Metabolic Syndrome Abstracts 1 – Alzheimer’s Disease

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Metabolic syndrome over 10 years and cognitive functioning in late midlife: the Whitehall II study
            (Akbaraly et al., 2010) Download
OBJECTIVE: Evidence that the metabolic syndrome is a risk factor for poor cognition is mixed and is focused mainly on the elderly population; rarely is an adjustment made for socioeconomic factors. We examined this association in late midlife, with particular focus on cumulative effects and the role of socioeconomic circumstances. RESEARCH DESIGN AND METHODS: Analyses were performed for 4,150 white participants from the Whitehall II study. Metabolic syndrome, using the National Cholesterol Education Program Adult Treatment Panel III criteria, was assessed three times over the 10-year follow-up (1991-2001). Cognitive function was assessed using a battery of six tests at the end of the follow-up. RESULTS: After adjustment for demographic variables, health behaviors, and health status, participants with persistent metabolic syndrome (at least two of the three screenings) over the 10-year follow-up had lower cognitive performance than participants who never had metabolic syndrome. No significant differences in cognitive function were observed between participants with nonpersistent metabolic syndrome (one of the three screenings) and those who never had metabolic syndrome during the follow-up. Adjustment for adult occupational position attenuated this association by between 41 and 86%, depending on the measure of cognitive function. Adjustment for education had little effect. CONCLUSIONS: Only persistent metabolic syndrome was associated with lower cognitive performance in late midlife. Adult occupational position but not education had a substantial impact on this association; these results highlight the importance of adult socioeconomic circumstances in identifying and targeting risk factors for cognitive aging.

Estrogen regulation of glucose metabolism and mitochondrial function: therapeutic implications for prevention of Alzheimer's disease
            (Brinton, 2008) Download
Estrogen-induced signaling pathways in hippocampal and cortical neurons converge upon the mitochondria to enhance mitochondrial function and to sustain aerobic glycolysis and citric acid cycle-driven oxidative phosphorylation and ATP generation. Data derived from experimental and clinical paradigms investigating estrogen intervention in healthy systems and prior to neurodegenerative insult indicate enhanced neural defense and survival through maintenance of calcium homeostasis, enhanced glycolysis coupled to the citric acid cycle (aerobic glycolysis), sustained and enhanced mitochondrial function, protection against free radical damage, efficient cholesterol trafficking and beta amyloid clearance. The convergence of E(2) mechanisms of action onto mitochondrial is also a potential point of vulnerability when activated in a degenerating neural system and could exacerbate the degenerative processes through increased load on dysregulated calcium homeostasis. The data indicate that as the continuum of neurological health progresses from healthy to unhealthy so too do the benefits of estrogen or hormone therapy. If neurons are healthy at the time of estrogen exposure, their response to estrogen is beneficial for both neuronal survival and neurological function. In contrast, if neurological health is compromised, estrogen exposure over time exacerbates neurological demise. The healthy cell bias of estrogen action hypothesis provides a lens through which to assess the disparities in outcomes across the basic to clinical domains of scientific inquiry and on which to predict future applications of estrogen and hormone therapeutic interventions sustain neurological health and to prevent age-associated neurodegenerative diseases such as Alzheimer's. Overall, E(2) promotes the energetic capacity of brain mitochondria by maximizing aerobic glycolysis (oxidative phosphorylation coupled to pyruvate metabolism). The enhanced aerobic glycolysis in the aging brain would be predicted to prevent conversion of the brain to using alternative sources of fuel such as the ketone body pathway characteristic of Alzheimer's.

Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers
            (De Felice et al., 2009) Download
Synapse deterioration underlying severe memory loss in early Alzheimer's disease (AD) is thought to be caused by soluble amyloid beta (Abeta) oligomers. Mechanistically, soluble Abeta oligomers, also referred to as Abeta-derived diffusible ligands (ADDLs), act as highly specific pathogenic ligands, binding to sites localized at particular synapses. This binding triggers oxidative stress, loss of synaptic spines, and ectopic redistribution of receptors critical to plasticity and memory. We report here the existence of a protective mechanism that naturally shields synapses against ADDL-induced deterioration. Synapse pathology was investigated in mature cultures of hippocampal neurons. Before spine loss, ADDLs caused major downregulation of plasma membrane insulin receptors (IRs), via a mechanism sensitive to calcium calmodulin-dependent kinase II (CaMKII) and casein kinase II (CK2) inhibition. Most significantly, this loss of surface IRs, and ADDL-induced oxidative stress and synaptic spine deterioration, could be completely prevented by insulin. At submaximal insulin doses, protection was potentiated by rosiglitazone, an insulin-sensitizing drug used to treat type 2 diabetes. The mechanism of insulin protection entailed a marked reduction in pathogenic ADDL binding. Surprisingly, insulin failed to block ADDL binding when IR tyrosine kinase activity was inhibited; in fact, a significant increase in binding was caused by IR inhibition. The protective role of insulin thus derives from IR signaling-dependent downregulation of ADDL binding sites rather than ligand competition. The finding that synapse vulnerability to ADDLs can be mitigated by insulin suggests that bolstering brain insulin signaling, which can decline with aging and diabetes, could have significant potential to slow or deter AD pathogenesis.

Alzheimer's disease is type 3 diabetes
         De La Monte 2008, Download

Contribution of metabolic syndrome components to cognition in older individuals
            (Dik et al., 2007) Download
OBJECTIVE: Recent evidence suggests that the metabolic syndrome and inflammation affect cognitive decline in old age and that they reinforce each other. However, it is not known what the roles of the individual components of the metabolic syndrome on cognition are. RESEARCH DESIGN AND METHODS: The sample consisted of 1,183 participants in the Longitudinal Aging Study Amsterdam who were aged 65-88 years. Metabolic syndrome (U.S. National Cholesterol Education Program definition) and its individual components and the inflammatory markers C-reactive protein (CRP) and alpha1-antichymotrypsin (ACT) were assessed. Cognitive assessments included general cognition (Mini-Mental State Examination), memory (verbal learning test), fluid intelligence (Raven's Matrices), and information processing speed (coding task). RESULTS: Of the sample, 36.3% had metabolic syndrome. Metabolic syndrome was significantly associated with all cognitive measures (P < 0.05). Of the individual components, hyperglycemia was most strongly and significantly associated with cognitive function (multivariate adjusted models; B values, indicating differences in scores between both groups, ranging from -0.38 to -1.21). There was a significant interaction between metabolic syndrome and inflammation on cognition (P < 0.01-0.09). Metabolic syndrome was negatively associated with cognition in subjects with high inflammation (highest tertile for both CRP and ACT; B values ranging from -0.86 to -1.94, P < 0.05), whereas an association was absent in subjects with low inflammation (B values ranging from -0.10 to -0.70). CONCLUSIONS: Subjects with metabolic syndrome showed poorer cognitive performance than subjects without metabolic syndrome, especially those with high levels of inflammation. Hyperglycemia was the main contributor of the association of metabolic syndrome with cognition.


Is insulin resistant brain state a central feature of the metabolic-cognitive syndrome?
            (Frisardi et al., 2010a) Download
Cumulative evidence suggests that metabolic syndrome (MetS) may be important in the development of mild cognitive impairment, vascular dementia, and Alzheimer's disease (AD). As such, these patients might be described as having "metabolic-cognitive syndrome"--MetS plus cognitive impairment of degenerative or vascular origin. While peripheral insulin resistance appears to be of primary pathophysiological importance in MetS, the definitions of MetS and its components do not include any reference to insulin resistance or hyperinsulinemia. In the present article, we discuss the role of these factors in the development of cognitive decline and dementia, including underlying mechanisms that influence amyloid-beta (Abeta) peptide metabolism and tau protein hyperphosphorylation, the principal neuropathological hallmarks of AD. In AD, an age-related desynchronization of biological systems results, involving stress components, cortisol and noradrenaline, reactive oxygen species, and membrane damage as major candidates that precipitates an insulin resistant brain state (IRBS) with decreased glucose/energy metabolism and the increased formation of hyperphosphorylated tau protein and Abeta. Unfortunately, it is very difficult to include the measurement of peripheral insulin resistance in the current MetS criteria or the identification of IRBS for the metabolic-cognitive syndrome. However, since inflammation has been suggested among the MetS components, we propose IRBS as an additional feature of the metabolic-cognitive syndrome to also identify a molecular profile in patients at high risk of developing predementia or dementia syndromes.

Metabolic-cognitive syndrome: a cross-talk between metabolic syndrome and Alzheimer's disease
            (Frisardi et al., 2010b) Download
A growing body of epidemiological evidence suggested that metabolic syndrome (MetS) and Mets components (impaired glucose tolerance, abdominal or central obesity, hypertension, hypertriglyceridemia, and reduced high-density lipoprotein cholesterol) may be important in the development of age-related cognitive decline (ARCD), mild cognitive impairment (MCI), vascular dementia, and Alzheimer's disease (AD). These suggestions proposed in these patients the presence of a "metabolic-cognitive syndrome", i.e. a MetS plus cognitive impairment of degenerative or vascular origin. This could represent a pathophysiological model in which to study in depth the mechanisms linking MetS and MetS components with dementia, particularly AD, and predementia syndromes (ARCD or MCI), suggesting a possible integrating view of the MetS components and their influence on cognitive decline. In the present article, we discussed the role of these factors in the development of cognitive decline and dementia, including underlying mechanisms, supporting their influence on beta-amyloid peptide metabolism and tau protein hyperphosphorylation, the principal neuropathological hallmarks of AD. In the next future, trials could then be undertaken to determine if modifications of these MetS components including inflammation, another factor probably related to MetS, could lower risk of developing cognitive decline. Future research aimed at identifying mechanisms that underlie comorbid associations of MetS components will not only provide important insights into the causes and interdependencies of predementia and dementia syndromes, but will also inspire novel strategies for treating and preventing cognitive disorders.

The link between iron, metabolic syndrome, and Alzheimer's disease
            (Grunblatt et al., 2011) Download
Both Alzheimer's disease (AD), the most common form of dementia, and type-2 diabetes mellitus (T2DM), a disease associated with metabolic syndrome (MetS), affect a great number of the world population and both have increased prevalence with age. Recently, many studies demonstrated that pre-diabetes, MetS, and T2DM are risk factors in the development of AD and have many common mechanisms. The main focus of studies is the insulin resistance outcome found both in MetS as well as in brains of AD subjects. However, oxidative stress (OS)-related mechanisms, which are well known to be involved in AD, including mitochondrial dysfunction, elevated iron concentration, reactive oxygen species (ROS), and stress-related enzyme or proteins (e.g. heme oxygenase-1, transferrin, etc.), have not been elucidated in MetS or T2DM brains although OS and iron are involved in the degeneration of the pancreatic islet beta cells. Therefore, this review sets to cover the current literature regarding OS and iron in MetS and T2DM and the similarities to mechanisms in AD both in human subjects as well as in animal models.

Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease
            (Kapogiannis and Mattson, 2011) Download
Epidemiological, neuropathological, and functional neuroimaging evidence implicates global and regional disruptions in brain metabolism and energetics in the pathogenesis of cognitive impairment. Nerve cell microcircuits are modified by excitatory and inhibitory synaptic activity and neurotrophic factors. Ageing and Alzheimer's disease cause perturbations in cellular energy metabolism, level of excitation or inhibition, and neurotrophic factor release, which overwhelm compensatory mechanisms and result in dysfunction of neuronal microcircuits and brain networks. A prolonged positive energy balance impairs the ability of neurons to adapt to oxidative and metabolic stress. Results from experimental studies in animals show how disruptions caused by chronic positive energy balance, such as diabetes, lead to accelerated cognitive ageing and Alzheimer's disease. Therapeutic interventions to allay cognitive dysfunction that target energy metabolism and adaptive stress responses (such as neurotrophin signalling) have been effective in animal models and in preliminary studies in humans.

Brain mitochondrial dysfunction as a link between Alzheimer's disease and diabetes
            (Moreira et al., 2007) Download
It has been argued that in late-onset Alzheimer's disease a disturbance in the control of neuronal glucose metabolism consequent to impaired insulin signalling strongly resembles the pathophysiology of type 2 diabetes in non-neural tissue. The fact that mitochondria are the major generators and direct targets of reactive oxygen species led several investigators to foster the idea that oxidative stress and damage in mitochondria are contributory factors to several disorders including Alzheimer's disease and diabetes. Since brain possesses high energetic requirements, any decline in brain mitochondria electron chain could have a severe impact on brain function and particularly on the etiology of neurodegenerative diseases. This review is primarily focused in the discussion of brain mitochondrial dysfunction as a link between diabetes and Alzheimer's disease.

Metabolic syndrome and the role of dietary lifestyles in Alzheimer's disease
            (Pasinetti and Eberstein, 2008) Download
Since Alzheimer's disease (AD) has no cure or preventive treatment, an urgent need exists to find a means of preventing, delaying the onset, or reversing the course of the disease. Clinical and epidemiological evidence suggests that lifestyle factors, especially nutrition, may be crucial in controlling AD. Unhealthy lifestyle choices lead to an increasing incidence of obesity, dyslipidemia and hypertension--components of the metabolic syndrome. These disorders can also be linked to AD. Recent research supports the hypothesis that calorie intake, among other non-genetic factors, can influence the risk of clinical dementia. In animal studies, high calorie intake in the form of saturated fat promoted AD-type amyloidosis, while calorie restriction via reduced carbohydrate intake prevented it. Pending further study, it is prudent to recommend to those at risk for AD--e.g. with a family history or features of metabolic syndrome, such as obesity, insulin insensitivity, etc.--to avoid foods and beverages with added sugars; to eat whole, unrefined foods with natural fats, especially fish, nuts and seeds, olives and olive oil; and to minimize foods that disrupt insulin and blood sugar balance.


Metabolic syndrome and risk for incident Alzheimer's disease or vascular dementia: the Three-City Study
            (Raffaitin et al., 2009) Download
OBJECTIVE: Associations between metabolic syndrome and its individual components with risk of incident dementia and its different subtypes are inconsistent. RESEARCH DESIGN AND METHODS: The 7,087 community-dwelling subjects aged > or =65 years were recruited from the French Three-City (3C) cohort. Hazard ratios (over 4 years) of incident dementia and its subtypes (vascular dementia and Alzheimer's disease) and association with metabolic syndrome (defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria) and its individual components (hypertension, large waist circumference, high triglycerides, low HDL cholesterol, and elevated fasting glycemia) were estimated in separate Cox proportional hazard models. RESULTS: Metabolic syndrome was present in 15.8% of the study participants. The presence of metabolic syndrome increased the risk of incident vascular dementia but not Alzheimer's disease over 4 years, independent of sociodemographic characteristics and the apolipoprotein (apo) Eepsilon4 allele. High triglyceride level was the only component of metabolic syndrome that was significantly associated with the incidence of all-cause (hazard ratio 1.45 [95% CI 1.05-2.00]; P = 0.02) and vascular (2.27 [1.16-4.42]; P = 0.02) dementia, even after adjustment of the apoE genotype. Diabetes, but not impaired fasting glycemia, was significantly associated with all-cause (1.58 [1.05-2.38]; P = 0.03) and vascular (2.53 [1.15-5.66]; P = 0.03) dementia. CONCLUSIONS: The observed relation between high triglycerides, diabetes, and vascular dementia emphasizes the need for detection and treatment of vascular risk factors in older individuals in order to prevent the likelihood of clinical dementia.

Diabetes is associated with increased rate of cognitive decline in questionably demented elderly
            (Ravona-Springer et al., 2010) Download
BACKGROUND: This study examines whether the association of diabetes with the rate of cognitive decline varies according to dementia severity. METHODS: Longitudinal study on subjects residing in nursing homes and assisted living (n = 342). The Mini Mental State Examination (MMSE) was used to measure the rate of cognitive decline in diabetic and nondiabetic subjects who were nondemented (Clinical Dementia Rating, CDR = 0; n = 125), questionably demented (CDR = 0.5; n = 58) or frankly demented (CDR > or =1; n = 89) at baseline. Diagnosis of diabetes was ascertained by review of medical records and history. RESULTS: Diabetes was associated with an increased rate of decline in the MMSE score of questionably demented subjects (p < 0.0001). In frankly demented subjects, diabetes tended to be associated with less cognitive decline (p = 0.04). Diabetes was not associated with the rate of MMSE decline in nondemented subjects (p = 0.89). CONCLUSION: In individuals with questionable dementia (CDR = 0.5), diabetes is associated with a faster rate of cognitive decline as measured by the MMSE, but not in nondemented (CDR = 0) or frankly demented (CDR > or =1) individuals.

(Pre)diabetes, brain aging, and cognition
            (S. Roriz-Filho et al., 2009) Download
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 neurothrophic 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-beta (Abeta) 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 Abeta, brain hyperinsulinism may deprive Abeta 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, diabetes subjects are more prone to develop extense and earlier-than-usual leukoaraiosis (White Matter High-Intensity Lesions - WMHL). WMHL are usually present at different degrees in brain scans of elderly people. People with more advanced WMHL are at increased risk for executive dysfunction, cognitive impairment and dementia. Clinical phenotypes associated with insulin resistance possibly represent true clinical models for brain and systemic aging.

Body mass index over the adult life course and cognition in late midlife: the Whitehall II Cohort Study
            (Sabia et al., 2009) Download
BACKGROUND: The extent to which cognition in late midlife is influenced by lifetime obesity is unclear. OBJECTIVE: We examined the association between body mass index (BMI) over the adult life course and cognition in late midlife and assessed the cumulative effects of obesity and underweight. DESIGN: Data from the Whitehall II Study were examined. BMI at 25 y (early adulthood) was self-reported at phase 1 and was measured in early midlife (mean age = 44 y; phase 1) and in late midlife (mean age = 61 y; phase 7). Cognition (n = 5131) was assessed in late midlife (phase 7) by using the Mini-Mental State Examination and tests of memory and executive function, all of which were standardized to T scores (mean +/- SD: 50 +/- 10). RESULTS: Both underweight and obesity were associated with lower cognition in late midlife and with early adulthood, early midlife, and late midlife measures of BMI. Being obese at 2 or 3 occasions was associated with lower Mini-Mental State Examination scores and scores of memory and executive function in analyses adjusted for age, sex, and education [difference (95% CI) in mean T scores compared with normal-weight group: -1.51 (-2.77, -0.25), -1.27 (-2.46, -0.07), and -1.35 (-2.45, -0.24), respectively]. Participants who were underweight at > or =2 occasions from early adulthood to late midlife had lower executive function [difference (95% CI) in mean T score: -4.57 (-6.94, -2.20)]. A large increase in BMI from early to late midlife was associated with lower executive function. CONCLUSIONS: Long-term obesity and long-term underweight in adulthood are associated with lower cognitive scores in late midlife. Public health messages should promote a healthy weight at all ages.

Insulin-resistance and metabolic syndrome are related to executive function in women in a large family-based study
            (Schuur et al., 2010) Download
While type 2 diabetes is well-known to be associated with poorer cognitive performance, few studies have reported on the association of metabolic syndrome (MetS) and contributing factors, such as insulin-resistance (HOMA-IR), low adiponectin-, and high C-reactive protein (CRP)-levels. We studied whether these factors are related to cognitive function and which of the MetS components are independently associated. The study was embedded in an ongoing family-based cohort study in a Dutch population. All participants underwent physical examinations, biomedical measurements, and neuropsychological testing. Linear regression models were used to determine the association between MetS, HOMA-IR, adiponectin levels, CRP, and cognitive test scores. Cross-sectional analyses were performed in 1,898 subjects (mean age 48 years, 43% men). People with MetS had significantly higher HOMA-IR scores, lower adiponectin levels, and higher CRP levels. MetS and high HOMA-IR were associated with poorer executive function in women (P = 0.03 and P = 0.009). MetS and HOMA-IR are associated with poorer executive function in women.

Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Abeta deposition in an Alzheimer mouse model with diabetes
            (Takeda et al., 2010) Download
Recent epidemiological studies suggest that diabetes mellitus is a strong risk factor for Alzheimer disease. However, the underlying mechanisms remain largely unknown. In this study, to investigate the pathophysiological interaction between these diseases, we generated animal models that reflect the pathologic conditions of both diseases. We crossed Alzheimer transgenic mice (APP23) with two types of diabetic mice (ob/ob and NSY mice), and analyzed their metabolic and brain pathology. The onset of diabetes exacerbated Alzheimer-like cognitive dysfunction without an increase in brain amyloid-beta burden in double-mutant (APP(+)-ob/ob) mice. Notably, APP(+)-ob/ob mice showed cerebrovascular inflammation and severe amyloid angiopathy. Conversely, the cross-bred mice showed an accelerated diabetic phenotype compared with ob/ob mice, suggesting that Alzheimer amyloid pathology could aggravate diabetes. Similarly, APP(+)-NSY fusion mice showed more severe glucose intolerance compared with diabetic NSY mice. Furthermore, high-fat diet feeding induced severe memory deficits in APP(+)-NSY mice without an increase in brain amyloid-beta load. Here, we created Alzheimer mouse models with early onset of cognitive dysfunction. Cerebrovascular changes and alteration in brain insulin signaling might play a pivotal role in this relationship. These findings could provide insights into this intensely debated association.

Association of cognitive performance with the metabolic syndrome and with glycaemia in middle-aged and older European men: the European Male Ageing Study
            (Tournoy et al., 2010) Download
BACKGROUND AND AIMS: Metabolic syndrome has been reported to have adverse effects on cognition although the results are conflicting. We investigated the association between metabolic syndrome and cognitive function in a population sample of middle-aged and older European men and whether any observed association could be explained by lifestyle or other confounding factors. METHODS: A total of 3369 men in the 40- to 79-year age group were recruited from population registers in eight centres for participation in the European Male Ageing Study. The subjects completed a questionnaire instrument and several cognitive function tests including the Rey-Osterrieth Complex Figure test, the Camden Topographical Recognition Memory test and the Digit Symbol Substitution Test. Metabolic syndrome data were assessed at an invited visit and metabolic syndrome was defined by the National Cholesterol Education Program's Adult Treatment Panel-III criteria. Associations between cognitive performance and metabolic syndrome were explored using linear regression. RESULTS: Complete cognitive and metabolic syndrome data from 3152 subjects were included in the analysis, of whom 1007 (32%) fulfilled criteria for metabolic syndrome. After adjustment for putative health and lifestyle confounders, no significant associations were found between any of the cognitive function scores and metabolic syndrome or between cognitive performance and high-sensitivity C-reactive protein. Analysis of the individual metabolic syndrome factors, however, revealed an inverse association between the level of glucose and cognitive performance. CONCLUSIONS: Metabolic syndrome was not associated with cognitive impairment in this population. Of the individual components of the syndrome, diabetes was associated with poorer performances in memory, executive functions and processing speed, associations that warrant further investigation.

Potential role of estrogen in the pathobiology and prevention of Alzheimer's disease
            (Wharton et al., 2009) Download
Over a decade of converging findings from clinical, observational and basic science research indicate that estrogen administration during the menopausal transition exerts beneficial effects on cognition and decreases a woman's risk of developing Alzheimer's disease (AD) later in life. This review article stresses the research focus of AD prevention, and introduces hormone therapy (HT) as a probable catalyst that may achieve this goal. Furthermore, this article outlines 3 mechanisms proposed to mediate estrogen's beneficial effects, discusses the controversy surrounding HT administration, and presents the most promising estrogen related research in AD prevention and treatment. Although controversial, cumulative evidence suggests that the potential of estrogen initiated during perimenopause to prevent AD needs to be systematically evaluated.

Metabolic syndrome: a potential culprit for Alzheimer's disease?
            (Wu et al., 2008) Download


The metabolic syndrome, inflammation, and risk of cognitive decline
            (Yaffe et al., 2004) Download
CONTEXT: Several studies have reported an association between the metabolic syndrome and cardiovascular disease. Despite an increasing awareness that cardiovascular risk factors increase risk of cognitive decline and dementia, there are few data on the metabolic syndrome and cognition. OBJECTIVE: To determine if the metabolic syndrome is a risk factor for cognitive decline and if this association is modified by inflammation. DESIGN AND SETTING: A 5-year prospective observational study conducted from 1997 to 2002 at community clinics at 2 sites. PARTICIPANTS: A total of 2632 black and white elders (mean age, 74 years). MAIN OUTCOME MEASURES: Association of the metabolic syndrome (measured using National Cholesterol Education Program guidelines) and high inflammation (defined as above median serum level of interleukin 6 and C-reactive protein) with change in cognition (Modified Mini-Mental State Examination [3MS]) at 3 and 5 years. Cognitive impairment was defined as at least a 5-point decline. RESULTS: Compared with those without the metabolic syndrome (n = 1616), elders with the metabolic syndrome (n = 1016) were more likely to have cognitive impairment (26% vs 21%, multivariate adjusted relative risk [RR], 1.20; 95% confidence interval [CI], 1.02-1.41). There was a statistically significant interaction with inflammation and the metabolic syndrome (P = .03) on cognitive impairment. After stratifying for inflammation, those with the metabolic syndrome and high inflammation (n = 348) had an increased likelihood of cognitive impairment compared with those without the metabolic syndrome (multivariate adjusted RR, 1.66; 95% CI, 1.19-2.32). Those with the metabolic syndrome and low inflammation (n = 668) did not exhibit an increased likelihood of impairment (multivariate adjusted RR, 1.08; 95% CI, 0.89-1.30). Stratified multivariate random-effects models demonstrated that participants with the metabolic syndrome and high inflammation had greater 4-year decline on 3MS (P = .04) compared with those without the metabolic syndrome, whereas those with the metabolic syndrome and low inflammation did not (P = .44). CONCLUSION: These findings support the hypothesis that the metabolic syndrome contributes to cognitive impairment in elders, but primarily in those with high level of inflammation.

Metabolic syndrome and cognitive disorders: is the sum greater than its parts?
            (Yaffe, 2007) Download
Given the anticipated exponential increase in both the incidence and prevalence of dementia, it is critical to identify preventative strategies and improved treatments for this disorder. The metabolic syndrome is comprised of 5 cardiovascular risk factors that include abdominal obesity, hypertriglyceridemia, low high-density lipoprotein levels, hypertension, and hyperglycemia. The prevalence of the metabolic syndrome, similar to that for cognitive disorders, increases dramatically with age. Several possible mechanisms may explain an association between the metabolic syndrome and cognitive decline including microvascular and macrovascular disease, inflammation, adiposity, and insulin resistance. Although some of the individual components of the metabolic syndrome have been linked to risk of developing dementia and cognitive impairment, few studies have looked at the components of the metabolic syndrome as a whole. We found, in 3 separate studies involving elders of different ethnicities, that the metabolic syndrome is a risk factor for accelerated cognitive aging. This was especially true for elders with the metabolic syndrome and with elevated serum level of inflammation. If metabolic syndrome is associated with increased risk of developing cognitive impairment, regardless of mechanism, then early identification and treatment of these individuals might offer avenues for disease course modification.

The metabolic syndrome and development of cognitive impairment among older women
            (Yaffe et al., 2009) Download
BACKGROUND: Several studies support a role for cardiovascular risk factors in cognitive aging. The metabolic syndrome, a constellation of cardiovascular risk factors, is common in elderly people. A growing but conflicting body of literature suggests that the metabolic syndrome may be associated with cognitive impairment. OBJECTIVE: To investigate the association between the metabolic syndrome and its components and incident cognitive impairment in older women. DESIGN: We prospectively determined if the metabolic syndrome and its components were associated with a 4-year risk of developing cognitive impairment (dementia, mild cognitive impairment, or low global cognitive test score). SETTING: The study was conducted at 180 clinical centers in 25 countries. PARTICIPANTS: A total of 4895 older women (mean age, 66.2 years) with osteoporosis who were part of an ancillary study to determine clinically relevant cognitive impairment were included in this study. These women were free of baseline cognitive impairment and had metabolic syndrome component measures. MAIN OUTCOME MEASURES: Clinically significant cognitive impairment was defined to include women with clinically adjudicated dementia or MCI and women who had a Short Blessed test score greater than 6 (consistent with impairment), but whose cases were not clinically adjudicated. Logistic regression analysis was used to examine the association between presence of the metabolic syndrome and development of clinically significant cognitive impairment. RESULTS: A total of 497 women (10.2%) had the metabolic syndrome and, of these, 36 (7.2%) developed cognitive impairment compared with 181 (of 4398 or 4.1%) without the syndrome (age-adjusted odds ratio, 1.66; 95% confidence interval, 1.14-2.41). The mean (SD) number of metabolic syndrome components for all women was 1.0 (1.1); 518 women (10.6%) were obese, 895 (18.3%) had hypertriglyceridemia, 1200 (24.5%) had low high-density lipoprotein cholesterol levels, 1944 (39.7%) had high blood pressure, and 381 (7.8%) had high fasting blood glucose levels. There was a 23.0% age-adjusted increase in the risk of developing cognitive impairment (odds ratio, 1.23; 95% confidence interval, 1.09-1.39) per unit increase in the number of components. Further multivariable adjustment somewhat reduced the effect. CONCLUSION: We found an association between the metabolic syndrome and the number of components and risk of developing cognitive impairment in older women. Additional studies are needed to determine if screening and close management of these at-risk elderly women would diminish the incidence of cognitive impairment.

 


References

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