Bcl-2 functionally interacts with inositol 1,4,5-trisphosphate receptors to regulate calcium release from the ER in response to inositol 1,4,5-trisphosphate

Inositol 1,4,5-trisphosphate (InsP3) receptors (InsP3Rs) are channels responsible for calcium release from the endoplasmic reticulum (ER). We show that the anti-apoptotic protein Bcl-2 (either wild type or selectively localized to the ER) significantly inhibited InsP3-mediated calcium release and elevation of cytosolic calcium in WEHI7.2 T cells. This inhibition was due to an effect of Bcl-2 at the level of InsP3Rs because responses to both anti-CD3 antibody and a cell-permeant InsP3 ester were decreased. Bcl-2 inhibited the extent of calcium release from the ER of permeabilized WEHI7.2 cells, even at saturating concentrations of InsP3, without decreasing luminal calcium concentration. Furthermore, Bcl-2 reduced the open probability of purified InsP3Rs reconstituted into lipid bilayers. Bcl-2 and InsP3Rs were detected together in macromolecular complexes by coimmunoprecipitation and blue native gel electrophoresis. We suggest that this functional interaction of Bcl-2 with InsP3Rs inhibits InsP3R activation and thereby regulates InsP3-induced calcium release from the ER

Hemodynamic differences in children with dichotic listening deficits: Preliminary results from an fMRI study during a cued listening task

Functional magnetic resonance images were acquired while children with and without dyslexia identified incongruous words embedded within fairy tale segments in a quasidichotic listening task. All children produced greater activation in the left hemisphere than in the right hemisphere during the binaural separation listening task. Children with dyslexia, who had a higher incidence of a dichotic left ear deficit from prescanning behavioral tests, produced fewer hits and more misses than control children while monitoring their left ears in the scanner. Control children produced stronger left hemispheric activation for ipsilateral left ear input than right hemispheric activation for ipsilateral right ear input, but ipsilateral activation patterns in children with dyslexia were symmetrical. Children with dyslexia who monitored their right ears first produced the lowest left hemispheric activation overall, suggesting that priming of the right ear may have inhibited the ability of children with a left ear deficit to adequately identify target words presented toward their left ears while in the scanner

Cognitive Impact of Lacunar Infarcts and White Matter Hyperintensity Volume

Background: Subcortical lacunar infarcts and white matter hyperintensities (WMH) are common neuroradiological findings, but few studies associate between these insults and cognition in a community-dwelling population. Methods: The Dallas Heart Study is a population-based initiative whose assessments included demographic and clinical findings including brain MRI and the Montreal Cognitive Assessment (MoCA). The presence and number of lacunes in subjects aged over 55 years were assessed by study physicians. The WMH volume was measured by an automated method. The association between the presence and number of lacunar infarcts and of WMH volume with the total MoCA score and subdomains was assessed using linear regression with adjustment for age, gender and self-reported ethnicity. Results: In 609 subjects with valid data, both the presence and the increasing number of lacunes were associated with lower MoCA scores, even after adjusting for demographic variables. The presence of lacunes was also associated with lower scores in the memory, executive and attention subdomains. The WMH volume was not significantly associated with the MoCA score. Conclusion: The presence and increasing number of lacunes in midlife is associated with a lower performance in multiple domains of a cognitive screening measure after adjusting for demographic factors

Cognitive Impact of Lacunar Infarcts and White Matter Hyperintensity Volume

Background: Subcortical lacunar infarcts and white matter hyperintensities (WMH) are common neuroradiological findings, but few studies associate between these insults and cognition in a community-dwelling population. Methods: The Dallas Heart Study is a population-based initiative whose assessments included demographic and clinical findings including brain MRI and the Montreal Cognitive Assessment (MoCA). The presence and number of lacunes in subjects aged over 55 years were assessed by study physicians. The WMH volume was measured by an automated method. The association between the presence and number of lacunar infarcts and of WMH volume with the total MoCA score and subdomains was assessed using linear regression with adjustment for age, gender and self-reported ethnicity. Results: In 609 subjects with valid data, both the presence and the increasing number of lacunes were associated with lower MoCA scores, even after adjusting for demographic variables. The presence of lacunes was also associated with lower scores in the memory, executive and attention subdomains. The WMH volume was not significantly associated with the MoCA score. Conclusion: The presence and increasing number of lacunes in midlife is associated with a lower performance in multiple domains of a cognitive screening measure after adjusting for demographic factors

Automated quantification of white matter disease extent at 3 T: comparison with volumetric readings

PURPOSE: To develop and validate an algorithm to automatically quantify white matter hyperintensity (WMH) volume. MATERIALS AND METHODS: Images acquired as part of the Dallas Heart Study, a multiethnic, population-based study of cardiovascular health, were used to develop and validate the algorithm. 3D magnetization prepared rapid acquisition gradient echo (MP-RAGE) and 2D fluid-attenuated inversion recovery (FLAIR) images were acquired from 2082 participants. Images from 161 participants (7.7% of the cohort) were used to set an intensity threshold to maximize the agreement between the algorithm and a qualitative rating made by a radiologist. The resulting algorithm was run on the entire cohort and outlier analyses were used to refine the WMH volume measurement. The refined, automatic WMH burden estimate was then compared to manual quantitative measurements of WMH volume in 28 participants distributed across the range of volumes seen in the entire cohort. RESULTS: The algorithm showed good agreement with the volumetric readings of a trained analyst: the Spearman\u27s Rank Order Correlation coefficient was r = 0.87. Linear regression analysis showed a good correlation WMHml[automated] = 1.02 × WMHml[manual] - 0.48. Bland-Altman analysis showed a bias of 0.34 mL and a standard deviation of 2.8 mL over a range of 0.13 to 41 mL. CONCLUSION: We have developed an algorithm that automatically estimates the volume of WMH burden using an MP-RAGE and a FLAIR image. This provides a tool for evaluating the WMH burden of large populations to investigate the relationship between WMH burden and other health factors

Effect of leukocyte telomere length on total and regional brain volumes in a large population-based cohort

IMPORTANCE: Telomere length has been associated with dementia and psychological stress, but its relationship with human brain size is unknown. OBJECTIVE: To determine if peripheral blood telomere length is associated with brain volume. DESIGN, SETTING, AND PARTICIPANTS: Peripheral blood leukocyte telomere length and brain volumes were measured for 1960 individuals in the Dallas Heart Study, a population-based, probability sample of Dallas County, Texas, residents, with a median (25th-75th percentile) age of 50 (42-58) years. Global and 48 regional brain volumes were assessed from the automated analysis of magnetic resonance imaging. MAIN OUTCOMES AND MEASURES: Telomere length and global and regional brain volumes. RESULTS: Leukocyte telomere length was associated with total cerebral volume (β [SE], 0.06 [0.01], P \u3c.001) including white and cortical gray matter volume (β [SE], 0.04 [0.01], P = .002; β [SE], 0.07 [0.02], P \u3c.001, respectively), independent of age, sex, ethnicity, and total intracranial volume. While age was associated with the size of most subsegmental regions of the cerebral cortex, telomere length was associated with certain subsegmental regions. Compared with age, telomere length (TL) explained a sizeable proportion of the variance in volume of the hippocampus, amygdala, and inferior temporal region (hippocampus: βTL [SE], 0.08 [0.02], R2, 0.91% vs βage [SE], -0.16 [0.02], R2, 3.80%; amygdala: βTL [SE], 0.08 [0.02], R2, 0.78% vs βage [SE],-0.19 [0.02], R2,4.63%; inferior temporal: βTL [SE], 0.07 [0.02], R2, 0.92% vs βage [SE], -0.14 [0.02], R2, 3.98%) (P \u3c.001 for all). The association of telomere length and the size of the inferior and superior parietal, hippocampus, and fusiform regions was stronger in individuals older than 50 years than younger individuals (inferior parietal: β\u3e50 [SE], 0.13 [0.03], P \u3c.001 vs β≤50 [SE], 0.02 [0.02], P = .51, P for interaction = .001; superior parietal: β\u3e50 [SE], 0.11 [0.03], P \u3c.001 vs β≤50 [SE], 0.01 [0.02], P = .71, P for interaction = .004; hippocampus: β\u3e50 [SE], 0.10 [0.03], P = .004 vs β≤50 [SE], 0.05 [0.02], P = .07, P for interaction = .04; fusiform: β\u3e50 [SE], 0.09 [0.03], P = .002, β≤50 [SE], 0.03 [0.02], P = .31, P for interaction = .03). The volume of the hippocampus, amygdala, superior and inferior temporal, precuneus, lateral orbitofrontal, posterior cingulate, thalamus and ventral diencephalon were independently associated with telomere length after adjustment for all covariates (age, gender, ethnicity, total intracranial volume, body mass index, blood pressure, diabetes, smoking status, and APOE genotype). CONCLUSIONS AND RELEVANCE: To our knowledge, this is the first population-based study to date to evaluate telomere length as an independent predictor of global and regional brain size. Future studies are needed to determine how telomere length and anatomic structural changes are related to cognitive function, dementia, and psychological disease