Laura H. Coker

Relationship Between Baseline Glycemic Control and Cognitive Function in Individuals With Type 2 Diabetes and Other Cardiovascular Risk Factors: The Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) trial

OBJECTIVE—Diabetes is associated with cognitive decline and dementia. However, the relationship between the degree of hyperglycemia and cognitive status remains unclear. This was explored using baseline cognitive measures collected in the ongoing Memory in Diabetes (MIND) substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. RESEARCH DESIGN AND METHODS—The relationship of A1C and fasting plasma glucose (FPG) levels to performance on four cognitive tests was assessed, adjusting for age and other determinants of cognitive status. The tests were the Digit Symbol Substitution Test (DSST), Mini Mental Status Examination (MMSE), Rey Auditory Verbal Learning Test, and Stroop Test. RESULTS—A statistically significant age-adjusted association was observed between the A1C level and the score on all four cognitive tests. Specifically, a 1% higher A1C value was associated with a significant 1.75-point lower DSST score (95% CI −1.22 to −2.28; P < 0.0001), a 0.20-point lower MMSE score (−0.11 to −0.28; P < 0.0001), a 0.11-point lower memory score (−0.02 to −0.19, P = 0.0142), and a worse score (i.e., 0.75 s more) on the Stroop Test (1.31–0.19, P = 0.0094). The association between the DSST score and A1C persisted in all multiple linear regression models. FPG was not associated with test performance. CONCLUSIONS—Higher A1C levels are associated with lower cognitive function in individuals with diabetes. The effect of glucose lowering on cognitive function will be determined by the ongoing ACCORD-MIND trial.

Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label substudy

Background Persons with type 2 diabetes (T2D) are at risk for cognitive impairment and brain atrophy. The ACCORD Memory in Diabetes (MIND) Study investigated whether persons randomized to an intensive glycaemic therapeutic strategy targeting HbA1c to <6% had better cognitive function and a larger brain volume at 40 months than persons randomized to a standard strategy targeting HbA1c to 7%–7.9%.BACKGROUND People with type 2 diabetes are at risk of cognitive impairment and brain atrophy. We aimed to compare the effects on cognitive function and brain volume of intensive versus standard glycaemic control. METHODS The Memory in Diabetes (MIND) study was done in 52 clinical sites in North America as part of Action to Control Cardiovascular Risk in Diabetes (ACCORD), a double two-by-two factorial parallel group randomised trial. Participants (aged 55-80 years) with type 2 diabetes, high glycated haemoglobin A(1c) (HbA(1c)) concentrations (>7·5%; >58 mmol/mol), and a high risk of cardiovascular events were randomly assigned to receive intensive glycaemic control targeting HbA(1c) to less than 6·0% (42 mmol/mol) or a standard strategy targeting HbA(1c) to 7·0-7·9% (53-63 mmol/mol). Randomisation was via a centralised web-based system and treatment allocation was not masked from clinic staff or participants. We assessed our cognitive primary outcome, the Digit Symbol Substitution Test (DSST) score, at baseline and at 20 and 40 months. We assessed total brain volume (TBV), our primary brain structure outcome, with MRI at baseline and 40 months in a subset of participants. We included all participants with follow-up data in our primary analyses. In February, 2008, raised mortality risk led to the end of the intensive treatment and transition of those participants to standard treatment. We tested our cognitive function hypotheses with a mixed-effects model that incorporated information from both the 20 and 40 month outcome measures. We tested our MRI hypotheses with an ANCOVA model that included intracranial volume and factors used to stratify randomisation. This study is registered with ClinicalTrials.gov, number NCT00182910. FINDINGS We consecutively enrolled 2977 patients (mean age 62·5 years; SD 5·8) who had been randomly assigned to treatment groups in the ACCORD study. Our primary cognitive analysis was of patients with a 20-month or 40-month DSST score: 1378 assigned to receive intensive treatment and 1416 assigned to receive standard treatment. Of the 614 patients with a baseline MRI, we included 230 assigned to receive intensive treatment and 273 assigned to receive standard treatment in our primary MRI analysis at 40 months. There was no significant treatment difference in mean 40-month DSST score (difference in mean 0·32, 95% CI -0·28 to 0·91; p=0·2997). The intensive-treatment group had a greater mean TBV than the standard-treatment group (4·62, 2·0 to 7·3; p=0·0007). INTERPRETATION Although significant differences in TBV favoured the intensive treatment, cognitive outcomes were not different. Combined with the non-significant effects on other ACCORD outcomes, and increased mortality in participants in the intensive treatment group, our findings do not support the use of intensive therapy to reduce the adverse effects of diabetes on the brain in patients with similar characteristics to those of our participants. FUNDING US National Institute on Aging and US National Heart, Lung, and Blood Institute.

Common variants at 12q14 and 12q24 are associated with hippocampal volume

Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimers disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10−7. In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10−11) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10−11). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10−7) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10−7); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.

Fourteen-year longitudinal study of vascular risk factors, APOE genotype, and cognition: The ARIC MRI Study

Strokes, vascular risk factors, and apolipoprotein E (APOE) genotype are associated with cognitive decline in the elderly, but definitive evidence that these affect cognition as early as middle age is limited.

Midlife hypertension and 20-year cognitive change: the atherosclerosis risk in communities neurocognitive study.

IMPORTANCE Hypertension is a treatable potential cause of cognitive decline and dementia, but its greatest influence on cognition may occur in middle age. OBJECTIVE To evaluate the association between midlife (48-67 years of age) hypertension and the 20-year change in cognitive performance. DESIGN, SETTING, AND PARTICIPANTS The Atherosclerosis Risk in Communities cohort (1990-1992 through 2011-2013) underwent evaluation at field centers in Washington County, Maryland, Forsyth County, North Carolina, Jackson, Mississippi, and the Minneapolis, Minnesota, suburbs. Of 13 476 African American and white participants with baseline cognitive data, 58.0% of living participants completed the 20-year cognitive follow-up. EXPOSURES Hypertension, prehypertension, or normal blood pressure (BP) at visit 2 (1990-1992) constituted the primary exposure. Systolic BP at visit 2 or 5 (2011-2013) and indication for treatment at visit 2 based on the Eighth Joint National Committee (JNC-8) hypertension guidelines constituted the secondary exposures. MAIN OUTCOMES AND MEASURES Prespecified outcomes included the 20-year change in scores on the Delayed Word Recall Test, Digit Symbol Substitution Test, and Word Fluency Test and in global cognition. RESULTS During 20 years, baseline hypertension was associated with an additional decline of 0.056 global z score points (95% CI, -0.100 to -0.012) and prehypertension was associated nonsignificantly with 0.040 more global z score points of decline (95% CI, -0.085 to 0.005) compared with normal BP. Individuals with hypertension who used antihypertensives had less decline during the 20 years than untreated individuals with hypertension (-0.050 [95% CI, -0.003 to -0.097] vs -0.079 [95% CI, -0.156 to -0.002] global z score points). Having a JNC-8-specified indication for initiating antihypertensive treatment at baseline was associated with a greater 20-year decline (-0.044 [95% CI, -0.085 to -0.003] global z score points) than not having an indication. We observed effect modification by race for the continuous systolic BP analyses (P = .01), with each 20-mm Hg increment at baseline associated with an additional decline of 0.048 (95% CI, -0.074 to -0.022) points in global cognitive z score in whites but not in African Americans (decline, -0.020 [95% CI, -0.026 to 0.066] points). Systolic BP at the end of follow-up was not associated with the preceding 20 years of cognitive change in either group. Methods to account for bias owing to attrition strengthened the magnitude of some associations. CONCLUSIONS AND RELEVANCE Midlife hypertension and elevated midlife but not late-life systolic BP was associated with more cognitive decline during the 20 years of the study. Greater decline is found with higher midlife BP in whites than in African Americans.

Primary hyperparathyroidism, cognition, and health-related quality of life.

Objective:To provide a rigorous and critical review of studies in which formal neuropsychological (NP) testing and measurement of health-related quality of life (HRQL) were conducted pre- and post-parathyroidectomy for primary hyperparathyroidism (PHPT). These data contribute to the discussion on the utility of surgical intervention for nonclassic PHPT. Summary Background Data:PHPT is a complex endocrinopathy involving calcium metabolism and a potent hormone made by the parathyroid glands. Approximately 1.5% of Americans age 65 years and older, representing more than 3.9 million people, have PHPT, and the prevalence in postmenopausal women is estimated at 3.4%. Current National Institutes of Health guidelines for curative, surgical intervention of PHPT exclude 80% of patients with hyperparathyroid disease who have subjective neurobehavioral and physical symptoms that affect the quality of their lives. Methods:An electronic search was conducted of prospective studies in which cognitive functioning was measured with formal NP tests and HRQL was measured with valid and reliable instruments before and following parathyroidectomy for PHPT. Results:In studies conducted pre- and post-parathyroidectomy for PHPT, 6 small studies of cognitive functioning report inconsistent findings; however, 7 well-designed studies of HRQL report improvement across multiple domains following surgery. Conclusions:Surgical treatment of PHPT is a viable option for patients with laboratory diagnosed, “nonclassic” PHPT. Formal NP testing and evaluation of HRQL are useful tools that may assist physicians in choosing whom to refer for parathyroidectomy. Further longitudinal study of NP functioning and HRQL in patients with laboratory diagnosed PHPT is warranted.

A Genome-Wide Association Study of Depressive Symptoms

BACKGROUND Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms. METHODS In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p<1×10(-5)) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies. RESULTS The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05×10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19×10(-3)). This 5q21 region reached genome-wide significance (p = 4.78×10(-8)) in the overall meta-analysis combining discovery and replication studies (n = 51,258). CONCLUSIONS The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.

Nimodipine neuroprotection in cardiac valve replacement: report of an early terminated trial.

BACKGROUND We conducted a double-blind, randomized clinical trial in patients undergoing cardiac valve replacement to determine whether nimodipine, a dihydropyridine calcium antagonist, reduced the risk of new neurological, neuro-ophthalmologic, or neuropsychological deficits-common complications associated with cardiac surgery-1 week after surgery. METHODS AND RESULTS Enrollment for a total of 400 patients started in May 1992 and was stopped in September 1994, with 150 patients randomized to the study. Nimodipine was given to the patients during the perioperative period. Patients underwent examinations before surgery and at approximately 1 week, 1 month, and 6 months after surgery. Major adverse events, including deaths and strokes, were monitored monthly. The trial was terminated early because of both an unexpected disparity in death rates between groups and a lack of evidence of a beneficial effect of nimodipine. New deficits were observed in 72% of the placebo group versus 77% of the nimodipine group (p=.55). In the 6-month follow-up period, 8 deaths (10.7%) occurred in the nimodipine group (n=75) compared with 1 death (1.3) in the placebo group (n=74) (p=.02). Major bleeding occurred in 10 patients in the nimodipine group versus 3 in the placebo group (13.3% versus 4.1%; P=.04). Six (46.2%) of the 13 patients with major bleeding died compared with 3 deaths (2.2%) among the 136 patients without major bleeding. CONCLUSIONS Our findings add to the growing evidence that calcium antagonists have a prohemorrhagic effect in some patients and suggest that nimodipine use should be restricted perioperatively in patients scheduled for cardiac valve replacement.

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.

Early Adult to Midlife Cardiovascular Risk Factors and Cognitive Function

Background— Studies have linked midlife and late-life cardiovascular risk factors (CVRFs) to cognitive function, yet little is known about CVRF exposure in early adulthood and subsequent cognitive function. In addition, most studies rely on single assessments of CVRFs, which may not accurately reflect long-term exposure. We sought to determine the association between cumulative exposure to CVRFs from early to middle adulthood and cognitive function at midlife. Methods and Results— In a prospective study of 3381 adults (age, 18–30 years at baseline) with 25 years of follow-up, we assessed cognitive function at year 25 (2010–2011) with the Digit Symbol Substitution Test, Stroop Test, and Rey Auditory Verbal Learning Test analyzed with standardized z scores. The primary predictor was 25-year cumulative exposure estimated by areas under the curve for resting systolic and diastolic blood pressures, fasting blood glucose, and total cholesterol. Higher cumulative systolic and diastolic blood pressures and fasting blood glucose were consistently associated with worse cognition on all 3 tests. These associations were significant primarily for exposures above recommended guidelines; cognitive test z scores were between 0.06 and 0.30 points less, on average, for each 1-SD increase in risk factor area under the curve after adjustment for age, race, sex, and education (P<0.05 for all). Fewer significant associations were observed for cholesterol. Conclusions— Cumulative exposure to CVRFs from early to middle adulthood, especially above recommended guidelines, was associated with worse cognition in midlife. The meaning of this association and whether it warrants more aggressive treatment of CVRFs earlier in life require further investigation.