Annadora J Bruce-Keller
email: annadora.bruce-keller@pbrc.edu

Jeffrey N Keller

Christopher D Morrison

Obesity and Vulnerability of the CNS

Keywords: age, cognition, dementia, high-fat diet, oxidative stress

The incidence of obesity is increasing worldwide, and is especially pronounced in developed western countries. While the consequences of obesity on metabolic and cardiovascular physiology are well established, epidemiological and experimental data are beginning to establish that the central nervous system (CNS) may also be detrimentally affected by obesity and obesity-induced metabolic dysfunction. In particular, data show that obesity in human populations is associated with cognitive decline and enhanced vulnerability to brain injury, while experimental studies in animal models confirm a profile of heightened vulnerability and decreased cognitive function. This review will describe findings from human and animal studies to summarize current understanding of how obesity affects the brain.

Furthermore, studies aimed at identifying key elements of body-brain dialog will be discussed to assess how various metabolic and adipose-related signals could adversely affect the CNS. Overall, data suggest that obesity-induced alterations in metabolism may significantly synergize with age to impair brain function and accelerate age-related diseases of the nervous system. Thus, enhanced understanding of the effects of obesity and obesity-related metabolic dysfunction on the brain are especially critical as increasing numbers of obese individuals approach advanced age.

A C C E P T E D M A N U S C R I P T Introduction

The epidemic of obesity has become pandemic, defined as an epidemic occurring over a wide geographic area and affecting an exceptionally high proportion of the population. The rise in obesity rates was first noted in the US, but has spread to other industrialized nations and it is even now being documented in developing countries. Indeed, the global extent of the obesity pandemic was formally recognized by the World Health Organization (WHO) in 1997, and worldwide obesity rates are increasing dramatically [START_REF] Caballero | The global epidemic of obesity: an overview[END_REF]. Estimates from the WHO indicate that as of 2005, at least 400 million adults (9.8%) were obese. Unlike most global health concerns, the obesity crisis is even more severe in developed nations. From 1960 to 2004, the prevalence of obesity in the US has more than doubled among adults from 13.3% to 32.1%, while the percentage of Americans overweight during the same period has increased from 44.8% to 66%, with most of this rise occurring since 1980 [START_REF]Chartbook on Trends in the Health of Americans[END_REF]. Obesity is clinically identified based on measurements of body mass index [START_REF] Mei | Validity of body mass index compared with other body-composition screening indexes for the assessment of body fatness in children and adolescents[END_REF], but can be generally defined as the physiological condition in which excess body fat has accumulated to an extent that can negatively affect health. This definition is based on the dramatically enhanced risk for a myriad of disease conditions with obesity, including type 2 diabetes, cardiovascular disease, gastrointestinal and respiratory difficulties, and many types of cancer (reviewed in [4]). Furthermore, obesity is very closely associated with metabolic syndrome, which is characterized by a group of metabolic disorders that can include abdominal obesity, insulin resistance or glucose intolerance, atherogenic dyslipidemia, elevated blood pressure, and increased expression of prothrombotic and proinflammatory markers (reviewed in [START_REF] Olufadi | Clinical and laboratory diagnosis of the metabolic syndrome[END_REF]).

Based on the large body of evidence that strongly indicates that obesity accelerates the onset and exaggerates the severity of a myriad of age-related disorders diseases, including hypertension [START_REF] Hubert | Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study[END_REF], [START_REF] Stamler | Weight and blood pressure. Findings in hypertension screening of 1 million Americans[END_REF], myocardial infarction [START_REF] Piegas | Risk factors for myocardial infarction in Brazil[END_REF], and stroke [START_REF] Walker | Body size and fat distribution as predictors of stroke among U.S. men[END_REF], [START_REF] Rexrode | A prospective study of body mass index, weight change, and risk of stroke in women[END_REF], one could theorize that obesity accelerates age and age-related pathologies. Thus, it is possible that obesity might synergistically interact with the aging process to significantly accelerate the development of age-related disease and speed functional declines in large proportions of the US and global population. The clinical significance of this possibility

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is amplified by observations that obesity rates amongst the elderly may be even higher than in the general population, as estimates indicate that 72% of Americans aged 60 and over are overweight with 32.4% obese [START_REF] Wang | The obesity epidemic in the United States--gender, age, socioeconomic, racial/ethnic, and geographic characteristics: a systematic review and metaregression analysis[END_REF]. Thus, to address this ominous potential public health crisis, it is necessary that clinicians and investigators work together to better understand the etiology of obesity-induced alterations to overall health in both clinical and experimental settings.

One especially costly and debilitating deficit of aging is the loss of cognitive function and the onset of dementia. All cognitive disorders, including dementia, become more common with age.

Indeed, it has been estimated that dementia affects as many as 6-10% of people in industrialized nations aged 65 or older, 40-60% of whom may have Alzheimer's disease [START_REF] Hendrie | Epidemiology of dementia and Alzheimer's disease[END_REF], [START_REF] Riedel-Heller | Incidence of dementia according to DSM-III-R and ICD-10: results of the Leipzig Longitudinal Study of the Aged (LEILA75+), Part 2[END_REF], [START_REF] Wimo | The magnitude of dementia occurrence in the world[END_REF], [START_REF] Ferri | Global prevalence of dementia: a Delphi consensus study[END_REF], [START_REF] Brunnström | Prevalence of dementia subtypes: A 30year retrospective survey of neuropathological reports[END_REF].

Despite it's strong association with age, dementia has been proposed as a mainly preventable condition with a large number of modifiable risk factors, including obesity, metabolic syndrome, and cardiovascular disease [START_REF] Haan | Can dementia be prevented? Brain aging in a population-based context[END_REF]. In light of the 1 billion overweight and 300 million obese individuals worldwide [START_REF] James | The worldwide obesity epidemic[END_REF], a better understanding of the degree to which, and the mechanisms by which, obesity affects the brain could not only result in significant advances in public health, but could also unmask the pathophysiologic processes that might underlie age-related cognitive dysfunction and dementia.

Association of obesity with CNS abnormalities and dysfunction in clinical human studies

As discussed above, the CNS may be one of the more crucial sites at the intersection of age and obesity. This relationship is highlighted by observations of gross abnormalities in overall brain structure and architecture associated with obesity. For example, in regression studies in which the effects of age and body mass index (BMI) on brain volume and cognition demonstrated that both age and increased BMI were associated with decreased brain volume [START_REF] Ward | The effect of body mass index on global brain volume in middle-aged adults: a cross sectional study[END_REF]. Other studies have confirmed alterations of brain morphology in overweight and obese young adults, and it has been shown that particularly in the frontal lobe, clinical obesity is associated with reductions in focal gray matter volume and enlarged orbitofrontal white matter [START_REF] Pannacciulli | Brain abnormalities in human obesity: a voxel-based morphometric study[END_REF]. Thus, these studies demonstrate that obesity in otherwise healthy middle-aged adults is associated with axonal and/or myelin abnormalities in white matter with

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decreases in grey matter volumes, which could reflect loss of neurons. Because frontal lobe white matter is more prone to the effects of aging than in other lobes, these data could reflect accelerated aging in obese individuals. Interestingly, these structural abnormalities may be reversible, as it has been reported that structural changes in the brains of obese patients may partially revert with dieting.

Specifically, a recent magnetic resonance imaging study has shown that white matter volumes in several basal brain regions are greater in obese subjects compared with lean subjects, with a positive correlation between white matter volume in basal brain structures and waist to hip ratio. More importantly, the detected white matter alterations were partially reversed by dieting [START_REF] Haltia | Brain white matter expansion in human obesity and the recovering effect of dieting[END_REF]. Regional gray matter volumes (which would reflect neuronal cell number and/or expansion) did not differ significantly in obese and lean subjects, and were not affected by dieting [START_REF] Haltia | Brain white matter expansion in human obesity and the recovering effect of dieting[END_REF]. However, it is important to note that these studies were done in non-geriatric populations, indicating that while dieting may reverse some changes, the neurobiological and functional alterations in obese individuals that do not lose weight may be present for decades, and it is not known if they remain reversible with advancing age. In addition to, or possible because of age-related structural changes, brain aging is associated with enhanced vulnerability to and decreased recovery from injury and/or damage For example, aging is associated with decreased recovery from traumatic brain injury [START_REF] Bashore | Older age, traumatic brain injury, and cognitive slowing: some convergent and divergent findings[END_REF], and likewise, epidemiological data suggests that obese patients suffer more complications and higher mortality than lean patients after traumatic brain injury, an adverse relationship that is further complicated by age [START_REF] Brown | Obesity and traumatic brain injury[END_REF]. It should be noted, however, that complete consensus regarding the effects of obesity on traumatic injury has not yet been achieved. Indeed, while some studies have shown that obesity is an independent predictor of mortality following blunt trauma [START_REF] Neville | Obesity is an independent risk factor of mortality in severely injured blunt trauma patients[END_REF], other studies have failed to detect increases in mortality following traumatic injury in obese patients, although it was noted that obese individuals had longer hospital stays compared to non-obese patients [START_REF] Duane | Obesity and outcomes after blunt trauma[END_REF]. In relation to other forms of injury, advanced age is a major risk factor for stroke, and has been reported to increase the severity of stroke-induced brain dysfunction [START_REF] Popa-Wagner | The response of the aged brain to stroke: too much, too soon?[END_REF]. Elevated adiposity and obesity are also reported to increase the risk of stroke. For example, epidemiological studies have revealed that obesity increases the risk of ischemic stroke [START_REF] Rexrode | A prospective study of body mass index, weight change, and risk of stroke in women[END_REF], [START_REF] Kurth | Body mass index and the risk of stroke in men[END_REF], [START_REF] Abbott | Body mass index and thromboembolic stroke in nonsmoking men in older middle age. The Honolulu Heart Program[END_REF].

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These studies are also important in that they indicate that the increased risk for stroke in overweight or obese subjects is independent of diabetes, hypertension, or hypercholesterolemia [START_REF] Kurth | Body mass index and the risk of stroke in men[END_REF]. Additionally, there is evidence indicating that obesity not only increases stroke incidence, but also might increase stroke-induced damage, as ischemic events in obese patients are reported to be associated with increased complications and higher mortality rates [START_REF] Clavijo | Metabolic syndrome in patients with acute myocardial infarction is associated with increased infarct size and in-hospital complications[END_REF], [START_REF] Weitbrecht | Long-term prognosis of cerebral infarct in comparison with a normal population[END_REF].

In terms of brain function, obesity may disrupt cognition, as studies have reported deficits in learning, memory, and executive functioning in obese when compared to nonobese patients [START_REF] Elias | Lower cognitive function in the presence of obesity and hypertension: the Framingham Heart Study[END_REF], [START_REF] Elias | Obesity, diabetes and cognitive deficit: the Framingham Heart Study[END_REF], [START_REF] Waldstein | Interactive relations of central versus total obesity and blood pressure to cognitive function[END_REF]. Other studies of young and middle-aged healthy adults have confirmed the association of obesity with behavioral declines in executive function [START_REF] Gunstad | Elevated body mass index is associated with executive dysfunction in otherwise healthy adults[END_REF]. Overall, current evidence suggests that obesity and the consequences of obesity, including midlife hypertension, diabetes, and cerebrovascular disease, contribute significantly to cognitive decline and accelerate the development of dementia [START_REF] Qiu | The epidemiology of the dementias: an update[END_REF]. For example, retrospective studies have found that an elevation in BMI of only a single unit associates with a 36% increase in Alzheimer's disease in women [START_REF] Kanaya | Change in cognitive function by glucose tolerance status in older adults: a 4-year prospective study of the Rancho Bernardo study cohort[END_REF], while a prospective study of a large cohort of people in New York City revealed that those with low-calorie or low-fat diets had significantly lower risks for Alzheimer disease than did those with higher calorie intake [START_REF] Luchsinger | Caloric intake and the risk of Alzheimer disease[END_REF]. Similar studies have reported that abdominal adiposity in the elderly increased the incidence of dementia even after correcting for age [START_REF] Jeong | Interactive effect of obesity indexes on cognition[END_REF], [START_REF] Yaffe | Metabolic syndrome and cognitive decline in elderly latinos: findings from the SALSA Study[END_REF], [START_REF] Taylor | Cognitive dysfunction associated with metabolic syndrome[END_REF]. It is important to note that in these studies, cognitive decline was determined using established and commonly used cognitive assessments like the mini mental status exam, delayed word-list recall, and coding tasks.

Overall, these reports collectively indicate that obesity in humans is associated with increases in brain injury and decreases in brain function. These studies are important in that they underscore the significant public health concern that is developing as increasing percentages of the population continue to age while carrying the additional physiological burden of obesity. Indeed, brain injury and dementia may be among the most costly clinical conditions to treat, as patients are not able to work and may require institutionalization. However, the relationship between obesity and dementia suggests that a careful and controlled study of obesity in experimental settings could help to unravel the

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pathophysiological mechanisms of age-related dementia. Elucidation of the physiological mechanisms whereby obesity accelerates the progression of age-related brain dysfunction could lead to a better understanding of, and thus a better clinical management of, unsuccessful brain aging. Thus, there has been considerable research impetus in recent years to put well-developed animal models of obesity to use to understand the pathogenesis of obesity-induced CNS dysfunction.

Association of obesity with CNS dysfunction in experimental animal studies

In general, animal models of obesity can be generated with environmental manipulation (diet induced obesity), spontaneous mutants (ob/ob or db/db mice, fa/fa Zucker rats), genetically engineered transgenic animals (CRF or Agrp transgenic mice) or mechanical intervention (chemical lesion of the ventromedial hypothalamus), and use of these animal models has contributed strongly to the understanding of human obesity (reviewed in [START_REF] Tschöp | Rodent obesity models: an overview[END_REF], [START_REF] Casper | Relevance of animal models to human eating disorders and obesity[END_REF]). Genetic models of obesity have been valuable

for their utility in identifying genes linked to human obesity, and for elucidating specific pathways that regulate body weight and the pathogenesis for obesity-related metabolic syndromes. The ob/ob leptin deficient mouse gains weight rapidly (recognizable at about 4 weeks of age) and may reach three times the normal weight of wildtype controls. In addition to obesity and hyperphagia, mutant mice exhibit transient diabetes-like syndrome of hyperglycemia, glucose intolerance, elevated plasma insulin, and impaired wound healing (reviewed in [START_REF] Lindström | The physiology of obese-hyperglycemic mice [ob/ob mice[END_REF]). Obesity in this model is characterized by an increase in both number and size of adipocytes, and injection of leptin into obese homozygotes sharply reduces body weight, decreases food intake, increases energy expenditure, and restores fertility. This specific model has been used to measure of effects of obesity on the brain [START_REF] Itateyama | Hypothalamic neuronal histamine in genetically obese animals: its implication of leptin action in the brain[END_REF], [START_REF] Terao | Inflammatory and injury responses to ischemic stroke in obese mice[END_REF]. However, it can be questioned whether the results obtained from genetic models of obesity arise from the obese phenotype itself or rather the model's genetic/pharmacological background. Thus, diet-induced models of obesity are thought by some to better model obesity in humans, particularly in Western industrialized nations in which high fat/high calorie diets are commonplace. Studies in which specially formulated

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high fat or calorie experimental animals revealed that such diets promote obesity, hyperglycemia, whole-body insulin resistance, and generalized metabolic syndrome function [START_REF] Tschöp | Rodent obesity models: an overview[END_REF], [START_REF] Oakes | Mechanisms of liver and muscle insulin resistance induced by chronic high-fat feeding[END_REF], [START_REF] Buettner | High-fat diets: modeling the metabolic disorders of human obesity in rodents[END_REF]. Indeed, dietary manipulation studies in experimental animals have lead to important advances in the field, including a better understanding of the relative health benefits of fish-based versus animal-based fats [START_REF] Buettner | High-fat diets: modeling the metabolic disorders of human obesity in rodents[END_REF]. However, an important downside to this approach is the variability in definition of the term "dietary manipulation". Indeed, while numerous investigators have used this approach, neither the exact content nor composition of the diets employed is standardized. For example, while some investigators employ well-defined, commercially available high fat diets in which the fat component replaces carbohydrate and/or protein components, others have simply added fat to a standard rodent chow, leading to an unbalanced diet composition with respect to nutrient content [START_REF] Buettner | High-fat diets: modeling the metabolic disorders of human obesity in rodents[END_REF]. Unfortunately, then, various diets with very different fat and/or calorie compositions are summarized under the term "dietinduced obesity" in the literature. While diet-induced models of obesity may thus be better experimental representations of obesity in humans, the wide variation in available diets precludes easy comparisons across studies using different diet formulations. However, observations that remain consistent across both genetic and different diet-induced models of obesity likely highlight a common physiological process that is also likely to accordingly transcend species differences to participate in the human condition, and several excellent reviews are available that systematically describe the currently available animal models of obesity [START_REF] Tschöp | Rodent obesity models: an overview[END_REF], [START_REF] Lindström | The physiology of obese-hyperglycemic mice [ob/ob mice[END_REF], [START_REF] Buettner | High-fat diets: modeling the metabolic disorders of human obesity in rodents[END_REF], [START_REF] Buettner | Defining high-fat-diet rat models: metabolic and molecular effects of different fat types[END_REF], [START_REF] Dziedzic | Various dietary fats differentially change the gene expression of neuropeptides involved in body weight regulation in rats[END_REF].

One of the earliest reports of adverse effects of experimental obesity on brain pathology described alterations to the lipid composition of myelin in genetically obese mice. While dysfunction of peripheral myelin and sensory neuropathy is a well established characteristic of type 2 diabetes [START_REF] Said | Diabetic neuropathy--a review[END_REF],

[51], this study reported that genetically obese (ob/ob) mice had decreased overall levels of myelin and marked alterations to the fatty acid composition of the myelin as compared to wild type mice [START_REF] Sena | Brain myelin of genetically obese mice[END_REF]. The use of a genetic model for these studies is significant in that it suggests that increased adiposity, rather than increase in dietary lipids, is sufficient to alter the composition of brain myelin. This study is

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9 supported by more recent imaging studies in humans that also have revealed changes in white matter and myelin abnormalities in association with obesity [START_REF] Jagust | What can imaging reveal about obesity and the brain?[END_REF], [START_REF] Gazdzinski | Body mass index and magnetic resonance markers of brain integrity in adults[END_REF]. While the human studies have not been followed up by pathology studies to characterize the actual molecular and biochemical changes to human myelin in obese patients, an obvious consequence of altered myelination would be altered synaptic transmission, and indeed, animal studies have confirmed that experimental obesity is associated with a wide array of cognitive abnormalities [START_REF] Greenwood | High-fat diets, insulin resistance and declining cognitive function[END_REF], [START_REF] Winocur | Studies of the effects of high fat diets on cognitive function in a rat model[END_REF]. For example, diet-induced obesity and insulin-resistance have both been shown by several groups to decrease spatial learning skills in rats [START_REF] Stranahan | Diet-induced insulin resistance impairs hippocampal synaptic plasticity and cognition in middleaged rats[END_REF], [START_REF] Jurdak | Diet-induced obesity and spatial cognition in young male rats[END_REF], [START_REF] Molteni | A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning[END_REF]. Other studies have likewise shown that diet-induced obesity is able to synergize with traumatic brain injury in decreasing hippocampal plasticity and learning [START_REF] Wu | A saturated-fat diet aggravates the outcome of traumatic brain injury on hippocampal plasticity and cognitive function by reducing brain-derived neurotrophic factor[END_REF]. Studies have also examined biochemical and histological indices of synaptic dysfunction and report that obesity is associated with decreases in dendritic spine density [START_REF] Stranahan | Diet-induced insulin resistance impairs hippocampal synaptic plasticity and cognition in middleaged rats[END_REF] and in the expression of synaptic marker proteins such as synapsin and GAP-43 [START_REF] Molteni | A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning[END_REF], [START_REF] Wu | A saturated-fat diet aggravates the outcome of traumatic brain injury on hippocampal plasticity and cognitive function by reducing brain-derived neurotrophic factor[END_REF], [START_REF] Wu | The interplay between oxidative stress and brain-derived neurotrophic factor modulates the outcome of a saturated fat diet on synaptic plasticity and cognition[END_REF]. Interestingly, these studies of synaptic markers also reported decreases in local levels of the neurotrophic factor BDNF, suggesting that brain regulation of growth factor synthesis could be regulated by obesity and/or metabolic syndromes. As it is well established that BDNF supports synaptic plasticity and neuronal excitability [START_REF] Jovanovic | Synapsins as mediators of BDNF-enhanced neurotransmitter release[END_REF], and appears to be important for maintaining learning and memory function, particularly in aging [START_REF] Croll | Expression of BDNF and trkB as a function of age and cognitive performance[END_REF], [START_REF] Kovalchuk | Postsynaptic induction of BDNF-mediated long-term potentiation[END_REF], [START_REF] Kovalchuk | Postsynaptic induction of BDNF-mediated long-term potentiation[END_REF], these studies again support the hypothesis that obesity is able to accelerate the physiological indices of brain aging.

Studies have also documented that experimental obesity can synergize with other pathophysiological conditions related to brain aging. For instance, obesity induced by a high calorie diet has been shown to increase insoluble amyloid burden and decrease cognitive performance in a transgenic mouse model of Alzheimer's disease [START_REF] Cao | Intake of sucrose-sweetened water induces insulin resistance and exacerbates memory deficits and amyloidosis in a transgenic mouse model of Alzheimer disease[END_REF]. Complementary studies have also demonstrated that the obesity-related peptide leptin (see Section 4 below) is able to regulate the secretion and uptake of amyloid beta peptides in vitro [START_REF] Fewlass | Obesityrelated leptin regulates Alzheimer's Abeta[END_REF]. In relation to stroke, studies have shown that blood-brain barrier dysfunction and infarct volume following middle cerebral artery occlusion is increased in genetically obese mice compared to non-obese wild type mice [START_REF] Terao | Inflammatory and injury responses to ischemic stroke in obese mice[END_REF]. Finally, it has also been established that

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ACCEPTED MANUSCRIPT 10 neurodegeneration induced by specific neurotoxins is increased by both genetic [START_REF] Sriram | Obesity exacerbates chemically induced neurodegeneration[END_REF] and diet-induced obesity [START_REF] Choi | Enhanced susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity in high-fat diet-induced obesity[END_REF].

Although the physiologic mechanisms whereby obesity adversely affects the brain are not understood (see Section 4, below), both experimental and human studies have shown that obesity is associated with increased oxidative stress, which has been implicated in cognitive declines seen in neurodegenerative diseases [START_REF] Ames | Oxidants, antioxidants, and the degenerative diseases of aging[END_REF], [START_REF] Liu | Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-alpha-lipoic acid[END_REF], and indeed has been suggested to be altered by diet [START_REF] Mattson | Meal size and frequency affect neuronal plasticity and vulnerability to disease: cellular and molecular mechanisms[END_REF]. For example, several studies have shown that administration of high fat or high calorie diets to rodents increases free radical generation [START_REF] Zhang | High dietary fat induces NADPH oxidaseassociated oxidative stress and inflammation in rat cerebral cortex[END_REF] and protein oxidation [START_REF] Souza | Highly palatable diet consumption increases protein oxidation in rat frontal cortex and anxiety-like behavior[END_REF] in the brain. Furthermore, it has been shown in the Zucker genetic model of rat obesity that endothelial cell dysfunction in this model is caused by oxidative stress secondary to overactivation of NADPH oxidase, which in turn is caused by circulating free fatty acids [START_REF] Chinen | Vascular lipotoxicity: endothelial dysfunction via fatty-acid-induced reactive oxygen species overproduction in obese Zucker diabetic fatty rats[END_REF]. Interestingly, NADPH oxidase has also been shown in human studies to mediate obesity-induced oxidative stress in both blood mononuclear cells [START_REF] Patel | Prolonged reactive oxygen species generation and nuclear factor-kappaB activation after a high-fat, high-carbohydrate meal in the obese[END_REF] and endothelial cells [START_REF] Silver | Overweight and obese humans demonstrate increased vascular endothelial NAD(P)H oxidase-p47(phox) expression and evidence of endothelial oxidative stress[END_REF]. Finally, it should be noted that it has been demonstrated that administration of the lipid-soluble antioxidant Vitamin E not only reverses oxidative modification to proteins in the brains of rats given a high-fat diet, but also normalizes levels of BDNF, synapsin I and cyclic AMP-response element-binding protein (CREB), and prevents obesity-induced alterations to cognitive function [START_REF] Wu | The interplay between oxidative stress and brain-derived neurotrophic factor modulates the outcome of a saturated fat diet on synaptic plasticity and cognition[END_REF]. It should be noted, however, that it is not clear at this point if oxidative stress in genetic or diet-induced animal models of obesity are a result of obesity per se, or more related to obesity-related metabolic syndrome. Thus, available data from animal models indicates that obesity and/or metabolic syndrome can induce neuropathology and cognitive dysfunction and can also synergize with pathological conditions and/or environmental toxins to accelerate CNS dysfunction. Thus, investigation into the dialog of peripheral signals of adiposity with the CNS is necessary to dissect out the mechanisms of obesity-induced brain pathology.

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Potential mediators of obesity-related CNS dysfunction

The mechanism(s) by which obesity results in brain injury and/or dysfunction are uncertain and subject to extensive speculation. While postulated indirect mechanisms include the effects of hyperglycemia on brain energetics and/or vascular damage to the central nervous system [START_REF] Morley | The metabolic syndrome and aging[END_REF], it is well known that consumption of a high fat diet and/or increased adiposity causes dramatic changes in the profile of bioactive serum lipids, including cholesterol. While an association between cholesterol and cognitive function could be explained based on increased risk stroke or cerebrovascular hypoperfusion, many studies have examined the role of serum cholesterol in brain function independent of vascular effects. In general, results are mixed, with some studies noting a correlation between lipid levels and cognitive function, whereas other studies do not [START_REF] Reitz | Impact of plasma lipids and time on memory performance in healthy elderly without dementia[END_REF], [START_REF] Rogers | Reducing hypertriglyceridemia in elderly patients with cerebrovascular disease stabilizes or improves cognition and cerebral perfusion[END_REF], [START_REF] Atzmon | Plasma HDL levels highly correlate with cognitive function in exceptional longevity[END_REF]. Positive studies related to the role of cholesterol in dementia have primarily related to effects of statin drug use, but these studies have also yielded mixed results, with a generally diminished risk for dementia although some of the tests did not achieve statistical significance [START_REF] Sparks | Atorvastatin for the treatment of mild to moderate Alzheimer disease preliminary results[END_REF].

Interestingly, there is compelling evidence that triglycerides and/or free fatty acids might mediate CNS alterations in obese individuals. In general, triglycerides are good candidates to study the pathogenesis of obesity as other lipid mediators, particularly cholesterol, are subject to complex genetic control. Recent studies have indeed highlighted a potentially important role for triglycerides in the cognitive and pathological alterations in obesity. For example, it has been shown that direct administration of triglycerides can impair hippocampal long-term potentiation, and that lowering triglycerides pharmacologically with gemfibrozil reduces the expression of markers of oxidative stress in the brains of obese mice [START_REF] Farr | Obesity and hypertriglyceridemia produce cognitive impairment[END_REF]. These studies are further supported by clinical studies in which it has been shown that elevated triglycerides are associated with poor cognitive performance in patients with type 2 diabetes [START_REF] Perlmuter | Triglyceride levels affect cognitive function in non-insulin-dependent diabetes[END_REF], and by studies in which the reduction of hypertriglyceridemia with gemfibrozil improved cerebral blood flow and function on the cognitive capacity screening examination [START_REF] Rogers | Reducing hypertriglyceridemia in elderly patients with cerebrovascular disease stabilizes or improves cognition and cerebral perfusion[END_REF].

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Finally, triglycerides have been shown to impair leptin transport through the blood-brain barrier [START_REF] Banks | Triglycerides induce leptin resistance at the blood-brain barrier[END_REF],

indicating that the well-characterized phenomena of leptin resistance may be related in part to the action of triglycerides at the blood-brain barrier. Another potential means whereby triglycerides could adversely affect the brain is through their breakdown into free fatty acids, which can also be formed and released directly from adipocytes. Indeed, there is abundant evidence that alterations in free fatty acid metabolism play a key role in many of the local and systemic manifestations of obesity, including insulin resistance, pancreatic beta cell injury, and dyslipidemia [START_REF] Boden | Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-B pathway in rat liver[END_REF], [START_REF] Lee | Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships[END_REF], [START_REF] Petruzzelli | Targeting the liver in the metabolic syndrome: evidence from animal models[END_REF]. In specific relation to the brain, GPR40, a putative free fatty acid receptor, has been localized to the hippocampus [START_REF] Ma | Expression of free fatty acid receptor GPR40 in the neurogenic niche of adult monkey hippocampus[END_REF], and the saturated free fatty acids palmitic acid and lauric acid have both been shown to cause inflammatory signaling in cultured macrophages [START_REF] Laine | Palmitic acid induces IP-10 expression in human macrophages via NF-kappaB activation[END_REF], [START_REF] Aronis | Lipotoxic effects of triacylglycerols in J774.2 macrophages[END_REF], and also to modulate astrocytic and microglial signaling [START_REF] Patil | Palmitic and stearic fatty acids induce Alzheimer-like hyperphosphorylation of tau in primary rat cortical neurons[END_REF]. Conversely, oleic acid has been shown to be ineffective at inducing an inflammatory phenotype in immunocompetent cells [START_REF] Laine | Palmitic acid induces IP-10 expression in human macrophages via NF-kappaB activation[END_REF]. Finally, circulating glucocorticoids have also been studied in terms of their ability to perturb brain function in models of obesity. Obesity is strongly associated with elevated circulating endogenous glucocorticoids, possibly through chronic activation of the sympathetic nervous system [START_REF] Dallman | Glucocorticoids, chronic stress, and obesity[END_REF], and a recent series of elegant studies has provided evidence that elevated glucocorticoids could mediate the effects of diabetes on hippocampal neurogenesis, synaptic plasticity, and cognitive performance [START_REF] Stranahan | Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons[END_REF], [START_REF] Stranahan | Accelerated cognitive aging in diabetic rats is prevented by lowering corticosterone levels[END_REF].

In addition to bioactive lipids, serum factors related to adiposity could adversely affect the brain.

Indeed, adipose tissue is no longer considered to be an inert tissue functioning solely as an energy store, but is emerging as an important factor in the regulation of many pathological processes [START_REF] Frühbeck | Overview of adipose tissue and its role in obesity and metabolic disorders[END_REF], [START_REF] Rocha | The multiple facets of the fat tissue[END_REF].

Numerous secreted products of adipose tissue have been identified and characterized, and given the moniker "adipokines". Over 50 adipokines have been identified, and generally function as hormones to influence energy homeostasis and feeding behavior [START_REF] Ahima | Adipokines in obesity[END_REF]. Furthermore, some adipokines, particularly adiponectin and leptin may provide an important link between obesity, insulin resistance and related inflammatory disorders [START_REF] Fantuzzi | Adipose tissue, adipokines, and inflammation[END_REF] gustatory perception can be sufficient to modulate plasma insulin and glucose turnover, as saccharin was shown to induce cephalic-phase insulin release, and to increase hepatic glucose production in rats [119]. Thus, the potential exists for modulation of longevity and metabolism via environmental sensing, although the degree to which this potential scenario might participate in the physiologic complications of obesity in humans is not at all resolved.

Conclusions and Unanswered Questions

It is now very clear that nutrition, as an integral component of human physiology, has the ability to modulate cognitive function and CNS responses to injury. There is great concern therefore, to critically evaluate and understand the mechanisms by which nutrition and particularly obesity can affect neuroplasticity and cognitive function. As summarized in this review, there is compelling evidence that obesity modulates brain responses, and may in particular accelerate brain aging and age-related neurodegeneration. While it is not currently known how obesity disrupts brain homeostasis during aging, numerous clinical and rodent studies strongly link diet-induced metabolic disturbances to the development of dementia. The progressive nature by which diet-induced obesity promotes brain disturbances raises the possibility that the careful implementation and study of this model will lead to better understanding of the linkages between metabolism and the brain, and might also unravel the complex relationship between brain function and measurable aspects of brain pathology.

  An additional key issue to resolve relates to the role of maternal obesity in the cognitive strength and health of offspring and the further predisposition of the offspring to obesity and/or enhanced CNS responses to obesity. A C C E P T E D M A N U S C R I P T A C C E P T E D M A N U S C R I P T A C C E P T E D M A N U S C R I P T A C C E P T E D M A N U S C R I P T A C C E P T E D M A N U S C R I P T A C C E P T E D M A N U S C R I P T

  ,[100]. Leptin, originally identified in 1994 as the[START_REF] Brunnström | Prevalence of dementia subtypes: A 30year retrospective survey of neuropathological reports[END_REF] kDa product of the ob ] may also be important in CNS responses to obesity. Leptin is best known for its action as an afferent adiposity signal to the brain that suppresses appetite and increases energy expenditure[102]. Leptin enters the brain via a saturable transport mechanism [103] and while it is known that leptin acts on hypothalamic centers to regulate feeding behavior, leptin receptors (OBR) are widely expressed in numerous extra-hypothalamic regions of the brain, including the hippocampus, cerebellum, amygdale, and brain stem [104], [105],[106]. While the full extant of leptin's actions on the brain have not been characterized, the past decade of research has not only revealed that leptin receptors are widely expressed in the CNS, but has also identified numerous additional functions for this hormone in the brain [107]. In particular, there is evidence that leptin influences neuronal excitability via the activation and trafficking of potassium channels in several brain regions, which may be important in regulation of food intake, cognition, and also anti-convulsant effects[108]. A number of studies have also identified a role for leptin in cognitive processes[109]. For example, it has been shown that direct administration of leptin into the dentate gyrus enhances long term potentiation [110], lack of nutritional resources (via defects in olfaction) can increase lifespan via a physiologic stress response similar to caloric restriction[115]. It should be noted that the converse -the perception of adequate or excess resources via exposure to food-related odorants -does not appear to decrease lifespan in animals that are not calorically restricted[117]. However, other studies have indicated that

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	A C C E P T E D M A N U S C R I P T avoidance and Morris water-maze tasks [111]. Finally, leptin has been shown to modulate the inflammatory signaling in microglia [112], [113] which could affect brain inflammatory and oxidative pathways. As a final note, there is a body of data that suggests a potential scenario whereby the sensory A C C E P T E D gene [101and that intravenous administration of leptin to rats facilitates behavioral performance in passive M A N U S C R I P T
	perception (generally via olfaction or taste) of calories or nutrients might significantly influence the
	activity of metabolic hormones and modulate lifespan [114], [115]. For example, studies in both
	Drosophila melanogaster and Caenorhabditis elegans have shown that genetic mutations that cause
	defects in sensory cilia or their support cells, or in sensory signal transduction, significantly extend
	lifespan [116], [117]. Furthermore, exposure of Drosophila to food-derived odorants has been shown to
	partially reverse the longevity-extending effects of dietary restriction [117]. While the mechanisms
	13 14

whereby sensory perception regulates lifespan is not entirely clear, effects on insulin/IGF (insulin-like growth factor) signaling are thought to be involved

[118]

. Overall, these data indicate that a perceived


Shayna A Wrighten

Gerardo G Piroli

Claudia A Grillo

Ph.D Lawrence P Reagan
email: lpreagan@med.sc.edu

A look inside the diabetic brain: Contributors to diabetes-induced brain aging

Keywords: Hippocampus, insulin, glucose, cognition, Alzheimer's disease, obesity

Central nervous system (CNS) complications resulting from diabetes is a problem that is gaining more acceptance and attention. Recent evidence suggests morphological, electrophysiological and cognitive changes, often observed in the hippocampus, in diabetic individuals. Many of the CNS changes observed in diabetic patients and animal models of diabetes are reminiscent of the changes seen in normal aging. The central commonalities between diabetes-induced and age-related CNS changes have led to the theory of advanced brain aging in diabetic patients. This review summarizes the findings of the literature as they relate to the relationship between diabetes and dementia and discusses some of the potential contributors to diabetes-induced CNS impairments.

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Introduction

Diabetes mellitus is an endocrine disorder of carbohydrate metabolism resulting from inadequate insulin release (insulin-dependent diabetes mellitus, or type 1 diabetes; T1D) or insulin insensitivity (non-insulin-dependent diabetes mellitus, or type 2 diabetes; T2D), both of which result in hyperglycemia if uncontrolled. T1D is believed to occur in response to an autoimmune destruction of insulin producing pancreatic ß cells, whereas T2D may be triggered or worsened by a number of factors including obesity, hypertension, and other features of the metabolic syndrome. For many years it has been well accepted that diabetes often results in microvascular and macrovascular disease, leading to complications such as retinopathy, peripheral neuropathy, stroke and coronary heart disease [START_REF]The diabetes control and complications trial research group, The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes-Mellitus[END_REF]. There is now evidence illustrating that both T1D and T2D can also cause complications within the central nervous system (CNS). Manifestations of diabetes-induced CNS complications may include structural alterations or brain atrophy, as well as changes in electrophysiological properties that ultimately result in deficits in cognitive performance [START_REF] Gispen | Cognition and synaptic plasticity in diabetes mellitus[END_REF]. These diabetes-induced CNS complications may be associated with or exacerbated by cardiovascular disease, including hypertension [START_REF] Elias | Obesity, diabetes and cognitive deficit: The Framingham Heart Study[END_REF][START_REF] Peila | Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study[END_REF] and cerebral vascular complications [START_REF] Brown | A simple deep breathing test reveals altered cerebral autoregulation in type 2 diabetic patients[END_REF][START_REF] Jimenez-Bonilla | Assessment of cerebral perfusion and cerebrovascular reserve in insulin-dependent diabetic patients without central neurological symptoms by means of Tc-99m-HMPAO SPET with acetazolamide[END_REF][START_REF] Kannel | Diabetes and Cardiovascular-Disease -Framingham Study[END_REF][START_REF] Tuttolomondo | Diabetic and non-diabetic subjects with ischemic stroke: Differences, subtype distribution and outcome[END_REF]. Additional factors that may contribute to diabetes-induced cognitive impairment include disrupted insulin signaling and glucose homeostasis in the CNS [START_REF] Reagan | The As and Ds of stress: Metabolic, morphological and behavioral consequences[END_REF].

Under normal circumstances glucose is the predominant metabolic fuel source of the adult brain and is transported to the CNS from the periphery via facilitative glucose transporters [START_REF] Mcewen | Glucose transporter expression in the central nervous system: relationship to synaptic function[END_REF]. Since the brain can neither synthesize nor store glucose for extended periods of time, it is essential that proper glucose regulation be achieved in the periphery

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5 human studies will be referred to and acknowledged for contributions made in providing insight into mechanisms relevant to the clinical setting.

The relationship between cognitive decline and diabetes

There is an increasing appreciation that cognitive decline occurs in both T1D and T2D. However, there are differences concerning the relative degree of cognitive dysfunction and the way in which these cognitive abnormalities are manifested in the two sub-types of diabetes. For example, although there may be commonalities between the underlying mechanisms involved in diabetes-induced cognitive impairments, many studies have shown that T1D is more likely to be associated with psychomotor slowing and reductions in mental efficiency [START_REF] Brands | The effects of type 1 diabetes on cognitive performance: a meta-analysis[END_REF], while cognitive deficits in T2D are often in the areas of psychomotor efficiency, attention, learning and memory and executive function [START_REF] Convit | Links between cognitive impairment in insulin resistance: an explanatory model[END_REF]. Moreover, some studies suggest that diabetes-induced CNS complications occur more rapidly in T2D than in T1D. For instance, in a comparative study of cognitive function, those with more than 30 years of T1D had comparable cognitive profiles to T2D patients with seven years of disease duration [START_REF] Brands | Cognitive functioning and brain MRI in patients with type 1 and type 2 diabetes mellitus: a comparative study[END_REF]. Also, when compared to T2D patients, T1D patients had better brain magnetic resonance imaging (MRI) ratings [START_REF] Brands | Cognitive functioning and brain MRI in patients with type 1 and type 2 diabetes mellitus: a comparative study[END_REF],

which measure changes in brain volume, silent infarcts and white matter lesions (WML).

Hyperintense lesions, as measured by T2-weighted and proton density MRI, occur in white matter (referred to as white matter hyperintensities, WMH or WML) as well as in gray matter [START_REF] O'brien | Cognitive associations of subcortical white matter lesions in older people[END_REF][START_REF] Pantoni | The Significance of Cerebral White-Matter Abnormalities 100 Years After Binswangers Report -A Review[END_REF]. The clinical significance of WML remains undetermined [START_REF] Pantoni | The Significance of Cerebral White-Matter Abnormalities 100 Years After Binswangers Report -A Review[END_REF][START_REF] Schmidt | The natural course of MRI white matter hyperintensities[END_REF]; however, WML have been associated with diabetes, AD, normal aging, impairments in cognition, and accelerated cognitive decline [START_REF] O'brien | Cognitive associations of subcortical white matter lesions in older people[END_REF][START_REF] Pantoni | The Significance of Cerebral White-Matter Abnormalities 100 Years After Binswangers Report -A Review[END_REF][START_REF] Fernando | White matter lesions in an unselected cohort of the elderly -Molecular pathology suggests origin from chronic hypoperfusion injury[END_REF][START_REF] Jongen | Structural brain imaging in diabetes: A methodological perspective[END_REF][START_REF] Longstreth | Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people -The cardiovascular health study[END_REF][START_REF] Tiehuis | Diabetes increases atrophy and vascular lesions on brain MRI in patients with symptomatic arterial disease[END_REF]. As such, increases in WML The differential effects of T2D and T1D upon cognition raise the question of the underlying causes for the cognitive differences in these two diseases. One potential clue as to why T1D and T2D may differ in the progression of cognitive impairment is a potential interaction between diabetes and age [START_REF] Kamal | Learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: interaction of diabetes and ageing[END_REF][START_REF] Reagan | Insulin signaling effects on memory and mood[END_REF]. This theory is consistent with the fact that T2D is more prevalent with increasing age and the observation by Biessels and Kappelle that clinically relevant decreases in cognitive function are more likely to occur in elderly T2D patients [START_REF] Biessels | Increased risk of Alzheimer's disease in Type II diabetes: insulin resistance of the brain or insulin-induced amyloid pathology?[END_REF]. Additionally, T1D is a disease that often affects individuals before the age of 18 [START_REF] Daneman | Type 1 diabetes[END_REF] which presents the possibility that developmental compensations may contribute to the less severe cognitive deficits observed in T1D patients when compared to T2D patients. Another possible explanation for the differential effects of T1D and T2D upon cognitive function is insulin resistance, a feature more prevalent in T2D than in T1D. In support of this hypothesis, insulin resistance was identified as the best predictor of T2D diagnosis in a study of pre-diabetic individuals [START_REF] Abdul-Ghani | What is the best predictor of future type 2 diabetes?[END_REF]. Additionally, insulin resistance is associated with a host of conditions including, hyperglycemia, hyperinsulinemia, hypertension, dyslipidemia, and increased central adiposity collectively termed the metabolic syndrome [START_REF] Kumari | Minireview: mechanisms by which the metabolic syndrome and diabetes impair memory[END_REF]. Many features of the metabolic syndrome may contribute to cognitive impairment independently or in combination with one another [START_REF] Kumari | Minireview: mechanisms by which the metabolic syndrome and diabetes impair memory[END_REF]. Although the incidence of cognitive deterioration is more prevalent in older T2D, younger T2D and T1D patients are not immune to the deleterious consequences of diabetes upon brain structure and function.

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Type 1 diabetes and cognitive impairment

T1D is a life-long disorder usually diagnosed in younger individuals (50-60% younger than 18 years of age) [START_REF] Daneman | Type 1 diabetes[END_REF] and therefore raises concern regarding how this disease and its treatment may impact cognitive performance. In this regard, it has been reported that children with T1D show impairment on tasks of declarative memory compared to age matched non-diabetic controls [START_REF] Hershey | A prospective study of severe hypoglycemia and long-term spatial memory in children with type 1 diabetes[END_REF]. Typically, T1D is treated in either a conventional or intensive manner with exogenous insulin [START_REF]The diabetes control and complications trial research group, The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes-Mellitus[END_REF]. Insulin treatment increases the risk of hypoglycemic episodes [START_REF]The diabetes control and complications trial research group, The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes-Mellitus[END_REF][START_REF] Davis | Impact of improved glycaemic control on rates of hypoglycaemia in insulin dependent diabetes mellitus[END_REF], and increases the potential for cycling between hypoglycemia and hyperglycemia, both of which can be harmful to the brain, especially the developing brain [START_REF] Guleria | Hyperglycemia inhibits retinoic acidinduced activation of Rac1, prevents differentiation of cortical neurons, and causes oxidative stress in a rat model of diabetic pregnancy[END_REF][START_REF] Perantie | Regional brain volume differences associated with hyperglycemia and severe hypoglycemia in youth with type 1 diabetes[END_REF][START_REF] Yamada | Repetitive hypoglycemia in young rats impairs hippocampal long-term potentiation[END_REF]. Additionally, both hyperglycemia and hypoglycemia are known to cause acute cerebral dysfunction [START_REF] Ryan | Cognitive Deficits in Adolescents Who Developed Diabetes Early in Life[END_REF] and are associated with decline in intellectual performance [START_REF] Kumari | Minireview: mechanisms by which the metabolic syndrome and diabetes impair memory[END_REF]. While some investigators report no independent correlation between preceding severe hypoglycemic events and cognitive function in adult T1D patients [START_REF] Ferguson | Cognitive ability and brain structure in type 1 diabetes: relation to microangiopathy and preceding severe hypoglycemia[END_REF], several clinical studies report that hypoglycemic events negatively affect cognition. For example, Hershey et al reported that children with more frequent and earlier onset of hypoglycemic events had worse performance on tests of short and long delay spatial memory than did other tested groups [START_REF] Hershey | Frequency and timing of severe hypoglycemia affects spatial memory in children with type 1 diabetes[END_REF]. A higher frequency of hypoglycemic events during a relatively short period of time, as is more often the case in diabetic children than adults, could account for discrepancies between studies. Nonetheless, these studies emphasize the importance of maintaining good glycemic control for diabetes patients.

It is important to note that although T1D patients may perform less well on some cognitive tasks when compared to control subjects, scores for diabetes patients are often

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within the normal cognitive range [START_REF] Brands | Cognitive performance, psychological well-being, and brain magnetic resonance imaging in older patients with type 1 diabetes[END_REF]. In a study comparing young to middle aged T1D patients with age-matched controls, the diabetic persons performed more poorly on tests of executive function, short term memory, psychomotor efficiency and a measure of mental efficiency; however, all subjects scored within a normal cognitive range [START_REF] Weinger | The effects of type 1 diabetes on cerebral white matter[END_REF].

These results imply that although there are deficits in cognition in T1D, these deficits are mild and may not fall below ratings of the general population. However, the potential unfortunate outcome of these 'mild' cognitive deficits in T1D patients is a predisposition for more rapid deterioration of cognitive function in later life. Indeed, cumulative CNS complications in the hippocampus may lead to cognitive decline, as well as increased risk for neurological comorbidities [START_REF] Reagan | Insulin signaling effects on memory and mood[END_REF][START_REF] Starr | Diabetes, sugar-coated but harmful to the brain[END_REF].

Diabetes and the hippocampus in type 1 diabetes

The hippocampus is an important structure for the integration of learning and memory in the mammalian CNS [START_REF] Squire | Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans[END_REF] and is particularly sensitive to changes in glucose homeostasis. For example, improper glucose homeostasis may impact the electrophysiological properties of hippocampal neurons. In particular, studies performed on rodent models of T1D and models of improper glucose regulation show dysfunctional synaptic plasticity with specific deficits in long-term potentiation (LTP) and long-term depression (LTD) [START_REF] Artola | Diabetes mellitus concomitantly facilitates the induction of long-term depression and inhibits that of long-term potentiation in hippocampus[END_REF][START_REF] Kamal | Hippocampal synaptic plasticity in streptozotocin-diabetic rats: impairment of long-term potentiation and facilitation of long-term depression[END_REF][START_REF] Kamal | Synaptic transmission changes in the pyramidal cells of the hippocampus in streptozotocininduced diabetes mellitus in rats[END_REF]. Typically these animal models have impairments in LTP and an enhancement of LTD when compared to controls. These electrophysiological changes may be an underlying contributor to some of the impairments exhibited by diabetic animal models on cognitive performance. Indeed, STZ diabetic rats that exhibit these

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electrophysiological changes in LTP and LTD perform less well on spatial memory tasks when compared with control rats [START_REF] Biessels | Water maze learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: effects of insulin treatment[END_REF].

Clinical imaging studies have provided insight into additional factors that may contribute to cognitive deficits observed in T1D patients, including structural and morphological changes in the hippocampus. In this regard, the odds for better performance on delayed memory tasks were greater in T1D patients with no periventricular WMH [START_REF] Weinger | The effects of type 1 diabetes on cerebral white matter[END_REF]. However, this study as well as others identified no overall changes in brain matter composition or volume in T1D patients [START_REF] Perantie | Regional brain volume differences associated with hyperglycemia and severe hypoglycemia in youth with type 1 diabetes[END_REF][START_REF] Brands | Cognitive performance, psychological well-being, and brain magnetic resonance imaging in older patients with type 1 diabetes[END_REF][START_REF] Weinger | The effects of type 1 diabetes on cerebral white matter[END_REF]. Conversely, some reports have identified changes in brain structures and brain volume in T1D [START_REF] Musen | Effects of type 1 diabetes on gray matter density as measured by voxel-based morphometry[END_REF][START_REF] Lobnig | Hippocampal volume and cognitive performance in long-standing Type 1 diabetic patients without macrovascular complications[END_REF][START_REF] Ferguson | Influence of an early-onset age of type 1 diabetes on cerebral structure and cognitive function[END_REF][START_REF] Perros | Brain abnormalities demonstrated by magnetic resonance imaging in adult IDDM patients with and without a history of recurrent severe hypoglycemia[END_REF]. The discrepancies in brain imaging studies of T1D may be related to patient age, age of diabetes onset, hypoglycemic events, or differences in statistical analysis. Some studies have shown that age of diabetes onset may be one of the most critical contributors to CNS structural abnormalities [START_REF] Ferguson | Influence of an early-onset age of type 1 diabetes on cerebral structure and cognitive function[END_REF], although this may be a secondary effect related to the number of hypoglycemic and/or hyperglycemic events experienced by the patient.

Structural analyses in the hippocampus of experimental models of T1D have yielded more consistent findings.

In histological studies, STZ diabetic rats display morphological changes in the hippocampus, including dendritic atrophy in the CA3 pyramidal neurons [START_REF] Magarinos | Experimental diabetes in rats causes hippocampal dendritic and synaptic reorganization and increased glucocorticoid reactivity to stress[END_REF]. In addition, T1D rats exhibit redistribution of the synaptic proteins synaptophysin and postsynaptic density 95 (PSD-95), which could be indicative of ongoing synaptogenesis in the hippocampus of STZ rats [START_REF] Grillo | Immunocytochemical analysis of synaptic proteins provides new insights into diabetes-mediated plasticity in the rat hippocampus[END_REF]. Collectively, these clinical and pre-clinical data illustrate that the extent of cognitive impairment and brain morphology abnormalities in T1D remains to be unequivocally determined. However, the literature to date suggest

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that structural changes, which may underlie cognitive decline, are likely occurring in T1D patients, effects that may have detrimental consequences over extended periods of time.

Type 2 diabetes and cognitive impairment

A number of studies have examined the relationship between T2D and cognition.

Some studies suggest that cognitive performance does not differ between T2D patients and non-diabetic controls when the influence of age, premorbid IQ, body mass index (BMI) and depression are taken into account [START_REF] Asimakopoulou | Neuropsychological functioning in older people with Type 2 diabetes: the effect of controlling for confounding factors[END_REF]. However, many clinical and preclinical studies contradict this finding and support the concept that T2D is associated with cognitive decline. In this regard, T2D patients have been identified as having minimental state examination (MMSE, a measure of cognitive ability) scores in the impaired range when compared to age-matched controls [START_REF] Dey | Cognitive function in younger type II diabetes[END_REF]. Moreover, lower cognitive scores on performances of general cognition, verbal memory, and category fluency have also been reported in men and women with T2D [START_REF] Okereke | Type 2 Diabetes Mellitus and Cognitive Decline in Two Large Cohorts of Community-Dwelling Older Adults[END_REF]. These findings are in agreement with other studies suggesting an increased occurrence of cognitive impairment in older T2D

individuals [START_REF] Manschot | Metabolic and vascular determinants of impaired cognitive performance and abnormalities on brain magnetic resonance imaging in patients with type 2 diabetes[END_REF]. More recently, Convit and coworkers reported that the cognitive deficits in T2D patients may be more selective for hippocampal-related memory performance and that these deficits are correlated with the degree of glycemic control [START_REF] Gold | Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes[END_REF]. These clinical data are supported by observations from animal models of T2D. For instance, the db/db mouse exhibits deficits in the water maze, a hippocampal-dependent spatial learning task [START_REF] Li | Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents[END_REF]. Moreover, our previous studies revealed that type 2 Zucker fa/fa diabetic rats perform more poorly compared to their lean littermates in the variableinterval delayed alternation test of learning and memory [START_REF] Winocur | Memory impairment in obese Zucker rats: An investigation of cognitive function in an animal model of insulin resistance and obesity[END_REF]. It can be concluded from

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11 these studies that T2D subjects experience deficits in hippocampal-based cognitive performance, deficits that may be attributed to changes in brain structure and volume.

Hippocampal structure and function in type 2 diabetes

A number of studies suggest that patients with T2D are more likely to have structural brain abnormalities [START_REF] Manschot | Metabolic and vascular determinants of impaired cognitive performance and abnormalities on brain magnetic resonance imaging in patients with type 2 diabetes[END_REF][START_REF] Korf | Brain aging in very old men with type 2 diabetes -The Honolulu-Asia Aging Study[END_REF], such as cerebral infarcts [START_REF] Heijer | Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI[END_REF], when compared with T1D patients and non-diabetic individuals. In an MRI study of subjects with vascular disease, patients with T2D were more likely to have a smaller brain parenchymal fraction and more WMH than patients with vascular disease but without diabetes [START_REF] Tiehuis | Diabetes increases atrophy and vascular lesions on brain MRI in patients with symptomatic arterial disease[END_REF].

Alternatively, a review of imaging studies measuring structural brain changes in diabetic patients found no consistent data concerning WML but found a correlation between brain atrophy and T2D [START_REF] Van Harten | Brain imaging in patients with diabetes -A systematic review[END_REF]. In particular, the hippocampus and other temporal lobe structures appear to have high susceptibility to diabetes-associated atrophy [START_REF] Gold | Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes[END_REF][START_REF] Heijer | Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI[END_REF][START_REF] Manschot | Brain magnetic resonance imaging correlates of impaired cognition in patients with type 2 diabetes[END_REF], and most studies of T2D-related structural rearrangement provide evidence for the occurrence of some identifiable CNS damage, especially within the hippocampus [START_REF] Starr | Diabetes, sugar-coated but harmful to the brain[END_REF]. Changes in hippocampal morphology may be accompanied by electrophysiological changes in T2D, which may contribute to cognitive decline. For example, electrophysiological deficits are observed in the hippocampus of experimental models of T2D such as the db/db mouse and the Zucker rat [START_REF] Li | Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents[END_REF][START_REF] Gerges | Impaired long-term potentiation in obese zucker rats: possible involvement of presynaptic mechanism[END_REF]. In the clinical setting, a study of middle aged T2D patients identified differences between right, left and overall P300 wave latencies in diabetics compared to controls [START_REF] Dey | Cognitive function in younger type II diabetes[END_REF]. The P300 wave is a cortical neurophysiological characteristic reflecting the speed of neuronal events underlying information processing and appears to be strongly associated with attention and short-term memory. Changes in P300 are

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12 important to note due to the fact that T2D-induced cognitive changes often include deficits in attention and learning and memory [START_REF] Convit | Links between cognitive impairment in insulin resistance: an explanatory model[END_REF]. Interestingly, changes in P300 wave are also a trait observed in normal aging [START_REF] Wilson | Neurocognitive aging: prior memories hinder new hippocampal encoding[END_REF], which provides a potential functional deficit common to both diabetes and normal brain aging. Overall, these studies provide data indicating that cognitive decline is a neurological consequence of T2D that may be partly attributable to structural rearrangement and changes in the electrophysiological properties of hippocampal neurons. Importantly, these neurological consequences of diabetes appear to parallel those observed in the aging brain.

Aging, Neurodegenerative Diseases and Diabetes

The normal aging brain

The process of normal aging is characterized by decreased ability to remember new facts, decline in cognitive performance, structural and morphological brain changes, modifications in electrophysiological properties, and increased risk of diabetes and insulin resistance [START_REF] Wilson | Neurocognitive aging: prior memories hinder new hippocampal encoding[END_REF][START_REF] Uylings | Neuronal changes in normal human aging and Alzheimer's disease[END_REF]. There is a trend for a slight decrease in brain weight and volume in aged people [START_REF] Uylings | Neuronal changes in normal human aging and Alzheimer's disease[END_REF] and a correlation between atrophy rates and decline in cognitive ability [START_REF] Jack | Brain atrophy rates predict subsequent clinical conversion in normal elderly and amnestic MCI[END_REF][START_REF] Saykin | Older adults with cognitive complaints show brain atrophy similar to that of amnestic MCI[END_REF]. In a six year longitudinal study of older individuals, brain atrophy was reported to be most correlated with age, heavy drinking and glycosylated hemoglobin index (HbA1c), an indicator of long term glycemic control [START_REF] Enzinger | Risk factors for progression of brain atrophy in aging: six-year follow-up of normal subjects[END_REF].

Reorganization of the structural and chemical balance of the hippocampus in aged people and animals can be correlated to age-related memory deficits and changes in synaptic plasticity [START_REF] Wilson | Neurocognitive aging: prior memories hinder new hippocampal encoding[END_REF][START_REF] Golomb | Hippocampal formation size in normal human aging: a correlate of delayed secondary memory performance[END_REF][START_REF] Smith | Circuit-specific alterations in hippocampal synaptophysin immunoreactivity predict spatial learning impairment in aged rats[END_REF][START_REF] Rusinek | Regional brain atrophy rate predicts future cognitive decline: 6-year longitudinal MR imaging study of normal aging[END_REF]. For example, with increasing age, there is a decrease in the number of synapses in the dentate gyrus and specific synapse loss of cortical inputs to the

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13 hippocampus in both humans and animals [START_REF] Wilson | Neurocognitive aging: prior memories hinder new hippocampal encoding[END_REF]. In aged rats, the hippocampus has approximately one-third fewer synaptic contacts from the entorhinal cortex when compared to younger rats [START_REF] Wilson | Neurocognitive aging: prior memories hinder new hippocampal encoding[END_REF]. In addition to decreased synapse number, hippocampal interneuron populations are decreased in the aged brain; specifically, GAD67 immunoreactive interneurons are decreased in the CA1 region of the hippocampus of old rats [START_REF] Shi | Stereological quantification of GAD-67-immunoreactive neurons and boutons in the hippocampus of middle-aged and old Fischer 344 x Brown Norway rats[END_REF]. These data compliment reports of decreases in specific interneuronal populations in other hippocampal regions such as the hilus [START_REF] Cadacio | Hilar neuropeptide Y interneuron loss in the aged rat hippocampal formation[END_REF]. Decline in hippocampal interneuron populations may have functional consequences since interneurons have been shown to be crucial for a variety of cognitive functions including memory [START_REF] Buzsaki | Temporal structure in spatially organized neuronal ensembles: a role for interneuronal networks[END_REF]. As described above, many of these changes observed in the aging hippocampus are also seen in diabetic patients and animal models of diabetes, changes that may predispose diabetic subjects to neurodegenerative diseases such as AD. The commonalities between the diabetic brain and the aging brain support the idea that diabetes induces advanced brain aging, especially in T2D patients [START_REF] Ryan | Why is learning and memory dysfunction in Type 2 diabetes limited to older adults?[END_REF]. However, advanced age is a risk factor for both diabetes and cognitive decline. As a result, it is challenging to differentiate between these factors in order to determine whether diabetes induces brain aging or interacts with normal aging to create an exacerbated phenotype. A concept referred to as "the brain reserve hypothesis" may provide insight into this question.

The brain reserve hypothesis was first suggested to explain incongruence between pathological brain damage and cognitive and functional performance in older individuals [START_REF] Coffey | Re lation of education to brain size in normal aging -Implications for the reserve hypothesis[END_REF]. This hypothesis is based on the theory that individuals with higher levels of education have an increased capacity to make adjustments so that cognition does not suffer in response to brain atrophy or structural changes [START_REF] Coffey | Re lation of education to brain size in normal aging -Implications for the reserve hypothesis[END_REF]. A modified theory of brain

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Diabetes and age-related comorbidities: Alzheimer's disease

Alzheimer's disease (AD) is the most common form of dementia in the United

States [START_REF] Meyer | Is mild cognitive impairment prodromal for vascular dementia like Alzheimer's disease?[END_REF][START_REF] Blennow | Alzheimer's disease[END_REF]. Risk factors for AD may include age, genetics, a variety of cardiovascular complications and diabetes [START_REF] Sabayan | Role of Insulin Metabolism Disturbances in the Development of Alzheimer Disease: Mini Review[END_REF]. The onset of AD is generally subtle, followed by a progressive decrease in cognitive function characterized by memory loss [START_REF] Blennow | Alzheimer's disease[END_REF][START_REF] Yaari | Alzheimer's disease[END_REF].

Histologically, AD is identified by an abundance of neuritic plaques and neurofibrillary tangles in areas of the cerebral cortex, hippocampus and other temporal lobe structures of postmortem tissue [START_REF] Blennow | Alzheimer's disease[END_REF][START_REF] Gandy | The role of cerebral amyloid beta accumulation in common forms of Alzheimer disease[END_REF]. Neuritic plaques are formed from an accumulation of amyloid-ß (Aß) peptide which is produced by cleavage of amyloid precursor protein (APP) [START_REF] Blennow | Alzheimer's disease[END_REF]. Neurofibrillary tangles are composed of abnormally hyperphosphorylated tau protein, an axonal protein that promotes microtubule assembly and stability [START_REF] Blennow | Alzheimer's disease[END_REF]. to non-diabetic controls [START_REF] Arvanitakis | Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function[END_REF], findings that are consistent with a number of other studies [START_REF] Peila | Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study[END_REF][START_REF] Luchsinger | Adiposity and Alzheimer's disease[END_REF][START_REF] Ott | Diabetes mellitus and the risk of dementia: The Rotterdam Study[END_REF][START_REF] Kuusisto | Association between features of the insulin resistance syndrome and Alzheimer's disease independently of apolipoprotein E4 phenotype: cross sectional population based study[END_REF] but not all [START_REF] Burns | White matter lesions are prevalent but differentially related with cognition in aging and early Alzheimer disease[END_REF]. In addition, some researchers have identified an association between borderline non-overt diabetes and increased AD risk [START_REF] Xu | The effect of borderline diabetes on the risk of dementia and Alzheimer's disease[END_REF]. One plausible explanation for potential increased risk of AD in diabetes is insulin resistance. Plasma insulin levels are elevated in type 2 patients and in AD patients [START_REF] Sabayan | Role of Insulin Metabolism Disturbances in the Development of Alzheimer Disease: Mini Review[END_REF][START_REF] Luchsinger | Adiposity and Alzheimer's disease[END_REF][START_REF] Craft | Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease: relationship to severity of dementia and apolipoprotein E genotype[END_REF], which reflects insulin resistance. Additionally, in AD patients, administration of insulin increases plasma levels of Aß [START_REF] Kulstad | Differential modulation of plasma beta-amyloid by insulin in patients with Alzheimer disease[END_REF], which would potentially increase CNS levels of Aß that could accumulate into neuritic plaques. In control non-demented subjects, insulin causes a decrease in plasma Aß levels [START_REF] Kulstad | Differential modulation of plasma beta-amyloid by insulin in patients with Alzheimer disease[END_REF], further supporting differences in the insulin system of AD patients compared to non-AD subjects. Unlike the increases in plasma insulin levels, there is a decrease in cerebrospinal fluid (CSF) levels of insulin in AD patients compared to non-AD controls and a positive correlation between CSF insulin and dementia severity in AD [START_REF] Craft | Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease: relationship to severity of dementia and apolipoprotein E genotype[END_REF]. Such results would support the idea that insulin resistance may be a contributor to cognitive impairment and dementia in AD patients.

Some researchers suggest that insulin aids in the clearance of Aß, at least in the periphery [START_REF] Kulstad | Differential modulation of plasma beta-amyloid by insulin in patients with Alzheimer disease[END_REF], but others support the concept that insulin leads to the release of intracellular Aß, thereby increasing secretion into the extracellular space and facilitating

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Aß accumulation [START_REF] Sabayan | Role of Insulin Metabolism Disturbances in the Development of Alzheimer Disease: Mini Review[END_REF]. Under physiological conditions, insulin signaling cascades have been implicated in the regulation of tau phosphorylation [START_REF] Hooper | The GSK3 hypothesis of Alzheimer's disease[END_REF]. Briefly, insulin signaling leads to the activation of phosphoinositide 3-kinase (PI3K), which phosphorylates and activates Akt. Activated Akt in turn phosphorylates and inactivates the cytoplasmic enzyme glycogen synthase kinase-3ß (GSK3ß). In the brain, GSK3ß is one of the kinases involved in the phosphorylation of tau [START_REF] Hooper | The GSK3 hypothesis of Alzheimer's disease[END_REF]. In the normal brain, insulin signaling activation reduces the phosphorylation state of tau, whereas deficits in insulin signaling could cause hyperphosphorylation of tau [START_REF] Hooper | The GSK3 hypothesis of Alzheimer's disease[END_REF]. Whether these mechanisms contribute to hyperphosphorylation of tau in AD patients or diabetes patients remains to be verified.

However, hyperphosphorylation of tau is observed in experimental models of diabetes.

In a study of Alzheimer-associated pathologies in animal models of diabetes, both T1D and T2D rats exhibited decreases in phosphorylated Akt and phosphorylated GSK-3ß

[100], which may have contributed to the development of histological AD features.

Additionally, tau is hyperphosphorylated in STZ diabetic mice [101-103]. Moreover, histological studies from our lab show that there is hyperphosphorylated tau immunoreactivity in the hippocampus of fatty Zucker rats, AD-like pathology that is not observed in lean control rats (Figure 1).

There are a limited number of human postmortem studies that have examined histological features of AD in the diabetic brain and these studies have yielded inconsistent findings. Some studies report no association [104,105], while another study reports a negative correlation between diabetes and the presence of neuritic plaques and neurofibrillary tangles [106]. A number of possibilities could explain the discrepancy between postmortem and clinical data relating AD to diabetes. For example, diabetic

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17 individuals with comorbid AD may be less likely to survive to an older age and therefore may not be included in these postmortem studies [106]. Additionally, there is the possibility that diabetes does not increase the risk of developing histological features of AD but instead creates a cognitive phenotype that resembles the clinical symptoms of AD, a phenotype which may be more pronounced in individuals of older age. In support of this concept, data from the Religious Orders study show a correlation between diabetes and clinical symptoms of AD [START_REF] Arvanitakis | Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function[END_REF] while no correlation was later found between postmortem histopathological AD features and diabetes in this same population [104].

Nonetheless, as detailed above, some features associated with AD are observed in diabetic patients and would support the idea of diabetes increasing the risk of AD or ADlike symptoms. The association between increased risks of developing mild cognitive impairment (MCI) or AD in diabetes patients requires further analysis, including additional post-mortem studies assessing histopathological features such as hyperphosphorylated tau. It is crucial that further investigation be continued in order to elucidate the mechanistic mediators that increase neuronal vulnerability and thereby facilitate cognitive decline and progression of AD symptomatology in diabetic patients.

Potential contributors to diabetes-induced brain aging

Insulin and glucose

The and indirectly regulates particular neurotransmitters, such as epinephrine [START_REF] Kopf | Effects of posttraining administration of insulin on retention of a habituation response in mice: Participation of a central cholinergic mechanism[END_REF][121][122][123].

Insulin also modulates basal synaptic transmission [124-126] and restores normal synaptic plasticity in the hippocampus of animal models of diabetes [START_REF] Biessels | Water maze learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: effects of insulin treatment[END_REF]. Additionally, cognitive training strengthens insulin signaling in the hippocampus of non-diabetic rats

[127], effects that may further enhance the functional activities of neurotransmitters that are critical for synaptic plasticity and cognitive function. Under pathological conditions, previous studies have revealed that hyperglycemia, endocrine dysfunction, deficits in hippocampal plasticity and behavioral performance observed in experimental models of diabetes are inhibited by insulin replacement [START_REF] Biessels | Water maze learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: effects of insulin treatment[END_REF]128]. Such results suggest that decreases in insulin receptor (IR) activity may be an initiating factor producing deficits in hippocampal plasticity and ultimately cognitive decline.

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Another important contributor to brain function, especially as it relates to cognition, is glucose. In this regard, fasting plasma glucose levels were negatively correlated with episodic memory and recall in a study of normal healthy women [129].

Also, glucose administration improves cognitive performance in people and animals irrespective of pre-existing cognitive impairments [START_REF] Greenwood | Glucose treatment reduces memory deficits in young adult rats fed high-fat diets[END_REF][START_REF] Kaplan | Cognitive performance is associated with glucose regulation in healthy elderly persons and can be enhanced with glucose and dietary carbohydrates[END_REF]114,130,131]. During hippocampal-dependent cognitive tasks, extracellular levels of glucose are decreased in the hippocampus of rodents, implying increased glucose uptake and utilization by cells [START_REF] Mcnay | Decreases in rat extracellular hippocampal glucose concentration associated with cognitive demand during a spatial task[END_REF]. The intimate connection between glucose and cognition [129,132] reinforces the importance of maintaining the delicate balance of glucose levels within the brain. Studies in experimental models of diabetes provide additional support for the importance of tight glycemic control. For example, moderate recurrent hypoglycemia throughout life improved performance on a hippocampal dependent cognitive task in the euglycemic state in male rats, as compared to control animals. However, during acute hypoglycemia, recurrent hypoglycemic animals performed no better than chance on a maze task [133].

These data suggest that familiarity with the experience of hyperglycemia or hypoglycemia may cause the brain to become more efficient at utilizing glucose and other means of energy during cognitive tasks, but only when sufficient glucose is available. Although these data suggest that a more constant glycemic index is perhaps better than fluctuations between glycemic states, harmful CNS consequences may nonetheless accompany a non-euglycemic environment, including blood-brain barrier dysfunction, [122] deep subcortical white matter lesions and other structural deficits [START_REF] Perantie | Regional brain volume differences associated with hyperglycemia and severe hypoglycemia in youth with type 1 diabetes[END_REF][START_REF] Manschot | Metabolic and vascular determinants of impaired cognitive performance and abnormalities on brain magnetic resonance imaging in patients with type 2 diabetes[END_REF]. Although the data on the effects of glycemic control show a bit of discrepancy,

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overall, it appears that bouts of hypoglycemia and hyperglycemia can cause a significant contribution to cognitive performance impairments via a variety of mechanisms [134].

Advanced glycation end products and oxidative stress

In addition to altering cognitive performance, poor glycemic control increases the

HPA axis dysfunction

Many pathological conditions are associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation, including diabetes (For review see [START_REF] Reagan | The As and Ds of stress: Metabolic, morphological and behavioral consequences[END_REF]). The relationship between glucocorticoids (GCs) and obesity, a common feature in T2D patients, is relevant in terms of induction of insulin resistance. In this sense, lipolysis induced by GCs increases free fatty acid levels in blood, which in turn causes hyperglycemia through the stimulation of hepatic gluconeogenesis and a reduction in glucose uptake by competing with glucose for oxidation [151]. Consequently, a compensatory increment in insulin secretion leads to hyperinsulinemia, downregulation of insulin receptors and insulin resistance. Short-term corticosterone (CORT) administration to rats produces [START_REF] Li | Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents[END_REF][START_REF] Gerges | Impaired long-term potentiation in obese zucker rats: possible involvement of presynaptic mechanism[END_REF] and impaired performance of hippocampaldependent tasks [START_REF] Li | Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents[END_REF][START_REF] Winocur | Memory impairment in obese Zucker rats: An investigation of cognitive function in an animal model of insulin resistance and obesity[END_REF]. Such results indicate that decreases in leptin signaling contribute to deficits in hippocampal synaptic plasticity and suggest that leptin resistance,

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Conclusions

Through findings from both human and animal studies, the underlying mechanisms involved in diabetes-induced CNS complications are coming under greater scrutiny and becoming better appreciated. It is extremely difficult to decipher a causal relationship between many of the endocrine and metabolic changes observed in diabetes and to appoint specific contributions of each factor. It is unlikely that any single factor is solely responsible for the CNS complications in diabetic subjects. Rather, a variety of factors likely act in additive or synergistic ways to impair neuronal homeostasis, increase neuronal vulnerability and eventually contribute to cognitive decline (see figure 2). Since some studies suggest that diabetic patients exhibit cognitive performance that is within the normal range, the magnitude or importance of memory decline in diabetic patients is often debated. However, the combination of the structural and functional changes within the hippocampus that elicit subtle decreases in cognitive function may be progressive and silently lead to increased risk of age-related neurological disorders. Indeed, the deleterious consequences of diabetes undoubtedly accumulate over time and ultimately produce detrimental effects in the CNS. Such realities emphasize the importance of patient education as it relates to maintaining a healthy life style through diet, exercise and medication. Additionally, there is a continued need for clinicians and pre-clinical scientists to identify the factors that are involved in the etiology and progression of the neurological complications of diabetes, as well as the fundamental basis that may cause

  may lead to the development of a cognitive phenotype similar to that of aged individuals.

  tau function and may lead to synapse dysfunction, neuron degeneration and cognitive impairment [91]. Some clinical and epidemiological studies have demonstrated an association between diabetes and the development of comorbid AD. Data from the Religious Orders study, a study of aging in Catholic priests, nuns and brothers across the US, show a 65% increased risk of developing clinical manifestations of AD in diabetic patients compared

  discovery of centrally located insulin receptors [107,108] has lead to a greater appreciation of the multi-faceted functions of insulin within the CNS. The expression of insulin receptors in the hippocampus has driven the hypothesis that insulin is an important contributor to or regulator of cognitive function [109,110] a theory supported A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 18 by clinical evidence. For example, chronic intranasal insulin administration improves cognitive performance in both AD and non-demented individuals [17,88,111-113], and acute insulin administration has been shown to improve declarative memory in AD patients [114]. Moreover, administration of the insulin sensitizer, rosiglitazone, ameliorates cognitive decline in non-diabetic AD patients [115]. Rosiglitazone-induced cognitive improvement is also observed in animal models of AD [116], which may be mediated in part through increases in dendritic spine density, an effect of rosiglitazone observed in primary cortical cultures [117]. Insulin is also known to exert direct and indirect effects over various neurotransmitter systems. For example, insulin increases Nmethyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA) and gamma-aminobutyric acid (GABA) receptor surface expression [118-120],

  accumulation of advanced glycation end products (AGE)[135], products formed by the non-enzymatic reaction between sugars and amino groups, and oxidative stress in the brain, which may lead to cellular and molecular damage[136]. In this regard, AGE and oxidative stress have both been identified as potential contributors to diabetes-induced brain aging[START_REF] Biessels | Ageing and diabetes: implications for brain function[END_REF]137]. Accumulated AGE are present in normal aging and in certain pathological conditions such as AD and diabetes [138-141]. Among the actions of AGE are effects on extracellular matrix proteins and basement membrane components which can cause or facilitate vascular complications [135,142]. Additionally, AGE generation increases proinflammatory mechanisms in the vessels which enhance oxidative stress. An increase in oxidative stress leads to AGE accumulation and thus creates an unremitting cycle [140] which may contribute to a host of complications and imbalances. In physiological conditions there is a delicate balance between the synthesis of oxygen free radicals and the activities of anti-oxidant pathways to protect the organism; an imbalance of the oxidant/anti-oxidant equilibrium favoring the former creates a situation of oxidative stress [143]. Studies from animal models have strengthened the relationship between oxidative stress, aging and cognitive performance. For example, increases in oxidative stress in the rat hippocampus are associated with decreases in behavioral performance in hippocampal-dependent learning and memory paradigms, such A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 21 as the Morris water maze [144,145]. During aging, antioxidant enzyme activity and expression decreases [146-148], suggesting that oxidative status may shift towards accumulation of oxidative stress products. There are similar imbalances in oxidant/antioxidant pathways in animal models of diabetes. For example, there are increases in prooxidant pathways and decreases in anti-oxidant pathways [9]. The free radical hypothesis of aging proposes that aging is the result of random harmful effects on tissue due to oxygen free radicals [149,150], a hypothesis that may be applicable to diabetic individuals as well. As such, deleterious AGE accumulation and imbalances in oxidative stress status may be among the etiological factors that contribute to the pathogenesis of age-related and diabetes-induced cognitive impairments. The potential for disruption of proper AGE metabolism and oxidative stress status in diabetes [137] provide additional explanations as to how diabetes might worsen or accelerate the brain aging process.

Figure legends Figure 1 .

 legends1 Figure legends

Figure 2 .

 2 Figure 2. Potential mechanistic mediators of diabetes-induced brain aging. The

  R I P T to diabetes has been discussed by Ryan and Geckle, which proposes that older individuals have less brain reserve making them more susceptible to diabetesinduced CNS changes[START_REF] Ryan | Why is learning and memory dysfunction in Type 2 diabetes limited to older adults?[END_REF]. It is possible that this revised hypothesis is not only applicable to older diabetic patients but perhaps to all diabetic patients irrespective of age. If this hypothesis is correct, diabetes patients would be more susceptible to CNS insults arising from diabetes and less capable of adapting in order to reduce or eliminate cognitive deficits. The addition of an increasing number of insults, such as the features of the metabolic syndrome in T2D or hypoglycemic episodes in T1D patients, would further increase CNS vulnerability. As such, poorly controlled diabetes would create a neuronal milieu in which diabetes patients are more vulnerable to the aging process and age-related diseases such as AD.

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Acknowledgements

The authors' work is supported in part by Juvenile Diabetes Research Foundation grant number 2-03-675 (LPR), NIH grant number NS047728 (LPR) and the Alfred P. Sloan Foundation (SAW). The authors would like to acknowledge the efforts of their collaborators, including: Dr. Bruce McEwen (The Rockefeller University); Dr. Maureen Charron (Albert Einstein College of Medicine); Dr. Carol Greenwood and Dr. Gordon Winocur (University of Toronto); Dr. Randall Sakai (University of Cincinnati); and Dr. Steven Wilson, (University of South Carolina School of Medicine).

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