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Miami, FL, United States

Shan D.,University of Alabama at Birmingham | Mount D.,University of Alabama at Birmingham | Moore S.,University of Alabama | Haroutunian V.,Mount Sinai School of Medicine | And 3 more authors.
Schizophrenia Research | Year: 2014

Excitatory amino acid transporter 2 (EAAT2) belongs to a family of Na+ dependent glutamate transporters that maintain a low synaptic concentration of glutamate by removing glutamate from the synaptic cleft into astroglia and neurons. EAAT2 activity depends on Na+ and K+ gradients generated by Na+/K+ ATPase and ATP. Hexokinase 1 (HK1), an initial enzyme of glycolysis, binds to mitochondrial outer membrane where it couples cytosolic glycolysis to mitochondrial oxidative phosphorylation, producing ATP utilized by the EAAT2/Na+/K+ ATPase protein complex to facilitate glutamate reuptake. In this study, we hypothesized that the protein complex formed by EAAT2, Na+/K+ ATPase and mitochondrial proteins in human postmortem prefrontal cortex may be disrupted, leading to abnormal glutamate transmission in schizophrenia. We first determined that EAAT2, Na+/K+ ATPase, HK1 and aconitase were found in both EAAT2 and Na+/K+ ATPase interactomes by immunoisolation and mass spectrometry in human postmortem prefrontal cortex. Next, we measured levels of glutamate transport complex proteins in subcellular fractions in the dorsolateral prefrontal cortex and found increases in the EAAT2B isoform of EAAT2 in a fraction containing extrasynaptic membranes and increased aconitase 1 in a mitochondrial fraction. Finally, an increased ratio of HK1 protein in the extrasynaptic membrane/mitochondrial fraction was found in subjects with schizophrenia, suggesting that HK1 protein is abnormally partitioned in this illness. Our findings indicate that the integrity of the glutamate transport protein complex may be disrupted, leading to decreased perisynaptic buffering and reuptake of glutamate, as well as impaired energy metabolism in schizophrenia. © 2014 Elsevier B.V. Source

Moon Y.P.,Columbia University | Paik M.C.,Columbia University | Sacco R.L.,Evelyn F Mcknight Brain Institute | Sacco R.L.,University of Miami | Elkind M.S.V.,Mount Sinai School of Medicine
Stroke | Year: 2011

Background and Purpose-The Framingham coronary heart disease (CHD) risk score estimates 10-year risk of myocardial infarction (MI) and CHD death. Because preventive approaches to CHD and stroke are similar, a composite outcome may be more appropriate. We compared 10-year risk of (1) MI or CHD death; and (2) stroke, MI, or CHD death among individuals free of vascular disease. Methods-The Northern Manhattan Study contains a prospective, population-based study of stroke-and CHD-free individuals 40 years of age followed for a median of 10 years for vascular events. Framingham coronary heart disease risk score was calculated for each individual and for each category of predicted risk, Kaplan-Meier observed 10-year cumulative probabilities were calculated for (1) MI or CHD death; and (2) stroke, MI, or CHD death. The cumulative probability of (1) was subtracted from (2), and 95% CIs for the difference were obtained with 1000 bootstrap samples. Using stratified analyses by race-ethnicity, we compared risk differences among race-ethnic groups. RESULTS-: Among 2613 participants (53% Hispanic, 25% non-Hispanic black, and 20% non-Hispanic white), observed 10-year risk of MI or CHD death was 14.20%. With stroke in the outcome, observed risk was 21.98% (absolute risk difference, 7.78%; 95% CI, 5.86% to 9.75%). The absolute risk difference among blacks was significantly larger than among whites (P=0.01). Conclusions-In this multiethnic urban population, adding stroke to the risk stratification outcome cluster resulted in a 55% relative increase in estimated risk and crossing of the absolute risk threshold (>20% over 10 years) considered for preventive treatments such as statins. © 2011 American Heart Association, Inc. Source

Xue B.,University of Iowa | Zhang Z.,Nanyang Institute of Technology | Beltz T.G.,University of Iowa | Guo F.,University of Iowa | And 3 more authors.
American Journal of Physiology - Regulatory Integrative and Comparative Physiology | Year: 2015

The present study tested the hypotheses that 1) ERα in the brain plays a key role in the estrogen-protective effects against ANG II-induced hypertension, and 2) that the subfornical organ (SFO) is a key site where ERα mediates these protective actions. In this study, a “floxed” ERα transgenic mouse line (ERαflox) was used to create models in which ERα was knocked down in the brain or just in the SFO. Female mice with ERα ablated in the nervous system (Nestin-ERα– mice) showed greater increases in blood pressure (BP) in response to ANG II. Furthermore, females with ERα knockdown specifically in the SFO [SFO adenovirus-Cre (Ad-Cre) injected ERαflox mice] also showed an enhanced pressor response to ANG II. Immunohistochemical (IHC), RT-PCR, and Western blot analyses revealed a marked reduction in the expression of ERα in nervous tissues and, in particular, in the SFO. These changes were not present in peripheral tissues in Nestin- ERα– mice or Ad-Cre-injected ERαflox mice. mRNA expression of components of the renin-angiotensin system in the lamina terminalis were upregulated in Nestin-ERα– mice. Moreover, ganglionic blockade on day 7 after ANG II infusions resulted in a greater reduction of BP in Nestin-ERα– mice or SFO Ad-Cre-injected mice, suggesting that knockdown of ERα in the nervous system or the SFO alone augments central ANG II-induced increase in sympathetic tone. The results indicate that interfering with the action of estrogen on SFO ERα is sufficient to abolish the protective effects of estrogen against ANG II-induced hypertension. © 2015 the American Physiological Society. Source

Glazer H.,Evelyn F Mcknight Brain Institute | Dong C.,Evelyn F Mcknight Brain Institute | Yoshita M.,Hokuriku National Hospital | Rundek T.,Evelyn F Mcknight Brain Institute | And 5 more authors.
Neurology | Year: 2015

Objective: Memory has been examined in subjects with imaging markers of cerebrovascular disease, but learning has been less well studied. We examined the relationship among subclinical cerebrovascular disease, cerebral volumes, and verbal learning in an ethnically and racially diverse community sample. Methods: A clinically stroke-free subset of Northern Manhattan Study participants underwent cognitive testing and brain MRI with quantification of white matter hyperintensity volume (WMHV) and total cerebral volume (TCV) using semiautomated segmentation. We used generalized linear regression and mixed models to examine the association between imaging findings and verbal learning. Results: There were 1,272 participants (61% women, mean age 70 ± 9 years). Participants with greater WMHV and smaller TCV remembered fewer total words on a list-learning task (β-0.83 per SD change in WMHV, 95% confidence interval [CI]-1.22 to-0.45, p < 0.0001; and β 0.48 per SD change in TCV, 95% CI 0.05 to 0.90, p 0.03, respectively). Subclinical brain infarction (SBI) was not associated with total words learned (β-0.04, 95% CI-1.08 to 1.00, p 0.94). Those with greater WMHV had increased odds of a flatter learning slope. After excluding participants with SBI, the association between total words learned and WMHV remained significant. All measurements were adjusted for age, education, race/ethnicity, medical insurance status, and the presence of SBI. Conclusions: White matter hyperintensities, a marker of cerebral small vessel disease, may have an impact on learning slope. This suggests that verbal learning performance can be incorporated into neuropsychological measures for vascular cognitive impairment and that cerebrovascular disease discovered on imaging affects the ability to learn new information. © 2015 American Academy of Neurology. Source

Wright C.B.,Evelyn F Mcknight Brain Institute | Flores A.,University of Miami | Flores A.,Autonomous University of Barcelona
Neurology: Clinical Practice | Year: 2015

Summary Unlike many neurodegenerative causes of cognitive impairment and dementia, vascular damage is preventable. Despite the heterogeneity of vascular cognitive impairment (VCI) and the complexity of its clinical presentations, the potential for limiting progression and changing the trajectory of damage makes it all the more important for physicians to be educated about the syndrome and to remain vigilant when taking care of patients. In this review, we outline an approach to patients with possible VCI, summarize current treatment and prevention guidelines, and provide an overview with case examples. © 2015 American Academy of Neurology. Source

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