Faculty Bibliography

AIMS: To determine whether middle-aged individuals with metabolic syndrome, both with and without type 2 diabetes, exhibit cognitive impairments, and to determine the role of each metabolic syndrome component in those associations. METHODS: 143 participants were drawn from ongoing studies of normal aging. Metabolic syndrome was diagnosed in 73 participants (age: 60.4 +/- 8.4 years), who were contrasted with 70 age- and education-matched controls. RESULTS: Metabolic syndrome was associated with reductions in recall (p = 0.006), lower overall intellectual functioning (p = 0.013), and nearly significant reductions in learning (p = 0.066) and executive functioning (p = 0.050). These effects were only marginally attenuated when controlling for type 2 diabetes diagnosis. Of the 5 components of the metabolic syndrome, insulin resistance was the only significant predictor of variance in learning and recall. In addition, the number of metabolic syndrome criteria met was inversely associated with cognitive performance. CONCLUSIONS: These results indicate that impairments in cognitive functioning associated with metabolic syndrome and type 2 diabetes may begin as early as middle age and are primarily due to insulin resistance. These results demonstrate the importance of screening at-risk adults for insulin resistance in order to initiate lifestyle modifications to reverse or prevent these cognitive changes

Declarative memory impairment is frequently reported among adults with type 2 diabetes mellitus (T2DM), who also demonstrate hippocampal volume reduction. Our goals were to ascertain whether emotional memory, which is mediated by neural circuits overlapping those of declarative memory, is also affected. In addition we wanted to characterize cerebral white matter (WM) involvement in T2DM. We studied 24 middle-aged and elderly patients with T2DM who were free of obvious vascular pathology or a psychiatric disorder, and 17 age- and education-matched healthy individuals with no evidence of insulin resistance. We examined emotional and neutral memory and performed a whole-brain voxelwise WM assessment utilizing diffusion tensor imaging (DTI). We found clear evidence of impairment in declarative memory among diabetic subjects and in addition found some preliminary support to suggest a possible blunting of the memory facilitation by emotional material among female but not male diabetics. This report is also the first DTI assessment among individuals with T2DM, which after accounting for overt WM damage, revealed diffuse but predominantly frontal and temporal WM microstructural abnormalities, with extensive involvement of the temporal stem. Hierarchical regression analyses demonstrated that immediate, but not delayed, emotional memory performance was explained by temporal stem FA, independent of age, poor metabolic regulation, and systolic blood pressure. Given that the temporal lobe memory networks appear to be particularly vulnerable to the deleterious effects of T2DM, this may help explain the observed memory impairments among diabetics. Future efforts should better clarify, with a larger sample, whether emotional memory is affected in adults with T2DM and whether there are clear gender effects

Brain-derived neurotrophic factor (BDNF) plays a regulatory role in neuronal differentiation and synaptic plasticity and has been linked to glucose regulation and cognition. Associations among plasma BDNF, cognition, and insulin function were explored. Forty-one participants with impaired insulin function (IIF), ranging from insulin resistance to type 2 diabetes mellitus (T2DM), were matched with 41 healthy controls on gender, age, education, and IQ. Participants received complete medical, neurological, psychiatric, and neuropsychological evaluations. IIF individuals had significantly lower plasma BDNF levels than controls, particularly females, and higher BDNF levels were associated with poorer explicit memory in IIF females, suggesting that higher levels within this group may reflect the body's efforts to respond to damage. After accounting for age, education, and HbA1c, BDNF significantly predicted 13.1-23.5% of the variance in explicit memory in IIF women. These findings suggest that BDNF elevations within diseased groups may not always be a marker of health

Cognitive deficits and hippocampal atrophy, features that are shared with aging and dementia, have been described in type 2 diabetes mellitus (T2DM). T2DM is associated with obesity, hypertension, dyslipidemia, hypothalamic pituitary adrenocortical (HPA) axis abnormalities and inflammation, all of which have been shown to negatively impact the brain. However, since most reports in T2DM focused on glycemic control, the relative contribution of these modifying factors to the impairments observed in T2DM remains unclear. We contrasted 41 middle-aged dementia-free volunteers with T2DM (on average 7 years since diagnosis) with 47 age-, education-, and gender-matched non-insulin resistant controls on cognition and brain volumes. HPA axis activity and other modifiers that accompany T2DM were assessed to determine their impact on brain and cognition. Individuals with T2DM had specific verbal declarative memory deficits, reduced hippocampal and prefrontal volumes, and impaired HPA axis feedback control. Diminished cortisol suppression after dexamethasone and dyslipidemia were associated with decreased cognitive performance, whereas obesity was negatively related to hippocampal volume. Moreover, prefrontal volume was influenced by worse glycemic control. Thus, obesity and altered cortisol levels may contribute to the impact of T2DM on the hippocampal formation, resulting in decreased verbal declarative memory performance

There is emerging evidence from healthy individuals, as well as direct and indirect evidence from psychiatric and neurological patients with disease-related hippocampal atrophy, linking the cortisol awakening response (CAR) to hippocampal volume. Type 2 diabetes mellitus (T2DM) is a metabolic disease that is also accompanied by hippocampal atrophy, and therefore can serve as a model for ascertaining the relationship between CAR and hippocampal volume. We contrasted a group of 18 individuals with T2DM with 12 matched controls on MRI-based hippocampal volume and salivary diurnal cortisol profile including CAR. Individuals with T2DM had smaller hippocampal volumes and exhibited a blunting of the CAR relative to controls, while diurnal cortisol was not affected. Across all subjects, fasting insulin and hippocampal volume were associated with the CAR, independent of diagnosis. Our findings support the hypothesis that hippocampal integrity is an important predictor of the CAR

OBJECTIVE: To determine the impact of insulin resistance short of diabetes on the arteriolar-to-venular ratio (AVR) and whether AVR is related to cerebral atrophy. DESIGN: Cross-sectional study. PARTICIPANTS: Forty-six nondiabetic subjects with normal glucose tolerance and varying degrees of insulin resistance ranging in age from 43 to 77 years. METHODS: Insulin resistance was assessed by fasting insulin and the homeostasis model assessment. Arteriolar-to-venular ratio was determined using digital retinal photography with a nonmydriatic camera, and retinal data were analyzed using a reliable semiautomated method. Cerebral atrophy was derived by means of manual tracing and thresholding procedures on structural magnetic resonance images. MAIN OUTCOME MEASURES: Arteriolar-to-venular ratio and cerebral atrophy. RESULTS: Hyperinsulinemia negatively impacted AVR. Furthermore, AVR was associated with cerebral atrophy. Both of these findings were independent of the effects of age and hypertension. CONCLUSIONS: These novel findings indicate that insulin resistance short of diabetes and independent of age and hypertension has a negative impact on retinal vessel health. Moreover, impaired retinal vessel health related to brain atrophy also was independent of hypertension and white matter hyperintensities. Given the connections between retinal and cerebral vasculature, this may offer a partial explanation for the presence of cognitive and brain abnormalities among individuals with insulin resistance. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article

Our objective was to ascertain the nature of the associations between C-reactive protein (CRP) and cognition, and to examine how they are affected by gender and obesity. We evaluated 62 females and 63 males between 42 and 82 years of age. There were 20 lean females with a body mass index (BMI) of <25 kg/m2 and 42 overweight or obese females, with BMIs > or =25 kg/m2. There were 14 lean males and 49 with BMIs >/=25 kg/m2. CRP was associated with lower scores on cognitive tests of frontal lobe function among females and these associations were driven by the overweight/obese female group. In these data no associations between CRP and cognition were found among males. Obesity-associated inflammation is much more prominent in females and it appears to be associated with cognitive dysfunction, particularly of frontal lobe tasks.

Empathy is a multidimensional construct consisting of cognitive (inferring mental states) and emotional (empathic concern) components. Despite a paucity of research, individuals on the autism spectrum are generally believed to lack empathy. In the current study we used a new, photo-based measure, the Multifaceted Empathy Test (MET), to assess empathy multidimensionally in a group of 17 individuals with Asperger syndrome (AS) and 18 well-matched controls. Results suggested that while individuals with AS are impaired in cognitive empathy, they do not differ from controls in emotional empathy. Level of general emotional arousability and socially desirable answer tendencies did not differ between groups. Internal consistency of the MET's scales ranged from .71 to .92, and convergent and divergent validity were highly satisfactory

Type 2 diabetes mellitus appears to directly impair cognition and brain function, independent of its associated cardiovascular disease. This is supported by the presence of similar findings among adults with insulin resistance (pre-diabetes) and obese children with type 2 diabetes, years before overt cardiovascular disease. Hippocampal based memory performance is impaired early in the disease, although deficits in executive function, attention, and psychomotor speed are also seen in more chronic disease and/or poorer disease control, particularly in the presence of co-morbidities such as hypertension. Although there has been some speculation as to possible links between diabetes and Alzheimer's Disease based on associations found in population studies, no convincing empirical evidence has been put forth and brain autopsy studies, the gold standard of Alzheimer's diagnosis, have not supported such a link. Future studies should focus on understanding the mechanisms for the cognitive impairments associated with type 2 diabetes. We propose that insulin resistance-associated impairments in vascular reactivity and endothelial function are possible candidates as they may impact substrate delivery across the blood-brain-barrier. These are important issues given the obesity epidemic and the associated rising prevalence of insulin resistance and type 2 diabetes