Pattern of progression in advanced hepatocellular carcinoma treated with ramucirumab.

BACKGROUND & AIMS: Radiological progression patterns to first-line sorafenib have been associated with post-progression and overall survival in advanced hepatocellular carcinoma, but these associations remain unknown for therapies in second- and later-line settings. This post hoc analysis of REACH and REACH-2 examined outcomes by radiological progression patterns in the second-line setting of patients with advanced hepatocellular carcinoma treated with ramucirumab or placebo. METHODS: Patients with advanced hepatocellular carcinoma, Child-Pugh A and Eastern Cooperative Oncology Group Performance Status 0 or 1 with prior sorafenib were randomized to receive ramucirumab 8mg/kg or placebo every 2 weeks. Among 625 patients with ≥1 progression pattern (new extrahepatic lesion [including new macrovascular invasion], new intrahepatic lesion, extrahepatic growth or intrahepatic growth), data were analysed by trial and for pooled individual patient data for REACH-2 and REACH (alpha-fetoprotein ≥400 ng/mL). Cox models evaluated prognostic implications of progression patterns on overall and post-progression survival. RESULTS: Post-progression survival was worse among those with new extrahepatic lesions in REACH (HR 2.33, 95% CI 1.51-3.60), REACH-2 (HR 1.49, 95% CI 0.72-3.08) and the pooled population (HR 1.75, 95% CI 1.12-2.74) compared to other progression patterns. Overall survival was also significantly reduced in those with new extrahepatic lesions across studies. Ramucirumab provided an overall survival benefit across progression patterns, including patients with new extrahepatic lesions (HR 0.56, 95% CI 0.39-0.80) in the pooled population. CONCLUSIONS: The emergence of new extrahepatic lesions in the second-line setting is a poor prognostic factor for post-progression survival. The benefit of ramucirumab for overall survival was consistent across progression patterns.

Regional Gray Matter Volume Links Rest-Activity Rhythm Fragmentation With Past Cognitive Decline.

OBJECTIVES: We examined the extent to which measures of neurodegeneration and cerebrovascular disease explain the rest-activity rhythm (RAR)-cognition link. METHODS: Seventy participants (mean age at MRI = 86, standard deviation (SD) = 2.6; 53% female) had cognitive, MRI, and accelerometer data. The slope of cognitive decline was defined applying a mixed model to 10 repeated Modified Mini Mental Status Test (3MS) measures over 14 years. Regional gray matter volume (GMV), white matter hyperintensities, and RARs were measured around year 12. RESULTS: Past 3MS decline was related to RAR fragmentation (per SD ß = -0.43, 95% confidence interval: -0.73, -0.14) and lower posterior parietal GMV (per standard deviation ß = 0.47, 95% confidence interval: 0.14, 0.79). Higher RAR fragmentation was related to lower posterior parietal GMV (Pearson r = -0.39, n = 70, p = 0.0007), which attenuated the association of RAR fragmentation and past cognitive decline by 17%. CONCLUSIONS: Longitudinal studies are warranted to understand the temporal relations and mechanisms linking RAR fragmentation and neurodegeneration.

Shared neural substrates of cognitive function and postural control in older adults.

INTRODUCTION: Poor cognitive function and postural control co-occur in older adults. It is unclear whether they share neural substrates. METHODS: Postural sway error during a novel visual tracking (VT) condition and gray matter volume (GMV) were compared between participants with normal cognition (NC), mild cognitive impairment (MCI), or dementia (n = 179, mean age 82, 56% females, 56% white). Associations between VT error, cognitive function, and GMV were examined. RESULTS: Greater VT error was associated with having dementia compared to NC or MCI (odds ratio [95% CI] = 2.15 [1.38, 3.36] and 1.58 [1.05, 2.38]). Regions with lower GMV related to greater VT error and worse cognition were: bilateral hippocampi, parahippocampi, entorhinal, and parietal cortices (all P ≤0.05). GMV of bilateral hippocampi and left parahippocampus explained >20% of VT error between dementia and NC. DISCUSSION: Postural control during visuospatial tasks and dementia may share neural substrates, specifically memory-related regions.

Trajectory of Postconcussive Symptoms 12 Months After Deployment in Soldiers With and Without Mild Traumatic Brain Injury: Warrior Strong Study.

We analyzed data from a cohort of recently deployed soldiers from 2 US Army bases, Fort Carson and Fort Bragg (2009 to 2015). Soldiers with and without a recent history of mild traumatic brain injury (mTBI) on deployment were evaluated within days of return and at 3, 6, and 12 months. Those with mTBI were more likely than those without to endorse ≥1 postconcussive symptom as "severe" and/or "very severe" (47% vs. 21%, baseline; adjusted relative risk (RR) = 1.71, 95% confidence interval: 1.51, 1.93, all time points), which remained significant after adjusting for posttraumatic stress disorder (adjusted RR = 1.34, 95% confidence interval: 1.20, 1.50). Prevalence and relative risks for 3 of the most common baseline symptoms remained constant over time: sleep problems (RR = 2.19), forgetfulness (RR = 2.56), and irritability (RR = 2.73). The pattern was slightly different for headache (baseline, RR = 3.44; 12 months, RR = 3.26), due to increased prevalence of headache in those without mTBI. The prevalence of clinically relevant postconcussive symptoms remained relatively constant over 1 year of follow-up, whether or not symptoms were associated with concussion. Service members with recent mTBI reported more symptoms than those without at all time points.

Neuroimaging correlates of lateral postural control in older ambulatory adults.

BACKGROUND: In older adults, impaired postural control contributes to falls, a major source of morbidity. Understanding central mechanisms may help identify individuals at risk for impaired postural control. AIMS: To determine the relationship between gray matter volume (GMV), white matter hyperintensities (WMH), mean diffusivity (MD), and fractional anisotropy (FA) with lateral postural control. METHODS: Neuroimaging and postural control were assessed in 193 community-dwelling older adults (mean age 82, 55.4% female, 44.6% black). GMV, WMH, and diffusion tensor-derived markers of microstructure (MD and FA) were quantified for total brain and regions of interest. Lateral postural control was defined as the root mean square error (RMSE) of lateral sway during a visual feedback test. Associations were assessed with linear regression, adjusted for total brain atrophy and risk factors for impaired postural control. RESULTS: RMSE was higher for women than men (p < 0.001) and inversely correlated with gait speed (r = - 0.20, p = 0.01), modified mini-mental state (r = - 0.27, p < 0.001), digit symbol substitution test (r = - 0.20, p = 0.01) and quadriceps strength (r = - 0.18, p = 0.01). RMSE was inversely associated with GMV of bilateral precuneus (r = - 0.26, p = 0.01) and FA of corpus callosum and selected tracts in the right hemisphere (anterior thalamic radiation, cingulum, inferior longitudinal and fronto-occipital fasciculi), independent of covariates (r = - 0.34 to - 0.18, p ≤ 0.04). DISCUSSION: Lower GMV and microstructural white matter integrity in selected networks can explain worse lateral postural control in older ambulatory adults without neurologic diseases. CONCLUSION: Neuroimaging markers of poor postural control in healthy aging may help identify increased fall risk and design preventative fall strategies.

Longitudinal changes in physical function and physical activity in older adults.

BACKGROUND: physical function (PF) and physical activity (PA) both decline as adults age and have been linked to negative outcomes, including dementia, depression and cardiovascular diseases. Although declines in each are associated with numerous negative outcomes, the longitudinal relationship between these two measures is unclear. OBJECTIVE: to examine the dynamic, bidirectional associations between declines in PF and PA. DESIGN: prospective cohort. SETTING: the Monongahela-Youghiogheny Healthy Aging Team (MYHAT) study. SUBJECTS: about 1,404 men and women, 76.96 ± 7.2 years, 62.4% female and 95.2% white. METHODS: over nine annual assessment cycles, PF was evaluated via the timed Up-and-Go task and PA via a self-reported questionnaire. Piecewise latent growth models examined bidirectional associations between PA and PF to determine whether the initial values (intercept) or early slope (cycles 1-5) (in either PF or PA) predicted later slope (cycles 5-9) (in either PF or PA). RESULTS: initial PF significantly predicted early (standardised ß= -0.10, P < 0.001) and later (standardised ß= -0.09, P = 0.01) PA slopes. Initial PA significantly predicted later (standardised ß = -0.09, P = 0.04) but not early PF slope. Associations were independent of baseline memory test scores, baseline cognitive status, later cognitive status and age. Early physical function slope neither predicts later PA slope nor did early PA slope predict later PF slope (both P values >0.10). CONCLUSIONS: the relationship between PF and PA is bidirectional, with PF more consistently predicting declines of PA, both in the short- and long-term. Intervening on PF impairments may improve PA engagement, which could in turn promote PF and translate to beneficial effects on cognitive function, cardiovascular health and mood.

The Impact of Post-Traumatic Stress Disorder on the Burden of Migraine: Results From the National Comorbidity Survey-Replication.

BACKGROUND: Post-traumatic stress disorder (PTSD) has been linked with migraine in prior studies. OBJECTIVE: To evaluate the individual and joint burdens of migraine and PTSD in a population-based cohort. METHODS: The National Comorbidity Survey-Replication (NCS-R) is a general population study conducted in the United States from February 2001-April 2003. PTSD and migraine were assessed, and four groups defined based on their migraine and PTSD status. The four groups included those with no migraine and no PTSD (controls, n=4535), those with migraine and without PTSD (migraine alone, n=236), those with PTSD and without migraine (PTSD alone, n=244), and those with both migraine and PTSD (mig+PTSD, n=68). Logistic and Poisson regression models were used to assess the association between dichotomous/multilevel outcome variables indicating financial, health, and interpersonal burdens and each migraine/PTSD group. RESULTS: Compared to controls, those with Mig+PTSD were more likely to be in the low poverty index (48% vs 41%, AOR 2.16; CI: 1.10, 4.24) and were less likely to be working for pay or profit in the past week (50% vs 68%, AOR 0.42; CI: 0.24, 0.74) but not those with migraine or PTSD alone. Additionally, the number of days where work quality was cut due to physical or mental health or substance abuse in the past month was greater in all groups compared to controls: (1) migraine alone: mean 2.57 (SEM 0.32) vs mean 1.09 (SEM 0.08) days, ARR=2.39; CI: 2.19, 2.62; (2) PTSD alone: mean 2.43 (SEM 0.33) vs mean 1.09 (SEM 0.08) days, ARR=2.09; CI: 1.91, 2.29; (3) mig+PTSD: mean 8.2 (SEM 0.79) vs 1.09 (SEM 0.08) days, ARR 6.79; CI 6.16, 7.49; and was over 2.5-fold greater in those mig+PTSD than migraine alone (mean 8.0 [SEM 0.79] vs 2.6 days [SEM 0.72], ARR 2.77; CI: 2.45, 3.14). The likelihood of having difficulty getting along or maintaining a social life was also increased in all groups relative to controls: (1) migraine alone: 21% vs 5.4%, AOR 4.20; CI: 2.62, 6.74; (2) PTSD alone: 18% vs 5.4%, AOR 3.40; CI: 2.40, 4.82; (3) Mig+PTSD: 39% vs 5.4%, AOR 9.95; CI: 5.72, 17.32, and was 2-fold greater in those with Mig+PTSD as compared to those with migraine alone (AOR 2.32; CI: 1.15, 4.69). CONCLUSIONS: These findings support the need for those who treat migraine patients to be aware of the comorbidity with PTSD, as these patients may be particularly prone to adverse financial, health, and interpersonal disease burdens.

The demographic and medical correlates of plasma aß40 and aß42.

Plasma amyloid ß-42 (Aß42) and Aß42/Aß40 are increasingly recognized as biomarkers for dementia, with low levels indicating increased risk. Little is known about the demographic and medical correlates of plasma Aß40 or Aß42. In 997 community-dwelling, nondemented older adults from the Health, Aging, and Body Composition Study, we determined the cross-sectional association between a wide range of demographic and medical variables with Aß40 and Aß42. In multivariate stepwise linear regression models, Aß40 was significantly associated with race (ß=-14.70, F=22.01, P<0.0001), age (ß=1.34, F=6.39, P=0.01), creatinine (ß=52.91, F=151.77, P<0.0001), and the serum brain-derived neurotrophic factor (ß=-0.0004, F=7.34, P=0.007); Aß42 was significantly associated with race (ß=-3.72, F=30.83, P<0.0001), sex (ß=1.39, F=4.32, P=0.04), education (ß=1.50, F=4.78, P=0.03), apolipoprotein E e4 genotype (ß=-2.82, F=16.57, P<0.0001), and creatinine (ß=9.32, F=120.09, P<0.0001). These correlates should be considered as potential confounders in future studies investigating plasma Aß as a biomarker of dementia. Understanding fully how these correlates mediate or modify the association between plasma Aß and dementia will be a fundamental step in determining the biological pathways through which plasma Aß40 and Aß42 are associated with dementia, and in determining their full potential as biomarkers.

Influence of Striatal Dopamine, Cerebral Small Vessel Disease, and Other Risk Factors on Age-Related Parkinsonian Motor Signs.

OBJECTIVE: Parkinsonian motor signs are common and disabling in older adults without Parkinson's disease (PD), but its risk factors are not completely understood. We assessed the influence of striatal dopamine levels, cerebral small vessel disease, and other factors on age-related parkinsonian motor signs in non-PD adults. METHODS: Striatal dopamine transporter (DAT) binding was quantified via [11C]-CFT positron emission tomography in 87 neurologically intact adults (20-85 years, 57.47% female) with concurrent data on: Unified Parkinson's Disease Rating Scale motor (UPDRSm), white matter hyperintensities (WMH), and other risk factors (grip strength, vibratory sensitivity, cardio- and cerebro-vascular comorbidities). Sex-adjusted nonparametric models first estimated the associations of age, DAT, WMH, and other factors with UPDRSm; next, interactions of age by DAT, WMH, or other factors were tested. To quantify the influence of DAT, WMH, and other risk factors on the main association of age with UPDRSm, multivariable mediation models with bootstrapped confidence intervals (CI) were used. RESULTS: Older age, lower DAT, higher WMH, and worse risk factors significantly predicted worse UPDRSm (sex-adjusted p < .04 for all). DAT, but not WMH or other factors, positively and significantly interacted with age (p = .02). DAT significantly reduced the age-UPDRSm association by 30% (results of fully adjusted mediation model: indirect effect: 0.027; bootstrapped 95% CI: 0.0007, 0.074). CONCLUSIONS: Striatal dopamine appears to influence to some extent the relationship between age and parkinsonian signs. However, much of the variance of parkinsonian signs appears unexplained. Longitudinal studies to elucidate the multifactorial causes of this common condition of older age are warranted.

Posttraumatic vs nontraumatic headaches: A phenotypic analysis in a military population.

OBJECTIVE: To describe and compare phenotypic features of posttraumatic headaches (PTH) and headaches unrelated to concussion. METHODS: Participants are a random sample of recently deployed soldiers from the Warrior Strong cohort, consisting of soldiers with (n = 557) and without (n = 1,030) a history of a recent mild traumatic brain injury (mTBI; concussion). mTBI+ soldiers were subdivided as PTH+ (n = 230) and PTH- (n = 327). Headache classification was based on a detailed phenotypic questionnaire. Medical encounters for headache were documented for the year after deployment. RESULTS: The findings here are limited to the soldiers with headaches, consisting of 94% of the mTBI+ soldiers and 76% of the mTBI- soldiers. Other than headache duration, all headache/migraine features were more common or more severe in the PTH+ group compared to the nonconcussed group (mTBI-) and compared to the concussed group with nontraumatic headaches (PTH-). Headaches were largely similar in the mTBI- and PTH- groups. The features most specific to PTH+ included allodynia, visual aura, sensory aura, daily headache, and continuous headache. Medical consultation for headache was most common in the PTH+ group (62%) vs the PTH- group (20%) or the mTBI- group (13%) (p < 0.008). CONCLUSIONS: In this cohort of recently deployed soldiers, PTHs are more severe, frequent, and migraine-like and more often associated with medical consultation compared to headaches presumed unrelated to concussion. Future observational studies are needed to verify and characterize the PTH phenotype, which could be followed by treatment trials with appropriate and possibly novel outcomes for prespecified subgroups. CLINICALTRIALSGOV IDENTIFIER: NCT01847040.

Associations of Usual Pace and Complex Task Gait Speeds With Incident Mobility Disability.

BACKGROUND/OBJECTIVES: To assess whether gait speed under complex conditions predicts long-term risk for mobility disability as well as or better than usual-pace gait speed. DESIGN: Longitudinal cohort study. SETTING/PARTICIPANTS: Subsample of Health Aging and Body Composition study with follow-up from 2002 to 2003 to 2010 to 2011, including 337 community-dwelling adults (mean age = 78.5 years, 50.7% female, 26.1% black). MEASUREMENTS: Associations of gait speed measured under usual-pace, fast-pace, dual-task, and narrow-path conditions with mobility disability, defined by any self-reported difficulty walking » mile assessed annually, were tested by Cox proportional hazard models adjusted for demographic and health characteristics. Models were fitted for each walking condition, and R2 statistics were used to compare predictive value across models. Models were repeated for persistent mobility disability, defined as at least two consecutive years of mobility disability. RESULTS: Mobility disability occurred in 204 (60.5%) participants over the 8-year follow-up. There was a lower hazard of developing mobility disability with faster gait speed under all conditions. Hazard ratios, confidence intervals, and R2 of gait speed predicting mobility disability were similar across all four walking conditions (R2 range = 0.22-0.27), but were strongest for dual-task gait speed (hazard ratio [95% confidence interval], R2 of fully adjusted models = 0.81 [0.75-0.88], 0.27). Results were comparable for persistent mobility disability (R2 range = 0.26-0.28). CONCLUSION: Slower gait speed under both usual-pace and complex conditions may be a clinical indicator of future risk of mobility disability. These results support the call for increased use of gait speed measures in routine geriatric care. J Am Geriatr Soc 67:2072-2076, 2019.

Qualitative neurological gait abnormalities, cardiovascular risk factors and functional status in older community-dwellers without neurological diseases: The Healthy Brain Project.

BACKGROUND: Neurologic gait abnormalities (NGA) increase risk for falls and dementia, but their pathophysiologic substrates or association with disability have been poorly investigated. We evaluated the association of NGA with clinical characteristics and functional status in older community-dwellers. METHODS: Gait characteristics were measured in older community-dwellers without neurological or psychological diseases participating to the Health Aging Body Composition study. NGA were rated using standardized readings of video-recorded short walks, combined with standard neurological exam. We tested cross-sectional associations with demographics, vascular risk factors, comorbidities, cognitive function and disability. RESULTS: Of 177 participants (median age [IQR] = 82 [4] years, 55% women, 58% Caucasian), 49 (27.7%) had NGA. The most prevalent sub-types were unsteady (10.7%), hemiparetic (4.5%) and parkinsonian (4%). In multivariable logistic regression models, diabetes was associated with higher risk (OR = 3.24, 95% CI = 1.38-7.59), whereas higher physical activity (OR = 0.89, 95% CI = 0.80-0.99) and gait speed (OR = 0.04, 95% CI = 0.005-0.27) with lower risk of NGA. Prevalence of NGA was associated with difficulty in at least 1 activity of daily living, adjusting for confounders (OR = 2.90, 95% CI = 1.11-7.58). After adjusting for gait speed, this association was attenuated to non-significance (OR = 2.13, 95% CI = 0.71-6.37). CONCLUSIONS: In our sample of community-dwelling older adults without neurological diseases, NGA, detected with a standardized neurological exam, part of usual physicians' training, were common. The relationships with diabetes and reduced physical activity might suggest vascular dysfunction as an underlying contributor to NGA. These results, if confirmed by longitudinal studies, which should also disentangle the relationship between NGA, gait speed and disability, might add information for preventing and managing mobility disability.

Complex Walking Tasks and Risk for Cognitive Decline in High Functioning Older Adults.

BACKGROUND: Performance on complex walking tasks may provide a screen for future cognitive decline. OBJECTIVE: To identify walking tasks that are most strongly associated with subsequent cognitive decline. METHODS: Community-dwelling older adults with Modified Mini-Mental State (3MS) >85 at baseline (n = 223; mean age = 78.7, 52.5% women, 25.6% black) completed usual-pace walking and three complex walking tasks (fast-pace, narrow-path, visuospatial dual-task). Slope of 3MS scores for up to 9 subsequent years (average = 5.2) were used to calculate a cognitive maintainer (slope ≥0) or decliner (slope <0) outcome variable. Logistic regression models assessed associations between gait speeds and being a cognitive decliner. A sensitivity analysis in a subsample of individuals (n = 66) confirmed results with adjudicated mild cognitive impairment (MCI) or dementia at 8-9 years post-walking assessment. RESULTS: Cognitive decliners were 52.5% of the sample and on average were slower for all walking tasks compared to maintainers. In models adjusted for demographic and health variables, faster fast-pace (OR = 0.87 per 0.1 m/s, 95% CI: 0.78, 0.97) and dual-task (OR = 0.84 per 0.1 m/s, 95% CI: 0.73, 0.96) gait speeds were associated with lower likelihood of being a cognitive decliner. Usual-pace gait speed was not associated (OR = 0.96 per 0.1 m/s, 95% CI: 0.85, 1.08). Results were nearly identical in analyses with adjudicated MCI or dementia as the outcome. CONCLUSION: Fast-pace and dual-task walking may provide simple and effective tools for assessing risk for cognitive decline in older individuals with high cognitive function. Such screening tools are important for strategies to prevent or delay onset of clinically meaningful change.

Long-term changes in retinal vascular diameter and cognitive impairment in type 1 diabetes.

OBJECTIVE: To assess associations between cognitive impairment and longitudinal changes in retinal microvasculature, over 18 years, in adults with type 1 diabetes. RESEARCH DESIGN AND METHODS: Participants of the Pittsburgh Epidemiology of Diabetes Complications Study received ≥3 fundus photographs between baseline (1986-1988) and time of cognitive assessment (2010-2015: N = 119; 52% male; mean age and type 1 diabetes duration 43 and 34 years, respectively). Central retinal arteriolar equivalent and central retinal venular equivalent were estimated via computer-based methods; overall magnitude and speed of narrowing were quantified as cumulative average and slope, respectively. Median regression models estimated associations of central retinal arteriolar equivalent and central retinal venular equivalent measures with cognitive impairment status, adjusted for type 1 diabetes duration. Interactions with HbA1c, proliferative retinopathy and white matter hyperintensities were assessed. RESULTS: Compared with participants without cognitive impairment, those with clinically relevant cognitive impairment experienced 1.8% greater and 31.1% faster central retinal arteriolar equivalent narrowing during prior years (t = -2.93, p = 0.004 and t = -3.97, p < 0.0001, respectively). Interactions with HbA1c, proliferative retinopathy and white matter hyperintensities were not significant. No associations were found between central retinal arteriolar equivalent at baseline, at time of cognitive testing, or any central retinal venular equivalent measures, and cognitive impairment. CONCLUSION: Long-term arterial retinal changes could indicate type 1 diabetes-related cognitive impairment. Studies examining longitudinal central retinal arteriolar equivalent changes as early biomarkers of cognitive impairment risk are warranted.

Longitudinal Associations Between Walking Speed and Amount of Self-reported Time Spent Walking Over a 9-Year Period in Older Women and Men.

Background: Age-related limitations in mobility and decreased physical activity appear to be linked cross-sectionally; however, large-scale, longitudinal analyses of the associations between age-related changes in mobility and engagement in physical activity are lacking. In this longitudinal study, we hypothesized that early mobility limitations would contribute to later decreases in physical activity to a larger degree than the reciprocal association of early decreases in physical activity to later mobility limitations. Methods: Participants were 2,876 initially well-functioning community-dwelling older adults (aged 70-79 years at baseline; 52% women; 39% black) studied over a 9-year period. Usual walking speed and self-reported physical activity (based on minutes per week of walking) were assessed at Years 0 (ie, baseline), 4, and 9. A cross-lagged, longitudinal model assessed the bidirectional associations between walking speed and physical activity over time. Results: Early change in walking speed between Years 0 and 4 predicted late change in physical activity between Years 4 and 9 (ß = .13 p < .001). However, early change in physical activity did not predict late change in walking speed (ß = -.01, p = .79). The difference between these two predictive associations was highly significant (p < .001). Associations were independent of baseline demographic and physical health variables, as well as longitudinal changes in grip and quadriceps strength. Conclusions: The results suggest declining walking speed as a precursor to declining engagement in physical activity, but the converse association was not evident. Improving walking speed may be a method to increase physical activity among elderly individuals.

Dopamine-Related Genotypes and Physical Activity Change During an Intervention: The Lifestyle Interventions and Independence for Elders Study.

OBJECTIVES: To determine whether intervention-induced physical activity (PA) changes in sedentary older adults differed according to dopamine-related genotype. DESIGN: Randomized clinical trial (Lifestyle Interventions and Independence for Elders Trial (2010-13)). SETTING: Multicenter study, 8 U.S. PARTICIPANTS: Volunteer sample of sedentary adults aged 70 to 89 at risk of disability (N=1635). INTERVENTIONS: Structured PA versus health education (HE) for an average of 2.6 years. MEASUREMENTS: Single-nucleotide polymorphisms of dopamine-related genes (dopamine receptor (DR) D1, DRD2, DRD3, and catechol-O-methyltransferase (COMT)) were assessed. Average moderate to vigorous PA (MVPA) was calculated using accelerometry (min/d) at baseline and 6, 12, and 24 months. Between-arm MVPA differences according to genotype and genotype with square root-transformed MVPA separately according to arm were tested, stratified according to race, and adjusted for multiple comparisons. RESULTS: White participants in the PA arm (n=513) had higher average square root transformed MVPA (4.91±1.91)than those in the HE arm (n=538) (4.51±1.82) (p=.001). Between-arm differences were greater for DRD2 Met/Met (high dopamine; HE: 4.76±1.80, PA: 5.53±1.60, p=.03) than Val/Val (low dopamine; HE: 4.58±1.92, PA: 4.81±1.83, p=.16); results were similar for COMT. In the PA arm, DRD2 Met/Met was associated with higher average MVPA (5.39±2.00) than Met/Val (4.46±2.51) (p=.01) and Val/Val (4.65±2.71) (p=.01). There were no associations for other genes. Associations were not significant in blacks but followed similar trends. CONCLUSION: Higher dopamine signaling may support changes in PA during an intervention. The role of dopamine-related pathways in promoting PA participation and enhancing response to interventions in sedentary older adults should be studied. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01072500.

Disease severity and slower psychomotor speed in adults with sickle cell disease.

Psychomotor slowing is common in children with sickle cell disease (SCD), but little is known about its severity in adults. We conducted a cross-sectional study to quantify psychomotor speed, measured with the digit symbol substitution test (DSST), in relationship with disease severity in adults with SCD attending an outpatient clinic (n = 88, age 36.3 years). Genotype was used to group patients in "severe" (homozygous for hemoglobin S or compound heterozygous with ß0 thalassemia) or "moderate" groups (compound heterozygous for HbS, with either HbC or ß+ thalassemia). Analyses were repeated after exclusion of patients with a history of stroke (n = 11). Mild impairment in processing speed was detectable in both the "severe" and the "moderate" group (30% and 9%, respectively; age-adjusted P = .14). Compared with the "moderate" group, those in the "severe" group had significantly lower standardized DSST scores (P = .004), independent of adjustment for factors that differed between the groups: hemoglobin, ferritin, hydroxyurea use, blood pressure parameters, and stroke history. Results were similar after excluding patients with stroke. Psychomotor slowing in SCD differs in relationship to genotype; this difference appears unrelated to history of stroke or severity of anemia and other risk factors examined cross-sectionally. Although less prevalent, mild cognitive impairment was also detectable in patients with a less severe genotype. Longitudinal studies of SCD should include all diseases genotypes and examine factors that would reduce the risk of slow processing speed and perhaps more general cognitive impairment in each subgroup.

Catechol-O-Methyltransferase Genotype and Gait Speed Changes over 10 Years in Older Adults.

OBJECTIVES: To determine the association between catechol-O-methyltransferase (COMT) genotype and 6-m walk time and to determine whether these associations are quadratic in nature, similar to previously reported U-shaped associations between dopamine and gait and cognition. DESIGN: Prospective cohort study. SETTING: Health, Aging and Body Composition Study. PARTICIPANTS: Black (n = 850) and white (n = 1,352) men and women with a mean age of 73.5 ± 2.85 at baseline. MEASUREMENTS: Mixed models were used to assess the association between the COMT genotype and 6-m walk time, cross-sectionally and longitudinally over 10 years. Models were assessed unstratified and stratified according to race because allele distributions were different between white and black participants. RESULTS: There was a significant U-shaped association between COMT genotype and 6-m walk time: those with higher (Val/Val) and lower (Met/Met) dopamine slowed more over 10 years (0.22 ± 0.02 seconds per visit and 0.23 ± 0.02 seconds per visit, respectively) than those with the intermediate (Met/Val) dopamine (0.20 ± 0.02 seconds per visit) (P = .005). Stratified results showed a significant relationship in black (P = .01) but not white (P = .15) participants. CONCLUSION: These findings indicate a role of dopaminergic regulation of gait speed in community-dwelling older adults and of prefrontal cortex involvement in gait performance. Future work should investigate the molecular integrity of dopaminergic networks and gait changes over time and structural changes in the brain with COMT and gait decline in older adults.

Slowing gait and risk for cognitive impairment: The hippocampus as a shared neural substrate.

OBJECTIVE: To identify the shared neuroimaging signature of gait slowing and cognitive impairment. METHODS: We assessed a cohort of older adults (n = 175, mean age 73 years, 57% female, 65% white) with repeated measures of gait speed over 14 years, MRI for gray matter volume (GMV) at year 10 or 11, and adjudicated cognitive status at year 14. Gait slowing was calculated by bayesian slopes corrected for intercepts, with higher values indicating faster decline. GMV was normalized to intracranial volume, with lower values indicating greater atrophy for 10 regions of interest (hippocampus, anterior and posterior cingulate, primary and supplementary motor cortices, posterior parietal lobe, middle frontal lobe, caudate, putamen, pallidum). Nonparametric correlations adjusted for demographics, comorbidities, muscle strength, and knee pain assessed associations of time to walk with GMV. Logistic regression models calculated odds ratios (ORs) of gait slowing with dementia or mild cognitive impairment with and without adjustment for GMV. RESULTS: Gait slowing was associated with cognitive impairment at year 14 (OR per 0.1 s/y slowing 1.47; 95% confidence interval 1.04-2.07). The right hippocampus was the only region that was related to both gait slowing (ρ = -0.16, p = 0.03) and cognitive impairment (OR 0.17, p = 0.009). Adjustment for right hippocampal volume attenuated the association of gait slowing with cognitive impairment by 23%. CONCLUSIONS: The association between gait slowing and cognitive impairment is supported by a shared neural substrate that includes a smaller right hippocampus. This finding underscores the value of long-term gait slowing as an early indicator of dementia risk.

Cognitive resilience to apolipoprotein E ε4: contributing factors in black and white older adults.

IMPORTANCE: Apolipoprotein E (APOE) ε4 is an established risk factor for cognitive decline and the development of dementia, but other factors may help to minimize its effects. OBJECTIVE: Using APOE ε4 as an indicator of high risk, we investigated factors associated with cognitive resilience among black and white older adults who are APOE ε4 carriers. DESIGN, SETTING, AND PARTICIPANTS: Participants included 2487 community-dwelling older (aged 69-80 years at baseline) black and white adults examined at 2 community clinics in the prospective cohort Health, Aging, and Body Composition (Health ABC) study. The baseline visits occurred from May 1997 through June 1998. Our primary analytic cohort consisted of 670 APOE ε4 carriers (329 black and 341 white participants) who were free of cognitive impairment at baseline and underwent repeated cognitive testing during an 11-year follow-up (through 2008) using the Modified Mini-Mental State Examination. MAIN OUTCOMES AND MEASURES: We stratified all analyses by race. Using the Modified Mini-Mental State Examination scores, we assessed normative cognitive change in the entire cohort (n = 2487) and classified the APOE ε4 carriers as being cognitively resilient vs nonresilient by comparing their cognitive trajectories with those of the entire cohort. We then conducted bivariate analyses and multivariable random forest and logistic regression analyses to explore factors predictive of cognitive resilience in APOE ε4 carriers. RESULTS: Among white APOE ε4 carriers, the strongest predictors of cognitive resilience were, in relative order of importance, no recent negative life events, a higher literacy level, advanced age, a higher educational level, and more time spent reading. Among black APOE ε4 carriers, the strongest predictors of cognitive resilience were, in relative order of importance, a higher literacy level, a higher educational level, female sex, and the absence of diabetes mellitus. In follow-up logistic regression models, higher literacy level (adjusted odds ratio [OR], 9.50 [95% CI, 2.67-60.89]), a higher educational level (adjusted OR for college graduate vs less than high school, 3.81 [95% CI, 1.13-17.56]), and age (adjusted OR for 73-76 vs 69-72 years, 2.01 [95% CI, 1.13-3.63]) had significant independent effects in predicting cognitive resilience among white APOE ε4 carriers. Among black APOE ε4 carriers, a higher literacy level (adjusted OR, 2.27 [95% CI, 1.29-4.06]) and a higher educational level (adjusted OR for high school graduate/some college vs less than high school, 2.86 [95% CI, 1.54-5.49]; adjusted OR for college graduate vs less than high school, 2.52 [95% CI, 1.14-5.62]) had significant independent effects in predicting cognitive resilience. CONCLUSIONS AND RELEVANCE: Although APOE ε4 carriers are at high risk for cognitive decline, our findings suggest possible intervention targets, including the enhancement of cognitive reserve and improvement of other psychosocial and health factors, to promote cognitive resilience among black and white APOE ε4 carriers.