechanistic level by using animal models. Specifically, we predict that SCRD should be observed in schizophrenia-relevant mouse models. There is a rapidly accumulating body of evidence which supports this prediction, as summarised in this review. In light of these emerging data, we highlight other models which warrant investigation, and address the potential challenges associated with modelling schizophrenia and SCRD in rodents. Our view is that an understanding of the mechanistic overlap between SCRD and schizophrenia will ultimately lead to novel treatment approaches, which will not only ameliorate SCRD in schizophrenia patients, but also will improve their broader health problems and overall quality of life.
99 citations
TL;DR: It is concluded that dopaminergic therapy has a specific effect on both the DMN integrity and task-related brain activations in cognitively unimpaired PD patients, and these effects seem to be dose-dependent.
Abstract: Disturbances in the default mode network (DMN) have been described in many neurological and psychiatric disorders including Parkinson’s disease (PD). The DMN is characterized by basal activity that increases during rest or passive visual fixation and decreases (“deactivates”) during cognitive tasks. The network is believed to be involved in cognitive processes. We examined the DMN in PD patients on dopaminergic medication with normal cognitive performance compared to age- and gender-matched healthy controls (HC) using fMRI and three methodological procedures: independent component analysis of resting-state data, analysis of deactivation during a complex visual scene-encoding task, and seed-based functional connectivity analysis. In the PD group, we also studied the effect of dopaminergic medication on the DMN integrity. We did not find any difference between the PD and HC groups in the DMN, but using the daily levodopa equivalent dose as a covariate, we observed an enhanced functional connectivity of the DMN in the posterior cingulate cortex and decreased activation in the left parahippocampal gyrus during the cognitive task. We conclude that dopaminergic therapy has a specific effect on both the DMN integrity and task-related brain activations in cognitively unimpaired PD patients, and these effects seem to be dose-dependent.
94 citations
TL;DR: The role of kynurenine metabolism which interacts with other neurochemicals is discussed as a major contributing pathophysiological mechanism in major depression and the future therapeutic opportunities are discussed.
Abstract: There are circumferential evidences that major depression is associated with mild pro-inflammatory state. Both physiological and psychological stress can induce increased production of pro-inflammatory mediators, reactive oxygen species (ROS) and hypothalamo-hypophyseal-adrenal axis disturbances. While both pro-inflammatory mediators and ROS could activate the tryptophan breakdown and kynurenine pathway with a shift toward the neurotoxic arm, chronic hypercortisolism could also enhance tryptophan breakdown and induce neurodegenerative changes. The imbalanced kynurenine metabolism in terms of neuroprotective and neurotoxic effects was demonstrated in major depression, and in drug-induced neuropsychiatric side effects, such as interferon-treated depression. The changes in periphery are shown to be associated with central changes. Those changes might be partly contributed by genetic factors. While some of the currently available antidepressants could reverse the pro-inflammatory state of the depressed patients, these medications could not efficiently improve those metabolic and neurochemical changes within the period that could induce clinical improvement. In this review, the role of kynurenine metabolism which interacts with other neurochemicals is discussed as a major contributing pathophysiological mechanism in major depression. Moreover, the future therapeutic opportunities are also discussed in this review.
93 citations
TL;DR: The findings that have gained support indicate that genetic variants of RORA and CRY1 associate with depressive disorder, those of R ORB and NR1D1 with bipolar disorder, and those of NPAS2 andCRY2 with seasonal affective disorder or winter depression.
Abstract: Circadian clocks are driven by signals from the habitat to match the solar day and to reset their phase relative to local time A key function of the circadian clocks allows individuals to anticipate routine environmental conditions and to adjust their behaviors to the change of conditions In clinical practice mood, anxiety and alcohol use disorders are often comorbid conditions Clinical data have demonstrated that there are abnormalities in the circadian rhythms in patients with mood disorders and those with alcohol use disorders Recent findings of molecular genetics have yielded the first insight into the targets of interest Circadian clock gene variants are a fruitful target for elucidation of the pathogenesis The findings that have gained support indicate that genetic variants of RORA (rs2028122) and CRY1 (rs2287161) associate with depressive disorder, those of RORB (rs7022435, rs3750420, rs1157358, rs3903529) and NR1D1 (rs2314339) with bipolar disorder, and those of NPAS2 (rs11541353) and CRY2 (rs10838524) with seasonal affective disorder or winter depression Concerning anxiety disorders and alcohol use disorders, the current findings are preliminary and need further verification to explain the association of ARNTL2, being suggestive only, with social phobia (rs2306073) and with alcohol abuse (rs7958822, rs4964057)
88 citations
TL;DR: Further evidence that sleep and circadian timing are profoundly altered in patients with bipolar disorder is provided and it is tentatively suggested that sleep may be altered prior to the first manic episode in subjects at high risk.
Abstract: Sleep is highly altered during affective episodes in patients with bipolar disorder. There is accumulating evidence that sleep is also altered in euthymic states. A deficit in sleep regulation may be a vulnerability factor with aetiological relevance in the development of the disease. This study aims to explore the objective, subjective and lifetime sleep characteristics of patients with manifest bipolar disorder and persons with an elevated risk of developing the disease. Twenty-two patients with bipolar I and II disorder, nine persons with an elevated risk of developing the disorder and 28 healthy controls were evaluated with a structured interview to characterize subjective and lifetime sleeping habits. In addition, participants wore an actimeter for six nights. Patients with bipolar disorder had longer sleep latency and duration compared with healthy controls as determined by actigraphy. The subjective and lifetime sleep characteristics of bipolar patients differed significantly from healthy controls. The results of participants with an elevated risk of developing the disorder had subjective and lifetime characteristics that were largely analogous to those of patients with manifest bipolar disorder. In particular, both groups described recurring insomnia and hypersomnia, sensitivity to shifts in circadian rhythm, difficulties awakening and prolonged sleep latency. This study provides further evidence that sleep and circadian timing are profoundly altered in patients with bipolar disorder. It may also tentatively suggest that sleep may be altered prior to the first manic episode in subjects at high risk.
TL;DR: It is concluded that despite its higher levels in peripheral blood products, neurons of the brain and spinal cord represent the principal source of aSyn in human CSF.
Abstract: The source of Parkinson disease-linked α-synuclein (aSyn) in human cerebrospinal fluid (CSF) remains unknown. We decided to measure the concentration of aSyn and its gradient in human CSF specimens and compared it with serum to explore its origin. We correlated aSyn concentrations in CSF versus serum (QaSyn) to the albumin quotient (Qalbumin) to evaluate its relation to blood–CSF barrier function. We also compared aSyn with several other CSF constituents of either central or peripheral sources (or both) including albumin, neuron-specific enolase, β-trace protein and total protein content. Finally, we examined whether aSyn is present within the structures of the choroid plexus (CP). We observed that QaSyn did not rise or fall with Qalbumin values, a relative measure of blood–CSF barrier integrity. In our CSF gradient analyses, aSyn levels decreased slightly from rostral to caudal fractions, in parallel to the recorded changes for neuron-specific enolase; the opposite trend was recorded for total protein, albumin and β-trace protein. The latter showed higher concentrations in caudal CSF fractions due to the diffusion-mediated transfer of proteins from blood and leptomeninges into CSF in the lower regions of the spine. In postmortem sections of human brain, we detected highly variable aSyn reactivity within the epithelial cell layer of CP in patients diagnosed with a range of neurological diseases; however, in sections of mice that express only human SNCA alleles (and in those without any Snca gene expression), we detected no aSyn signal in the epithelial cells of the CP. We conclude from these complementary results that despite its higher levels in peripheral blood products, neurons of the brain and spinal cord represent the principal source of aSyn in human CSF.
TL;DR: Evaluated whether a long-lasting suppression of cortical excitability could be induced by prolonged cathodal tDCS, and the impact of brain-derived neurotrophic factor (BDNF) gene polymorphisms, on tDCS after-effects.
Abstract: Weak cathodal transcranial direct current stimulation (tDCS) of the human hand area modulates corticospinal excitability with a suppression of motor-evoked potentials (MEPs) evoked by transcranial magnetic stimulation (TMS). The changes in excitability persist beyond the time of stimulation if tDCS is given for several minutes and can remain stable for an hour or more. The aim of present study was to evaluate whether a long-lasting suppression of cortical excitability could be induced by prolonged cathodal tDCS (20 min of stimulation). We also explored the impact of brain-derived neurotrophic factor (BDNF) gene polymorphisms, on tDCS after-effects. Cortical excitability to single and paired-pulse TMS was evaluated both for the stimulated and contralateral hemisphere, before and up to 24 h after 20 min of cathodal tDCS. We evaluated threshold and amplitude of MEPs, short interval intracortical inhibition (SICI), and intracortical facilitation (ICF). tDCS produced a pronounced suppression of MEP amplitude that was still significant at 3 h after the end of stimulation. The BDNF genotype had not influence on tDCS after-effects. Thresholds for MEPs, SICI and ICF were not affected. No significant effect was observed in the contralateral hemisphere. Twenty minutes of cathodal tDCS is capable of inducing a long-lasting suppression of the excitability of the human motor cortex.
TL;DR: Findings highlight the reciprocal links between ADHD symptoms, sleep and diurnal preference and suggest individuals likely to suffer from ADHD and/or insomnia disorder were significantly more evening oriented than controls.
Abstract: Inattention is a core symptom of attention deficit hyperactivity disorder (ADHD) and one of the main impairments resulting from insomnia disorders. These disorders have also been reported to be linked with disturbances in circadian rhythms and with increased eveningness. To explore these associations, more than 550 adults were surveyed across Romania. Using self-reported questionnaires, the presence and severity of ADHD and insomnia symptoms were determined, together with sleep and circadian typology parameters. ADHD symptoms were more frequent and severe among younger individuals. Subjects with probable ADHD complained more frequently of sleep disturbance of the insomnia type (more than 50 %) and reported shorter sleep durations and longer sleep latencies and more frequent unwanted awakenings. Individuals likely to suffer from ADHD and/or insomnia disorder were significantly more evening oriented than controls. Inattention was associated with both insomnia and eveningness, while impulsivity was associated with poor sleep. Hyperactivity and sleep timing were associated with poor sleep only in probable insomnia group. These findings highlight the reciprocal links between ADHD symptoms, sleep and diurnal preference.
TL;DR: Experimental data are in line with previous clinical experience showing that Botox® and Xeomin® can be compared using a 1:1 conversion ratio, and allows easy exchange of both BT drugs in a therapeutic setting, and direct comparison of efficacy, adverse effects and costs.
Abstract: The biological potency of botulinum toxin (BT) drugs is determined by a standardised LD50 assay. However, the potency labelling varies vary amongst different BT drugs. One reason for this may be differences in the LD50 assays applied. When five unexpired batches of onabotulinumtoxinA (Botox(®)) and incobotulinumtoxinA (Xeomin(®)) are compared in the Xeomin(®) batch release assay, the potency variability of both BT drugs fell within the range allowed by the European Pharmacopoiea. Statistical analyses failed to detect differences in the potency labelling of both products. Although the existence of a conversion ratio has been questioned recently, our experimental data are in line with previous clinical experience showing that Botox(®) and Xeomin(®) can be compared using a 1:1 conversion ratio. Identical potency labelling allows easy exchange of both BT drugs in a therapeutic setting, and direct comparison of efficacy, adverse effects and costs.
TL;DR: A Working Group has convened to review the current status of proposed biomarkers of neurodegeneration according to the following criteria and to develop a consensus statement on biomarker candidates for evaluation of disease-modifying therapeutics in PD.
Abstract: Reliable biomarkers that can be used for early diagnosis and tracking disease progression are the cornerstone of the development of disease-modifying treatments for Parkinson’s disease (PD). The German Society of Experimental and Clinical Neurotherapeutics (GESENT) has convened a Working Group to review the current status of proposed biomarkers of neurodegeneration according to the following criteria and to develop a consensus statement on biomarker candidates for evaluation of disease-modifying therapeutics in PD. The criteria proposed are that the biomarker should be linked to fundamental features of PD neuropathology and mechanisms underlying neurodegeneration in PD, should be correlated to disease progression assessed by clinical rating scales, should monitor the actual disease status, should be pre-clinically validated, and confirmed by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. To date, available data have not yet revealed one reliable biomarker to detect early neurodegeneration in PD and to detect and monitor effects of drug candidates on the disease process, but some promising biomarker candidates, such as antibodies against neuromelanin, pathological forms of α-synuclein, DJ-1, and patterns of gene expression, metabolomic and protein profiling exist. Almost all of the biomarker candidates were not investigated in relation to effects of treatment, validated in experimental models of PD and confirmed in independent studies.
TL;DR: In contrast to the findings in adult patients, adolescent patients with AN did not display a marked deficit in set-shifting abilities, but demonstrated a perfectionistic cognitive style that was characterized by increased RTs in shift trials but improved accuracy.
Abstract: Deficits in set-shifting abilities have been robustly described in adult patients with anorexia nervosa (AN). These deficits are associated with behavioral traits, such as rigidity and perfectionism, and are independent of starvation. However, little is known about neurocognitive deficits in juvenile patients with AN. The brain circuits that support set shifting are not fully mature in these patients. One possibility is that neuroendocrinological changes, such as elevated cortisol levels, contributing to alterations in cognitive performance in individuals with AN. Set-shifting abilities (Visual Set-Shifting Task), cortisol levels, self-reported perfectionism and obsessive personality traits were assessed in 28 female adolescent patients with AN before (T0) and after (T1) weight rehabilitation and compared with 27 age- and IQ-matched healthy controls (CG). Compared with the CG, AN patients showed increased reaction times (RT) in shift trials (p < 0.001) and reduced error rates in both shift and non-shift trials across time points (p < 0.05). Across all subjects, perfectionism was associated with increased RTs during shift trials at T1 (r = 0.35, p < 0.05). Subjects with lower cortisol levels showed increased RTs and more errors in non-shift trials (p < 0.05). In contrast to the findings in adult patients, adolescent patients with AN did not display a marked deficit in set-shifting abilities. Instead, they demonstrated a perfectionistic cognitive style that was characterized by increased RTs in shift trials but improved accuracy. One could speculate that the shorter duration of illness and the incomplete maturation of the prefrontal cortices contribute to these findings.
TL;DR: Altered functional activation in the same brain regions of affective and cognitive cortico-striatal-thalamic circuits as for adult OCD patients despite some variations in the direction of activation difference is indicated.
Abstract: Obsessive compulsive disorder (OCD) is a frequent psychiatric disorder with a prevalence of 1-3 %, and it places an enormous burden on patients and their relatives Up to 50 % of all cases suffer from onset in childhood or adolescence, and the disorder often takes a chronic course with a poor long-term prognosis Paediatric OCD, with its high familiality, is often referred to as a distinct OCD subtype that coincides with a developmental period in which the prefrontal cortex exhibits extensive structural and functional maturation In the present review, we included all studies examining cognitive brain activation in children and/or adolescents with OCD We conducted extensive literature searches for relevant articles (Pubmed, ScienceDirect) and summarize, tabulate, and discuss their results For the eight activation studies using functional magnetic resonance imaging, we also performed preliminary meta-analyses to assess the most consistent hypo- and hyperactivation in paediatric OCD patients during cognitive task performance The review of literature as well as our preliminary meta-analyses of paediatric studies indicated altered functional activation in the same brain regions of affective and cognitive cortico-striatal-thalamic (CST) circuits as for adult OCD patients despite some variations in the direction of activation difference The still small number of studies that examined brain activation in paediatric OCD patients thereby largely converged with previous findings in adult patients and with the established neurobiological models of CST circuit dysfunction in OCD
TL;DR: The most important lines of evidence in favor of a neurodegenerative nature of essential tremor are: the anatomic and neuroimaging data demonstrating a pathologic process involving the cerebellum and/or brainstem; the progression of symptom severity with disease duration; and the lack of spontaneous remission of this condition.
Abstract: There are many lines of evidence supporting the idea that essential tremor is more than simply a monosymptomatic disorder and that all the clinical manifestations of this frequent disorder are sustained by a neurodegenerative process. The most important lines of evidence in favor of a neurodegenerative nature of essential tremor are: the anatomic and neuroimaging data demonstrating a pathologic process involving the cerebellum and/or brainstem; the progression of symptom severity with disease duration; and the lack of spontaneous remission of this condition. All of this evidence is supported by recent studies that are summarized in this review.
TL;DR: Elevated CSF levels of C3 and C4 in AD compared with MCI without progression to AD, and elevated CSf levels of CR1 in MCI-AD and AD when these groups were merged provide support for aberrant complement regulation as a part in the AD process, but the changes are not diagnostically useful.
Abstract: Alzheimer’s disease (AD) is strongly associated with loss of synapses The complement system has been shown to be involved in synaptic elimination Several studies point to an association between AD and the complement system The purpose of this study was to examine the association of cerebrospinal fluid (CSF) levels of complement components 3 and 4 (C3 and C4, respectively), and complement receptor 1 (CR1) with AD in 43 patients with AD plus dementia, 42 patients with mild cognitive impairment (MCI) who progressed to AD during follow-up (MCI-AD), 42 patients with stable MCI and 44 controls Complement levels were also applied in a multivariate model to determine if they provided any added value to the core AD biomarkers Aβ42, T-tau and P-tau We found elevated CSF levels of C3 and C4 in AD compared with MCI without progression to AD, and elevated CSF levels of CR1 in MCI-AD and AD when these groups were merged These results provide support for aberrant complement regulation as a part in the AD process, but the changes are not diagnostically useful
TL;DR: It is demonstrated that this putative marker of central cholinergic activity differs among MCI subtypes, suggesting that the amnestic-MD type of MCI might be a phenotype of incipient AD, however, this hypothesis would be better addressed in a longitudinal study of individual patients.
Abstract: Mild cognitive impairment (MCI) is considered a transitional stage between normal aging and a diagnosis of clinically probable Alzheimer disease (AD). The role of the cholinergic system in MCI is not clearly defined and needs to be further investigated. A transcranial magnetic stimulation (TMS) protocol, the short latency afferent inhibition (SAI), may give direct information about the function of some cholinergic pathways in the human motor cortex. We aimed to evaluate in the present study the relationship of SAI to the specific clinical subtypes of MCI. SAI was examined in 20 patients with amnestic MCI (10 SD, 10 MD), twenty patients with nonamnestic MCI (10 SD, 10 MD) and ten control subjects. Motor threshold, central motor conduction time, intracortical inhibition and facilitation to paired-TMS were also evaluated. Mean SAI was significantly reduced in amnestic MCI-MD patients when compared with the controls, while it was not significantly different in amnestic MCI-SD patients and in nonamnestic patients. SAI was increased after administration of a single dose of donepezil in a subgroup of four amnestic MCI-MD patients. The other TMS parameters did not differ significantly between the four MCI groups and the control group. We demonstrated that this putative marker of central cholinergic activity differs among MCI subtypes. The amnestic-MD type of MCI might be a phenotype of incipient AD. However, this hypothesis would be better addressed in a longitudinal study of individual patients. TMS studies may be useful in identifying MCI individuals in whom cholinergic degeneration is occurred and therefore at increased risk of conversion to AD.
TL;DR: Elevated BDNF expression in the dorsal horn was required to develop and maintain neuropathic pain, and minocycline could only prevent mechanical allodynia in the early stages, possibly by inhibiting BDNF release from microglia.
Abstract: Recent studies have suggested that activated glia in the spinal cord may play a vital role at different times during spinal nerve ligation (SNL)-induced neuropathic pain; therefore, glial activation inhibitors have been used as effective painkillers. Brain-derived neurotrophic factor (BDNF) is also known to be a powerful pain modulator, but it remains unclear how it contributes to the glial activation inhibitor-based treatment. This study revealed the following results: (1) intrathecal administration of minocycline (a microglial activation inhibitor) could prevent mechanical allodynia during the initiation of SNL-induced neuropathic pain, and its action was associated with the elimination of BDNF overexpression in the dorsal horn; (2) the spinal injection of fluorocitrate (an astrocytic activation inhibitor) but not minocycline could reverse mechanical allodynia during the maintenance phase of SNL-induced pain, and its action was also related to a decrease in BDNF overexpression in the dorsal horn; and (3) treatment with TrkB/Fc (a BDNF-sequestering protein) had a similar effect during both the early development and maintenance periods. These results led to the following conclusions: (1) elevated BDNF expression in the dorsal horn was required to develop and maintain neuropathic pain; (2) minocycline could only prevent mechanical allodynia in the early stages, possibly by inhibiting BDNF release from microglia; and (3) fluorocitrate could reverse existing mechanical allodynia, and its action was associated with the inhibition of BDNF upregulation induced by astrocytic activation.
TL;DR: It is added to the body of evidence that non-genetic biological and psychosocial risk factors have an impact on ADHD symptom severity and differentially influence comorbid disorders in ADHD.
Abstract: Attention-deficit/hyperactivity disorder (ADHD) is a genetically as well as environmentally determined disorder with a high rate of psychiatric comorbidity. In this study, non-genetic biological and psychosocial risk factors for ADHD symptom severity and comorbid disorders were assessed in 275 children with ADHD, aged 5–13 years, mean age 9.7 (SD 1.9). Pre-/perinatal biological and lifetime psychosocial risk factors as well as data on parental ADHD were obtained. A different pattern of risk factors emerged for inattentive and hyperactive-impulsive ADHD symptoms. Inattentive symptoms were strongly influenced by psychosocial risk factors, whereas for hyperactive-impulsive symptoms, predominantly biological risk factors emerged. Hyperactive-impulsive symptoms also were a strong risk factor for comorbid oppositional defiant (ODD) and conduct disorder (CD). Smoking during pregnancy was a risk factor for comorbid CD but not ODD and further differential risk factors were observed for ODD and CD. Comorbid anxiety disorder (AnxD) was not related to ADHD symptoms and additional biological and psychosocial risk factors were observed. This study adds to the body of evidence that non-genetic biological and psychosocial risk factors have an impact on ADHD symptom severity and differentially influence comorbid disorders in ADHD. The findings are relevant to the prevention and treatment of ADHD with or without comorbid disorders.
TL;DR: The CSF biomarkers may give insight into ALS pathophysiology and may be useful for early, presymptomatic diagnosis, therapeutic monitoring and the development of new therapeutic strategies.
Abstract: Amyotrophic lateral sclerosis (ALS, ‘Lou Gehrig disease’) is the most common, progressive, neurodegenerative, motor neuron disease, causing damage to upper and lower motor neurons, leading to paralysis and death within 3–5 years. Majority of ALS cases are sporadic ALS (SALS) and only 5–10 % of cases are familial ALS (FALS). Pathogenesis of ALS is complicated and still unclear, including genetic, glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, neurofilament accumulation, impaired trophic support, altered glial function, viral infection, immune imbalance and impairment of the blood–brain, blood–spinal cord and blood–cerebrospinal fluid barriers (BBB/BSCB/BCSFB). The CSF analysis is still one of the basic laboratory tools and might reflect pathophysiological alterations in the course of the disease and could provide an insight into disease pathomechanisms. The most important aim of its analysis is evaluation of blood-CSF barrier, which is altered in 46 % of ALS patients. The CSF biomarkers may give insight into ALS pathophysiology and may be useful for early, presymptomatic diagnosis, therapeutic monitoring and the development of new therapeutic strategies. This review summarizes the general concepts of biomarkers in CSF of ALS patients and their potential usefulness in further research.
TL;DR: Empiric treatment with at least oral magnesium is warranted in all migraine sufferers because both oral and intravenous magnesium are widely available, extremely safe, very inexpensive and for patients who are magnesium deficient can be highly effective.
Abstract: Magnesium, the second most abundant intracellular cation, is essential in many intracellular processes and appears to play an important role in migraine pathogenesis. Routine blood tests do not reflect true body magnesium stores since <2% is in the measurable, extracellular space, 67% is in the bone and 31% is located intracellularly. Lack of magnesium may promote cortical spreading depression, hyperaggregation of platelets, affect serotonin receptor function, and influence synthesis and release of a variety of neurotransmitters. Migraine sufferers may develop magnesium deficiency due to genetic inability to absorb magnesium, inherited renal magnesium wasting, excretion of excessive amounts of magnesium due to stress, low nutritional intake, and several other reasons. There is strong evidence that magnesium deficiency is much more prevalent in migraine sufferers than in healthy controls. Double-blind, placebo-controlled trials have produced mixed results, most likely because both magnesium deficient and non-deficient patients were included in these trials. This is akin to giving cyanocobalamine in a blinded fashion to a group of people with peripheral neuropathy without regard to their cyanocobalamine levels. Both oral and intravenous magnesium are widely available, extremely safe, very inexpensive and for patients who are magnesium deficient can be highly effective. Considering these features of magnesium, the fact that magnesium deficiency may be present in up to half of migraine patients, and that routine blood tests are not indicative of magnesium status, empiric treatment with at least oral magnesium is warranted in all migraine sufferers.
TL;DR: It is assumed that LCIG can provoke PNP most likely of malnutritional origin, and the assessment of predisposing factors before treatment as well as neurophysiological and laboratory screenings appear necessary.
Abstract: Levodopa/Carbidopa intestinal gel infusion (LCIG) for Parkinson's disease is under debate to provoke polyneuropathy (PNP). In our cohort of 20 thus treated patients, two developed debilitating axonal PNP with deficient pyridoxin and folate levels, and marginal cobalamin. Homocysteine was highly elevated. The neuropathies responded to vitamin replacement. We assume that LCIG can provoke PNP most likely of malnutritional origin. To avoid this side effect, the assessment of predisposing factors before treatment as well as neurophysiological and laboratory screenings appear necessary.
TL;DR: Recent data on plasma β-amyloid (Aβ) is discussed and the issues that have arisen in establishing it as a reliable biomarker of AD are examined, to improve clinical trial design and analysis.
Abstract: Alzheimer’s disease (AD) affects more than twenty-five million people worldwide and is the most common form of dementia. Symptomatic treatments have been developed, but effective intervention to alter disease progression is needed. Targets have been identified for disease-modifying drugs, but the results of clinical trials have been disappointing. Peripheral biomarkers of disease state may improve clinical trial design and analysis, increasing the likelihood of successful drug development. Amyloid-related measures, presumably reflecting principal pathology of AD, are among the leading cerebrospinal fluid and neuroimaging biomarkers, and measurement of plasma levels of amyloid peptides has been the focus of much investigation. In this review, we discuss recent data on plasma β-amyloid (Aβ) and examine the issues that have arisen in establishing it as a reliable biomarker of AD.
TL;DR: Depression and cognitive disturbances were the determinants of patient’s QoL, while motor disturbances and depression were the predictors of the caregiver burden.
Abstract: The aim of this study was to identify determinants of functional disability, patient’s quality of life (QoL) and caregivers’ burden in Huntington’s disease (HD). Eighty HD patients participated in the study. Motor and behavioral disturbances as well as cognitive impairment were assessed using motor, behavioral and cognitive parts of the Unified Huntington Disease Rating Scale (UHDRS); Hamilton Depression Rating Scale was used to assess depression. Disability, health-related QoL and the impact of the disease on the caregivers were assessed using the following methods: UHDRS Functional Assessment Score, SF-36 Scale and Caregiver Burden Inventory. Multiple regression analysis showed that motor disturbances, cognitive impairment, apathy and disease duration were the independent predictors of disability. Depression and cognitive disturbances were the determinants of patient’s QoL, while motor disturbances and depression were the predictors of the caregiver burden. Patient’s disability and QoL as well as caregivers’ burden should be taken into consideration while planning treatment strategy and the results of the present study show that the predictors of those treatment targets are different.
TL;DR: The results suggest that the deficits of the ADHDtotal group are attributable to ADHD rather than to comorbidity, as there was a trend of a poorer performance on some of the outcome measures.
Abstract: Compared to the high number of studies that investigated executive functions (EF) in children with attention-deficit/hyperactivity disorder (ADHD), a little is known about the EF performance of adults with ADHD. This study compared 37 adults with ADHD (ADHDtotal) and 32 control participants who were equivalent in age, intelligence quotient (IQ), sex, and years of education, in two domains of EF—set shifting and working memory. Additionally, the ADHDtotal group was subdivided into two subgroups: ADHD patients without comorbidity (ADHD−, n = 19) and patients with at least one comorbid disorder (ADHD+, n = 18). Participants fulfilled two measures for set shifting (i.e., the trail making test, TMT and a computerized card sorting test, CKV) and one measure for working memory (i.e., digit span test, DS). Compared to the control group the ADHDtotal group displayed deficits in set shifting and working memory. The differences between the groups were of medium-to-large effect size (TMT: d = 0.48; DS: d = 0.51; CKV: d = 0.74). The subgroup comparison of the ADHD+ group and the ADHD− group revealed a poorer performance in general information processing speed for the ADHD+ group. With regard to set shifting and working memory, no significant differences could be found between the two subgroups. These results suggest that the deficits of the ADHDtotal group are attributable to ADHD rather than to comorbidity. An influence of comorbidity, however, could not be completely ruled out as there was a trend of a poorer performance in the ADHD+ group on some of the outcome measures.
TL;DR: Findings provide further support for the role for the KP, particularly IDO, in anhedonia in adolescent MDD, and emphasize the importance of dimensional approaches in the investigation of psychiatric disorders.
Abstract: To address the heterogeneous nature of adolescent major depression (MDD), we investigated anhedonia, a core symptom of MDD. We recently reported activation of the kynurenine pathway (KP), a central neuroimmunological pathway which metabolizes tryptophan (TRP) into kynurenine (KYN) en route to several neurotoxins, in a group of highly anhedonic MDD adolescents. In this study, we aimed to extend our prior work and examine the relationship between KP activity and anhedonia, measured quantitatively, in a group of MDD adolescents and in a combined group of MDD and healthy control adolescents. Thirty-six adolescents with MDD (22 medication-free) and 20 controls were included in the analysis. Anhedonia scores were generated based on clinician- and subject-rated assessments and a semi-structured clinician interview. Blood KP metabolites, collected in the AM after an overnight fast, were measured using high-performance liquid chromatography. The rate-limiting enzyme of the KP, indoleamine 2,3-dioxygenase (IDO), was estimated by the ratio of KYN/TRP. Pearson correlation tests were used to assess correlations between anhedonia scores and KP measures while controlling for MDD severity. IDO activity and anhedonia scores were positively correlated in the group psychotropic medication-free adolescents with MDD (r = 0.42, P = 0.05) and in a combined group of MDD subjects and healthy controls (including medicated patients: r = 0.30, P = 0.02; excluding medicated patients: r = 0.44, P = 0.004). In conclusions, our findings provide further support for the role for the KP, particularly IDO, in anhedonia in adolescent MDD. These results emphasize the importance of dimensional approaches in the investigation of psychiatric disorders.