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Neurobiology
Cognitive subtypes of probable Alzheimer's disease robustly identified in four cohorts
Apr 21, 2017   Alzheimer's & Dementia : The Journal Of The Alzheimer's Association
Scheltens NME, Tijms BM, Koene T, Barkhof F, Teunissen CE,   . . . . . .   , van der Flier WM, Alzheimer's Disease Neuroimaging Initiative, German Dementia Competence Network, University of California San Francisco Memory and Aging Center, Amsterdam Dementia Cohort
Cognitive subtypes of probable Alzheimer's disease robustly identified in four cohorts
Apr 21, 2017
Alzheimer's & Dementia : The Journal Of The Alzheimer's Association
Patients with Alzheimer's disease (AD) show heterogeneity in profile of cognitive impairment. We aimed to identify cognitive subtypes in four large AD cohorts using a data-driven clustering approach. We included probable AD dementia patients from the Amsterdam Dementia Cohort (n = 496), Alzheimer's Disease Neuroimaging Initiative (n = 376), German Dementia Competence Network (n = 521), and University of California, San Francisco (n = 589). Neuropsychological data were clustered using nonnegative matrix factorization. We explored clinical and neurobiological characteristics of identified clusters. In each cohort, a two-clusters solution best fitted the data (cophenetic correlation >0.9): one cluster was memory-impaired and the other relatively memory spared. Pooled analyses showed that the memory-spared clusters (29%-52% of patients) were younger, more often APOE e4 negative, and had more severe posterior atrophy compared with the memory-impaired clusters (all P 
Using Multivariate Base Rates to Interpret Low Scores on an Abbreviated Battery of the Delis-Kaplan Executive Function System
Apr 21, 2017   Archives Of Clinical Neuropsychology : The Official Journal Of The National Academy Of Neuropsychologists
Karr JE, Garcia-Barrera MA, Holdnack JA, Iverson GL
Using Multivariate Base Rates to Interpret Low Scores on an Abbreviated Battery of the Delis-Kaplan Executive Function System
Apr 21, 2017
Archives Of Clinical Neuropsychology : The Official Journal Of The National Academy Of Neuropsychologists
Executive function consists of multiple cognitive processes that operate as an interactive system to produce volitional goal-oriented behavior, governed in large part by frontal microstructural and physiological networks. Identification of deficits in executive function in those with neurological or psychiatric conditions can be difficult because the normal variation in executive function test scores, in healthy adults when multiple tests are used, is largely unknown. This study addresses that gap in the literature by examining the prevalence of low scores on a brief battery of executive function tests. The sample consisted of 1,050 healthy individuals (ages 16-89) from the standardization sample for the Delis-Kaplan Executive Function System (D-KEFS). Seven individual test scores from the Trail Making Test, Color-Word Interference Test, and Verbal Fluency Test were analyzed. Low test scores, as defined by commonly used clinical cut-offs (i.e., ≤25th, 16th, 9th, 5th, and 2nd percentiles), occurred commonly among the adult portion of the D-KEFS normative sample (e.g., 62.8% of the sample had one or more scores ≤16th percentile, 36.1% had one or more scores ≤5th percentile), and the prevalence of low scores increased with lower intelligence and fewer years of education. The multivariate base rates (BR) in this article allow clinicians to understand the normal frequency of low scores in the general population. By use of these BRs, clinicians and researchers can improve the accuracy with which they identify executive dysfunction in clinical groups, such as those with traumatic brain injury or neurodegenerative diseases.
MDMA does not alter responses to the Trier Social Stress Test in humans
Apr 22, 2017   Psychopharmacology
Bershad AK, Miller MA, de Wit H
MDMA does not alter responses to the Trier Social Stress Test in humans
Apr 22, 2017
Psychopharmacology
±3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a stimulant-psychedelic drug with unique social effects. It may dampen reactivity to negative social stimuli such as social threat and rejection. Perhaps because of these effects, MDMA has shown promise as a treatment for post-traumatic stress disorder (PTSD). However, the effect of single doses of MDMA on responses to an acute psychosocial stressor has not been tested. In this study, we sought to test the effects of MDMA on responses to stress in healthy adults using a public speaking task. We hypothesized that the drug would reduce responses to the stressful task. Volunteers (N = 39) were randomly assigned to receive placebo (N = 13), 0.5 mg/kg MDMA (N = 13), or 1.0 mg/kg MDMA (N = 13) during a stress and a no-stress session. Dependent measures included subjective reports of drug effects and emotional responses to the task, as well as salivary cortisol, heart rate, and blood pressure. The stress task produced its expected increase in physiological responses (cortisol, heart rate) and subjective ratings of stress in all three groups, and MDMA produced its expected subjective and physiological effects. MDMA alone increased ratings of subjective stress, heart rate, and saliva cortisol concentrations, but contrary to our hypothesis, it did not moderate responses to the Trier Social Stress Test. Despite its efficacy in PTSD and anxiety, MDMA did not reduce either the subjective or objective responses to stress in this controlled study. The conditions under which MDMA relieves responses to negative events or memories remain to be determined.
Endogenous Two-Photon Excited Fluorescence Imaging Characterizes Neuron and Astrocyte Metabolic Responses to Manganese Toxicity
Apr 22, 2017   Scientific Reports
Stuntz E, Gong Y, Sood D, Liaudanskaya V, Pouli D, Quinn KP, Alonzo C, Liu Z, Kaplan DL, Georgakoudi I
Endogenous Two-Photon Excited Fluorescence Imaging Characterizes Neuron and Astrocyte Metabolic Responses to Manganese Toxicity
Apr 22, 2017
Scientific Reports
As neurodegenerative conditions are increasingly linked to mitochondrial dysfunction, methods for studying brain cell metabolism at high spatial resolution are needed to elucidate neurodegeneration mechanisms. Two-photon excited fluorescence (TPEF) imaging is a non-destructive, high-resolution technique for studying cell metabolism via endogenous fluorescence of reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) and flavin adenine dinucleotide (FAD). We employed TPEF to study the metabolism of primary rat astrocyte and neuronal cultures under normal growth conditions and in response to manganese (Mn) treatment. Histograms of pixel-wise optical redox ratio, defined as FAD/(FAD + NAD(P)H), revealed three distinct redox distributions and significant differences in their relative weights between astrocytes and neurons. When treated with Mn, both cell types exhibited redox ratio shifts consistent with increased oxidative stress. However, the manner in which the redox distributions was affected was distinct for the two cell types. Furthermore, NAD(P)H fluorescence lifetime imaging revealed an increase in bound NAD(P)H fraction upon Mn treatment for neurons, consistent with enhanced apoptosis. Astrocytes showed a decrease in bound fraction, possibly due to a shift towards glycolytic metabolism in response to impaired respiration. These results exhibit TPEF's utility for characterizing detailed metabolic changes of different brain cell types in response to neurotoxins.
The spacing effect for structural synaptic plasticity provides specificity and precision in plastic changes
Apr 22, 2017   The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
San MA, Rela L, Gelb BD, Pagani MR
The spacing effect for structural synaptic plasticity provides specificity and precision in plastic changes
Apr 22, 2017
The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
In contrast to trials of training without intervals (massed training), training trials spaced over time (spaced training) induce a more persistent memory identified as long-term memory (LTM). This phenomenon known as "the spacing effect for memory" is poorly understood. LTM is supported by structural synaptic plasticity; however, how synapses integrate spaced stimuli remains elusive. Here, we analyzed events of structural synaptic plasticity at the single synapse level after distinct patterns of stimulation in motoneurons of Drosophila We found that the spacing effect is a phenomenon detected at synaptic level, which determine the specificity and the precision in structural synaptic plasticity. Whereas a single pulse of stimulation (massed) induced structural synaptic plasticity, the same amount of stimulation divided in three spaced stimuli completely prevented it. This inhibitory effect was determined by the length of the inter-stimulus intervals. The inhibitory effect of the spacing was lost by suppressing the activity of Ras or MAPK, while the overexpression of Ras-WT enhanced it. Moreover, dividing the same total time of stimulation into five or more stimuli produced a higher precision in the number of events of plasticity. Ras mutations associated with intellectual disability abolish the spacing effect and made that neurons decoded distinct stimulation patterns as massed stimulation. This evidence suggests that the spacing effect for memory may results from the effect of the spacing in synaptic plasticity, which appear to be a property not limited to neurons involved in learning and memory. We propose a model of spacing-dependent structural synaptic plasticity.SIGNIFICANCE STATEMENTLong-term memory (LTM) induced by repeated trials spaced over time is known as the spacing effect, a common property in the animal kingdom. Altered mechanisms in the spacing effect have been found in animal models of disorders with intellectual disability, such as Noonan syndrome. Although LTM is sustained by structural synaptic plasticity, how synapses integrate spaced stimuli and decode them into specific plastic changes remains elusive. Here, we show that the spacing effect is a phenomenon detected at synaptic level, which determines the properties of the response in structural plasticity, including precision of such response. Whereas suppressing or enhancing Ras/MAPK signaling changed how synapses decode a pattern of stimuli, a disease-related Ras allele abolished the spacing effect for plastic changes. Copyright © 2017 the authors.
Visually-evoked 3-5 Hz membrane potential oscillations reduce the responsiveness of visual cortex neurons in awake behaving mice
Apr 22, 2017   The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Einstein MC, Polack PO, Tran DT, Golshani P
Visually-evoked 3-5 Hz membrane potential oscillations reduce the responsiveness of visual cortex neurons in awake behaving mice
Apr 22, 2017
The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Low frequency membrane potential (Vm) oscillations were once thought to only occur in sleeping and anesthetized states. Recently, low frequency Vm oscillations have been described in inactive awake animals, but it is unclear if they shape sensory processing in neurons and whether they occur during active awake behavioral states. To answer these questions, we performed two-photon guided whole-cell Vm recordings from primary visual cortex layer 2/3 excitatory and inhibitory neurons in awake mice during passive visual stimulation and performance of visual and auditory discrimination tasks. We recorded stereotyped 3-5 Hz Vm oscillations where the Vm baseline hyperpolarized as the Vm underwent high amplitude rhythmic fluctuations lasting 1-2 seconds in duration. When 3-5 Hz Vm oscillations coincided with visual cues, excitatory neuron responses to preferred cues were significantly reduced. Despite this disruption to sensory processing, visual cues were critical for evoking 3-5 Hz Vm oscillations when animals performed discrimination tasks and passively viewed drifting grating stimuli. Using pupilometry and animal locomotive speed as indicators of arousal, we found that 3-5 Hz oscillations were not restricted to unaroused states and that they occurred equally in aroused and unaroused states. Therefore, low frequency Vm oscillations play a role in shaping sensory processing in visual cortical neurons, even during active wakefulness and decision making.SIGNIFICANCE STATEMENTA neuron's membrane potential (Vm) strongly shapes how information is processed in sensory cortices of awake animals. Yet, very is little known about how low frequency Vm oscillations influence sensory processing and whether they occur in aroused awake animals. By performing 2-photon guided whole-cell recordings from layer 2/3 excitatory and inhibitory neurons in the visual cortex of awake behaving animals, we found visually-evoked stereotyped 3-5 Hz Vm oscillations that disrupt excitatory responsiveness to visual stimuli. Moreover, these oscillations occurred when animals were in high and low arousal states as measured by animal speed and pupilometry. These findings show for the first time that low frequency Vm oscillations can significantly modulate sensory signal processing even in awake active animals. Copyright © 2017 the authors.
Inhibition of Drp1 Ameliorates Synaptic Depression, Aβ Deposition and Cognitive Impairment in Alzheimer's Disease Model
Apr 22, 2017   The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Baek SH, Park SJ, In Jeong J, Hyun Kim S, Han J,   . . . . . .   , Kim J, Han JW, Koh JY, Cho DH, Jo DG
Inhibition of Drp1 Ameliorates Synaptic Depression, Aβ Deposition and Cognitive Impairment in Alzheimer's Disease Model
Apr 22, 2017
The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Excessive mitochondrial fission is a prominent early event, and contributes to mitochondrial dysfunction, synaptic failure and neuronal cell death in the progression of Alzheimer's disease (AD). However, it remains to be determined whether inhibition of excessive mitochondrial fission is beneficial in mammal models of AD. To determine whether dynamin-related protein 1 (Drp1), a key regulator of mitochondrial fragmentation, can be a disease-modifying therapeutic target for AD, we examine the effects of Drp1 inhibitor on mitochondrial and synaptic dysfunctions induced by oligomeric β-amyloid (Aβ) in neurons, and neuropathology and cognitive functions in APP/PS1 double transgenic AD mice. Inhibition of Drp1 alleviates mitochondrial fragmentation, loss of mitochondrial membrane potential, reactive oxygen species (ROS) production, ATP reduction, and synaptic depression in Aβ-treated neurons. Furthermore, Drp1 inhibition significantly improves learning and memory, and prevents mitochondrial fragmentation, lipid peroxidation, BACE1 expression and Aβ deposition in the brain of AD model. These results provide evidence that Drp1 plays an important role in Aβ-mediated and AD-related neuropathology, and in cognitive decline in an AD animal model. Thus, inhibiting excessive Drp1-mediated mitochondrial fission may be an efficient therapeutic avenue for AD.SIGNIFICANCE STATEMENTMitochondrial fission relies on the evolutionary conserved Drp1 protein. Drp1 activity and mitochondria fragmentation are significantly elevated in the brains of sporadic AD cases. In the present study, we first demonstrated that the inhibition of Drp1 restored Aβ-mediated mitochondrial dysfunctions and synaptic depression in neurons, and significantly reduced lipid peroxidation, BACE1 expression, and Aβ deposition in the brain of AD mice. As a result, memory deficits in AD mice were rescued by Drp1 inhibition. These results suggest that neuropathology and combined cognitive decline can be attributed to hyper-activation of Drp1 in the pathogenesis of AD. Therefore, inhibitors of excessive mitochondrial fission, such as Drp1 inhibitors, may be new strategy for AD. Copyright © 2017 the authors.
Dual-functional nanoparticles for precise drug delivery to Alzheimer's disease lesions: targeting mechanisms, pharmacodynamics and safety
Apr 22, 2017   International Journal Of Pharmaceutics
Zheng X, Zhang C, Guo Q, Wan X, Shao X, Liu Q, Zhang Q
Dual-functional nanoparticles for precise drug delivery to Alzheimer's disease lesions: targeting mechanisms, pharmacodynamics and safety
Apr 22, 2017
International Journal Of Pharmaceutics
Alzheimer's disease (AD) is the most common form of dementia and is characterized by the cerebral accumulation of extracellular amyloid plaques. In a previous study, this histopathological hallmark was used as a target on a dual-functional nanoparticle (TQNP) to deliver biotechnological drugs, such as the H102 peptide, a β-sheet breaker, to AD lesions precisely. This delivery system could reduce the amyloid-β (Aβ) burden in the brains of AD model mice, as well as ameliorated the memory impairment of the mice. Regretfully, the mechanism how nanoparticles penetrated the BBB and subsequently targeted to the plaques is still unclear. In this study, the internalization, subcellular fate and transportation of the nanoparticles on bEnd.3 cells and an in vitro BBB model, demonstrated that TQNP could be taken up through various routes, including caveolae-mediated endocytosis, suggesting that some of TQNP were able to cross the BBB intact. Then, the TQNP were visualized to specifically bind to the Aβ plaques. TQNP targeting to amyloid plaques might lead to enhanced therapeutic efficacy, which was further evaluated in APP/PS1 transgenic mice. The TQNP/H102 obtained better ability in decreasing amyloid plaques, increasing Aβ-degrading enzymes, reducing tau protein phosphorylation, protecting synapses and improving the spatial learning and memory of transgenic mice than nanoparticles modified with a single ligand. And good biocompatibility of TQNP was indicated with subacute toxicity assays. In conclusion, TQNP was a valuable nanodevice for the precise delivery for biotechnological drugs to treat AD. Copyright © 2017. Published by Elsevier B.V.
Sigma-1 receptor in brain ischemia/reperfusion: Possible role in the NR2A-induced pathway to regulate brain-derived neurotrophic factor
Apr 22, 2017   Journal Of The Neurological Sciences
Xu Q, Ji XF, Chi TY, Liu P, Jin G, Chen L, Zou LB
Sigma-1 receptor in brain ischemia/reperfusion: Possible role in the NR2A-induced pathway to regulate brain-derived neurotrophic factor
Apr 22, 2017
Journal Of The Neurological Sciences
Sigma-1 receptor (σ1r) activation could attenuate the learning and memory deficits in the AD model, ischemia model and others. In our previous study, the activation of σ1r increased the expression of brain-derived neurotrophic factor (BDNF), possibly through the NR2A-induced pathway, and σ1r agonists might function as neuroprotectant agents in vascular dementia. Here, we used σ1r knockout mice to confirm the role of σ1r. Furthermore, an antagonist of NR2A was first used to investigate whether the NR2A-induced pathway is the necessary link between σ1r and BDNF. The operation of brain ischemia/reperfusion was induced by bilateral common carotid artery occlusion for 20min in C57BL/6 and σ1r knockout mice as the ischemic group. A σ1r agonist, PRE084 (1mg/kg, i.p.), and NR2A antagonist, PEAQX (10mg/kg, i.p.), were administered once daily throughout the experiment. Behavioral tests were performed starting on day 8. On day 22 after brain ischemia/reperfusion, mice were sacrificed and brains were immediately collected and the injured and the hippocampus was isolated and stored at -80°C for western blot analysis. After ischemic operation, contrast with the σ1r knockout mice, PRE084 significantly ameliorated learning and memory impairments in the behavioral evaluation, and prevented the protein decline of BDNF, NR2A, CaMKIV and TORC1 expression in wild-type mice. However, the effects of PRE084 on CaMKIV-TORC1-CREB and BDNF, even for learning and memory impairment, were antagonized by the co-administration of PEAQX, an antagonist of NR2A. The activation of σ1r improves the impairment of learning and memory in the ischemia/reperfusion model, and the expression of BDNF, which may have been achieved through the NR2A-CaMKIV-TORC1 pathway. Copyright © 2017. Published by Elsevier B.V.
Heterogeneous ribonuclear protein A3 (hnRNP A3) is present in dipeptide repeat protein containing inclusions in Frontotemporal Lobar Degeneration and Motor Neurone disease associated with expansions in C9orf72 gene
Apr 22, 2017   Acta Neuropathologica Communications
Davidson YS, Flood L, Robinson AC, Nihei Y, Mori K, Rollinson S, Richardson A, Benson BC, Jones M, Snowden JS, Pickering-Brown S, Haass C, Lashley T, Mann DMA
Heterogeneous ribonuclear protein A3 (hnRNP A3) is present in dipeptide repeat protein containing inclusions in Frontotemporal Lobar Degeneration and Motor Neurone disease associated with expansions in C9orf72 gene
Apr 22, 2017
Acta Neuropathologica Communications
Frontotemporal Lobar Degeneration (FTLD) encompasses certain related neurodegenerative disorders which alter behaviour, personality and language. Heterogeneous ribonuclear proteins (hnRNPs) maintain RNA metabolism and changes in their function may underpin the pathogenesis of FTLD. Immunostaining for hnRNP A1, A2/B1 and A3 was performed on sections of temporal cortex with hippocampus from 61 patients with FTLD, stratified by pathological hallmarks into FTLD-tau and FTLD-TDP type A, B and C subtypes, and by genetics into patients with C9orf72 expansions, MAPT or GRN mutations, or those without known mutation. Four patients with Motor Neurone Disease (MND) with C9orf72 expansions and 10 healthy controls were also studied. Semi-quantitative analysis assessed hnRNP staining intensity in dentate gyrus (DG) and CA4 region of hippocampus, and temporal cortex (Tcx) in the different pathological and genetic groups.Immunostaining for hnRNP A1, A2/B1 and A3 revealed no consistent changes in pattern or amount of physiological staining across any of the pathological or genetic groups. No immunostaining of any inclusions resembling TDP-43 immunoreactive neuronal cytoplasmic inclusions or dystrophic neurites, was seen in either Tcx or DG of the hippocampus in any of the FTLD cases investigated for hnRNP A1, A2/B1 and A3. However, immunostaining for hnRNP A3 showed that inclusion bodies, resembling those TDP-43 negative, p62-immunopositive structures containing dipeptide repeat proteins (DPR) were variably observed in hippocampus and cerebellum. The proportion of cases showing hnRNP A3-immunoreactive DPR, and the number of hnRNP A3-positive inclusions within cases, was significantly greater in DG than in cells of CA4 region and cerebellum, but the latter was significantly less in all three regions compared to that detected by p62 immunostaining.
The temporal paradox of Hebbian learning and homeostatic plasticity
Apr 21, 2017   Current Opinion In Neurobiology
Zenke F, Gerstner W, Ganguli S
The temporal paradox of Hebbian learning and homeostatic plasticity
Apr 21, 2017
Current Opinion In Neurobiology
Hebbian plasticity, a synaptic mechanism which detects and amplifies co-activity between neurons, is considered a key ingredient underlying learning and memory in the brain. However, Hebbian plasticity alone is unstable, leading to runaway neuronal activity, and therefore requires stabilization by additional compensatory processes. Traditionally, a diversity of homeostatic plasticity phenomena found in neural circuits is thought to play this role. However, recent modelling work suggests that the slow evolution of homeostatic plasticity, as observed in experiments, is insufficient to prevent instabilities originating from Hebbian plasticity. To remedy this situation, we suggest that homeostatic plasticity is complemented by additional rapid compensatory processes, which rapidly stabilize neuronal activity on short timescales. Copyright © 2017 Elsevier Ltd. All rights reserved.
Collagenosis of the Deep Medullary Veins: An Underrecognized Pathologic Correlate of White Matter Hyperintensities and Periventricular Infarction?
Apr 21, 2017   Journal Of Neuropathology And Experimental Neurology
Keith J, Gao FQ, Noor R, Kiss A, Balasubramaniam G, Au K, Rogaeva E, Masellis M, Black SE
Collagenosis of the Deep Medullary Veins: An Underrecognized Pathologic Correlate of White Matter Hyperintensities and Periventricular Infarction?
Apr 21, 2017
Journal Of Neuropathology And Experimental Neurology
White matter hyperintensities (WMH) are prevalent. Although arteriolar disease has been implicated in their pathogenesis, venous pathology warrants consideration. We investigated relationships of WMH with histologic venous, arteriolar and white matter abnormalities and correlated findings with premortem neuroimaging. Three regions of periventricular white matter were sampled from archived autopsy brains of 24 pathologically confirmed Alzheimer disease (AD) and 18 age-matched nonAD patients. Using trichrome staining, venous collagenosis (VC) of periventricular veins (200 µm) veins (laVS) was measured. Correlations were made between WMH in premortem neuroimaging and vascular and white matter pathology. We found greater VC (U(114) = 2092.5, p = 0.005 and U(114) = 2121.5, p = 0.002 for small and medium caliber veins, respectively) and greater laVS (t(110) = 3.46, p = 0.001) in patients with higher WMH scores; WMH scores correlated with VC (rs(114) = 0.27, p = 0.004) and laVS (rs(110) = 0.38, p 
A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK
Apr 21, 2017   Brain : A Journal Of Neurology
Morgan S, Shatunov A, Sproviero W, Jones AR, Shoai M,   . . . . . .   , Orrell RW, Fratta P, Hardy J, Pittman A, Al-Chalabi A
A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK
Apr 21, 2017
Brain : A Journal Of Neurology
Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of motor neurons. About 25 genes have been verified as relevant to the disease process, with rare and common variation implicated. We used next generation sequencing and repeat sizing to comprehensively assay genetic variation in a panel of known amyotrophic lateral sclerosis genes in 1126 patient samples and 613 controls. About 10% of patients were predicted to carry a pathological expansion of the C9orf72 gene. We found an increased burden of rare variants in patients within the untranslated regions of known disease-causing genes, driven by SOD1, TARDBP, FUS, VCP, OPTN and UBQLN2. We found 11 patients (1%) carried more than one pathogenic variant (P = 0.001) consistent with an oligogenic basis of amyotrophic lateral sclerosis. These findings show that the genetic architecture of amyotrophic lateral sclerosis is complex and that variation in the regulatory regions of associated genes may be important in disease pathogenesis. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.
Egocentric and Allocentric Visuospatial Working Memory in Premotor Huntington's Disease: a Double Dissociation with Caudate and Hippocampal Volumes
Apr 21, 2017   Neuropsychologia
Possin KL, Kim H, Geschwind MD, Moskowitz T, Johnson ET, Sha SJ, Apple A, Xu D, Miller BL, Finkbeiner S, Hess CP, Kramer JH
Egocentric and Allocentric Visuospatial Working Memory in Premotor Huntington's Disease: a Double Dissociation with Caudate and Hippocampal Volumes
Apr 21, 2017
Neuropsychologia
Our brains represent spatial information in egocentric (self-based) or allocentric (landmark-based) coordinates. Rodent studies have demonstrated a critical role for the caudate in egocentric navigation and the hippocampus in allocentric navigation. We administered tests of egocentric and allocentric working memory to individuals with premotor Huntington's disease (pmHD), which is associated with early caudate nucleus atrophy, and controls. Each test had 80 trials during which subjects were asked to remember 2 locations over 1-sec delays. The only difference between these otherwise identical tests was that locations could only be coded in self-based or landmark-based coordinates. We applied a multiatlas-based segmentation algorithm and computed point-wise Jacobian determinants to measure regional variations in caudate and hippocampal volumes from 3T MRI. As predicted, the pmHD patients were significantly more impaired on egocentric working memory. Only egocentric accuracy correlated with caudate volumes, specifically the dorsolateral caudate head, right more than left, a region that receives dense efferents from dorsolateral prefrontal cortex. In contrast, only allocentric accuracy correlated with hippocampal volumes, specifically intermediate and posterior regions that connect strongly with parahippocampal and posterior parietal cortices. These results indicate that the distinction between egocentric and allocentric navigation applies to working memory. The dorsolateral caudate is important for egocentric working memory, which can explain the disproportionate impairment in pmHD. Allocentric working memory, in contrast, relies on the hippocampus and is relatively spared in pmHD. Copyright © 2017. Published by Elsevier Ltd.
Whole-genome sequencing suggests mechanisms for 22q11.2 deletion-associated Parkinson's disease
Apr 21, 2017   PloS One
Butcher NJ, Merico D, Zarrei M, Ogura L, Marshall CR, Chow EWC, Lang AE, Scherer SW, Bassett AS
Whole-genome sequencing suggests mechanisms for 22q11.2 deletion-associated Parkinson's disease
Apr 21, 2017
PloS One
To investigate disease risk mechanisms of early-onset Parkinson's disease (PD) associated with the recurrent 22q11.2 deletion, a genetic risk factor for early-onset PD. In a proof-of-principle study, we used whole-genome sequencing (WGS) to investigate sequence variants in nine adults with 22q11.2DS, three with neuropathologically confirmed early-onset PD and six without PD. Adopting an approach used recently to study schizophrenia in 22q11.2DS, here we tested candidate gene-sets relevant to PD. No mutations common to the cases with PD were found in the intact 22q11.2 region. While all were negative for rare mutations in a gene-set comprising PD disease-causing and risk genes, another candidate gene-set of 1000 genes functionally relevant to PD presented a nominally significant (P = 0.03) enrichment of rare putatively damaging missense variants in the PD cases. Polygenic score results, based on common variants associated with PD risk, were non-significantly greater in those with PD. The results of this first-ever pilot study of WGS in PD suggest that the cumulative burden of genome-wide sequence variants may contribute to expression of early-onset PD in the presence of threshold-lowering dosage effects of a 22q11.2 deletion. We found no evidence that expression of PD in 22q11.2DS is mediated by a recessive locus on the intact 22q11.2 chromosome or mutations in known PD genes. These findings offer initial evidence of the potential effects of multiple within-individual rare variants on the expression of PD and the utility of next generation sequencing for studying the etiology of PD.
Ketamine administered pregnant rats impair learning and memory in offspring via the CREB pathway
Apr 21, 2017   Oncotarget
Li X, Guo C, Li Y, Li L, Wang Y, Zhang Y, Li Y, Chen Y, Liu W, Gao L
Ketamine administered pregnant rats impair learning and memory in offspring via the CREB pathway
Apr 21, 2017
Oncotarget
Ketamine has been reported to impair the capacity for learning and memory. This study examined whether these capacities were also altered in the offspring and investigated the role of the CREB signaling pathway in pregnant rats, subjected to ketamine-induced anesthesia. On the 14th day of gestation (P14), female rats were anesthetized for 3 h via intravenous ketamine injection (200 mg/Kg). Morris water maze task, contextual and cued fear conditioning, and olfactory tasks were executed between the 25th to 30th day after birth (B25-30) on rat pups, and rats were sacrificed on B30. Nerve density and dendritic spine density were examined via Nissl's and Golgi staining. Simultaneously, the contents of Ca2+/Calmodulin-Dependent Protein Kinase II (CaMKII), p-CaMKII, CaMKIV, p-CaMKIV, Extracellular Regulated Protein Kinases (ERK), p-ERK, Protein Kinase A (PKA), p-PKA, cAMP-Response Element Binding Protein (CREB), p-CREB, and Brain Derived Neurotrophic Factor (BDNF) were detected in the hippocampus. We pretreated PC12 cells with both PKA inhibitor (H89) and ERK inhibitor (SCH772984), thus detecting levels of ERK, p-ERK, PKA, p-PKA, p-CREB, and BDNF. The results revealed that ketamine impaired the learning ability and spatial as well as conditioned memory in the offspring, and significantly decreased the protein levels of ERK, p-ERK, PKA, p-PKA, p-CREB, and BDNF. We found that ERK and PKA (but not CaMKII or CaMKIV) have the ability to regulate the CREB-BDNF pathway during ketamine-induced anesthesia in pregnant rats. Furthermore, ERK and PKA are mutually compensatory for the regulation of the CREB-BDNF pathway.
The HSP90 chaperone machinery
Apr 21, 2017   Nature Reviews. Molecular Cell Biology
Schopf FH, Biebl MM, Buchner J
The HSP90 chaperone machinery
Apr 21, 2017
Nature Reviews. Molecular Cell Biology
The heat shock protein 90 (HSP90) chaperone machinery is a key regulator of proteostasis under both physiological and stress conditions in eukaryotic cells. As HSP90 has several hundred protein substrates (or 'clients'), it is involved in many cellular processes beyond protein folding, which include DNA repair, development, the immune response and neurodegenerative disease. A large number of co-chaperones interact with HSP90 and regulate the ATPase-associated conformational changes of the HSP90 dimer that occur during the processing of clients. Recent progress has allowed the interactions of clients with HSP90 and its co-chaperones to be defined. Owing to the importance of HSP90 in the regulation of many cellular proteins, it has become a promising drug target for the treatment of several diseases, which include cancer and diseases associated with protein misfolding.
Regulation of Human Brain Microvascular Endothelial Cell Adhesion and Barrier Functions by Memantine
Apr 21, 2017   Journal Of Molecular Neuroscience : MN
Wang F, Zou Z, Gong Y, Yuan D, Chen X, Sun T
Regulation of Human Brain Microvascular Endothelial Cell Adhesion and Barrier Functions by Memantine
Apr 21, 2017
Journal Of Molecular Neuroscience : MN
Vascular risk factors have been linked to cognitive decline and dementia in the elderly. Microvascular inflammation, especially of the endothelium, may contribute to the progression of neurodegenerative events in Alzheimer's disease (AD). Memantine, an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, is a licensed drug used for the treatment of moderate to severe AD. However, little information is available regarding its anti-inflammatory effects on the endothelium. In this study, we investigated the effects of memantine on human brain microvascular endothelial dysfunction induced by the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α). Our results show that memantine prevents the attachment of monocyte THP-1 cells to human brain microvascular endothelial cells (HBMVEs). An in vitro BBB model experiment displayed that memantine could rescue TNF-α-induced disruption of the in vitro BBB model. In addition, memantine also interferes with monocyte transmigration across the BBB model. Our results indicate that TNF-α significantly increased the expression of cell adhesion molecules, such as ICAM-1, VCAM-1, and E-selectin, which was prevented by pretreatment with memantine. Mechanistically, memantine reversed activation of the transcription factor NF-κB by preventing the phosphorylation and degradation of its inhibitor IκBα. Our data is the first to describe a novel anti-inflammatory mechanism driven by the endothelial cell-mediated neuroprotective effects of memantine.
Clinical validity of biochemical and molecular analysis in diagnosing Leigh syndrome: a study of 106 Japanese patients
Apr 21, 2017   Journal Of Inherited Metabolic Disease
Ogawa E, Shimura M, Fushimi T, Tajika M, Ichimoto K,   . . . . . .   , Kishita Y, Okazaki Y, Takahashi S, Ohtake A, Murayama K
Clinical validity of biochemical and molecular analysis in diagnosing Leigh syndrome: a study of 106 Japanese patients
Apr 21, 2017
Journal Of Inherited Metabolic Disease
Leigh syndrome (LS) is a progressive neurodegenerative disorder of infancy and early childhood. It is clinically diagnosed by typical manifestations and characteristic computed tomography (CT) or magnetic resonance imaging (MRI) studies. Unravelling mitochondrial respiratory chain (MRC) dysfunction behind LS is essential for deeper understanding of the disease, which may lead to the development of new therapies and cure. The aim of this study was to evaluate the clinical validity of various diagnostic tools in confirming MRC disorder in LS and Leigh-like syndrome (LL). The results of enzyme assays, molecular analysis, and cellular oxygen consumption rate (OCR) measurements were examined. Of 106 patients, 41 were biochemically and genetically verified, and 34 had reduced MRC activity but no causative mutations. Seven patients with normal MRC complex activities had mutations in the MT-ATP6 gene. Five further patients with normal activity in MRC were identified with causative mutations. Conversely, 12 out of 60 enzyme assays performed for genetically verified patients returned normal results. No biochemical or genetic background was confirmed for 19 patients. OCR was reduced in ten out of 19 patients with negative enzyme assay results. Inconsistent enzyme assay results between fibroblast and skeletal muscle biopsy samples were observed in 33% of 37 simultaneously analyzed cases. These data suggest that highest diagnostic rate is reached using a combined enzymatic and genetic approach, analyzing more than one type of biological materials where suitable. Microscale oxygraphy detected MRC impairment in 50% cases with no defect in MRC complex activities.
Editorial: Memory Processes in Medial Temporal Lobe: Experimental, Theoretical and Computational Approaches
Apr 21, 2017   Frontiers In Systems Neuroscience
Cutsuridis V, Yoshida M
Decreased Levels of Foldase and Chaperone Proteins Are Associated with an Early-Onset Amyotrophic Lateral Sclerosis
Apr 21, 2017   Frontiers In Molecular Neuroscience
Filareti M, Luotti S, Pasetto L, Pignataro M, Paolella K,   . . . . . .   , Chiò A, Corbo M, Bendotti C, Beghi E, Bonetto V
Decreased Levels of Foldase and Chaperone Proteins Are Associated with an Early-Onset Amyotrophic Lateral Sclerosis
Apr 21, 2017
Frontiers In Molecular Neuroscience
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive upper and lower motor neuron degeneration. One of the peculiar clinical characteristics of ALS is the wide distribution in age of onset, which is probably caused by different combinations of intrinsic and exogenous factors. We investigated whether these modifying factors are converging into common pathogenic pathways leading either to an early or a late disease onset. This would imply the identification of phenotypic biomarkers, that can distinguish the two populations of ALS patients, and of relevant pathways to consider in a therapeutic intervention. Toward this aim a differential proteomic analysis was performed in peripheral blood mononuclear cells (PBMC) from a group of 16 ALS patients with an age of onset ≤55 years and a group of 16 ALS patients with an age of onset ≥75 years, and matched healthy controls. We identified 43 differentially expressed proteins in the two groups of patients. Gene ontology analysis revealed that there was a significant enrichment in annotations associated with protein folding and response to stress. We next validated a selected number of proteins belonging to this functional group in 85 patients and 83 age- and sex-matched healthy controls using immunoassays. The results of the validation study confirmed that there was a decreased level of peptidyl-prolyl cis-trans isomerase A (also known as cyclophilin A), heat shock protein HSP 90-alpha, 78 kDa glucose-regulated protein (also known as BiP) and protein deglycase DJ-1 in PBMC of ALS patients with an early onset. Similar results were obtained in PBMC and spinal cord from two SOD1G93A mouse models with an early and late disease onset. This study suggests that a different ability to upregulate proteins involved in proteostasis, such as foldase and chaperone proteins, may be at the basis of a different susceptibility to ALS, putting forward the development of therapeutic approaches aiming at boosting the protein quality control system.
Editorial: The CB2 Cannabinoid System: A New Strategy in Neurodegenerative Disorder and Neuroinflammation
Apr 21, 2017   Frontiers In Neuroscience
Contino M, Capparelli E, Colabufo NA, Bush AI
Protein Quality Control by Molecular Chaperones in Neurodegeneration
Apr 21, 2017   Frontiers In Neuroscience
Ciechanover A, Kwon YT
Protein Quality Control by Molecular Chaperones in Neurodegeneration
Apr 21, 2017
Frontiers In Neuroscience
Protein homeostasis (proteostasis) requires the timely degradation of misfolded proteins and their aggregates by protein quality control (PQC), of which molecular chaperones are an essential component. Compared with other cell types, PQC in neurons is particularly challenging because they have a unique cellular structure with long extensions. Making it worse, neurons are postmitotic, i.e., cannot dilute toxic substances by division, and, thus, are highly sensitive to misfolded proteins, especially as they age. Failure in PQC is often associated with neurodegenerative diseases, such as Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), and prion disease. In fact, many neurodegenerative diseases are considered to be protein misfolding disorders. To prevent the accumulation of disease-causing aggregates, neurons utilize a repertoire of chaperones that recognize misfolded proteins through exposed hydrophobic surfaces and assist their refolding. If such an effort fails, chaperones can facilitate the degradation of terminally misfolded proteins through either the ubiquitin (Ub)-proteasome system (UPS) or the autophagy-lysosome system (hereafter autophagy). If soluble, the substrates associated with chaperones, such as Hsp70, are ubiquitinated by Ub ligases and degraded through the proteasome complex. Some misfolded proteins carrying the KFERQ motif are recognized by the chaperone Hsc70 and delivered to the lysosomal lumen through a process called, chaperone-mediated autophagy (CMA). Aggregation-prone misfolded proteins that remain unprocessed are directed to macroautophagy in which cargoes are collected by adaptors, such as p62/SQSTM-1/Sequestosome-1, and delivered to the autophagosome for lysosomal degradation. The aggregates that have survived all these refolding/degradative processes can still be directly dissolved, i.e., disaggregated by chaperones. Studies have shown that molecular chaperones alleviate the pathogenic symptoms by neurodegeneration-causing protein aggregates. Chaperone-inducing drugs and anti-aggregation drugs are actively exploited for beneficial effects on symptoms of disease. Here, we discuss how chaperones protect misfolded proteins from aggregation and mediate the degradation of terminally misfolded proteins in collaboration with cellular degradative machinery. The topics also include therapeutic approaches to improve the expression and turnover of molecular chaperones and to develop anti-aggregation drugs.
Vascular Cognitive Impairment in a Memory Clinic Population: Rationale and Design of the "Utrecht-Amsterdam Clinical Features and Prognosis in Vascular Cognitive Impairment" (TRACE-VCI) Study
Apr 21, 2017   JMIR Research Protocols
Boomsma JMF, Exalto LG, Barkhof F, van den Berg E, de Bresser J, Heinen R, Koek HL, Prins ND, Scheltens P, Weinstein HC, van der Flier WM, Biessels GJ
Vascular Cognitive Impairment in a Memory Clinic Population: Rationale and Design of the "Utrecht-Amsterdam Clinical Features and Prognosis in Vascular Cognitive Impairment" (TRACE-VCI) Study
Apr 21, 2017
JMIR Research Protocols
Vascular Cognitive Impairment (VCI) refers to cognitive dysfunction due to vascular brain injury, as a single cause or in combination with other, often neurodegenerative, etiologies. VCI is a broad construct that captures a heterogeneous patient population both in terms of cognitive and noncognitive symptoms and in terms of etiology and prognosis. This provides a challenge when applying this construct in clinical practice. This paper presents the rationale and design of the TRACE-VCI study, which investigates the clinical features and prognosis of VCI in a memory clinic setting. The TRACE-VCI project is an observational, prospective cohort study of 861 consecutive memory clinic patients with possible VCI. Between 2009 and 2013, patients were recruited through the Amsterdam Dementia Cohort of the VU University Medical Centre (VUMC) (N=665) and the outpatient memory clinic and VCI cohort of the University Medical Centre Utrecht (UMCU) (N=196). We included all patients attending the clinics with magnetic resonance imaging (MRI) evidence of vascular brain injury. Patients with a primary etiology other than vascular brain injury or neurodegeneration were excluded. Patients underwent an extensive 1-day memory clinic evaluation including an interview, physical and neurological examination, assessment of biomarkers (including those for Alzheimer-type pathologies), extensive neuropsychological testing, and an MRI scan of the brain. For prognostic analyses, the composite primary outcome measure was defined as accelerated cognitive decline (change of clinical dementia rating ≥1 or institutionalization) or (recurrent) major vascular events or death over the course of 2 years. The mean age at baseline was 67.7 (SD 8.5) years and 46.3% of patients (399/861) were female. At baseline, the median Clinical Dementia Rating was 0.5 (interquartile range [IQR] 0.5-1.0) and the median Mini-Mental State Examination score was 25 (IQR 22-28). The clinical diagnosis at baseline was dementia in 52.4% of patients (451/861), mild cognitive impairment in 24.6% (212/861), and no objective cognitive impairment in the remaining 23.0% (198/861). The TRACE-VCI study represents a large cohort of well-characterized patients with VCI in a memory clinic setting. Data processing and collection for follow-up are currently being completed. The TRACE-VCI study will provide insight into the clinical features of memory clinic patients that meet VCI criteria and establish key prognostic factors for further cognitive decline and (recurrent) major vascular events.
Serum uric acid level is linked to the disease progression rate in male patients with multiple system atrophy
Apr 22, 2017   Clinical Neurology And Neurosurgery
Fukae J, Fujioka S, Yanamoto S, Mori A, Nomi T, Hatano T, Fukuhara K, Ouma S, Hattori N, Tsuboi Y
Serum uric acid level is linked to the disease progression rate in male patients with multiple system atrophy
Apr 22, 2017
Clinical Neurology And Neurosurgery
Multiple system atrophy (MSA) is a progressive neurodegenerative disorder that may be caused in part by oxidative stress. Uric acid (UA) protects neurons in neurodegenerative disorders via antioxidative effects. The aim of this study was to investigate the relationship between the serum UA concentration and disease progression in MSA patients. A total of 53 Japanese MSA patients were enrolled in this study. The disease progression rate was estimated by the rate of global disability scale change per year. The relationship between the serum UA concentration and disease progression was assessed by Spearman's correlation analysis. Disease progression depending on the UA concentration was also estimated by multivariate logistic regression analysis. MSA patients with the highest serum UA concentration had lower disease progression rates than those with the lowest concentration. Spearman's correlation analysis showed an inverse correlation between the serum UA concentration and disease progression in male patients. Multivariate logistic regression analysis confirmed that the UA concentration was independently related to disease progression only in male patients. These results suggest that serum UA may be associated with disease progression in male patients with MSA. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

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