Ramit Ravona-Springer

Diabetes mellitus in midlife and the risk of dementia three decades later

Objective: To examine the association between diabetes in midlife (1963–1968) and dementia more than three decades later (1999–2001). Methods: The authors characterized dementia using standard methods for 1,892 participants among 2,606 survivors of 10,059 participants in the Israeli Ischemic Heart Disease study, a longitudinal investigation of the incidence of and risk factors for cardiovascular disease among Jewish male civil servants in Israel. Face to face interviews were conducted with the 652 subjects identified as possibly demented by the Modified Telephone Interview for Cognitive Status. Logistic regression analysis was performed to assess the association of diabetes with dementia controlling for sociodemographic and cardiovascular variables compared to those with no cognitive impairment. Results: Of 1,892 assessed subjects (mean age 82 at assessment), 309 (16.3%) had dementia. Diabetic subjects had significantly more dementia than non-diabetic subjects (χ2 = 7.54, df = 1, p = 0.006, OR 2.83 [95% CI = 1.40 to 5.71]). Those who survived to the time of this study were younger and healthier than those who died. Conclusions: Evidence for diabetes as a risk factor for dementia was found, similar to other epidemiologic studies. In contrast to the earlier studies, however, the authors linked diabetes in midlife to dementia more than three decades later in the very old survivors of a large male cohort.

Haptoglobin genotype modulates the relationships of glycaemic control with cognitive function in elderly individuals with type 2 diabetes

Aims/hypothesisThe purpose of this study was to investigate whether the association of glycaemic control with cognitive function is modulated by the haptoglobin 1-1 (Hp 1-1) genotype in cognitively normal elderly individuals with type 2 diabetes.MethodsIn this cross-sectional study, we examined 793 participants who were genotyped for Hp (80 Hp 1-1 carriers and 713 Hp 1-1 non-carriers) enrolled in the Israel Diabetes and Cognitive Decline (IDCD) study. Glycaemic control was operationally defined by HbA1c level. The outcome measures were performance in four cognitive domains (episodic memory, attention/working memory, language/semantic categorisation, executive function) and overall cognition, a composite of the domains. Effect sizes were obtained from hierarchical linear regression analyses for each outcome measure, controlling for demographics, type 2 diabetes-related characteristics, cardiovascular risk factors, and their interactions with Hp genotype.ResultsInteraction analyses showed significantly stronger associations of HbA1c with poorer cognitive function among Hp 1-1 carriers than non-carriers; attention/working memory (pu2009<u20090.001) and overall cognition (pu2009=u20090.003). For these two cognitive domains, associations were significant for Hp 1-1 carriers despite the small sample size (pu2009<u20090.00001 and pu2009=u20090.001, respectively), but not for non-carriers.Conclusions/interpretationOur findings suggest that patients with type 2 diabetes and poor glycaemic control carrying the Hp 1-1 genotype may be at increased risk of cognitive impairment, particularly in the attention/working memory domain. The association of glycaemic control with this domain may indicate cerebrovascular mechanisms.

Hemoglobin A1c Variability Predicts Symptoms of Depression in Elderly Individuals With Type 2 Diabetes

OBJECTIVE This study aimed to analyze the relationship of variability in hemoglobin A1c (HbA1c) over years with subsequent depressive symptoms. RESEARCH DESIGN AND METHODS Subjects (n = 837) were participants of the Israel Diabetes and Cognitive Decline (IDCD) study, which aimed to examine the relationship of characteristics of long-term type 2 diabetes with cognitive decline. All pertain to a diabetes registry established in 1998, which contains an average of 18 HbA1c measurements per subject. The results presented here are based on the IDCD baseline examination. Symptoms of depression were assessed using the 15-item version of the Geriatric Depression Scale (GDS). To quantify the association between variability in glycemic control (measured as the SD of HbA1c measurements [HbA1c-SD]) since 1998 with the number of depression symptoms at IDCD baseline, incidence rate ratios (IRRs) and corresponding 95% CIs were estimated via negative binomial regression modeling and used to account for the overdispersion in GDS scores. RESULTS Subjects’ ages averaged 72.74 years (SD 4.63 years), and the mean number of years in the diabetes registry was 8.7 (SD 2.64 years). The mean GDS score was 2.16 (SD 2.26); 10% of subjects had a GDS score ≥6, the cutoff for clinically significant depression. Mean HbA1c significantly correlated with HbA1c-SD (r = 0.6625; P < 0.0001). The SD, but not the mean, of HbA1c measurements was significantly associated with the number of subsequent depressive symptoms. For each additional 1% increase in HbA1c-SD, the number of depressive symptoms increased by a factor of 1.31 (IRR = 1.31 [95% CI 1.03–1.67]; P = 0.03). CONCLUSIONS Variability in glycemic control is associated with more depressive symptoms.

Haptoglobin 1-1 Genotype Modulates the Association of Glycemic Control With Hippocampal Volume in Elderly Individuals With Type 2 Diabetes

Recent evidence suggests that glycemic control is associated with cognitive function in older patients with type 2 diabetes who are carriers of the haptoglobin (Hp) 1-1 genotype compared with noncarriers. We assessed whether poor glycemic control in Hp 1-1 carriers is more strongly associated with smaller hippocampal volume than in noncarriers. Hippocampal volume was generated from high-resolution structural T1 MRI obtained for 224 participants (28 Hp 1-1 carriers [12.5%] and 196 noncarriers [87.5%]) from the Israel Diabetes and Cognitive Decline (IDCD) study, who had a mean (SD) number of years in the Maccabi Healthcare Services (MHS) registry of 8.35 (2.63) and a mean (SD) HbA1c level of 6.66 (0.73)% [49 mmol/mol]. A stronger negative association between right hippocampal volume and HbA1c was found in patients with the Hp 1-1 genotype, with a 0.032-mL decrease in right hippocampal volume per 14% increase in HbA1c (P = 0.0007) versus a 0.009-mL decrease in Hp 1-1 noncarriers (P = 0.047), after adjusting for total intracranial volume, age, sex, follow-up years in the registry, and cardiovascular factor (interaction, P = 0.025). This indicates that 29.66% of the total variance in right hippocampal volume is explained by HbA1c levels among Hp 1-1 carriers and that 3.22% is explained by HbA1c levels among Hp 1-1 noncarriers. Our results suggest that the hippocampus of Hp 1-1 carriers may be more vulnerable to the insults of poor glycemic control.

Ethnicity/culture modulates the relationships of the haptoglobin (Hp) 1-1 phenotype with cognitive function in older individuals with type 2 diabetes.

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.

Potential contribution of the Alzheimer's disease risk locus BIN1 to episodic memory performance in cognitively normal Type 2 diabetes elderly.

In recent years, several promising susceptibility loci for late-onset Alzheimers disease (AD) were discovered, by implementing genome-wide association studies (GWAS) approach. Recent GWAS meta-analysis has demonstrated the association of 19 loci (in addition to the APOE locus) with AD in the European ancestry population at genome-wide significance level. Since Type 2 Diabetes (T2D) is a substantial risk factor for cognitive decline and dementia, the 19 single nucleotide polymorphisms (SNPs) that represent the 19 AD loci were studied for association with performance in episodic memory, a primary cognitive domain affected by AD, in a sample of 848 cognitively normal elderly Israeli Jewish T2D patients. We found a suggestive association of SNP rs6733839, located near the bridging integrator 1 (BIN1) gene, with this phenotype. Controlling for demographic (age, sex, education, disease duration and ancestry) covariates, carriers of two copies of the AD risk allele T (TT genotype) performed significantly worse (p=0.00576; p=0.00127 among Ashkenazi origin sub-sample) in episodic memory compared to carriers of the C allele (CT+CC genotypes). When including additional potential covariates (clinical and APOE genotype), results remained significant (p=0.00769; p=0.00148 among Ashkenazi). Interestingly, as validated in multiple large studies, BIN1 is one of the most established AD risk loci, with a high odds ratio. Although preliminary and require further replications, our findings support a contribution of BIN1 to individual differences in episodic memory performance among T2D patients.

A spectrum of contributions of type 2 diabetes and related metabolic characteristics to dementia

Findings from epidemiological, clinical and preclinical studies in recent years point to the role of metabolic factors in brain disease in general (De Felice and Ferreira, 2014; Gorelick et al., 2011), and particularly in Alzheimers disease (AD) (De Felice and Ferreira, 2014; de la Monte and Tong, 2014). Type 2 diabetes (T2D) and pre-diabetic states—such as insulin resistance (Craft et al., 2013), poor glycemic control (Ma et al., 2014; Ravona-Springer et al., 2014) in non-diabetic subjects (Enzinger et al., 2005), and obesity (Emmerzaal et al., 2014)—affect brain structure and function and are involved in the neuropathological pathways leading to neurodegeneration. In light of the borderline efficacy of currently approved medications for the treatment of AD (Tan et al., 2014), the failure of numerous clinical trials to prove efficacy of other medications developed for treatment of the disease, and the relatively good efficacy of medical (American Diabetes, 2010) and life-style (Hays et al., 2008) interventions in ameliorating or preventing other, non-brain-related complications of T2D, these findings raise the possibility that such interventions may have a beneficial effect on the brain. In this issue of European Neuropsychopharmacology, several articles review the literature on the relationship of T2D and related conditions with brain structure, function, and neurodegeneration from different viewpoints. Werner et al. provide evidence for the expression and function of insulin, the insulin-like growth factors (IGF1, IGF2), and their receptors in the brain. Their roles in the development and function of the central nervous system (CNS) include, among others, neuronal survival, neurogenesis, angiogenesis, neurotransmission, regulation of food intake, and cognition. Interestingly, these factors are shown to be involved in the clearance of amyloid-beta—the hallmark neuropathological feature of AD—from the brain, and its degradation through insulin degrading enzyme (IDE). De la Monte further reviews the evidence pointing towards the metabolic nature of AD based on the impairment of brain responsiveness to insulin, utilization of

Age Modulates the Association of Caffeine Intake With Cognition and With Gray Matter in Elderly Diabetics

BackgroundnThe association between caffeine and cognitive performance has not been tested in older individuals with type 2 diabetes (T2D). Its association with brain volume in T2D has been tested only in animals.nnnMethodsnWe examined the association of caffeine with cognitive function and brain volume in a sample of elderly diabetics participating in the Israel Diabetes and Cognitive Decline Study (n = 638) and the moderating effect of age on this association. In a subsample (n = 185) with magnetic resonance imaging, we also examined these associations with gray and white matter volumes (GM/WM).nnnResultsnUsing linear regression adjusting for cognition-related covariates, we found that higher caffeine intake was associated with better function in overall cognition (p = .018), attention/working memory (p = .002), executive functioning (p = .047), and semantic categorization (p = .026). Interaction analyses of caffeine intake with age were significant for semantic categorization (p = .025), and approached significance for overall cognition (p = .066). This association was driven by the older group (above-median) for whom the association of caffeine intake with semantic categorization (p = .001), attention/working memory (p = .007), executive functioning (p = .005), and overall cognition (p = .002) were significant. In the magnetic resonance imaging subsample, there was an interaction (p = .034) of caffeine intake with age for GM volume; in the older group, higher caffeine intake was associated with greater GM volume (β = .198, p = .033).nnnConclusionsnCaffeine intake may have a beneficial role in cognitive functioning of elderly adults with T2D, which may be moderated by age. Greater GM volume may be a mechanism underlying the association of higher caffeine intake with better cognitive function.

Depressive Symptoms Are Associated with Cognitive Function in the Elderly with Type 2 Diabetes

Background: Type 2 diabetes (T2D) is a metabolic condition associated with poor clinical and cognitive outcomes including vascular disease, depressive symptoms, cognitive impairment, and dementia. In the general elderly population, depression has been consistently identified as a risk factor for cognitive impairment/decline. However, the association between depression and cognitive function in T2D has been understudied. Objective: We investigated the association between depression and cognitive function in a large sample of cognitively normal elderly with T2D. Methods: In this cross-sectional study, we examined 738 participants, aged 65–88 years old, enrolled in the Israel Diabetes and Cognitive Decline study. For each cognitive domain (Episodic Memory, Executive Function, Attention/Working Memory, Language/Semantic Categorization) and Overall Cognition, multiple linear regressions assessed its association with depression (score greater than 5 on the 15-item version of the Geriatric Depression Scale [GDS]), adjusting for age, sex, and education. Results: Depression (nu200a=u200a66, 8.9%) was associated with worse performance on tasks of Executive Function (pu200a=u200a0.004), Language/Semantic Categorization (pu200a<u200a0.001), and Overall Cognition (pu200a<u200a0.002), but not Episodic Memory (pu200a=u200a0.643) or Attention/Working Memory (pu200a=u200a0.488). Secondary analyses using GDS as a continuous variable did not substantially change the results. Adjusting also for a history of antidepressant medication use slightly weakened the findings. Conclusion: Significant associations of depression with several cognitive domains and Overall Cognition even in cognitively normal elderly with T2D, suggest that depression may have a role in impaired cognitive function in T2D, which may be attenuated by antidepressants.

Chromatic multifocal pupillometer for objective early diagnosis of mild cognitive impairment

The pupil responses of 15 cognitively normal subjects (ages 60-74) were examined in response to 76 focal red and blue light stimuli using a chromatic multifocal pupillometer (CMP). Subjects with low cognitive scores as determined as by Montreal Cognitive Assessment testing, presented significantly weaker and sluggish pupil responses in peripheral and central locations of the visual field in response to red and blue light. Our findings suggests that the CMP may present a novel objective, non-invasive, low cost technique for early diagnosis of cognitive decline that may serve for Alzheimer Disease prevention and as sensitive outcome measure of therapeutic effects.