OBJECTIVE: The aim of this study was to examine whether insulin resistance, assessed by HOMA of insulin resistance (HOMA-IR), is an independent predictor of cognitive decline. RESEARCH DESIGN AND METHODS: The roles of HOMA-IR, fasting insulin and glucose, HbA1c, and hs-CRP as predictors of cognitive performance and its change were evaluated in the Finnish nationwide, population-based Health 2000 Health Examination Survey and its 11-year follow-up, the Health 2011 study (n = 3,695, mean age at baseline 49.3 years, 55.5% women). Categorical verbal fluency, word-list learning, and word-list delayed recall were used as measures of cognitive function. Multivariate linear regression analysis was performed and adjusted for previously reported risk factors for cognitive decline. RESULTS: Higher baseline HOMA-IR and fasting insulin levels were independent predictors of poorer verbal fluency performance (P = 0.0002 for both) and of a greater decline in verbal fluency during the follow-up time (P = 0.004 for both). Baseline HOMA-IR and insulin did not predict word-list learning or word-list delayed recall scores. There were no interactions between HOMA-IR and apolipoprotein E ε4 (APOEε4) genotype, hs-CRP, or type 2 diabetes on the cognitive tests. Fasting glucose and hs-CRP levels at baseline were not associated with cognitive functioning. CONCLUSIONS: Our results show that higher serum fasting insulin and insulin resistance predict poorer verbal fluency and a steeper decline in verbal fluency during 11 years in a representative sample of an adult population. Prevention and treatment of insulin resistance might help reduce cognitive decline later in life.

Purpose The purpose of this study was to investigate the effects of ageing, sex and body mass index (BMI) on translocator protein (TSPO) availability in healthy subjects using positron emission tomography (PET) and the radioligand [¹¹C]PBR28. Methods [¹¹C]PBR28 data from 140 healthy volunteers (72 males and 68 females; N = 78 with HAB and N = 62 MAB genotype; age range 19–80 years; BMI range 17.6–36.9) were acquired with High Resolution Research Tomograph at three centres: Karolinska Institutet (N = 53), Turku PET centre (N = 62) and Yale University PET Center (N = 25). The total volume of distribution (V_T) was estimated in global grey matter, frontal, temporal, occipital and parietal cortices, hippocampus and thalamus using multilinear analysis 1. The effects of age, BMI and sex on TSPO availability were investigated using linear mixed effects model, with TSPO genotype and PET centre specified as random intercepts. Results There were significant positive correlations between age and V_T in the frontal and temporal cortex. BMI showed a significant negative correlation with V_T in all regions. Additionally, significant differences between males and females were observed in all regions, with females showing higher V_T. A subgroup analysis revealed a positive correlation between V_T and age in all regions in male subjects, whereas age showed no effect on TSPO levels in female subjects. Conclusion These findings provide evidence that individual biological properties may contribute significantly to the high variation shown in TSPO binding estimates, and suggest that age, BMI and sex can be confounding factors in clinical studies.

Background and Objectives Chronic low-grade inflammation, commonly associated with cardiovascular diseases and risk factors, has been associated inconclusively with cognitive decline and dementia. The aim of our study was to evaluate whether low-grade inflammation, measured in midlife, is associated with a decline in cognitive performance after a 10-year follow-up. We hypothesized that low-grade inflammation, estimated by interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and high-sensitivity CRP (hs-CRP), is a predictor of cognitive decline in the general population. Methods This prospective cohort study is based on a Finnish nationwide, population-based Health 2000 Examination Survey, its supplemental examinations in 2000–2001, and the follow-up Health 2011 Survey. Cognitive performance at baseline and at follow-up was assessed with categorical verbal fluency (VF), word-list learning (WLL), and word-list delayed recall (WLDR). Baseline low-grade inflammation was measured with IL-6, TNF-α, and hs-CRP in 2001. Associations between low-grade inflammation and cognitive performance were analyzed with multivariable linear models adjusted for age, sex, education, APOE ε4 genotype, type 2 diabetes, hypertension, hypercholesterolemia, body mass index, depressive symptoms, smoking, and baseline cognition. Results Nine hundred fifteen participants aged 45–74 years (median age 54 years, 55% women) were included in the analysis. Both higher IL-6 and TNF-α at baseline predicted poorer performance in VF and WLL at 10-year follow-up (VF: IL-6 β: −1.14, p = 0.003, TNF-α β: −1.78, p = 0.008; WLL: IL-6 β: −0.61, p = 0.007, TNF-α β: −0.86, p = 0.03). Elevated IL-6 also predicted a greater decline in VF and WLL after a 10-year follow-up (VF: β: −0.81, p = 0.01; WLL: β: −0.53, p = 0.008). Baseline TNF-α did not predict cognitive decline, and hs-CRP did not predict cognitive performance or decline after 10-years. Discussion Our results suggest that low-grade inflammation in midlife is an independent risk factor for poorer cognitive performance later in life. Of the studied markers, IL-6 and TNF-α seem to be stronger predictors for cognitive performance and decline than hs-CRP.

Objective To examine whether midlife insulin resistance is an independent risk factor for brain amyloid accumulation in vivo after 15 years, and whether this risk is modulated by APOE ε4 genotype. Methods This observational study examined 60 elderly volunteers without dementia (mean age at baseline 55.4 and at follow-up 70.9 years, 55.5% women) from the Finnish population-based, nationwide Health2000 study with [¹¹C]Pittsburgh compound B–PET imaging in 2014–2016. The participants were recruited according to their homeostatic model assessment of insulin resistance (HOMA-IR) values in the year 2000, and their APOE ε4 genotype. The exposure group (IR+, n = 30) consisted of individuals with HOMA-IR >2.17 at baseline (highest tertile of the Health2000 study population), and the control group (IR−, n = 30) consisted of individuals with HOMA-IR <1.25 at baseline (lowest tertile). The groups were enriched for APOE ε4 carriers, resulting in 50% (n = 15) APOE ε4 carriers in both groups. Analyses were performed with multivariate logistic and linear regression. Results An amyloid-positive PET scan was found in 33.3% of the IR− group and 60.0% of the IR+ group (odds ratio 3.0, 95% confidence interval 1.1–8.9, p = 0.04). The increased risk was seen in carriers and noncarriers of APOE ε4 genotype. Higher midlife, but not late-life continuous HOMA-IR was associated with a greater brain amyloid burden at follow-up after multivariate adjustments for other cognitive and metabolic risk factors (β = 0.11, 95% confidence interval 0.002–0.22, p = 0.04). Conclusions These results indicate that midlife insulin resistance is an independent risk factor for brain amyloid accumulation in elderly individuals without dementia.

Imaging brain glucose metabolism with fluorine-labelled fluorodeoxyglucose ([¹⁸F]-FDG) positron emission tomography (PET) has long been utilized to aid the diagnosis of memory disorders, in particular in differentiating Alzheimer’s disease (AD) from other neurological conditions causing cognitive decline. The interest for studying brain glucose metabolism in the context of metabolic disorders has arisen more recently. Obesity and type 2 diabetes—two diseases characterized by systemic insulin resistance—are associated with an increased risk for AD. Along with the well-defined patterns of fasting [¹⁸F]-FDG-PET changes that occur in AD, recent evidence has shown alterations in fasting and insulin-stimulated brain glucose metabolism also in obesity and systemic insulin resistance. Thus, it is important to clarify whether changes in brain glucose metabolism are just an epiphenomenon of the pathophysiology of the metabolic and neurologic disorders, or a crucial determinant of their pathophysiologic cascade. In this review, we discuss the current knowledge regarding alterations in brain glucose metabolism, studied with [¹⁸F]-FDG-PET from metabolic disorders to AD, with a special focus on how manipulation of insulin levels affects brain glucose metabolism in health and in systemic insulin resistance. A better understanding of alterations in brain glucose metabolism in health, obesity, and neurodegeneration, and the relationships between insulin resistance and central nervous system glucose metabolism may be an important step for the battle against metabolic and cognitive disorders.