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.

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.

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.

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.

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.

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.

Trajectories of peripheral interleukin-6, structure of the hippocampus, and cognitive impairment over 14 years in older adults.

We aimed to investigate if trajectory components (baseline level, slope, and variability) of peripheral interleukin-6 (IL-6) over time were related to cognitive impairment and smaller hippocampal volume and if hippocampal volume explained the associations between IL-6 and cognitive impairment. Multivariable regression models were used to test the association between IL-6 trajectory components with change in neuroimaging measures of the hippocampus and with cognitive impairment among 135 older adults (70-79 years at baseline) from the Healthy Brain Project over 14 years. IL-6 variability was positively associated with cognitive impairment (odds ratio [OR] = 5.86, 95% confidence interval [CI]: 1.24, 27.61) and with greater decrease per year of gray matter volume of the hippocampus (ß = -0.008, standard error = 0.004, p = 0.03). After adjustment for hippocampal volume, the OR of cognitive impairment decreased for each unit of IL-6 variability and CIs widened (OR = 4.36, 95% CI: 0.67, 28.29). Neither baseline levels nor slopes of IL-6 were related to cognitive impairment or hippocampal volume. We believe this has potential clinical and public health implications by suggesting adults with stable levels of peripheral IL-6 may be better targets for intervention studies for slowing or preventing cognitive decline.

Older adults with limited literacy are at increased risk for likely dementia.

BACKGROUND: Low literacy is common among the elderly and possibly more reflective of educational attainment than years of school completed. We examined the association between literacy and risk of likely dementia in older adults. METHODS: Participants were 2,458 black and white elders (aged 71-82) from the Health, Aging and Body Composition study, who completed the Rapid Estimate of Adult Literacy in Medicine and were followed for 8 years. Participants were free of dementia at baseline; incidence of likely dementia was defined by hospital records, prescription for dementia medication, or decline in Modified Mini-Mental State Examination score. We conducted Cox proportional hazard models to evaluate the association between literacy and incidence of likely dementia. Demographics, education, income, comorbidities, lifestyle variables, and apolipoprotein E (APOE) ε4 status were included in adjusted analyses. RESULTS: Twenty-three percent of participants had limited literacy (<9th-grade level). Limited literacy, as opposed to adequate literacy (≥9th-grade level), was associated with greater incidence of likely dementia (25.5% vs17.0%; unadjusted hazard ratio [HR] = 1.75, 95% confidence interval 1.44-2.13); this association remained significant after adjustment. There was a trend for an interaction between literacy and APOE ε4 status (p = .07); the association between limited literacy and greater incidence of likely dementia was strong among ε4 noncarriers (unadjusted HR = 1.85) but nonsignificant among ε4 carriers (unadjusted HR = 1.25). CONCLUSIONS: Limited literacy is an important risk factor for likely dementia, especially among APOE ε4-negative older adults, and may prove fruitful to target in interventions aimed at reducing dementia risk.

Change in inflammatory markers and cognitive status in the oldest-old women from the Study of Osteoporotic Fractures.

OBJECTIVES: To determine the association between interleukin-6 (IL-6), IL-6 soluble receptor (sR), and soluble tumor necrosis factor receptor-1 (sTNF-R1) and cognitive status in the oldest-old women. DESIGN: Twenty-year longitudinal cohort study. SETTING: Four clinical sites in the United States. PARTICIPANTS: Women from the Study of Osteoporotic Fractures (N = 905; mean age 88.3 ± 2.8 at cognitive status adjudication). MEASUREMENTS: At Year 20, cognitive status was adjudicated as normal, mild cognitive impairment (MCI), or dementia. Inflammatory markers were measured from blood serum at Years 10 and 16 in a random sample of women. RESULTS: Over 10 years, 199 (22.0%) women developed MCI and 145 (16.0%) dementia. There were no significant associations between IL-6 or sTNF-R1 and cognitive status. High IL-6-sR (≥ 37,401.36 pg/mL, highest tertile) at Year 16 was significantly associated with lower risk of dementia (odds ratio (OR) = 0.54, 95% confidence interval (CI) = 0.30-0.97) than in women with lower levels (<37,401.36 pg/mL, lower two tertiles). Women with high IL-6-sR at both time points (OR = 0.39, 95% CI = 0.17-0.89) or who transitioned to a high level (OR = 0.35, 95% CI = 0.14-0.88) had a lower risk of dementia. CONCLUSION: In this cohort of white, high-functioning oldest-old women, a consistently high or an increasing level of IL-6-sR was associated with lower risk of dementia. Compared with other studies of younger-old adults, this suggests that the effect of inflammation on dementia may differ in younger-old and the oldest-old individuals. Understanding these differences will be crucial in interpreting results from ongoing clinical trials and in targeting therapeutic strategies to the oldest-old individuals.

Trajectories of inflammatory markers and cognitive decline over 10 years.

We aimed to examine trajectories of inflammatory markers and cognitive decline over 10 years. Cox proportional hazards models were used to examine the association between interleukin-6 and C-reactive protein (CRP) trajectory components (slope, variability, and baseline level) and cognitive decline among 1323 adults, aged 70-79 years in the Health, Aging, and Body Composition Study. We tested for interactions by sex and apolipoprotein E (APOE) genotype. In models adjusted for multiple covariates and comorbidities, extreme CRP variability was significantly associated with cognitive decline (hazard ratio [HR] 1.6, 95% confidence interval [CI]: 1.1-2.3). This association was modified by sex and APOE e4 (p < 0.001 for both), such that the association remained among women (HR = 1.8; 95% CI: 1.1, 3.0) and among those with no APOE e4 allele (HR = 1.6; 95% CI: 1.1, 2.5). There were no significant associations between slope or baseline level of CRP and cognitive decline nor between interleukin-6 and cognitive decline. We believe CRP variability likely reflects poor control of or greater changes in vascular or metabolic disease over time, which in turn is associated with cognitive decline.

The role of peripheral inflammatory markers in dementia and Alzheimer's disease: a meta-analysis.

BACKGROUND: Studies that have investigated the association between markers of inflammation and risk of dementia are conflicting. Therefore, the researchers conducted a systematic review and meta-analysis of observational studies with the hypothesis that an increased level of peripheral proinflammatory markers would be associated with risk of all-cause dementia or Alzheimer's disease (AD). METHODS: The researchers conducted a literature search of observational studies indexed in the PubMed and PsycInfo databases. Selected studies included those with at least one peripheral inflammatory biomarker and its association with risk of all-cause dementia or AD. Random effects models were used to generate pooled hazard ratios (HRs) comparing the top versus bottom quantile of inflammatory marker level. Heterogeneity was assessed using the I (2) statistic. RESULTS: Seven studies were identified, combining for a total 5,717 participants, 746 cases of all-cause dementia and 565 cases of AD. An increased level of C-reactive protein was associated with a 45% increased risk of all-cause dementia (HR: 1.45; 95% CI: 1.10, 1.91). Similarly, a higher level of interleukin-6 was associated with a 32% increased risk (HR: 1.32; 95% CI: 1.06, 1.64) of all-cause dementia. For AD alone, the association with C-reactive protein was less pronounced (HR: 1.21; 95% CI: 1.03, 1.42) and interleukin-6 was not associated with risk of AD (HR: 1.06; 95% CI: 0.83, 1.35). No significant heterogeneity was found in any of the meta-analyses (I (2) = 0%-40%, p ≥ .16). CONCLUSIONS: An increased peripheral level of inflammatory markers is associated with a modest increase in risk of all-cause dementia. Evidence for an association with risk of AD alone is limited.