Aging/Alzheimer's Disease

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12503/21751

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MOBILE INTERDISCIPLINARY GERIATRIC HEALTHCARE IN THE COMMUNITY
(2014-03) O'Jile, Judith R.; Aaron, Debra; Buckley, Brielle; Sallee, Donna; Large, Stephanie E.; Johnson, Leigh; O'Bryant, Sid E.
Purpose (a): This is a community-based geriatric primary care model designed to reach Medicaid eligible elders as well as childless adult “near elders” (ages 50-64) using mobile teams and clinics to reduce hospitalizations, increase access to care, and improve patient quality of life. This is a new initiative for UNTHSC that utilizes mobile teams and clinics to increase access to care by providing appropriate care within the community. Medical teams, led by physician assistants (PAs) or nurse practitioners (NPs), that incorporate Community Health Workers (CHWs) and others (pharmacy, physical therapy, social work), will provide care to patients within community settings and clinics. Additionally, CHWs will educate elders about Medicaid and assist with enrollment when necessary. The Community Health Workers will also provide case management to high risk patients.To meet the urgent care needs of our patients and reduce ER utilization, a nurse advice telephone line has been created for patients to call when they have urgent care issues or questions. This enhancement of geriatric primary care services will expand encounters to a significant portion of Medicaid- eligible elders within RHP 10. Methods (b): The MIGHTY Care program will see 3071 patients and roughly 15,000 encounters over the five year grant. Our program goals include decrease in admission rates, decrease in 30 day re-admission rates for preventable causes, increase in patient satisfaction regarding patient involvement in medical decision making, and increases in quality of life. The team identified several steps that must be completed in order to achieve the project goals, which included identifying stakeholders, geocoding population demographics in order to determine the best sites for our standing clinics, proper training on tenets ofshared decision making and customer service, community outreach, and others. Results (c): The primary community stakeholders identified were Senior Citizen Services, Goodwill Industries, and the Community Food Bank. We had several meetings with these facilities to discuss the potential of setting a community based clinic in their locations. Additionally, the team has conducted community talks, flu shot clinics, and other community outreach presentations. In preparation for seeing patients at these sites, we are deepening our relationships by providing educational programs for patients and staff members. At this time we are continuing to develop other possible candidates for alliances. Conclusions (d): The MIGHTY Care program offers an innovative solution to many of the issues that plague our current system. We will provide cost-saving community-based care that will improve patient outcomes and the patients’ satisfaction with their care.
ELEVATED SERUM CREATININE LEVELS DIFFERENTIALLY IMPACT COGNITIVE FUNCTIONING AMONG MEXICAN AMERICAN ELDERS AND NON-HISPANIC WHITES: A PROJECT FRONTIER STUDY
(2014-03) Regina, Stephen P.; Johnson, Leigh
Objective: Kidney function decreases with age and is commonly observed in the elderly. Even mildly decreased kidney function is associated with increased vascular disease and cerebrovascular disease, and is believed to influence risk of Alzheimer’s disease (AD). Mexican Americans are reported to exhibit a decreased serum creatinine (SCr) distribution relative to that of Non-Hispanic Whites . It has been suggested that blood-based measures of kidney function may have a predictive role in the future for identifying patients who may benefit from detailed cognitive screening . The aim of this study was to determine the effects of impaired renal function as assessed by elevated SCr on cognition among Mexican American and Non-Hispanic White elders. Method: Data were analyzed from 487 participants (n= 192, Mexican American; n= 295, Non-Hispanic White) enrolled in Project FRONTIER, a community-based study of health issues in rural-dwelling adults and elders. Cognition was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Serum creatinine was reported by CMP. Linear regressions were utilized to examine the relationships between decreased measures of cognitive functioning and ethnicity when SCr level is elevated. Results: Among those who are Non-Hispanic white, elevated SCr levels were associated with poorer performance on tasks related to immediate memory (RBANS Immediate Memory Index, B[SE]= -3.12[1.32], t=-2.36, p=0.019) and language (RBANS Language Index, B[SE]=-2.04[0.79], t= -2.56, p=0.011). Concerning those who were Hispanic and of Mexican American decent, elevated SCr levels were found to be significantly negative associated with attention (RBANS Attention Index, B[SE]= -4.57[2.18], t=-2.08, p=0.038) and executive functioning (EXIT25, B[SE]= 1.90[0.82], t=2.29, p=0.023). Conclusions: This study emphasizes the ethnic differences observed with elevated levels of serum creatinine, which is a marker of kidney function. The results supported a differential relationship between creatinine and cognitive functioning, implicating that among Non-Hispanic Whites, elevated levels were associated with decreased performance on tasks of memory and language; whereas, among Hispanic Mexican Americans, there was a relationship between decreased performance on tasks of attention and executive functioning with elevations in the level of creatinine in serum.
RELATIONSHIP BETWEEN WORRY AND DEPRESSION IN ELDERLY MEXICAN-AMERICANS
(2014-03) Sosa, Horacio; Johnson, Leigh; Hall, James; Edwards, Melissa; O'Bryant, Sid E.
Purpose (a): Research has found a strong correlation between worry and mental and physical health. Later stages of life particularly entail increased stress related to multiple health problems, financial matters, etc., which often are associated with increased worry, anxiety and/or depression. In addition, worry has been linked to cognitive decline in the elderly. Our research has demonstrated that specific symptoms of depression (called the DepE) are related to cognitive impairment and can be used to identify a subgroup of individuals at greater risk for developing Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD). The goal of this study was to examine the relationship between DepE and worry in an elderly Mexican-American population. Methods (b): Data was collected from 253 Mexican-Americans (198 women, 60 men) enrolled in the Health and Aging Brain Study among Latino Elders (HABLE), a recently developed community-based study of factors related to aging. The mean age of the sample was 60 years, and the average years of education were 8. Worry was assessed using the Penn State Worry Questionnaire, and DepE was calculated using items from GDS30. The sample was divided into two groups based on DepE scores (high- and low-risk). Independent sample t-test was used to analyze the data. Results (c): The independent sample t-test showed a significant difference between the two groups (t = -10.4, p <0.05). Individuals with higher DepE scores have significantly higher scores in the PSWQ (Mean [SD] = 54 [16]), than those with low DepE scores (32 [13]). PSWQ items endorsed by the high-risk group include high worry under pressure (57%), an inability to dismiss worry (53%), consciousness about generalized worry (52%), a general tendency to worry (48%), and an inability to control worry (47%). Conclusions (d): DepE has been validated in multiple independent cohorts. Higher scores on the DepE are related to poor cognition and diagnosis of Mild Cognitive Impairment and Alzheimer’s disease (4). The results of this study suggest individuals with higher DepE scores have significantly higher worry, almost indicative of Generalized Anxiety Disorder according the PSWQ interpretation. This is consistent with literature linking worry to cognitive decline.
THE EFFECT OF LS-1-137, A NOVEL PHENYLACETAMIDE SIGMA 1 RECEPTOR SELECTIVE AGONIST ON SCOPOLAMINE-DEPENDENT COGNITIVE DEFICIT IN C57BL/6J MICE.
(2014-03) Malik, Maninder; Rangel-Barajas, Claudia; Griffin, Suzy; Sumien, Nathalie; Singh, Meharvan; Maurice, Tangui; Mach, Robert; Luedtke, Robert R.
Cognitive deficits are observed in aged population and in patients with Alzheimer’s Disease, Parkinson’s Disease, traumatic brain injury and stroke. Cognitive deficits often involve alterations in brain signaling. Currently available therapeutic drugs provide only symptomatic relief and generally become ineffective as disease progresses. Therefore, novel therapeutic agents are needed to retard and/or arrest the progressive loss of memory forming cells. Scopolamine-induced memory impairment model provides a relatively rapid and reversible screening paradigm for cognition enhancement drug discovery. In this study, mice were administered scopolamine and were used to evaluate the ability of LS-1-137, a novel drug, to improve the cognitive deficits. Our study results indicate that LS-1-137 may represent a novel therapeutic agent for the treatment of age and disease related cognitive deficits. Purpose (a): Cognitive deficits are observed in patients with Alzheimer’s Disease, Parkinson’s Disease, traumatic brain injury and stroke. These deficits often involve alterations in cholinergic signaling. Currently available therapeutic drugs provide only symptomatic relief and generally become ineffective as a neurodegenerative disorder progresses. Therefore, novel therapeutic agents are needed to retard and/or arrest the progressive loss of memory forming cells. Methods (b): A filtration-binding assay was used to characterize the binding properties of a novel sigma compound at D2-like dopamine receptors, muscarinic receptors and at sigma receptors. Co-immunoprecipitation assay was used for the quantification of Sigma 1 receptor-binding immunoglobulin protein (BiP) complex formation. LS-1-137 mediated brain-derived neurotrophic factor (BDNF) release was analyzed using enzyme-linked immunosorbent assay (ELISA). In this study, male C57BL/6J mice injected with scopolamine were used as experimental model to evaluate the in vivo cognitive properties of the test drug. The neuroprotective properties were evaluated using water maze and active avoidance test. Results (c): LS-1-137 binds with high affinity (Ki = 3.2 nM) at sigma 1 receptors and is 80-fold selective for sigma 1 compared to sigma 2 receptor. LS-1-137 binds with low affinity at D2-like (D2, D3 and D4) dopamine and muscarinic receptors. LS-1-137 was found to partially reverse the learning and memory deficits associated with scopolamine administration using a water maze test and an active avoidance task. LS-1-137 treatment modulates sigma 1 receptor- BiP complex formation and also triggers the release of BDNF from rat astrocytes. Conclusions (d): LS-1-137 may represent a novel candidate cognitive enhancer for the treatment of cholinergic muscarinic-dependent cognitive deficits.
INTERACTION OF APOE GENOTYPE, ANTIOXIDANTS AND EXERCISE ON BRAIN FUNCTION.
(2014-03) Chaudhari, Kiran; Wong, Jessica M.; Vann, Philip H.; Sumien, Nathalie
Huge rise in the incidence of azheimer's disease is projected with baby boomers' retiring age. There are very few drugs in market to manage this condition. Doctors and care takers often depend on the lifestyle modification to assist the definitive drug therapy. Most common form of lifestyle modification is exercise and diet rich in antioxidants. Further, APOE4 is a gene that is commonly expressed and a well established genetic risk factor for Alzheimer's development. We identified role of gender and APOE4 in affecting the benefits of lifestyle modification. We used a mouse model that express human APOE4 and develops memory loss at early age. This model is routinely used for alzheimer's disease related experiments. We treated these mice with treadmill based exercise and fed them with diet rich in antioxidants like vitamin C and vitamin E. After treatment these mice were tested for learning and memory abilities using interesting and non stressful techniques that involve swimming, running on rotating rod etc. We found that exercise and antioxidants are more beneficial in combination in only some of the tests. The benefits of the combination of exercise and antioxidants depends on sex, APOE genotype and age of the mouse. Purpose (a): The ε4 allele of apolipoprotein E (ApoE) has been associated with increased risk for the development of late-onset Alzheimer’s disease (AD). To prevent or reduce the appearance of brain dysfunction, a healthy lifestyle, such as exercising and eating antioxidants, is often recommended. Physical activity has been shown to have an allele-specific beneficial effect on cognition in humans and rodents. Antioxidant therapy is often suggested to improve brain function, as increased oxidative stress has been correlated with brain dysfunction, especially in ε4 carriers. Health conscious individuals are likely to combine exercise with antioxidant intake to increase protection; however recent studies have indicated a potential negative interaction of these two factors. In some cases, antioxidant intake abolished the beneficial effects of exercise. Our study aimed at determining the nature of the interaction between exercise and antioxidants on functional outcomes in a model of increased AD risk. Methods (b): Male and female mice (12month), expressing the human ApoE3 or E4, were placed under one of the treatment: Sedentary/control diet (SedCon), Sedentary /antioxidant-rich diet (Vitamins E-195mg/kg body weight/day and C-287mg/kg body weight/day; SedEC), Exercise/control diet (ExCon), Exercise/ antioxidant-rich diet (ExEC), for 8 weeks prior to behavioral testing including coordinated running (rotorod), spatial learning and memory (Morris water maze) and discriminated avoidance (T-maze). Results (c): Overall, ApoE3 mice performed better than ApoE4 mice on the rotorod test and ExEC treatment improved the performance of the male ApoE3 only. The ExEC treatment improved spatial learning in both male and female ApoE4 mice, whereas ExCon improved performance only in the ApoE4 females. Maximum spatial learning was improved with ExEC in males regardless of genotype but only in the ApoE3 females. In the discriminated avoidance task, initial learning was improved with ExCon treatment in ApoE3 mice regardless of gender. Cognitive flexibility was improved by ExEC treatment in ApoE3 male and female and in ApoE4 females but not in male ApoE4. Conclusions (d): These results indicate that genotype and sex are critical determinants in the functional outcomes of the treatment regimens.
VIGOROUS PHYSICAL ACTIVITY ASSOCIATED WITH HIGHER SCORES ON THE MMSE IN AN OLDER HISPANIC MEXICAN AMERICAN POPULATION: A HEALTH & AGING BRAIN AMONG LATINO ELDERS (HABLE) STUDY
(2014-03) Schwarzkopf, Heinz; Edwards, Melissa; Johnson, Leigh A.
Background: Physical activity has been shown to delay the onset and effects of cognitive decline, dementia and Alzheimer’s disease in the elderly. Few studies have evaluated the effects of physical activity among Hispanic Mexican Americans, a minority segment of the population, which has been shown to be less active when compared to non-Hispanic Whites. This study serves to evaluate the relationship between physical activity and cognition among Hispanic Mexican American, adults and elders Methods: Preliminary data was analyzed on 19 Hispanic Mexican Americans enrolled in the Health and Aging Brain Study among Latino Elders (HABLE), a recently developed community-based study of factors related to aging. The International Physical Activity Questionnaire (IPAQ) was utilized to assess physical activity and global cognitive functioning was evaluated with the Mini Mental Status Exam (MMSE). Separate linear regressions were conducted to analyze the relationship between hours spent engaging in either vigorous, moderate, or walking forms of physical activity and global cognitive functioning. Covariates included age, gender, education and language of test administration. Results: The results indicated that level of physical activity among Hispanic Mexican Americans differentially impacted cognitive functioning. Among those in the sample who engaged in vigorous activity, there was a significant relationship on global cognition such that increased hours of vigorous activity was positively related to global cognition (p=0.04). There was no significant association found between hours of moderate (p=0.74) or walking (p=0.70) physical activity and cognition. Conclusions: This study demonstrated the impact of level of physical activity on cognitive functioning among Hispanic Mexican Americans. . Vigorous physical activity was significantly related to better cognition among Hispanic Mexican Americans and more research is needed to further explore this relationship.
EFFECT OF ANTIOXIDANTS SUPPLEMENTATION AND MODERATE EXERCISE ON MOTOR FUNCTION IN YOUNG AND OLD MICE
(2014-03) Sidhu, Akram; Vann, Philip; Wong, Jessica; Sumien, Nathalie
The present study provided an assessment of the effect of exercise and/or vitamins on anxiety, coordinated running and motor function in young and old mice. Our data indicate that the effect of exercise and antioxidant supplementation may vary depending the age of the subject. Furthermore, there seem to be an increase their beneficial outcomes on motor function, when exercise is combined with antioxidant supplementation. Purpose (a): Aging is associated with a decline in psychomotor functioning and ability to learn new motor learning skills. Interventions such as exercise and antioxidants supplementation when investigated independently seem to have a beneficial impact on motor function in both human and animal subjects. A large number of health conscious individuals often combine exercise with vitamin supplementation, anticipating a synergistic effect maximizing their performance. Recent studies have also indicated a potential for an antagonistic action of the antioxidants on the beneficial effects of exercise. To date, it has not been well established what the nature of the interaction between antioxidant supplementation and exercise is in terms of functional outcomes and whether age will influence the outcomes. This study investigated the effects of moderate exercise and antioxidant supplementation on the motor performance of young and old mice. Methods (b): Separate groups of young (4 months), and old (20 months) male C57BL/6J mice were placed under one of the following treatments: Sedentary/control diet (SedCon), Sedentary/antioxidant-rich diet (vitamin E (128 IU/kg/d of body weight) and vitamin C (189 mg/kg/d of body weight); SedEC); Exercise/control diet (ExCon); Exercise/antioxidant-rich diet (ExEC). After 8 weeks of pre-treatment, the mice underwent a series of behavioral tests while remaining on their respective condition (elevated plus maze, spontaneous activity; coordinated running, wire suspension, and bridge walking). Results (c): Our preliminary data suggested that the time spent in the closed arms was increased in all treated mice compared to controls, and that the increase seemed more evident in the young mice. The latency to fall from a rotating rod seemed to be increased in the ExEC young and old mice when compared to all the other groups. The ExCon group had higher latency to fall while the other treatment groups seemed to have lower latencies when compared to SedCon within the young group. In the old group, only the ExEC group had higher latencies that the SedCon group while the others did not seem to differ. Latencies to fall from the bridge were increased in young groups where mice exercised (ExCon and ExEC), while they were decreased in SedEC and ExCon old mice compared to controls. Conclusions (d): Our data indicated that exercise and antioxidant supplementation can affect motor performance of young and old mice. Though preliminary, there seemed to be a differential effect dependent on the age of the mice. Lastly, there seem to be some type of interaction between antioxidant supplementation and exercise that may increase their beneficial outcomes.
THE LINK BETWEEN METABOLIC RISK FACTORS AND COGNITIVE AND AFFECTIVE FUNCTIONING
(2014-03) Cao, Linda M.; Edwards, Melissa L.; O' Bryant, Sid; Johnson, Leigh A.
Metabolic syndrome (MetS) is a group of risk factors that collectively affects cardiovascular functioning. Some research studies have shown a negative association between metabolic risk factors and cognitive and affective functioning. Currently, there is a limited amount of literature examining the implication of MetS on affective and cognitive functioning. The current study sought to address this gap in the literature and specifically explore the relationship between MetS and affective status as well as the MetS –cognition link. Purpose (a): Metabolic syndrome (MetS) is a group of risk factors that collectively affects cardiovascular functioning. Some research studies have shown a negative association between metabolic risk factors and cognitive and affective functioning. There is a limited amount of literature examining the implication of MetS on affective and cognitive functioning. The current study sought to address this gap in the literature and specifically explore the relationship between MetS and affective status as well as the MetS –cognition link. Methods (b): Data were analyzed on 431 participants (With MetS n=366; without MetS n=165) from Project FRONTIER (Facing Rural Obstacles Now to health Through Intervention, Education, and Research). Metabolic syndrome was determined based on if participants met three of the five risk factors (yes/no). Risk factors for MetS include abdominal obesity, dyslipidemia (elevated serum triglycerides, low HDL), elevated fasting glucose, and elevated blood pressure. Cognitive functioning was measured utilizing the RBANS (Repeatable Battery for the Assessment of Neuropsychological Status), MMSE (Mini Mental Status Exam), Executive Interview 25-iteMetS (EXIT25) and affective status using the GDS (Geriatric Depression Scale) and BAI (Beck Anxiety Inventory). Independent sample T-tests were utilized to explore the relationship between MetS and affective functioning as well as examine the MetS-cognition link. Results (c): The analyses revealed significant mean group differences between those who meet criteria for MetS compared to those who do not. Conclusions (d): The result of this study suggests that the metabolic risk factors are related to cognitive and affective symptoms. It is important to investigate the relationship between factors related to cardiovascular disease and cognition as well as affective functioning in an effort to enhance a physician’s clinical diagnosis and enable better treatment of patients with chronic diseases.
THE ROLE OF OXIDATIVE STRESS, INFLAMMATION, AND METABOLIC FACTORS IN ALZHEIMER’S DISEASE RISK AMONG NON-HISPANIC WHITE AND MEXICAN AMERICAN MALES
(2014-03) Septien, Spencer J.; Barber, Robert C.; Cunningham, Rebecca
Research suggests that the biological marker profile associated with Alzheimer's disease (AD) differs between non-Hispanic whites and Mexican Americans. High levels of oxidative stress are thought to precede the development of classical AD pathology including that of neurofibrillary tangles and senile plaques. Assuming a relationship between levels of oxidative stress and the pathogenesis of AD, we chose to analyze the serum biological markers of male Mexican American and non-Hispanic white AD patients under conditions of high or low oxidative stress. We stratified the sample based on the level of oxidative stress, using a cut point of 12 μM serum homocysteine. Special consideration was given to markers associated with inflammation and metabolic disease, which have been shown to impact AD pathophysiology. Baseline levels of testosterone and glutathione s transferase (GST) were also measured for each demographic. Inflammatory involvement was apparent in both Mexican American men and non-Hispanic white males, with a much more profound affect among non-Hispanic whites. Metabolic factor involvement did not appear to be as significant among non-Hispanic white males in contrast to a clear involvement in Mexican American men. Levels of oxidative stress did not appear to alter the inflammatory or metabolic profile relationship in either demographic. Baseline levels of testosterone and GST were higher in Mexican Americans. Analysis suggests that ethnicity and oxidative stress impact AD pathophysiology and associated serum markers. Purpose (a): Research suggests that the biological marker profile associated with Alzheimer's disease (AD) differs between non-Hispanic whites and Mexican Americans. High levels of oxidative stress are thought to precede the development of classical AD pathology including that of neurofibrillary tangles and senile plaques. Methods (b): Assuming a relationship between levels of oxidative stress and the pathogenesis of AD, we chose to analyze the serum biological markers of male Mexican American and non-Hispanic white AD patients under conditions of high or low oxidative stress. We stratified the sample based on the level of oxidative stress, using a cut point of 12 μM serum homocysteine. Special consideration was given to markers associated with inflammation and metabolic disease, which have been shown to impact AD pathophysiology. Baseline levels of testosterone and glutathione s transferase (GST) were also measured for each demographic. Results (c): Inflammatory involvement was apparent in both Mexican American men and non-Hispanic white males, with a much more profound affect among non-Hispanic whites. Metabolic factor involvement did not appear to be as significant among non-Hispanic white males in contrast to a clear involvement in Mexican American men. Levels of oxidative stress did not appear to alter the inflammatory or metabolic profile relationship in either demographic. Baseline levels of testosterone and GST were higher in Mexican Americans. Conclusions (d): Analysis suggests that ethnicity and oxidative stress impact AD pathophysiology and associated serum markers.
CURCUMIN SUPPLEMENTATION IMPROVES CERTAIN ASPECTS OF COGNITION AND ALLEVIATES INFLAMMATION, INDEPENDENT OF ADIPOSITY
(2014-03) Sarker, Marjana R.; Franks, Susan F.; Sumien, Nathalie; Filipetto, Frank; Forster, Michael
The study was designed to investigate the effects of curcumin on blood based biomarkers and mental health in a chronic mid-life obese state. 3 groups were studied, mice on a regular diet, on a calorically restricted diet and on a regular diet supplemented with curcumin. These mice were kept on their respective diets for 12 weeks. Two behavioral studies to investigate mental health in particular memory, were utilized. Our results conclude that curcumin dietary treatment positively affects specific domains of mental health possibly by the lowering of inflammation but this effect is independent of fat loss. Purpose (a): Midlife obesity has been recently associated with cognitive impairment that may be attributed to chronic, obesity-related inflammation and oxidative stress. Commonly used laboratory mice fed ad libitum are an analogue of weight gain in middle aged humans, since accumulating fat is more often the result of food intake exceeding energy expenditure and not solely because of a high fat diet. The current study addressed the hypothesis that curcumin supplementation, by attenuating obesity and adiposity -related inflammation, would improve cognition in a midlife obesity animal model. Methods (b): C57BL/6J male mice were maintained under ad libitum (AL) feeding until they reached peak weight at 15 months of age, as a model of inactivity-related weight gain. The mice were subsequently assigned in groups of 19 to: (i) remain on AL, (ii) receive 30% caloric restriction (CR) or (iii) receive curcumin in their AL diet (1000 mg/kg diet, CURC) for 12 weeks. Mice underwent tail bleeds for the inflammatory markers, interleukin 6 (IL-6) and C-reactive protein (CRP) and, after 8 weeks of dietary treatment, spatial cognitive function was tested using a Morris water maze, followed by testing for cognitive flexibility using a discriminated avoidance, serial reversal task. Visceral (VAT) and subcutaneous (SAT) adipose tissue was collected after 12 weeks of the treatments. Results (c): Mice maintained on CR weighed significantly less than mice on the CURC and AL diets by the third week of treatment. Food intake of the CURC group was significantly higher than AL. Mice on CR and CURC diets took fewer trials than AL to reach criterion during the second reversal session of discriminated avoidance, suggesting that both conditions improved cognitive flexibility. However, there were no significant differences between the groups in their spatial cognitive performance. Mice maintained on CR had significantly less VAT and SAT compared to mice on CURC and AL. Curcumin supplementation did not significantly impact IL-6 levels but it did reduce CRP relative to AL mice. Conclusions (d): Results suggest that in a midlife obesity animal model, curcumin supplementation has positive effects on frontal cortical functions that may be linked to an anti-inflammatory action. It appears that these effects may be independent of adiposity. Curcumin intake may also facilitate energy expenditure or diminish efficiency, as suggested by the increase in energy intake in the absence of weight loss in the CURC mice. Future studies will determine the metabolic and cognitive consequences of higher curcumin doses.
PRESENILIN-1 IS INVOLVED IN THE AGE-PROVOKING EFFECT OF REPEATED ETHANOL WITHDRAWAL.
(2014-03) Metzger, Daniel; Das, Hriday; Jung, Marianna
Alcohol is the most abused drug in the United States, and its abuse often creates a medical disorder (alcoholism) of which symptoms include withdrawal syndromes upon the abrupt cessation of drinking. Ethanol withdrawal (EW) syndromes (e.g. anxiety and seizure) are largely hyperexcitatory due to the upregulation of excitatory molecule, glutamate. We have previously demonstrated that repeated exposure to and withdrawal (called repeated EW herein) from ethanol hastens brain aging through increasing stress-activated protein p38. In this study, we intended to characterize the effects of repeated EW on the expression of age-related protein presenilin-1 (PS1) and PS1's relationship with p38. PS1 has been shown to be over-expressed in the brain with Alzheimer's disease. Young adult or old rats received a control diet or an ethanol diet for 4 weeks and withdrawn for two weeks. This procedure was repeated once more. Rats were then humanely sacrificed at the end of the ethanol program and whole brains were collected to measure PS1 level using an immunoblot method. Separately, HT22 cells were exposed to glutamate (5 mM) for 24 hours with or without the inhibitor of p38 (SB203580) treatment and then tested for PS1 levels. PS1 expression was significantly higher in old rats than young rats and in repeated EW rats than control diet rats. Glutamate treatment dramatically increases PS1 level in a manner that is attenuated by cotreatment with p38 inhibitor. These data suggest that repeated EW acts as an age-provoking stressor through PS1-upregulation. The increase in PS1 appears to be mediated through glutamate-induced p38. These observations provide a new mechanistic insight into glutamate-p38-PS1 link underlying the aging-like effect of repeated EW. Supported by NIH/AA018747 and IAADR. Purpose (a): In this study, we intended to characterize the effects of repeated EW on the expression of age-related protein presenilin-1 (PS1) and PS1's relationship with p38. PS1 has been shown to be over-expressed in the brain with Alzheimer's disease. Methods (b): Young adult or old rats received a control diet or an ethanol diet for 4 weeks and withdrawn for two weeks. This procedure was repeated once more. Rats were then humanely sacrificed at the end of the ethanol program and whole brains were collected to measure PS1 level using an immunoblot method. Separately, HT22 cells were exposed to glutamate (5 mM) for 24 hours with or without the inhibitor of p38 (SB203580) treatment and then tested for PS1 levels. Results (c): PS1 expression was significantly higher in old rats than young rats and in repeated EW rats than control diet rats. Glutamate treatment dramatically increases PS1 level in a manner that is attenuated by cotreatment with p38 inhibitor. These data suggest that repeated EW acts as an age-provoking stressor through PS1-upregulation. The increase in PS1 appears to be mediated through glutamate-induced p38. Conclusions (d): These observations provide a new mechanistic insight into glutamate-p38-PS1 link underlying the aging-like effect of repeated EW.
COMORBID DIABETES AND DEPRESSION AND INCREASED RISK FOR COGNITIVE IMPAIRMENT IN MEXICAN AMERICANS
(2014-03) Dickensheets, Tony; Johnson, Leigh; Hall, James; Obryant, Sid
Background: By 2050, the percent of Hispanics in America age 65 and above will nearly triple compared to other ethnic groups. During this timeframe, the numbers of Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI, a prodromal stage to AD) cases among Hispanic elders is expected to grow exponentially. Given that 65% of the U.S. Hispanic population is Mexican American (MA), this ethnic group represent the fastest growing segment of the aging population, which will be disproportionately impacted by MCI and /AD in the near future. Recent work from our group suggest that depression is a significant risk factor for MCI and AD among Mexican Americans while many other “established” risk factors among non-Hispanic whites (i.e. education, gender, hypertension, diabetes, ApoEε4 genotype) are not. Another important risk factor among this population is diabetes (DM). Depression and DM have been shown to be pathologically linked several times in the past, however little research has examined the affect that comorbidity of depression and DM has on cognitive impairment in an ethnically diverse sample Purpose (a): To determine whether there is a connection between depression, diabetes and Alzheimer's disease in the Mexican American population. Methods (b): Methods: This study used data from three separate cohorts: HABLE, TARCC, and Project FRONTIER. In HABLE data was collected from 208 MA (AGE= 62years; EDU=7years); TARCC had 2080 Non- Hispanic white (AGE=75; EDU=15years) and 543 MA (AGE=70; EDU=11); Project FRONTIER had 330 non-Hispanic white (AGE=65; EDU=13) and 233 MA (AGE=55; EDU=7years). Logistic regression analyses were conducted to examine comorbid diagnosis of depression and diabetes on Alzheimer’s disease diagnosis or a diagnosis of Mild Cognitive Impairment. Covariates entered into the model were age, education, and gender. Results (c): Results: Comorbid diagnosis of diabetes and depression was significantly related to diagnosis of Mild Cognitive Impairment in Mexican Americans across all three cohorts: TARCC (odds ratio [OR]= 8.6, 95% CI=1.5 to 2.7); HABLE (odds ratio [OR]= 2.4, 95% CI= 1.3-3.2), and FRONTIER (odds ratio [OR]= 2.6, 95% CI=1.2 to 6.4). TARCC was the only cohort with a large enough sample of AD patients to run the analyses split by ethnicity. In TARCC, comorbidity was related to AD diagnosis in MA (odds ratio [OR]= 10.4, 95%=1.2-2.7), and narrowly related in Non-Hispanic Whites (odds ratio [OR]= 8.3, 95%=.14 to 1.4). Conclusions (d): Discussion: Comorbid diagnosis of depression and diabetes increases risk for diagnosis of cognitive impairment, and Mexican Americans were found to be at greater risk than non- Hispanic whites for Mild Cognitive Impairment. These findings were validated across multiple cohorts, and could have significant clinical implications.
RBAP48 AS A POTENTIAL MEMORY GENE
(2014-03) Manheim, Jessica; Rybalchenko, Nataliya; Singh, Meharvan
Aging individuals tend to experience cognitive decline, which provide an opportunity to investigate why some individuals age successfully while others do not. Our study investigates RbAp48, a gene related to cognitive function, to determine if the expression of this “memory gene” declines with age. Our data suggests that RbAp48 does decrease with age, and future studies will test whether steroid hormones, which have known influences on cognitive function, play a role in regulating RbAp48 gene expression. Purpose (a): With aging, there is a tendency for humans to experience cognitive decline. These variations in cognitive functioning provide an opportunity to investigate the reasons why some individuals age successfully versus those that do not. In a comprehensive analysis of gene regulation in the normal aging processes, it was recently shown that the histone binding protein, RbAp48, is implicated in age-related memory loss. Given the suggested role of RbAp48 in cognitive function, we sought to determine if, in animal models of aging currently being used in our laboratory, RbAp48 declines with age. Methods (b): We evaluated the expression of RbAp48 in the hippocampus of female C57Bl/6 mice that were 7.5 months and 25.5 months of age, representing young adult and old mice. RbAp48 mRNA was assessed using reverse transcriptase (rt) conversion of RNA to cDNA, followed by real time polymerase chain reaction (PCR). In parallel, the levels of GAPDH, a “housekeeping” gene, was measured to take into consideration variation in starting material. Differences in expression of RbAp48 were based on the delta-delta CT methodology published by Livak and Schmittgen (2001). Statistical evaluation of differences between experimental groups was determined using a two-tailed t-test. Results (c): Our data revealed an approximate 21% reduction in the levels of RbAp48 mRNA in the 25.5 month mice, compared to the 7.5 month mice. While not statistically significant (n=3, p=0.0791), we anticipate that these data warrant further analysis and expansion of our sample size to more reliably ascertain differences as a function of chronological age. Conclusions (d): These studies suggest that the expression of RbAp48, a presumptive “memory gene”, declines with age. Our future studies will determine if the steroid hormones, estrogen and progesterone, which have known influences on cognitive function, regulate the expression of RbAp48.

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