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Journal Cover Journal of Neural Transmission
  [SJR: 1.034]   [H-I: 86]   [2 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0300-9564 - ISSN (Online) 1435-1463
   Published by Springer-Verlag Homepage  [2355 journals]
  • Risky decision-making and affective features of impulse control disorders
           in Parkinson’s disease
    • Authors: Alice Martini; Simon J. Ellis; James A. Grange; Stefano Tamburin; Denise Dal Lago; Greta Vianello; Nicola M. J. Edelstyn
      Pages: 131 - 143
      Abstract: Impulse control disorders (ICDs) in Parkinson’s disease (PD) are considered dopaminergic treatment side effects. Cognitive and affective factors may increase the risk of ICD in PD. The aim is to investigate risky decision-making and associated cognitive processes in PD patients with ICDs within a four-stage conceptual framework. Relationship between ICDs and affective factors was explored. Thirteen PD patients with ICD (ICD+), 12 PD patients without ICD (ICD−), and 17 healthy controls were recruited. Overall risky decision-making and negative feedback effect were examined with the Balloon Analogue Risk Task (BART). A cognitive battery dissected decision-making processes according to the four-stage conceptual framework. Affective and motivational factors were measured. ANOVA showed no effect of group on overall risky decision-making. However, there was a group × feedback interaction [F (2, 39) = 3.31, p = 0.047]. ICD+, unlike ICD− and healthy controls, failed to reduce risky behaviour following negative feedback. A main effect of group was found for anxiety and depression [F(2, 38) = 8.31, p = 0.001], with higher symptoms in ICD+ vs. healthy controls. Groups did not differ in cognitive outcomes or affective and motivational metrics. ICD+ may show relatively preserved cognitive function, but reduced sensitivity to negative feedback during risky decision-making and higher symptoms of depression and anxiety.
      PubDate: 2018-02-01
      DOI: 10.1007/s00702-017-1807-7
      Issue No: Vol. 125, No. 2 (2018)
       
  • Self-perception and determinants of color vision in Parkinson’s
           disease
    • Authors: Alexander U. Brandt; Hanna G. Zimmermann; Timm Oberwahrenbrock; Justine Isensee; Thomas Müller; Friedemann Paul
      Pages: 145 - 152
      Abstract: Visual dysfunction is common in patients with Parkinson’s disease (PD). The objective of this study was to investigate the perceived impact of visual dysfunction and especially color vision loss on PD patients, and to identify retinal and disease factors associated with color vision. Thirty PD patients and thirty-four healthy controls were included. Participants performed the Farnsworth–Munsell Hue-100 test (FMT). Patients answered the National Eye Institute Visual Function Questionnaire (NEI-VFQ), Unified Parkinson’s Disease Rating Scale (UPDRS) assessment, and underwent optical coherence tomography with measurement of retinal nerve fiber layer, ganglion cell layer + inner plexiform layer (GCIPL), and outer nuclear and photoreceptor layer. Dopaminergic treatment was assessed as levodopa equivalent dose (LED). Vision domains significantly worse in PD patients compared to normative data were General Vision, Near Activities, Distance Activities, Vision-Specific Dependency, Driving, and Peripheral Vision. Worse NEI-VFQ total scores were associated with worse UPDRS, higher LED, and higher age, but not with FMT, visual acuity, or OCT measures. Only two patients (7%) reported problems with color vision. In contrast, patients performed significantly worse in the FMT than healthy controls and 17 (56.7%) patients were outside the 95th percentile of normative data. In multiple regression analyses, lower LED and higher age were associated with worse color vision in the FMT. PD patients are not aware of color vision deficits. Given the impact of color vision loss on everyday tasks in other conditions, future research should investigate the impact of vision deficits on disease burden in PD.
      PubDate: 2018-02-01
      DOI: 10.1007/s00702-017-1812-x
      Issue No: Vol. 125, No. 2 (2018)
       
  • Evaluation of autonomic functions of patients with multiple system atrophy
           and Parkinson’s disease by head-up tilt test
    • Authors: Chikako Watano; Yuri Shiota; Keiichi Onoda; Abdullah Md Sheikh; Seiji Mishima; Eri Nitta; Shozo Yano; Shuhei Yamaguchi; Atsushi Nagai
      Pages: 153 - 162
      Abstract: The aim of this study was to evaluate the autonomic neural function in Parkinson’s disease (PD) and multiple system atrophy (MSA) with head-up tilt test and spectral analysis of cardiovascular parameters. This study included 15 patients with MSA, 15 patients with PD, and 29 healthy control (HC) subjects. High frequency power of the RR interval (RR-HF), the ratio of low frequency power of RR interval to RR-HF (RR-LF/HF) and LF power of systolic BP were used to evaluate parasympathetic, cardiac sympathetic and vasomotor sympathetic functions, respectively. Both patients with PD and MSA showed orthostatic hypotension and lower parasympathetic function (RR-HF) at tilt position as compared to HC subjects. Cardiac sympathetic function (RR-LF/HF) was significantly high in patients with PD than MSA at supine position. RR-LF/HF tended to increase in MSA and HC, but decreased in PD by tilting. Consequently, the change of the ratio due to tilting (ΔRR-LF/HF) was significantly lower in patients with PD than in HC subjects. Further analysis showed that compared to mild stage of PD, RR-LF/HF at the supine position was significantly higher in advanced stage. By tilting, it was increased in mild stage and decreased in the advanced stage of PD, causing ΔRR-LF/HF to decrease significantly in the advanced stage. Thus, we demonstrated that spectral analysis of cardiovascular parameters is useful to identify sympathetic and parasympathetic disorders in MSA and PD. High cardiac sympathetic function at the supine position, and its reduction by tilting might be a characteristic feature of PD, especially in the advanced stage.
      PubDate: 2018-02-01
      DOI: 10.1007/s00702-017-1816-6
      Issue No: Vol. 125, No. 2 (2018)
       
  • High-definition transcranial direct current stimulation of the
           dorsolateral prefrontal cortex for tinnitus modulation: a preliminary
           trial
    • Authors: Giriraj Singh Shekhawat; Sven Vanneste
      Pages: 163 - 171
      Abstract: Tinnitus is the perception of sound in the absence of its external source. Non-invasive neuromodulation techniques have been used in the past decade to investigate the impact of stimulation on tinnitus perception. The objective is to invest the impact of high-definition transcranial direct current stimulation (HD-tDCS) of dorsolateral prefrontal cortex (DLPFC) stimulation on tinnitus loudness and annoyance. Thirteen participants underwent two sessions of HD-tDCS (real and sham) in a double blind, sham controlled, randomized trial. The washout period between the real and sham stimulation session was 1 week. Tinnitus loudness and annoyance was measured using a ten-point tinnitus loudness/annoyance numeric rating scale at the baseline, after 5, 10, 15 and 20 min of stimulation. There was a significant reduction in the tinnitus loudness after the HD-tDCS of DLPFC. A comparison of the different time points (5, 10, 15 and 20 min) with the baseline measurement for tinnitus loudness showed a statistically significant reduction after 15 min (t = 1.82, p = 0.047) and 20 min (t = 1.82, p = 0.047) of stimulation using the real HD-tDCS; this effect was not observed for tinnitus annoyance. HD-tDCS of DLPFC is a safe technique for tinnitus modulation. The most common transient sensations experienced during HD-tDCS were tingling, sleepiness and scalp pain. HD-tDCS of DLPFC resulted in transient tinnitus loudness suppression after 15 min of stimulation. We propose the optimum stimulation duration for HD-tDCS of DLPFC for tinnitus suppression to be 15 min instead of 20 min.
      PubDate: 2018-02-01
      DOI: 10.1007/s00702-017-1808-6
      Issue No: Vol. 125, No. 2 (2018)
       
  • Botulinum toxin therapy in patients with oral anticoagulation: is it
           safe'
    • Authors: Christoph Schrader; Markus Ebke; Fereshte Adib Saberi; Dirk Dressler
      Pages: 173 - 176
      Abstract: When used therapeutically, botulinum toxin (BT) has to be injected into its target tissues. All manufacturers warn not to do so in patients with oral anticoagulation to avoid haematoma. We wanted to study the haematoma frequency (HF) in patients with anticoagulation receiving BT therapy. 32 patients (16 females, 16 males, age 69.3 ± 10.0 years) with blepharospasm (n = 6), hemifacial spasm (n = 8), post-stroke spasticity (n = 16), and cervical dystonia (n = 2) received BT therapy (needle size 27G, post-injection tissue compression) whilst on anticoagulation (anticoagulation group, AG). 32 patients matched for disease, target muscles, age, and gender received identical BT therapy without anticoagulation (control group, CG). Anticoagulation was performed with phenprocoumon. International normalised ratio (INR) at the time of BT injection was in all patients within the recommended margins of 2.0 and 3.0 (mean 2.6 ± 0.27). Overall HF was 3.0% in AG and 1.8% in CG (not significant). All hematomas occurred in blepharospasm patients (AG 5.2%, CG 2.6%, not significant) and hemifacial spasm patients (AG 3.9%, CG 2.9%, not significant). In cervical dystonia and spasticity there were no haematomas. Throughout an observation period of 4 years, none of the haematomas was surgically relevant. Haematomas are a rare complication of BT therapy, mainly occurring in periocular injections. Anticoagulation only marginally increases HF, provided INR is controlled and appropriate injection techniques are used. Surgically relevant haematomas do not occur. Interruption of oral anticoagulation to perform BT therapy is not justified.
      PubDate: 2018-02-01
      DOI: 10.1007/s00702-017-1809-5
      Issue No: Vol. 125, No. 2 (2018)
       
  • Amyloid β oligomers (AβOs) in Alzheimer’s disease
    • Authors: Barbara Mroczko; Magdalena Groblewska; Ala Litman-Zawadzka; Johannes Kornhuber; Piotr Lewczuk
      Pages: 177 - 191
      Abstract: The causative role of amyloid β 1–42 (Aβ42) aggregation in the pathogenesis of Alzheimer’s disease (AD) has been under debate for over 25 years. Primarily, scientific efforts have focused on the dyshomeostasis between production and clearance of Aβ42. This imbalance may result from mutations either in genes for the substrate, i.e., amyloid precursor protein or in genes encoding presenilin, the enzyme of the reaction that generates Aβ42. Currently, it is supposed that soluble oligomers of amyloid beta (AβOs) and not fibrillar Aβ42 within neuritic plaques may be the toxic factors acting on a very early stage of AD, perhaps even initiating pathological cascade. For example, soluble AβOs isolated from AD patients’ brains reduced number of synapses, inhibited long-term potentiation, and enhanced long-term synaptic depression in brain regions responsible for memory in animal models of AD. Concentrations of AβOs in the cerebrospinal fluid (CSF) of AD patients are often reported higher than in non-demented controls, and show a negative correlation with mini-mental state examination scores. Furthermore, increased Aβ42/oligomer ratio in the CSF of AD/MCI patients indicated that the presence of soluble AβOs in CSF may be linked to lowering of natively measured monomeric Aβ42 by epitopes masking, and hence, concentrations of AβOs in the CSF are postulated to as useful AD biomarkers.
      PubDate: 2018-02-01
      DOI: 10.1007/s00702-017-1820-x
      Issue No: Vol. 125, No. 2 (2018)
       
  • Fluid biomarker agreement and interrelation in dementia due to
           Alzheimer’s disease
    • Authors: Panagiotis Alexopoulos; For the Alzheimer’s Disease Neuroimaging Initiative; Jennifer Roesler; Lukas Werle; Nathalie Thierjung; Iliana Lentzari; Marion Ortner; Timo Grimmer; Nikolaos Laskaris; Antonios Politis; Philippos Gourzis; Alexander Kurz; Robert Perneczky
      Pages: 193 - 201
      Abstract: The cerebrospinal fluid (CSF) levels of β-amyloid 42, total tau, and phosphorylated tau 181 are supposed to be all continuously abnormal in dementia due to Alzheimer’s disease (AD), being the most advanced disease stage. The aim of the present study, which included a monocentric and a multicentric sample (N = 119 and 178, respectively), was to investigate the degree of CSF biomarker agreement and interrelation in AD dementia. Based on previously published cut-off values, biomarker values were categorized as positive or negative for AD (dichotomization strategy) and as either positive, negative, or borderline (trichotomization strategy). The statistical analyses relied on distance correlation analysis and kappa (k) statistics. Poor agreement (k < 0.4) and low interrelations between the studied biomarkers were detected in all cases with the exception of the interrelation between the markers total tau and phosphorylated tau 181, especially in the monocentric sample. Interestingly, lower interrelation and agreement degrees were observed in carriers of the Apolipoprotein E ε4 allele compared to non-carriers. The clinical phenotype currently referred to as “AD dementia” is characterized by an inhomogeneous CSF biomarker profile, possibly mirroring the complex genesis of AD-typical dementia symptoms and pointing to the necessity of shedding more light on the hypothesis of biomarker stability over time in symptomatic AD.
      PubDate: 2018-02-01
      DOI: 10.1007/s00702-017-1810-z
      Issue No: Vol. 125, No. 2 (2018)
       
  • An unexpected improvement in spatial learning and memory ability in
           alpha-synuclein A53T transgenic mice
    • Authors: Qi Liu; YuYu Xu; WenPing Wan; ZeGang Ma
      Pages: 203 - 210
      Abstract: Growing evidence suggests, as Parkinson’s disease (PD) progresses, that its non-motor symptoms appear prior to or in parallel with its motor deficits. Alpha-synuclein A53T transgenic mouse (A53T) is an essential tool to investigate the onsets and the extents of PD non-motor symptoms. Our aim is to investigate spatial learning and memory ability in A53T mice. In our rotarod tests, no motor coordination impairments were detected in mice of 3, 6, 9, and 12 months old. We then investigated their spatial learning and memory ability through Morris water maze in 3- and 9-month-old mice. No significant difference in escape latency was detected among the A53T mice and the control mice. However, an unexpected improvement in spatial learning and memory ability was observed in the probe session among the A53T mice. Reversal learning by Morris water maze also indicated that 3- and 9-month-old A53T mice exhibited a better cognitive flexibility compared to their littermate controls. Further studies by western blots showed that alpha-synuclein expressions in hippocampus of the A53T mice were noticeably up-regulated. The immunofluorescence staining of 5-bromo-2-deoxyuridine (Brdu) and doublecortin (DCX) demonstrated that neither the Brdu-positive neurons nor the Brdu/DCX positive neurons in hippocampus were significantly altered between the two groups. These results suggest that our A53T mice exhibit improved spatial learning and memory ability prior to their motor coordination deficits. These results are not induced by neurogenesis in the hippocampus.
      PubDate: 2018-02-01
      DOI: 10.1007/s00702-017-1819-3
      Issue No: Vol. 125, No. 2 (2018)
       
  • Issues on the diagnosis and etiopathogenesis of mood disorders:
           reconsidering DSM-5
    • Authors: Kazuyoshi Ogasawara; Yukako Nakamura; Hiroyuki Kimura; Branko Aleksic; Norio Ozaki
      Pages: 211 - 222
      Abstract: The authors present a narrative review from the diagnostic and nosologic viewpoints of mood disorders (bipolar and depressive ones) by revisiting the revision from the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders, Text Revision to DSM-5, including the following: the separation of the bipolar and depressive sections; the addition of increased energy and continuation of symptoms to the hypo/manic criteria; the elimination of mixed episodes; the creation of new categories and specifiers (“other specified bipolar and related disorder”, “disruptive mood dysregulation disorder”, “with anxious distress”, “with mixed features”, “with peripartum onset”); the categorization of hypo/manic episodes during antidepressant treatment into bipolar disorder; the elimination of the “bereavement exclusion”; the ambiguous separation between bipolar I and II; the insufficient distinction between “other specified bipolar and related disorders” and major depressive disorder; the differentiation regarding borderline personality disorder; agitation; premenstrual dysphoric disorder; and society and psychiatry. Through this analysis, we point out both the achievements and limitations of DSM-5. In addition, to examine the future direction of psychiatry, we introduce our cohort study regarding maternal depression and an outline of the National Institute of Mental Health’s Research Domain Criteria project in the US. Finally, we advocate the importance of elucidating etiopathogeneses by starting from or going beyond the DSM operational diagnostic system, which has shown great efficacy.
      PubDate: 2018-02-01
      DOI: 10.1007/s00702-017-1828-2
      Issue No: Vol. 125, No. 2 (2018)
       
  • Trace lithium and mental health
    • Authors: Nobuyoshi Ishii; Takeshi Terao
      Pages: 223 - 227
      Abstract: Lithium therapy is generally accepted as a first-line treatment for bipolar disorder, and it is also identified as one of the best augmenting options for treatment-resistant depression. Furthermore, lithium has been investigated in association with suicide, dementia and aggressiveness. In this review, we examined articles about the effects of very small amounts of lithium in treating suicide, dementia, bipolar disorder and temperament, to assess the present state of trace lithium’s effect on mental state. The results indicate that trace lithium may be effective for suicide prevention but randomized, placebo-controlled trials are required to draw a definite conclusion. Indications for using trace lithium in treating such conditions as dementia, bipolar disorder and temperament are supported by very limited evidence and such effects are yet to be determined.
      PubDate: 2018-02-01
      DOI: 10.1007/s00702-017-1824-6
      Issue No: Vol. 125, No. 2 (2018)
       
  • Low left amygdala volume is associated with a longer duration of unipolar
           depression
    • Authors: Maxim Zavorotnyy; Rebecca Zöllner; L. R. Schulte-Güstenberg; L. Wulff; S. Schöning; U. Dannlowski; H. Kugel; V. Arolt; C. Konrad
      Pages: 229 - 238
      Abstract: The amygdala plays a crucial role in the pathogenesis of major depressive disorder (MDD). While robust findings support a negative impact of illness duration on hippocampal volume in MDD, morphometric studies of the amygdala have yielded inhomogeneous results. Considering the methodical problems of automatic segmentation methods, a standardized segmentation protocol with proven inter- and intra-rater reliability was employed using high-resolution magnetic resonance imaging. To identify the effect of MDD on amygdala morphometry, 23 unipolar depressed patients who responded to antidepressant medication and 30 age-matched healthy controls (HC) were enrolled. First, gray matter volumes (GMV) of the bilateral amygdala were delineated manually in 3D by three blinded experts using the MultiTracer. The whole brain GMV was determined by using voxel-based morphometry. Second, the differences of the whole brain and the bilateral amygdala GMV values between MDD and HC were calculated with t-statistics. The GMV of the whole brain and the amygdala did not differ between HC and MDD patients. Third, MDD characteristics were correlated with amygdala GMV. Within the normal range, the left amygdala GMV was larger in patients with later onset and smaller in cases of prolonged depression. In line with prior reports of depressed patients responding to antidepressant treatment, amygdala GMV was negatively related to illness duration, suggesting volume loss with disease progression. It remains unclear as to whether the association between illness duration and GMV reduced left amygdala volume indicates a neurotoxic effect of prolonged MDD or is rather a negative predictor of chronic depression.
      PubDate: 2018-02-01
      DOI: 10.1007/s00702-017-1811-y
      Issue No: Vol. 125, No. 2 (2018)
       
  • Cross-national gender variations of digit ratio (2D:4D) correlate with
           life expectancy, suicide rate, and other causes of death
    • Authors: Bernd Lenz; Johannes Kornhuber
      Pages: 239 - 246
      Abstract: The second-to-fourth finger length ratio (2D:4D) is an indication of prenatal sex hormone exposure, and has sex-specifically been associated with several lethal illnesses including ischemic heart disease, diverse cancers, and suicide. Our primary aim was to verify that 2D:4D sex-specifically relates to life expectancy and suicide numbers on a national level (23 countries). We also used a hypothesis-free approach to investigate associations with other causes of death [p value adjustment for multiple hypothesis testing using the false discovery rate procedure (FDR)]. All parameters were normalized to the national mean (of males and females) and analyzed across nations. Normalized male 2D:4D correlated positively with normalized male life expectancy (at birth, r = 0.46, p = 0.029; at the age of 60, r = 0.44, p = 0.038) and negatively with normalized male suicide rates (r = − 0.49, p = 0.017). In the exploratory analyses, the normalized male 2D:4D values were negatively associated with the normalized male deaths rates from communicable, maternal, perinatal, and nutritional conditions [r = − 0.65, p(FDR) = 0.011], respiratory infections [r = − 0.69, p(FDR) = 0.008], asthma [r = − 0.65, p(FDR) = 0.011], neurological conditions [r = − 0.56, p(FDR) = 0.046], and Alzheimer’s disease and other dementias [r = − 0.59, p(FDR) = 0.036]. The normalized female parameters showed the same cross-national correlations. In line with the previous individual level findings, the results suggest that prenatal sex hormone effects are sex-specifically involved in suicide and neurological conditions. Moreover, we provide novel national level evidence that prenatal sex hormone priming may sex-specifically influence life expectancy and death risk from respiratory diseases.
      PubDate: 2018-02-01
      DOI: 10.1007/s00702-017-1815-7
      Issue No: Vol. 125, No. 2 (2018)
       
  • A randomized, double-blind, placebo-controlled, proof-of-concept trial of
           creatine monohydrate as adjunctive treatment for bipolar depression
    • Authors: Ricardo Alexandre Toniolo; Michelle Silva; Francy de Brito Ferreira Fernandes; José Antonio de Mello Siqueira Amaral; Rodrigo da Silva Dias; Beny Lafer
      Pages: 247 - 257
      Abstract: Depressive episodes are a major cause of morbidity and dysfunction in individuals suffering from bipolar disorder. Currently available treatments for this condition have limited efficacy and new therapeutic options are needed. Extensive research in the pathophysiology of bipolar disorder points to the existence of mitochondrial and bioenergetic dysfunction. We hypothesized that creatine monohydrate, a nutraceutical that works as a mitochondrial modulator, would be effective as an adjunctive therapy for bipolar depression. We conducted a double-blind trial in which 35 patients with bipolar disorder type I or II in a depressive episode by DSM-IV criteria and in use of regular medication for the treatment of this phase of the disease were randomly allocated into two adjunctive treatment groups for 6 weeks: creatine monohydrate 6 g daily (N = 17) or placebo (N = 18). Primary efficacy was assessed by the change in the Montgomery–Åsberg Depression Rating Scale (MADRS). We did not find a statistically significant difference in the comparison between groups for the change in score on the MADRS after 6 weeks in an intention-to-treat (ITT) analysis (p = 0.560; Cohen’s d = 0.231). However, we found significant superiority of creatine add-on vs. placebo when we considered the remission criterion of a MADRS score ≤ 12 at week 6 analyzing the outcome of the 35 randomized patients on ITT (52.9% remission in the creatine group vs. 11.1% remission in the placebo group) and of the 23 completers (66.7% remission in the creatine group vs. 18.2% remission in the placebo group) (p = 0.012; OR = 9.0 and p = 0.036; OR = 9.0, respectively). Two patients who received creatine switched to hypomania/mania early in the trial. No clinically relevant physical side-effects were reported or observed. This proof-of-concept study, aiming to restore brain bioenergetics using an adjunctive mitochondrial modulator, is not conclusive on the efficacy of creatine add-on for bipolar depression, but suggests that this compound may have a role in the adjunctive treatment of this phase of the illness. Further investigation through randomized controlled trials with larger samples should be conducted to verify the efficacy of creatine supplementation for bipolar depression and also for subsyndromal depressive symptoms.
      PubDate: 2018-02-01
      DOI: 10.1007/s00702-017-1817-5
      Issue No: Vol. 125, No. 2 (2018)
       
  • Common functional variants of the glutamatergic system in Autism spectrum
           disorder with high and low intellectual abilities
    • Authors: Andreas G. Chiocchetti; Afsheen Yousaf; Hannah S. Bour; Denise Haslinger; Regina Waltes; Eftichia Duketis; Tomas Jarczok; Michael Sachse; Monica Biscaldi; Franziska Degenhardt; Stefan Herms; Sven Cichon; Jörg Ackermann; Ina Koch; Sabine M. Klauck; Christine M. Freitag
      Pages: 259 - 271
      Abstract: The genetic architecture underlying Autism spectrum disorder (ASD) has been suggested to differ between individuals with lower (IQ ≤ 70; LIQ) and higher intellectual abilities (IQ > 70; HIQ). Among the identified pathomechanisms, the glutamatergic signalling pathway is of specific interest in ASD. We investigated 187 common functional variants of this neurotransmitter system for association with ASD and with symptom severity in two independent samples, a German (German-ALL: N = 583 families) and the Autism Genome Project cohort (AGP-ALL: N = 2001 families), split into HIQ, and LIQ subgroups. We did not identify any association withstanding correction for multiple testing. However, we report a replicated nominal significant under-transmission (OR < 0.79, p < 0.04) of the AKAP13 rs745191-T allele in both LIQ cohorts, but not in the much larger HIQ cohorts. At the phenotypic level, we nominally replicated associations of CAMK2A-rs2241694 with non-verbal communication in both combined LIQ and HIQ ASD cohorts. Variants PLD1-rs2124147 and ADCY1-rs2461127 were nominally associated with impaired non-verbal abilities and AKAP2-rs3739456 with repetitive behaviour in both LIQ cohorts. All four LIQ-associated genes are involved in G-protein coupled signal transduction, a downstream pathway of metabotropic glutamate receptor activation. We conclude that functional common variants of glutamatergic genes do not have a strong impact on ASD, but seem to moderately affect ASD risk and phenotypic expression. Since most of our nominally replicated hits were identified in the LIQ cohort, further investigation of the glutamatergic system in this subpopulation might be warranted.
      PubDate: 2018-02-01
      DOI: 10.1007/s00702-017-1813-9
      Issue No: Vol. 125, No. 2 (2018)
       
  • Correction to: Evidence-based treatment of neurogenic orthostatic
           hypotension and related symptoms
    • Authors: Sabine Eschlböck; Gregor Wenning; Alessandra Fanciulli
      Pages: 273 - 274
      Abstract: Unfortunately, Author has now noticed two mistakes in Fig. 1. Author has written “peripher” instead of “peripheral” and “Secundary” instead of “Secondary”.
      PubDate: 2018-02-01
      DOI: 10.1007/s00702-017-1814-8
      Issue No: Vol. 125, No. 2 (2018)
       
  • Pharmacological aspects of the neuroprotective effects of irreversible
           MAO-B inhibitors, selegiline and rasagiline, in Parkinson’s disease
    • Authors: Éva Szökő; Tamás Tábi; Peter Riederer; László Vécsei; Kálmán Magyar
      Abstract: The era of MAO-B inhibitors dates back more than 50 years. It began with Kálmán Magyar’s outstanding discovery of the selective inhibitor, selegiline. This compound is still regarded as the gold standard of MAO-B inhibition, although newer drugs have also been introduced to the field. It was revealed early on that selective, even irreversible inhibition of MAO-B is free from the severe side effect of the non-selective MAO inhibitors, the potentiation of tyramine, resulting in the so-called ‘cheese effect’. Since MAO-B is involved mainly in the degradation of dopamine, the inhibitors lack any antidepressant effect; however, they became first-line medications for the therapy of Parkinson’s disease based on their dopamine-sparing activity. Extensive studies with selegiline indicated its complex pharmacological activity profile with MAO-B-independent mechanisms involved. Some of these beneficial effects, such as neuroprotective and antiapoptotic properties, were connected to its propargylamine structure. The second MAO-B inhibitor approved for the treatment of Parkinson’s disease, rasagiline also possesses this structural element and shows similar pharmacological characteristics. The preclinical studies performed with selegiline and rasagiline are summarized in this review.
      PubDate: 2018-02-07
      DOI: 10.1007/s00702-018-1853-9
       
  • Dopamine receptors: homomeric and heteromeric complexes in l -DOPA-induced
           dyskinesia
    • Authors: Oscar Solís; Rosario Moratalla
      Abstract: The current standard treatment for Parkinson disease focuses on restoring striatal dopamine levels using l-3,4-dihydroxyphenylalanine (l-DOPA). However, disease progression and chronic treatment are associated with motor side effects such as l-DOPA-induced dyskinesia (LID). Dopamine receptor function is strongly associated with the mechanisms underlying LID. In fact, increased D1R signaling is associated with this motor side effect. Compelling evidence demonstrates that dopamine receptors in the striatum can form heteromeric complexes, and heteromerization can lead to changes in the functional and pharmacological properties of receptors compared to their monomeric subtypes. Currently, the most promising strategy for therapeutic intervention in dyskinesia originates from investigations of the D1R–D3R heteromers. Interestingly, there is a correlation between the expression of D1R–D3R heteromers and the development of LID. Moreover, D3R stimulation can potentiate the D1R signaling pathway. The aim of this review is to summarize current knowledge of the distinct roles of heteromeric dopaminergic receptor complexes in LID.
      PubDate: 2018-02-07
      DOI: 10.1007/s00702-018-1852-x
       
  • Neuropathology and biochemistry of early onset familial Alzheimer’s
           disease caused by presenilin-1 missense mutation Thr116Asn
    • Authors: Stanislav Sutovsky; Tomas Smolek; Peter Turcani; Robert Petrovic; Petra Brandoburova; Santosh Jadhav; Petr Novak; Johannes Attems; Norbert Zilka
      Abstract: The majority (~ 55%) of early onset familial Alzheimer disease (FAD) is caused by mutations in the presenilin 1 gene (PSEN1). Here, we describe a family with early onset FAD with a missense mutation in the PSEN1 gene (Thr116Asn). Five family members developed dementia in the third decade of life. One subject underwent autopsy. The onset of clinical symptoms was at the age of 37 years and the disease progressed rapidly. The clinical picture was characterised by progressive memory impairment, amnestic aphasia, and gait disturbances. Neuropathological assessment revealed widespread β-amyloid (Thal phase 5) and tau (Braak stage 6) pathology. Abundant deposition of diffuse and cored plaques was distributed in cortical and subcortical areas, as well as in the cerebellum, while cotton wool plaques were observed mainly in the occipital cortex. Cerebral amyloid angiopathy was present throughout the brain. In the neocortex, tau pathology, especially neuropil threads, was more abundant in the frontal and occipital cortex and in the hippocampus. Proteomic analyses revealed that the pattern of sarkosyl-insoluble tau was similar to the one seen in sporadic AD. No α-synuclein or TDP-43 pathology was found either in cortical nor in subcortical areas. Here, we present the first comprehensive neuropathological and biochemical study of early onset FAD with a missense mutation Thr116Asn in the presenilin 1 gene. In contrast to other PS1-linked AD patients, the present subject developed cotton wool plaques which were not associated with spastic paraparesis.
      PubDate: 2018-02-05
      DOI: 10.1007/s00702-018-1850-z
       
  • Signal transduction in l -DOPA-induced dyskinesia: from receptor
           sensitization to abnormal gene expression
    • Authors: Giada Spigolon; Gilberto Fisone
      Abstract: A large number of signaling abnormalities have been implicated in the emergence and expression of l-DOPA-induced dyskinesia (LID). The primary cause for many of these changes is the development of sensitization at dopamine receptors located on striatal projection neurons (SPN). This initial priming, which is particularly evident at the level of dopamine D1 receptors (D1R), can be viewed as a homeostatic response to dopamine depletion and is further exacerbated by chronic administration of l-DOPA, through a variety of mechanisms affecting various components of the G-protein-coupled receptor machinery. Sensitization of dopamine receptors in combination with pulsatile administration of l-DOPA leads to intermittent and coordinated hyperactivation of signal transduction cascades, ultimately resulting in long-term modifications of gene expression and protein synthesis. A detailed mapping of these pathological changes and of their involvement in LID has been produced during the last decade. According to this emerging picture, activation of sensitized D1R results in the stimulation of cAMP-dependent protein kinase and of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa. This, in turn, activates the extracellular signal-regulated kinases 1 and 2 (ERK), leading to chromatin remodeling and aberrant gene transcription. Dysregulated ERK results also in the stimulation of the mammalian target of rapamycin complex 1, which promotes protein synthesis. Enhanced levels of multiple effector targets, including several transcription factors have been implicated in LID and associated changes in synaptic plasticity and morphology. This article provides an overview of the intracellular modifications occurring in SPN and associated with LID.
      PubDate: 2018-02-02
      DOI: 10.1007/s00702-018-1847-7
       
  • Role of adenosine A 2A receptors in motor control: relevance to
           Parkinson’s disease and dyskinesia
    • Authors: Annalisa Pinna; Marcello Serra; Micaela Morelli; Nicola Simola
      Abstract: Adenosine is an endogenous purine nucleoside that regulates several physiological functions, at the central and peripheral levels. Besides, adenosine has emerged as a major player in the regulation of motor behavior. In fact, adenosine receptors of the A2A subtype are highly enriched in the caudate–putamen, which is richly innervated by dopamine. Moreover, several studies in experimental animals have consistently demonstrated that the pharmacological antagonism of A2A receptors has a facilitatory influence on motor behavior. Taken together, these findings have envisaged A2A receptors as a promising target for symptomatic therapies aimed at ameliorating motor deficits. Accordingly, A2A receptor antagonists have been extensively studied as new agents for the treatment of Parkinson’s disease (PD), the epitome of motor disorders. In this review, we provide an overview of the effects that adenosine A2A receptor antagonists elicit in rodent and primate experimental models of PD, with regard to the counteraction of motor deficits as well as to manifestation of dyskinesia and motor fluctuations. Moreover, we briefly present the results of clinical trials of A2A receptor antagonists in PD patients experiencing motor fluctuations, with particular regard to dyskinesia. Finally, we discuss the interaction between A2A receptor antagonists and serotonin receptor agonists, since combined administration of these drugs has recently emerged as a new potential therapeutic strategy in the treatment of dyskinesia.
      PubDate: 2018-02-02
      DOI: 10.1007/s00702-018-1848-6
       
 
 
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