Midlife Obesity Research Articles

Mineralocorticoid receptor antagonism prevents obesity-induced cerebral artery remodeling and reduces white matter injury in rats.

Midlife obesity is a risk factor for dementia development. Obesity has also been linked to hyperaldosteronism, and this can be modeled in rats by high fat (HF) feeding from weaning. Aldosterone, or activation of the mineralocorticoid receptor (MR) causes cerebrovascular injury in lean hypertensive rats. We hypothesized that rats fed a HF diet would show inward middle cerebral artery (MCA) remodeling that could be prevented by MR antagonism. We further proposed that the cerebral artery remodeling would be associated with white mater injury. Three-week-old male Sprague-Dawley rats were fed a HF diet±the MR antagonist canrenoic acid (Canr) for 17weeks. Control rats received normal chow (control NC). MCA structure was assessed by pressure myography. The MCAs from HF fed rats had smaller lumens and thicker walls when compared to arteries from control NC rats; Canr prevented the MCA remodeling associated with HF feeding. HF feeding increased the mRNA expression of markers of cell proliferation and vascular inflammation in cerebral arteries and Canr treatment prevented this. White mater injury was increased in the rats fed the HF diet and this was reduced by Canr treatment. The expression of doublecortin, a marker of new and immature neurons was reduced in HF fed rats, and MR antagonism normalized this. These data suggest that HF feeding leads to MR dependent remodeling of the MCA and this is associated with markers of dementia development.

Abstract MP26: Obesity is Associated With Accelerated Epigenetic Aging in Midlife: The Coronary Artery Risk Development in Young Adults (CARDIA) Study

Background: Obesity is associated with increased risk of cardiovascular and other age-related diseases that may represent accelerated aging. As methylation levels in DNA change with aging, epigenetic age (EA), which integrates whole-genome methylation has emerged as a novel biomarker of aging and has been associated with mortality and age-related morbidity. Epigenetic age acceleration (EAA), is based on the residual value of 353 previously defined methylation markers regressed on chronologic age (CA), and is thus independent of CA. Therefore, we sought to examine the association of obesity and EAA in midlife. Methods: A subset of participants in the CARDIA cohort (n=1200) randomly selected (balanced on race and sex) underwent genome-wide DNA methylation profiling with the Illumina EPIC array from exam year 15 (2000-01 [age 33-45 years]) and 20 (2005-06 [38-50 years] for calculation of EAA. Body mass index (BMI) was measured at Y15 and Y20, respectively. We used linear regression to examine the association of obesity (independent variable) with EAA after adjusting for CA, race, sex, education, study center, smoking status, physical activity, and alcohol intake. Results: Participants were 52% female and 41% black and had mean BMI 28.5±6.2 kg/m 2 at Y15 and 29.2±6.4 kg/m 2 at Y20. At Y15, participants who were obese had 1.04 (0.38) years higher EAA compared to normal BMI participants (p<0.01, Figure) . Similar results were observed at Y20. Results were similar when evaluating the association of BMI continuously with EAA (p<0.05). Conclusions: EAA is a promising molecular biomarker of aging associated with obesity. Changes in DNA methylation may serve as an intermediate phenotype prior to the onset of age-associated pathologies related to obesity.

Friends With Health Benefits: The Long-Term Benefits of Early Peer Social Integration for Blood Pressure and Obesity in Midlife

In adults, greater social integration is associated with reduced risk of cardiovascular disease, including hypertension. Social integration earlier in life may be similarly associated with cardiovascular risk. Using a longitudinal sample of 267 Black and White men, we examined whether greater social integration with peers during childhood and adolescence, assessed by parent report, prospectively predicts lower blood pressure and body mass index two decades later in adulthood and whether these effects differ by race, given well-documented racial disparities in hypertension. Boys who were reported by their parents to be more socially integrated with peers evidenced lower blood pressure and body mass index in adulthood, and this effect was not accounted for by body mass index in childhood, childhood socioeconomic status, childhood hostility, childhood physical health, extraversion measured in adolescence, or concurrent adult self-reports of social integration. Results did not differ by race, but analyses were not powered to detect interactions of small effect size.

A prospective study of marital quality and body weight in midlife.

Few studies have gone beyond studying marital status to examine effects of marital quality on body weight. This study examined the association of marital quality with weight change and incident obesity in midlife. It differentiated positive and negative components of marital quality considering overall marital quality, marital support, and marital strain. Data are from 2,636 adults from the Midlife in the United States study who participated in 2 waves of data collection 10 years apart. Marital quality was self-reported. Body weight was assessed with self-reported height and weight. Generalized estimating equations examined primary associations also considering potential confounders and mediating factors including sociodemographics, baseline health conditions, and health behaviors. Overall marital quality was inversely associated with weight gain (β = -0.70, 95% confidence interval [CI] [-1.38, -0.01]). Marital support was inversely related to both weight gain (β = -1.48, 95% CI [-2.80, -0.16]) and incident obesity (risk ratio = 0.79, 95% CI [0.65, 0.96]). Marital strain was not associated with either weight change or incident obesity. The association between marital support and incident obesity remained when marital strain was simultaneously included in the model. There was evidence that the associations of marital support and marital strain with incident obesity might differ by gender, and were evident only in men. This study shows a supportive marital relationship is associated with healthier body weight in midlife. It also indicates marital support may have effects over and beyond the mere absence of marital strain. Findings suggest the potential utility of involving spouses/partners in obesity prevention and treatment. (PsycINFO Database Record

Neurotoxic chemicals in adipose tissue: A role in puzzling findings on obesity and dementia.

Midlife obesity is associated with increased risk of dementia, whereas late-life obesity is commonly associated with a lower risk of dementia. Although methodologic issues are often discussed in this apparent risk reversal, chronic exposure to low-dose organochlorine pesticides (OCPs), an emerging risk factor for dementia in general populations, may contribute to a direct explanation for these differences. OCPs are strong lipophilic chemicals with very long half-lives (several years), primarily stored in adipose tissue and very slowly released and metabolized over years. As serum concentrations of neurotoxic OCPs strongly correlate with brain OCPs (r = 0.95), any condition enhancing the release of OCPs from the adipose tissue into circulation would increase the risk of dementia. Increased release of OCPs from adipose tissue typically occurs in (1) dysfunctional adipocytes accompanied by uncontrolled lipolysis and (2) weight loss. Weight gain may help sequester circulating OCPs in adipose tissue. As obesity is the most common reason that adipocytes become dysfunctional, midlife obesity can increase dementia risk through the chronic release of OCPs into circulation. However, late-life obesity potentially decreases dementia risk because weight loss after midlife will increase the release of OCPs while weight gain may actually decrease the release. These countervailing forces may underlie paradoxical associations with dementia of obesity in midlife vs late life which is influenced by weight change after midlife. This hypothesis should be tested in future experimental and human studies on obesity and dementia.

Spotlight on the January 23 issue

#### Notable in Neurology this week This issue features an article that illustrates the ability of CSF biomarkers to predict disease progression in progressive supranuclear palsy and another that reports an increased risk of oral clefts associated with maternal use of high-dose topiramate early in pregnancy. A featured Medical Hypothesis article outlines the theory that exposure to low-dose organochlorine pesticides explains the difference in the association of midlife and late-life obesity with dementia risk. ### MicroRNAs in CSF as prodromal biomarkers for Huntington disease in the PREDICT-HD study In this study, the authors identified …

The proportion of dementia attributable to common modifiable lifestyle factors in Barbados.

ABSTRACTObjectiveTo understand what number and proportion of dementia cases in Barbados are attributable to modifiable lifestyle factors and what effect a reduction in these risk factors would have on future dementia prevalence.MethodsThis was an observational study using Levin's Attributable Risk formula, which assumes independence of risk factors, to calculate the population attributable risk (PAR) of dementia (all-cause) for six risk factors: midlife obesity, physical inactivity, smoking, low educational attainment, diabetes mellitus, and midlife hypertension in Barbados. A recently-published, modified formula was utilized to account for non-independence of risk factors using secondary data for Barbados. The number and proportion of dementia cases attributable to each risk factor and to all risk factors combined were computed, as was the effect that any reduction in these risk factors might have on future dementia prevalence.ResultsAccounting for the fact that risk factors do not operate independently, 50.9% (1 526 cases) were attributable to the combined effect of the six risk factors under study. According to the analysis, if each risk factor were reduced by 5% – 20% per decade, dementia prevalence could be 3.3% – 31.8% lower by 2050.ConclusionUsing a largely theoretical model, the six modifiable lifestyle factors were estimated to be attributable to 50.9% of dementia cases in Barbados. Since the risk factors have much in common, any intervention that targets one of them could significantly reduce future dementia prevalence.

Online assessment of risk factors for dementia and cognitive function in healthy adults.

Several potentially modifiable risk factors for cognitive decline and dementia have been identified, including low educational attainment, smoking, diabetes, physical inactivity, hypertension, midlife obesity, depression, and perceived social isolation. Managing these risk factors in late midlife and older age may help reduce the risk of dementia; however, it is unclear whether these factors also relate to cognitive performance in older individuals without dementia. Data from 14201 non-demented individuals aged >50years who enrolled in the online PROTECT study were used to examine the relationship between cognitive function and known modifiable risk factors for dementia. Multivariate regression analyses were conducted on 4 cognitive outcomes assessing verbal and spatial working memory, visual episodic memory, and verbal reasoning. Increasing age was associated with reduced performance across all tasks. Higher educational achievement, the presence of a close confiding relationship, and moderate alcohol intake were associated with benefits across all 4 cognitive tasks, and exercise was associated with better performance on verbal reasoning and verbal working memory tasks. A diagnosis of depression was negatively associated with performance on visual episodic memory and working memory tasks, whereas being underweight negatively affected performance on all tasks apart from verbal working memory. A history of stroke was negatively associated with verbal reasoning and working memory performance. Known modifiable risk factors for dementia are associated with cognitive performance in non-demented individuals in late midlife and older age. This provides further support for public health interventions that seek to manage these risk factors across the lifespan.

The relationship between obesity and cognitive health and decline.

The relationship between obesity and cognitive impairment is important given the globally ageing population in whom cognitive decline and neurodegenerative disorders will carry grave individual, societal and financial burdens. This review examines the evidence for the link between obesity and cognitive function in terms of both the immediate effects on cognitive performance, and effects on the trajectory of cognitive ageing and likelihood of dementia. In mid-life, there is a strong association between obesity and impaired cognitive function. Anthropometric measures of obesity are also associated with reduced neural integrity (e.g. grey and white matter atrophy). Increasing age coupled with the negative metabolic consequences of obesity (e.g. type 2 diabetes mellitus) are likely to significantly contribute to cognitive decline and incidence of dementia. Stress is identified as a potential risk factor promoting abdominal obesity and contributing to impaired cognitive function. However, the potentially protective effects of obesity against cognitive decline in older age require further examination. Finally, surgical and whole diet interventions, which address obesity may improve cognitive capacity and confer some protection against later cognitive decline. In conclusion, obesity and its comorbidities are associated with impaired cognitive performance, accelerated cognitive decline and neurodegenerative pathologies such as dementia in later life. Interventions targeting mid-life obesity may prove beneficial in reducing the cognitive risks associated with obesity.

Differential effects of voluntary treadmill exercise and caloric restriction on tau pathogenesis in a mouse model of Alzheimer's disease-like tau pathology fed with Western diet

BackgroundTau is a microtubule-associated protein that becomes pathological when it undergoes hyperphosphorylation and aggregation as seen in Alzheimer's disease (AD). AD is mostly sporadic, with environmental, biological and/or genetic risks factors, interacting together to promote the disease. In the past decade, reports have suggested that obesity in midlife could be one of these risk factors. On the other hand, caloric restriction and physical exercise have been reported to reduce the incidence and outcome of obesity as well as AD. MethodsWe evaluated the impact of voluntary physical exercise and caloric restriction on tau pathology during 2months in hTau mice under high caloric diet in order to evaluate if these strategies could prevent AD-like pathology in obese conditions. ResultsWe found no effects of obesity induced by Western diet on both Tau phosphorylation and aggregation compared to controls. However, exercise reduced tau phosphorylation while caloric restriction exacerbated its aggregation in the brains of obese hTau mice. We then examined the mechanisms underlying changes in tau phosphorylation and aggregation by exploring major tau kinases and phosphatases and key proteins involved in autophagy. However, there were no significant effects of voluntary exercise and caloric restriction on these proteins in hTau mice that could explain our results. ConclusionIn this study, we report differential effects of voluntary treadmill exercise and caloric restriction on tau pathogenesis in our obese mice, namely beneficial effect of exercise on tau phosphorylation and deleterious effect of caloric restriction on tau aggregation. Our results suggest that lifestyle strategies used to reduce metabolic disorders and AD must be selected and studied carefully to avoid exacerbation of pathologies.

Excessive Gestational Weight Gain and Subsequent Maternal Obesity at Age 40: A Hypothetical Intervention.

To model the hypothetical impact of preventing excessive gestational weight gain on midlife obesity and compare the estimated reduction with the US Healthy People 2020 goal of a 10% reduction of obesity prevalence in adults. We analyzed 3917 women with 1 to 3 pregnancies in the prospective US National Longitudinal Survey of Youth, from 1979 to 2012. We compared the estimated obesity prevalence between 2 scenarios: gestational weight gain as reported and under the scenario of a hypothetical intervention that all women with excessive gestational weight gain instead gained as recommended by the Institute of Medicine (2009). A hypothetical intervention was associated with a significantly reduced estimated prevalence of obesity for first (3.3 percentage points; 95% confidence interval [CI] = 1.0, 5.6) and second (3.0 percentage points; 95% CI = 0.7, 5.2) births, and twice as high in Black as in White mothers, but not significant in Hispanics. The population attributable fraction was 10.7% (95% CI = 3.3%, 18.1%) in first and 9.3% (95% CI = 2.2%, 16.5%) in second births. Development of effective weight-management interventions for childbearing women could lead to meaningful reductions in long-term obesity.

FORECASTING DEMENTIA CASES AND PREVALENCE: TAKING CURRENT RISK FACTOR PREVALENCE TRENDS INTO ACCOUNT

Dementia prevalence in the UK has been reported to be decreasing but this is not the case worldwide. The burden of dementia in the UK has still been forecasted to increase in the future, making it a top priority. As there is currently no cure for dementia, it will be important to prevent dementia through modifiable risk factors. The aim is to see whether the reported change in prevalence could be due to changes in risk factors and also which risk factors, with interventions, could prevent the most dementia cases in the future. Data from the second Cognitive Function and Ageing Study (CFAS II), Health Survey for England (HSE), Office for National Statistics and comprehensive systematic reviews have been collated to forecast dementia prevalence and dementia cases from 2011 to 2030. The model combined future population estimates, current age and gender specific dementia prevalence, risk associated with dementia and the changing prevalence of risk factors. The trends for midlife obesity and stroke were found to increase prevalence of dementia and dementia cases above that of population ageing alone. Education was the only protective factor for dementia and could greatly attenuate future cases of dementia. Although midlife hypertension, midlife physical inactivity and smoking are associated with increased risk of dementia, the rate that the prevalence of these risk factors is decreasing by could make up for the increase in risk. The outlook is optimistic if trends in education, midlife physical inactivity, midlife hypertension and smoking continue but further decreases in the latter three of these risk factors and the prevention of midlife obesity and stroke could further help decrease expected dementia cases in the future.

ELEVATED CENTRAL AND PERIPHERAL INFLAMMATORY PROFILES IN A POPULATION AT RISK FOR ALZHEIMER’S DISEASE

Mid-life obesity and hypertension, two interconnected healthcare epidemics, increase the risk of cognitive decline and age-related neurodegeneration. These vascular risk factors are most common in women and African Americans, who are also at higher risk for Alzheimer's disease (AD). Elevated inflammatory signaling cascades are a primary characteristic of obesity and hypertension. Peripheral inflammation has been linked to cognitive decline and neurodegeneration. However, the mechanistic links remain unknown. Here we tested the hypothesis that obesity and hypertension are mechanistically linked to AD through a multistage process that involves dysregulation of the renin angiotensin system (RAS), systemic inflammation and a heightened peripheral immune response, followed by increased immune cell trafficking into the brain thereby leading to chronic inflammation. Cognitively normal, middle aged participants with a parental history of Alzheimer's disease were enrolled. Blood and CSF were centrifuged for isolation of immune cells for immunophenotyping by multicolor flow cytometry; supernatant biofluids were collected for measurement of inflammatory factors by multiplexed immunoassays. Deep immunophenotyping analysis of CSF revealed that individuals with high blood pressure displayed altered brain immune cell profiles, including elevated central memory T cells, compared to those with normal blood pressure. This same T cell population was altered in obese (BMI >30) compared to non-obese individuals (BMI 18.5–23.9). Altered immune cell profiles were also detected in participants who suffered from disturbed sleep, a common complaint of those who suffer from Alzheimer's disease. Profiling immune cell populations in the CSF is a novel approach in the neurodegeneration field that may reveal opportunities for therapeutic intervention with targeted immunomodulatory therapies. AD risk factors associated with hypertension correlate with altered central and peripheral immune cell profiles in cognitively normal middle-aged participants. Our results demonstrate that immune cell dysfunction is detectable in cognitively intact hypertensive individuals at risk for AD and suggest that RAS-targeted interventions may afford therapeutic benefit to delay onset of AD.

Obesity and Co-morbid Conditions Are Associated with Specific Neuropsychiatric Symptoms in Mild Cognitive Impairment.

Background: Neuropsychiatric symptoms (NPSs) in MCI, and midlife obesity increase the likelihood of developing Alzheimer’s disease. It is unknown whether obesity or related health conditions modify the risk of NPS or severity of cognitive impairment in MCI.Methods: One hundred and thirteen subjects with MCI were assessed near the time of MCI diagnosis. The sample was divided by BMI and related disorders, type-2 diabetes (T2D) and obstructive sleep apnea (OSA) to measure the relationship of these groups with NPS and severity of MCI. NPSs scores were evaluated based on the Neuropsychiatric Inventory-Questionnaire (NPI-Q) and Geriatric Depression Scale, along with NPI-Q clusters. MCI-severity was estimated based on a composite z-score of neuropsychological tests.Results: Obese and overweight subjects represented 65% of the sample and were on average 7 years younger than normal weight subjects. The presence of obesity, T2D and OSA status modified the prevalence and severity of specific NPI-Q symptom clusters, specifically affective symptoms were more frequent across groups and severe in OB and T2D. Total NPS scores were higher for subjects with T2D and OSA although MCI-severity did not differ across groups.Conclusion: MCI subjects with obesity, T2D and OSA demonstrated a higher susceptibility to psychopathologic changes.

Midlife risk factor exposure and incidence of cardiac arrest depending on cardiac or non-cardiac origin

ObjectiveLittle is known about midlife risk factors of future cardiac arrest. Our objective was to evaluate cardiovascular risk factors in midlife in relation to the risk of cardiac arrest (CA) of cardiac and non-cardiac origin later in life. MethodsWe cross-matched individuals of the population based Malmö Diet and Cancer study (n=30,447) with the local CA registry of the city of Malmö. Baseline exposures were related to incident CA. ResultsDuring a mean follow-up of 17.6±4.6years, 378 CA occurred, of whom 17.2% survived to discharge. Independent midlife risk factors for CA of cardiac origin included coronary artery disease {HR 2.84 (1.86–4.34) (p<0.001)}, diabetes mellitus {HR 2.37 (1.61–3.51) (p<0.001)} and smoking {HR 1.95 (1.49–2.55) (p<0.001)}. Dyslipidemia and history of stroke were also significantly associated with an elevated risk for CA of cardiac origin.Independent midlife risk factors for CA of non-cardiac origin included obesity (BMI>30kg/m2) {HR 2.37 (1.51–3.71) (p<0.001)}, smoking {HR 2.05 (1.33–3.15) (p<0.001)} and being on antihypertensive treatment {HR 2.25 (1.46–3.46) (p<0.001)}. ConclusionApart from smoking, which increases the risk of CA in general, the midlife risk factor pattern differs between CA of cardiac and non-cardiac origin. Whereas CA of cardiac origin is predicted by history of cardiovascular disease, dyslipidemia and diabetes mellitus, the main risk factors for CA of non-cardiac origin are obesity and hypertension. In addition to control of classical cardiovascular risk factors for prevention of CA, our results suggest that prevention of midlife obesity may reduce the risk of CA of non-cardiac origin.

Abdominal obesity and white matter microstructure in midlife.

The aging U.S. population and the recent rise in the prevalence of obesity are two phenomena of great importance to public health. In addition, research suggests that midlife body mass index (BMI) is a risk factor for dementia, a particularly costly disease, in later life. BMI could influence brain health by adversely impacting cerebral white matter. Recently, greater BMI has been associated with lower white matter fractional anisotropy (FA), an index of tissue microstructure, as measured by diffusion-tensor imaging in midlife. The aim of this study was to investigate the role of abdominal obesity, the most metabolically active adipose tissue compartment, and white matter microstructure in midlife. Community dwelling participants (N = 168) between the ages of 40-62 underwent MRI scanning at 3T and a general health assessment. Inferences were made on whole brain white matter tracts using full-tensor, high-dimension normalization, and tract-based spatial statistics. Higher waist circumference was associated with higher FA, indicating more directional diffusion in several white matter tracts controlling for age, sex, triglycerides, systolic blood pressure, fasting glucose, and HDL-cholesterol. Post hoc analysis revealed that greater waist circumference was associated with lower axial diffusivity, indicating lower parallel diffusion; lower radial diffusivity, indicating lower perpendicular diffusion; and lower mean diffusivity, indicating restricted diffusion. This is the first study to report a positive relationship between obesity and FA, indicating a more complicated view of this relationship in the aging brain. Hum Brain Mapp 38:3337-3344, 2017. © 2017 Wiley Periodicals, Inc.

High Fat Diet Increases Cognitive Decline and Neuroinflammation in a Model of Orexin Loss

Midlife obesity is a risk factor for cognitive decline and is associated with the earlier onset of Alzheimer's disease (AD). Diets high in saturated fat can potentiate the onset of obesity, microglial activation, and neuroinflammation. Signaling deficiencies in the hypothalamic peptide orexin A (OXA) and/or orexin fiber loss are linked to neurodegeneration in humans and animal models. Prior studies in orexin/ataxin‐3 (O/A3) mice, a transgenic mouse model of orexin neurodegeneration, demonstrate that OXA treatment improves cognitive processes. In separate studies we have demonstrate that OXA can suppress neuroinflammation and is neuroprotective against the saturated fatty acid palmitate. Our overall hypothesis is that OXA treatment attenuates hippocampal neuroinflammation and prevents cognitive decline in obesity during high fat diet (HFD) feeding. Our short term goal for this project is to determine if OXA loss increases neuroinflammation and impairs cognition during HFD feeding. To examine this, we tested male O/A3 mice (7–8 mo. of age) in a two‐way active avoidance (TWAA) hippocampus‐dependent memory task. We tested whether 1) OXA loss impaired cognitive function; 2) HFD worsened cognitive impairment; and 3) HFD increased microglial activation and neuroinflammation. We show that O/A3 mice have significant impairments in TWAA task learning vs. wild type (WT) mice (increased escapes p&lt;0.05, reduced avoidances p&lt;0.0001). Mice were then placed on HFD (45% total fat, 31.4% saturated fat) or remained on normal chow (NC; 4% total fat and 1% saturated fat), and TWAA was retested at 2 and 4 weeks. Learning impairment was evident at both 2 and 4 weeks in O/A3 mice fed HFD for following diet exposure vs. WT mice on normal chow or HFD (increased escapes, reduced avoidances p&lt;0.05). Additionally, O/A3 mice had increased gene expression of the microglial activation marker, Iba‐1 (measured via qRT‐PCR, p&lt;0.001). Characterization of the microglial immune response (M1 neurotoxic vs. M2 protective phenotypes) is ongoing and will include gene and protein markers (such as TNF‐α, iNOS, UCP2, and Arg1). Collectively, our results indicate that OXA loss impairs memory, and that HFD accelerates hippocampus‐dependent learning deficits and the onset of neuroinflammation. Future studies will focus on restoration of OXA within hippocampal circuits to reduce neuroinflammation and improve cognitive functionSupport or Funding InformationThis work was funded by the US Department of Veterans Affairs BLR&amp;D IK2 BX001686 and IS1 BX003083A (to TAB), the University of Minnesota Healthy Foods, Healthy Lives Institute (to JPN and TAB), MnDRIVE Brain Conditions Fellowship in Neuromodulation (to CMD), and the Minnesota Veterans Medical Research &amp; Education Foundation (to TAB).

Butyrate restores HFD-induced adaptations in brain function and metabolism in mid-adult obese mice.

Midlife obesity affects cognition and increases risk of developing dementia. Recent data suggest that intake of the short chain fatty acid butyrate could improve memory function, and may protect against diet-induced obesity by reducing body weight and adiposity. We examined the impact of a high-fat diet (HFD) followed by intervention with 5% (w/w) dietary butyrate, on metabolism, microbiota, brain function and structure in the low-density-lipoprotein receptor knockout (LDLr-/-) mouse model in mid and late life. In mid-adult mice, 15 weeks of HFD-induced adiposity, liver fibrosis and neuroinflammation, increased systolic blood pressure and decreased cerebral blood flow, functional connectivity assessed with neuroimaging. The subsequent 2 months butyrate intervention restored these detrimental effects to chow-fed control levels. Both HFD and butyrate intervention decreased variance in fecal microbiota composition. In late-adult mice, HFD showed similar detrimental effects and decreased cerebral white and gray matter integrity, whereas butyrate intervention attenuated only metabolic parameters. HFD induces detrimental effects in mid- and late-adult mice, which can be attenuated by butyrate intervention. These findings are consistent with reported associations between midlife obesity and cognitive impairment and dementia in humans. We suggest that butyrate may have potential in prevention and treatment of midlife obesity.

Proportion of dementia in Australia explained by common modifiable risk factors

BackgroundAt present, dementia has no known cure. Interventions to delay onset and reduce prevalence of the disease are therefore focused on risk factor reduction. Previous population attributable risk estimates for western countries may have been underestimated as a result of the relatively low rates of midlife obesity and the lower weighting given to that variable in statistical models.MethodsLevin’s Attributable Risk which assumes independence of risk factors was used to calculate the proportion of dementia attributable to seven modifiable risk factors (midlife obesity, physical inactivity, smoking, low educational attainment, diabetes mellitus, midlife hypertension and depression) in Australia. Using a recently published modified formula and survey data from the Australia Diabetes, Obesity and Lifestyle Study, a more realistic population attributable risk estimate which accounts for non-independence of risk factors was calculated. Finally, the effect of a 5–20% reduction in each risk factor per decade on future dementia prevalence was computed.ResultsTaking into consideration that risk factors do not operate independently, a more conservative estimate of 48.4% of dementia cases (117,294 of 242,500 cases) was found to be attributable to the seven modifiable lifestyle factors under study. We calculated that if each risk factor was to be reduced by 5%, 10%, 15% and 20% per decade, dementia prevalence would be reduced by between 1.6 and 7.2% in 2020, 3.3–14.9% in 2030, 4.9–22.8% in 2040 and 6.6–30.7% in 2050.ConclusionOur largely theory-based findings suggest a strong case for greater investment in risk factor reduction programmes that target modifiable lifestyle factors, particularly increased engagement in physical activity. However, further data on risk factor treatment and dementia risk reduction from population-based studies are needed to investigate whether our estimates of potential dementia prevention are indeed realistic.

Using Multistate Observational Studies to Determine Role of Hypertension and Diabetes as Risk Factors for Dementia.

Background:Evidence suggests that modifiable risk factors which can be targeted by prevention are vascular diseases, such as diabetes, midlife hypertension (HTN), midlife obesity, midlife cholesterol, mid- and late-life depression as well as lifestyle factors such as smoking, physical inactivity, and poor diet.Methods:A comprehensive search of the National Library of Medicine's PubMed database and Google Scholar was conducted. A combinations of medical subject headings and free text words that included search terms related to the exposure (e.g., prevalence, HTN, raised BP, high BP, diabetes, high blood sugar, DM, India, state), were combined with search terms related to the outcomes (e.g., prevalence, disease burden, estimate, dementia, India). The filters included were English for the language category and humans for the study category.Results:The PubMed search initially identified 269 references, and a total of 204 abstracts were screened by inclusion criteria. Full-text assessment of 136 articles on prevalence of dementia resulted in 20 relevant articles from which the different regions of the country were identified. Based on the search conducted according to the regions; 287abstracts of the prevalence of HTN and 577 on the prevalence of diabetes mellitus were screened. There were 43 full-text articles on the prevalence of HTN and diabetes from the regions where the prevalence of dementia was available. Of these potentially relevant articles were 14 in number.Conclusion:Despite the uncertainty in the role, the data analysis, therefore, points to a role in the prevention of HTN and diabetes to prevent dementia.