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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    • "As discussed by Reger and colleagues, differences in potential confounding factors such as BMI and control for AD genetic risk factors (i.e., presence of APOEí µí¼€4) or AD severity may have accounted for differences between these studies. More recently, findings from Suzanne Crafts group have shown that CSF insulin levels are reduced in early stages of AD or in the mild cognitively impairment [45] and diets rich in fats and sugar lower CSF insulin levels in healthy adults and this was associated with reductions in cognitive functioning [46]. Whether changes in peripheral insulin levels reflect changes in brain insulin levels is unclear. "
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    DESCRIPTION: Type 2 diabetes (T2DM), Alzheimer’s disease (AD), and insulin resistance are age-related conditions and increased prevalence is of public concern. Recent research has provided evidence that insulin resistance and impaired insulin signalling may be a contributory factor to the progression of diabetes, dementia, and other neurological disorders. Alzheimer’s disease (AD) is the most common subtype of dementia. Reduced release (for T2DM) and decreased action of insulin are central to the development and progression of both T2DM and AD. A literature search was conducted to identify molecular commonalities between obesity, diabetes, and AD. Insulin resistance affects many tissues and organs, either through impaired insulin signalling or through aberrant changes in both glucose and lipid (cholesterol and triacylglycerol) metabolism and concentrations in the blood. Although epidemiological and biological evidence has highlighted an increased incidence of cognitive decline and AD in patients with T2DM, the common molecular basis of cell and tissue dysfunction is rapidly gaining recognition. As a cause or consequence, the chronic inflammatory response and oxidative stress associated with T2DM, amyloid-β (Aβ) protein accumulation, and mitochondrial dysfunction link T2DM and AD.
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    • "In addition to genetic mutations, polymorphisms or familial risk factors, lifestyle factors such as insulin resistance and/or type 2 diabetes also play an important role in the risk of developing AD. Adults in their seventies with type 2 diabetes have an abnormal pattern of brain glucose uptake despite normal cognitive scores (Baker et al., 2011). Young women with mild insulin resistance due to polycystic ovary syndrome have 9–14% lower glucose uptake in parts of the temporal and parietal cortex, regions which are also affected by low glucose uptake in early AD (Castellano et al., 2015a). "
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    ABSTRACT: Brain energy metabolism in Alzheimer’s disease (AD) is characterized mainly by temporo-parietal glucose hypometabolism. This pattern has been widely viewed as a consequence of the disease, i.e. deteriorating neuronal function leading to lower demand for glucose. This review will address deteriorating glucose metabolism as a problem specific to glucose and one that precedes AD. Hence, ketones and medium chain fatty acids (MCFA) could be an alternative source of energy for the aging brain that could compensate for low brain glucose uptake. MCFA in the form of dietary medium chain triglycerides (MCT) have a long history in clinical nutrition and are widely regarded as safe by government regulatory agencies. The importance of ketones in meeting the high energy and anabolic requirements of the infant brain suggest they may be able to contribute in the same way in the aging brain. Clinical studies suggest that ketogenesis from MCT may be able to bypass the increasing risk of insufficient glucose uptake or metabolism in the aging brain sufficiently to have positive effects on cognition.
    10/2015; DOI:10.1051/ocl/2015025
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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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