In previous studies, we consistently found that approximately 30% of asymptomatic healthy older adults silently aspirated liquids during a flexible endoscopic evaluation of swallowing (FEES), and that their aspiration status was stable for the following year. However, no studies have systematically evaluated effects of silent aspiration on lung parenchyma and airways. We used computed tomography (CT) to compare lungs of healthy older adult aspirators versus nonaspirators. We hypothesized that CT images would show pulmonary differences in healthy older adult aspirators versus nonaspirators.
Fifty healthy older adults (25 aspirators and 25 nonaspirators) who participated in a previous FEES were randomly selected. CT scans were performed; on inspiration, lung views were taken at 1.25 mm and 2.5 mm windows; on expiration, lung views were taken at 2.5 mm. CT scans were reviewed by radiologists blinded to group assignment. Outcomes included bronchiectasis, bronchiolectasis, bronchial wall thickening, parenchymal band, fibrosis, air trapping, intraluminal airway debris, and tree-in-bud pattern.
Chi-square analyses between aspirators and nonaspirators found no statistically significant differences between aspirators and nonaspirators for any outcomes (p > 0.05). Logistic regression analyses adjusted for smoking did not change the results.
There were no differences in pulmonary CT findings between healthy older adult aspirators and nonaspirators. This study adds to the evidence that some aspiration may be within the range of normal for older adults, or at least does not contribute to a change in pulmonary appearance on CT images.
aspiration; computed tomography; pulmonary; swallowing
Data on cardiovascular diseases (CVD) and cognitive decline are conflicting. Our objective was to investigate if CVD is associated with an increased risk for cognitive decline and to examine whether hypertension, diabetes, or adiposity modify the effect of CVD on cognitive functioning.
Methods and Results
Prospective follow‐up of 6455 cognitively intact, postmenopausal women aged 65 to 79 years old enrolled in the Women's Health Initiative Memory Study (WHIMS). CVD was determined by self‐report. For cognitive decline, we assessed the incidence of mild cognitive impairment (MCI) or probable dementia (PD) via modified mini‐mental state examination (3 MS) score, neurocognitive, and neuropsychiatric examinations. The median follow‐up was 8.4 years. Women with CVD tended to be at increased risk for cognitive decline compared with those free of CVD (hazard ratio [HR], 1.29; 95% CI: 1.00, 1.67). Women with myocardial infarction or other vascular disease were at highest risk (HR, 2.10; 95% CI: 1.40, 3.15 or HR, 1.97; 95% CI: 1.34, 2.87). Angina pectoris was moderately associated with cognitive decline (HR 1.45; 95% CI: 1.05, 2.01) whereas no significant relationships were found for atrial fibrillation or heart failure. Hypertension and diabetes increased the risk for cognitive decline in women without CVD. Diabetes tended to elevate the risk for MCI/PD in women with CVD. No significant trend was seen for adiposity.
CVD is associated with cognitive decline in elderly postmenopausal women. Hypertension and diabetes, but not adiposity, are associated with a higher risk for cognitive decline. More research is warranted on the potential of CVD prevention for preserving cognitive functioning.
cardiovascular diseases; cognitive decline; postmenopausal women
Physical function declines, and markers of inflammation increase with advancing age,
even in healthy persons. Microbial translocation (MT) is the systemic exposure to
mucosal surface microbes/microbial products without overt bacteremia and has been
described in a number of pathologic conditions. We hypothesized that markers of MT,
soluble CD14 (sCD14) and lipopolysaccharide (LPS) binding protein (LBP), may be a source
of chronic inflammation in older persons and be associated with poorer physical
We assessed cross-sectional relationships among two plasma biomarkers of MT (sCD14 and
LBP), physical function (hand grip strength, short physical performance battery [SPPB],
gait speed, walking distance, and disability questionnaire), and biomarkers of
inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis
factor-alpha (TNF-α), TNF-α soluble receptor 1 [TNFsR1]) in 59 older
(60–89 years), healthy (no evidence of acute or chronic illness) men and
LBP was inversely correlated with SPPB score and grip strength (p
= .02 and p < .01, respectively) and positively correlated
with CRP (p = 0.04) after adjusting for age, gender, and body
mass index. sCD14 correlated with IL-6 (p = .01), TNF-α
(p = .05), and TNFsR1 (p < .0001).
Furthermore, the correlations between LBP and SPPB and grip strength remained
significant after adjusting for each inflammatory biomarker.
In healthy older individuals, LBP, a surrogate marker of MT, is associated with worse
physical function and inflammation. Additional study is needed to determine whether MT
is a marker for or a cause of inflammation and the associated functional
Microbial translocation; Inflammation; Physical function; Microbiome
This analysis delineates the predisposing, need, and enabling factors that are significantly associated with regular and recent dental care in a multi-ethnic sample of rural older adults.
A cross-sectional comprehensive oral health survey conducted with a random, multi-ethnic (African American, American Indian, white) sample of 635 community-dwelling adults aged 60 years and older was completed in two rural southern counties.
Almost no edentulous rural older adults received dental care. Slightly more than one-quarter (27.1%) of dentate rural older adults received regular dental care and slightly more than one-third (36.7%) received recent dental care. Predisposing (education) and enabling (regular place for dental care) factors associated with receiving regular and recent dental care among dentate participants point to greater resources being the driving force in receiving dental care. Contrary to expectations of the Behavioral Model of Health Services, those with the least need (e.g., better self-rated oral health) received regular dental care; this has been referred to as the Paradox of Dental Need.
Regular and recent dental care are infrequent among rural older adults. Those not receiving dental care are those who most need care. Community access to dental care and the ability of older adults to pay for dental care must be addressed by public health policy to improve the health and quality of life of older adults in rural communities.
dental care utilization; aging; gerontology; rural health; minority health; public health policy
To identify treatable risk factors for aspiration in older adults—particularly those associated with sarcopenia – we examined tongue composition. We hypothesized that 1) isometric and swallowing posterior tongue strength would positively correlate with posterior tongue adiposity, and 2) healthy older adults who aspirate would have greater tongue adiposity than healthy older adults who did not aspirate.
Participants were 40 healthy adults, comprised of 20 aspirators (Mean age = 78 years) and 20 non-aspirators (Mean age = 81 years), as identified via flexible endoscopic evaluation of swallowing. Measures of maximal isometric posterior tongue strength and posterior swallowing tongue strength were acquired via tongue manometry. An index of posterior tongue adiposity was acquired via computed tomography for a 1 cm region of interest.
Posterior tongue adiposity was correlated with posterior tongue isometric (r = .32, p = 0.05) but not swallowing pressures (p > 0.05) as examined with separate partial correlation analyses. Tongue adiposity did not significantly differ as a function of age, gender, or aspiration status (p > 0.05).
Lower posterior isometric tongue strength was associated with greater posterior tongue adiposity. However, aspiration in healthy older adults was not affected by posterior tongue adiposity. This finding offers insight into the roles of tongue composition and strength in healthy older adults.
Tongue; Adiposity; Fat; Swallowing; Older Adults; Computed Tomography
This analysis examines the associations of oral health with social integration among ethnically diverse (African American, American Indian, white) rural older adults. Data are from a cross-sectional survey of 635 randomly selected community-dwelling adults aged 60+. Measures include self-rated oral health, number of teeth, number of oral health problems, social engagement, and social network size. Minority elders have poorer oral health than do white older adults. Most rural elders have substantial social engagement and social networks. Better oral health (greater number of teeth) is directly associated with social engagement, while the relationship of oral health to social network size is complex. The association of oral health with social engagement does not differ by ethnicity. Poorer oral health is associated with less social integration among African American, American Indian and white elders. More research on the ways oral health affects the lives of older adults is warranted.
Oral health disparities; social engagement; social network; rural aging
To better understand the contribution of age to the development of osteoarthritis (OA).
Surgical destabilization of the medial meniscus (DMM) was used to model OA in 12 week-old and 12 month-old male C57/BL6 mice. OA severity was evaluated histologically. RNA used for microarrays and real-time PCR was isolated from joint tissue collected from the medial side of the joint, including cartilage, meniscus, subchondral bone, and joint capsule with synovium. Computational analysis was used to identify patterns of gene expression and immunohistochemistry to evaluate tissue distribution of selected proteins.
OA was more severe in older mice than young. Only 55 genes showed a similar expression with DMM-induced OA in the two age groups while 493 genes showed differential expression, the majority having increased expression in older mice. Functional categories for similarly expressed genes included extracellular matrix and cell adhesion related genes; differentially expressed genes included muscle structure and development and immunoglobulin domain genes. Comparison of expression in the sham control joints revealed an age-related decrease in matrix gene expression and an increase in immune and defense response genes. IL-33 was present in multiple joint tissue cells while CCL21 was more localized to chondrocytes and meniscal cells. Periostin was found in the extracellular matrix of cartilage and meniscus.
Age affects both the basal pattern of gene expression in joint tissues and the response to surgically-induced OA. Examining tissue from the joint beyond only cartilage revealed novel genes and proteins that would be important to consider in OA.
Despite successful approaches to preserve organs, tissues, and isolated cells, the maintenance of stem cell viability and function in body fluids during storage for cell distribution and transportation remains unexplored. The aim of this study was to characterize urine-derived stem cells (USCs) after optimal preservation of urine specimens for up to 24 hours. A total of 415 urine specimens were collected from 12 healthy men (age range 20–54 years old). About 6×104 cells shed off from the urinary tract system in 24 hours. At least 100 USC clones were obtained from the stored urine specimens after 24 hours and maintained similar biological features to fresh USCs. The stored USCs had a “rice grain” shape in primary culture, and expressed mesenchymal stem cell surface markers, high telomerase activity, and normal karyotypes. Importantly, the preserved cells retained bipotent differentiation capacity. Differentiated USCs expressed myogenic specific proteins and contractile function when exposed to myogenic differentiation medium, and they expressed urothelial cell-specific markers and barrier function when exposed to urothelial differentiation medium. These data demonstrated that up to 75% of fresh USCs can be safely persevered in urine for 24 hours and that these cells stored in urine retain their original stem cell properties, indicating that preserved USCs could be available for potential use in cell-based therapy or clinical diagnosis.
This study categorizes older adults living in rural areas by denture status, assesses the frequency of wearing dentures during meals, and determines whether denture status or use is associated with dietary quality or the number of foods avoided. A multi-ethnic population-based sample of adults ≥60 years (N=635) in the rural US was interviewed. Survey included denture use, removing dentures before eating, and foods avoided due to oral health problems. Dietary intakes were converted into Healthy Eating Index-2005 scores. Sixty percent wore removable dentures of some type; 55% never, 27% sometimes, and 18% always removed dentures when eating. More frequent removal was associated with lower dietary quality and more foods avoided. Those with severe tooth loss had the lowest dietary quality and avoided the most foods. Many rural older adults wear dentures. Learning how they adapt to denture use will offer insight into their nutritional self-management and help explain differences in dietary quality.
Scant data exist on normal bolus dwell time assessed during Flexible Endoscopic Evaluation of Swallowing (FEES). The purpose of this study was to examine bolus dwell time in healthy older adults. Since it has been previously reported that some healthy older adults aspirate, we also sought to determine if bolus dwell time varied as function of aspiration status.
Seventy-six healthy volunteers from the 7th, 8th, and 9th decades of life participated. Dwell times were analyzed via FEES as a function of pharyngeal location, liquid type, delivery method, purée type, viscosity, age, and gender.
Longer dwell times were evidenced with the eldest participants, straw delivery, and the smallest volume. Adults in the 9th decade were 4.8 (p = 0.01) and 3.8 (p = 0.02) times more likely to have longer dwell times at the vallecula and 7.1 (p = 0.002) and 3.8 (p = 0.02) at the pyriform sinus than those in the 7th and 8th decades, respectively. Longer dwell times at the vallecula and pyriform sinuses were 2 and 2.38 times (p < 0.0001) more likely for straw than cup delivery, respectively. Five ml boluses were 1.5 times (p < 0.05) more likely to result in longer dwell times than larger volumes. Bolus dwell times did not significantly differ as a function of aspiration status.
Advanced age, straw delivery, and small volumes yielded longer dwell times. These variables should be considered before diagnosing an abnormal bolus dwell time in elder patients.
pharyngeal response; bolus dwell times; swallow; older adults; endoscopic; FEES
Recently, subclinical aspiration has been identified in approximately 30% of community-dwelling older adults. Given that the tongue is a key component of the safe swallow, we hypothesized healthy older adults who aspirate will generate less tongue strength than adults who do not aspirate. Furthermore, as muscle weakness may reflect a global effect of aging, we further investigated whether tongue strength is correlated with handgrip strength.
We assessed 78 healthy community-dwelling older adults (M = 77.3 years, SD = 7.26) for aspiration status (37% aspirators) via flexible endoscopic evaluation of swallowing. Maximal isometric anterior and posterior tongue strength, anterior and posterior swallowing tongue strength, and maximum handgrip strength were measured.
Isometric tongue strength was significantly lower in aspirators versus nonaspirators (p = .03) at both the anterior (463 vs 548 mmHg, respectively) and posterior lingual locations (285 vs 370 mmHg, respectively). Likewise, swallowing tongue strength was significantly lower in aspirators versus nonaspirators at both the anterior (270 vs 317 mmHg, respectively) and posterior lingual locations (220 vs 267 mmHg, respectively). There was no difference between aspirators and nonaspirators’ handgrip strength (p > .05), although handgrip strength was correlated with posterior tongue strength (r = .34, p = .005).
Lower anterior and posterior isometric and swallowing tongue strength were dependent on aspiration status. Lower lingual strength in healthy adults may predispose them to aspiration. The correlation between tongue and handgrip strength is consistent with the hypothesis that impaired oropharyngeal strength reflects global age-related declines in muscle strength.
Swallowing; Tongue; Handgrip; Aspiration; Healthy
To quantify: (1) prevalence of dry mouth; (2) association of dry mouth with beverage intake and dietary quality; and (3) association of dry mouth with self-reported dietary accommodations to oral health deficits.
Cross-sectional study; data from self-reports.
A multi-stage cluster sampling design was used to recruit 622 participants aged 60+ from rural North Carolina counties with substantial African American and American Indian populations.
Data included the 11-item Xerostomia Inventory (XI); higher scores connote greater impact from dry mouth; a food frequency questionnaire (converted into Health Eating Index-2005 scores); and survey items on foods modified before consumption or avoided due to oral health problems.
Dry mouth was associated with being female, lower education, and income below the poverty level. Although overall beverage consumption did not vary with dry mouth, consumption of certain sugar-sweetened beverages was positively associated with dry mouth. Overall dietary quality did not differ with dry mouth, but more severe dry mouth was associated with lower intake of whole grains and higher intakes of total fruits. Dry mouth was strongly associated with self-reported modification and avoidance of foods. Those in the highest tertile of dry mouth were more likely to modify several foods compared to the lowest tertile, and were more likely to avoid three or more foods.
Older adults appear to modify foods or selectively avoid foods in response to perceived dry mouth. Despite these behaviors, dry mouth does not result in reduced dietary quality.
xerostomia; rural; nutrition; oral health
Constraint-induced movement therapy (CIMT) has received considerable attention as an intervention to enhance motor recovery and cortical reorganization after stroke.
The present study represents the first multicenter effort to measure cortical reorganization induced by CIMT in subjects who are in the subacute stage of recovery.
A total of 30 stroke subjects in the subacute phase (>3 and <9 months poststroke) were recruited and randomized into experimental (receiving CIMT immediately after baseline evaluation) and control (receiving CIMT after 4 months) groups. Each subject was evaluated using transcranial magnetic stimulation (TMS) at baseline, 2 weeks after baseline, and at 4-month follow-up (ie, after CIMT in the experimental groups and before CIMT in the control groups). The primary clinical outcome measure was the Wolf Motor Function Test.
Both experimental and control groups demonstrated improved hand motor function 2 weeks after baseline. The experimental group showed significantly greater improvement in grip force after the intervention and at follow-up (P = .049). After adjusting for the baseline measures, the experimental group had an increase in the TMS motor map area compared with the control group over a 4-month period; this increase was of borderline significance (P = .053).
Among subjects who had a stroke within the previous 3 to 9 months, CIMT produced statistically significant and clinically relevant improvements in arm motor function that persisted for at least 4 months. The corresponding enlargement of TMS motor maps, similar to that found in earlier studies of chronic stroke subjects, appears to play an important role in CIMT-dependent plasticity.
Plasticity; Recovery; Transcranial magnetic stimulation; Upper extremity
The medical and personal circumstances of older persons present challenges for designing and analyzing clinical research studies in which they participate. These challenges presented by elderly study samples are not unique but they are sufficiently distinctive to warrant deliberate and systematic attention. Their distinctiveness originates in the multifactorial etiologies of geriatric health syndromes and the multiple morbidities accruing with aging at the end of life. The objective of this article is to identify a set of statistical challenges arising in research with older persons that should be considered conjointly in the practice of clinical research and that should be addressed systematically in the training of biostatisticians intending to work with gerontologists, geriatricians, and older study participants. The statistical challenges include design and analytical strategies for multicomponent interventions, multiple outcomes, state transition models, floor and ceiling effects, missing data, and mixed methods. The methodological and pedagogical themes of this article will be integrated by a description of a proposed subdiscipline of “gerontologic biostatistics” and supported by the introduction of new set of statistical resources for researchers working in this area. These conceptual and methodological resources have been developed in the context of several collaborating Claude D. Pepper Older Americans Independence Centers.
clinical research; statistics; aging; study design
1) quantify the association between food avoidance and modification due to oral health problems; 2) quantify the relationship between these nutritional self-management strategies and dietary quality; and 3) determine foods associated with these self-management strategies.
Rural North Carolina
Six hundred thirty-five community-dwelling adults aged 60 years and older.
Demographic and food frequency data and oral health assessments were obtained during home visits. Avoidance (none, 1–2 foods, 3–14 foods) and modification (0–3 foods, 4–5 foods) was assessed for foods representing oral health challenges. Food frequency data were converted into Healthy Eating Index-2005 (HEI-2005) scores. Linear regression models tested the significance of associations between HEI-2005 measures and food avoidance and modification.
Thirty-five percent of the sample avoided 3–14 foods and 28% modified 4–5 foods. After adjusting for age, sex, ethnicity, poverty, education, and tooth loss, the total HEI-2005 score was lower (P<0.001) for persons avoiding more foods and higher for persons modifying more foods (P<0.001). Those avoiding 3–14 foods consumed more saturated fat and energy from solid fat and added sugar and lower intake of non-hydrogenated fats than those avoiding <3 foods. Those who modified 4–5 foods consumed less saturated fat and solid fat and added sugar but more total grains than those modifying <4 foods.
Food avoidance and modification due to oral health problems are associated with significant differences in dietary quality. Approaches to minimize food avoidance and promote food modification by persons having eating difficulties due to oral health conditions are needed.
dietary behaviors; minority health; oral health
Poor oral health influences the dietary quality of older individuals. The objective of this study was to relate the number of teeth to adherence to 2005 Dietary Guidelines for Americans among an ethnically diverse sample of older adults.
Design, setting, and subjects
A block cluster design was used to obtain a sample of 635 community dwelling older adults in two North Carolina counties with large African American and American Indian populations. Data were weighted to census data for ethnicity and gender. Dietary intakes were assessed using a food frequency questionnaire and converted into Healthy Eating Index-2005 (HEI-2005) scores.
326 participants had severe tooth loss (0-10 teeth) compared to 305 participants with 11+ teeth. After controlling for socioeconomic factors, those with 0-10 teeth had lower total HEI-2005 scores and consumed less Total Fruit, Meat and Beans, and Oils and more calories from Solid Fat, Alcohol, and Added Sugar compared to those with 11+ teeth. Less than 1% of those with 0-10 teeth and 4% of those with 11+ teeth met overall HEI-2005 recommendations. Those with 0-10 teeth were less likely to eat recommended amounts of Total Vegetables, Dark Green and Orange Vegetables, and Calories from Solid Fat, Alcohol, and Added Sugar.
Older adults with severe tooth loss are less likely than those with moderate to low tooth loss to meet current dietary recommendations. Nutrition interventions for older adults should take oral health status into consideration and include strategies that specifically address this as a barrier to healthful eating.
Older adults; dental health; diet quality; nutrition interventions
Purpose: Dietary variation is important for health maintenance and disease prevention among older adults. However, oral health deficits impair ability to bite and chew foods. This study examines the association between oral health and foods avoided or modified in a multiethnic rural population of older adults. It considers implications for nutrition and medical service provision to this population. Design and Methods: In-home interviews and oral examinations were conducted with 635 adults in rural North Carolina counties with substantial African American and American Indian populations. Avoidance and modification data were obtained for foods representing different dental challenges and dietary contributions. Data were weighted to census data for ethnicity and sex. Bivariate analyses of oral health measures and foods avoided used chi-square and logistic regression tests. Multivariable analyses used proportional odds or nominal regression models. Results: Whole fruits and raw vegetables were the most commonly avoided foods; substantial proportions of older adults also avoided meats, cooked vegetables, and other foods. Food avoidance was significantly associated with self-rated oral health, periodontal disease, bleeding gums, dry mouth, having dentures, and having fewer anterior and posterior occlusal contacts. Associations persisted when controlling for demographic and socioeconomic status indicators. From 24% to 68% of participants reported modifying specific fruits, vegetables, and meats. Modifying harder foods was related to location of teeth and periodontal disease and softer foods to oral pain and dry mouth. Implications: Food services for older adults should consider their oral health status. Policy changes are needed to provide oral health care in benefits for older adults.
Nutrition; Elderly; Rural; Dentition; Dentures; Congregate meals programs
The 2005 Dietary Guidelines have increased emphasis on Americans consuming a wide range of healthful foods and further reducing the consumption of less healthful ones. These recommendations are challenging for rural elders whose functional limitations, fewer resources, and limited access to foods negatively affect the quality of their diets. The purpose of this study was to characterize the diet quality of a multi-ethnic population-based sample of older adults (n=635) in the southern US. Data were collected via home visit; dietary intakes were assessed using a food frequency questionnaire and converted into Healthy Eating Index-2005 (HEI-2005) scores used to monitor adherence to Dietary Guidelines. The mean total HEI-2005 score was 61.9/100 with fewer than 2% meeting the recommended score of 80/100. After controlling for age, gender, marital status, poverty status, and education, African Americans (n=136) had higher total HEI-2005 scores compared to American Indians (n=195) and Non-Hispanic Whites (n=304) (64.5 vs. 60.1 and 61.1 respectively, p=.001). Certain HEI-2005 foods were consumed in greater amounts by particular groups, such as total fruit and meat and beans (African Americans), whole fruit and grains (African Americans and American Indians), milk (Non-Hispanic Whites), and calories from solid fat, alcohol, and added sugars (American Indians). The overall diet quality of these rural elders was not adequate as determined by the HEI-2005; however, intakes of dark green and orange vegetables were adequate, and many participants were in compliance with the added fat and sugar guidelines. Determination of factors that promote or prevent the consumption of healthful foods among rural elders may help tailor nutrition education programs for these vulnerable communities.
Older adults; diet quality; healthy eating index; rural diets
Dendritic cells (DC) play a central role in primary immune responses and become potent stimulators of the adaptive immune response after undergoing the critical process of maturation. Understanding the dynamics of DC maturation would provide key insights into this important process. Time course microarray experiments can provide unique insights into DC maturation dynamics. Replicate experiments are necessary to address the issues of experimental and biological variability. Statistical methods and averaging are often used to identify significant signals. Here a novel strategy for filtering of replicate time course microarray data, which identifies consistent signals between the replicates, is presented and applied to a DC time course microarray experiment.
The temporal dynamics of DC maturation were studied by stimulating DC with poly(I:C) and following gene expression at 5 time points from 1 to 24 hours. The novel filtering strategy uses standard statistical and fold change techniques, along with the consistency of replicate temporal profiles, to identify those differentially expressed genes that were consistent in two biological replicate experiments. To address the issue of cluster reproducibility a consensus clustering method, which identifies clusters of genes whose expression varies consistently between replicates, was also developed and applied. Analysis of the resulting clusters revealed many known and novel characteristics of DC maturation, such as the up-regulation of specific immune response pathways. Intriguingly, more genes were down-regulated than up-regulated. Results identify a more comprehensive program of down-regulation, including many genes involved in protein synthesis, metabolism, and housekeeping needed for maintenance of cellular integrity and metabolism.
The new filtering strategy emphasizes the importance of consistent and reproducible results when analyzing microarray data and utilizes consistency between replicate experiments as a criterion in both feature selection and clustering, without averaging or otherwise combining replicate data. Observation of a significant down-regulation program during DC maturation indicates that DC are preparing for cell death and provides a path to better understand the process. This new filtering strategy can be adapted for use in analyzing other large-scale time course data sets with replicates.
Hypertension (HTN) is a risk factor for dementia and animal studies suggest that centrally active (cross the blood brain barrier) angiotensin converting enzyme (ACE) inhibitors may protect against dementia beyond HTN control.
Participants in the Cardiovascular Health Study cognition substudy (mean age 75 yrs) with treated HTN and no diagnosis of heart failure (n= 1054) were followed for a median of 6 years to determine whether cumulative exposure to ACE inhibitors (as a class and by central activity), compared to other antihypertensive agents, was associated with lower risk of incident dementia, cognitive decline (by the modified mini mental state exam, 3MSE), or incident disability in instrumental activities of daily living (IADL).
Among 414 participants exposed to ACE inhibitors and 640 not, there were 158 cases of incident dementia. Compared to other anti-HTN drugs, there was no association between exposure to all ACE inhibitors and risk of dementia (HR 1.01, 95% CI 0.88–1.15), difference in 3MSE scores (−0.32 points/yr, p=0.15), or odds of IADL disability (OR (95% CI) 1.06 (0.99–1.14). Adjusted results were similar. However, centrally active ACE inhibitors were associated with 65% less decline in 3MSE scores per year of exposure (p= 0.01) and non-centrally active ACE inhibitors were associated with greater risk of incident dementia (adjusted HR 1.20 (1.00–1.43) per year of exposure) and greater odds of IADL disability (adjusted OR 1.16 (1.03–1.30) per year of exposure) compared to other anti-HTN drugs.
While ACE inhibitors as a class do not appear to be independently associated with dementia risk or cognitive decline in older hypertensive adults, there may be within class differences in regards to these outcomes. These results should be confirmed with an RCT of a centrally active ACE inhibitor in the prevention of cognitive decline and dementia.
Chronic subclinical inflammation may contribute to impaired physical function in older adults; however, more data are needed to determine whether inflammation is a common mechanism for functional decline, independent of disease or health status.
We examined associations between physical function and inflammatory biomarkers in 542 older men and women enrolled in four clinical studies at Wake Forest University between 2001 and 2006. All participants were at least 55 years and had chronic obstructive pulmonary disease, congestive heart failure, high cardiovascular risk, or self-reported physical disability. Uniform clinical assessments were used across studies, including grip strength; a Short Physical Performance Battery (SPPB; includes balance, 4-m walk, and repeated chair stands); inflammatory biomarker assays for interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and C-reactive protein (CRP); and anthropometric measures.
Higher levels of CRP and IL-6, but not TNF-α, were associated with lower grip strength and SPPB scores and longer times to complete the 4-m walk and repeated chair stands tests, independent of age, gender, and race. More importantly, these relationships were generally independent of disease status. Further adjustment for fat mass, lean mass, or percent body fat altered some of these relationships but did not significantly change the overall results.
Elevated CRP and IL-6 levels are associated with poorer physical function in older adults with various comorbidities, as assessed by a common battery of clinical assessments. Chronic subclinical inflammation may be a marker of functional limitations in older persons across several diseases/health conditions.
Inflammation; Physical function; Aging; Comorbidities
We have developed an animal model of alcohol self-administration that initially employs schedule-induced polydipsia (SIP) to establish reliable ethanol consumption under open access (22 h/d) conditions with food and water concurrently available. SIP is an adjunctive behavior that is generated by constraining access to an important commodity (e.g., flavored food). The induction schedule and ethanol polydipsia generated under these conditions affords the opportunity to investigate the development of drinking typologies that lead to chronic, excessive alcohol consumption.
Adult male cynomolgus monkeys (Macaca fascicularis) were induced to drink water and 4% (w/v in water) ethanol by a Fixed-Time 300 seconds (FT-300 seconds) schedule of banana-flavored pellet delivery. The FT-300 seconds schedule was in effect for 120 consecutive sessions, with daily induction doses increasing from 0.0 to 0.5 g/kg to 1.0 g/kg to 1.5 g/kg every 30 days. Following induction, the monkeys were allowed concurrent access to 4% (w/v) ethanol and water for 22 h/day for 12 months.
Drinking typographies during the induction of drinking 1.5 g/kg ethanol emerged that were highly predictive of the daily ethanol intake over the next 12 months. Specifically, the frequency in which monkeys ingested 1.5 g/kg ethanol without a 5-minute lapse in drinking (defined as a bout of drinking) during induction strongly predicted (correlation 0.91) subsequent ethanol intake over the next 12 months of open access to ethanol. Blood ethanol during induction were highly correlated with intake and with drinking typography and ranged from 100 to 160 mg% when the monkeys drank their 1.5 g/kg dose in a single bout. Forty percent of the population became heavy drinkers (mean daily intakes >3.0 g/kg for 12 months) characterized by frequent “spree” drinking (intakes >4.0 g/kg/d).
This model of ethanol self-administration identifies early alcohol drinking typographies (gulping the equivalent of 6 drinks) that evolve into chronic heavy alcohol consumption in primates (drinking the equivalent of 16 to 20 drinks per day). The model may aid in identifying biological risks for establishing harmful alcohol drinking.
Monkeys; Self-Administration; Ethanol; Schedule-Induced Polydipsia; Animal Models
Older heart failure (HF) patients exhibit exercise intolerance during activities of daily living. We hypothesized that reduced lower extremity blood flow (LBF) due to reduced forward cardiac output would contribute to submaximal exercise intolerance in older HF patients.
Methods and Results
Twelve HF patients both with preserved and reduced left ventricular ejection fraction (LVEF) (aged 68 ± 10 years) without large (aorta) or medium sized (iliac or femoral artery) vessel atherosclerosis, and 13 age and gender matched healthy volunteers underwent a sophisticated battery of assessments including a) peak exercise oxygen consumption (peak VO2), b) physical function, c) cardiovascular magnetic resonance (CMR) submaximal exercise measures of aortic and femoral arterial blood flow, and d) determination of thigh muscle area. Peak VO2 was reduced in HF subjects (14 ± 3 ml/kg/min) compared to healthy elderly subjects (20 ± 6 ml/kg/min) (p = 0.01). Four-meter walk speed was 1.35 ± 0.24 m/sec in healthy elderly verses 0.98 ± 0.15 m/sec in HF subjects (p < 0.001). After submaximal exercise, the change in superficial femoral LBF was reduced in HF participants (79 ± 92 ml/min) compared to healthy elderly (222 ± 108 ml/min; p = 0.002). This occurred even though submaximal stress-induced measures of the flow in the descending aorta (5.0 ± 1.2 vs. 5.1 ± 1.3 L/min; p = 0.87), and the stress-resting baseline difference in aortic flow (1.6 ± 0.8 vs. 1.7 ± 0.8 L/min; p = 0.75) were similar between the 2 groups. Importantly, the difference in submaximal exercise induced superficial femoral LBF between the 2 groups persisted after accounting for age, gender, body surface area, LVEF, and thigh muscle area (p ≤ 0.03).
During CMR submaximal bike exercise in the elderly with heart failure, mechanisms other than low cardiac output are responsible for reduced lower extremity blood flow.
Temporal gene expression profiles characterize the time-dynamics of expression of specific genes and are increasingly collected in current gene expression experiments. In the analysis of experiments where gene expression is obtained over the life cycle, it is of interest to relate temporal patterns of gene expression associated with different developmental stages to each other to study patterns of long-term developmental gene regulation. We use tools from functional data analysis to study dynamic changes by relating temporal gene expression profiles of different developmental stages to each other.
We demonstrate that functional regression methodology can pinpoint relationships that exist between temporary gene expression profiles for different life cycle phases and incorporates dimension reduction as needed for these high-dimensional data. By applying these tools, gene expression profiles for pupa and adult phases are found to be strongly related to the profiles of the same genes obtained during the embryo phase. Moreover, one can distinguish between gene groups that exhibit relationships with positive and others with negative associations between later life and embryonal expression profiles. Specifically, we find a positive relationship in expression for muscle development related genes, and a negative relationship for strictly maternal genes for Drosophila, using temporal gene expression profiles.
Our findings point to specific reactivation patterns of gene expression during the Drosophila life cycle which differ in characteristic ways between various gene groups. Functional regression emerges as a useful tool for relating gene expression patterns from different developmental stages, and avoids the problems with large numbers of parameters and multiple testing that affect alternative approaches.