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

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

ObjectivesTo 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.DesignProspective cohort study.SettingHealth, Aging and Body Composition Study.ParticipantsBlack (n = 850) and white (n = 1,352) men and women with a mean age of 73.5 ± 2.85 at baseline.MeasurementsMixed 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.ResultsThere 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.ConclusionThese 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

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

The Demographic and Medical Correlates of Plasma A&bgr;40 and A&bgr;42

Plasma amyloid β-42 (Aβ42) and Aβ42/Aβ40 are increasingly recognized as biomarkers for dementia, with low levels indicating increased risk. Little is known about the demographic and medical correlates of plasma Aβ40 or Aβ42. 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 Aβ40 and Aβ42. In multivariate stepwise linear regression models, Aβ40 was significantly associated with race (β=-14.70, F=22.01, P<0.0001), age (β=1.34, F=6.39, P=0.01), creatinine (β=52.91, F=151.77, P<0.0001), and the serum brain-derived neurotrophic factor (β=-0.0004, F=7.34, P=0.007); Aβ42 was significantly associated with race (β=-3.72, F=30.83, P<0.0001), sex (β=1.39, F=4.32, P=0.04), education (β=1.50, F=4.78, P=0.03), apolipoprotein E e4 genotype (β=-2.82, F=16.57, P<0.0001), and creatinine (β=9.32, F=120.09, P<0.0001). These correlates should be considered as potential confounders in future studies investigating plasma Aβ as a biomarker of dementia. Understanding fully how these correlates mediate or modify the association between plasma Aβ and dementia will be a fundamental step in determining the biological pathways through which plasma Aβ40 and Aβ42 are associated with dementia, and in determining their full potential as biomarkers

Slowing gait and risk for cognitive impairment

ObjectiveTo identify the shared neuroimaging signature of gait slowing and cognitive impairment.MethodsWe 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.ResultsGait 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%.ConclusionsThe 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

ImportanceApolipoprotein 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.ObjectiveUsing 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 participantsParticipants 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 measuresWe 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.ResultsAmong 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 relevanceAlthough 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

Older Adults With Limited Literacy Are at Increased Risk for Likely Dementia

BackgroundLow 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.MethodsParticipants 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.ResultsTwenty-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).ConclusionsLimited 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

Anemia and risk of dementia in older adults

ObjectiveTo determine whether anemia is associated with incident dementia in older adults.MethodsWe studied 2,552 older adults (mean age 76.1 years; 38.9% black; 51.8% female) participating in the Health, Aging, and Body Composition study and free of dementia at baseline. We defined anemia using WHO criteria (hemoglobin concentration <13 g/dL for men and <12 g/dL for women). Dementia diagnosis was determined by dementia medication use, hospital records, or a change in modified mini-mental state (3MS) score of more than 1.5 SD from mean. Discrete time Cox proportional hazard regression models were used to examine the hazard for developing dementia associated with anemia.ResultsOf 2,552 participants, 393 (15.4%) older adults had anemia at baseline [corrected]. Over 11 years of follow-up, 455 (17.8%) participants developed dementia. In the unadjusted model, those with baseline anemia had an increased risk of dementia (23% vs. 17%, hazard ratio = 1.64; 95% confidence interval 1.30, 2.07) compared to those without anemia. The association remained significant after adjusting for demographics, APOE ε4, baseline 3MS score, comorbidities, and renal function. Additional adjustment for other anemia measures (mean corpuscular volume, red cell distribution width), erythropoietin, and C-reactive protein did not appreciably change the results. There was no interaction by sex and race on risk of developing dementia.ConclusionAmong older adults, anemia is associated with an increased risk of developing dementia. Findings suggest that further study of anemia as a risk factor for dementia and a target for intervention for cognitive health is warranted