Greenbaum L.,Sheba Medical Center at Tel Hashomer |
Greenbaum L.,The Joseph Sagol Neuroscience Center |
Lerer B.,Hebrew University of Jerusalem
Frontiers in Neurology | Year: 2015
Antipsychotic-induced movement disorders are major side effects of antipsychotic drugs among schizophrenia patients, and include antipsychotic-induced parkinsonism (AIP) and tardive dyskinesia (TD). Substantial pharmacogenetic work has been done in this field, and several susceptibility variants have been suggested. In this paper, the genetics of antipsychotic-induced movement disorders is considered in a broader context. We hypothesize that genetic variants that are risk factors for AIP and TD may provide insights into the pathophysiology of motor symptoms in Parkinson's disease (PD). Since loss of dopaminergic stimulation (albeit pharmacological in AIP and degenerative in PD) is shared by the two clinical entities, genes associated with susceptibility to AIP may be modifier genes that influence clinical expression of PD motor sub-phenotypes, such as age at onset, disease severity, or rate of progression. This is due to their possible functional influence on compensatory mechanisms for striatal dopamine loss. Better compensatory potential might be beneficial at the early and later stages of the PD course. AIP vulnerability variants could also be related to latent impairment in the nigrostriatal pathway, affecting its functionality, and leading to subclinical dopaminergic deficits in the striatum. Susceptibility of PD patients to early development of L-DOPA induced dyskinesia (LID) is an additional relevant sub-phenotype. LID might share a common genetic background with TD, with which it shares clinical features. Genetic risk variants may predispose to both phenotypes, exerting a pleiotropic effect. According to this hypothesis, elucidating the genetics of antipsychotic-induced movement disorders may advance our understanding of multiple aspects of PD and it clinical course, rendering this a potentially rewarding field of study. © 2015 Greenbaum and Lerer.
Fogelson N.,University of La Coruña |
Fogelson N.,The Joseph Sagol Neuroscience Center
Neuroscience and Biobehavioral Reviews | Year: 2015
The objective of the current review is to integrate information from a series of studies, employing a paradigm that evaluates local contextual processing using electrophysiological measures. Collectively these studies provide an overview of how utilization of predictive context changes as a function of stimulus modality and across different patient populations, as well as the networks that may be critical for this function. The following aspects of local contextual processing will be discussed and reviewed: (i) the correlates associated with contextual processing that have been identified in healthy adults, (ii) stimulus modality effects, (iii) specific alterations and deficits of local contextual processing in aging and across different neurological and psychiatric patient populations, including patients with prefrontal cortex lesions, Parkinson's disease, schizophrenia, and major depressive disorder, (iv) the potential for utilizing the correlates of local context as biomarkers for frontal cognitive dysfunction and (v) the role of frontal networks in the processing of contextual information. Overall findings show that behavioral and neural correlates associated with processing of local context are comparable across stimulus modalities, but show specific alterations in aging and across different neurological and psychiatric disorders. © 2015 Elsevier Ltd.
Gaisler-Salomon I.,Cancer Research Center |
Gaisler-Salomon I.,Haifa University |
Gaisler-Salomon I.,Columbia University |
Kravitz E.,Tel Aviv University |
And 7 more authors.
Neurobiology of Aging | Year: 2014
Adenosine to inosine (A-to-I) RNA editing is a base recoding process within precursor messenger RNA, catalyzed by members of the adenosine deaminase acting on RNA (ADAR) family. A notable example occurs at the Q/R site of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptor subunit GluA2. Abnormally, low editing at this site leads to excessive calcium influx and cell death. We studied hippocampus and caudate samples from Alzheimer's disease (AD) patients and age-matched healthy controls, using direct sequencing and a high accuracy primer-extension technique to assess RNA editing at the Q/R GluA2 site. Both techniques revealed lower, more variable RNA editing in AD, specific to the hippocampus and the GluA2 site. Deficient editing also characterized the hippocampus of apolipoprotein ε4 allele carriers, regardless of clinical diagnosis. In AD, messenger RNA expression of neuronal markers was decreased in the hippocampus, and expression of the Q/R-site editing enzyme ADAR2 was decreased in caudate. These findings provide a link between neurodegenerative processes and deficient RNA editing of the GluA2 Q/R site, and may contribute to both diagnosis and treatment of AD. © 2014 Elsevier Inc.
Maggio N.,The Joseph Sagol Neuroscience Center |
Maggio N.,The Chaim Sheba Medical Center |
Shavit-Stein E.,The Joseph Sagol Neuroscience Center |
Dori A.,The Joseph Sagol Neuroscience Center |
And 5 more authors.
Frontiers in Molecular Neuroscience | Year: 2013
Transient systemic inflammation has been shown to cause altered behavior both in humans and in laboratory animals through activation of microglia and heightened level of cytokines detected in the brain and in the body. Furthermore, both activated microglia and the increased cytokines level have been associated with the sudden clinical deterioration in demented people or in aged patients upon systemic inflammation. Whilst it is increasingly becoming clear the role of transient systemic inflammation in promoting dementia in aged individuals, it is still a matter of debate whether prolonged systemic inflammation might persistently modify the brain. In this study, we examined the influence of a systemic long term inflammatory event on synaptic plasticity. We report that while a short exposure to LPS produces transient deficit in long term potentiation (LTP) expression, systemic prolonged inflammation impairs LTP in slices of animals previously primed by a Complete Freund's adjuvant injection. Interestingly, steroids are able to modulate this effect: whereas glucocorticosteroid (GR) activation further reduces LTP, mineralocorticosteroid receptors (MR) activation promotes the full recovery of LTP. We believe that this research advances the current understandings on the role of the immune system in the onset and progression of cognitive deficits following long lasting systemic inflammation, and proposes possible insights on future strategies in order to prevent early dementia in these predisposed individuals. © 2013 Maggio, Shavit-Stein, Dori, Blatt and Chapman.
Boussi-Gross R.,The Institute of Hyperbaric Medicine |
Golan H.,Nuclear Medicine Institute |
Volkov O.,Nuclear Medicine Institute |
Bechor Y.,The Institute of Hyperbaric Medicine |
And 7 more authors.
Neuropsychology | Year: 2015
Objective: Several recent studies have shown that hyperbaric oxygen (HBO2) therapy carry cognitive and motor therapeutic effects for patients with acquired brain injuries. The goal of this study was to address the specific effects of HBO2 on memory impairments after stroke at late chronic stages. Method: A retrospective analysis was conducted on data of 91 stroke patients 18 years or older (mean age ~60 years) who had either ischemic or hemorrhagic stroke 3-180 months before HBO2 therapy (M = 30-35 months). The HBO2 protocol included 40 to 60 daily sessions, 5 days per week, 90 min each, 100% oxygen at 2ATA, and memory tests were administered before and after HBO2 therapy using NeuroTrax's computerized testing battery. Assessments were based on verbal or nonverbal, immediate or delayed memory measures. The cognitive tests were compared with changes in the brain metabolic state measured by single-photon emission computed tomography. Results: Results revealed statistically significant improvements (p < .0005, effect sizes medium to large) in all memory measures after HBO2 treatments. The clinical improvements were well correlated with improvement in brain metabolism, mainly in temporal areas. Conclusions: Although further research is needed, the results illustrate the potential of HBO2 for improving memory impairments in poststroke patients, even years after the acute event. © 2014 American Psychological Association.
Otahal J.,Academy of Sciences of the Czech Republic |
Folbergrova J.,Academy of Sciences of the Czech Republic |
Kovacs R.,Charité - Medical University of Berlin |
Kunz W.S.,University of Bonn |
And 2 more authors.
International Review of Neurobiology | Year: 2014
Epilepsy is one of the most common neurologic disorders affecting a substantial part of the population worldwide. Epileptic seizures represent the situation of increased neuronal activity associated with the enhanced demands for sufficient energy supply. For that purpose, very efficient regulatory mechanisms have to operate to ensure that cerebral blood flow, delivery of oxygen, and nutrients are continuously adapted to the local metabolic needs. The sophisticated regulation has to function in concert at several levels (systemic, tissue, cellular, and subcellular). Particularly, mitochondria play a key role not only in the energy production, but they are also central to many other processes including those leading to neuronal death. Impairment of any of the involved pathways can result in serious functional alterations, neurodegeneration, and potentially in epileptogenesis. The present review will address some of the important issues concerning vascular and metabolic changes in pathophysiology of epilepsy. © 2014 Elsevier Inc.
PubMed | Hebrew University of Jerusalem and The Joseph Sagol Neuroscience Center
Type: Journal Article | Journal: Journal of molecular neuroscience : MN | Year: 2016
Cognitive deficits, especially memory loss, are common following many types of brain insults which are associated with neuroinflammation, although the underlying mechanisms are not entirely clear. The present study aimed to characterize the long-term cognitive and behavioral impairments in a mouse model of neuroinflammation in the absence of other insults and to evaluate the therapeutic potential of D-cycloserine (DCS). DCS is a co-agonist of the NMDA receptor that ameliorates cognitive deficits in models of TBI and stroke. Using a mouse model of global neuroinflammation induced by intracisternal (i.c.) administration of endotoxin (LPS), we found long-lasting microgliosis, memory deficits, impaired LTP, and reduced levels of the obligatory NR1 subunit of the NMDA receptor. A single administration of DCS, 1day after i.c. LPS reduced microgliosis, reversed the cognitive deficits and restored LTP and NR1 levels. These results demonstrate that neuroinflammation alone, in the absence of trauma or ischemia, can cause persistent (>6months) memory deficits linked to deranged NNMDA receptor function and suggest a possible role for NMDA co-agonists in reducing the cognitive sequelae of neuroinflammation.
PubMed | Tel Aviv University, Mount Sinai School of Medicine, The Joseph Sagol Neuroscience Center and Simon Fraser University
Type: Journal Article | Journal: Alzheimer's & dementia : the journal of the Alzheimer's Association | Year: 2016
Waist circumference is associated with type 2 diabetes (T2D) and cognition, yet the relationship between waist circumference and cognition in individuals with T2D is not well understood.We studied the relationship of waist circumference with five cognitive outcomes (executive functioning, language/semantic categorization, attention/working memory, episodic memory, and an overall cognition measure) in 845 cognitively normal elderly with type 2 diabetes (T2D).In women, waist circumference was correlated with significantly lower language and/or semantic categorization performance (P<.0001), executive functioning (P=.026), and overall cognition (P=.003) after controlling for age, education, BMI, and cardiovascular, diabetes-related, APOE 4, and inflammatory potential confounders. Attention/working memory (P=.532) and episodic memory (P=.144) were not associated with waist circumference. These correlations were not found in men.These results suggest that central adiposity in elderly women with T2D may increase their risk for dementia.
PubMed | Tel Aviv University, Mount Sinai School of Medicine, The Joseph Sagol Neuroscience Center, Technion - Israel Institute of Technology and Maccabi Healthcare Services
Type: Journal Article | Journal: International journal of geriatric psychiatry | Year: 2016
The haptoglobin (Hp) genotype has been associated with cognitive function in type 2 diabetes. Because ethnicity/culture has been associated with both cognitive function and Hp genotype frequencies, we examined whether it modulates the association of Hp with cognitive function.This cross-sectional study evaluated 787 cognitively normal older individuals (>65 years of age) with type 2 diabetes participating in the Israel Diabetes and Cognitive Decline study. Interactions in two-way analyses of covariance compared Group (Non-Ashkenazi versus Ashkenazi Jews) on the associations of Hp phenotype (Hp 1-1 versus non- Hp 1-1) with five cognitive outcome measures. The primary control variables were age, gender, and education.Compared with Ashkenazi Jews, non-Ashkenazi Jews with the Hp 1-1 phenotype had significantly poorer cognitive function than non-Hp 1-1 in the domains of Attention/Working Memory (p = 0.035) and Executive Function (p = 0.023), but not in Language/Semantic Categorization (p = 0.432), Episodic Memory (p = 0.268), or Overall Cognition (p = 0.082). After controlling for additional covariates (type 2 diabetes-related characteristics, cardiovascular risk factors, Mini-mental State Examination, and extent of depressive symptoms), Attention/Working Memory (p = 0.038) and Executive Function (p = 0.013) remained significant.Older individuals from specific ethnic/cultural backgrounds with the Hp 1-1 phenotype may benefit more from treatment targeted at decreasing or halting the detrimental effects of Hp 1-1 on the brain. Future studies should examine differential associations of Hp 1-1 and cognitive impairment, especially for groups with high prevalence of both, such as African-Americans and Hispanics.
Normal human CD4(+) helper T cells express Kv11 voltage-gated K(+) channels, and selective Kv11 block in T cells induces by itself robust TNFα production and secretion and activation of the NFκB non-canonical pathway
PubMed | Hebrew University of Jerusalem, Immunis e.V. and Immunotherapy Research Center, Pain Medicine Institute, Immunotherapy Research Center and 6 more.
Type: Journal Article | Journal: Journal of neural transmission (Vienna, Austria : 1996) | Year: 2016
TNF is a very potent and pleiotropic pro-inflammatory cytokine, essential to the immune system for eradicating cancer and microorganisms, and to the nervous system, for brain development and ongoing function. Yet, excess and/or chronic TNF secretion causes massive tissue damage in autoimmune, inflammatory and neurological diseases and injuries. Therefore, many patients with autoimmune/inflammatory diseases receive anti-TNF medications. TNF is secreted primarily by CD4(+) T cells, macrophages, monocytes, neutrophils and NK cells, mainly after immune stimulation. Yet, the cause for the pathologically high and chronic TNF secretion is unknown. Can blocking of a particular ion channel in T cells induce by itself TNF secretion? Such phenomenon was never revealed or even hypothesized. In this interdisciplinary study we discovered that: (1) normal human T cells express Kv1.1 voltage-gated potassium channel mRNA, and the Kv1.1 membrane-anchored protein channel; (2) Kv1.1 is expressed in most CD4(+)CD3(+) helper T cells (mean CD4(+)CD3(+)Kv1.1(+) T cells of 7 healthy subjects: 53.0922.17%), but not in CD8(+)CD3(+) cytotoxic T cells (mean CD8(+)CD3(+)Kv1.1(+) T cells: 4.123.04%); (3) electrophysiological whole-cell recordings in normal human T cells revealed Kv currents; (4) Dendrotoxin-K (DTX-K), a highly selective Kv1.1 blocker derived from snake toxin, increases the rate of rise and decay of Kv currents in both resting and activated T cells, without affecting the peak current; (5) DTX-K by itself induces robust TNF production and secretion by normal human T cells, without elevating IFN, IL-4 and IL-10; (6) intact Ca(2+) channels are required for DTX-induced TNF secretion; (7) selective anti-Kv1.1 antibodies also induce by themselves TNF secretion; (8) DTX-K activates NFB in normal human T cells via the unique non-canonical-pathway; (9) injection of Kv1.1-blocked human T cells to SCID mice, causes recruitment of resident mouse cells into the liver, alike reported after TNF injection into the brain. Based on our discoveries we speculate that abnormally blocked Kv1.1 in T cells (and other immune cells?), due to either anti-Kv1.1 autoimmune antibodies, or Kv1.1-blocking toxins alike DTX-K, or Kv1.1-blocking genetic mutations, may be responsible for the chronic/excessive TNF in autoimmune/inflammatory diseases. Independently, we also hypothesize that selective block of Kv1.1 in CD4(+) T cells of patients with cancer or chronic infectious diseases could be therapeutic, since it may: a. augment beneficial secretion and delivery of TNF to the disease-affected sites; b. induce recruitment and extravasation of curative immune cells and factors; c. improve accessibility of drugs to the brain and few peripheral organs thanks to TNF-induced increased permeability of organs barriers.