MD; PhD Matheus Roriz-Cruz

MD Jarbas S Roriz-Filho

OT, M.Sc Ticiana M De-Sá-Roriz

NP, M.Sc Idiane Rosset

MD Ana Camozzato

PhD Antonio C Santos

PhD Márcia L F Chaves

PhD Júlio César Moriguti

Dr Paul Dear

Fraser

Dr Ben Oostra

MD Jarbas De Sá Roriz-Filho

M.Sc † ; Idiane Rosset Ot

M.Sc ‡ ; Ana L Gnp

MD Camozzato

Mini Review for 'Diabetes and Nervous System' (Supplement of the BBA) (Pre)Diabetes, brain aging, and cognition

Keywords: diabetes, insulin, 'brain aging', cognition, dementia

Cognitive dysfunction and dementia have recently been proven to be common (and underrecognized) complications of Diabetes Mellitus (DM). In fact, several studies have evidenced that phenotypes associated with obesity and/or alterations on insulin homeostasis are at increased risk for developing cognitive decline and dementia, including not only vascular dementia, but also Alzheimer's Disease (AD). These phenotypes include prediabetes, diabetes, and the metabolic syndrome. Both types 1 and 2 Diabetes are also important risk factors for decreased performance in several neuropsychological functions. Chronic Hyperglycemia and hyperinsulinemia primarily stimulates the formation of Advanced Glucose Endproducts (AGEs), which leads to an overproduction of Reactive Oxygen Species (ROS). Protein glycation and increased oxidative stress are the two main mechanisms involved in biological aging, both being also probably related to the etiopathogeny of AD. AD patients were found to have lower than normal cerebrospinal fluid levels of insulin. Besides its traditional glucoregulatory importance, insulin has significant neurothropic properties in the brain. How can clinical hyperinsulinism be a risk factor for AD whereas lab experiments evidence insulin to be an important neurothrophic factor? These two apparent paradoxal findings may be reconciliated by evoking the concept of insulin resistance. Whereas insulin is clearly neurothrophic at moderate concentrations, too much insulin in the brain may be associated with reduced amyloid-β (Aβ) clearance due to competition for their common and main depurative mechanism -the Insulin-Degrading Enzyme (IDE). Since IDE is much more selective for insulin than for Aβ, brain hyperinsulinism may deprive Aβ of its main clearance mechanism. Hyperglycemia and hyperinsulinemia seems to accelerate brain aging also by inducing tau hyperphosphorylation and amyloid oligomerization, as well as by leading to widespread brain microangiopathy. In fact,

Introduction

Diabetes Mellitus (DM) is one of the most important and prevalent chronic diseases. It currently affects 250 million people worldwide, with 6 million new cases reported each year [START_REF] Cole | Molecular connexions between dementia and diabetes[END_REF]. This prevalence rises with age from 12% in people aged 65 to 70 to 15% in people over age 80 [START_REF] Wild | Global prevalence of diabetes: estimates for the year 2000 and projections for 2030[END_REF]. DM is a systemic disease that can damage any organ in the body [START_REF] Zhao | Prevalence of other diabetesassociated complications and comorbidities and its impact on health care charges among patients with diabetic neuropathy[END_REF]. Complications include pathologic changes involving both small and large vessels, cranial and peripheral nerves, skin, and eyes. These organic lesions may lead to hypertension, renal failure, vision loss, autonomic and peripheral neuropathy, peripheral vascular disease, myocardial infarction and cerebrovascular disease, including stroke [START_REF] Zhao | Prevalence of other diabetesassociated complications and comorbidities and its impact on health care charges among patients with diabetic neuropathy[END_REF].

In recent years, significantly more interest has been dedicated to the effect of diabetes on the brain. Along with cerebrovascular disease, diabetes is implicated in the development of other neurological co-morbidities. Less addressed and not as well recognized complications of DM are cognitive dysfunction and dementia. Like diabetes, cognitive dysfunction represents another serious problem and is rising in prevalence worldwide, especially among the elderly [START_REF] Thomas | Estimating the prevalence of dementia in elderly people: a comparison of the Canadian Study of Health and Aging and National Population Health Survey approaches[END_REF]. Diabetes mellitus has been implicated as risk factor for dementia not only of vascular type but also to Alzheimer's Disease (AD) [START_REF] Ott | Diabetes mellitus and the risk of dementia: the Rotterdam Study[END_REF] Patients with type 1 Diabetes Mellitus (T1DM) and type 2 Diabetes Mellitus (T2DM) have been found to present cognitive deficits, associated with reduced performance on multiple domains of cognitive function. Cognitive impairment due to diabetes mainly occur at two main periods: during the first 5-7 years of life when brain systems is in development; and the period when the brain undergoes neurodegenerative changes due to aging (older than 65 years) [START_REF] Biessels | Cognition and diabetes: a lifespan perspective[END_REF].

Anatomic brain alterations have been identified in patients with both T1DM and T2DM [START_REF] Luchsinger | Diabetes mellitus and risk of Alzheimer's disease and dementia with stroke in a multiethnic cohort[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][START_REF] Macknight | Diabetes mellitus and the risk of dementia, Alzheimer's disease and vascular cognitive impairment in the Canadian study of health and aging[END_REF][START_REF] Arvanitakis | Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function[END_REF][START_REF] Gispen | Cognition and synaptic plasticity in diabetes mellitus[END_REF][START_REF] Watson | Modulation of memory by insulin and glucose: neuropsychological observation in Alzheimer's disease[END_REF][START_REF] Lazarus | White matter lesions on magnetic resonance imaging and their relationship with vascular risk factors in memory clinic attenders[END_REF]. These include generalized brain atrophy and greater high-intensity lesion

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volumes, predominantly in the subcortical regions [START_REF] Lazarus | White matter lesions on magnetic resonance imaging and their relationship with vascular risk factors in memory clinic attenders[END_REF]. Patients with diabetes mellitus are more likely to present earlier and more extense leukoaraiosis (White Matter Hyperintense Lesions (WMHLs) [START_REF] Dejgaard | Evidence for diabetic encephalopathy[END_REF]. Leukoaraiosis is a feature usually found in brain scans performed in subjects over 80 years-old [START_REF] Akisaki | Cognitive dysfunction associates with white matter hyperintensities and subcortical atrophy on magnetic resonance imaging of the elderly diabetes mellitus Japanese elderly diabetes intervention trial (J-EDIT)[END_REF]. The nature of these WMHLs is uncertain, but investigators have hypothesized that they could represent demyelination, increased water content or gliosis [START_REF] Biessels | Cerebral function in diabetes mellitus[END_REF]. Magnetic Resonance Imaging (MRI) has also demonstrated that subjects with T2DM have hippocampal and amygdala atrophy relative to control subjects [START_REF] Heijer | Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI[END_REF]. The hippocampus and amygdala are responsible for such functions as memory and behavior and, coincidentally, are also found to be atrophied in AD [START_REF] Heijer | Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI[END_REF]. In addition, post-mortem studies of brains of DM patients with dementia often reveal the coexistence of both brain microvascular lesions and extense amyloid plaque burden, a characteristic of AD. This phenomenon suggests that diabetes is a risk factor for both vascular dementia (VD) and AD [START_REF] Jellinger | The pathology of "vascular dementia": a critical update[END_REF].

Many studies suggest that the risk of cognitive decline and neurodegeneration is increased not only in DM, but also in patients with pre-diabetes and Metabolic Syndrome (MetS) [START_REF] Luchsinger | Hyperinsulinemia and risk of Alzheimer disease[END_REF]. Individuals with pre-diabetes are defined as those presenting impaired fasting glucose and/or impaired glucose tolerance [START_REF] Yaffe | Diabetes, impaired fasting glucose, and development of cognitive impairment in older women[END_REF], what increase their risk of developing frank DM. Those subjects already present insulin resistance (IR) as a pathophysiological mechanism that is often associated with MetS. [START_REF] Luchsinger | Hyperinsulinemia and risk of Alzheimer disease[END_REF][START_REF] Yaffe | Diabetes, impaired fasting glucose, and development of cognitive impairment in older women[END_REF]. Metabolic Syndrome, in turn, is a cluster of interrelated cardiometabolic risk factors including visceral obesity, dyslipidemia (elevated triglycerides and/or low HDL-cholesterol), hypertension, dysglycemia (pre-diabetes or diabetes) [START_REF] Matsuo | Metabolic Syndrome is Strongly Associated With Chronic Subclinical Inflammation in Patients Achieving Optimal Low-Density Lipoprotein-Cholesterol Levels in Secondary Prevention of Cardiovascular Disease[END_REF] Subjects with the MetS often also present a proinflammatory/prothrombotic state. MetS has already been associated with silent strokes, cognitive impairment, vascular dementia, Alzheimer's disease and the 'Frontal-Subcortical (geriatric) Syndrome' (FSCS). [see 22 for a review].

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The exact pathophysiology of cognitive dysfunction and cerebral lesions in diabetes mellitus is not completely understood, but it is likely that hyperglycemia, vascular disease, hypoglycemia, and insulin resistance play significant roles [START_REF] Kodl | Cognitive Dysfunction and Diabetes Mellitus[END_REF].

Diabetes mellitus may accelerate the brain aging process, as it accelerates cerebral atrophy [START_REF] Biessels | Ageing and diabetes: implications for brain function[END_REF], thus reducing cognitive reserve and the threshold for the development of AD symptoms. In addition, DM may interfere with cerebral amyloid and tau metabolism [START_REF] Gasparini | Potential roles of insulin and IGF-1 in Alzheimer's disease[END_REF]. Alterations in insulin and glucose homoeostasis in the periphery may affect brain insulin and its receptor functions [START_REF] Gasparini | Potential roles of insulin and IGF-1 in Alzheimer's disease[END_REF], promoting increasing oligomerization of β-amyloid, and inducing tau hyperphosphorylation [START_REF] Gasparini | Potential roles of insulin and IGF-1 in Alzheimer's disease[END_REF][START_REF] Craft | Insulin and neurodegenerative disease: shared and specific mechanisms[END_REF]. Insulin resistance seems also to accelerate biological aging by fostering the formation of Advanced Glycation End-products (AGE) and, consequently, ROS (Reactive Oxygen Species) [START_REF] Smith | Radical AGEing in Alzheimer's disease[END_REF]. The relation between insulin and the metabolism of amyloid-β peptide (Aβ) and tau in particular has been receiving increasing attention over the past few years [START_REF] Gasparini | Potential roles of insulin and IGF-1 in Alzheimer's disease[END_REF][START_REF] Craft | Insulin and neurodegenerative disease: shared and specific mechanisms[END_REF].

2. Global and Specific Subtypes of Cognitive Dysfunction in:

Type 1 Diabetes

Neuropsychological studies have shown that patients with T1DM perform worse than patients without T1DM on several cognitive functions. Although the degree of magnitude is variable, this worse performance in cognitive functions is already noticeable during childhood [START_REF] Desrocher | Neurocognitive correlates of type 1 diabetes mellitus in childhood[END_REF]. These cognitive functions include specific deficits of intelligence, attention, processing speed, memory, and executive skills [START_REF] Brands | Cognitive performance, psychological well-being, and brain magnetic resonance imaging in older patients with type 1 diabetes[END_REF][START_REF] Ryan | Cognitive dysfunction in adults with type 1 (insulin-dependent) diabetes mellitus of long duration: effects of recurrent hypoglycaemia and other chronic complications[END_REF][START_REF] Ryan | Cognitive efficiency declines over time in adults with type 1 diabetes: effects of micro-and macrovascular complications[END_REF][START_REF] Weinger | The effects of type 1 diabetes on cerebral white matter[END_REF][START_REF] Hershey | Craft Conventional versus intensive diabetes therapy in children with type 1 diabetes: effects on memory and motor speed[END_REF][START_REF] Ryan | Neurobehavioral complications of type I diabetes. Examination of possible risk factors[END_REF][START_REF] Skenazy | Neuropsychological findings in diabetes mellitus[END_REF][START_REF] Northam | Andrewes Neuropsychological complications of IDDM in children 2 years after disease onset[END_REF][START_REF] Schoenle | Impaired intellectual development in children with type I diabetes: association with HbA(1c), age at diagnosis and sex[END_REF][START_REF] Northam | Neuropsychological profiles of children with type 1 diabetes 6 years after disease onset[END_REF].

Cognitive deficits were mainly identified in information processing speed [START_REF] Brands | Cognitive performance, psychological well-being, and brain magnetic resonance imaging in older patients with type 1 diabetes[END_REF][START_REF] Ryan | Cognitive dysfunction in adults with type 1 (insulin-dependent) diabetes mellitus of long duration: effects of recurrent hypoglycaemia and other chronic complications[END_REF] and psychomotor abilities. The progression and accumulation of these specific deficits can

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lead to global deficits and dementia in diabetic patients [START_REF] Ryan | Cognitive efficiency declines over time in adults with type 1 diabetes: effects of micro-and macrovascular complications[END_REF][START_REF] Weinger | The effects of type 1 diabetes on cerebral white matter[END_REF]. The cognitive performance of diabetic patients is summarized in table 1 and the neurocognitive tests utilized on these studies are shown on table 2.

In addition, other deficits were also identified such as those involving motor speed [START_REF] Hershey | Craft Conventional versus intensive diabetes therapy in children with type 1 diabetes: effects on memory and motor speed[END_REF][START_REF] Ryan | Neurobehavioral complications of type I diabetes. Examination of possible risk factors[END_REF][START_REF] Skenazy | Neuropsychological findings in diabetes mellitus[END_REF] and strength [START_REF] Skenazy | Neuropsychological findings in diabetes mellitus[END_REF], vocabulary [START_REF] Northam | Andrewes Neuropsychological complications of IDDM in children 2 years after disease onset[END_REF][START_REF] Schoenle | Impaired intellectual development in children with type I diabetes: association with HbA(1c), age at diagnosis and sex[END_REF], general intelligence [START_REF] Northam | Andrewes Neuropsychological complications of IDDM in children 2 years after disease onset[END_REF][START_REF] Wessels | Cognitive performance in type 1 diabetes patients is associated with cerebral white matter volume[END_REF],

visuoconstructional praxis [START_REF] Northam | Andrewes Neuropsychological complications of IDDM in children 2 years after disease onset[END_REF], attention [START_REF] Wessels | Cognitive performance in type 1 diabetes patients is associated with cerebral white matter volume[END_REF], memory [START_REF] Weinger | The effects of type 1 diabetes on cerebral white matter[END_REF], and executive function [START_REF] Weinger | The effects of type 1 diabetes on cerebral white matter[END_REF][START_REF] Northam | Neuropsychological profiles of children with type 1 diabetes 6 years after disease onset[END_REF]. A recent meta-analysis analyzed 33 studies of cognitive function in adults with T1DM and found significant reductions in overall cognition, both fluid and crystallized intelligence, speed of information processing, psychomotor efficiency, visual and sustained attention, mental flexibility, and visual perception, when compared with controls [START_REF] Brands | The effects of type 1 diabetes on cognitive performance: a meta-analysis[END_REF]. There was no significant difference in motor speed, memory, selective attention, and language. Lowered cognitive performance in diabetic patients appeared to be associated with the presence of microvascular complications, but not with the occurrence of severe hypoglycemic episodes or with poor metabolic control [START_REF] Brands | The effects of type 1 diabetes on cognitive performance: a meta-analysis[END_REF].

Many longitudinal studies have found lower intelligence quotient (IQ) scores, reduced mental efficiency, and worse school performance in children with T1DM [START_REF] Schoenle | Impaired intellectual development in children with type I diabetes: association with HbA(1c), age at diagnosis and sex[END_REF][START_REF] Northam | Neuropsychological profiles of children with type 1 diabetes 6 years after disease onset[END_REF][START_REF] Fox | Gender differences in memory and learning in children with insulin-dependent diabetes mellitus (IDDM) over a 4-year follow-up interval[END_REF][START_REF] Dahlquist | School performance in children with type 1 diabetes-a population-based register study[END_REF]. Nevertheless there are many factors that can influence on the cognitive performance of these patients. The age of onset of diabetes mellitus and the quality of glycemic control are possibly the two most important ones. In a population of children with T1DM evaluated 6 years after disease onset, those who developed T1DM at less than 4 years of age had impaired executive skills, attention, and processing speed when compared with those who were diagnosed after 4 years of age [START_REF] Northam | Neuropsychological profiles of children with type 1 diabetes 6 years after disease onset[END_REF]. The 'early-onset effect' has been attributed to the adverse effects of metabolic disturbances on the developing brain and appears to persist through adulthood [START_REF] Ryan | Why is cognitive dysfunction associated with the development of diabetes early in life? The diathesis hypothesis[END_REF].

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Adequate glycemic control also appears to be importantly associated with cognitive performance in patients with T1DM. Psychomotor abilities, motor speed [START_REF] Ryan | Cognitive dysfunction in adults with type 1 (insulin-dependent) diabetes mellitus of long duration: effects of recurrent hypoglycaemia and other chronic complications[END_REF][START_REF] Jacobson | Long-term effect of diabetes and its treatment on cognitive function[END_REF], attention, memory, verbal IQ scores [START_REF] Holmes | Neuropsychological profiles in men with insulindependent diabetes[END_REF][START_REF] Kaufman | Neurocognitive functioning in children diagnosed with diabetes before age 10 years[END_REF][START_REF] Perantie | Severe hypoglycemia vs. hyperglycemia: unique effects on cognition in youth with type 1 diabetes mellitus (TIDM)[END_REF], and academic achievements [START_REF] Kaufman | Neurocognitive functioning in children diagnosed with diabetes before age 10 years[END_REF] are improved with better glycemic control [START_REF] Perantie | Severe hypoglycemia vs. hyperglycemia: unique effects on cognition in youth with type 1 diabetes mellitus (TIDM)[END_REF]. On the Diabetes Control and Complications Trial (DCCT) patients with T1DM with mean serum glycated hemoglobin (HbA1c) lower than 7.4% performed significantly better on tests of motor speed and psychomotor efficiency than those subjects which mean HbAlc greater than 8.8%

during the 18-year follow-up [START_REF] Jacobson | Long-term effect of diabetes and its treatment on cognitive function[END_REF]. In addition, patients with acute hyperglycemia perform worse on tests of cognitive function, showing increased number of mental subtraction errors, loss of inhibition and focus, impaired speed of information processing, decreased attention, and impaired working memory [START_REF] Cox | Relationships between hyperglycemia and cognitive performance among adults with type 1 and type 2 diabetes[END_REF][START_REF] Rovet | Attentional functioning in children and adolescents with IDDM[END_REF]. Conversely, no association between multiple severe episodes of hypoglycemia and impaired cognitive function in patients with T1DM was found in the DCCT [START_REF] Jacobson | Long-term effect of diabetes and its treatment on cognitive function[END_REF].

In a metanalysis, the presence of other diabetic complications was associated with poorer cognitive function in most studies involving T1DM patients [START_REF] Brands | The effects of type 1 diabetes on cognitive performance: a meta-analysis[END_REF]. Deficits in fluid intelligence, information processing speed, attention, and concentration have been associated with the presence of retinopathy [START_REF] Ferguson | Cognitive ability and brain structure in type 1 diabetes: relation to microangiopathy and preceding severe hypoglycemia[END_REF]. Whereas complications like retinopathy and nephropathy usually require years of diabetes before becoming clinically apparent, the onset of cognitive impairment has been found to occur earlier in the course of disease among T1DM patients [START_REF] Northam | Andrewes Neuropsychological complications of IDDM in children 2 years after disease onset[END_REF]. Among children with T1DM, deficits in cognitive function have been detected as early as 2 years after diagnosis. In the follow-up, these children experienced less increase in general intelligence, vocabulary, block design, processing speed, and learning in general [START_REF] Northam | Andrewes Neuropsychological complications of IDDM in children 2 years after disease onset[END_REF]. Proliferative retinopathy, macrovascular complications, hypertension, and duration of diabetes were associated with poorer performance on tests measuring psychomotor speed and visuoconstructional

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ability [START_REF] Ryan | Cognitive dysfunction in adults with type 1 (insulin-dependent) diabetes mellitus of long duration: effects of recurrent hypoglycaemia and other chronic complications[END_REF][START_REF] Ryan | Cognitive efficiency declines over time in adults with type 1 diabetes: effects of micro-and macrovascular complications[END_REF][START_REF] Wessels | Cognitive performance in type 1 diabetes patients is associated with cerebral white matter volume[END_REF]. In another study, the occurrence of distal symmetrical polyneuropathy was related to worse cognitive function on most domains, except for memory [START_REF] Ryan | Cognitive dysfunction in adults with type 1 (insulin-dependent) diabetes mellitus of long duration: effects of recurrent hypoglycaemia and other chronic complications[END_REF].

Type 2 Diabetes

Patients with T2DM have also been found to have specific and global cognitive deficits characterized by decreases in psychomotor speed [START_REF] Gregg | Cummings Is diabetes associated with cognitive impairment and cognitive decline among older women? Study of Osteoporotic Fractures Research Group[END_REF][START_REF] Reaven | Relationship between hyperglycemia and cognitive function in older NIDDM patients[END_REF], complex motor functioning [START_REF] Reaven | Relationship between hyperglycemia and cognitive function in older NIDDM patients[END_REF], executive functions [START_REF] Reaven | Relationship between hyperglycemia and cognitive function in older NIDDM patients[END_REF][START_REF] Munshi | Cognitive dysfunction is associated with poor diabetes control in older adults[END_REF][START_REF] Perlmuter | Decreased cognitive function in aging non-insulin-dependent diabetic patients[END_REF], memory skills [START_REF] Munshi | Cognitive dysfunction is associated with poor diabetes control in older adults[END_REF][START_REF] Perlmuter | Decreased cognitive function in aging non-insulin-dependent diabetic patients[END_REF][START_REF] Messier | Impact of impaired glucose tolerance and type 2 diabetes on cognitive aging[END_REF], processing speed [START_REF] Messier | Impact of impaired glucose tolerance and type 2 diabetes on cognitive aging[END_REF],,immediate and delayed recall [START_REF] Grodstein | Type 2 diabetes and cognitive function in community-dwelling elderly women[END_REF], verbal fluency [START_REF] Reaven | Relationship between hyperglycemia and cognitive function in older NIDDM patients[END_REF][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], attention [START_REF] Fontbonne | Changes in cognitive abilities over a 4-year period are unfavorably affected in elderly diabetic subjects: results of the Epidemiology of Vascular Aging Study[END_REF] and visuospatial abilities [START_REF] Mooradian | Cortical function in elderly non-insulin dependent diabetic patients, Behavioral and electrophysiologic studies[END_REF]. Another neurocognitive dysfunction frequently observed in patients with T2DM is (vascular) depression, which is twice more common in these patients than among controls [START_REF] Bruce | Cognitive impairment, physical disability and depressive symptoms in older diabetic patients: the Fremantle Cognition in Diabetes Study[END_REF]. Besides sharing a common neurovascular pathogen with cognitive dysfunction, depression is also a cause of cognitive dysfunction by itself, since it may severely impairs attention [START_REF] Munshi | Cognitive dysfunction is associated with poor diabetes control in older adults[END_REF][START_REF] Bruce | Cognitive impairment, physical disability and depressive symptoms in older diabetic patients: the Fremantle Cognition in Diabetes Study[END_REF][START_REF] Roriz-Cruz | Stroke-Independent Association Between Metabolic Syndrome and Functional Dependence, Depression, and Low Quality of Life in Elderly Community-Dwelling Brazilian People[END_REF]. A comparison in the cognitive performance between T1DM and T2DM is summarized in table 1 and the neurocognitive tests utilized on these studies are shown on table 2.

Cross-sectional studies evaluating cognition in T2DM patients demonstrate that immediate noncontextual, verbal memory, processing speed, and brief cognitive screening measures are much worse in diabetic patients than among controls [START_REF] Awad | The Relationship between Impaired Glucose Tolerance, Type 2 Diabetes, and Cognitive Function[END_REF]. Six out of 11 population studies demonstrate that T2DM patients are more likely than controls to show poor performance on brief cognitive screening measures. All the other measures were less likely to show significant differences between well-treated type 2 diabetic patients and controls. Taken together, the results of well-controlled cross-

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sectional populational studies demonstrate that findings across all evaluated neuropsychological measures are inconsistent [START_REF] Awad | The Relationship between Impaired Glucose Tolerance, Type 2 Diabetes, and Cognitive Function[END_REF].

Longitudinal studies, however, almost universally reveal a higher risk of dementia or significant cognitive decline in diabetic populations [START_REF] Macknight | Diabetes mellitus and the risk of dementia, Alzheimer's disease and vascular cognitive impairment in the Canadian study of health and aging[END_REF][START_REF] Allen | The relationship between type 2 diabetes and cognitive dysfunction: longitudinal studies and their methodological limitations[END_REF]. Studies with cognitive screening instruments or batteries of more comprehensive neuropsychological tests show that the rate of cognitive decline due to aging is increased 1•5-fold to 2•0-fold in individuals with T2DM [START_REF] Cukierman | Cognitive decline and dementia in diabetes -systematic overview of prospective observational studies[END_REF], albeit a study of cognitive function in the oldest old (age at study entry 85 years) did not find any significant association between T2DM and accelerated cognitive decline [START_REF] Van Den Berg | The impact of diabetes mellitus on cognitive decline in the oldest of the old: a prospective population-based study[END_REF][START_REF] Biessels | Risk of dementia in diabetes mellitus: a systematic review[END_REF]. This particularity among the oldest-old population may be a form of 'survivor effect', in which T2DM people with more advanced vascular burden already died from myocardial infarction, stroke, or even dementia or obesity-associated neoplasms [START_REF] Van Den Berg | The impact of diabetes mellitus on cognitive decline in the oldest of the old: a prospective population-based study[END_REF]. Besides, as most westerners start to lose weight after middle age is over, many people above 80 might actually improve their T2DM control by losing weight. Alternatively, people with neoplasms or dementia may start to importantly lose weight even before the diagnosis of such conditions [START_REF] Van Den Berg | The impact of diabetes mellitus on cognitive decline in the oldest of the old: a prospective population-based study[END_REF]. This phenomenon, however, is not to be confused with the fact that mild-moderate caloric restriction (30%) through life extends lifespan in invertebrates and vertebrates, including primates and, probably, humans [START_REF] Mair | Aging and survival: the genetics of life span extension by dietary restriction[END_REF]. Among the main mechanisms by which caloric restriction extends lifespan seems to be the facts that it (1) increases insulin sensitivity and (2) decreases the formation of AGEs and (3) ROS, resulting in less oxidative stress [START_REF] Mair | Aging and survival: the genetics of life span extension by dietary restriction[END_REF].

The risk of Alzheimer's disease (relative risk [RR] 1•5-2•0) and vascular dementia (RR 2•0-2•5) is increased in T2DM [START_REF] Biessels | Risk of dementia in diabetes mellitus: a systematic review[END_REF]. If we assume the prevalence of T2DM to be about 15% in people older than 60 years, a RR of 1•5-2•0 translates into a diabetes attributable risk for dementia of 7-13% [START_REF] Biessels | Cognition and diabetes: a lifespan perspective[END_REF]. This increased risk remains

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significant even after adjusting for the presence of other vascular risk factors [START_REF] Grossman | Does diabetes protect or provoke Alzheimer's disease? Insights into the pathobiology and future treatment of Alzheimer's disease[END_REF].

Alzheimer's disease is by far the most common cause of dementia among people with T2DM. In fact, among all incident cases of dementia occurring in people with T2DM, Alzheimer's disease is the diagnosis in about 82.5% [START_REF] Yaffe | Diabetes, impaired fasting glucose, and development of cognitive impairment in older women[END_REF] to 91% of the situations [START_REF] Luchsinger | Hyperinsulinemia and risk of Alzheimer disease[END_REF].

As stated above, the enhanced risk for developing AD in diabetic patients remains strong even when vascular factors are controlled for, suggesting an importance of non-vascular mechanisms for AD pathogenesis [START_REF] Cole | The role of insulin and neurotrophic factor signaling in brain aging and Alzheimer's Disease[END_REF]. Several factors might contribute to the increased AD risk in diabetes mellitus, including defects in insulin signaling, accumulation of pathological Aβ, and hyperphosphorylated Tau [START_REF] Messier | Diabetes, Alzheimer's disease and apolipoprotein Genotype[END_REF]. Some studies have shown that the association between diabetes mellitus and Alzheimer's disease is particularly strong among Apolipoprotein E epsilon-4 allele (APOEε4) carriers. Indeed, individuals with T2DM who possess the APOEε4 allele have twice the risk of developing Alzheimer's disease, as compared with non-diabetics subjects with the APOEε4 allele [START_REF] Messier | Diabetes, Alzheimer's disease and apolipoprotein Genotype[END_REF]. Brain pathology from T2DM patients frequently includes heavy deposition of β-amyloid and Neurofibrilary Tangles (NFTs) [START_REF] Cole | The role of insulin and neurotrophic factor signaling in brain aging and Alzheimer's Disease[END_REF]. Moreover, amyloid deposition is markedly increased in individuals with both diabetes and the APOEε4 genotype [START_REF] Messier | Diabetes, Alzheimer's disease and apolipoprotein Genotype[END_REF][START_REF] Watson | The role of insulin resistance in the pathogenesis of Alzheimer's disease: implications for treatment[END_REF].

Glycemic control appears to play an important role in preserving cognitive performance among patients with T2DM [START_REF] Ryan | Circumscribed cognitive dysfunction in middle-aged adults with type 2 diabetes[END_REF]. In patients with T2DM, studies have demonstrated an inverse relationship between serum HbAlc and working memory [START_REF] Munshi | Cognitive dysfunction is associated with poor diabetes control in older adults[END_REF][START_REF] Perlmuter | Decreased cognitive function in aging non-insulin-dependent diabetic patients[END_REF], executive functioning [START_REF] Munshi | Cognitive dysfunction is associated with poor diabetes control in older adults[END_REF], learning [START_REF] Reaven | Relationship between hyperglycemia and cognitive function in older NIDDM patients[END_REF], and complex psychomotor performance [START_REF] Reaven | Relationship between hyperglycemia and cognitive function in older NIDDM patients[END_REF][START_REF] Sommerfield | Short-term, delayed, and working memory are impaired during hypoglycemia in individuals with type 1 diabetes[END_REF]. This finding supports the hypothesis that an inadequate glucose control is associated with worsening cognitive function. Another important finding is the association between both the duration and severity of T2DM at one side, and the degree of central (brain) and peripheral nervous system involvement, as demonstrated

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by decreased cognitive function and peripheral neuropathy, respectively. [START_REF] Gregg | Cummings Is diabetes associated with cognitive impairment and cognitive decline among older women? Study of Osteoporotic Fractures Research Group[END_REF][START_REF] Perlmuter | Decreased cognitive function in aging non-insulin-dependent diabetic patients[END_REF][START_REF] Fontbonne | Changes in cognitive abilities over a 4-year period are unfavorably affected in elderly diabetic subjects: results of the Epidemiology of Vascular Aging Study[END_REF].

Insulin-dependent T2DM subjects had a higher risk of major cognitive decline than those with an adequate metabolic control only with oral hypoglycemiants [START_REF] Widom | Glycemic control and neuropsychologic function during hypoglycemia in patients with insulin dependent diabetes mellitus[END_REF].Conversely, repetitive episodes of moderate to severe hypoglycemia have been implicated as one possible etiology for long-term cognitive dysfunction in T2DM [START_REF] Sommerfield | Short-term, delayed, and working memory are impaired during hypoglycemia in individuals with type 1 diabetes[END_REF],

even though the strongest evidence for memory disturbances is for the short period in which the subject is hypoglicemic [START_REF] Biessels | Cognitive function in patients with type 2 diabetes mellitus[END_REF][START_REF] Schmidt | Magnetic resonance imaging of the brain in diabetes. The cardiovascular determinants of dementia (CASCADE) study[END_REF].

Neuroimaging in Diabetes

Several studies on the cerebral structure of patients with T1DM and T2DM have evidenced cortical and subcortical atrophy, besides increased leukoaraiosis (WMHLs), which were associated with impaired cognitive performance even after controlling for cardiovascular risk factors such as hypertension [START_REF] Dejgaard | Evidence for diabetic encephalopathy[END_REF][START_REF] Akisaki | Cognitive dysfunction associates with white matter hyperintensities and subcortical atrophy on magnetic resonance imaging of the elderly diabetes mellitus Japanese elderly diabetes intervention trial (J-EDIT)[END_REF][START_REF] Heijer | Type 2 diabetes and atrophy of the medial temporal lobe structures[END_REF]. A strong interaction between diabetes and hypertension was observed, such that when the two conditions are present together, they result in a multiplicative greater risk for cortical brain atrophy [START_REF] Lognig | Hippocampal volume and cognitive performance in long-standing type 1 diabetic patients without macrovascular complications[END_REF]. A study involving elderly subjects have also found that hippocampus and amygdala atrophy were more pronounced in persons with T2DM [START_REF] Longstreth | Lacunar infarcts defined by magnetic resonance imaging of 3660 elderly people: the Cardiovascular Health Study[END_REF]. Interestingly, after further adjustment for classical vascular risk morbidity, these results remained statistically significant. However, a similar study in subjects with T1DM failed to identify significant reductions in hippocampal and amygdala volumes, although these subjects did present mild ventricular enlargement and slight global cerebral atrophy [START_REF] Vermeer | Incidence and risk factors of silent brain infarcts in the population-based Rotterdam Scan Study[END_REF].

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Population-based studies indicate that diabetes is a risk factor for silent and symptomatic brain infarcts seen with MRI [START_REF] Manschot | Brain magnetic resonance imaging correlates of impaired cognition in patients with type 2 diabetes[END_REF][START_REF] Gold | Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes[END_REF]. The presence of microvascular complications is associated with both reduced cognitive performance [START_REF] Ferguson | Cognitive ability and brain structure in type 1 diabetes: relation to microangiopathy and preceding severe hypoglycemia[END_REF] and accelerated cognitive decline [START_REF] Ryan | Cognitive efficiency declines over time in adults with type 1 diabetes: effects of micro-and macrovascular complications[END_REF]. In patients with T2DM, WMHLs and subcortical/ periventricular atrophy have been associated with reduced performance on tests of attention, executive function, information processing speed, and memory [START_REF] Akisaki | Cognitive dysfunction associates with white matter hyperintensities and subcortical atrophy on magnetic resonance imaging of the elderly diabetes mellitus Japanese elderly diabetes intervention trial (J-EDIT)[END_REF][START_REF] Musen | Effects of type 1 diabetes on gray matter density as measured by voxelbased morphometry[END_REF].

Diabetes severity and glycemic control may influence the degree of brain's lesion involvement. Some studies which have included elderly people in poor glycemic control found impairments in psychomotor efficiency and memory associated with WMHLs and subcortical brain atrophy [START_REF] Akisaki | Cognitive dysfunction associates with white matter hyperintensities and subcortical atrophy on magnetic resonance imaging of the elderly diabetes mellitus Japanese elderly diabetes intervention trial (J-EDIT)[END_REF]. Among well-controlled T2DM of less than 10 years duration, deficits on hippocampal-based memory performance and selective MRI atrophy of the hippocampus were found in comparison with age-matched controls.

[84]. Among these well-controlled individuals, HbA1c serum levels were inversely related to head-size adjusted hippocampal volumes. Higher HbA1c levels were also correlated with lower gray matter density in important areas for language, memory, and attention [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]. Higher HbA1c levels were also associated with reductions of gray matter in the right cuneus and precuneus regions, and reductions of white matter in the right posterior parietal region [START_REF] Wessels | Voxel-based morphometry demonstrates reduced grey matter density on brain MRI in patients with diabetic retinopathy[END_REF]. In addition, the occurrence of hypoglycemia in both T1DM and T2DM groups was correlated with increased cerebral atrophy in several cerebral regions, more specifically in certain areas of the frontal and temporal lobes, besides the thalamus [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][START_REF] Wessels | Voxel-based morphometry demonstrates reduced grey matter density on brain MRI in patients with diabetic retinopathy[END_REF][START_REF] Folstein | Mini-mental state: a practical method for grading the cognitive state for the clinician[END_REF].

Some other studies have been shown that the presence of peripheral diabetic complications is more associated with lesions of certain specific cerebral areas [START_REF] Musen | Effects of type 1 diabetes on gray matter density as measured by voxelbased morphometry[END_REF][START_REF] Wessels | Voxel-based morphometry demonstrates reduced grey matter density on brain MRI in patients with diabetic retinopathy[END_REF].

For example, T1DM patients with proliferative retinopathy had decreased gray matter density in the right inferior gyrus and right occipital lobe. They also presented

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significantly smaller white matter volume compared with those patients with diabetes but no retinopathy [START_REF] Wessels | Voxel-based morphometry demonstrates reduced grey matter density on brain MRI in patients with diabetic retinopathy[END_REF]. The occurrence of small, punctate, white-matter lesions is higher in patients with retinopathy than in those without it [START_REF] Ferguson | Cognitive ability and brain structure in type 1 diabetes: relation to microangiopathy and preceding severe hypoglycemia[END_REF].

Pre-diabetes and the Metabolic Syndrome (MetS)

Healthy individuals are able to maintain their plasma glucose levels constantly around 4-5mM and, when blood glucose rises following meals, the insulin secreted by the pancreas also rises to maintain normal glycemia [START_REF] Cole | Molecular connexions between dementia and diabetes[END_REF]. Insulin regulates the uptake of glucose by the tissues and it storage as glucogen. The major sites of insulin action are the liver, fat tissue, skeletal muscle and the brain, in special some regions with a high demand for glucose [START_REF] Cole | Molecular connexions between dementia and diabetes[END_REF]. When sensitivity to insulin is reduced on these tissues, this is termed Insulin Resistance (IR). The occurrence of IR combined with a pancreatic insufficiency to provide enough and prompt insulin secretion to maintain euglycemia is termed T2DM. The term 'pre-diabetes' is employed when, in the presence of IR, enough insulin is still produced to prevent overt diabetes, but it results in impaired fasting glucose and/or impaired glucose tolerance [START_REF] Cole | Molecular connexions between dementia and diabetes[END_REF][START_REF] Luchsinger | Hyperinsulinemia and risk of Alzheimer disease[END_REF][START_REF] Yaffe | Diabetes, impaired fasting glucose, and development of cognitive impairment in older women[END_REF].

In pre-diabetes, body tissues are exposed to abnormally high levels of insulin for extended periods, what may persist for many years/decades. Hyperinsulinemia seems to be implied in neurodegeneration and cognitive decline [START_REF] Luchsinger | Hyperinsulinemia and risk of Alzheimer disease[END_REF][START_REF] Yaffe | Diabetes, impaired fasting glucose, and development of cognitive impairment in older women[END_REF]. The hypothesis that diminished glucoregulatory control is related to decrements in cognitive performance is supported by studies which evaluated neuropsychological performance among prediabetic adults [START_REF] Yaffe | Diabetes, impaired fasting glucose, and development of cognitive impairment in older women[END_REF]. Impaired glucose tolerance and hyperinsulinemia were associated with reduced Mini Mental State Examination (MMSE) scores [START_REF] Folstein | Mini-mental state: a practical method for grading the cognitive state for the clinician[END_REF] and have also been linked to increased risk for mild cognitive impairment (MCI). Subjects with MCI are at

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increased risk for dementia. [START_REF] Yaffe | Diabetes, impaired fasting glucose, and development of cognitive impairment in older women[END_REF][START_REF] Kalmijn | Glucose intolerance, hyperinsulinaemia and cognitive function in a general population of elderly men[END_REF]. Interestingly, some studies have demonstrated that patients with impaired glucose tolerance may have the same pattern and severity of cognitive deficits as patients with T2DM [START_REF] Vanhanen | Risk for non-insulin-dependent diabetes in the normoglycaemic elderly is associated with impaired cognitive function[END_REF]. In another study, reduced glucose tolerance was associated with decreased general cognitive performance, memory deficits, and hippocampal atrophy on the MRI [START_REF] Convit | Reduced glucose tolerance is associated with poor memory performance and hippocampal atrophy among normal elderly[END_REF]. Multiple investigations on patients with impaired glucose tolerance have shown them to have lower MMSE and long-term memory scores [START_REF] Vanhanen | Laakso Cognitive function in an elderly population with persistent impaired glucose tolerance[END_REF], impaired verbal fluency [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], increased risk for Alzheimer's disease [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], and increased odds for vascular dementia [START_REF] Curb | Longitudinal association of vascular and Alzheimer's dementias, diabetes, and glucose tolerance[END_REF], as compared with control subjects. However, not all studies found that patients with pre-diabetes perform worse than normoglycemic individuals [START_REF] Fontbonne | Changes in cognitive abilities over a 4-year period are unfavorably affected in elderly diabetic subjects: results of the Epidemiology of Vascular Aging Study[END_REF][START_REF] Lindeman | A biethnic community survey of cognition in participants with type 2 diabetes, impaired glucose tolerance, and normal glucose tolerance: The New Mexico Elder Health Survey[END_REF][START_REF] Kumari | Diabetes and cognitive function in a middle-aged cohort: findings from the Whitehall II study[END_REF][START_REF] Scott | The association of non-insulin-dependent diabetes mellitus and cognitive function in an older cohort[END_REF].

Impaired glucose tolerance is one component of MetS, together with central obesity, hypertension, hypertriglyceridemia and reduced HDL-cholesterol. Each component of the MetS has been shown to be an independent risk factor for stroke, but hyperglycemia might be more important than the other components in the pathogenesis of both peripheral and central neuropathy [START_REF] Singleton | Therapy insight: neurological complications of pre-diabetes[END_REF]. Our group has recently evaluated 422 community-dwelling elderly (≥60) in Brazil, in order to investigate the association between cognitive impairment and the Frontal-Subcortical (Geriatric) Syndrome (FSCS), at one side, and MetS in the other side. FSCS, which is caused by ischemic disruption of the frontal-subcortical network, was defined as the presence of at least one frontal release sign (grasping, palmomental, snout, or glabellar) plus the coexistence of ≥3 the following criteria: (1) cognitive impairment, (2) late-onset depression, (3) neuromotor dysfunction, and (4) urgency incontinence. We found that MetS was significantly associated with FSCS (OR = 5.9; CI: 1.5-23.4) and cognitive impairment (OR = 2.2; CI: 1.1-4.6) among stroke-free subjects [START_REF] Roriz-Cruz | Cognitive impairment and the frontal-subcortical geriatric syndrome are associated with metabolic syndrome in a stroke-free population[END_REF].

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Obesity is associated with a significant reduction in insulin sensitivity, as insulin sensitivity inversely correlates with Body Mass Index (BMI) [START_REF] Ferrannini | on behalf of the European Group for the Study of Insulin Resistance (EGIR), Insulin resistance and hypersecretion in obesity[END_REF]. With the worldwide rapidly increasing prevalence of obesity, there is a corresponding increasing prevalence of insulin resistance and pre-diabetes [START_REF] Ferrannini | on behalf of the European Group for the Study of Insulin Resistance (EGIR), Insulin resistance and hypersecretion in obesity[END_REF][START_REF] Smith | Insulin resistance syndrome, prediabetes, and the prevention of type 2 diabetes mellitus[END_REF]. Fifty percent of adults have central obesity and the occurrence of central obesity in midlife increases the risk of dementia independent of diabetes and cardiovascular comorbidities [START_REF] Whitmer | Central obesity and increased risk of dementia more than three decades later[END_REF]. Generalized brain atrophy and regional alterations in gray matter volume occur in obese male subjects, suggesting that subjects with a high BMI are at greater risk for cognitive decline [START_REF] Taki | Relationship Between Body Mass Index and Gray Matter Volume in 1,428 Healthy Individuals[END_REF].

Pathophysiologic Mechanisms

Mechanisms underlying the development of nervous system lesions and cognitive dysfunction in patients with disturbances in the insulin homeostasis have not been completely elucidated. There are supporting evidence from many hypotheses in explain the pathophysiology of neurodegeneration associated with diabetes, prediabetes,

and MetS [START_REF] Ferrannini | on behalf of the European Group for the Study of Insulin Resistance (EGIR), Insulin resistance and hypersecretion in obesity[END_REF][START_REF] Smith | Insulin resistance syndrome, prediabetes, and the prevention of type 2 diabetes mellitus[END_REF]. The main hypotheses pointing to the potential implied mechanisms involves hyperglycemia, hypoglycemia, (micro)vascular disease, insulin resistance, and hyperinsulinism, all which are well-represented by the concept of MetS (Figure 1).

Besides, the MetS construct includes central obesity, hypertension, and dyslipidemia, all of which are related to hyperinsulinism [START_REF] Ferrannini | on behalf of the European Group for the Study of Insulin Resistance (EGIR), Insulin resistance and hypersecretion in obesity[END_REF]. The above three other components of MetS are not necessarily present in (pre)diabetes [START_REF] Ferrannini | on behalf of the European Group for the Study of Insulin Resistance (EGIR), Insulin resistance and hypersecretion in obesity[END_REF][START_REF] Smith | Insulin resistance syndrome, prediabetes, and the prevention of type 2 diabetes mellitus[END_REF], but are also important risk factors for cognitive dysfunction [START_REF] Roriz-Cruz | Cognitive impairment and the frontal-subcortical geriatric syndrome are associated with metabolic syndrome in a stroke-free population[END_REF]. The possibly involved mechanisms relating these other MetS components to cognitive dysfunction are not fully discussed in this review, but are also cited in Figure 1.

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Many cognitive dysfunctions associated with metabolic syndrome may have their common pathophysiologic mechanism unified by invoking the concept of the FSCS (22; see item 4, penultimate paragraph).

Hyperglycemia

Glucose is the main energy substrate of the human brain; however the occurrence of chronic hyperglycemia can be deleterious for the brain [START_REF] Magistretti | Cellular mechanisms of brain energy metabolism. Relevance to functional brain imaging and to neurodegenerative disorders[END_REF]. The brain, which constitutes only 2% of the human body weight, utilizes almost 25% of total body glucose [START_REF] Magistretti | Cellular mechanisms of brain energy metabolism. Relevance to functional brain imaging and to neurodegenerative disorders[END_REF]. The glucose metabolism is used not only for energy substrate but also the breakdown of glucose provides important compounds for neurons, including neurotransmitters such as acetylcholine and glutamate [START_REF] Schulingkamp | Insulin receptors and insulin action in the brain: Review and clinical implications[END_REF]. Several studies have

shown that hyperglycemia has toxic effects and can lead to slowly progressive functional and structural abnormalities in the brain [START_REF] Arvanitakis | Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function[END_REF]. Chronic hyperglycemia could, thus, be one of the determinants of cognitive decline in people with abnormal glucose metabolism [START_REF] Stewart | Type 2 diabetes mellitus, cognitive impairment and dementia[END_REF][START_REF] Strachan | Is type II diabetes associated with an increased risk of cognitive dysfunction? A critical review of published studies[END_REF].

The deleterious effects of hyperglycemia are mediated through an increased flux of glucose through the polyol and hexosamine pathways, disturbances of intracellular second messenger pathways, an imbalance in the generation and scavengers of ROS, and by AGEs [START_REF] Brownlee | Biochemistry and molecular cell biology of diabetic complications[END_REF]. Besides being directly implied in aging (last two processes), these phenomena also contributes to microvascular changes, what leads to microinfarcts and generalized brain atrophy/WMHL, which, in turn, result in cognitive decline and dementia [START_REF] Arvanitakis | Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function[END_REF][START_REF] Gold | Cognitive consequences of thalamic, basal ganglia, and deep white matter lacunes in brain aging and dementia[END_REF][START_REF] White | Cerebrovascular pathology and dementia in autopsied Honolulu-Asia Aging Study participants[END_REF]. Three mechanisms that mediate the toxic effects of hyperglycemia/hyperinsulinemia are responsible for the aging process of the brain, namely: (1) accumulation of AGEs; (2) increasing formation of ROS, with consequent

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increased oxidative stress; and (3) microvascular pathology [START_REF] Kodl | Cognitive Dysfunction and Diabetes Mellitus[END_REF][START_REF] White | Cerebrovascular pathology and dementia in autopsied Honolulu-Asia Aging Study participants[END_REF][START_REF] De La | Critically attained threshold of cerebral hypoperfusion: the CATCH hypothesis of Alzheimer's pathogenesis[END_REF]. Thus, these effects on cognition and brain structure might be responsible for the "accelerated brain aging" that occurs in subjects with diabetes [START_REF] Kodl | Cognitive Dysfunction and Diabetes Mellitus[END_REF][START_REF] Araki | MRI of the brain in diabetes mellitus[END_REF].

The finding of accelerated brain aging in DM is confirmed by experimental models in rats [START_REF] Kamal | Learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: interaction of diabetes and ageing[END_REF]. Alterations include neuroanatomical and neurochemical changes, impairments in stress reactivity and hypothalamic-pituitary-adrenal axis activity, as well as deficits in insulin signaling and neuroplasticity. Some studies have shown that RAGEs, galectin-3 (a proatherogenic molecule), and the polyol pathway activation were all increased in diabetic rat brains, whereas activity of the glycolytic enzyme glyceradehyde-3-phosphate dehydrogenase was decreased, indicating elevated superoxide levels [START_REF] Aragno | Up-regulation of advanced glycated products receptors in the brain of diabetic rats is prevented by antioxidant treatment[END_REF]. Neuronal apoptosis and suppression of cell proliferation/neurogenesis are observed in the hippocampus of diabetic rodents. Nuclear factor B transcription factors, a proinflammatory gene marker up-regulated by AGEs, and S-100 protein, a marker for brain injury that can bind to RAGEs, were both upregulated in the hippocampus of diabetic rats [START_REF] Kim | Treadmill exercise increases cell proliferation in dentate gyrus of rats with streptozotocininduced diabetes[END_REF][START_REF] Beauquis | Reduced hippocampal neurogenesis and number of hilar neurones in streptozotocin-induced diabetic mice: reversion by antidepressant treatment[END_REF][START_REF] Saravia | Hippocampal neuropathology of diabetes mellitus is relieved by estrogen treatment[END_REF][START_REF] Li | Hippocampal neuronal apoptosis in type 1 diabetes[END_REF]. These data suggest that insulin resistance, hyperinsulinism and hyperglycemia, causing accumulation of AGEs and ROS, may trigger a cascade of events that leads to neural aging and hippocampal atrophy, which may represent the initial neuronal damage in diabetes mellitus [START_REF] Magariños | Peritoneal implantation of microencapsulated porcine pancreatic islets in diabetic rats ameliorates severe hyperglycemia and prevents retraction and simplification of hippocampal dendrites[END_REF].

In addition, neurochemical changes have also been observed and may contribute to cognitive dysfunction. Insulin resistance impairs long-term potentiation, a fundamental mechanism for memory consolidation [START_REF] Kamal | Hippocampal synaptic plasticity in streptozotocin-diabetic rats: impairment of long-term potentiation and facilitation of long-term depression[END_REF]. Other, neurotransmitter functions which are altered in diabetes mellitus include decreased acetylcholine production [START_REF] Welsh | Effects of streptozotocin-induced diabetes on acetylcholine metabolism in rat brain[END_REF], decreased serotonin turnover, decreased dopamine activity, and increased norepinephrine [START_REF] Ramakrishnan | PKC-_mediated alterations of indoleamine contents in diabetic rat brain[END_REF][START_REF] Biessels | Water maze learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: effects of insulin treatment[END_REF].

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Hypoglycemia

A common and feared side effect of diabetes treatment is hypoglycemia. The risk of hypoglycemia is a barrier to achieving and maintaining optimal glycemic control. It is widely recognized that prolonged and severe hypoglycemia may leads to permanently brain damage, besides its immediate effects on the brain which acutely affects cognition, mood, and conscious level [START_REF] Mccall | The impact of diabetes on the CNS[END_REF][START_REF] Patrick | Fatal hypoglycaemia in insulintreated diabetes mellitus: clinical features and neuropathological changes[END_REF][START_REF] Auer | Hypoglycemic brain damage[END_REF]. What remains controversial is if repeated minor episodes of hypoglycemia may contribute to cognitive dysfunction [START_REF] Auer | Hypoglycemic brain damage[END_REF]. Hypoglycemia also exerts profound effects on various constituents of the blood and the vasculature. Although the effects are transient and unlikely to exert any longterm consequences on a healthy circulation, the potentially deleterious effects on a damaged vasculature should be considered. Recurrent exposure to hypoglycemia may exert an important adverse effect when the vasculature has already become compromised by macro-and microangiopathy [START_REF]The Diabetes Control and Complications Trial Research Group, The effect of intensive insulin treatment of diabetes on the development and progression of long term complications in insulin-dependent diabetes mellitus[END_REF].

In the presence of hypoglycemia, several responses occur within the brain, including activation of the central sympathetic nervous system, promoting physiological changes manifested as autonomic symptoms such as sweating, tremor, a pounding heart, hunger, and anxiety [START_REF] Cryer | Hypoglycaemia: the limiting factor in the glycaemic management of type 1 and type 2 diabetes[END_REF][START_REF] Mcaulay | Symptoms of hypoglycaemia in people with diabetes[END_REF]. Cognitive dysfunction is experienced subjectively in the form of neuroglycopenic symptoms, including difficulty in concentrating, drowsiness, and incoordination [START_REF] Mcaulay | Symptoms of hypoglycaemia in people with diabetes[END_REF]. Perception of these symptoms warns the patient, who prompt action is required to treat the hypoglycemia and restore blood glucose to normal levels.

Most cognitive modalities are impaired when blood glucose falls below 2.8 mMol/L.

Tests that require mental speed and that are complex or demand a high level of attention are affected most, while tests of simple motor function and reaction time are relatively preserved [START_REF] Deary | Effects of hypoglycaemia on cognitive function[END_REF].

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Recurrent severe hypoglycemia may occasionally cause sub-clinical cerebral injury or permanent cognitive impairment [START_REF] Warren | Hypoglycaemia and cognitive function[END_REF][START_REF] Deary | Symptoms of hypoglycaemia and effects on mental performance and emotions[END_REF]. In these cases, human autopsy studies have shown laminar, multifocal or diffuse necrosis and gliosis of the cerebral cortex and chromatolysis of ganglion cells [START_REF] Comi | Evoked potentials in diabetes mellitus[END_REF]. The regions more vulnerable to hypoglycemia include the cortex, basal ganglia, and hippocampus [START_REF] Patrick | Fatal hypoglycaemia in insulintreated diabetes mellitus: clinical features and neuropathological changes[END_REF]. In addition, there is a possible relationship between early nocturnal hypoglycemia during sleep (a time in which consolidation of memories occurs), and cognitive dysfunction [START_REF] Jauch-Chara | Hypoglycemia during sleep impairs consolidation of declarative memory in type 1 diabetic and healthy humans[END_REF].

Conversely, most studies have not shown neurocognitive deficits associated with nocturnal hypoglycemia induced later during the sleeping period [START_REF] Bendtson | Cognitive function in type 1 (insulindependent) diabetic patients after nocturnal hypoglycaemia[END_REF][START_REF] Matyka | Cognitive function and mood after profound nocturnal hypoglycaemia in prepubertal children with conventional insulin treatment for diabetes[END_REF].

Vascular disease

Diabetic patients have an increased risk of developing cerebrovascular disease, and many have established micro-and macrovascular complications of varying severity.

Cerebrovascular disease related to diabetes mellitus is more pronounced in the older age group. [START_REF] Allen | The relationship between type 2 diabetes and cognitive dysfunction: longitudinal studies and their methodological limitations[END_REF]. It is now well recognized from studies using both animal and human models that atherogenesis contains a significant inflammatory component, which contributes to its progression and to the subsequent emergence of thrombotic complications [START_REF] Wright | Vascular disease and diabetes: is hypoglycaemia an aggravating factor?[END_REF]. This has shifted the focus of research from an examination of traditional cardiovascular risk factors to the investigation of processes that involve the vasculature at a molecular level. These molecular processes preferentially affects cells that are directly implicated in atherogenesis, such as endothelial cells, macrophages, monocytes, platelets and smooth muscle cells [START_REF] Wright | Vascular disease and diabetes: is hypoglycaemia an aggravating factor?[END_REF].

Diabetes mellitus is an important risk factor for stroke and is also one of the most consistent predictors for recurrent stroke or for stroke after a Transient Ischemic Attach [START_REF] Hillen | Cause of stroke recurrence is multifactorial: patterns, risk factors, and outcomes of stroke recurrence in the South London Stroke Register[END_REF][START_REF] Johnston | A comparison of risk factors for recurrent TIA and stroke in patients diagnosed with TIA[END_REF]. This diabetes-related increased risk for recurrent stroke ranges from

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2.1 to 5.6 times the risk of nondiabetic patients [START_REF] Hankey | Long-term risk of first recurrent stroke in the Perth Community Stroke Study[END_REF][START_REF] Alter | Stroke in Lehigh Valley: risk factors for recurrent stroke[END_REF], and is independent of glucose control during the interstroke period [START_REF] Alter | Stroke recurrence in diabetics: does control of blood glucose reduce risk?[END_REF]. Diabetes and impaired glucose tolerance have been associated with increased Carotid Intima-Media Thickness (CIMT) [START_REF] Air | Diabetes, the metabolic syndrome, and ischemic stroke: : epidemiology and possible mechanisms[END_REF][START_REF] Brohall | Carotid artery intima-media thickness in patients with type 2 diabetes mellitus and impaired glucose tolerance: a systematic review[END_REF]. Diabetic patients who have a stroke have significantly greater CIMT than both diabetic subjects without stroke and nondiabetic patients [START_REF] Matsumoto | Correlation between common carotid arterial wall thickness and ischemic stroke in patients with type 2 diabetes mellitus[END_REF][START_REF] Chlumsky | Echocardiography and carotid sonography in diabetic patients after cerebrovascular attacks[END_REF]. Carotid Intima-Media Thickness is directly related to the duration of diabetes and glucose control, as evidenced by the Insulin Resistance Atherosclerosis Study [146].

Some studies have demonstrated the existence of a basal chronic systemic inflammatory state associated with endothelial dysfunction, platelet hyperactivity, and microvascular complications of retinopathy and nephropathy in diabetic patients [START_REF] Yngen | Enhanced P-selectin expression and increased soluble CD40 Ligand in patients with Type 1 diabetes mellitus and microangiopathy: evidence for platelet hyperactivity and chronic inflammation[END_REF][START_REF] Vestra | Acute-phasemarkers of inflammation and glomerular structure in patients with Type 2 diabete[END_REF][START_REF] Van Hecke | Inflammation and endothelial dysfunction are associated with retinopathy: the Hoorn Study[END_REF]. In the EURODIAB prospective complications study, inflammatory markers like C-reactive protein, interleukin-6 and tumor necrosis factor-α were found to be strongly and independently associated with vascular disease in people with T1DM [START_REF] Schram | EURODIAB Prospective Complications Study Group, Markers of inflammation are cross-sectionally associated with microvascular complications and cardiovascular disease in type 1 diabetes -the EURODIAB Prospective Complications Study[END_REF]. Even in the absence of vascular complications, surrogate markers of endothelial dysfunction, including C-reactive protein, vonWillebrand factor and vascular cell adhesion molecule-1 are elevated in T2DM patients [START_REF] Schalkwijk | Plasma concentration of C-reactive protein is increased in Type 1 diabetic patients without clinical macroangiopathy and correlates with markers of endothelial dysfunction: evidence for chronic inflammation[END_REF][START_REF] Targher | Increased plasma markers of inflammation and endothelial dysfunction and their association withmicrovascular complications in Type 1 diabetic patients without clinically manifest macroangiopathy[END_REF]. Moreover, plasma concentrations of the anti-inflammatory cytokine interleukin-10 are lower in people with type 2 diabetes [START_REF] Van Exel | Leiden 85 Plus Study, Low production capacity of interleukin-10 associates with the metabolic syndrome and Type 2 diabetes[END_REF].

Macrovascular and microvascular disease both cause significant morbidity and mortality in people with Diabetes mellitus. Thickening of capillary basement membranes, the hallmark of diabetic microangiopathy, has been found in the brains of patients with diabetes [154]. These patients have a 2-to 6-fold increased risk for thrombotic stroke. Vascular disease has long been hypothesized to contribute to abnormalities in cognition. [START_REF] Mccall | The impact of diabetes on the CNS[END_REF]. Macrovascular disease is not only more common, but is more aggressive and widespread in people with diabetes than in non-diabetic subjects

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ACCEPTED MANUSCRIPT [START_REF] Deckert | Prognosis of diabetics with diabetes onset before age 31[END_REF]. While this vascular outcome occurs both in T1DM and T2DM, its magnitude and severity is significantly greater in T2DM due to the co-existence of multiple cardiovascular risk factors, including hypertension and dyslipidaemia. Conversely, autopsy studies of patients with long-standing T1DM have shown important changes possibly related to microvascular disease, including diffuse brain degeneration, pseudocalcinosis, demyelination of cranial nerves and spinal cord, and nerve fibrosis [START_REF] Corrall | Increase in coagulation factor VIII activity in man following acute hypoglycaemia: mediation via an adrenergic mechanism[END_REF][START_REF] Ibbotson | The effect of insulininduced hypoglycaemia on Factor VIII: C concentrations and thrombin activity in subjects with type 1 (insulin-dependent) diabetes[END_REF].

Patients with DM have also been found to have decreased global rates of cerebral blood flow, which is correlated with disease duration. The association of ischemia and hyperglycemia may be more detrimental to the brain. Even modestly elevated blood glucose levels during a cerebrovascular event may contribute to greater infarcted areas [START_REF] Monnier | Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycaemia in patients with type 2 diabetes[END_REF]. Two possible mechanisms to explain the synergism between hyperglycemia and ischemia are lactate and glutamate accumulation. Hyperglycemia provides more substrate for lactate to form, worsening cellular acidosis, and providing accumulation of glutamate, which is also a strong neurotoxic neurotransmitor at very high concentrations [START_REF] Mccall | The impact of diabetes on the CNS[END_REF][START_REF] Li | Hyperglycemia enhances extracellular glutamate accumulation in rats subjected to forebrain ischemia[END_REF][START_REF] Coyle | Oxidative stress, glutamate, and neurodegenerative disorders[END_REF].

Diabetes mellitus is associated with a hypercoagulability state which is characterized by increased concentrations in anti-fibrinolytic and other procoagulant factors, as well as by alterations in Nitric Oxide (NO) metabolism. This hypercoagulability is associated with enhanced risk for thrombotic vascular events [START_REF] Romano | Association of inflammation markers with impaired insulin sensitivity and coagulative activation in obese healthy women[END_REF][START_REF] Ballantyne | Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident ischemic stroke in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study[END_REF][START_REF] Engstrom | Inflammation-sensitive plasma proteins, diabetes, and mortality and incidence of myocardial infarction and stroke: a population-based study[END_REF]. Plasminogen activator inhibitor-1 and antithrombin III, which inhibit fibrinolysis, as well as the tissue plasminogen activator antigen, a marker of impaired fibrinolysis, were consistently found to be elevated in IR phenotypes [START_REF] Aoki | Platelet-dependent thrombin generation in patients with diabetes mellitus: effects of glycemic control on coagulability in diabetes[END_REF][START_REF] Meigs | Hyperinsulinemia, hyperglycemia, and impaired hemostasis: the Framingham Offspring Study[END_REF][START_REF] Davi | Thrombin-antithrombin III complexes in type II diabetes mellitus[END_REF]. Some studies have further suggested that procoagulant factors, such as factor VII, factor VIII, and the von-Willebrand factor also rise with the degree of insulin resistance [START_REF] Romano | Association of inflammation markers with impaired insulin sensitivity and coagulative activation in obese healthy women[END_REF][START_REF] Mertens | Obesity, haemostasis and the fibrinolytic system[END_REF].

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Another important mechanism of diabetes hypercoagulability is platelet hyperreactivity.

Studies in diabetic patients have found an increased status for platelet aggregation, which is explained by increased platelet response to ADP and elevation of thromboxane A2 concentrations [START_REF] Mandal | Hyperaggregation of platelets detected by whole blood platelet aggregometry in newly diagnosed noninsulin-dependent diabetes mellitus[END_REF][START_REF] Tschoepe | Evidence for abnormal platelet glycoprotein expression in diabetes mellitus[END_REF]. This enhanced response to ADP may be mediated by the upregulation of GPIIb-III receptors and by the failure of insulin-induced inhibition of platelet aggregation that occurs in DM [START_REF] Halushka | Increased platelet thromboxane synthesis in diabetes mellitus[END_REF][START_REF] Trovati | Impaired insulin-induced platelet antiaggregating effect in obesity and in obese NIDDM patients[END_REF]. Patients with (pre)diabetes have also decreased endothelium-dependent vasodilatation; a consequence of either decreased NO production or impaired NO metabolism [START_REF] Hogikyan | Specific impairment of endothelium-dependent vasodilation in subjects with type 2 diabetes independent of obesity[END_REF][START_REF] Steinberg | Obesity/ insulin resistance is associated with endothelial dysfunction: implications for the syndrome of insulin resistance[END_REF][START_REF] Maejima | Increased basal levels of plasma nitric oxide in type 2 diabetic subjects: relationship to microvascular complications[END_REF].

Insulin resistance, tau hyperphosphorylation, and the amyloid cascade

Besides being a modulator of food intake and energy homoeostasis, insulin is, also an important neurothropic factor [START_REF] Gerozissis | Brain insulin and feeding: a bi-directional communication[END_REF][START_REF] Ling | Amyloid beta antagonizes insulin promoted secretion of the amyloid beta protein precursor[END_REF][START_REF] Farris | Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the betaamyloid precursor protein intracellular domain in vivo[END_REF][START_REF] Zhao | Role of insulin and insulin receptor in learning and memory[END_REF][START_REF] Banks | The source of cerebral insulin[END_REF][START_REF] Steen | Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease-is this type 3 diabetes?[END_REF]. It modulates brain activity, above all for such high glucose demanding functions such as memory. AD patients were found to have lower than normal CSF levels of insulin [START_REF] Steen | Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease-is this type 3 diabetes?[END_REF]. How can clinical hyperinsulinism be a risk factor for AD whereas lab experiments evidence insulin to be an important neurothrophic factor? These two apparent paradoxal findings may be reconciliated by evoking the concept of insulin resistance. Whereas insulin is clearly neurothrophic at moderate concentrations, too much insulin in the brain may be associated with reduced amyloid-β (Aβ) clearance due to competition for both principal depurative mechanisms -the Insulin-Degrading Enzyme (IDE) [START_REF] Farris | Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the betaamyloid precursor protein intracellular domain in vivo[END_REF]. Since IDE is much more selective for insulin than for Aβ, brain hyperinsulinism may deprive Aβ of its main clearance mechanism [START_REF] Farris | Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the betaamyloid precursor protein intracellular domain in vivo[END_REF].

Insulin crosses the blood-brain barrier, and might even be produced locally in the brain, exerting its effects on cells by binding to a specific cell surface receptor

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ACCEPTED MANUSCRIPT [START_REF] Banks | The source of cerebral insulin[END_REF][START_REF] Steen | Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease-is this type 3 diabetes?[END_REF]. Insulin receptors are distributed throughout the brain, being abundant in the hippocampus and the cortex [START_REF] Bondy | Signaling by insulin-like growth factor 1 in brain[END_REF]. Binding of insulin to its receptor activates the intrinsic tyrosine kinase activity of the cytoplasmic domain of the insulin receptor. This leads to autophosphorylation of tyrosine residues, what initiates several intracellular signaling cascades [START_REF] Kahn | The insulin receptor and the molecular mechanism of insulin action[END_REF][START_REF] White | The insulin signaling system[END_REF][START_REF] Withers | Perspective: the insulin signaling system-a common link in the pathogenesis of type 2 diabetes[END_REF]. In the brain, insulin influences the release and reuptake of neurotransmitters, and also appears to improve learning and memory [START_REF] Zhao | Insulin and the models of learning and memory[END_REF]. The initial components of the insulin receptor signaling cascade in the brain are largely similar to those of the periphery [START_REF] Zhao | Insulin and the models of learning and memory[END_REF][START_REF] Saltiel | Insulin signalling and the regulation of glucose and lipid metabolism[END_REF]. The downstream targets of the cascade are quite different, however, probably involving neuronal glutamate receptors, among others [START_REF] Zhao | Insulin and the models of learning and memory[END_REF].

Insulin receptor-mediated signal transduction controls the activity of several enzymes in a cascade-like manner. Phosphatidylinositol 3-kinase (PI3K) is insulinregulated and activates protein kinase B (PKB, also known as Akt) [START_REF] Alessi | Mechanism of activation and function of protein kinase B[END_REF][START_REF] Vanhaesebroeck | The PIK3K-PDK1 connection: more than just a road to PKB[END_REF]. PIP3 recruits PKB, to the plasma membrane, where it is phosphorylated and activated by specific protein kinases [START_REF] Lizcano | The insulin signalling pathway[END_REF]. PKB has many important cellular targets including glycogen synthase kinase 3 (GSK3). Phosphorylation of the N-terminal region of GSK3 by PKB causes inactivation of GSK3, reducing the phosphorylation of glycogen synthase (GS). Dephosphorylated GS is the active form of the enzyme. The active GS increases the rate of conversion of glucose 6-phosphate to glycogen. This pathway links the insulin receptor at the cell surface with enzymes of glycogen metabolism within the cell [START_REF] Cross | Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B[END_REF]. In this way, GSK3 generally opposes the actions of insulin. Thus, GSK3 inhibits glycogen synthesis, glucose uptake, and also alters the expression of genes regulated by insulin [START_REF] Skoog | Vascular aspects in Alzheimer's disease[END_REF].

Glycogen synthase kinase 3 is highly expressed in all eukaryotes cells and is involved in a number of physiological processes ranging from glycogen metabolism to

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gene transcription [START_REF] Woodgett | Molecular cloning and expression of glycogen synthase kinase-3/factor A[END_REF]. There are two isoforms of the enzyme that are ubiquitously expressed in mammals: GSK3α and GSK3β [START_REF] Woodgett | Molecular cloning and expression of glycogen synthase kinase-3/factor A[END_REF][START_REF] Hansen | Chromosomal mapping and mutational analysis of the coding region of the glycogen synthase kinase-3alpha and beta isoforms in patients with NIDDM[END_REF][START_REF] Shaw | Isolation and chromosomal mapping of human glycogen synthase kinase-3 alpha and -3 beta encoding genes[END_REF]. There is evidence that GSK3 plays a central role in AD, and that its deregulation accounts for many of the pathological hallmarks of the disease in both sporadic and familial AD cases, leading to formulation of the 'GSK3 hypothesis of AD' [START_REF] Hooper | The GSK3 hypothesis of Alzheimer's disease[END_REF]. Glycogen synthase kinase 3 is implicated in the hyperphosphorylation of tau, increased production of β-amyloid and in inflammatory responses. Glycogen synthase kinase 3 also reduces acetylcholine synthesis and is a key mediator of apoptosis. These findings are in accordance with alterations present in AD, including cholinergic deficit, memory impairment and neuronal loss [START_REF] Hoshi | Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase I/glycogen synthase kinase 3beta in brain[END_REF][START_REF] Turenne | Glycogen synthase kinase3 beta phosphorylates serine 33 of p53 and activates p53's transcriptional activity[END_REF].

There is increasing evidence linking insulin resistance to cognitive decline and dementia in diabetes [START_REF] Biessels | Ageing and diabetes: implications for brain function[END_REF][START_REF] De La Monte | Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer's disease[END_REF]. There are alterations in cerebral insulin receptor signaling, leading to a cerebral insulin resistant state. Alterations in brain's insulin and its receptor may disrupt glucose homoeostasis and affect amyloid metabolism. The formation of AGEs and ROS may play an important role in translating insulin resistance into amyloid deposition and tau phosphorylation [START_REF] Gasparini | Potential roles of insulin and IGF-1 in Alzheimer's disease[END_REF][START_REF] Craft | Insulin and neurodegenerative disease: shared and specific mechanisms[END_REF]. Indeed, cerebral insulin resistance has been implicated in accumulation of amyloid-β-peptide (Aβ) and tau protein, which are the main components of senile plaques and neurofibrillary tangles (NFTs), respectively. These two neuropatholical features are the pathological hallmark of Alzheimer's disease [START_REF] Gasparini | Potential roles of insulin and IGF-1 in Alzheimer's disease[END_REF][START_REF] Gasparini | Potential roles of insulin and IGF-1 in Alzheimer's disease[END_REF]. One hypothesis to explain the above relationships is that GSK3 activity might be enhanced in patients with insulin resistance, representing a possible link between insulin resistance and Alzheimer's disease [START_REF] Alvarez | Wnt-3a overcomes h-amyloid toxicity in rat hippocampal neurons[END_REF][START_REF] Atwood | Dramatic aggregation of Alzheimer Ah by Cu (II) is induced by conditions representing physiological acidosis[END_REF].

Several studies point to an intriguing relationship between diabetes mellitus and Alzheimer's disease. Patients with AD have lower Cerebrospinal fluid insulin levels and reduced insulin-mediated glucose disposal when compared to healthy control subjects

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ACCEPTED MANUSCRIPT [START_REF] Craft | Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease: relationship to severity of dementia and apolipoprotein E genotype[END_REF][START_REF] Craft | Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer's disease: interactions with apolipoprotein E genotype[END_REF]. While there is very little insulin mRNA in the brain, recent ultra-sensitive PCR data show that insulin message can be detected in postmortem human brain, being reduced in AD brains. This finding leaded the authors to suggest that Alzheimer's disease could be a ''type III diabetes'' due to a marked reduction in CNS insulin concentrations [START_REF] Steen | Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease-is this type 3 diabetes?[END_REF][START_REF] Rivera | Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer's disease: link to brain reductions in acetylcholine[END_REF]. In addition, knockout of the insulin receptor gene is not sufficient to cause cognitive deficits or neurodegeneration even though some regions show enhanced GSK3β activity. [START_REF] Schubert | Role for neuronal insulin resistance in neurodegenerative diseases[END_REF]. The observation that activation of the insulin receptor was impaired in brain autopsy samples of AD patients, has given rise to the notion that Alzheimer's disease could be qualified as "an insulin resistant brain state" [START_REF] Frolich | Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease[END_REF].

Another important link between insuin resistance and the amyloid cascade may be related to the IDE. Insulin degrading enzyme is a metalloprotease enzyme responsible for insulin degradation and is also the main enzyme responsible for Aβ degradation [START_REF] Farris | Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the betaamyloid precursor protein intracellular domain in vivo[END_REF]. Insulin degrading enzyme is secreted to the extracellular space by microglial cells in the brain, where it degrades Aβ peptide, leading to reduced Aβ peptide concentration in the brain, thus reducing aggregation and plaque formation. [START_REF] Qiu | Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation[END_REF]. Insulin degrading enzyme levels have been reported to be decreased in the brains of AD patients [START_REF] Perez | Prion peptide induces neuronal cell death through a pathway involving glycogen synthase kinase 3[END_REF][START_REF] Cook | Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon4 allele[END_REF], especially in the hippocampus [START_REF] Caccamo | Age-and regiondependent alterations in Abeta-degrading enzymes: implications for Abeta-induced disorders[END_REF]. It has also been hypothesized that hyperinsulinaemia in people with pre-diabetes and T2DM effectively sequesters IDE, reducing Aβ peptide degradation. This would increase levels of Aβ peptide, and promote many of the pathological features associated with Alzheimer's disease. Supporting this model, the affinity for the binding of insulin to IDE is much greater than the one for the Aβ peptide [START_REF] Qiu | Degradation of amyloid betaprotein by a metalloprotease secreted by microglia and other neural and non-neural cells[END_REF].

In patients with Alzheimer's disease, IDE expression in the hippocampus is substantially reduced, relative to controls, in particular among patients with the

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APOEε4. This latter observation could explain the potential interaction between diabetes and the APOEε4 genotype in multiplying the risk of dementia [START_REF] Cook | Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon4 allele[END_REF]. Curiously, although the presence of the APOEε4 is associated with an increased incidence of Alzheimer's disease [START_REF] Corder | Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families[END_REF], it seems that insulin resistance is only a significant risk factor for AD in those patients without APOEε4 [START_REF] Convit | Reduced glucose tolerance is associated with poor memory performance and hippocampal atrophy among normal elderly[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]. Subjects with AD without the APOEε4 had also improved memory scores in the setting of hyperinsulinemia, which was not the case for people with at least one APOEε4 allele [START_REF] Craft | Insulin metabolism in Alzheimer's disease differs according to apolipoprotein E genotype and gender[END_REF][START_REF] Craft | Insulin effects on glucose metabolism, memory, and plasma amyloid precursor protein in Alzheimer's disease differ according to apolipoprotein-E genotype[END_REF]. However, in the Honolulu-Asia Aging Study, those subjects with both T2DM and the APOEε4 allele had an additive increased risk of dementia and Alzheimer's pathology [START_REF] Peila | Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: the Honolulu-Asia aging study[END_REF]. In despite of this apparent contradiction, it seems that IR, T2DM and APOEε4 are distinct risk factors for the development of Alzheimer's disease, a hypothesis that is supported by the fact that those with diabetes had a lower prevalence of the APOEε4 [START_REF] Nielson | Apolipoprotein-E genotyping of diabetic dementia patients: is diabetes rare in Alzheimer's disease?[END_REF].

(Pre)Diabetes and non-age-related psychiatric diseases.

The relationship between pre-diabetes/diabetes mellitus and some non-age-related psychiatric diseases go beyond the scope of this review. We could not, however, let unmentioned that patients with mental illnesses such as schizophrenia, schizoaffective, and bipolar disorders have an increased prevalence of metabolic syndrome and diabetes mellitus -as compared with the general population [START_REF] Newcomer | Metabolic syndrome and mental illness[END_REF].

The high prevalence of metabolic syndrome in schizophrenic patients has assumed greater significance since the increasing use of second-generation antipsychotics. These drugs have been associated with substantial weight gain, a major risk factor for glucose metabolism abnormalities [START_REF] Taylor | Atypical antipsychotics and weight gain-a systematic review[END_REF]. Conversely, several studies [START_REF] Spelman | Impaired glucose tolerance in first-episode drug-naïve patients with schizophrenia[END_REF][START_REF] Cohn | Insulin resistance and adiponectin levels in drug-free patients with schizophrenia: a preliminary report[END_REF][START_REF] Venkatasubramanian | Insulin and insulin-like growth factor-1 abnormalities in antipsychoticnaive schizophrenia[END_REF] have been

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suggesting that schizophrenia is associated with abnormal glucose metabolism independently of antipsychotic use. In addition, some studies have suggested that firstdegree relatives of schizophrenic patients are at increased risk of diabetes [START_REF] Mukherjee | Family history of type 2 diabetes in schizophrenic patients[END_REF]. These findings suggest schizophrenia might also be associated with abnormalities in glucose metabolism, regardless of the use of antipsychotics [START_REF] Fernandez-Egea | Glucose abnormalities in the siblings of people with schizophrenia[END_REF].

Conclusions

The present review reinforces the view that diabetes is strongly associated with multiple alterations in the proper functioning of the brain. T1DM and T2DM. An important and common complication of both T1DM and T2DM is cognitive dysfunction. As expected, however, the specific alterations in cognitive abilities between the two types of diabetes do not completely overlap. In patients with T1DM, specific and global deficits evolving speed of information processing, psychomotor efficiency, attention, mental flexibility, and visual perception seem to be present, whereas in patients with T2DM, an increase in memory deficits, a reduction in psychomotor speed, and a reduced frontal lobe/executive function have been found.

Differences in methodology across studies, including inadequate sample sizes, difficulty in identifying valid control groups and differing test sensitivities, may account for the variability in these findings between the two main types of DM. Alternatively, hyperinsulinemia and comorbidities (MetS components) in T2DM, but not in T1DM, might be contributing to some of these differences.

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It is also important to consider the age of onset of the diabetes, the glycemic control status, and the presence of diabetic complications. The impact of diabetes on cognitive functions seems to be greater in older people with worse glycemic control and long duration of the disease.

Neuroimaging studies also highlighted several structural cerebral changes that occur Many studies have revealed that people with pre-diabetes also are at increased risk for developing adverse anatomical and functional brain changes. As a consequence, mild cognitive decline may develop even before of the installation of frank diabetes.

Neuropsychological profile of individuals with impaired glucose tolerance appears to

mimic what is typically observed in individuals with age-associated memory impairment. However, not all studies found that patients with pre-diabetes perform worse than normoglycemic individuals. Given that cognitive impairment is not invariably found in older diabetic patients, it is necessary to understand the factors that

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lead to cognitive impairment and the other ones that protect from DM-associated neurodegeneration.

The underlying neuropathologic changes associated with DM have been described

to be very similar to the ones usually associated with 'pure' aging. In fact, DM is probably strongly associated with an accelerated biological aging. Central neurological complications associated with DM include an increased risk for dementia of both vascular and Alzheimer's type. However, there are few detailed epidemiological studies considering specific vascular risk factors vis-à-vis the risk in developing Alzheimer's, Vascular, or mixed-type dementia. Studies involving large population-based cohorts of elderly people with pre-diabetes and DM, accessing the progress of (pre)diabetes, MetS, vascular disease, and cognition are necessary. Accelerated brain aging and disturbances of insulin metabolism in the brain may be additional factors that link DM to AD. This hypothesis should be tested in prospective studies that include measures of amyloid and tau-protein metabolism.

Perspectives

The establishment of a close relationship between insulin resistance and

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neurodegeneration, studies utilizing available drugs to improve insulin sensitivity, such as metformin and the thiazolidinediones [START_REF] Strachan | Insulin and cognitive function[END_REF]. However, there is as yet no evidence that they can decrease the risk of cognitive decline besides and beyond their hypoglycemiant effect [START_REF] Strachan | Insulin and cognitive function[END_REF]. New methods like the application of intranasal insulin, which is able to quickly pass through the blood-brain barrier, are also promising [START_REF] Reger | Intranasal insulin improves cognition and modulates beta-amyloid in early AD[END_REF], but results are still conflicting [START_REF] Reger | Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype[END_REF]. Therefore, more research is need before intranasal insulin and insulin sensitivity enhancers can be considered useful in preventing and treating cognitive dysfunction, be it in the presence or not of disturbances in the blood glucose homeostasis.

A

Psychomotor efficiency

Grooved Pegboard task; Response Inhibition task.

General intelligence

Verbal IQ score; Vocabulary and Block Design tasks.

See references 23 and 62 for details about the performance of diabetic subjects in each test, as compared to controls.

  in association with DM. Many populational studies have shown that DM is a risk factor for (silent) cerebral infarcts and is associated with a slight degree of cortical and subcortical atrophy. Most MRI studies revealed an association between DM and the occurrence of lacunar infarcts and WMHLs. In line with observations from studies of cognitive function in DM, findings from populational studies also indicate that poorer glycemic control is associated with accelerated cerebral atrophy. The degree of cortical atrophy encountered in DM subjects suggests that diabetes may also have global, nonvascular effects on the brain. Alternatively, small-vessel disease may contribute for this generalized brain atrophy frequently found in DM individuals. Several molecular and biochemical experiments in cellular and animal lab models also supports the hypothesis that mechanisms other than vascular disease are involved in the increased risk of AD in DM.

Alzheimer's disease

  could open a large vein for the development of novel preventive and therapeutic interventions for these conditions. One possible future direction that might arise in studying the molecular changes that occur in the brain in the presence of insulin resistance is the elucidation of the pathophysiology of the AD. Besides, the discovery of the most important link(s) between DM and AD would be of extreme importance. Assuming that insulin resistance is the main mechanism involved in A C C E P T E D M A N U S C R I P T

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Figure 1 .

 1 Figure 1. Key components of the Metabolic Syndrome (MetS) and their possible pathophysiological links with cognitive decline.

Table 1 .

 1 Summary of cognitive functions found to be affected in Type 1 (T1DM) and Type 2 Diabetes Mellitus (T2DM). -does not seem to be affected or evidence lacking. Note: domains marked by asterisks have particularly strong supporting data (see refs.23 and 62).

	Cognitive Functions	T1DM	T2DM
	Verbal Memory	↓	↓*
	Nonverbal Memory	↓	↓*
	Attention	↓*	↓
	Visuospatial Performance	↓*	_
	Processing Speed	↓*	↓*
	Executive Function	↓*	↓*
	Psychomotor efficiency	↓*	_
	General intelligence	↓	_
	↓: decreased;

Table 2 .

 2 Main types of cognitive tests utilized in the specific assessment of the diverse cognitive subfunctions cited in table 1. Processing Speed Reaction time measures; Digit Symbol Coding subtest of the WAIS-R; Trails A (Spreen & Strauss, 1991); Stroop tasks (color or word naming) (Spreen & Strauss, 1991).

	Cognitive Functions	Assessment
	Verbal Memory	Paragraph recall/Contextual tasks (immediate; delayed);
		Word List Recall/Noncontextual tasks; (immediate;
		delayed); Verbal recognition.
	Nonverbal Memory	Figural reproductions (immediate; delayed).
	Attention	Arithmetic performance (e.g., serial subtraction tasks);
		Digit Span subtest of the WAIS-R (Wechsler, 1981) and
		WAIS-III (Wechsler, 1997); Block Span (E. Kaplan et al.,
		1991).
	Visuospatial Performance Measures requiring construction and organization of
		objects or designs.
	Executive Function	Letter and category fluency measures; Abstract
		conceptualization measures; Measures of verbal and
		nonverbal reasoning abilities; Working memory tasks;
		Wisconsin Card Sorting (Berg, 1948); Trails B (Spreen &
		Strauss, 1991); Stroop (Interference trial); (Spreen &
		Strauss, 1991).

Acknowledgements

None.

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