Normal Elderly Research Articles

P4‐148: Microtubule‐associated protein tau H2 haplotype is associated with frontotemporal atrophy in cognitively normal elders

P4‐148: Microtubule‐associated protein tau H2 haplotype is associated with frontotemporal atrophy in cognitively normal elders

IC‐O2‐01: Microtubule‐associated protein tau H2 haplotype is associated with frontotemporal atrophy in cognitively normal elders

IC‐O2‐01: Microtubule‐associated protein tau H2 haplotype is associated with frontotemporal atrophy in cognitively normal elders

Identification of Alzheimer disease-associated variants in genes that regulate retromer function

The proteolytic processing of amyloid precursor protein (APP) to generate the neurotoxic amyloid β (Aβ) peptide is central to the pathogenesis of Alzheimer disease (AD). The endocytic system mediates the processing of APP by controlling its access to secretases that cleave APP. A key mediator of APP localization is SorL1—a membrane protein that has been genetically linked to AD. The retromer complex is a conserved protein complex required for endosome-to-Golgi retrieval of a number of physiologically important membrane proteins including SorL1. Based on the prior suggestion that endocytosis and retromer sorting pathways might be involved, we hypothesized that variants in other genes in this pathway might also modulate AD risk. Genetic association of AD with 451 polymorphisms in 15 genes encoding retromer or retromer-associated proteins was tested in a Caucasian sample of 8309 AD cases and 7366 cognitively normal elders using individual single nucleotide polymorphism (SNP)- and gene-based tests. We obtained significant evidence of association with KIAA1033 (VEGAS p = 0.025), SNX1 (VEGAS p = 0.035), SNX3 (p = 0.0057), and RAB7A (VEGAS p = 0.018). Ten KIAA1033 SNPs were also significantly associated with AD in a group of African Americans (513 AD cases, 504 control subjects). Findings with four significant SNX3 SNPs in the discovery sample were replicated in a community-based sample of Israeli-Arabs (124 AD cases, 142 control subjects). We show that Snx3 and Rab7A proteins interact with the cargo-selective retromer complex through independent mechanisms to regulate the membrane association of retromer and thereby are key mediators of retromer function. These data implicate additional AD risk genes in the retromer pathway and formally demonstrate a direct link between the activity of the retromer complex and the pathogenesis of AD.

Performances of Verbal Fluency Task in Normal Elderly: Effects of Gender and Educational Level by Categories

Performances of Verbal Fluency Task in Normal Elderly: Effects of Gender and Educational Level by Categories

Multicenter validation of a bedside antisaccade task as a measure of executive function

To create and validate a simple, standardized version of the antisaccade (AS) task that requires no specialized equipment for use as a measure of executive function in multicenter clinical studies. The bedside AS (BAS) task consisted of 40 pseudorandomized AS trials presented on a laptop computer. BAS performance was compared with AS performance measured using an infrared eye tracker in normal elders (NE) and individuals with mild cognitive impairment (MCI) or dementia (n = 33). The neuropsychological domain specificity of the BAS was then determined in a cohort of NE, MCI, and dementia (n = 103) at UCSF, and the BAS was validated as a measure of executive function in a 6-center cohort (n = 397) of normal adults and patients with a variety of brain diseases. Performance on the BAS and laboratory AS task was strongly correlated and BAS performance was most strongly associated with neuropsychological measures of executive function. Even after controlling for disease severity and processing speed, BAS performance was associated with multiple assessments of executive function, most strongly the informant-based Frontal Systems Behavior Scale. The BAS is a simple, valid measure of executive function in aging and neurologic disease.

Left Temporal Lobe Subcortical Hyperintensities Correlate with Verbal Learning and Memory in Alzheimer's Disease and Normal Elderly (P03.087)

Objective: To examine the relationship between temporal lobe (TL) SH volumes and CVLT performance in a group of AD patients [n=139, mean age(SD)=73.8(9.2)] and normal elderly [NC; n=69, mean age(SD)=70(8.2)]. Background Subcortical hyperintensities (SH) are commonly observed on Proton Density (PD) and T2-weighted (T2) MRIs in the elderly and are believed to indicate cerebral small vessel disease (Wolf et al. 2000), often associated with decreased performance on various neuropsychological tests (DeGroot et al. 2000), particularly in speed of information processing (Nordahl et al. 2006). The California Verbal Learning Test (CVLT; Delis et al. 1986) is commonly used to measure verbal learning and memory and has been shown to predict conversion from mild cognitive impairment (MCI) to Alzheimer9s Disease (AD; Lekeu et al. 2010). Design/Methods: The Lesion Explorer (LE; Ramirez et al. 2011) processing pipeline was used to quantify SH and the Semi-Automated Brain Region Extraction (SABRE; Dade et al. 2004) parcellation method was used to obtain standardized regional tissue compartment volumes. Linear regression using backwards elimination of non-significant variables was used to analyze the relationship between volumetric data and neuropsychological scores. Age, years of education and brain parenchymal fraction were included as covariates. Non-parametric tests (Mann-Whitney) were used for group comparisons as required. Results: When comparing left and right TL SH, a significant inverse relationship was found between the total acquisition CVLT score and left TL SH (β=-0.211, p Conclusions: The cerebrovascular contribution to the expression of dementia has been increasingly recognized in AD and cognitive aging and in the conversion from MCI to dementia (Carmichael et. al, 2010). This study suggests that SH are associated with learning deficits in AD and NC and should be accounted for when studying brain behaviour relationships in these groups. Disclosure: Dr. Black has received personal compensation for activities with Novartis Pharmaceuticals, Pfizer, GlaxoSmithKline, Roche Pharmaceuticals, and Bristol-Myers Squibb. Dr. Black has received research support from Novartis Pharmaceuticals, Pfizer, Roche, and GlaxoSmithKline. Dr. McNeely has nothing to disclose. Dr. Ramirez has received personal compensation for activities with Pfizer as a speaker. Dr. Scorrano has received personal compensation for activities with Pfizer as a speaker. Dr. Szilagyi has received personal compensation for activities with Pfizer, Inc as a speaker. Dr. Kiss has nothing to disclose. Dr. Stuss has nothing to disclose.

Physical Activity and Cognitive Trajectories in Cognitively Normal Middle-Aged and Elderly Adults: Longitudinal Findings from the Adult Children Study (S24.002)

Objective: To examine the association between physical activity levels and cognitive functioning over 1-6 years of follow-up in a sample of cognitively normal healthy middle-aged and older adults. We hypothesized that higher levels of physical activity would be associated with better cognitive performance at baseline and on subsequent follow-up assessments. Background As Alzheimer9s disease research shifts focus from curative treatments to prevention measures, physical activity has become an area of interest. There is emerging evidence suggesting that increased physical activity may protect against cognitive decline, the primary symptom of Alzheimer9s disease. In the existing literature on physical activity and dementia risk, most of the studies are cross sectional, and use measures that assess general cognitive functioning. It was our aim to strengthen the findings of previous cross-sectional studies by using a large sample and an increased number of sensitive cognitive tests, and also to show that these effects can be seen longitudinally. Design/Methods: One-hundred seventy-three middle-aged and elderly (mean age 60.7 +/- 8 years) cognitively normal participants (Clinical Dementia Rating of 0) completed a self-report measure of physical activity derived from the Nurses9 Health Study Exercise Questionnaire and a comprehensive battery of neuropsychological tests, including measures of processing speed, basic attention, executive functioning, and episodic memory. Cross-sectional data were analyzed with hierarchical linear regression modeling, and longitudinal data were analyzed with linear mixed modeling. Results: In our cross sectional analyses, we found that higher physical activity levels were significantly associated with better performance on tests of processing speed, executive functioning, and verbal episodic memory. However, levels of physical activity had no significant associations with cognitive functioning over 1-6 years of follow-up. Conclusions: Our results suggest that physical activity levels do not predict cognitive trajectories in middle aged and older cognitively normal populations. Supported by: National Institute on Aging grants: P50 AG05681, P01 AG03991, and P01 AG026276; the Charles and Joanne Knight Alzheimer Research Initiative of the Washington University Alzheimer9s Disease Research Center, St. Louis, MO. Disclosure: Dr. Pizzie has nothing to disclose. Dr. Hindman has nothing to disclose. Dr. Roe has nothing to disclose. Dr. Head has nothing to disclose. Dr. Grant has received research support from Pfizer Inc. Dr. Morris has received personal compensation for activities with AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Company, Elan Pharmaceuticals, Genentech, Inc., Eli Lilly & Company, Merck & Co., Inc., Novartis, Otsuka, Pfizer Inc, Schering Plough Corporation, and Wyeth. Dr. Morris has received research support from Janssen Alzheimer Immunotherapy Program, Eli Lilly & Company, and Pfizer Inc. Dr. Hassenstab has nothing to disclose.

Age Effects on Cortical Thickness in Cognitively Normal Elderly Individuals (P03.103)

Age Effects on Cortical Thickness in Cognitively Normal Elderly Individuals (P03.103)

Systemic Inflammatory Markers, Cognition and Brain Structure among Cognitively Normal Elderly (P02.061)

Objective: To establish whether systemic inflammatory markers predict brain small vessel disease, brain volumes, and cognitive performance in cognitively normal elderly subjects. Background There is increasing evidence inflammation may be linked to dementia, and to the cognitive decline associated with aging. Higher concentrations of peripheral C-reactive protein (CRP) and interleukin 6 (IL-6) have been observed in dementia and AD patients compared to control subjects. Several studies have also shown that inflammatory markers are linked to lower brain volumes, white matter lesions (WMLs) and silent brain infarcts; however, these results have not been replicated. Design/Methods: We analyzed demographic, medical, biochemical, neuropsychological, and brain imaging data from 740 cognitively normal subjects from the Cardiovascular Health Cognition Study. CRP was measured at baseline and at visit 5, while IL-6 was only measured at baseline. On the other hand, the MRI and the cognition assessment were performed at visit 10. The grey matter (GM) volumes were analyzed using Voxel-Based Morphometry (VBM). Visual ratings of white matter lesions are used to determine the severity of brain SVD. Results: Baseline CRP levels predicted poorer cognitive performance in cognitively normal elderly a decade later. Baseline IL-6 levels predicted poorer cognitive performance 5 and 10 years later and also predicted increased white matter lesions and lower grey matter volume. This association between inflammatory markers and cognition or neuroimaging findings persisted after adjusting for sociodemographic variables and ApoE4 status, but disappeared when adjusted by vascular risk factors. Finally, the VBM analysis showed that baseline CRP levels predict GM volume loss in the inferior parietal lobule bilaterally. Conclusions: This highlights the effects of cumulative exposure to vascular risk factors on brain structure and cognition, and suggests that vascular risk factors mediate the association between inflammatory markers and cognitive performance or brain structural changes. Disclosure: Dr. Riverol has nothing to disclose. Dr. Becker has nothing to disclose. Dr. Lopez has received personal compensation for activities with Lundbeck and Johnson & Johnson as a consultant. Dr. Raji has nothing to disclose. Dr. Thompson has nothing to disclose. Dr. Carmichael has nothing to disclose. Dr. Gach has nothing to disclose. Dr. Longstreth has nothing to disclose. Dr. Fried has received personal compensation for activities with Pfizer Inc and Bayer Pharmaceuticals as a consultant. Dr. Fried has received personal compensation in an editorial capacity for ACP. Dr. Fried has received research support from Merck & Co., Inc. and Roche Diagnostics. Dr. Tracy has nothing to disclose. Dr. Kuller has nothing to disclose.

The Body Mass Index and Related Factors of Aged Living in a District of Istanbul, Turkey

To determine the nutritional status of elderly by body mass index (BMI) and to investigate associated factors. This is a cross-sectional, descriptive and analytic study done among 309 elderly, in the Besiktas district of Istanbul from January to December 2008. The interviews were performed face-to-face. Anthropometric measurements (height, weight) were taken and BMI was calculated and classified according to World Health Organization standards. According to BMI classification, 1.6% were underweight, 15.2% were normal, 32.4% were overweight, 46.3% were obese and 4.5% were morbidly obese. A gradually lower BMI was observed with the progression of age. According to the study, obesity rates tended to be higher in those with inferior educational background. The study also revealed that diabetes mellitus is more prevalent in those that are overweight, obese and morbidly obese than those that are underweight and normal. In addition, hypertension is a more common ailment along obese and morbidly obese elders. On the contrary, osteoporosis is more prevalent among underweight and normal elders than those that are classified as obese and morbidly obese. BMI provides valuable insight in lieu of nutritional status and health state of the elderly in the primary health care unit.

Small-worldness of functional networks in Alzheimer's disease

To construct the functional networks of human brains by resting-state functional magnetic resonance imaging (fMRI) and examine whether or not the small-world property of functional brain networks changes in patients with Alzheimer disease (AD). A total of 33 AD patients and 20 healthy old volunteers were recruited. Their cognitive functions were evaluated by the mini-mental state examination (MMSE) and Mattis dementia rating scale (DRS). The resting-state BOLD-fMRI data were acquired and preprocessed. Then the correlation coefficient of every pair of 90 regions was calculated and correlation matrix Z (N×N, N = 90) generated by Fisher Z transformation. The small-world property of functional brain networks was tested for AD patients and normal elders according to the definition of small-worldness. The changes of relevant parameters in AD patients were examined by two sample t-tests. Behavioral results: the MMSE scores of AD group and normal controls (NOR) were 20.60 ± 2.30 and 28.20 ± 1.80 respectively. The DRS scores of AD and NOR groups were 96.00 ± 10.82 and 123.22 ± 13.74 respectively. The MMSE and DRS scores were statistically different between two groups. Calculation of small-world parameters: Within the range of 0.1 ≤ Sparsity ≤ 0.4, both groups satisfied the small-world property. However, the clustering coefficient Cp and the average shortest path Lp of AD group were significantly higher than those of NOR group at each threshold (P < 0.05). The functional brain networks in AD patients still have the property of small-world. But the levels of Cp and Lp are higher in AD patients than those in normal controls. It suggests that the capacity of information transmission in functional brain networks and the ability of information integration in different brain regions in AD patients are impaired. This finding is of great importance in elucidating the pathological mechanisms of AD from the viewpoint of networks.

Surgery and Brain Atrophy in Cognitively Normal Elderly Subjects and Subjects Diagnosed with Mild Cognitive Impairment

Structural magnetic resonance imaging is used to longitudinally monitor the progression of Alzheimer disease from its presymptomatic to symptomatic phases. Using magnetic resonance imaging data from the Alzheimer's Disease Neuroimaging Initiative, we tested the hypothesis that surgery would impact brain parameters associated with progression of dementia. Brain images from the neuroimaging initiative database were used to study normal volunteer subjects and patients with mild cognitive impairment for the age group 55 to 90 inclusive. We compared changes in regional brain anatomy for three visits that defined two intervisit intervals for a surgical cohort (n = 41) and a propensity matched nonsurgical control cohort (n = 123). The first interval for the surgical cohort contained the surgical date. Regional brain volumes were determined with Freesurfer and quantitatively described with J-image software (University of California at San Francisco, San Francisco, California). Statistical analysis used Repeated Measures ANCOVA (SPSS, v.18.0; Chicago, IL). We found that surgical patients, during the first follow-up interval (5-9 months), but not subsequently, had increased rates of atrophy for cortical gray matter and hippocampus, and lateral ventricle enlargement, as compared with nonsurgical controls. A composite score of five cognitive tests during this interval showed reduced performance for surgical patients with mild cognitive impairment. Elderly subjects after surgery experienced an increased rate of brain atrophy during the initial evaluation interval, a time associated with enhanced risk for postoperative cognitive dysfunction. Although there was no difference in atrophy rate by diagnosis, subjects with mild cognitive impairment suffered greater subsequent cognitive effects.

Expressive Language Function in the Normal Elderly: Effects of Gender and Educational Level

고령화 사회로 접어들면서 노화에 따른 의사소통 능력의 저하에 대한 관심이 증대되고 있다. 본 연구는 고령자의 성별과 교육정도(‘무학’ 집단, ‘1-6년’ 집단, ‘7년 이상’ 집단)에 따른 언어표현 능력의 차이를 알아보는 것을 목적으로 하였다. 연구대상은 경기 및 충청 지역에 거주하는 65세 이상 고령자 40명(남성 19명, 여성 21명)으로 하였다. 언어표현 능력은 단어수준으로는 대면이름대기(한국판 보스톤 이름대기 검사, K-BNT)와 의미적, 음운적 구어유창성 과제를, 문장 수준에서는 단어 정의하기 과제를 사용하였다. 본 연구의 결과를 요약하면 다음과 같다. 첫째, 성별에 의한 차이는 K-BNT에서만 유의하게 나타났으며, 남성이 여성에 비해 높은 수행을 보였다. 둘째, 교육정도에 따른 세 집단 간의 차이를 살펴보면, 의미적 구어유창성 과제의 수행은 집단 간 차이가 유의하지 않았지만, K-BNT, 음운적 구어유창성, 정의하기 과제에서는 ‘무학’ 집단에 비해 ‘7년 이상’ 집단의 수행이 유의하게 높았다. 성별과 교육정도에 따른 상호작용 효과는 나타나지 않았다. 이와 같은 결과로부터 고령자의 언어표현 능력은 성별과 교육정도에 의한 차이가 나타나며, 교육정도에 의한 차이가 더 다양한 과제에서 나타남을 알 수 있다.

Vascular Risk Factors, White Matter Hyperintensities and Hippocampal Volume in Normal Elderly Individuals

Background/Aims: Hippocampal atrophy has been identified as marker for the development of Alzheimer’s dementia (AD). To what extent vascular risk factors and white matter hyperintensities (WMH) affect hippocampal volume (HV) in asymptomatic elderly subjects and thus may impact such a predictive capacity is controversial. Methods: We analysed 287 participants of the Austrian Stroke Prevention Study (mean age 66.6 ± 6.6 years) with a Mini Mental State Examination score ≧27 who were free of neuropsychiatric disease and had undergone MRI including coronal T₁-weighted sequences allowing for semi-automatic assessment of HV. Global brain volume (BV) was measured using SIENAX. WMH were rated according to the Fazekas scale and segmented to obtain WMH volumes. Results: Higher age was associated with lower absolute and normalized HV, a lower BV and higher WMH volume. None of the vascular risk factors had an impact on HV except for high-density lipoprotein. This effect disappeared after normalization of HV. WMH severity and volume did not affect HV either. Conclusion: Our data indicate HV loss in parallel with the whole brain and suggest no specific vulnerability towards vascular risk factors or age-related WMH in a cognitively intact normal elderly population. This also supports the utility of HV measurements to identify impending AD.

Coronary Artery Disease Is Associated with Cognitive Decline Independent of Changes on Magnetic Resonance Imaging in Cognitively Normal Elderly Adults

To examine in cognitively normal elderly adults whether vascular factors predict cognitive decline and whether these associations are mediated by magnetic resonance imaging (MRI) measures of subclinical vascular brain injury. Prospective multisite longitudinal study of subcortical ischemic vascular diseases. Memory and aging centers in California. Seventy-four participants who were cognitively normal at entry and underwent at least two neuropsychological evaluations and two MRI examinations over an average follow-up of 6.9 years. Item response theory was used to create composite scores of global, verbal memory, and executive functioning. Volumetric MRI measures included white matter hyperintensities (WMHs), silent brain infarcts (SBIs), hippocampus, and cortical gray matter (CGM). Linear mixed-effects models were used to examine the associations between vascular factors, MRI measures, and cognitive scores. History of coronary artery disease (CAD) was associated with greater declines in global cognition, verbal memory, and executive function. The CAD associations remained after controlling for changes in WMHs, SBIs, and hippocampal and CGM volumes. History of CAD may be a surrogate marker for clinically significant atherosclerosis, which also affects the brain. Structural MRI measures of WMHs and SBIs do not fully capture the potential adverse effects of atherosclerosis on the brain. Future longitudinal studies of cognition should incorporate direct measures of atherosclerosis in cerebral arteries, as well as more sensitive neuroimaging measures.

Effects of Anosognosia on Perceived Stress and Cortisol Levels in Alzheimer’s Disease

Anosognosia, or unawareness of one's own cognitive deficits, may cause issues when measuring perceived stress and cortisol levels in Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI). The goal of this study was to examine the effects of anosognosia on perceived stress and salivary cortisol levels in normal elderly (NE) adults, MCI individuals, newly diagnosed AD patients, and long-lasting AD patients, suspected to show more anosognosia. An anosognosia index for perceived stress was computed by subtracting the score on the Perceived Stress Scale measured in the participants and their relative. Cortisol levels were measured four times a day over two nonconsecutive days. Greater anosognosia for dementia correlated with greater anosognosia for perceived stress in the group as a whole. However, no correlation between cortisol levels and either anosognosia for dementia or perceived stress was observed. Our results suggest that measuring perceived stress in AD patients may be influenced by anosognosia.

A Comparison of the Prospective Memory among College Students, Normal Elderly, and Parkinson's Disease Patients

A Comparison of the Prospective Memory among College Students, Normal Elderly, and Parkinson's Disease Patients

Comparisons of Respiratory Function and Activities of Daily Living between Spinal Cord Injury and Stroke Patients and Normal Elderly People

Comparisons of Respiratory Function and Activities of Daily Living between Spinal Cord Injury and Stroke Patients and Normal Elderly People

Evaluation of Lower Limb Motor Function Using Wireless Motion Sensors-A Comparison of Normal Elderly Subjects and those Requiring Support Level 1

This study quantitatively compared lower limb motility of normal subjects and those requiring support level 1 (support_1). We developed a wireless inertia sensor with an embedded tri-axial accelerometer and angular velocity sensor. Six normal elderly subjects and ten elderly subjects who were classified as support_1 by the Japanese care insurance system participated in the study. We attached the wireless motion sensors to the center of the lower back and both thighs in the subjects. Subjects were then asked to walk 10 m and perform a stepping exercise. For the evaluation, the cadence, pitch angle, and pitch angular velocity of the thigh auto-correlation function and root mean square (RMS) on the lower back were calculated. The autocorrelation coefficient function for the support_1 subjects was smaller than in the normal subjects, while the RMS was larger in support_1. These differences indicated that the gait and balance abilities of the support_1 subjects were poorer than those of the normal subjects. This suggests that our wireless motion sensor is useful for assessing the motility of the lower limbs while walking and climbing steps.

White matter lesions and brain gray matter volume in cognitively normal elders

Cerebral white matter lesions (WMLs) reflect small vessel disease, are common in elderly individuals, and are associated with cognitive impairment. We sought to determine the relationships between WMLs, age, gray matter (GM) volume, and cognition in the Cardiovascular Health Study (CHS). From the Cardiovascular Health Study we selected 740 cognitively normal controls with a 1.5 T magnetic resonance imaging (MRI) scan of the brain and a detailed diagnostic evaluation. WML severity was determined using a standardized visual rating system. GM volumes were analyzed using voxel-based morphometry implemented in the Statistical Parametric Mapping software. WMLs were inversely correlated with GM volume, with the greatest volume loss in the frontal cortex. Age-related atrophy was observed in the hippocampus and posterior cingulate cortex. Regression analyses revealed links among age, APOE*4 allele, hypertension, WMLs, GM volume, and digit symbol substitution test scores. Both advancing age and hypertension predict higher WML load, which is itself associated with GM atrophy. Longitudinal data are needed to confirm the temporal sequence of events leading to a decline in cognitive function.