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Background High body mass index (BMI) is a risk factor for type 2 diabetes and cardiovascular disease. However, its relationships with indices of carotid stiffness and plaque volume are unclear. We investigated associations of long-term measurements of BMI with indices of carotid stiffness and atherosclerosis among non-demented diabetes patients from the Israel Diabetes and Cognitive Decline (IDCD) study. Methods Carotid ultrasound indices [carotid intima media thickness (cIMT), distensibility, elastography and plaque volume] were assessed in N = 471 participants. Mean BMI across all MHS diabetes registry measurements and trajectories of BMI were calculated. BMI was categorized into three trajectory groups representing: a relatively stable normal weight (n = 185, 44%), overweight trajectory (n = 188, 44.8%) and a trajectory of obesity (n = 47, 11.2%). Linear and logistic regressions estimated associations of carotid indices with mean BMI and BMI trajectories. Results Compared to the normal weight trajectory, an obesity trajectory was associated with carotid distensibility (β = − 3.078, p = 0.037), cIMT (β = 0.095, p = 0.004), and carotid elastography (β = 0.181, p = 0.004) but not with plaque volume (β = 0.066, p = 0.858). Compared with the normal weight trajectory, an obesity trajectory was associated with increased odds for impaired carotid distensibility (OR = 2.790, p = 0.033), impaired cIMT (OR = 5.277, p = 0.001) and large carotid plaque volume (OR = 8.456, p = 0.013) but not with carotid elastography (OR = 1.956, p = 0.140). Mean BMI was linearly associated with Distensibility (β = − 0.275, p = 0.005) and cIMT (β = 0.005, p = 0.026). Conclusions Long-term measurements of adiposity are associated with indices of carotid stiffness and plaque volume among older type 2 diabetes adults.

Older adults with type 2 diabetes (T2D) are at increased risk for depression, cognitive decline, and dementia compared to those without T2D. Little is known about the association of simultaneous changes in depression symptoms and cognitive decline over time.Subjects (n=1021; mean age 71.6 [SD=4.6]; 41.2% female) were initially cognitively normal participants of the Israel Diabetes and Cognitive Decline study who underwent evaluations of depression and cognition approximately every 18 months. Cognitive tests were summarized into four cognitive domains: episodic memory, attention/working memory, executive functions, and semantic categorization. The average of the z-scores of the four domains defined global cognition. Depression symptoms were assessed using the Geriatric Depression Scale, 15-item version. We fit a random coefficients model of changes in depression and in cognitive functions, adjusting for baseline sociodemographic and cardiovascular variables.Higher number of depression symptoms at baseline was significantly associated with lower baseline cognitive scores in global cognition (estimate = -0.1175, SE = 0.021, DF = 1,014, t = -5.59; p0.001), executive functions (estimate = -0.186, SE = 0.036, DF = 1,013, t = -5.15; p = 0.001), semantic categorization (estimate = -0.155, SE = 0.029, DF = 1,008, t = -5.3; p0.001), and episodic memory (estimate = -0.08165, SE = 0.027, DF = 1,035, t = -2.92; p = 0.0036), but not with rate of decline in any cognitive domain. During follow-up, a larger increase in number of depression symptoms, was associated with worse cognitive outcomes in global cognition (estimate = -0.1053, SE = 0.027, DF = 1,612, t = -3.77; p = 0.0002), semantic categorization (estimate = -0.123, SE = 0.036, DF = 1,583, t = -3.36; p = 0.0008), and in episodic memory (estimate = -0.165, SE = 0.055, DF = 1,622, t = -3.02; p = 0.003), but the size of this effect was constant over time.In elderly with T2D, increase in depression symptoms over time is associated with parallel cognitive decline, indicating that the natural course of the two conditions progresses concurrently and suggesting common underlying mechanisms".

First-degree family history is an established risk factor for Alzheimer's disease (AD). We investigated the association of late-onset AD risk loci with cognitive functioning among 315 offspring of AD patients. Participants were cognitively normal Jewish individuals, aged 40–65 years, from the Israel Registry for Alzheimer's Prevention (IRAP) study. Twenty-two single-nucleotide polymorphisms (SNPs) within these loci and the APOE E4 allele were included in the final analyses, and a polygenic risk score was also calculated. Using linear regression (assuming an additive genetic model), we found a significant association only for SNP rs9473117, located near the CD2-associated protein (CD2AP) gene, with global cognition. Controlling for demographic variables (age, sex, years of education, and ancestry), the late-onset AD risk allele C was associated with lower global cognitive functioning (p = 0.0005), and withstood correction for multiple testing. After adjusting for additional characteristics (APOE E4 status and then also for cardiovascular factors), the results remained essentially unchanged (p = 0.0003 and p = 0.0005, respectively). In secondary analyses examining specific cognitive domains, rs9473117 was similarly associated with episodic memory (p = 0.005), language (p = 0.009), and working memory/attention (p = 0.018) but not with executive functions (p = 0.27). Again, the results were similar after adjusting for APOE E4 status and cardiovascular factors. The polygenic risk score was not associated with global cognitive functioning or with any of the 4 domains. In conclusion, our findings suggest a contribution of the CD2AP locus to cognitive functioning in middle-aged individuals with a parental history of AD. Further validations, including in longitudinal studies, are required.

Type 2 diabetes (T2D) is associated with motor impairments and a higher dementia risk. The relationships of motor decline with cognitive decline in T2D older adults has rarely been studied. Using data from the Israel Diabetes and Cognitive Decline study (N = 892), we examined associations of decline in motor function with cognitive decline over a 54-month period.Motor function measures were strength (handgrip) and gait speed (time to walk 3 m). Participants completed a neuropsychologic battery of 13 tests transformed into z-scores, summarized into 4 cognitive domains: episodic memory, attention/working memory, executive functions, and language/semantic categorization. The average of the 4 domains' z-scores defined global cognition. Motor and cognitive functions were assessed in 18-months intervals. A random coefficients model delineated longitudinal relationships of cognitive decline with baseline and change from baseline in motor function, adjusting for sociodemographic, cardiovascular, and T2D-related covariates.Slower baseline gait speed levels were significantly associated with more rapid decline in global cognition (P = .004), language/semantic categorization (P = .006) and episodic memory (P = .029). Greater decline over time in gait speed was associated with an accelerated rate of decline in global cognition (P = .050), attention/working memory (P = .047) and language/semantic categorization (P.001). Baseline strength levels were not associated with cognitive decline but the rate of declining strength was associated with an accelerated decline in executive functions (P = .025) and language/semantic categorization (P = .006).In T2D older adults, the rate of decline in motor function, beyond baseline levels, was associated with accelerated cognitive decline, suggesting that cognitive and motor decline share common neuropathologic mechanisms in T2D.

AIMS/HYPOTHESIS: There are established relationships between adiposity (obesity) and higher dementia risk, faster cognitive decline and associated neural injury. Type 2 diabetes is strongly linked to greater adiposity and has been consistently associated with neural injury and poor cognitive outcomes. However, although obesity is a major cause of type 2 diabetes, there is limited evidence on the association of adiposity with brain atrophy among individuals with type 2 diabetes. METHODS: We examined the association of BMI (a measure of adiposity), and of long-term trajectories of BMI (three empirically identified groups of trajectories—’normal’, ‘overweight’ and ‘obese’—using SAS macro PROC TRAJ), with regional brain volume, in a sample of older individuals (aged 64–84) with type 2 diabetes participating in the Israel Diabetes and Cognitive Decline Study (n=198). RESULTS: Using linear regression, we found that greater BMI was associated with smaller volumes of the inferior frontal gyrus (IFG) (r=−0.25, p=0.001) and the middle temporal gyrus (r=−0.19; p=0.010) after adjusting for sociodemographic covariates and total intracranial volume. In addition, there were significant differences between BMI trajectory groups in IFG volume (F=4.34, p=0.014), such that a long-term trajectory of obesity was associated with a smaller volume. Additional adjustment for cardiovascular and diabetes-related potential confounders did not substantively alter the results. There were no associations of adiposity with superior frontal gyrus, middle frontal gyrus or total grey matter volumes. CONCLUSIONS/INTERPRETATION: In older adults with type 2 diabetes, long-term adiposity may have a detrimental impact on volume of brain regions relevant to cognitive functioning. Further studies to identify the underlying mechanisms are warranted.

Physical fitness is an important contributor to healthy aging that improves cognition. Older adults who engage in cardiorespiratory fitness activities show less cognitive decline.To examine whether physical fitness acts as a potential protective mechanism shielding against the negative associations between age and cognition. Specifically, we examined whether physical fitness mediates the relationship between age and processing speed.114 (M = 63.80, SD = 10.63) senior executives completed a computerized cognitive battery composed of four processing speed tasks. Level of physical fitness was assessed on a treadmill stress test and reported in metabolic equivalents (METs).Older age was associated with slower processing speed (r = 0.25, p = 0.007), whereas greater physical fitness was associated with faster processing speed (r = -0.30, p = 0.001). Path analysis indicated that the association between age and processing speed was fully mediated by the level of physical fitness (Indirect effect: β = 0.10, p = 0.008; Direct effect: β = 0.16, p = 0.20).The findings indicate that physical fitness is a strong mediator of the relationship between age and processing speed and imply that physical fitness makes a major contribution to cognitive reserve during the aging process. The results may suggest that the decrease in physical fitness during aging may partially account for slower cognitive processing.

Mild cognitive impairment (MCI) is a prodromal syndrome often linked to the eventual emergence of dementia syndromes such as Alzheimer’s disease (AD) and vascular dementia (VaD). Research regarding the potential treatment of MCI is reviewed. Current research suggests that neurocognitive decline associated with MCI that may evolve into a dementia syndrome is potentially managed by treating cardiovascular risk factors, appropriate diet and physical exercise, challenging mental activity, intervention for any neuropsychiatric issues, and encouraging meaningful psychosocial relationships. Recent research also suggests potentially better effect on neuropsychological functioning when medication such as donepezil is used to manage both dementia and MCI.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

OBJECTIVE: Depression and cognitive impairment are highly prevalent in type 2 diabetes (T2D) yet little is known about how their relationship varies by sex. DESIGN: Population-based cross-sectional study. SETTING: Community. PARTICIPANTS: Eight hundred and ninety seven non-demented elderly with type 2 diabetes aged ≥ 65 participating in the Israel Diabetes and Cognitive Decline (IDCD) Study. MEASUREMENTS: Cognition was evaluated by a comprehensive neuropsychological battery and depressive symptoms were assessed by the Geriatric Depression Scale (GDS). RESULTS: In all but the executive function domain, the association of depressive symptoms with poorer cognitive function was stronger in women than men, with a significant interaction for language/semantic categorization and missed significance for episodic memory. Using a cutoff of GDS≥ 6 for clinical depression, women with depression had significantly poorer language/semantic categorization, memory and overall cognitive function. Inclusion of anti-depressants in the model did not alter substantively the associations. CONCLUSION: Our results suggest that depressed T2D women may have poorer cognitive performance, highlighting the significance of sex-specific personalized management of depression in elderly diabetics.

Objectives: Personality may constitute an important domain of influence on cognitive function in old-adults. We assessed the relationship of personality traits and cognitive performance in individu...

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 (n = 66, 8.9%) was associated with worse performance on tasks of Executive Function (p = 0.004), Language/Semantic Categorization (p

BACKGROUND: The 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. METHODS: We 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). RESULTS: Using 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). CONCLUSIONS: Caffeine 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.

Introduction Older adults with type 2 diabetes are at high risk of cognitive decline and dementia and form an important target group for dementia risk reduction studies. Despite evidence that computerized cognitive training (CCT) may benefit cognitive performance in cognitively healthy older adults and those with mild cognitive impairment, whether CCT may benefit cognitive performance or improve disease self-management in older diabetic adults has not been studied to date. In addition, whether adaptive difficulty levels and tailoring of interventions to individuals' cognitive profile are superior to generic training remains to be established. Methods Ninety community-dwelling older (age ≥ 65) diabetic adults are recruited and randomized into a tailored and adaptive computerized cognitive training condition or to a generic, nontailored, or adaptive CCT condition. Both groups complete an 8-week training program using the commercially available CogniFit program. The intervention is augmented by a range of behavior-change techniques, and participants in each condition are further randomized into a global or cognition-specific phone-based self-efficacy (SE) condition, or a no-SE condition. The primary outcome is global cognitive performance immediately after the intervention. Secondary outcomes include diabetes self-management, meta-memory, mood, and SE. Discussion This pilot study is the first trial evaluating the potential benefits of home-based tailored and adaptive CCT in relation to cognitive and disease self-management in older diabetic adults. Methodological strengths of this trial include the double-blind design, the clear identification of the proposed active ingredients of the intervention, and the use of evidence-based behavior-change techniques. Results from this study will indicate whether CCT has the potential to lower the risk of diabetes-related cognitive decline. The outcomes of the trial will also advance our understanding of essential intervention parameters required to improve or maintain cognitive function and enhance disease self-management in this at-risk group.

Objectives: Recent large-scale meta-analysis of genome-wide association studies (GWAS) from multiple cohorts, demonstrated the association of the single nucleotide polymorphism (SNP) rs17518584, with processing speed (measured by the Digit Symbol Substitution Test (DSST) or the Letter Digit Substitution Test (LDST)), at GWAS significance level. This SNP is located within the cell adhesion molecule 2 (CADM2) gene. We aimed to validate this finding in our sample of 944 cognitively normal Jewish elderly individuals with type 2 diabetes (T2D), a population which is at risk for cognitive decline and dementia.Methods: Using linear regression, we studied the association of rs17518584 with DSST performance, adjusting for demographic, T2D-related characteristics and cardiovascular factors. In secondary analyses, associations with performance in four cognitive domains (episodic memory, language/semantic categorisation, attention/working memory and executive function) and overall cognition were examined.Resu...

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.

Introduction Type 2 diabetes (T2D) is a risk factor for dementia. Ischemia due to vascular pathology is hypothesized to be an underlying mechanism for this association. Hyperbaric oxygen therapy (HBOT) is a treatment in which oxygen‐enriched air (up to 100%) is administered to patients in a chamber at a pressure above one atmosphere absolute. HBOT is approved for the treatment of T2D ischemic non‐healing wounds. Evidence from animal studies and small clinical trials suggests that HBOT improves hypoxic/ischemic brain injuries, consequently inducing brain angiogensis, leading to cognitive improvement. Methods We present the design of the first double‐blind, placebo‐controlled, clinical trial on brain and cognitive outcomes in elderly (n = 154) with T2D and mild cognitive impairment to compare the effects of HBOT versus sham (normal air with 1.1 ATA pressure in the first and last 5 minutes of the session). Eligible candidates are randomized with equal probability to HBOT and sham. Outcomes are assessed before and after treatment, and at 6‐ and 12‐month follow‐up. The primary cognitive outcome is global cognitive change, indexed by a composite sum of z‐scores of four executive functions and four episodic memory tests. The primary neurobiological outcome is cerebral blood flow (CBF; via arterial spin labeling magnetic resonance imaging [ASL‐MRI]) and cerebral glucose utilization via fluorodeoxyglucose positron emission tomography (FDG‐PET). Secondary outcome measures are specific cognitive domains (executive function and episodic memory) and functional measures (Clinical Dementia Rating sum of boxes, activities of daily living). Efficacy analyses will be performed for the intent‐to‐treat sample. Discussion Recent studies suggest that HBOT induces neuroplasticity and improves cognition in post‐stroke and traumatic brain injury patients. However, its effect on cognition, cerebral blood flow, and brain glucose utilization in T2D patients at high dementia risk is yet to be determined. If effective, this study may provide strong evidence for the brain and cognitive benefits of HBOT in this population.

The association between several Single Nucleotide Polymorphisms (SNPs) within the transcription factor 7-like 2 (TCF7L2) gene and Type 2 Diabetes (T2D) as well as additional T2D-related traits is well established. Since alteration in total and regional brain volumes are consistent findings among T2D individuals, we studied the association of four T2D susceptibility SNPS within TCF7L2 (rs7901695, rs7903146, rs11196205, and rs12255372) with volumes of white matter hyperintensities (WMH), gray matter, and regional volumes of amygdala and hippocampus obtained from structural MRI among 191 T2D elderly Jewish individuals. Under recessive genetic model (controlling for age, sex and intracranial volume), we found that for all four SNPs, carriers of two copies of the T2D risk allele (homozygous genotype) had significantly smaller amygdalar volume: rs7901695- CC genotype vs. CT + TT genotypes, p = 0.002; rs7903146-TT vs. TC + CC, p = 0.003; rs11196205- CC vs. CG + GG, p = 0.0003; and rs12255372- TT vs. TG + GG, p = 0.003. Adjusting also for T2D-related covariates, body mass index (BMI), and ancestry did not change the results substantively (rs7901695, p = 0.003; rs7903146, p = 0.005; rs11196205, p = 0.001; and rs12255372, p = 0.005). Conditional analysis demonstrated that only rs11196205 was independently associated with amygdalar volume at a significant level. Separate analysis of left and right amygdala revealed stronger results for left amygdalar volume. Taken together, we report association of TCF7L2 SNPs with amygdalar volume among T2D elderly Jewish patients. Further studies in other populations are required to support these findings and reach more definitive conclusions.

Objectives Despite their impact on daily functioning, we have limited understanding of the executive functioning of older adults with bipolar disorder (OABD). Even less is known about the possible differences in the executive functioning of OABD and older adults with unipolar depression (OADEP). Methods After excluding acutely ill patients, the executive functioning of OABD was compared to that of OADEP and healthy controls (n = 22, n = 20, n = 22; respectively). Cognitive insight, a sub-domain of executive functioning, was operationalized as the discrepancy between the participants' self-reported cognitive functioning and appraisals that were made by their care partners. To complement the cognitive profiling, the groups were compared in information processing speed, verbal memory, and visual-spatial memory. Results OABD were impaired in several cognitive domains compared to healthy controls, most prominently in executive functioning and memory. OABD had poorer executive functioning and visual-spatial memory than OADEP. The findings also tentatively point toward intact cognitive insight among OABD, while OADEP seem to have a heightened level of awareness of their cognitive impairment. Conclusions OABD have a unique profile of cognitive impairment compared to OADEP. It is characterized by a more severe cognitive impairment, accompanied by relatively intact cognitive insight. The findings may help clarify the cognitive profile of OABD and assist in the development of cognitive rehabilitation programs tailored to their needs. They should, however, be considered preliminary and await further research.

Purpose: To identify early retinal biomarkers for Alzheimer disease (AD) using multimodal imaging. Methods: Infra-red (IR) and multicolor fundus imaging and spectral domain optic coherence tomography (SD-OCT) were performed in 108 offspring of AD patients (FH+) and 44 age-matched controls (FH-). All subjects were tested for cognitive function by executive function and episodic memory tests. MRI brain imaging was performed on a 3T MRI. Results: In FH+ subjects, lower performance in memory was associated with thicker peri-papillary temporal-superior RNFL (r=-0.220; p=.016). In FH- subjects, the correlation was in the opposite direction (r=0.335; p=.013). In FH+, left Hippocampal volume was associated with larger total macular thickness (r=0.212; p=.028), as well as thicker macular RNFL (r=0.216; p=.025), macular GCL (r=0.221; p=.022), and macular IPL (r=0.285, p=.003). Similar results were found in the right eye. Conclusions: The thickness of inner retinal layers and peripapillary RNFL are associated with cognitive functioning and hippocampal volume in asymptomatic subjects at high risk for AD and may present novel biomarkers for very early detection of AD.

Introduction Waist circumference is associated with type 2 diabetes (T2D) and cognition, yet the relationship between waist circumference and cognition in individuals with T2D is not well understood. Methods We studied the relationship of waist circumference with five cognitive outcomes (executive functioning, language/semantic categorization, attention/working memory, episodic memory, and an overall cognition measure) in 845 cognitively normal elderly with type 2 diabetes (T2D). Results In women, waist circumference was correlated with significantly lower language and/or semantic categorization performance ( P P = .026), and overall cognition ( P = .003) after controlling for age, education, BMI, and cardiovascular, diabetes-related, APOE e4, and inflammatory potential confounders. Attention/working memory ( P = .532) and episodic memory ( P = .144) were not associated with waist circumference. These correlations were not found in men. Discussion These results suggest that central adiposity in elderly women with T2D may increase their risk for dementia.

Associative processes, such as the encoding of associations between words in a list, can enhance episodic memory performance and are thought to deteriorate with age. Here, we examine the nature of age-related deficits in the encoding of associations, by using a free recall paradigm with visual arrays of objects. Fifty-five participants (26 young students; 20 cognitive healthy older adults; nine patients with Mild Cognitive Impairment, MCI) were shown multiple slides (experimental trials), each containing an array of nine common objects for recall. Most of the arrays contained three objects from three semantic categories, each. In the remaining arrays, the nine objects were unrelated. Eye fixations were also monitored during the viewing of the arrays, in a subset of the participants. While for young participants the immediate recall was higher for the semantically related arrays, this effect was diminished in healthy elderly and totally absent in MCI patients. Furthermore, only in the young group did the sequence of eye fixations show a semantic scanning pattern during encoding, even when the related objects were non- adjacent in the array. Healthy elderly and MCI patients were not influenced by the semantic relatedness of items during the array encoding, to the same extent as young subjects, as observed by a lack of (or reduced) semantic scanning. The results support a version of the encoding of the association aging-deficit hypothesis.

To investigate the nature of the association of normal levels of total cholesterol with cognitive function and the contribution of age to this association.A sample of 61 senior executives, who were summoned for an annual medical examination with approximately four measurements of total cholesterol during 4 years, were examined with a computerized cognitive battery assessing mental processing speed as a sensitive measure of cognitive decline. We examined the association of total cholesterol with processing speed and the moderating effect of age on this association.A multiple regression analysis yielded a significant interaction between cholesterol and age for processing speed (p = .045). In order to examine the source of the interaction, simple slope analysis was performed. A significant negative high correlation was found for young subjects (p = .021), while no significant correlation was observed at middle (p = .286) or older (p = .584) age. The difference in slopes was robust to adjustment for potential confounding factors, including body mass index, and fasting glucose.Within the normal range, higher total cholesterol levels were associated with better processing speed in younger ages and this association diminished with increasing age. Our findings highlight the important role of brain cholesterol in good cognitive functioning.

We explored the association of plasma glucose levels within the normal range with processing speed in high functioning young elderly, free of type 2 diabetes mellitus (T2DM). A sample of 41 participants (mean age = 64.7, SD = 10; glucose 94.5 mg/dL, SD = 9.3), were examined with a computerized cognitive battery. Hierarchical linear regression analysis showed that higher plasma glucose levels, albeit within the normal range (

Objective 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. Methods This cross-sectional study evaluated 787 cognitively normal older individuals (>65 years of age) with type 2 diabetes participating in the Israel Diabetes and Cognitive Decline study. Interactions in two-way analyses of covariance compared Group (Non-Ashkenazi versus Ashkenazi Jews) on the associations of Hp phenotype (Hp 1-1 versus non- Hp 1-1) with five cognitive outcome measures. The primary control variables were age, gender, and education. Results Compared with Ashkenazi Jews, non-Ashkenazi Jews with the Hp 1-1 phenotype had significantly poorer cognitive function than non-Hp 1-1 in the domains of Attention/Working Memory (p = 0.035) and Executive Function (p = 0.023), but not in Language/Semantic Categorization (p = 0.432), Episodic Memory (p = 0.268), or Overall Cognition (p = 0.082). After controlling for additional covariates (type 2 diabetes-related characteristics, cardiovascular risk factors, Mini-mental State Examination, and extent of depressive symptoms), Attention/Working Memory (p = 0.038) and Executive Function (p = 0.013) remained significant. Conclusions Older individuals from specific ethnic/cultural backgrounds with the Hp 1-1 phenotype may benefit more from treatment targeted at decreasing or halting the detrimental effects of Hp 1-1 on the brain. Future studies should examine differential associations of Hp 1-1 and cognitive impairment, especially for groups with high prevalence of both, such as African–Americans and Hispanics. Copyright © 2015 John Wiley & Sons, Ltd.

The pleiotropic contribution of statins on cognition is uncertain. From 840 patients in the cohort from the Israel Diabetes and Cognitive Decline Study, we identified 61 non-statin users and compared them with 45 patients who had used statins at least 90% of the time. Analysis of covariance was performed to compare mean cognitive z-scores between statin users and non-users while adjusting for socio-demographic, diabetes-related, and cardiovascular covariates which included change in cholesterol by year. Overall cognition, memory, and executive function was found to be significantly better in statin users (p < 0.0008). This suggests a positive effect of statins on cognitive function of type 2 diabetes patients that is independent of cholesterol levels.

Objective Glycated hemoglobin (HbA1c) and C-reactive protein (CRP) have been associated with cognitive impairment independently. However, it is unclear if their combination exacerbates poor cognitive function. We assessed whether long-term glycemic level and glycemic variability modulate the association of systemic inflammation with cognitive function, in a sample of cognitively normal older people with type 2 diabetes. Methods A retrospective cohort study of 777 randomly selected participants from ~11,000 patients in the Maccabi Healthcare Services Diabetes Registry, as part of the Israel Diabetes and Cognitive Decline study. Subjects averaged 18 (±9.4) HbA1c measures in the Maccabi Healthcare Services Registry, which were used to calculate long-term glycemic level (HbA1c-mean) and glycemic variability (HbA1c-standard deviation (SD)). Linear regression models assessed the interactions of CRP, a marker of systemic inflammation, with HbA1c-mean and HbA1c-SD on subjects' performance in tests of Memory, Executive Functions, Attention, and Semantic Categorization. Results Quadratic interactions of CRP with HbA1c-SD approached significance for executive functions and overall cognition. However, after Bonferroni adjustment, none of the interactions of CRP with HbA1c were statistically significant. In partial correlations according to HbA1c-SD tertiles, CRP was weakly correlated in the middle tertile with decreased performance in the domains of semantic categorization (r = −0.166, p = 0.011), executive functions (r = −0.136, p = 0.038), and overall cognition (r = −0.157, p = 0.016). Conclusions Glycated hemoglobin does not substantially modulate the association of CRP with cognition in a sample of cognitively normal, community dwelling older people with relatively well-managed type 2 diabetes. Copyright © 2015 John Wiley & Sons, Ltd.

Background The relationship of obesity with risk for dementia is complex and may change with age. Objective To analyze the relationship between measures of obesity at age 40-65 and dementia prevalence in survivors 36 years later. Methods Obesity-related measures of triceps and subscapular skinfold thickness were assessed in 1963 in n = 9,760 men aged 40-65 participating in the Israel Ischemic Heart Disease study. Cognitive evaluation and assessment of dementia prevalence were performed in n = 1,643 participants of the original cohort who survived until 1999/2000 (age ≥76 years) and had anthropometric measures in 1963. Results Age-adjusted prevalence of dementia in survivors in 1999/2000 by baseline triceps skinfold quintile was 20.5%, 21.2%, 17.6%, 15.6%, and 14.5%, respectively, from lowest to highest (p = 0.006 in trend test). Using logistic regression, a 6-mm increment of triceps skinfold was associated with an age and BMI-adjusted odds ratio of 0.81 (95% CI, 0.70-0.94) for dementia prevalence among survivors. Age-adjusted risk for dementia by subscapular skinfold quintile demonstrated 20.5%, 17.1%, 15.7%, 19.4%, and 18.1%, respectively, in groups of subjects by subscapular skinfold quintile from lowest to highest (p = 0.6 in trend test). Conclusions Lower triceps skinfold at age 40-65, reflecting diminished peripheral fat, was associated with higher dementia prevalence in late life, potentially suggesting a protective role of peripheral fat to brain health.

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.

Objectives: Recent large-scale meta-analysis of genome-wide association studies (GWAS) from multiple cohorts, demonstrated the association of the single nucleotide polymorphism (SNP) rs17518584, with processing speed (measured by the Digit Symbol Substitution Test (DSST) or the Letter Digit Substitution Test (LDST)), at GWAS significance level. This SNP is located within the cell adhesion molecule 2 (CADM2) gene. We aimed to validate this finding in our sample of 944 cognitively normal Jewish elderly individuals with type 2 diabetes (T2D), a population which is at risk for cognitive decline and dementia. Methods: Using linear regression, we studied the association of rs17518584 with DSST performance, adjusting for demographic, T2D-related characteristics and cardiovascular factors. In secondary analyses, associations with performance in four cognitive domains (episodic memory, language/semantic categorisation, attention/working memory and executive function) and overall cognition were examined. Results: Controlling for sex, age at cognitive assessment, years of education and ancestry, we found a significant association of rs17518584 with DSST performance (P = 0.013), consistent with the originally reported effect direction. Results remained significant even when the additional covariates (T2D-related and cardiovascular factors) were included in the analysis (P = 0.034). Moreover, this SNP was significantly associated with performance in the cognitive domains of language/semantic categorisation and executive function, as well as overall cognition. Conclusions: Taken together, irrespective of T2D-related characteristics and cardiovascular factors, our findings provide independent support for the association of CADM2 SNP rs17518584 with processing speed (and demonstrate association with additional cognitive phenotypes), among cognitively normal elderly individuals with T2D.

The variable length poly-T, rs10524523 ('523') located within the TOMM40 gene, was recently associated with several phenotypes of cognitive function. The short (S) allele is associated with later AD onset age and better cognitive performance, compared to the longer alleles (long and very-long (VL)). There is strong linkage disequilibrium between variants in the TOMM40 and APOE genes. In this study, we investigated the effect of '523' on cognitive performance in a sample of cognitively normal Jewish elderly with type 2 diabetes, a group at particularly high risk for cognitive impairment. Using a MANCOVA procedure, we compared homozygous carriers of the S/S allele (N=179) to carriers of the VL/VL allele (N=152), controlling for demographic and cardiovascular covariates. The S/S group performed better than the VL/VL group (p=0.048), specifically in the executive function (p=0.04) and episodic memory (p=0.050) domains. These results suggest that previous findings of an association of the TOMM40 short allele with better cognitive performance, independently from the APOE variant status, are pertinent to elderly with diabetes.

Background/Aims: Impaired motor function has been associated with cognitive impairment and dementia, but this relationship is poorly understood in elderly with type 2 diabetes (T2D). We thus investigated it in a large sample (n = 726) of cognitively normal elderly with T2D. Methods: In this cross-sectional study, hierarchical linear regressions assessed correlations of 3 motor measures (timed walk, grip strength, and self-reported motor difficulties) with episodic memory, attention/working memory, semantic categorization, executive function, and overall cognition controlling for demographics. Results: Longer timed walk and weaker grip strength were associated with poorer performance in all cognitive domains except episodic memory. Conclusions: Associations of motor and cognitive functions in T2D and non-T2D samples are consistent. A lack of association of motor function with episodic memory may suggest non-Alzheimer's disease-related underlying mechanisms.

Objective To evaluate the relationships of age, education, and gender with performance on neuropsychological tests in a cognitively intact, older Israeli sample with type 2 diabetes (T2D). Methods We examined 862 participants, 65–84 years old, enrolled in the Israel Diabetes and Cognitive Decline study. Multiple regression assessed associations of performance on 17 neuropsychological tests, including the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery, with age, education, and gender. Results Higher education and younger age were consistently associated with better performance. Women outperformed men on all memory tasks; men outperformed women on two non-verbal measures. These patterns of demographic associations with cognitive performance were very similar to those of US cohorts. Conclusions In a cognitively intact, older Israeli sample with T2D, better test performance is associated primarily with higher education, followed by younger age and gender differences. Although T2D is associated with cognitive deficits, it recapitulates the patterns of relationships between cognitive performance and demographic characteristics seen in non-T2D diabetic samples. Copyright © 2013 John Wiley & Sons, Ltd.

Objective: To analyze the relationship between body weight variability and dementia more than 3 decades later. Methods: The measurement of body weight variability was based on 3 successive weight recordings taken from over 10,000 apparently healthy tenured working men participating in the Israel Ischemic Heart Disease study, in which cardiovascular risk factors and clinical status were assessed in 1963, 1965, and 1968, when subjects were 40–70 years of age. Groups of men were stratified according to quartiles of SD of weight change among 3 measurements (1963/1965/1968): ≤1.15 kg, 1.16–1.73 kg, 1.74–2.65 kg, and ≥2.66 kg. The prevalence of dementia was assessed more than 36 years later in approximately one-sixth of them who survived until 1999/2000 (minimum age 76 years) and underwent cognitive evaluation (n = 1,620). Results: Survivors9 dementia prevalence rates were 13.4%, 18.4%, 20.1%, and 19.2% in the first to fourth quartiles of weight change SD, respectively ( p for trend = 0.034). Compared to the first quartile of weight change SD and adjusted for diabetes mellitus, body height, and socioeconomic status, a multivariate analysis demonstrated that the odds ratio for dementia was 1.42 (95% confidence interval [CI] 0.95–2.13), 1.59 (95% CI 1.05–2.37), and 1.74 (95% CI 1.14–2.64) in quartiles 2–4 of weight change SD respectively. This relationship was independent of the direction of weight changes. Conclusion: Midlife variations in weight may antecede late-life dementia.

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.