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2.  Tau expression varies in different brain regions and disease state 
Neurobiology of aging  2013;34(7):1922.e7-1922.e12.
Progressive supranuclear palsy (PSP) is the most common atypical parkinsonian disorder. Abnormal tau inclusions, in selected regions of the brain, are a hallmark of the disease and the H1 haplotype of MAPT, the gene encoding tau, is the major risk factor in PSP. A 3-repeat and 4-repeat tau isoform ratio imbalance has been strongly implicated as a cause of disease. Thus, understanding tau isoform regional expression in disease and pathology-free states is crucial to elucidating mechanisms involved in PSP and other tauopathies. We used a tau-isoform specific fluorescent assay to investigate relative 4R-tau expression in 6 different brain regions in PSP cases and healthy controls. We identified marked difference in 4R-tau relative expression, both across brain regions and between MAPT haplotypes. Highest 4R-tau expression levels were identified in the globus pallidus as compared to pons, cerebellum and frontal cortex. 4R-tau expression levels were related to both the MAPT H1 and H1c haplotypes. Similar regional variation was seen in both PSP cases and controls.
PMCID: PMC3642280  PMID: 23428180
3.  Impulsivity is Associated with Uric Acid: Evidence from Humans and Mice 
Biological psychiatry  2013;75(1):10.1016/j.biopsych.2013.02.024.
The ability to control impulses varies greatly, and difficulty with impulse control can have severe consequences; in the extreme, it is the defining feature of many psychiatric disorders. Evidence from disparate lines of research suggests that uric acid is elevated in psychiatric disorders characterized by high impulsivity, such as ADHD and bipolar disorder. The present research tests the hypothesis that impulsivity is associated with higher uric acid in humans and mice.
Using two longitudinal, non-clinical community samples (total N=6883), we test whether there is an association between uric acid and normal variation in trait impulsivity measured with the Revised NEO Personality Inventory. We also examined the effect of uric acid on behavior by comparing wild-type mice (WT), which naturally have low levels of uric acid, to mice genetically modified (UOX) to accumulate high levels of uric acid.
In both human samples, the emotional aspects of trait impulsivity, specifically Impulsiveness and Excitement-Seeking, were associated with higher levels of uric acid concurrently and when uric acid was measured 3–5 years later. Consistent with the human data, the UOX mice displayed significantly more exploratory and novelty-seeking behavior than the WT mice.
Higher uric acid was associated with impulsivity in both humans and mice. The identification of biological markers of impulsivity may lead to a better understanding of the physiological mechanisms involved in impulsivity, and may suggest potential targets for therapeutic intervention.
PMCID: PMC3859133  PMID: 23582268
Impulsivity; Personality traits; Uric Acid; Mouse Model; Excitement-Seeking; Impulse Control
4.  Elevated serum fibroblast growth factor 21 is associated with hypertension in community-dwelling adults 
Journal of human hypertension  2012;27(6):397-399.
Fibroblast growth factor 21 (FGF21), a recently discovered endocrine factor, plays an important role in glucose and lipid metabolism and may contribute to the development of atherosclerosis and coronary heart disease. The present cross sectional study examined the relationship of FGF21 with hypertension in 744 community-dwelling adults who participated in the Baltimore Longitudinal Study of Aging.
PMCID: PMC4059993  PMID: 23190795
aging; fibroblast growth factor 21; hypertension
5.  Vitamin D and Risk of Cognitive Decline in Elderly Persons 
Archives of internal medicine  2010;170(13):1135-1141.
To our knowledge, no prospective study has examined the association between vitamin D and cognitive decline or dementia.
We determined whether low levels of serum 25-hydroxyvitamin D (25[OH]D) were associated with an increased risk of substantial cognitive decline in the InCHIANTI population–based study conducted in Italy between 1998 and 2006 with follow-up assessments every 3 years. A total of 858 adults 65 years or older completed interviews, cognitive assessments, and medical examinations and provided blood samples. Cognitive decline was assessed using the Mini-Mental State Examination (MMSE), and substantial decline was defined as 3 or more points. The Trail-Making Tests A and B were also used, and substantial decline was defined as the worst 10% of the distribution of decline or as discontinued testing.
The multivariate adjusted relative risk (95% confidence interval [CI]) of substantial cognitive decline on the MMSE in participants who were severely serum 25 (OH)D deficient (levels <25 nmol/L) in comparison with those with sufficient levels of 25(OH)D (≥75 nmol/L) was 1.60 (95% CI, 1.19-2.00). Multivariate adjusted random-effects models demonstrated that the scores of participants who were severely 25(OH)D deficient declined by an additional 0.3 MMSE points per year more than those with sufficient levels of 25(OH)D. The relative risk for substantial decline on Trail-Making Test B was 1.31 (95% CI, 1.03-1.51) among those who were severely 25(OH)D deficient compared with those with sufficient levels of 25(OH)D. No significant association was observed for Trail-Making Test A.
Low levels of vitamin D were associated with substantial cognitive decline in the elderly population studied over a 6-year period, which raises important new possibilities for treatment and prevention.
PMCID: PMC4053858  PMID: 20625021
7.  Comparison of Clinical Presentation, Left Ventricular Morphology and Hemodynamics, and Exercise Tolerance in Obese versus Non-Obese Patients with Hypertrophic Cardiomyopathy 
The American journal of cardiology  2013;112(8):1182-1189.
Obesity is independently associated with left ventricular (LV) hypertrophy and thus may be an important modifier of the hypertrophic cardiomyopathy (HC) phenotype. We examined if obesity modifies the clinical presentation, LV morphology, outflow hemodynamics and exercise tolerance in HC. In this cross-sectional study, 88 obese (body mass index, BMI≥30 kg/m2) and 154 non-obese (BMI<30 kg/m2) patients from the Johns Hopkins HC clinic were compared with respect to a variety of clinical and LV echocardiographic measurements. Obese patients (36.4%) were more likely to report exertional dyspnea (p=0.04) and chest pain (p=0.002), and had higher prevalence of hypertension (p=0.008). LV posterior wall thickness (p=0.01) but not the septal wall (p≥0.21) was significantly higher in obese patients, resulting in an increased LV mass index (p=0.003). No significant differences in LV systolic and diastolic function were observed, but obesity was associated with higher LV stroke volume (p=0.03), inducible LV outflow tract gradients (p=0.045) and chance of developing LV outflow tract obstruction during stress (p=0.035). In multivariate analysis, BMI was associated with increased posterior (but not septal) wall thickness (β=0.15, p=0.02) and LV mass index (β=0.18, p=0.005), particularly in those with hypertension. Obesity was also associated with reduced exercise time and functional capacity, and BMI independently correlated with reduced exercise tolerance. In conclusion, obesity is associated with larger LV mass, worse symptoms, lower exercise tolerance and labile obstructive hemodynamics in HC. The association with increased outflow tract gradients has particular importance as contribution of obesity to the pressure gradients may influence clinical decisions in labile obstructive HC.
PMCID: PMC4042005  PMID: 24079444
hypertrophic cardiomyopathy; obesity; hypertension; body mass index; left ventricular mass
8.  Thyroid STAtus and 6-Year Mortality in Elderly People Living in a Mildly Iodine-Deficient Area: The Aging in the Chianti Area (InCHIANTI) Study 
The relationship between thyroid dysfunction and mortality in elderly subjects is still undefined. In this population study we tested the hypothesis that in older subjects, living in a mildly iodine-deficient area, thyroid dysfunction may be associated with increased mortality independent of potential confounders.
Longitudinal study
Total of 951 subjects aged 65 years and older
Plasma thyrotropin (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) concentrations and demographic features were evaluated in participants of the Aging in the Chianti Area (InCHIANTI) study, aged 65 years or older. Participants were classified according to thyroid function test. Kaplan-Meier survival and Cox proportional hazards models adjusted for confounders were used in the analysis.
A total of 819 participants were euthyroid, 83 had Subclinical hyperthyroidism (SHyper), and 29 had Subclinical hypothyroidism (SHypo). Overt Hypo- and Hyperthyroidism were found in 5 and 15 subjects, respectively. During a median of six-years of follow-up, N 210 deaths occurred (22.1 %) of which 98 (46.6%) due to cardiovascular causes. Kaplan–Meier analysis revealed higher overall mortality for SHyper (P<0.04) as compared to euthyroid subjects. After adjusting for multiple confounders, participants with SHyper (Hazard Ratio[HR]:1.65; 95% Confidence Interval [CI]: 1.02–2.69) had significantly higher all-cause mortality than those with normal thyroid function. No significant association was found between SHyper and cardiovascular mortality.
In euthyroid subjects, TSH was found to be predictive of a reduced risk of all-cause mortality (HR: 0.76; 95% CI, 0.57–0.99)
SHyper is an independent risk factor for all-cause mortality in the older population. Low-normal circulating TSH should be carefully monitored in euthyroid elderly individuals.
PMCID: PMC3686888  PMID: 23647402
subclinical hyperthyroidism; aging; mortality
9.  Proximal Superficial Femoral Artery Occlusion, Collateral Vessels, and Walking Performance in Peripheral Artery Disease 
JACC. Cardiovascular imaging  2013;6(6):687-694.
We studied associations of MRI-measured SFA occlusions with functional performance, leg symptoms, and collateral vessel number in PAD. We studied associations of collateral vessel number with functional performance in PAD.
Associations of magnetic resonance imaging (MRI)-detected superficial femoral artery (SFA) occlusion and collateral vessel number with functional performance among individuals with peripheral artery disease (PAD) have not been reported.
457 participants with an ankle brachial index (ABI) < 1.00 had MRI measurement of the proximal SFA with twelve consecutive 2.5 millimeter cross-sectional images. An occluded SFA was defined as an SFA in which at least one segment was occluded. A non-occluded SFA was defined as absence of any occluded slices. Collateral vessels were visualized with magnetic resonance angiography (MRA). Lower extremity functional performance was measured with the six-minute walk, four-meter walking velocity at usual and fastest pace, and the short physical performance battery (SPPB) (0-12 scale, 12=best).
Adjusting for age, sex, race, comorbidities, and other confounders, the presence of an SFA occlusion was associated with poorer six-minute walk performance (1,031 vs. 1,169 feet, P=0.006), slower fast-paced walking velocity (1.15 vs. 1.22 meters/second, P =0.042), and lower SPPB score (9.07 vs. 9.75, P=0.038) compared to the absence of an SFA occlusion. More numerous collateral vessels were associated with better six-minute walk performance (0-3 collaterals-1,064 feet, 4-7 collaterals-1,165 feet, ≥ 8 collaterals-1,246 feet, P trend=0.007), faster usual-paced walking speed (0-3 collaterals-0.84 meters/second, 4-7 collaterals-0.88 meters/second, ≥ 8 collaterals-0.91 meters/second, P trend=0.029), and faster rapid-paced walking speed (0-3 collaterals-1.17 meters/second, 4-7 collaterals-1.22 meters/second, ≥ 8 collaterals-1.29 meters/second, P trend=0.002), adjusting for age, sex, race, comorbidities, ABI, and other confounders.
Among PAD participants, MRI-visualized occlusions in the proximal SFA are associated with poorer functional performance, while more numerous collaterals are associated with better functional performance.
Clinical Trial ID
PMCID: PMC3766720  PMID: 23647796
atherosclerotic plaque; intermittent claudication; peripheral arterial disease; physical functioning
10.  Associations of Calf Skeletal Muscle Characteristics and Peripheral Nerve Function with Self-Perceived Physical Functioning and Walking Ability in Persons with Peripheral Arterial Disease 
We determined whether more adverse calf muscle characteristics and poorer peripheral nerve function were associated with impairments in self-perceived physical functioning and walking ability in persons with lower extremity peripheral arterial disease (PAD). Participants included 462 persons with PAD; measures included the ankle-brachial index (ABI), medical history, electrophysiologic characteristics of nerves, and computed tomography of calf muscle. Self-perceived physical functioning and walking ability were assessed using the 36-Item Short Form Health Survey (SF-36) and the Walking Impairment Questionnaire (WIQ). Results were adjusted for age, sex, race, ABI, body-mass index, comorbidities, and other confounders. Lower calf muscle area was associated with a poorer SF-36 physical function (PF) score (overall p trend<0.001, 33.76 PF score for the lowest quartile vs. 59.74 for the highest, pair wise p<0.001) and a poorer WIQ walking distance score (p trend=0.001, 29.71 WIQ score for the lowest quartile vs. 48.43 for the highest, pair wise p<0.001). Higher calf muscle percent fat was associated with a poorer SF-36 PF score (p trend<0.001, 53.76 PF score for the lowest quartile vs. 40.28 for the highest, pair wise p=0.009). Slower peroneal nerve conduction velocity was associated with a poorer WIQ speed score (p trend=0.023, 30.49 WIQ score for the lowest quartile vs. 40.48 for the highest, pair wise p=0.031). In summary, adverse calf muscle characteristics and poorer peripheral nerve function are associated significantly and independently with impairments in self-perceived physical functioning and walking ability in PAD persons.
PMCID: PMC4034534  PMID: 21471147
peripheral arterial disease; calf muscle characteristics; peripheral nerve function; quality of life
11.  Longitudinal imaging pattern analysis (SPARE-CD index) detects early structural and functional changes before cognitive decline in healthy older adults 
Neurobiology of aging  2012;33(12):2733-2745.
This article investigates longitudinal imaging characteristics of early cognitive decline during normal aging, leveraging on high-dimensional imaging pattern classification methods for the development of early biomarkers of cognitive decline. By combining magnetic resonance imaging (MRI) and resting positron emission tomography (PET) cerebral blood flow (CBF) images, an individualized score is generated using high-dimensional pattern classification, which predicts subsequent cognitive decline in cognitively normal older adults of the Baltimore Longitudinal Study of Aging. The resulting score, termed SPARE-CD (Spatial Pattern of Abnormality for Recognition of Early Cognitive Decline), analyzed longitudinally for 143 cognitively normal subjects over 8 years, shows functional and structural changes well before (2.3–2.9 years) changes in neurocognitive testing (California Verbal Learning Test [CVLT] scores) can be measured. Additionally, this score is found to be correlated to the [11C] Pittsburgh compound B (PiB) PET mean distribution volume ratio at a later time. This work indicates that MRI and PET images, combined with advanced pattern recognition methods, may be useful for very early detection of cognitive decline.
PMCID: PMC4023476  PMID: 22365049
Cognitive impairment; Magnetic resonance imaging; Positron emission tomography; Support vector machines; Classification
12.  Harmonization of Neuroticism and Extraversion phenotypes across inventories and cohorts in the Genetics of Personality Consortium: an application of Item Response Theory 
van den Berg, Stéphanie M. | de Moor, Marleen H. M. | McGue, Matt | Pettersson, Erik | Terracciano, Antonio | Verweij, Karin J. H. | Amin, Najaf | Derringer, Jaime | Esko, Tõnu | van Grootheest, Gerard | Hansell, Narelle K. | Huffman, Jennifer | Konte, Bettina | Lahti, Jari | Luciano, Michelle | Matteson, Lindsay K. | Viktorin, Alexander | Wouda, Jasper | Agrawal, Arpana | Allik, Jüri | Bierut, Laura | Broms, Ulla | Campbell, Harry | Smith, George Davey | Eriksson, Johan G. | Ferrucci, Luigi | Franke, Barbera | Fox, Jean-Paul | de Geus, Eco J. C. | Giegling, Ina | Gow, Alan J. | Grucza, Richard | Hartmann, Annette M. | Heath, Andrew C. | Heikkilä, Kauko | Iacono, William G. | Janzing, Joost | Jokela, Markus | Kiemeney, Lambertus | Lehtimäki, Terho | Madden, Pamela A. F. | Magnusson, Patrik K. E. | Northstone, Kate | Nutile, Teresa | Ouwens, Klaasjan G. | Palotie, Aarno | Pattie, Alison | Pesonen, Anu-Katriina | Polasek, Ozren | Pulkkinen, Lea | Pulkki-Råback, Laura | Raitakari, Olli T. | Realo, Anu | Rose, Richard J. | Ruggiero, Daniela | Seppälä, Ilkka | Slutske, Wendy S. | Smyth, David C. | Sorice, Rossella | Starr, John M. | Sutin, Angelina R. | Tanaka, Toshiko | Verhagen, Josine | Vermeulen, Sita | Vuoksimaa, Eero | Widen, Elisabeth | Willemsen, Gonneke | Wright, Margaret J. | Zgaga, Lina | Rujescu, Dan | Metspalu, Andres | Wilson, James F. | Ciullo, Marina | Hayward, Caroline | Rudan, Igor | Deary, Ian J. | Räikkönen, Katri | Arias Vasquez, Alejandro | Costa, Paul T. | Keltikangas-Järvinen, Liisa | van Duijn, Cornelia M. | Penninx, Brenda W. J. H. | Krueger, Robert F. | Evans, David M. | Kaprio, Jaakko | Pedersen, Nancy L. | Martin, Nicholas G. | Boomsma, Dorret I.
Behavior Genetics  2014;44:295-313.
Mega- or meta-analytic studies (e.g. genome-wide association studies) are increasingly used in behavior genetics. An issue in such studies is that phenotypes are often measured by different instruments across study cohorts, requiring harmonization of measures so that more powerful fixed effect meta-analyses can be employed. Within the Genetics of Personality Consortium, we demonstrate for two clinically relevant personality traits, Neuroticism and Extraversion, how Item-Response Theory (IRT) can be applied to map item data from different inventories to the same underlying constructs. Personality item data were analyzed in >160,000 individuals from 23 cohorts across Europe, USA and Australia in which Neuroticism and Extraversion were assessed by nine different personality inventories. Results showed that harmonization was very successful for most personality inventories and moderately successful for some. Neuroticism and Extraversion inventories were largely measurement invariant across cohorts, in particular when comparing cohorts from countries where the same language is spoken. The IRT-based scores for Neuroticism and Extraversion were heritable (48 and 49 %, respectively, based on a meta-analysis of six twin cohorts, total N = 29,496 and 29,501 twin pairs, respectively) with a significant part of the heritability due to non-additive genetic factors. For Extraversion, these genetic factors qualitatively differ across sexes. We showed that our IRT method can lead to a large increase in sample size and therefore statistical power. The IRT approach may be applied to any mega- or meta-analytic study in which item-based behavioral measures need to be harmonized.
Electronic supplementary material
The online version of this article (doi:10.1007/s10519-014-9654-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4057636  PMID: 24828478
Personality; Item-Response Theory; Measurement; Genome-wide association studies; Consortium; Meta-analysis
13.  Changes in Brain Function Occur Years before the Onset of Cognitive Impairment 
The Journal of Neuroscience  2013;33(46):18008-18014.
To develop targeted intervention strategies for the treatment of Alzheimer's disease, we first need to identify early markers of brain changes that occur before the onset of cognitive impairment. Here, we examine changes in resting-state brain function in humans from the Baltimore Longitudinal Study of Aging. We compared longitudinal changes in regional cerebral blood flow (rCBF), assessed by 15O-water PET, over a mean 7 year period between participants who eventually developed cognitive impairment (n = 22) and those who remained cognitively normal (n = 99). Annual PET assessments began an average of 11 years before the onset of cognitive impairment in the subsequently impaired group, so all participants were cognitively normal during the scanning interval. A voxel-based mixed model analysis was used to compare groups with and without subsequent impairment. Participants with subsequent impairment showed significantly greater longitudinal rCBF increases in orbitofrontal, medial frontal, and anterior cingulate regions, and greater longitudinal decreases in parietal, temporal, and thalamic regions compared with those who maintained cognitive health. These changes were linear in nature and were not influenced by longitudinal changes in regional tissue volume. Although all participants were cognitively normal during the scanning interval, most of the accelerated rCBF changes seen in the subsequently impaired group occurred within regions thought to be critical for the maintenance of cognitive function. These changes also occurred within regions that show early accumulation of pathology in Alzheimer's disease, suggesting that there may be a connection between early pathologic change and early changes in brain function.
PMCID: PMC3828456  PMID: 24227712
14.  Predicting 3-year incident mobility disability in middle-aged and older adults using physical performance tests 
To identify a standard physical performance test that can predict 3-year incident mobility disability (IMD) independent of demographics
Longitudinal cohort study
Population-based older cohort
Community-living middle-aged and older persons (age: 50–85 years) without baseline mobility disability (n=622).
Mobility disability was ascertained at baseline and at 3-year follow-up using an established self-report method: self-reported inability to walk a quarter mile without resting or inability to walk up a flight of stairs unsupported. Physical performance tests included self-selected usual gait speed, time required to complete 5 times sit-to-stand (5tSTS) and 400 m brisk walking. Demographic variables age, sex, height and weight were recorded.
Overall, 13.5% participants reported 3-year IMD. Usual gait speed <1.2 m/s, requiring >13.6 seconds to complete 5tSTS and completing 400 m at <1.19m/s walking speed were highly predictive of future mobility disability independent of demographics.
Inability to complete 5tSTS in < 13.7 seconds can be a clinically convenient guideline for monitoring and for further assessment of middle-aged and older persons, in order to prevent or delay future mobility disability.
PMCID: PMC3637852  PMID: 23164980
mobility; disability; aging
15.  Quadriceps Strength, Quadriceps Power, and Gait Speed in Older U.S. Adults with Diabetes: Results from the National Health and Nutrition Examination Survey (NHANES), 1999–2002 
To examine the independent association of diabetes (and its duration and severity) with quadriceps strength, quadriceps power, and gait speed in a national population of older adults.
Cross-sectional nationally representative survey.
We examined 2573 adults ≥50 years of age in the National Health and Nutrition Examination Survey 1999–2002 who had assessment of quadriceps strength.
Diabetes was ascertained by questionnaire. Measurement of isokinetic knee extensors (quadriceps) strength was performed at 60 degrees/second. Gait speed was assessed using a 20-foot walk test. Multiple linear regression analyses were used to assess the association between diabetes status and outcomes, adjusting for potential confounders or mediators.
Among older U.S. adults, those with versus without diabetes had significantly slower gait speed (0.96±0.02 versus 1.08±0.01 m/s; p<0.001). After adjusting for demographics, weight, and height, diabetes was also associated with significantly lower quadriceps strength (−4.6±1.9 Newton-meters; p=0.02), quadriceps power (−4.9±2.0 Watts; p=0.02), in addition to gait speed (−0.05±0.02 m/s; p=0.002). Associations remained significant after adjusting for physical activity and C-reactive protein. After accounting for comorbidities (cardiovascular disease, peripheral neuropathy, amputation, cancer, arthritis, fracture, COPD), diabetes was only independently associated with gait speed (−0.04±0.02 m/s; p=0.02). Diabetes duration in men and women was negatively associated with age-adjusted quadriceps strength (−5.7 and −3.5 Newton-meters/decade of diabetes, respectively) and power (−6.1 and −3.8 Watts/decade of diabetes, respectively) (all p≤0.001, no significant interactions by gender). Hemoglobin A1c was not associated with outcomes accounting for body weight.
Compared to persons without diabetes, older U.S. adults with diabetes have lower quadriceps strength and quadriceps power that is related to the presence of comorbidities. Persons with diabetes also walk slower. Future studies should investigate the relationship of hyperglycemia with subsequent declines in leg muscle function.
PMCID: PMC3725774  PMID: 23617584
Type 2 diabetes mellitus; muscle loss; physical function; gait
16.  Hearing Loss and Gait Speed Among Older Adults in the United States 
Gait & posture  2012;38(1):10.1016/j.gaitpost.2012.10.006.
Previous studies have suggested that hearing loss, which is highly prevalent but undertreated in older adults, may be associated with gait and physical functioning. Determining if hearing loss is independently associated with gait speed is critical toward understanding whether hearing rehabilitative interventions could help mitigate declines in physical functioning in older adults.
We analyzed cross-sectional data from the 1999–2002 cycles of the National Health and Nutritional Examination Survey during which participants 50–69 years (n = 1180) underwent hearing and gait speed assessments. Hearing was defined by a pure tone average of hearing thresholds at 0.5–4 kHz tones in the better-hearing ear. Gait speed was obtained in a timed 20-foot (6.1 meter) walk. Linear and logistic regression models were used to examine the association between hearing loss and gait speed while adjusting for demographic and cardiovascular risk factors. Analyses incorporated sampling weights to yield results generalizable to the U.S. population.
In a model adjusted for demographic and cardiovascular risk factors, a 25 dB hearing loss was associated with slower gait speed (−0.05 m/s per 25 dB HL [95% CI: −0.09 – −0.02]) and a nearly two-fold increased odds of having a gait speed < 1.0 m/s (OR 2.0, 95% CI: 1.2 –3.3). The reduction in gait speed associated with a 25 dB hearing loss was equivalent to that associated with an age difference of nearly 12 years.
Greater hearing loss is independently associated with slower gait speed. Further studies investigating the mechanistic basis of this association and whether hearing rehabilitative interventions could affect gait and physical functioning are needed.
PMCID: PMC3845825  PMID: 23177614
17.  Estimating Energy Expenditure from Heart Rate in Older Adults: A Case for Calibration 
PLoS ONE  2014;9(4):e93520.
Accurate measurement of free-living energy expenditure is vital to understanding changes in energy metabolism with aging. The efficacy of heart rate as a surrogate for energy expenditure is rooted in the assumption of a linear function between heart rate and energy expenditure, but its validity and reliability in older adults remains unclear.
To assess the validity and reliability of the linear function between heart rate and energy expenditure in older adults using different levels of calibration.
Heart rate and energy expenditure were assessed across five levels of exertion in 290 adults participating in the Baltimore Longitudinal Study of Aging. Correlation and random effects regression analyses assessed the linearity of the relationship between heart rate and energy expenditure and cross-validation models assessed predictive performance.
Heart rate and energy expenditure were highly correlated (r = 0.98) and linear regardless of age or sex. Intra-person variability was low but inter-person variability was high, with substantial heterogeneity of the random intercept (s.d. = 0.372) despite similar slopes. Cross-validation models indicated individual calibration data substantially improves accuracy predictions of energy expenditure from heart rate, reducing the potential for considerable measurement bias. Although using five calibration measures provided the greatest reduction in the standard deviation of prediction errors (1.08 kcals/min), substantial improvement was also noted with two (0.75 kcals/min).
These findings indicate standard regression equations may be used to make population-level inferences when estimating energy expenditure from heart rate in older adults but caution should be exercised when making inferences at the individual level without proper calibration.
PMCID: PMC4005766  PMID: 24787146
18.  Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy 
The Journal of Experimental Medicine  2013;210(11):2223-2237.
Aging strongly promotes inflammation responses, which may predispose individuals after cancer therapies to lethal system toxicities and pathology that can be partially prevented by TNF blockade.
Cancer commonly occurs in the elderly and immunotherapy (IT) is being increasingly applied to this population. However, the majority of preclinical mouse tumor models assessing potential efficacy and toxicities of therapeutics use young mice. We assessed the impact of age on responses to systemic immune stimulation. In contrast to young mice, systemic cancer IT regimens or LPS given to aged mice resulted in rapid and lethal toxicities affecting multiple organs correlating with heightened proinflammatory cytokines systemically and within the parenchymal tissues. This inflammatory response and increased morbidity with age was independent of T cells or NK cells. However, prior in vivo depletion of macrophages in aged mice resulted in lesser cytokine levels, increased survival, and decreased liver histopathology. Furthermore, macrophages from aged mice and normal human elderly volunteers displayed heightened TNF and IL-6 production upon in vitro stimulation. Treatment of both TNF knockout mice and in vivo TNF blockade in aged mice resulted in significant increases in survival and lessened pathology. Importantly, TNF blockade in tumor-bearing, aged mice receiving IT displayed significant anti-tumor effects. These data demonstrate the critical role of macrophages in the age-associated hyper-inflammatory cytokine responses to systemic immunostimulation and underscore the importance of performing preclinical assessments in aged mice.
PMCID: PMC3804937  PMID: 24081947
19.  Systematic identification of trans-eQTLs as putative drivers of known disease associations 
Nature genetics  2013;45(10):1238-1243.
Identifying the downstream effects of disease-associated single nucleotide polymorphisms (SNPs) is challenging: the causal gene is often unknown or it is unclear how the SNP affects the causal gene, making it difficult to design experiments that reveal functional consequences. To help overcome this problem, we performed the largest expression quantitative trait locus (eQTL) meta-analysis so far reported in non-transformed peripheral blood samples of 5,311 individuals, with replication in 2,775 individuals. We identified and replicated trans-eQTLs for 233 SNPs (reflecting 103 independent loci) that were previously associated with complex traits at genome-wide significance. Although we did not study specific patient cohorts, we identified trait-associated SNPs that affect multiple trans-genes that are known to be markedly altered in patients: for example, systemic lupus erythematosus (SLE) SNP rs49170141 altered C1QB and five type 1 interferon response genes, both hallmarks of SLE2-4. Subsequent ChIP-seq data analysis on these trans-genes implicated transcription factor IKZF1 as the causal gene at this locus, with DeepSAGE RNA-sequencing revealing that rs4917014 strongly alters 3’ UTR levels of IKZF1. Variants associated with cholesterol metabolism and type 1 diabetes showed similar phenomena, indicating that large-scale eQTL mapping provides insight into the downstream effects of many trait-associated variants.
PMCID: PMC3991562  PMID: 24013639
20.  Diabetes, Peripheral Neuropathy, and Lower Extremity Function 
Diabetes among older adults causes many complications, including decreased lower extremity function and physical disability. Diabetes can cause peripheral nerve dysfunction, which might be one pathway through which diabetes leads to decreased physical function. The study aims were to determine: (1) whether diabetes and impaired fasting glucose are associated with objective measures of physical function in older adults, (2) which peripheral nerve function (PNF) tests are associated with diabetes, and (3) whether PNF mediates the diabetes-physical function relationship.
Research Design and Methods
This study included 983 participants, age 65 and older from the InCHIANTI Study. Diabetes was diagnosed by clinical guidelines. Physical performance was assessed using the Short Physical Performance Battery (SPPB), scored from 0-12 (higher values, better physical function) and usual walking speed (m/s). PNF was assessed via standard surface electroneurographic study of right peroneal nerve conduction velocity, vibration and touch sensitivity. Clinical cut-points of PNF tests were used to create a neuropathy score from 0-5 (higher values, greater neuropathy). Multiple linear regression models were used to test associations.
Results and Conclusion
12.8% (n=126) of participants had diabetes. Adjusting for age, sex, education, and other confounders, diabetic participants had decreased SPPB (β= −0.99; p< 0.01), decreased walking speed (β= −0.1m/s; p< 0.01), decreased nerve conduction velocity (β= −1.7m/s; p< 0.01), and increased neuropathy (β= 0.25; p< 0.01) compared to non-diabetic participants. Adjusting for nerve conduction velocity and neuropathy score decreased the effect of diabetes on SPPB by 20%, suggesting partial mediation through decreased PNF.
PMCID: PMC3987662  PMID: 24120281
21.  Personality and resilience to Alzheimer's disease neuropathology: A prospective autopsy study 
Neurobiology of aging  2012;34(4):1045-1050.
Alzheimer's disease (AD) neuropathology is found at autopsy in about 30% of cognitively normal older individuals. We examine whether personality traits are associated with such resilience to clinical dementia in individuals with AD neuropathology. Broad factors and specific facets of personality were assessed up to 28 years (M=11, SD=7) before onset of dementia and up to 30 years (M=15, SD=7) before death in a cohort (N=111) evaluated for AD neuropathology at autopsy. Individuals with higher baseline scores on vulnerability to stress, anxiety, and depression (neuroticism: OR=2.0, 95%CI=1.2-3.5), or lower scores on order and competence (conscientiousness: OR=0.4, 95%CI=0.2-0.9) were less likely to remain asymptomatic in the presence of AD neuropathology. Neuroticism (r=0.26), low agreeableness (r=-0.34), and some facets were also significantly associated with advanced stages of neurofibrillary tangles, but the associations between personality traits and risk of clinical dementia were mostly unchanged by controlling for Braak and CERAD scores. In sum, a resilient personality profile is associated with lower risk or delay of clinical dementia even in persons with AD neuropathology.
PMCID: PMC3541457  PMID: 23040035
Alzheimer's disease; dementia; asymptomatic; personality; neuroticism; depression; conscientiousness; prospective cohort study; autopsy; neurofibrillary tangles; Aβ neuritic plaques; neuropathology
22.  Skeletal Muscle Mitochondrial Energetics Are Associated With Maximal Aerobic Capacity and Walking Speed in Older Adults 
Lower ambulatory performance with aging may be related to a reduced oxidative capacity within skeletal muscle. This study examined the associations between skeletal muscle mitochondrial capacity and efficiency with walking performance in a group of older adults.
Thirty-seven older adults (mean age 78 years; 21 men and 16 women) completed an aerobic capacity (VO2 peak) test and measurement of preferred walking speed over 400 m. Maximal coupled (State 3; St3) mitochondrial respiration was determined by high-resolution respirometry in saponin-permeabilized myofibers obtained from percutanous biopsies of vastus lateralis (n = 22). Maximal phosphorylation capacity (ATPmax) of vastus lateralis was determined in vivo by 31P magnetic resonance spectroscopy (n = 30). Quadriceps contractile volume was determined by magnetic resonance imaging. Mitochondrial efficiency (max ATP production/max O2 consumption) was characterized using ATPmax per St3 respiration (ATPmax/St3).
In vitro St3 respiration was significantly correlated with in vivo ATPmax (r 2 = .47, p = .004). Total oxidative capacity of the quadriceps (St3*quadriceps contractile volume) was a determinant of VO2 peak (r 2 = .33, p = .006). ATPmax (r 2 = .158, p = .03) and VO2 peak (r 2 = .475, p < .0001) were correlated with preferred walking speed. Inclusion of both ATPmax/St3 and VO2 peak in a multiple linear regression model improved the prediction of preferred walking speed (r 2 = .647, p < .0001), suggesting that mitochondrial efficiency is an important determinant for preferred walking speed.
Lower mitochondrial capacity and efficiency were both associated with slower walking speed within a group of older participants with a wide range of function. In addition to aerobic capacity, lower mitochondrial capacity and efficiency likely play roles in slowing gait speed with age.
PMCID: PMC3593613  PMID: 23051977
Muscle; Mitochondria; Aging; Walking speed.
23.  Trajectories of Gait Speed Predict Mortality in Well-Functioning Older Adults: The Health, Aging and Body Composition Study 
Although gait speed slows with age, the rate of slowing varies greatly. To date, little is known about the trajectories of gait speed, their correlates, and their risk for mortality in older adults.
Gait speed during a 20-m walk was measured for a period of 8 years in initially well-functioning men and women aged 70–79 years participating in the Health, Aging and Body Composition study. We described the trajectories of gait speed and examined their correlates using a group-based mixture model. Also risk associated with different gait speed trajectories on all-cause mortality was estimated using a Cox-proportional hazard model.
Of 2,364 participants (mean age, 73.5±2.9 years; 52% women), we identified three gait speed trajectories: slow (n = 637), moderate (n = 1,209), and fast decline (n = 518). Those with fast decline slowed 0.030 m/s per year or 2.4% per year from baseline to the last follow-up visit. Women, blacks, and participants who were obese, had limited knee extensor strength, and had low physical activity were more likely to have fast decline than their counterparts. Participants with fast decline in gait speed had a 90% greater risk of mortality than those with slow decline.
Despite being well-functioning at baseline, a quarter of older adults experienced fast decline in gait speed, which was associated with an increased risk of mortality.
PMCID: PMC3593620  PMID: 23051974
Gait speed; Older adults; Mortality.
24.  Apolipoprotein E genotype, cardiovascular biomarkers and risk of stroke: Systematic review and meta-analysis of 14 015 stroke cases and pooled analysis of primary biomarker data from up to 60 883 individuals 
Background At the APOE gene, encoding apolipoprotein E, genotypes of the ε2/ε3/ε4 alleles associated with higher LDL-cholesterol (LDL-C) levels are also associated with higher coronary risk. However, the association of APOE genotype with other cardiovascular biomarkers and risk of ischaemic stroke is less clear. We evaluated the association of APOE genotype with risk of ischaemic stroke and assessed whether the observed effect was consistent with the effects of APOE genotype on LDL-C or other lipids and biomarkers of cardiovascular risk.
Methods We conducted a systematic review of published and unpublished studies reporting on APOE genotype and ischaemic stroke. We pooled 41 studies (with a total of 9027 cases and 61 730 controls) using a Bayesian meta-analysis to calculate the odds ratios (ORs) for ischaemic stroke with APOE genotype. To better evaluate potential mechanisms for any observed effect, we also conducted a pooled analysis of primary data using 16 studies (up to 60 883 individuals) of European ancestry. We evaluated the association of APOE genotype with lipids, other circulating biomarkers of cardiovascular risk and carotid intima-media thickness (C-IMT).
Results The ORs for association of APOE genotypes with ischaemic stroke were: 1.09 (95% credible intervals (CrI): 0.84–1.43) for ε2/ε2; 0.85 (95% CrI: 0.78–0.92) for ε2/ε3; 1.05 (95% CrI: 0.89–1.24) for ε2/ε4; 1.05 (95% CrI: 0.99–1.12) for ε3/ε4; and 1.12 (95% CrI: 0.94–1.33) for ε4/ε4 using the ε3/ε3 genotype as the reference group. A regression analysis that investigated the effect of LDL-C (using APOE as the instrument) on ischaemic stroke showed a positive dose-response association with an OR of 1.33 (95% CrI: 1.17, 1.52) per 1 mmol/l increase in LDL-C. In the separate pooled analysis, APOE genotype was linearly and positively associated with levels of LDL-C (P-trend: 2 × 10−152), apolipoprotein B (P-trend: 8.7 × 10−06) and C-IMT (P-trend: 0.001), and negatively and linearly associated with apolipoprotein E (P-trend: 6 × 10−26) and HDL-C (P-trend: 1.6 × 10−12). Associations with lipoprotein(a), C-reactive protein and triglycerides were non-linear.
Conclusions In people of European ancestry, APOE genotype showed a positive dose-response association with LDL-C, C-IMT and ischaemic stroke. However, the association of APOE ε2/ε2 genotype with ischaemic stroke requires further investigation. This cross-domain concordance supports a causal role of LDL-C on ischaemic stroke.
PMCID: PMC3619955  PMID: 23569189
Stroke; lipids; apolipoprotein E; cardiovascular disease; systematic review; meta-analysis; biomarkers
25.  Apolipoprotein E Epsilon 4 Allele Interacts with Sex and Cognitive Status to Influence All-Cause and Cause-Specific Mortality Among US Older Adults 
Apolipoprotein E ε4 (ApoE4 carrier) status, sex and cognitive impairment may interact to affect all-cause and cause-specific mortality risk.
To confirm associations of ApoE4 carrier status, sex and time-dependent cognitive status with mortality risk, and investigate these associations' joint effects in a cohort of community-dwelling US adults.
Design & Setting
Data from the Baltimore Longitudinal Study of Aging were used.
Of n=3,047 (First-visit Age:17–98y, 60.1% men), we selected a sample with complete genetic data and with ≥1 visit at age≥50y (n=1,461).
Time-to-death from all, cardiovascular or non-cardiovascular causes.
Survival probability was lower for ApoE4 carriers, particularly at oldest ages. Cox proportional hazards model for all-cause mortality yielded a hazard ratio (HR) for ApoE4 carrier vs. non-carriers of 1.31,95%CI:1.02–1.68. This association was also found for cardiovascular mortality. Time-dependent all-cause dementia (HR=1.73, 95%CI:1.33–2.26) and mild cognitive impairment (HR=1.95,95%CI:1.42–2.67) increased all-cause mortality risk, associations also detected for non-cardiovascular mortality. When individuals were free of cognitive impairment, a dose-response relationship with ε4 alleles was found for all-cause mortality (HR=1.40,95%CI:0.94–2.07 for 1 ε4, and HR=2.61; 95%CI:1.12–6.07 for 2 ε4). After Alzheimer's Disease-type (AD) dementia onset, carrying only 1 ε4 allele increased all-cause mortality risk by ~77% compared to non-carriers. ApoE4 carrier status increased all-cause mortality risk in men and interacted with time-dependent AD to increase the risk of this outcome (RERI=2.15; 95% CI:1.22–3.07).
We found that ApoE4 carrier status increased all-cause and cardiovascular mortality risks, while interacting with sex and time-dependent AD status to affect all-cause mortality.
PMCID: PMC3628727  PMID: 23581910
Apolipoprotein E genotype; dementia; mild cognitive impairment; mortality; cardiovascular disease

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