Harnessing cognitive trajectory clusterings to examine subclinical decline risk factors.

Cognitive decline in Alzheimer's disease and other dementias typically begins long before clinical impairment. Identifying people experiencing subclinical decline may facilitate earlier intervention. This study developed cognitive trajectory clusters using longitudinally based random slope and change point parameter estimates from a Preclinical Alzheimer's disease Cognitive Composite and examined how baseline and most recently available clinical/health-related characteristics, cognitive statuses and biomarkers for Alzheimer's disease and vascular disease varied across these cognitive clusters. Data were drawn from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal cohort study of adults from late midlife, enriched for a parental history of Alzheimer's disease and without dementia at baseline. Participants who were cognitively unimpaired at the baseline visit with ≥3 cognitive visits were included in trajectory modelling (n = 1068). The following biomarker data were available for subsets: positron emission tomography amyloid (amyloid: n = 367; [11C]Pittsburgh compound B (PiB): global PiB distribution volume ratio); positron emission tomography tau (tau: n = 321; [18F]MK-6240: primary regions of interest meta-temporal composite); MRI neurodegeneration (neurodegeneration: n = 581; hippocampal volume and global brain atrophy); T2 fluid-attenuated inversion recovery MRI white matter ischaemic lesion volumes (vascular: white matter hyperintensities; n = 419); and plasma pTau217 (n = 165). Posterior median estimate person-level change points, slopes' pre- and post-change point and estimated outcome (intercepts) at change point for cognitive composite were extracted from Bayesian Bent-Line Regression modelling and used to characterize cognitive trajectory groups (K-means clustering). A common method was used to identify amyloid/tau/neurodegeneration/vascular biomarker thresholds. We compared demographics, last visit cognitive status, health-related factors and amyloid/tau/neurodegeneration/vascular biomarkers across the cognitive groups using ANOVA, Kruskal-Wallis, χ2, and Fisher's exact tests. Mean (standard deviation) baseline and last cognitive assessment ages were 58.4 (6.4) and 66.6 (6.6) years, respectively. Cluster analysis identified three cognitive trajectory groups representing steep, n = 77 (7.2%); intermediate, n = 446 (41.8%); and minimal, n = 545 (51.0%) cognitive decline. The steep decline group was older, had more females, APOE e4 carriers and mild cognitive impairment/dementia at last visit; it also showed worse self-reported general health-related and vascular risk factors and higher amyloid, tau, neurodegeneration and white matter hyperintensity positive proportions at last visit. Subtle cognitive decline was consistently evident in the steep decline group and was associated with generally worse health. In addition, cognitive trajectory groups differed on aetiology-informative biomarkers and risk factors, suggesting an intimate link between preclinical cognitive patterns and amyloid/tau/neurodegeneration/vascular biomarker differences in late middle-aged adults. The result explains some of the heterogeneity in cognitive performance within cognitively unimpaired late middle-aged adults.

Associations between self-reported sleep patterns and health, cognition and amyloid measures: results from the Wisconsin Registry for Alzheimer's Prevention.

Previous studies suggest associations between self-reported sleep problems and poorer health, cognition, Alzheimer's disease pathology and dementia-related outcomes. It is important to develop a deeper understanding of the relationship between these complications and sleep disturbance, a modifiable risk factor, in late midlife, a time when Alzheimer's disease pathology may be accruing. The objectives of this study included application of unsupervised machine learning procedures to identify distinct subgroups of persons with problematic sleep and the association of these subgroups with concurrent measures of mental and physical health, cognition and PET-identified amyloid. Dementia-free participants from the Wisconsin Registry for Alzheimer's Prevention (n = 619) completed sleep questionnaires including the Insomnia Severity Index, Epworth Sleepiness Scale and Medical Outcomes Study Sleep Scale. K-means clustering analysis identified discrete sleep problem groups who were then compared across concurrent health outcomes (e.g. depression, self-rated health and insulin resistance), cognitive composite indices including episodic memory and executive function and, in a subset, Pittsburgh Compound B PET imaging to assess amyloid burden. Significant omnibus tests (P < 0.05) were followed with pairwise comparisons. Mean (SD) sample baseline sleep assessment age was 62.6 (6.7). Cluster analysis identified three groups: healthy sleepers [n = 262 (42.3%)], intermediate sleepers [n = 229 (37.0%)] and poor sleepers [n = 128 (20.7%)]. All omnibus tests comparing demographics and health measures across sleep groups were significant except for age, sex and apolipoprotein E e4 carriers; the poor sleepers group was worse than one or both of the other groups on all other measures, including measures of depression, self-reported health and memory complaints. The poor sleepers group had higher average body mass index, waist-hip ratio and homeostatic model assessment of insulin resistance. After adjusting for covariates, the poor sleepers group also performed worse on all concurrent cognitive composites except working memory. There were no differences between sleep groups on PET-based measures of amyloid. Sensitivity analyses indicated that while different clustering approaches resulted in different group assignments for some (predominantly the intermediate group), between-group patterns in outcomes were consistent. In conclusion, distinct sleep characteristics groups were identified with a sizable minority (20.7%) exhibiting poor sleep characteristics, and this group also exhibited the poorest concurrent mental and physical health and cognition, indicating substantial multi-morbidity; sleep group was not associated with amyloid PET estimates. Precision-based management of sleep and related factors may provide an opportunity for early intervention that could serve to delay or prevent clinical impairment.

NPC-0501 trial on the value of changing chemoradiotherapy sequence, replacing 5-fluorouracil with capecitabine, and altering fractionation for patients with advanced nasopharyngeal carcinoma.

BACKGROUND: A current recommendation for the treatment of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) is conventional fractionated radiotherapy (RT) with concurrent cisplatin followed by adjuvant cisplatin and 5-fluorouracil (PF). This randomized NPC-0501 trial evaluated the therapeutic effect of changing to an induction-concurrent sequence or accelerated-fractionation sequence, and/or replacing 5-fluorouracil with capecitabine (X). METHODS: Patients with American Joint Committee on Cancer/International Union Against Cancer stage III to stage IVB NPC initially were randomly allocated to 1 of 6 treatment arms (6-arm full-randomization cohort). The protocol was amended in 2009 to permit centers to opt out of randomization regarding fractionation (3-arm chemotherapy cohort). RESULTS: A total of 803 patients were accrued (1 of whom was nonevaluable) from 2006 to 2012. Based on the overall comparisons, neither changing the chemotherapy sequence nor accelerated fractionation improved treatment outcome. However, secondary analyses demonstrated that when adjusted for RT parameters and other significant factors, the induction-concurrent sequence, especially the induction-PX regimen, achieved significant improvements in progression-free survival (PFS) and overall survival. Efficacy varied among different RT groups: although no impact was observed in the accelerated-fractionation group and the 3-arm chemotherapy cohort, a comparison of the induction-concurrent versus concurrent-adjuvant sequence in the conventional-fractionation group demonstrated a significant benefit in PFS (78% vs 62% at 5 years; P = .015) and a marginal benefit in overall survival (84% vs 72%; P = .042) after adjusting for multiple comparisons. Comparison of the induction-PX versus the adjuvant-PF regimen demonstrated better PFS (78% vs 62%; P = .027) without an increase in overall late toxicity. CONCLUSIONS: For patients irradiated using conventional fractionation, changing the chemotherapy sequence from a concurrent-adjuvant to an induction-concurrent sequence, particularly using induction cisplatin and capecitabine, potentially could improve efficacy without an adverse impact on late toxicity. However, further validation is needed for confirmation of these findings.

Imbalanced randomization in clinical trials.

Randomization is a common technique used in clinical trials to eliminate potential bias and confounders in a patient population. Equal allocation to treatment groups is the standard due to its optimal efficiency in many cases. However, in certain scenarios, unequal allocation can improve efficiency. In superiority trials with more than two groups, the optimal randomization is not always a balanced randomization. In noninferiority (NI) trials, additive margin with equal variance is the http://www.statlab.wisc.edu/shiny/SSNI/.

Concurrent-Adjuvant Chemoradiation Therapy for Stage III-IVB Nasopharyngeal Carcinoma-Exploration for Achieving Optimal 10-Year Therapeutic Ratio.

PURPOSE: This is an updated combined analysis of 2 randomized studies (NPC-9901 and NPC-9902 trials) to evaluate the 10-year outcome attributed to the addition of concurrent-adjuvant chemotherapy for advanced locoregional nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Eligible patients with stage III-IVB nonkeratinizing NPC were randomly assigned to radiation therapy alone (RT: 218 patients) or chemoradiation therapy (CRT: 223 patients) using 3 cycles of cisplatin (100 mg/m2) concurrent with RT, followed by 3 cycles of cisplatin (80 mg/m2) and fluorouracil (1000 mg/m2/day for 4 days). All of the patients were irradiated with conventional fractionation to ≥66 Gy. The median follow-up was 13.9 years. RESULTS: Intention-to-treat analysis confirmed that the CRT group achieved significant improvement in 10-year failure-free rate (FFR: 62% vs 52%, P = .016), progression-free survival rate (PFS: 56% vs 44%, P = .008), and overall survival rate (OS: 60% vs 50%, P = .044). There was no significant increase in overall late toxicity rate (51% vs 48%, P = .34) or noncancer deaths (19% vs 16%, P = .52). Exploratory studies showed no difference in disease control between 2 or 3 cycles of concurrent cisplatin; however, patients given 3 concurrent cycles had a significant increase in hearing impairment (40% vs 24%, P = .017). Only those who continued to receive 2 or more cycles of adjuvant cisplatin-fluorouracil achieved significant improvement in distant control (73% vs 65%, P = .037) and maximal survival gain. CONCLUSION: The addition of concurrent cisplatin plus adjuvant cisplatin-fluorouracil could significantly improve overall survival and disease control without incurring a significant increase in late toxicity or noncancer deaths. Exploratory analyses suggested that both the concurrent and the adjuvant phases contributed to tumor control. Furthermore, the number of concurrent cycles could be reduced from 3 to 2 cycles in order to achieve a similar survival benefit without incurring an excessive increase in hearing impairment. This is a useful hypothesis that warrants further validation.

Extended Multiple-Field High-Definition transcranial direct current stimulation (HD-tDCS) is well tolerated and safe in healthy adults.

BACKGROUND: High definition transcranial direct current stimulation (HD-tDCS) has been administered over single brain regions for small numbers of sessions. Safety, feasibility and tolerability of HD-tDCS over multiple brain regions, multiple daily stimulations and long periods are not established. OBJECTIVE: We studied safety, feasibility and tolerability of daily HD-tDCS over 2-4 brain regions for 20 sessions in healthy adults. METHODS: Five healthy adults underwent physical and neurological examination, electrocardiogram (EKG), electroencephalogram (EEG) and cognitive screening (ImpACT) before, during and after HD-tDCS. Four networks (left/right temporoparietal and frontal) were stimulated in sequence (20 min each) using HD-tDCS in 20 daily sessions. Sessions 1-10 included sequential stimulation of both temporoparietal networks, sessions 11-15 stimulations of 4 networks and sessions 16-20 two daily stimulation cycles of 4 networks/cycle (1.5 mA/network). Side effects, ImpACT scores and EEG power spectrum were compared before and after HD-tDCS. RESULTS: All subjects completed the trial. Adverse events were tingling, transient redness at the stimulation site, perception of continuing stimulation after end of session and one self-resolving headache. EEG power spectrum showed decreased delta power in frontal areas several days after HD-tDCS. While at the group level ImpACT scores did not differ before and after stimulations, we found a trend for correlation between decreased EEG delta power and individual improvements in ImpACT scores after HD-tDCS. CONCLUSION: Prolonged, repeat daily stimulation of multiple brain regions using HD-tDCS is feasible and safe in healthy adults. Preliminary EEG results suggest that HD-tDCS may induce long lasting changes in excitability in the brain.

A multicenter, phase 3, randomized trial of concurrent chemoradiotherapy plus adjuvant chemotherapy versus radiotherapy alone in patients with regionally advanced nasopharyngeal carcinoma: 10-year outcomes for efficacy and toxicity.

BACKGROUND: Concurrent-adjuvant chemoradiotherapy (CRT) became a recommended treatment for locoregionally advanced nasopharyngeal carcinoma (NPC) with the first report of a significant survival benefit from the Intergroup 0099 study. However, data on late toxicities are lacking. Previous reports from the current NPC-9901 trial have raised concerns about a failure to improve overall survival (OS) because of an inadequate impact on distant control and increases in toxicities/noncancer deaths. Validation of the long-term therapeutic ratio is needed. METHODS: In this phase 3, randomized trial, patients with nonkeratinizing NPC (stage T1-4/N2-3/M0) were randomly assigned to radiotherapy alone (176 patients) or to CRT (172 patients) with concurrent cisplatin followed by adjuvant cisplatin plus fluorouracil. RESULTS: The early findings of significant improvements in tumor control were maintained: the CRT group achieved significantly higher 10-year overall failure-free (62% vs 50%; P = .01) and progression-free survival rates (56% vs 42%; P = .006) because of superior locoregional control (87% vs 74%; P = .003), whereas the impact on distant control remained insignificant (68% vs 65%; P = .24). The initial differences in toxicities diminished with longer follow-up: 52% versus 47% at 10 years for late toxicities (P = .20), 4.1% versus 2.8% for deaths due to treatment toxicity, and 15.1% versus 13.1% for deaths due to incidental/unknown causes. The OS rate for the CRT group reached statistical superiority at 10 years (62% vs 49%; P = .047). CONCLUSIONS: Long-term results have confirmed that CRT can significantly improve OS without excessive late toxicities for patients with regionally advanced NPC. However, more potent therapy is needed for improving distant control, especially for patients with stage IVA/B disease. Cancer 2017;123:4147-4157. © 2017 American Cancer Society.

Increased tumor response to neoadjuvant therapy among rectal cancer patients taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are commonly used antihypertensive medications that have been reported to affect aberrant angiogenesis and the dysregulated inflammatory response. Because of such mechanisms, it was hypothesized that these medications might affect the tumor response to neoadjuvant radiation in patients with rectal cancer. METHODS: One hundred fifteen patients who were treated with neoadjuvant radiation at the University of Wisconsin (UW) between 1999 and 2012 were identified. Univariate analyses were performed with anonymized patient data. In a second independent data set, 186 patients with rectal cancer who were treated with neoadjuvant radiation at the Queen's Medical Center of the University of Hawaii (UH) between 1995 and 2010 were identified. These data were independently analyzed as before. Multivariate analyses were performed with aggregate data. RESULTS: Among patients taking ACEIs/ARBs in the UW data set, a significant 3-fold increase in the rate of pathologic complete response (pCR) to neoadjuvant therapy (52% vs 17%, P = .001) was observed. This finding was confirmed in the UH data set, in which a significant 2-fold-increased pCR rate (24% vs 12%, P = .03) was observed. Identified patient and treatment characteristics were otherwise balanced between patients taking and not taking ACEIs/ARBs. No significant effect was observed on pCR rates with other medications, including statins, metformin, and aspirin. Multivariate analyses of aggregate data identified ACEI/ARB use as a strong predictor of pCR (odds ratio, 4.02; 95% confidence interval, 2.06-7.82; P < .001). CONCLUSIONS: The incidental use of ACEIs/ARBs among patients with rectal cancer is associated with a significantly increased rate of pCR after neoadjuvant treatment. Cancer 2016;122:2487-95. © 2016 American Cancer Society.

Quality of life outcomes from a dose-per-fraction escalation trial of hypofractionation in prostate cancer.

OBJECTIVE: This multi-institutional phase I/II trial explored patient-assessed tolerance of increasingly hypofractionated (HPFX) radiation for low/intermediate risk prostate cancer. METHODS: 347 patients enrolled from 2002 to 2010. Three increasing dose-per-fraction schedules of 64.7 Gy/22 fx, 58.08 Gy/16 fx and 51.6 Gy/12 fx were each designed to yield equivalent predicted late toxicity. Three quality of life (QoL) surveys were administered prior to treatment and annually upto 3 years. RESULTS: Bowel QoL data at 3years revealed no significant difference among regimens (p=0.469). Bowel QoL for all regimens declined transiently, largely recovering by three years, with only the 22 fraction decrement reaching significance. Bladder outcomes at 3 years were comparable (p=0.343) although, for all patients combined, a significant decline was observed from the baseline (p=0.008). Spitzer quality of life data revealed similarly excellent, 3-year means (p=0.188). International erectile function data also revealed no significant differences at 3 years although all measures except intercourse satisfaction worsened post-treatment. CONCLUSIONS: Three-year QoL changes for bowel, bladder and SQLI were modest and similar for 3 HPFX regimens spanning 2.94-4.3 Gy per fraction. These favorable patient-scored outcomes demonstrate the safety and tolerability of such regimens and may be leveraged to support further implementation of mild to moderately hypofractionated radiotherapy in the setting of low and intermediate-risk prostate cancer.

Beta-amyloid and cognitive decline in late middle age: Findings from the Wisconsin Registry for Alzheimer's Prevention study.

INTRODUCTION: The present study investigated the relationship between beta-amyloid (Aß) and cognition in a late middle-aged cohort at risk for Alzheimer's disease (AD). METHODS: One eighty-four participants (mean age = 60; 72% parental history of AD) completed a [C-11]Pittsburgh compound B positron emission tomography scan and serial cognitive evaluations. A global measure of Aß burden was calculated, and composite scores assessing learning, delayed memory, and executive functioning were computed. RESULTS: Higher Aß was associated with classification of psychometric mild cognitive impairment (MCI) at follow-up (P < .01). Linear mixed effects regression results indicated higher Aß was associated with greater rates of decline in delayed memory (P < .01) and executive functioning (P < .05). Apolipoprotein E (APOE) ε4 status moderated the relationship between Aß and cognitive trajectories (P values <.01). DISCUSSION: In individuals at risk for AD, greater Aß in late middle age is associated with increased likelihood of MCI at follow-up and steeper rates of cognitive decline.

Sample size under the additive hazards model.

BACKGROUND: The additive hazards model can be easier to interpret and in some cases fits better than the proportional hazards model. However, sample size formulas for clinical trials with time to event outcomes are currently based on either the proportional hazards assumption or an assumption of constant hazards. AIMS: The goal is to provide sample size formulas for superiority and non-inferiority trials assuming an additive hazards model but no specific distribution, along with evaluations of the performance of the formulas. METHODS: Formulas are presented that determine the required sample size for a given scenario under the additive hazards model. Simulations are conducted to ensure that the formulas attain the desired power. For illustration, the non-inferiority sample size formula is applied to the calculations in the SPORTIF III trial of stroke prevention in atrial fibrillation. CONCLUSION: Simulation results show that the sample size calculations lead to the correct power. Sample size is easily calculated using a tool that is available on the web at http://leemcdaniel.github.io/samplesize.html.

NSAID Use and Incident Cognitive Impairment in a Population-based Cohort.

Nonsteroidal anti-inflammatory drugs (NSAIDs) may prevent dementia, but previous studies have yielded conflicting results. This study estimated the association of prior NSAID use with incident cognitive impairment in the population-based Epidemiology of Hearing Loss Study (EHLS, n=2422 without cognitive impairment in 1998-2000). Prospectively collected medication data from 1988-1990, 1993-1995, and 1998-2000 were used to categorize NSAID use history at the cognitive baseline (1998-2000). Aspirin use and nonaspirin NSAID use were separately examined. Cox regression models were used to estimate the associations between NSAID use history at baseline and incident cognitive impairment in 2003-2005 or 2009-2010. Logistic regression analyses were used to estimate associations with a second outcome, mild cognitive impairment/dementia, available in 2009-2010. Participants using aspirin at baseline but not 5 years prior were more likely to develop cognitive impairment (adjusted hazard ratio=1.77; 95% confidence interval=1.11, 2.82; model 2), with nonsignificant associations for longer term use. Nonaspirin NSAID use was not associated with incident cognitive impairment or mild cognitive impairment/dementia odds. These results provided no evidence to support a potential protective effect of NSAIDs against dementia.

Quantile regression with a change-point model for longitudinal data: An application to the study of cognitive changes in preclinical alzheimer's disease.

Progressive and insidious cognitive decline that interferes with daily life is the defining characteristic of Alzheimer's disease (AD). Epidemiological studies have found that the pathological process of AD begins years before a clinical diagnosis is made and can be highly variable within a given population. Characterizing cognitive decline in the preclinical phase of AD is critical for the development of early intervention strategies when disease-modifying therapies may be most effective. In the last decade, there has been an increased interest in the application of change-point models to longitudinal cognitive outcomes prior to and after diagnosis. Most of the proposed statistical methodology for describing decline relies upon distributional assumptions that may not hold. In this article, we introduce a quantile regression with a change-point model for longitudinal data of cognitive function in persons bound to develop AD. A change-point in our model reflects the transition from the cognitive decline due to normal aging to the accelerated decline due to disease progression. Quantile regression avoids common distributional assumptions on cognitive outcomes and allows the covariate effects and the change-point to vary for different quantiles of the response. We provided an approach for estimating the model parameters, including the change-point, and presented inferential procedures based on the asymptotic properties of the estimators. A simulation study showed that the estimation and inferential procedures perform reasonably well in finite samples. The practical use of our model was illustrated by an application to longitudinal episodic memory outcomes from two cohort studies of aging and AD.

Preliminary results of trial NPC-0501 evaluating the therapeutic gain by changing from concurrent-adjuvant to induction-concurrent chemoradiotherapy, changing from fluorouracil to capecitabine, and changing from conventional to accelerated radiotherapy fractionation in patients with locoregionally advanced nasopharyngeal carcinoma.

BACKGROUND: A current recommendation for locoregionally advanced nasopharyngeal carcinoma (NPC) is conventional fractionated radiotherapy with concurrent cisplatin plus adjuvant cisplatin and fluorouracil (PF). In this randomized trial, the authors evaluated the potential therapeutic benefit from changing to an induction-concurrent chemotherapy sequence, replacing fluorouracil with oral capecitabine, and/or using accelerated rather than conventional radiotherapy fractionation. METHODS: Patients with stage III through IVB, nonkeratinizing NPC were randomly allocated to 1 of 6 treatment arms. The protocol was amended in 2009 to permit confining randomization to the conventional fractionation arms. The primary endpoint was progression-free survival. Secondary endpoints included overall survival and safety. RESULTS: In total, 803 patients were accrued, and 706 patients were randomly allocated to all 6 treatment arms. Comparisons of induction PF versus adjuvant PF did not indicate a significant improvement. Unadjusted comparisons of induction cisplatin and capecitabine (PX) versus adjuvant PF indicated a favorable trend in progression-free survival for the conventional fractionation arm (P = .045); analyses that were adjusted for other significant factors and fractionation reflected a significant reduction in the hazards of disease progression (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.36-0.80) and death (HR, 0.42; 95% CI, 0.25-0.70). Unadjusted comparisons of induction sequences versus adjuvant sequences did not reach statistical significance, but adjusted comparisons indicated favorable improvements by induction sequence. Comparisons of induction PX versus induction PF revealed fewer toxicities (neutropenia and electrolyte disturbance), unadjusted comparisons of efficacy were statistically insignificant, but adjusted analyses indicated that induction PX had a lower hazard of death (HR, 0.57; 95% CI, 0.34-0.97). Changing the fractionation from conventional to accelerated did not achieve any benefit but incurred higher toxicities (acute mucositis and dehydration). CONCLUSIONS: Preliminary results indicate that the benefit of changing to an induction-concurrent sequence remains uncertain; replacing fluorouracil with oral capecitabine warrants further validation in view of its convenience, favorable toxicity profile, and favorable trends in efficacy; and accelerated fractionation is not recommended for patients with locoregionally advanced NPC who receive chemoradiotherapy.

Long-term systemic inflammation and cognitive impairment in a population-based cohort.

OBJECTIVES: Evidence suggests inflammation is associated with cognitive impairment, but previous epidemiological studies have reported conflicting results. DESIGN: Prospective population-based cohort. SETTING: Epidemiology of Hearing Loss Study participants. PARTICIPANTS: Individuals without cognitive impairment in 1998-2000 (N = 2,422; 1,947 with necessary data). MEASUREMENTS: Cognitive impairment (Mini-Mental State Examination score <24 or diagnosis of dementia) was ascertained in 1998-2000, 2003-2005, and 2009-2010. Serum C-reactive protein (CRP) and interleukin-6 (IL-6) were measured in 1988-1990, 1998-2000, and 2009-2010; tumor necrosis factor-alpha was measured from 1998-2000. RESULTS: Participants with high CRP in 1988-1990 and 1998-2000 had lower risk of cognitive impairment than those with low CRP at both time points (hazard ratio (HR) = 0.46, 95% confidence interval (CI) = 0.26-0.80). Risk did not differ according to 10-year IL-6 profile or baseline inflammation category in the whole cohort. In sensitivity analyses restricted to statin nonusers, those with high IL-6 at both times had greater risk of cognitive impairment than those with low IL-6 at both times (HR = 3.35, 95% CI = 1.09-10.30). In secondary analyses, each doubling of IL-6 change over 20 years was associated with greater odds of cognitive impairment in 2009-2010 in the whole cohort (odds ratio (OR) = 1.40, 95% CI = 1.04-1.89), whereas a doubling of CRP change over 20 years was associated with cognitive impairment only in statin nonusers (OR = 1.32, 95% CI = 1.06-1.65). CONCLUSION: With data collected over 20 years, this study demonstrated greater likelihood of cognitive impairment in individuals with repeated high or increasing IL-6. The inconsistent CRP findings may reflect effects of statin medications, survival effects, or adverse effects associated with chronically low CRP. Further studies of long-term inflammation and cognitive impairment are needed.