GWAS for executive function and processing speed suggests involvement of the CADM2 gene.

To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.

Do systolic BP and pulse pressure relate to ventricular enlargement?

BACKGROUND AND PURPOSE: To evaluate the association between systolic, diastolic and pulse pressure, and increase in ventricular size (VS). Observations in laboratory animals suggest intraventricular pulse pressure (systolic-diastolic) may play a role in ventricular enlargement. METHODS: Initial magnetic resonance (MR) scans and vascular risk factors evaluation were performed in 1812 Atherosclerosis Risk in Communities participants in 1994-1995. In 2004-2006, 1130 participants underwent repeat MR. VS was rated using a validated nine-point scale. Multiple logistic regression analysis assessed association between blood pressure measures and pulse pressure, and the change between the MR scans of VS controlling for age, sex and race. RESULTS: At baseline 1112 participants (385 black women, 200 black men, 304 white women and 223 white men) had a mean age of 61.7 ± 4.3 years. In adjusted models pulse pressure at baseline was associated with an increase in VS [odds ratio (OR) 1.19, 95% confidence interval (CI) 1.01-1.40], as was systolic pressure (OR 1.28, 95% CI 1.03-1.58). CONCLUSIONS: Systolic pressure and pulse pressure are associated with future development of increased VS. The findings are consistent with the animal literature that increased pulse pressure predisposes to risk of future increased VS. High pulse pressure might play a role in the pathogenesis of normal pressure hydrocephalus.

Risk factors and solutions for the development of neurobehavioral changes after coronary artery bypass grafting.

BACKGROUND: As operative mortality for coronary artery bypass grafting has decreased, greater attention has focused on neurobehavioral complications of coronary artery bypass grafting and cardiopulmonary bypass. METHODS: To assess risk factors and to evaluate changes in surgical technique, between 1991 and 1994 we evaluated 395 patients undergoing coronary artery bypass grafting with an 11-part neurobehavioral battery administered preoperatively and at 1 and 6 weeks postoperatively. Patients were instrumented with 5-MHz focused continuous-wave carotid Doppler transducers intraoperatively to estimate cerebral microembolism as an instantaneous perturbation of the velocity signal. Microembolism data were quantitated and compared with surgical technical maneuvers during operation and with neurobehavioral deficit (> or = 20% decline from preoperative performance on two or more neurobehavioral tests) postoperatively. These data and patient demographics were statistically analyzed (chi2, t test) and the results at 2 years (1991 and 1992; group A) were used to influence surgical technique in 1993 and 1994 (group B). RESULTS: Significantly associated with new neurobehavioral deficits were increasing patient age (p < 0.05), more than 100 emboli per case (p < 0.04), and palpable aortic plaque (p < 0.02). Group B patients had a significant decline in the neurobehavioral event rate (group A, 69%, 140/203; versus group B, 60%, 115/192; p < 0.05) of postoperative neurobehavioral deficits at 1 week and at 1 month (group A, 29%, 52/180; versus group B, 18%, 35/198; p < 0.01). The stroke rate was less than 2% in both groups (p = not significant). Modifications of surgical technique used in group B patients included increased use of single cross-clamp technique, increased venting of the left ventricle, and application of transesophageal and epiaortic ultrasound scanning to locate and avoid trauma to aortic atherosclerotic plaques. CONCLUSIONS: Neurobehavioral changes after coronary artery bypass grafting are common and associated with cerebral microembolization. Surgical technical maneuvers designed to reduce emboli production may improve neurobehavioral outcome.

Guardianship for elders: process and issues.

1. Guardianship for the elderly is a complex legal and social issue that affects all individuals involved in the care of elderly clients. 2. Professionals from the medical, nursing, and legal fields are spear-heading policy changes to address the needs of elderly guardianship. 3. Government continues to enact reforms allowing states to act in the best interests of the ward and the guardian.

Vascular risk factors and longitudinal changes on brain MRI: the ARIC study.

OBJECTIVE: To evaluate associations between vascular risk factors and changes in burden of infarcts, ventricular size (VS), sulcal widening (SW), and white matter hyperintensities (WMH) in an initially middle-aged, biracial cohort from the Atherosclerosis Risk in Communities (ARIC) study. METHODS: Initial brain magnetic resonance (MR) scans and evaluations for vascular risk factors were performed in 1,812 ARIC participants in 1994-1995. In 2004-2006, 1,130 ARIC participants underwent repeat MR scans. MR scans were rated using a validated 9-point scale for VS, SW, and WMH. Infarcts were recorded. Multiple logistic regression analysis was used to assess associations between vascular risk factors and change between MR scans of one or more grades in VS, SW, WMH, or appearance of new infarcts, controlling for age, sex, and race. RESULTS: At baseline, the 1,112 participants with usable scans (385 black women, 200 black men, 304 white women, 223 white men) had a mean age of 61.7 ± 4.3 years. In adjusted models, diabetes at baseline was associated with incident infarcts (odds ratio [OR] 1.95, 95% confidence interval [CI] 1.29-2.95) and worsening SW (OR 2.10, 95% CI 1.36-3.24). Hypertension at baseline was associated with incident infarcts (OR 1.73, 95% CI 1.23-2.42). In subjects with the highest tertile of fasting blood sugar and systolic blood pressure at baseline, the risk of incident infarcts was 3.68 times higher (95% CI 1.89-7.19) than those in the lowest tertile for both. CONCLUSION: Both atrophic and ischemic imaging changes were driven by altered glycemic and blood pressure control beginning in midlife.

Postmenopausal hormone therapy and subclinical cerebrovascular disease: the WHIMS-MRI Study.

OBJECTIVE: The Women's Health Initiative Memory Study (WHIMS) hormone therapy (HT) trials reported that conjugated equine estrogen (CEE) with or without medroxyprogesterone acetate (MPA) increases risk for all-cause dementia and global cognitive decline. WHIMS MRI measured subclinical cerebrovascular disease as a possible mechanism to explain cognitive decline reported in WHIMS. METHODS: We contacted 2,345 women at 14 WHIMS sites; scans were completed on 1,424 (61%) and 1,403 were accepted for analysis. The primary outcome measure was total ischemic lesion volume on brain MRI. Mean duration of on-trial HT or placebo was 4 (CEE+MPA) or 5.6 years (CEE-Alone) and scans were conducted an average of 3 (CEE+MPA) or 1.4 years (CEE-Alone) post-trial termination. Cross-sectional analysis of MRI lesions was conducted; general linear models were fitted to assess treatment group differences using analysis of covariance. A (two-tailed) critical value of alpha = 0.05 was used. RESULTS: In women evenly matched within trials at baseline, increased lesion volumes were significantly related to age, smoking, history of cardiovascular disease, hypertension, lower post-trial global cognition scores, and increased incident cases of on- or post-trial mild cognitive impairment or probable dementia. Mean ischemic lesion volumes were slightly larger for the CEE+MPA group vs placebo, except for the basal ganglia, but the differences were not significant. Women assigned to CEE-Alone had similar mean ischemic lesion volumes compared to placebo. CONCLUSIONS: Conjugated equine estrogen-based hormone therapy was not associated with a significant increase in ischemic brain lesion volume relative to placebo. This finding was consistent within each trial and in pooled analyses across trials.

Retinal microvascular abnormalities and cognitive decline: the ARIC 14-year follow-up study.

BACKGROUND: Because retinal and cerebral arterioles share similar pathologic processes, retinal microvascular changes are expected to be markers of cerebral small vessel disease (SVD). To better understand the role of SVD in cognitive function, we investigated the relationship between retinal microvascular abnormalities and longitudinal changes in cognitive function in a community-based study. METHODS: A total of 803 participants underwent 4 cognitive assessments between 1990-1992 and 2004-2006, using the Word Fluency (WF) test, Digit Symbol Substitution (DSS), and Delayed Word Recall as well as retinal photography in 1993-1995. Covariate adjusted random effects linear models for repeated measures were used to determine the associations of cognitive change with specific retinal vascular abnormalities. RESULTS: Individuals with retinopathy showed declines in executive function and psychomotor speed, with 1) an average decline in WF of -1.64 words per decade (95% confidence interval [CI] -3.3, -0.02) compared to no decline in those without retinopathy +0.06 (95% CI -0.6, 0.8) and 2) a higher frequency of rapid decliners on the DSS test. CONCLUSION: Signs of retinal vascular changes, as markers of the cerebral microvasculature, are associated with declines in executive function and psychomotor speed, adding to the growing evidence for the role of microvascular disease in cognitive decline in the elderly.