Insulin Resistance and Alzheimer-like Reductions in Regional Cerebral Glucose Metabolism for Cognitively Normal Adults With Prediabetes or Early Type 2 Diabetes

Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.
Archives of neurology (Impact Factor: 7.42). 01/2011; 68(1):51-7. DOI: 10.1001/archneurol.2010.225
Source: PubMed


Insulin resistance is a causal factor in prediabetes (PD) and type 2 diabetes (T2D) and increases the risk of developing Alzheimer disease (AD). Reductions in cerebral glucose metabolic rate (CMRglu) as measured by fludeoxyglucose F 18-positron emission tomography (FDG-PET) in parietotemporal, frontal, and cingulate cortices are associated with increased AD risk and can be observed years before dementia onset.
To examine whether greater homeostasis model assessment insulin resistance (HOMA-IR) is associated with reduced resting CMRglu in areas vulnerable in AD in cognitively normal adults with newly diagnosed PD or T2D (PD/T2D), and to determine whether adults with PD/T2D have abnormal patterns of CMRglu during a memory encoding task.
Randomized crossover design of resting and activation FDG-PET.
University imaging center and Veterans Affairs clinical research unit.
Twenty-three older adults (mean [SEM] age, 74.4 [1.4] years) with no prior diagnosis of diabetes but who met American Diabetes Association glycemic criteria for PD (n = 11) or diabetes (n = 12) based on fasting or 2-hour oral glucose tolerance test (OGTT) glucose values and 6 adults (mean [SEM] age, 74.3 [2.8] years) with normal fasting glucose values and glucose tolerance. No participant met Petersen criteria for mild cognitive impairment.
Fasting participants underwent resting and cognitive activation FDG-PET imaging on separate days. Following a 30-minute transmission scan, subjects received an intravenous injection of 5 mCi of FDG, and the emission scan commenced 40 minutes after injection. In the activation condition, a 35-minute memory encoding task was initiated at the time of tracer injection. Subjects were instructed to remember a repeating list of 20 words randomly presented in series through earphones. Delayed free recall was assessed once the emission scan was complete.
The HOMA-IR value was calculated using fasting glucose and insulin values obtained during OGTT screening and then correlated with CMRglu values obtained during the resting scan. Resting CMRglu values were also subtracted from CMRglu values obtained during the memory encoding activation scan to examine task-related patterns of CMRglu.
Greater insulin resistance was associated with an AD-like pattern of reduced CMRglu in frontal, parietotemporal, and cingulate regions in adults with PD/T2D. The relationship between CMRglu and HOMA-IR was independent of age, 2-hour OGTT glucose concentration, or apolipoprotein E ε4 allele carriage. During the memory encoding task, healthy adults showed activation in right anterior and inferior prefrontal cortices, right inferior temporal cortex, and medial and posterior cingulate regions. Adults with PD/T2D showed a qualitatively different pattern during the memory encoding task, characterized by more diffuse and extensive activation, and recalled fewer items on the delayed memory test.
Insulin resistance may be a marker of AD risk that is associated with reduced CMRglu and subtle cognitive impairments at the earliest stage of disease, even before the onset of mild cognitive impairment.

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Available from: Laura D Baker, Oct 02, 2015
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    • "In order to determine whether a lower CMRg value with age is normal or represents a risk for AD, agenormalized reference values need to be established so as to be able to distinguish a normal from a pathological pattern; the former would not represent a risk factor for AD whereas the latter could. Like aging, changes in peripheral glucose metabolism leading towards insulin resistance and type 2 diabetes increases the risk of AD (Baker et al. 2011; Craft 2009; Craft et al. 2013). As with cognitive scores, should metabolic parameters be considered in including or excluding older persons from a reference group of cognitively healthy older people? "
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    ABSTRACT: Our primary objective in this study was to quantify whole brain and regional cerebral metabolic rates of glucose (CMRg) in young and older adults in order to determine age-normalized reference CMRg values for healthy older adults with normal cognition for age. Our secondary objectives were to-(i) report a broader range of metabolic and endocrine parameters including body fat composition that could form the basis for the concept of a 'metabolic phenotype' in cognitively normal, older adults, and (ii) to assess whether medications commonly used to control blood lipids, blood pressure or thyroxine affect CMRg values in older adults. Cognition assessed by a battery of tests was normal for age and education in both groups. Compared to the young group (25 years old; n = 34), the older group (72 years old; n = 41) had ~14 % lower CMRg (μmol/100 g/min) specifically in the frontal cortex, and 18 % lower CMRg in the caudate. Lower grey matter volume and cortical thickness was widespread in the older group. These differences in CMRg, grey matter volume and cortical thickness were present in the absence of any known evidence for prodromal Alzheimer's disease (AD). Percent total body fat was positively correlated with CMRg in many brain regions but only in the older group. Before and after controlling for body fat, HOMA2-IR was significantly positively correlated to CMRg in several brain regions in the older group. These data show that compared to a healthy younger adult, the metabolic phenotype of a cognitively-normal 72 year old person includes similar plasma glucose, insulin, cholesterol, triglycerides and TSH, higher hemoglobin A1c and percent body fat, lower CMRg in the superior frontal cortex and caudate, but the same CMRg in the hippocampus and white matter. Age-normalization of cognitive test results is standard practice and we would suggest that regional CMRg in cognitively healthy older adults should also be age-normalized.
    Biogerontology 09/2015; DOI:10.1007/s10522-015-9595-7 · 3.29 Impact Factor
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    • "Several studies report an increase in brain damage, including neuronal cell death associated to cognitive impairment in T2D [3] [4]. However, the impact of T2D in central nervous system (CNS) structure and function is still not fully understood [5]. "
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    ABSTRACT: Alterations in brain structure and function are a well-known long-term complication of type 2 diabetes (T2D). Although the mechanism(s) by which T2D lead(s) to cognitive dysfunction and neuronal cells degeneration continue(s) a matter of debate, vascular alterations emerged as major players in this scenario. This study was aimed to evaluate the antioxidant defenses and oxidative markers present in brain vessels and synaptosomes from 3- and 12-month-old Goto-Kakizaki (GK) rats, a spontaneous non-obese model of T2D, and Wistar control rats. A significant increase in manganese superoxide dismutase (MnSOD) activity and vitamin E levels and a significant decrease in aconitase and glutathione reductase (GR) activities, glutathione (GSH)/glutathione disulfide (GSSG) ratio, and GSH and malondialdehyde (MDA) levels were observed in brain vessels and synaptosomes from GK rats, and these effects were not significantly affected by aging. However, an age-dependent increase in hydrogen peroxide (H2O2) levels in both diabetic synaptosomes and vessels was observed. No significant alterations were observed in the activity of glutathione peroxidase (GPx) and GR in both brain vessels and synaptosomes from diabetic animals. In control rats, an age-dependent increase in the activity of GPx, GR, and MnSOD and vitamin E and MDA levels and an age-dependent decrease in GSH levels were observed in brain vessels. In contrast, a significant age-dependent increase in GSH levels and a decrease in vitamin E levels were observed in synaptosomes from control animals. Altogether, our results show that T2D and aging differently affect brain vessels and synaptosomes. However, both conditions increase the vulnerability of brain structures to degenerative events.
    Current Neurovascular Research 09/2014; 11(4). DOI:10.2174/1567202611666140903122801 · 2.25 Impact Factor
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    • "Four other genes in the top findings were previously implicated in other GWAS: PML in myopia [Meng et al., 2012], Paget's disease [Albagha et al., 2011], and height [Lango Allen et al., 2010]; TPD52 in monoamine metabolite levels in cerebrospinal fluid [Luykx et al., 2013]; GPR137B in working memory in response to olanzapine treatment in schizophrenia [McClay et al., 2011]; MTNR1B for multiple metabolic-and glucose-related phenotypes (e.g., fasting glucose [Prokopenko et al., 2009]; metabolic traits [Sabatti et al., 2009]). In addition to RIC3, MTNR1B is a particularly intriguing candidate given the role metabolic syndrome may play in risk for cognitive decline [Arvanitakis et al., 2004; Baker et al., 2011; Panza et al., 2010; Yaffe, 2007a, b]. Further mapping studies will be required to assess these candidates for causative noncoding or gene variation in cognitive maintenance. "
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    ABSTRACT: Objective Identify genetic factors associated with cognitive maintenance in late life and assess their association with gray matter (GM) volume in brain networks affected in aging. Methods We conducted a genome-wide association study of ∼2.4 M markers to identify modifiers of cognitive trajectories in Caucasian participants (N = 7,328) from two population-based cohorts of non-demented elderly. Standardized measures of global cognitive function (z-scores) over 10 and 6 years were calculated among participants and mixed model regression was used to determine subject-specific cognitive slopes. “Cognitive maintenance” was defined as a change in slope of ≥ 0 and was compared with all cognitive decliners (slope < 0). In an independent cohort of cognitively normal older Caucasians adults (N = 122), top association findings were then used to create genetic scores to assess whether carrying more cognitive maintenance alleles was associated with greater GM volume in specific brain networks using voxel-based morphometry. ResultsThe most significant association was on chromosome 11 (rs7109806, P = 7.8 × 10−8) near RIC3. RIC3 modulates activity of α7 nicotinic acetylcholine receptors, which have been implicated in synaptic plasticity and beta-amyloid binding. In the neuroimaging cohort, carrying more cognitive maintenance alleles was associated with greater volume in the right executive control network (RECN; PFWE = 0.01). Conclusions These findings suggest that there may be genetic loci that promote healthy cognitive aging and that they may do so by conferring robustness to GM in the RECN. Future work is required to validate top candidate genes such as RIC3 for involvement in cognitive maintenance. Hum Brain Mapp, 2014. © 2014 Wiley Periodicals, Inc.
    Human Brain Mapping 09/2014; 35(9). DOI:10.1002/hbm.22494 · 5.97 Impact Factor
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