The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Regional changes in type 1 cannabinoid receptor availability in Parkinson's disease in vivo

The type 1 cannabinoid receptor (CB1) is a crucial modulator of synaptic transmission in brain and has been proposed as a potential therapeutic target in Parkinson's disease (PD), especially for treatment of levodopa-induced dyskinesias (LID). Our aim was to measure CB1 levels in brains of PD patients in vivo and to investigate the relation between CB1 availability and LID. We studied 12 healthy controls and 29 PD patients (9 drug-naïve patients with early PD, 10 patients with advanced PD and LID, and 10 patients with advanced PD without LID). PD patients were examined using the Unified Parkinson's Disease Rating Scale (UPDRS) and the modified Abnormal Involuntary Movement Scale (mAIMS). All subjects underwent positron emission tomography (PET) with the CB1-selective radioligand [(18)F] MK-9470 and magnetic resonance imaging (MRI). PD patients showed an absolute decrease in CB1 availability in the substantia nigra. By contrast, CB1 availability was relatively increased in nigrostriatal, mesolimbic, and mesocortical dopaminergic projection areas. CB1 availability did not differ significantly between advanced PD patients with and without LID. Within the group of PD patients with LID, there was no significant correlation between CB1 availability and LID severity. These data demonstrate regional changes in CB1 availability in PD in vivo, but do not support a role for dysregulation of CB1 levels in the pathogenesis of LID.status: publishe

An in vivo [18F]MK-9470 microPET study of type 1 cannabinoid receptor binding in Wistar rats after chronic administration of valproate and levetiracetam

There is substantial evidence that the endocannabinoid system and in particular the type 1 cannabinoid receptor (CB1R) is involved in epilepsy. We evaluated the in vivo effect of chronic administration of the anti-epileptic drugs valproate (VPA) and levetiracetam (LEV) on rat brain CB1 receptors using the positron emission tomography (PET) tracer [(18)F]MK-9470. Six Wistar rats were treated with VPA (200mg/kg) or LEV (50mg/kg) IP daily for 2 weeks. Dynamic imaging after intravenous injection of 18 MBq [(18)F]MK-9470 was performed on a FOCUS 220 microPET at baseline and after chronic treatment. Six animals were used as controls and were injected with saline, using the same protocol. Parametric images based on standardized uptake values (SUV) were generated and were spatially normalized to Paxinos space. These CB1R images were analyzed using a predefined volume of interest (VOI)-based analysis. Differences in SUV values between chronic and baseline scans in each condition (saline, VPA and LEV treatment) were calculated in each VOI. Direct binding affinity of the drugs at CB1R was assessed by competitive binding assay in Chinese hamster ovarian cells expressing human CB1R. Chronic injections of saline did not produce significant changes in global [(18)F]MK-9470 binding (p=0.43), nor in tracer binding in individual VOIs. We found a significant increase in global cerebral [(18)F]MK-9470 binding after chronic VPA administration compared to sham treated animals (+32.5%, p<0.001), as well as in tracer binding in all individual VOIs. After chronic administration of LEV, there was no significant change in global cerebral CB1R binding (+6.9%, p=0.81), nor in tracer binding in individual VOIs. As VPA does not exhibit high affinity for CB1R (displacement of [(3)H]-SR141716A 1.3+/-14.0%), such upregulation is most likely caused by an indirect effect on the endocannabinoid system. This increase in CB1R tracer binding and possibly signaling may represent a supplementary and new mechanism of VPA, but not LEV, since activation of CB1Rs has been shown to decrease excitability and excitotoxicity on-demand.status: publishe

An in vivo [F-18]MK-9470 microPET study of type 1 cannabinoid receptor binding in Wistar rats after chronic administration of valproate and levetiracetam

There is substantial evidence that the endocannabinoid system and in particular the type 1 cannabinoid receptor (CB1R) is involved in epilepsy. We evaluated the in vivo effect of chronic administration of the anti-epileptic drugs valproate (VPA) and levetiracetam (LEV) on rat brain CB1 receptors using the positron emission tomography (PET) tracer [F-18]MK-9470. Six Wistar rats were treated with VPA (200 mg/kg) or LEV (50 mg/kg) IP daily for 2 weeks. Dynamic imaging after intravenous injection of 18 MBq [F-18]MK-9470 was performed on a FOCUS 220 microPET at baseline and after chronic treatment. Six animals were used as controls and were injected with saline, using the same protocol. Parametric images based on standardized uptake values (SUV) were generated and were spatially normalized to Paxinos space. These CB1R images were analyzed using a predefined volume of interest (VOI)-based analysis. Differences in SUV values between chronic and baseline scans in each condition (saline, VPA and LEV treatment) were calculated in each VOI. Direct binding affinity of the drugs at CB1R was assessed by competitive binding assay in Chinese hamster ovarian cells expressing human MR. Chronic injections of saline did not produce significant changes in global [F-18]MK-9470 binding (p = 0.43), nor in tracer binding in individual VOIs. We found a significant increase in global cerebral [F-18]MK-9470 binding after chronic VPA administration compared to sham treated animals (+32.5%, p < 0.001), as well as in tracer binding in all individual VOI. After chronic administration of LEV, there was no significant change in global cerebral CB1R binding (+6.9%, p = 0.81), nor in tracer binding in individual VOIs. As VPA does not exhibit high affinity for CB1R (displacement of [H-3]-SR141716A 1.3 +/- 14.0%), such upregulation is most likely caused by an indirect effect on the endocannabinoid system. This increase in CB1R tracer binding and possibly signaling may represent a supplementary and new mechanism of VPA, but not LEV, since activation of CB1Rs has been shown to decrease excitability and excitotoxicity on-demand. (C) 2008 Elsevier Ltd. All rights reserved

Is ioflupane I123 injection diagnostically effective in patients with movement disorders and dementia? Pooled analysis of four clinical trials

Objectives To pool clinical trials of similar design to assess overall sensitivity and specificity of ioflupane I123 injection (DaTSCAN or ioflupane (123I)) to detect or exclude a striatal dopaminergic deficit disorder (SDDD), such as parkinsonian syndrome and dementia with Lewy bodies.&lt;p&gt;&lt;/p&gt; Design Pooled analysis of three phase 3 and one phase 4 clinical trials. These four trials were selected because they were the four studies used for the US new drug application to the Food and Drug Administration (FDA).&lt;p&gt;&lt;/p&gt; Setting Multicentre, open-label, non-randomised.&lt;p&gt;&lt;/p&gt; Participants Patients with either a movement disorder or dementia, and healthy volunteers.&lt;p&gt;&lt;/p&gt; Interventions Ioflupane (123I) was administered.&lt;p&gt;&lt;/p&gt; Outcome measures Images were assessed by panels of 3–5 blinded experts and/or on-site nuclear medicine physicians, classified as normal or abnormal and compared with clinical diagnosis (reference standard) to determine sensitivity and specificity.&lt;p&gt;&lt;/p&gt; Results Pooling the four studies, 928 participants were enrolled, 849 were dosed and 764 completed their study. Across all studies, when images were assessed by on-site readers, ioflupane (123I) diagnostic effectiveness had an overall (95% CI) sensitivity of 91.9% (88.7% to 94.5%) and specificity of 83.6% (78.7% to 87.9%). When reads were conducted blindly by a panel of independent experts, the overall sensitivity was 88.7% (86.8% to 90.4%) and specificity was 91.2% (89.0% to 93.0%).&lt;p&gt;&lt;/p&gt; Conclusions In this pooled analysis, the visual assessment of ioflupane (123I) images provided high levels of sensitivity and specificity in detecting the presence/absence of an SDDD. Ioflupane (123I) imaging has the potential to improve diagnostic accuracy in patients with signs and symptoms of a movement disorder and/or dementia.&lt;p&gt;&lt;/p&gt

Ranking Technologies of Additive Manufacturing of Removable Complete Dentures by the Results of Their Mechanical Testing

In this study, a methodology was developed for ranking manufacturing technologies of removable complete dentures (RCDs) according to the results of their full-scale mechanical tests. The actuality of the study is motivated by establishing the advantages and drawbacks of 3D-printed RCDs in contrast with ones manufactured via an analog protocol. The RCDs were fabricated via four technological routes that included various combinations of subtractive technologies (hot polymerization/HP and CAD/CAM milling) and additive manufacturing (digital light processing/DLP) ones and the installation of commercially available cosmetic denture teeth (DT). In the mechanical tests, different blocks of teeth (incisors, canines, premolars and molars) were loaded. To solve the ranking problem, it was proposed to interpret the results of the mechanical tests in terms of the reliability, durability and compliance/stiffness criteria. For this purpose, the combined AHP-VIKOR method was applied. In addition, a computer simulation of the mechanical loading conditions and the response of the RCDs was performed based on the finite element method (FEM). As the key conclusion, it was stated that additive manufacturing (AM) methods are competitive and cost-effective techniques for the fabrication of RCDs

Varieties of modular ortholattices

SIGLECopy held by FIZ Karlsruhe; available from UB/TIB Hannover / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman