Frontiers in Clinical Drug Research - Dementia E-Book
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- Kategorie: Wissenschaft und neue Technologien
- Serie: Frontiers in Clinical Drug Research - Dementia
- Sprache: Englisch
Among neurodegenerative diseases, those that lead to a state ofdementia are the aim of severalinvestigations. Dementia is a chronic disease the prevalence of whichis increasing worldwide. Thenumber of dementia patients in the world is approximately 50 million,and it is estimated that thenumber of patients will reach 131.5 million by 2050. This increase willbe accompanied by asignificant increase in medical expenditures and other expenses,especially for elderly patients.Therefore, the maintenance cost of dementia in the future is expectedto be quite high. For thisreason, several investigations aim, firstly, to describe the keymechanisms involved in the originof dementia and, secondly, to establish preventive and therapeuticstrategies in order tounderstand and mitigate this debilitating pathology. This volume of Frontiers in Clinical Drug Research -Dementia explores the current comorbidities that cause cognitiveimpairment and the current management alternatives for clinical cases ofdementia. The reviews contributed in these volume will provide readers with acurrent perspective on the subject. The topics covered in this volume include:- Comorbidities inducing mild cognitive impairment - an evaluation ofthe risk caused by some pathological conditions- Tau-targeted therapy in Alzheimer's disease - history and currentstate- Emerging nanotherapeutic strategies in Alzheimer's disease- Implication of dehydroepiandrosterone on dementia related tooxidative stress- Polyphenol compounds as potential therapeutic agents in Alzheimer’sdisease The volume is a timely update on dementia treatment for clinicalphysicians, neurologists, gerontologists, pharmaceutical and medicinal chemistryresearchers, and physiologists.
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Seitenzahl: 532
Veröffentlichungsjahr: 2006
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Preface
List of Contributors
Comorbidities Inducing Mild Cognitive Impairment, an Evaluation of the Risk Caused by some Pathological Conditions
Yolanda Cruz1,Alejandra Romo1,Roxana Rodríguez-Barrera1,Almudena Chávez-Guerra1,Macarena Fuentes1,Antonio Ibarra*,1Abstract
Mild cognitive impairment has usually been associated with aging, however, in recent decades with the increase in the prevalence of pathologies such as obesity, diabetes mellitus, cardiovascular diseases, and even spinal cord injury, it has become evident that a significant percentage of people who suffer from one or more of these diseases are at greater risk of suffering from some level of cognitive impairment that can lead to the development of various types of dementia. In this chapter, we review the main characteristics and mechanisms that promote the development of this type of alteration in each of the mentioned pathologies and briefly describe the various ways in which they have been approached.
INTRODUCTION
As life expectancy grows, so does the prevalence of neurodegenerative diseases. Mild cognitive impairment (MCI), with dementia as its most evident prognosis, has a profound impact on public health as well as on patient’s life quality. Nowadays, 48 million people worldwide have been diagnosed with dementia, a number that is expected to rise to 131 million by 2050, yet clear diagnosis guidelines and standards of care for patients who suffer this debilitating disease are left wanting [1].
Cognitive functions are neural processes that help us carry out a task; there are 6 main cognitive domains: learning and memory, social functioning, language, visuospatial function, complex attention and executive functioning [2].
Cognitive impairment refers to a deficit in at least one domain. The term MCI was first used to describe stage 3 of the global deterioration scale (GDS), in which the subject presents subtle deficits in cognition without meeting the criteria for dementia. In the Key Symposium at Sweden (2004), the definition expanded, it now includes the affectation not only in memory but in other cognitive domains, and MCI was sub-classified as: amnestic (aMCI), non-amnestic (naMCI), single and multi-domain. Amnestic subtype refers to the impairment in the ability to recall information; memory being affected. Non-amnestic refers to the impairment in at least one non-memory cognitive domain, whereas memory remains unaffected [2-4].
Amnestic MCI is associated with greater risk of developing dementia such as Alzheimer´s Disease (AD), whereas naMCI may progress to other syndromes such as frontotemporal dementia, primary progressive aphasia, dementia with Lewis bodies, among others. Multi-domain, as the name says so, refers to the impairment of multiple cognitive domains; therefore, patients manifest subtle problems in daily life activities. It might represent a more advanced stage of the neurodegenerative process [3, 5].
In 2011, the National Institute on Aging-Alzheimer´s Association included biochemical and neuroimaging biomarkers in the diagnostic criteria for MCI, as some of these biomarkers are seen in subjects with MCI, and may predict later conversion to AD. These risk factors include: apolipoprotein E (APOE) ε4 allele, lower β amyloid 1-42 (Aβ42), higher phosphorylated tau (P-tau), higher total tau (t-tau), amyloid PET, among others [4].
The prevalence of MCI is mainly reported in people older than 65 years old, and it is estimated to be between 3 to 22%, although currently it is underdiagnosed, as it is not usually recognized by primary care physicians; annually, 5 to 31% will progress to dementia [2, 6].
Cognitive impairment is diagnosed using the criteria established in the Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-V) [2]; it is diagnosed when there is a deterioration of one or more cognitive domains at a higher level than expected at given age and education level, confirmed in an objective manner by a professional, without impairing social nor work abilities [6]. Although, there are no specific tests to diagnose MCI as the differences between normal aging and MCI can be difficult to determine. Furthermore, cognitive impairment is different among patients, with some displaying a single non-memory domain and others involving multiple cognitive domains. Once diagnosed, some people develop further neurodegenerative disorders such as dementia and AD, while others remain stable or even revert to pre-existing cognition levels [7].
The rising numbers of MCI have generated a surge of research from both clinical and investigation perspectives, but while a rising number of older adults suffer from different stages of pre-dementia, most remain undiagnosed [8]. Most doctors diagnose subjects with MCI based on evidence and symptoms provided by the patients themselves while trying to use reliable tools and techniques as to discriminate against those who present normal and pathological signs of aging. Criteria for MCI diagnosis was developed by a workgroup sponsored by the National Institute on Aging and the Alzheimer’s Association, who agreed on the following common guidelines [9]:
A change in cognition recognized by the affected individual or observersExistence of objective impairment in one or more cognitive domains: memory, planning, following instructions or decision-making processes being hinderedIndependence in functional activitiesAbsence of dementiaCognitive impairment is mostly associated to aging, but there are other diseases that can lead to its development, such as obesity, diabetes, cardiovascular diseases such as systemic arterial hypertension (SAH) and ischemia, spinal cord injury (SCI), among others. Each of these diseases has different mechanisms that lead to cognitive impairment, but they also share some of them. This chapter will discuss the mechanisms involved in the development of cognitive impairment in different diseases.
OBESITY AND COGNITIVE IMPAIRMENT
Definition and Epidemiology of Obesity
Obesity has become a social and psychological problem that affects around 650 million adults and 340 million children and adolescents worldwide [10]. It is characterized by being a chronic disease of multifactorial origin, which is defined as the excessive accumulation of adipose tissue in the body linked to a high risk of presenting other diseases. The World Health Organization (WHO) uses body mass index (BMI) as a metric to indicate body fatness, classifying obesity as a BMI ≥ 30 kg/m2 [11].
The worldwide prevalence of obesity increased in around 80% from 1980 to 2015, turning it into a pandemic [11, 12].
In 2016, the WHO indicated that there were more than 1.9 billion adults aged 18 and over who were overweight, of which more than 650 million were obese. In the same year, 39% of adults aged 18 and over (39% of men and 40% of women) were overweight. Therefore, about 13% of the world's adult population (11% of men and 15% of women) were obese [13].
In Mexico, the National Health and Nutrition Survey (ENSANUT, as per its Spanish acronym) 2018th edition, estimated that at national level, the percentage of adults 20 years of age or older who are overweight or obese was 75.2% (39.1% overweight and 36.1% obese), a percentage that has increased by 3.9% since 2012 [14].
According to the Organization for Economic Cooperation and Development (OECD), in 2017, the mean prevalence of obesity in adults was 19.5%. United States and Mexico have the highest prevalence of obesity, with >30% [12].
Etiology
Obesity is mainly linked to energy imbalance, where the energy intake exceeds the energy expenditure, due to adoption of energy and fat-rich diets and physical inactivity. The excess energy is stored in the adipose tissue as triglycerides [11].
Although obesity is linked to a positive energy balance, it is a multifactorial disease that is also associated to genetics, physiological, psychological and social factors, thus classified as an endocrine, nutritional and metabolic disease [12].
Another etiological factor that has been associated with the development of obesity is the gut microbiota composition. Gut microbiota is composed of bacteria, fungi, virus and Archea. Among these, bacteria of the phyla Firmicutes and Bacteroidetes correspond to 90% of the gut bacteria; Firmicutes/Bacteroidetes ratio has been associated to obesity in different experimental studies, but is not completely confirmed in humans. A systemic review carried out by Crovesy L, et al., (2020) showed that individuals with obesity showed higher Firmicutes counts and lower Bacteroidetes counts in the majority of studies [15], this ratio tends to increase with BMI higher than 33 [16]. Proteobacteria have been found to be higher in obesity, whereas some butyric acid producing bacteria such as Faecalibacterium prausnitzii are lower, leading to dysbiosis. Gut dysbiosis can cause greater calorie absorption, reduction in anorexigenic hormones such as glucagon like peptide-1 (GLP-1), increase in fat storage and damaged gut barrier, which contributes to lipopolysaccharide translocation and inflammation [15].
Obesity affects nearly all physiological functions, and increases the risk for developing other diseases such as diabetes, cardiovascular disease and cognitive impairment, among others, affecting socioeconomic productivity [11]. Obesity is also associated with decreased life expectancy of around 5 to 20 years lost [12].
Physiopathology of Cognitive Impairment in Obesity
Obesity has now been linked to cognitive decline, as brain imaging has showed neural atrophy in obese individuals [17]. Inflammation is proposed to be the link between obesity and cognitive impairment [18].
The distribution of adipose tissue in different anatomical deposits also has substantial implications for morbidity. In particular, intra-abdominal and subcutaneous abdominal fat are more important than subcutaneous fat present in the lower extremities. The release of fatty acids into the portal circulation has adverse metabolic actions, especially in the liver. It is likely that the adipokines and cytokines secreted from adipocyte deposits are involved in the systemic complications of obesity [19].
The adipose tissue is an endocrine organ that releases hormones, chemokines and cytokines (refered to as adipokines) such as interleukin (IL) -6, tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein (MCP-1), adiponectin and leptin; these molecules help regulate energy homeostasis, innate immunity and inflammation. Under overnutrition and hyper-anabolic state, adipocytes expand in size (hyperplasia) and number (hypertrophy); adipocyte hypertrophy impairs adipose tissue function and lowers its capacity to store lipids, therefore they reach a threshold, which leads to a stress response in these cells, resulting in hypoxia and death of adipocytes, and initiating an inflammatory response [20-22].
Hypertrophic adipocytes release MCP-1, promoting macrophage accumulation [23]. The volume of adipose tissue is correlated with increased levels of TNF-α, IL-6 and IL-1β, as well as C-reactive protein (CRP); it is also associated with a local infiltration of inflammatory cells [22].
Adipocytes also contain immune cells; under normal energy balance, both cells coordinate to regulate the storage and mobilization of energy according to the organism’s needs. When overnutrition happens, macrophages greatly increase in number and change to M1 phenotype, secreting pro-inflammatory cytokines such as TNF-α and IL-1β [20]. M1 macrophages induce polarized Th1 responses [22].
As adipocytes increase in size and overpass their capacity to store fatty acids, these get released into the bloodstream as free fatty acids (FFA), which bind to toll like receptors (TLR) such as TLR4 and TLR2; this promotes activation of nuclear factor kappa B (NF-κB), which increases the secretion of pro-inflammatory cytokines, as well as infiltration of macrophages in adipocytes [20].
Obesity is thus associated with low-grade inflammation that spreads from peripheral tissue to the brain. The hippocampus and the cortex are particularly vulnerable to inflammation; these are regions involved in cognitive processing, learning and memory [18].
Obesity, and primarily high BMI and waist circumference, have been linked to cognitive impairment, even in children and adolescents, as it negatively affects brain function and structure. Higher BMI is related to impaired episodic and working memory tasks and verbal learning [17, 24]. As the adipose tissue increases, it releases various adipokines that lead to peripheral low-grade inflammation, as well as systemic insulin resistance; these have been linked to white matter atrophy and disruption of the blood brain barrier (BBB) [17, 25].
Inflammation in the hippocampus inhibits long-term potentiation (LTP) and impairs neurogenesis. It also promotes the production of beta-amyloid, increasing the risk of both cognitive impairment and AD [25].
Obesity also affects executive functions (inhibitions, cognitive flexibility, working memory, decision making, verbal fluency, planning, attention), probably via an activation of innate immunity and therefore low-grade inflammation; inhibition and working memory seem to be the most affected functions [26].
Attention is crucial for humans and is considered a core executive function, compromising multiple brain networks, including alerting, orienting and executive control networks; it can be divided into selective and sustained attention. Selective attention refers to processing parts of the sensory input while excluding others; sustained attention refers to maintaining sensitivity to incoming stimuli, which may also be referred to as “concentration” [27, 28].
Obesity has been shown to impair both forms of attention even before being born. Maternal BMI might be linked to attention deficit hyperactivity disorder (ADHD) as a result of increased inflammation, lipotoxicity and oxidative stress in the fetoplacental unit [29]. In a chronic inflammatory state, maintaining attention may require greater cognitive effort [30]. Maternal obesity is also associated with impaired serotonergic (5-HT) and dopaminergic signaling, which may also contribute to the development of ADHD, as 5-HT has a role in neuronal migration, cortical neurogenesis and synaptogenesis in fetal brain development [29].
Obesity also induces changes in brain structures, such as brainstream and diencephalon reduction, lower cortical thickness, decrease gray and white-matter volume and integrity, decline in neuron and myelin viability. All of these changes lead to cognitive impairment [31].
Besides low-grade inflammation, another mechanism linking obesity to cognitive impairment, is the disruption of brain homeostasis caused by endothelial dysfunction. Obesity is linked to changes in nitric oxide (NO), as it disrupts specialized receptors on endothelial cells that facilitate its release. This seems to impair neurovascular coupling, causing neurodegeneration; obesity also seems to deteriorate tight junction proteins Zonula occludens-1 (ZO-1) and claudin-12, breaking down the BBB [31].
On the other hand, obesity will not only affect the person’s cognition, but may also affect their offspring’s. Both animal and human studies have shown that obesity during pregnancy leads to systemic and placental inflammation, dysregulated metabolic and neuro-endocrine signaling and increase in oxidative stress; this is linked to altered offspring neurogenesis, myelination, and synaptic plasticity in hippocampus and hypothalamus, thus leading to the probable development of cognitive impairment [32].
A cohort study carried out by Monthé-Drèze C, et al (2019), showed that pre-pregnant obesity is associated with lower cognitive scores in areas such as fine motor, visual motor and visual spatial function that may be partially mediated by maternal obesity-related inflammation confirmed by higher CRP plasma levels. Although, there is also a socio-demographic factor that should be taken into account, as obese mothers had a lower socioeconomic status [32].
Obesity is also associated with an increase in intestinal permeability, leading to higher lipopolysaccharide (LPS) levels in blood, which may be an important inflammatory trigger [20]. Intestinal permeability may be associated to an alteration in the gut microbiota derives from a poor diet.
Diet and Low-Grade Inflammation
One of the main causes of obesity is high fat and carbohydrate intake, which has been linked to MCI with special emphasis on learning and memory, caused by neurobiological changes in the hippocampus, such as damage to glycoregulation, decreased levels of neurotrophins, neuroinflammation and structural integrity disorders of the BBB [33].
Cohort studies claim that consumption of saturated fatty acids (SFA) is related to MCI, affecting learning and prospective memory capacity [34, 35]. Although the effects of SFA's cannot be measured by BMI, they can be identified by testing for hypertension and/or metabolic syndrome that have a strong correlation with BMI [33].
The intake of simple carbohydrates is also closely related to MCI, since there is evidence that the consumption of foods with high glycemic index (GI) affects postprandial memory, both in patients with Type II diabetes (children and women of normal weight) and in non-diabetics [33, 36]. It has also been suggested that a high GI is a mediating factor for the effects of simple carbohydrates on learning and memory [37].
Dietary factors may also have a role in the development of low-grade inflammation [18]. The immoderate intake of food from the Western diet, aside from the increase of weight and height, generates important neurological and metabolic damage triggered by an inflammatory process. Central inflammation can induce a number of processes such as oxidative stress and neuronal apoptosis [24]. A study conducted in metabolically obese, but normal weight, rodents (MONW) fed a high fat isocaloric diet, with 60% of kcal from fat, found an increase in the expression of mRNA of inflammatory markers (TNF-α) and proapoptotic markers (Casp3) in the hippocampus, even in the absence of body weight gain [38]. Likewise, astrogliosis can be observed, being this a characteristic of damage in the Central Nervous System (CNS) and a sign of MCI [39]. Another indicator of an inflammatory process is the accumulation of mRNA expression of amyloid precursor protein (App) that indicates an Alzheimer-like pathology, increasing the probability of amyloid deposition and pro-inflammatory effects promoting a vicious cycle of neuronal dysfunction [38].
High-fat diets also increase the number of dendritic cells (DC) in adipose tissue; DC induce differentiation of pro-inflammatory Th17 cells and polarization of M1 cells, leading to a pro-inflammatory profile. They are also linked to insulin resistance via serine phosphorylation of insulin receptor substrate I (IRS1) by TNF-α [21, 40].
High-fat diets have also been linked to cognitive impairment, as they stimulate LPS receptor and TLR4 on immune cells, initiating an inflammatory cascade via NF-κB activation [24]. They also change the gut microbiota composition, leading to dysbiosis. It is now believed that dysbiosis may play a role in cognitive impairment through the “microbiota-gut-brain axis”, as it is also associated to systemic inflammation [18].
LPS administration to animals has shown to induce cognitive impairment. LPS induce microglial activation and neuronal cell loss in the hippocampus, as well as an increase in pro-inflammatory cytokines both in serum and in brain, probably via activation of cyclooxygenase-2 (COX-2) and NF-κB, which upregulate the expression of pro-inflammatory cytokines. LPS also reduces the expression of anti-inflammatory cytokines such as IL-4 and IL-10 [41].
Treatment
Currently, there are some promising experimental treatments or therapies for cognitive impairment, but none have proved to be completely efficient. Nutrition interventions addressed to glucose control and lowering inflammation show cognitive benefits [17], thus, some possible interventions include dietary approach (for example, Dietary Approaches to Stop Hypertension (DASH) [42] or Mediterranean dietary pattern) [17].
One of the greatest clinical trials that analyzes Mediterranean diet (MedDiet) is the PREDIMED (PREvención con DIeta MEDiterránea) conducted in Spain from 2005 to 2010. In a subsample of this study of 1055 subjects, MedDiet containing either fats from nuts or olive oil, improved global cognition compared to a low-fat diet [43].
MedDiet exerts anti-inflammatory effects; it also reduces gut dysbiosis and improves endothelial function by increasing serum NO and decreasing reactive oxygen species (ROS) production, thus it has been linked to protective effects against cognitive decline [31].
Among MedDiet characteristics associated with neuroprotection is the consumption of mono- and polyunsaturated fats (MUFA and PUFA, respectively), fiber and antioxidants, from fish, extra-virgin olive oil (EVOO), vegetables and fruits. These exert anti-inflammatory and antioxidant effects that seem to be associated with a preservation of both gray and white matter and reduction of cerebrovascular disease [44]. It also reduces vascular risk by improving lipid profile (lower LDL and higher HDL cholesterol levels), and lowering lipid oxidation products, probably due to consumption of rich sources of vitamin E and C [45]. Vitamin C decreases IL-6 and IL-8, thus exerting an anti-inflammatory effect [46].
MedDiet also contributes to cognitive health by lowering the glycemic load and advanced glycation end products (AGEs), related to oxidative stress and inflammation, and also to obesity [47].
Another dietary pattern that has been associated with neuroprotection is the Mediterranean-DASH intervention for neurodegenerative delay (MIND diet), which, as its name says, is a combination of MedDiet and DASH [46]. The MIND diet was actually developed to protect the brain against dementia; the key components of the diet are plant-based foods such are EVOO, berries, green leafy vegetables, beans and nuts, while limiting animal foods (it only includes high amounts of fish) [48].
One of the main components of both MedDiet and MIND diet that promotes cognitive health is EVOO; it contains phenolic compounds, such as oleuropein, that are better antioxidants than vitamin C or E, and can reduce NF-KB nuclear translocation and activation. MUFA in olive oil also has been associated with protection against cognitive impairment, as it prevents inflammasome activation [49].
In obese individuals, weight reduction may have a positive effect in cognition. Bariatric surgery has shown to improve memory and executive functions, and to reduce peripheral inflammation in some individuals [17, 18, 20].
Exercise can also improve cognition or prevent cognitive decline by different mechanisms. Aerobic and resistance training has shown to decrease TNF-α levels in obese subjects and in general can reduce pro-inflammatory mediators such as IL-18, C-reactive protein and IL-1, as well as increase anti-inflammatory markers such as IL-10, and in rodents it has shown to promote a phenotypic conversion of M1 to M2 microglia, promoting an anti-inflammatory state in the hippocampus [31, 50, 51].
Exercise also increases gut microbiome diversity. High intensity training (HIT) and running have shown to improve memory, perhaps, by improving cerebral microcirculation, but also by increasing lactate; lactate seems to be necessary for long-term memory formation, as its accumulation in the hippocampus increases BDNF expression [31, 50].
Acute exercise stimulates synthesis of BDNF, whereas regular exercise has a positive effect on hippocampal volume; aerobic capacity correlates with brain size [50, 52]. Some of these effects might be associated with myokines produced by the contracting muscles and by the electrical stimulation; some of the myokines involved in the muscle-brain cross-talk are cathepsin B and irisin, which can cross the BBB and induce BDNF expression in the hippocampus via the peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1alpha). Irisin has been shown to be reduced in patients with AD [50].
Another pathway in which exercise may improve cognition via BDNF is the regulation by PGC-1alpha. Exercise can induce epigenetic modifications which lead to a demethylation of this gene; PGC-1alpha contributes to raising BDNF levels. Contracting muscles also release BDNF, which can cross the BBB [52].
Exercise also improves redox status by enhancing antioxidant capacity in the brain and improving mitochondrial function [50].
Physical activity increases concentration of some neurotransmitters such as dopamine, which is involved in adaptive memory formation [52].
DIABETES MELLITUS AND MILD COGNITIVE IMPAIRMENT
Definition and Epidemiology of Diabetes Mellitus
Diabetes mellitus (DM) includes a set of etiologically and clinically heterogeneous metabolic disorders that share hyperglycemia as a common feature [53]. This disease has rapidly expanded, in the year 2000, the International Diabetes Federation (IDF) estimated around 151 million adults with diabetes worldwide, by 2019 the IDF rose that estimation to 463 million patients, the number tripled in a period shorter than 20 years [54].
The WHO estimates that without preventive measures against diabetes, by the year 2045 there will be 629 million people suffering from diabetes in the world [55], a slightly more optimistic estimate than that of the IDF who calculate 700 million people for the same year [54, 56-62].
People with DM are at risk of presenting several complications, especially if they are not properly cared for or if they have some comorbidity such as obesity, hypertension and / or vascular disorders, which can contribute to the development of retinopathy, renal failure, cerebrovascular accidents (stroke), some types of cancer and even cognitive impairment [56-65]. These alterations impact directly on the diabetic patient quality of life and their everyday activities as well as their autonomy and are cause of discomfort, pain and depression [66].
The economic impact of diabetes and its complications on families and governments is very high; just the average expenditure of people diagnosed with diabetes in 2017 in the US was $ 16,750, of which $9,600 were directly attributed to diabetes, which implies an expenditure 2.3 times greater than that of people without it [67]. The IDF calculated that in 2019 the total health expenditure for DM was 760 billion dollars worldwide and estimates that this will continue to increase in the next 25 years, with an expenditure as high as 845 billion dollars for the year 2045 [54]. Diabetes is undoubtedly a serious public health and economic problem.
Etiology and Physiology of Diabetes Mellitus
The etiology of diabetes is heterogeneous as it affects populations differently according to age, race, ethnicity, geography, environmental factors, and socioeconomic status [68].
Type I Diabetes Mellitus (TIDM)
Type I diabetes mellitus (TIDM), usually presents during childhood or youth, although a lower percentage occurs in adulthood, it is characterized by the autoimmune destruction of pancreatic β cells causing low or absent insulin production [69]; its development is attributed to genetic alterations, environmental factors and infections [70].
In TIDM, infiltration of macrophages, CD4 + and CD8 + T lymphocytes into the pancreatic islets [69, 71] has been observed, leading to the destruction of β cells. In addition, the production of antibodies that attack self-antigens expressed by these cells is induced, such as insulin (IAA, antibodies against insulin), glutamate decarboxylase (GAD65, antibodies against glutamic acid decarboxylase 65) [72], the transporter of zinc 8 (ZnT8A, zinc transporter 8 autoantibody) [72, 73] and tyrosine phosphatase (IA-2AA, autoantibodies against protein tyrosine phos- phatase antigens) [74]. Predisposition to produce these autoantibodies has been associated with HLA class II alleles, mainly from HLA-DR and HLA-DQ loci [75].
On the other hand, it is also considered that TIDM can be caused by dysregulation of suppressor T cells. In healthy individuals, T reg cells maintain immune tolerance and prevent autoimmunity development [76].
The role of Treg cells in TIDM remains unclear, several studies evaluating the amount of Treg cells with CD4 + CD25 + / FOXP3 markers (immunosuppressive phenotype) in patients with TIDM have observed that they decrease [77], others that they increase in peripheral blood [78, 79] and some did not observe differences in their animal models of diabetes at all [80]; there are also other authors that describe modifications in its function which contribute to the development of the disease [81-84], this last theory being the most explored.
Other factors such as vitamin D deficiency [85, 86], infections caused by enteroviruses [87, 88], alterations of the intestinal microbiota either due to the excessive use of antibiotics or a change in diet [89, 90] and the intake of some types of food in certain stages of childhood, have also been linked to the development of TIDM. Although the interlocking of the various factors involved
in the development of the disease is not clearly known, various research groups continue looking for answers.
Type II Diabetes Mellitus (TIIDM)
Type II diabetes mellitus (TIIDM) occurs in 90% of all people diagnosed with diabetes [56]. It is considered a heterogeneous, chronic, metabolic disease, characterized by hyperglycemia mainly due to the development of insulin resistance and defective secretion by the β cells of the pancreas [91].
TIIDM is a polygenic disease that has been associated with a large number of genetic variants, only Muhammad et al, in 2017 found 50 genes with altered expression that showed interaction with genes associated with the development of TIIDM: ZEB1, USP16, IL6ST, ASPH, Eif4g1, RBL2, MEF2A, vapB and SOS2, these genes that affect the β cells of the pancreas, are involved in the secretion of various cytokines, in pancreatic islet cells and in the peripheral uptake of glucose by the muscles [92].
Insulin is an anabolic hormone that regulates the metabolism of carbohydrates, lipids and proteins; it is also a growth factor that controls cell proliferation and differentiation [93]. It is released by the β cells of the pancreas in response to hyperglycemia, travels through the bloodstream and binds to its receptors which are widely distributed in muscle, adipose tissue, liver and brain [94]. When insulin binds to its receptor, it autophosphorylates and in turn phosphorylates and recruits adapter proteins such as insulin receptor substrate (IRS) 1 and 2 that mediate the activation of signaling pathways: RAS / MAPK and phosphatidylinositol 3-kinase (PI3K) [95].
The RAS / MAPK pathway has been linked to the stimulation of gene expression of proteins associated with cell growth and proliferation [96]; the PI3K / AKT pathway is responsible for metabolic regulation; through the inhibition of GSK-3 it stimulates the synthesis of glycogen; through the activation of different substrates by AKT, it stimulates the translocation of the glucose transporter GLUT-4 from the intracellular compartments to the cell membrane, allowing the incorporation of glucose into the cells and reducing its levels in the blood [97].
Insulin resistance refers to the decrease of the body’s biological effects at certain insulin levels in specific tissues and is related to obesity, hepatic steatosis and atherosclerosis [98], this may be due to mutation or loss of insulin receptors, failure or inhibition in some region of insulin signal transduction by the action of cytokines, leptin, adiponectin and others [99].
In obese individuals, hyperglycemia and hyperlipidemia are common, which in the pancreatic cells can cause toxicity (glucotoxicity and lipotoxicity) that in turn induces a greater release of insulin as a compensatory measure [100, 101], toxicity causes the production of inflammatory mediators and free radicals favoring pro-apoptotic signals that lead to the death of β cells [102].
In conditions of obesity, adipose tissue undergoes hypertrophy and hyperplasia [103] which induces changes in its metabolic functions and produces a large amount of inflammatory adipokines such as: IL-6, TNF-α, MCP-1 and resistin causing a local and systemic low-grade inflammatory state [104]; in addition to increasing the release of fatty acids and ceramides that favor lipotoxicity in the pancreas [101] and their accumulation in muscle tissue it alters insulin signaling in the AKT pathway, inhibiting GLUT-4 transport [105] which contributes to hyperglycemia.
Some proinflammatory cytokines have been directly involved in the development of insulin resistance. The TNF-α produced by adipocytes in atrophied state activates the transcriptional factor PIMT that modulates the expression of GLUT-4, so glucose transport is affected in skeletal muscle tissue [106]. IL-6 alters the activation of the PI3K / AKT pathway and glycogen synthesis through the down-regulation of miR-200 in hepatocytes [107]. The low glucose uptake caused by thriving resistance contributes to the atrophy of β cells and adipocytes, generating a vicious cycle that causes TIIDM.
The Role of Insulin in the Brain
Brain tissue has a huge number of insulin receptors, especially in the hypothalamus, hippocampus, olfactory bulb, cortex, cerebellum, and striatum [108, 109].
The insulin receptor has two isoforms, type B, present mainly in peripheral tissues (muscle, liver and adipose tissue) [110] and type A, which has been described mainly in neurons [111]. However, Spencer's team using RT-PCR / FISH (fluorescent in situ hybridization) assay techniques, observed that both isoforms are present in astrocytes, microglia and neurons [112]. Insulin, in addition to binding to its receptor with high affinity, can bind to insulin-like growth factor receptors type 1 and 2 (IGFR), although with lower affinity, regulating systemic metabolism [113].
Insulin is synthesized and released in the pancreas, although the type of transporters involved is not yet defined, it is known that it crosses the BBB through a saturable transporter system independent of insulin receptors [114]. Although Kuwabara et al (2011), have observed that certain neurons and neural progenitor cells possess the ability to synthesize it / insulin [115].
Cells that possess insulin receptors have the same proteins that participate in signal transduction pathways as in peripheral cells, and many of them have been found to play an important role in brain functions [116]; in addition to intervening in energy homeostasis accompanied by other hormones (anorexins and orexins) in hypothalamic regions that modulate appetite and satiety [117]. For example, Pearson-Lealy et al., (2016), show how GLUT-4 transporters also translocate to the plasmatic membrane after memory training and their selective inhibition affects their acquisition, although prolonged inhibition favors short-term memory and damages the long term memory [118].
Insulin participation in excitatory synaptic transmission and plasticity in the hippocampus has been described by Zhao et al., (2019), they demonstrated that insulin improves the function of NMDA receptors and participates in electrophysiological processes since it influences the induction and expression of LTP and LTD required in memory and learning mechanisms [119]. Soto et al (2019), also observed in the same brain structures that the presence of insulin receptors and IGFRs are essential for the formation of the GluA1 subunit of AMPA receptors (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor), which are important for LTP to take place, their lack in the hypothalamus and amygdala cause deficiencies in spatial memory, cognitive and mood disturbances [113]. These data confirm that glutamatergic neurotransmission plays an essential role in synaptic plasticity, also described by Fried et al,. (2019), who observed that deficiency of glutamatergic metabolites are associated with poor plasticity [56].
In the same sense, it has also been observed that insulin participates in improving the synaptic currents mediated by GABA (γ-aminobutyric acid) in the brain amygdala, having metabolic and mood implications [120]. This ability of insulin to regulate neurotransmission is also due to the increased availability of receptors at the synapse [119].
On the other hand, insulin is also considered a neurotrophic factor that alongside IGF-1, has a large number of receptors in the hypothalamus and in the amygdala and participates directly in the regulation of neurogenesis [121].
Diabetes and Mild Cognitive Impairment
In recent years, the increase in the prevalence and incidence of TIIDM made evident that patients who acquire this disease are at greater risk of developing cognitive impairment and even dementia [122].
Cognitive alterations in people with DM are determined by various factors, such as; depression [123], low-density lipoprotein cholesterol levels (LDL-C) [124, 125], BMI, lack of physical activity [126], among others. But the two most important are: 1) time to onset of DM; 2) and uncontrolled glucose fluctuations [127]. In a cohort study with 5,653 participants, Tuligenga's team (2014) showed that middle-aged people (54 years) with known diabetes showed during the lapse of ten years a 45% decrease in memory, 29% in reasoning, and 24% decrease in global cognitive function; these data were associated with poor glycemic control [128]. Very similar results were found in the investigation by Xiu et al (2019), who mentioned that 58.6% of the patients studied with DM who passed 50 years had MCI [126]. In both cases it is mentioned that MCI is linked to the duration of diabetes.
Several investigations have evaluated the subtypes of MCI presented by patients with DM based on the Petersen classification [129], identifying that this class of patient can develop both amnestic MCI (memory disorders) and non-amnestic (impairment of some type of cognitive domain) [130], which means that patients present memory impairment, reduced attention span (visual and auditory) and information processing, resulting in impaired executive function [131, 132]; this type of cognitive function is essential for the performance of habitual activities since it includes behavioral organization and cognitive flexibility, necessary for solving problems [123, 133].
The diagnosis of MCI in people with DM is usually made by applying cognitive screening tools, such as Mini-mental State Examination (MMSE) and Montreal Cognitive Assessment (MOCA) to evaluate the cognitive function. In many cases, neuroimaging techniques are used to confirm the diagnosis or track the neuroanatomical changes that the brain undergoes over time or to understand how clinical changes are related to structural ones.
With the intention of understanding whether patients with DM have brain structural changes that can induce MCI, Moran et al (2019), used magnetic resonance imaging and observed that these patients have a lower baseline cortical thickness which they moderately related to presence of DM [134], showing that DM could contribute to neurodegeneration.
On the other hand, Groeneveld's team (2018) observed that the volume of gray matter is lower in the right temporal lobe and subcortical brain regions in patients with DM. The observed atrophy was present mainly in areas of vascular lesions usually caused by DM. Likewise; they noted that neural connectivity and volume of white matter is also reduced in patients with MCI [135]. Similarly, these structural changes in white matter were observed by Tan et al (2016), who, identified the most affected structural tracts – right cingulate, part of the frontal lobe and parietal lobes, and some thalamic regions– structures similar to those observed in people with AD disease [136].
Damage to the integrity of white matter is associated with cognitive alterations in patients with DM. Gao et al (2019), observed that lesions of the lower right frontal-occipital tract and the lower right longitudinal tract correlate with disturbances in attention and episodic memory, conditions commonly observed in patients with MCI [137].
The mechanisms that trigger this type of cognitive and structural alterations in the brain of people with DM remain unclear, but it has been observed that insulin resistance, alterations in insulin receptors, high glucose levels, mitochondrial dysfunction and inflammation play an important role in MCI.
The continuous increase in insulin and glucose in the brain causes hyperactivation of insulin signaling, which induces cells to lose sensitivity and modify their responses. It has also been reported that there is a decrease in the amount of insulin receptors [116] that can affect the synaptogenesis in the hypothalamus and amygdala, which directly affects neuroplasticity [113]. Liu et al,. (2015), also observed that the synaptic strength of LTP is altered, causing a decrease in synaptic connection forces, essential parameters for memory and learning [138]. At the same time, the incorporation of lipids such as ceramides and inflammatory molecules interfere with proper insulin signaling [139].
In a murine model of insulin resistance, it was observed that a high-fat diet causes the inactivation of IRS1 -adapter proteins that mediate insulin signaling pathways- causing a decrease in the translocation of GLUT-3 and GLUT-4 at cell membranes of neurons and the suppression of the ERK / CREB pathway, essential pathways for the acquisition of memory and learning [138]. Hyperglycemia has also been shown to affect the AMPK / AKT signaling pathway that contributes to insulin resistance and mitochondrial dysfunction in vitro [140].
The reduction in PI3K / AKT signaling during insulin resistance causes a greater activation of the enzyme glycogen synthase kinase (GSK-3β) that hyperphosphorylates the tau protein —abundantly found in the CNS— which causes their improper folding, forming fibrils [141]. These formations are directly associated with the development of Alzheimer's, and there is increasing evidence that links metabolic alterations with the development of this dementia [142].
Mitochondrial dysfunction is also caused by alterations in the PI3K / AKT signaling pathway, since it regulates the metabolic function of the mitochondria,
when it’s damaged, the mitochondria releases a large amount of free radicals that contribute to the activation of inflammation [143].
The increase in peripheral inflammatory cytokines has also been linked to the presence and development of MCI, mainly IL-6, TNF-α [144] and galactin [145]. TNF-α has been linked to the interruption of glucose transport and to the dysfunction of the BBB facilitating the infiltration of leukocytes [146], mainly granulocytes, in addition to hyperglycemic conditions and a lipid rich diet, it has been observed that there is an increase in the expression of microglia and active astrocytes in the hippocampus [147]. Microglia in the presence of free radicals and TNF-α acquires an inflammatory phenotype by inducing the activation of the enzyme nitric oxide synthase, which produces nitric oxide and generates a neurotoxic environment.
DM also affects neurogenesis through the reduction of BDNF [99] and the transcription factor Neuro D1 present in hippocampal stem cells [148], in both cases due to insulin receptors reduction on hippocampal cells. An investigation carried out by Bonds et al,. (2020), demonstrate that in a DM model, neurogenesis is reduced in the subgranular zone of the hippocampus, which implies a smaller number of new neurons that will migrate to the dentate gyrus, which can lead to its dysfunction and cognitive deficits [149].
All these alterations intervene in the gestation and development of MCI, the shape in which all these changes are articulated is not precisely known, their understanding will provide an opportunity to propose therapeutic alternatives that prevent its development.
Therapeutic Alternatives
One of the main factors associated with MCI is hyperglycemia, which is why several investigations propose drugs with a hypoglycemic and neuroprotective nature, we will describe the most important ones.
Metformin: activates AMPK signaling that is affected by insulin resistance and inhibits the activity of NAD (P) H oxidase, one of the enzymes that produces the freest radicals during mitochondrial dysfunction. In this way, the reduction in the amount of ROS reduces inflammation and cell death [150]. It affects TNF-α of different cell types, which decreases the secretion of pro-inflammatory cytokines.
Lithium: there is evidence on the neurotrophic and protective properties of this element, although it has been tested in a very small number of intervention trials. Epidemiological and imaging studies show that it is associated with lower rates of dementia and beneficial brain responses, with higher density of gray matter and greater metabolic integrity of brain tissue [151].
Lycopene: it is a phytochemical that belongs to the carotenoid family, it has antioxidant and anti-inflammatory properties, it has been tested in some models of dementia but there is a lack of evidence to determine its effect more strongly [152]. In a study by Yin et al,. (2014), they observed a neuroprotective effect in the treatment of damage caused by insulin resistance [153].
Insulin: since there is a decrease in the synthesis of insulin and in the amount of receptors mainly in the hippocampus, the insulin treatment is the one that has been most evaluated, it has improved the memory and cognition in rats in a model of Parkinson's disease [57]. It is also known that insulin activates the ERK and PI3K signaling cascade, which intervene in multiple functions such as cell growth, proliferative, survival, in protein and lipid synthesis, synaptogenesis and apoptosis. Bayunova et al,. (2018), also observed that it has neuroprotective effects on neurons of the cerebral cortex exposed to oxidative stress conditions in an in vitro study [154].
Given the great increase in the prevalence of DM and the risk of these people suffering from MCI, it determines the wide importance and urgency that exists to elucidate in greater detail how the mechanisms that generate it are unleashed and with it, to be able to propose effective therapeutic alternatives that allow improving the patients quality of life.
COGNITIVE IMPAIRMENT CAUSED BY VASCULAR ALTERATIONS
Epidemiology of Cardiovascular Diseases
Cardiovascular diseases (CVD) are a set of disorders of the heart and blood vessels [155]; they are the biggest cause of disability and premature deaths worldwide, only in 2017, 17.8 million cases were reported. In recent years, the number of persons affected by CVD has risen, according to the American Heart Association (AHA) net prevalence is 485.6 million, 28.5% more than in 2007 [156].
Among the whole set of CVD (peripheral vascular disease, ischemic heart disease, rheumatic, congenital, myocardiopathy, arterial hypertension and stroke), ischemic heart disease and stroke are the most frequent [157]. In 2016, in the United States, 43.2% of all deaths caused by CVD were due to ischemic heart disease, while 16.9% were caused by stroke and 9.8% by hypertension [158]. Regarding the causes of disability, both ischemic and hemorrhagic stroke account
for the larger rate of disability-adjusted life years (DALY), rising from 40 years of age and peaking at 5 DALY in the 74-79 years old group [157].
The AHA 2020 report mentions that, in the United States, direct and indirect costs derived from disability during the 2014-2015 period were $351.2 billion and it is estimated that for 2035 it will reach $749 billion, considering hospital expenses, medication, home care, etc., [156]. Because of the alarmingly high impact on deaths, disability and costs, governments have been working on strategies to ameliorate their population risk of CVD.
Some of the risk factors for developing CVD are: diabetes, hypertension, atherosclerosis, obesity, dyslipidemia, insulin resistance and smoking [158]. These risk factors are associated with well-known lifestyles and habits like diet, education level, physical activity and smoking habits, which can be modified. Which is why the WHO urges governments to promote campaigns that emphasize the benefits of having a healthy weight, increasing physical activity, quit smoking and having blood glucose and lipids checked periodically [159].
ETIOLOGY AND PHYSIOPATHOLOGY OF VASCULAR LESIONS
Atherosclerotic Plaque Formation
Ischemic heart disease and stroke are diseases with their origin in partial or complete disorders of the blood supply either to the brain (ischemic stroke) or heart (ischemic heart disease). The main cause of blood flow obstruction is atherosclerosis formation [160].
Atherosclerosis consists of atheroma plaque formation in medium and large size arteries intima, this plaque is formed mostly by a mixture of different lipids, smooth muscle cells, extracellular matrix, calcium (Ca2+) and immune cells [161]. Formation of this plaques is attributed to hyperlipidemia which is usually present in patients with obesity, insulin resistance and diabetes. High levels of LDL, vLDL (very low density lipids) and triglycerides accompanied with low HDL (high density lipoprotein) levels have also been linked to its development [162].
Plasmatic lipoproteins contain several types of apolipoproteins in its surface, the ones containing ApoB (LDL and vLDL) penetrate the superficial layer of the endotelial intima that covers the inside of the inner surface of the blood vessels, particularly those arranged in arterial branch bifurcations or high shearing degree zones [162].
