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Age-related changes in cognition are linked to decreased expression of somatotropins, GHRH and IGF-1. Mild cognitive impairment (MCI) and Alzheimer’s disease (AD) are heterogeneous conditions. The loss of GHRH signaling in the brain may be mechanistically involved in AD pathogenesis. The consequent need to identify AD at an early and perhaps more treatable stage has fueled research into blood-based, exosome biomarkers. Plasma exosomes from participants enrolled in a randomized, double-blind, placebo-controlled 20-week trial of GHRH administration, were isolated, precipitated, and enriched by immuno-absorption with anti-L1CAM antibody (neural adhesion protein) from adults with MCI and age-matched, cognitively normal controls (CNC). Extracted protein cargo from neuronally-derived exosomes (NDEs) were assessed by ELISAs for protein levels implicated in AD neuropathology and for synaptic proteins altered by AD. Plasma NDE concentrations of Aβ(1-42) were significantly increased while plasma NDE concentrations of NRGN, synaptophysin, synaptotagmin, and synaptopodin were significantly decreased in patients with MCI, independent of GHRH treatment. Plasma NDE concentrations of ptau-S396 and GAP43 were not affected by cognitive status (CNC versus MCI) or by GHRH treatment. Aβ(1-42), neurogranin (NRGN), synaptophysin, synaptotagmin, and synaptopodin demonstrated the highest diagnostic accuracy for distinguishing between CNC and MCI patients, while synaptophysin and synaptotagmin demonstrated moderate accuracy in distinguishing between placebo-treated and GHRH-treated, MCI patients.

Author(s): Espeland, Mark A; Chen, Jiu-Chiuan; Weitlauf, Julie; Hayden, Kathleen M; Rapp, Stephen R; Resnick, Susan M; Garcia, Lorena; Cannell, Brad; Baker, Laura D; Sachs, Bonnie C; Tindle, Hilary A; Wallace, Robert; Casanova, Ramon; Women's Health Initiative Memory Study Magnetic Resonance Imaging Study Group | Abstract: ObjectivesTo examine whether trajectories of global cognitive function over time in studies that change assessment protocols may be modeled based on an individual's performance relative to others in the study cohort.DesignExtended follow-up of a cohort originally enrolled in a clinical trial of postmenopausal hormone therapy.SettingThe Women's Health Initiative Memory Study switched from an in-person interview with the Modified Mini-Mental State Examination to a telephone-based interview with the modified Telephone Interview for Cognitive Status to assess global cognitive function over long-term follow-up.ParticipantsWomen aged 75 to 92 (N=2,561).MeasurementsAnnual cognitive assessments from participants, ranked according to age-, race- and ethnicity-adjusted performance levels, were used to identify distinct trajectories. Participants assigned to the resulting trajectories were compared for selected risk factor profiles.ResultsOur approach grouped participants into five trajectories according to relative cognitive performance over time. These groups differed significantly according to 3 known risk factors for cognitive decline-education level, apolipoprotein E-ϵ4 genotype, and type 2 diabetes mellitus-and a biomarker based on brain structure that has been linked to cognitive decline and Alzheimer's disease. Participants with consistently low relative levels of cognitive function over time and those whose relative performance over time declined to these levels tended to have poorer risk factor profiles.ConclusionLongitudinal measures of an individual's relative performance on different assessment protocols for global cognitive function can be used to identify trajectories of change over time that appear to have internal validity with respect to known risk factors.

Background Lifestyle interventions to reduce weight and increase activity may preserve higher-order cognitive abilities in overweight/obese adults with type 2 diabetes (T2D). Methods Adults (N = 5,084) with T2D who enrolled in a randomized clinical trial of a 10-year intensive lifestyle intervention (ILI) compared with diabetes support and education were queried at baseline and repeatedly during follow-up for complaints about difficulties in memory, problem-solving, and decision-making abilities. Results For those without baseline complaints, assignment to ILI was associated with lower odds that complaints would emerge during follow-up for decision-making ability (odds ratio [OR]=0.851, [95% CI, 0.748,0.967], p=0.014), and, among individuals who were not obese, lower odds that complaints would emerge about problem-solving ability (OR=0.694 [0.510,0.946]). No cognitive benefits from ILI were seen for individuals with baseline complaints about cognitive abilities. ILI may have exacerbated the severity of complaints about problem-solving ability during follow-up among individuals with baseline complaints and cardiovascular disease (OR=2.949 [1.378,6.311]). Conclusions A long-term multidomain ILI may reduce the likelihood that complaints about difficulties in higher-order cognitive abilities will emerge in T2D adults without pre-existing complaints. Among those with pre-existing complaints, the ILI did not prevent increases in complaint severity.

Introduction This study sought to determine whether 10 years of assignment to intensive lifestyle intervention (ILI) relative to diabetes support and education leads to better cognition. We examine intervention effects overall and among clinical subgroups, and report correlations between computer‐administered and interviewer‐administered cognitive batteries. Methods The Action for Health in Diabetes (Look AHEAD) was a 16‐site randomized controlled trial with overweight/obese individuals (aged 45–76) who had type 2 diabetes. The NIH Toolbox Cognition Battery tests developed to measure cognition across the lifespan were used to evaluate cognition. Results were compared with standard paper‐and‐pencil tests. The Toolbox and paper‐and‐pencil tests were administered an average of 10.9 years after randomization to 1002 participants. Results Toolbox measures significantly correlated with interviewer‐administered measures, with the strongest correlations between the Toolbox Fluid Cognition Composite and Trails B (r = −0.64, P .05 for all). Subgroup analyses identified different intervention effects within baseline body mass index groups for Picture Sequence Memory (P = .01), within baseline cardiovascular disease groups for Picture Vocabulary (P = .01) and Fluid Cognition Composite (P = .02) measures, and within baseline age groups for Picture Vocabulary (P = .02). Discussion Correlations between Toolbox and interviewer‐administered outcomes provide a measure of internal validity. Findings suggest no overall effect of the intervention on cognition and that an ILI resulting in weight loss may have negative implications for cognition in individuals aged ≥60, with previous history of cardiovascular disease, and those with body mass index ≥40.

IntroductionThe Institute of Translational Health Sciences (ITHS) promotes and supports translational research collaboration between clinicians, communities, and investigators across the five-state Washington, Wyoming, Alaska, Montana, and Idaho (WWAMI) region. The ITHS has developed a collaborative regional clinical research network, the Northwest Participant & Clinical Interactions Network (NW PCI), involving 12 diverse clinical health systems and academic institutions.MethodsThis descriptive article details NW PCI’s development, infrastructure and governance, tools, characteristics, and initial outcomes.ResultsRegional NW PCI sites are conducting largely industry-sponsored studies; they are interested in including more grant-funded research. Regional NW PCI sites had over 1,240 open studies involving over 6700 patients in 2016. NW PCI trials are largely industry-sponsored; NW PCI sites are interested in including more grant-funded research. In its first three years, the NW PCI Coordinating Center facilitated regional sites’ participation in 34 new grant and contract applications across diverse topics.ConclusionThe NW PCI model supports the goals of the developing CTSA Trial Innovation Network by increasing access to cutting-edge research across the Northwestern U.S., by supporting investigators seeking diverse populations, including those with rare diseases, for their research studies, and by providing settings to test implementation and dissemination of effective interventions.

Background We examined whether changes in metabolic factors over 10 years were associated with cognitive performance. Methods Participants from the Multi-Ethnic Study of Atherosclerosis were followed since baseline (2000–2002) with five clinical examinations. At exam 5 (2010–2012), they received a short cognitive battery (Cognitive Abilities Screening Instrument [CASI], Digit Symbol Coding [DSC], and Digit Span [DS]). We examined associations between baseline metabolic factors and their changes over time before cognitive testing. Results Among 4392 participants, baseline metabolic disorders (fasting glucose, systolic and diastolic blood pressures) were significantly associated with poorer CASI, DSC, and DS scores measured 10 years later. Increases in blood pressure were associated with lower cognitive performance. Results did not differ by race/ethnicity and were stronger among those without the APOE e4 allele. Conclusions Cognitive performance was associated with antecedent abnormalities in glucose metabolism and blood pressure increases. Findings appeared stronger among APOE e4-negative participants.

Background Large simple trials are potentially efficient and cost-effective approaches to assess interventions to preserve cognitive function in older adults. High-dose cocoa flavanols supplementation is a promising intervention that warrants additional testing. We describe the design, recruitment success, and baseline characteristics of the Cocoa Supplement and Multivitamin Outcomes Study for the Mind (COSMOS-Mind) trial. Methods COSMOS-Mind is an ancillary study to the large-scale and predominantly mail-based COSMOS randomized controlled clinical trial. COSMOS is assessing whether cocoa extract (including 600 mg/d cocoa flavanols) and a multivitamin reduce risks for major cardiovascular events and total invasive cancer. COSMOS-Mind uses telephone-based interviews to assess cognitive function and impairment to determine whether cocoa flavanols benefit cognitive function in adults aged 65 years or older, targeting the enrollment of 2000 participants to provide >90% statistical power across 3 years of annual follow-up. Results Of the 3224 COSMOS screenees who expressed interest in COSMOS-Mind, 2350 (76%) successfully completed baseline cognitive assessments and 2262 (96%) geographically diverse, eligible individuals were ultimately enrolled over one year. At baseline, the primary outcome, a composite of cognitive test scores, was inversely associated with age in a manner consistent with assumptions used in projections of statistical power. Conclusions Older adults are willing to enroll in large simple trials that include telephone-based cognitive assessments. Embedding these trials in large studies of other health outcomes is efficient and expands the scientific knowledge gained from the research. ClinicalTrials.gov Identifiers: NCT03035201 (COSMOS-Mind); NCT102422745 (parent COSMOS).

Cognitive function and physical function are associated however less is known about task complexity and how individual tasks relate to one another. This project seeks to describe the relationship between cognition and physical function measures across 22 tasks ranging in task complexity and difficulty. Data are from the baseline visits of a new longitudinal study, Brain Networks and Mobility Function (B-NET) Study, mean age: 76.0±4.2 years; 55% women, and 90% Caucasian. We hypothesize there would be a set of “complex” tasks that would intersect both cognitive and physical function abilities such as the Four Square Step Test or Dual Task. We conducted principal components analysis on data from the first 110 participants to describe what factors could be identified across cognition and physical function measures. Seven factors, explaining 73% of the variability, were identified: 1) a complex physical function (postural sway on foam, expanded Short Physical Performance Battery, 400 meter walk, Four Square Step Test, Dual Task), 2) physical strength (grip strength and leg press), 3) visual recall (Brief Visuospatial Memory Test- immediate and delayed), 4) Craft story recall (immediate and delayed), 5) global cognition & fluency (MoCA, category and word fluency) 6) auditory recall (Auditory Verbal Learning Test- immediate and delayed), and 7) executive function (Trail Making Test A & B). We did not identify factors that intersected both physical and cognitive tasks. These results may help to inform measurement selection in future studies that seek to evaluate components of function among older adults.

Brain pathologies are increasingly understood to confer mobility risk, but the malleability of functional brain networks may be a mechanism for mobility reserve. In particular, white matter hyperintensities (WMH) are strongly associated with mobility and alter functional network connectivity. To assess the potential role of brain networks as a mechanism of mobility reserve, 116 participants with MRI from the Brain Networks and Mobility Function (B-NET) were categorized into 4 groups based on median splits of SPPB scores and WMH burden: Expected Healthy (EH: low WMH, SPPB>10, N=45), Expected Impaired (EI: high WMH, SPPB10, N=24), Unexpected Impaired (EI: low WMH, SPPB

IN BRIEF There has been a concurrent dramatic rise in type 2 diabetes and dementia in the United States, and type 2 diabetes shares common genetic and environmental risk factors and underlying pathology with both vascular and Alzheimer’s dementias. Given the ability to identify this at-risk population and a variety of potential targeted treatments, type 2 diabetes represents a promising focus for a precision health approach to reduce the impact of cognitive decline and dementia in older adults.

To test whether average long-term glucose exposure is associated with cognitive and physical function in middle-aged and younger-old adults with type 2 diabetes mellitus.Prospective cohort study.Data obtained as part of the Action for Health in Diabetes (Look AHEAD) trial (NCT00017953) and Look AHEAD Movement and Memory ancillary study (NCT01410097).Overweight and obese individuals with type 2 diabetes mellitus aged 45 to 76 at baseline (N = 879).Glycosylated hemoglobin (HbA1c) was measured at regular intervals over 7 years, and objective measures of cognitive function (Trail-Making Test, Modified Stroop Color-Word Test, Digit Symbol-Coding, Rey Auditory Verbal Learning Test, Modified Mini-Mental State Examination) and physical function (Short Physical Performance Battery, expanded Physical Performance Battery, 400-m and 20-m gait speed) and strength (grip and knee extensor strength) were assessed at the Year 8 or 9 follow-up examination.Average HbA1c exposure was 7.0 ± 1.1% (53 ± 11.6 mmol/mol), with 57% of participants classified as having HbA1c levels of less than 7% (53 mmol/mol), 27% having levels of 7% to 8% (53-64 mmol/mol), and 16% having levels of greater than 8% (64 mmol/mol). After adjustment for age, sex, race, education, smoking status, alcohol intake, knee pain, physical fitness, body mass index, diabetes mellitus medication and statin use, ancillary year visit, and study arm and site, higher HbA1c was associated with worse physical but not cognitive function. Further adjustment for prevalent diabetes mellitus-related comorbidities made all associations nonsignificant. Results did not differ when stratified according to participant baseline age (60 vs ≥ 60).Results presented here suggest that, in the absence of diabetes mellitus-related complications, longitudinal glucose exposure is not associated with future cognitive and physical function. Optimal management of diabetes mellitus-related comorbidities may prevent or reduce the burden of disability associated with type 2 diabetes mellitus.

Laboratory-based polysomnography (PSG) is the gold standard assessment of sleep disordered breathing (SDB). In large cohort studies and clinical trials, however, these overnight procedures can be expensive and burdensome to participants, especially older adults. In preparation for a large observational study, we determined the feasibility of self-administering two devices mailed to participants' homes that estimate indices of SDB.In two separate studies, older women enrolled in the Women's Health Initiative (WHI) Memory Study extension aged mean (SD) 85.77 (2.98) years who were not using supplemental oxygen and consented to being in the feasibility study completed either an in-home, self-administered overnight sleep assessment using a multi-sensor device that measured oximetry, nasal pressure, chest effort, and snoring (ApneaLink(TM)) (N = 58), or a wrist-worn oximeter (NoninWristOx2(TM)) (N = 33). A follow-up questionnaire assessed the devices' acceptability and important sleep-related exposures.Although the multi-sensor device was assessed only in older women with no cognitive impairment, the proportion of completed interpretable sleep studies was low (54 %) and participants reported needing help to administer the device successfully. In contrast, the wrist-worn device was used in women with either no or mild cognitive impairment (MCI), completion rates were higher (100 %), and women reported being able to administer the device independently.These studies demonstrated that home-based self-administered assessments of SDB are feasible in older adults with and without cognitive impairment using wrist-worn oximetry. These data support the feasibility of using simple oximetry measurements to provide indices of overnight intermittent hypoxemia in large observational studies and clinical trials.

Background: Meta-analyses of observational studies associate adherence to several dietary patterns with cognitive health. However, limited evidence from full scale, randomized controlled trials precludes causal inference regarding dietary effects on cognitive function. Methods: The Women's Health Initiative (WHI) Dietary Modification (DM) randomized trial, in 48,835 postmenopausal women, included a subset of 1,606 WHI Memory Study (WHIMS) participants >= 65 years old, to assess low-fat dietary pattern influence on global cognitive function, evaluated with annual screening (Modified Mini–Mental State Examinations [3MSE]). Participants were randomized by a computerized, permuted block algorithm, stratified by age group and center, to a dietary intervention (40%) to reduce fat intake to 20% of energy and increase fruit, vegetable and grain intake or usual diet comparison groups (60%). The study outcome was possible cognition impairment (failed cognitive function screening) through the 8.5 year (median) dietary intervention. Those failing screening received a comprehensive, multi-phase cognitive function assessment to classify as: no cognitive impairment, mild cognitive impairment, or probable dementia. Exploratory analyses examined the composite endpoint of death after possible cognitive impairment through 18.7 years (median) follow-up. The WHI trials are registered at ClinicalTrials.gov:NCT00000611. Findings: Among the 1,606 WHIMS participants, the dietary intervention statistically significantly reduced the incidence of possible cognitive impairment (n = 126; hazard ratio [HR] 0.59 95% confidence interval [CI] 0.38–0. 91, P = 0.01) with HR for dietary influence on subsequent mild cognitive impairment of 0.65 (95% CI 0.35–1.19) and HR of 0.63 (95% CI 0.19–2.10) for probable dementia (PD). Through 18.7 years, deaths from all-causes after possible cognitive impairment were non-significantly lower in the dietary intervention group (0.56% vs 0.77%, HR 0.83 95% CI 0.35 to 2.00, P = 0.16). Interpretation: Adoption of a low-fat eating pattern, representing dietary moderation, significantly reduced risk of possible cognitive impairment in postmenopausal women. Funding: Several Institutes of the US National Institutes of Health. Keywords: Cognition, Dietary modification, Low-fat dietary pattern, Randomized clinical trial, Women's Health Initiative

Older individuals face barriers to participating in center-based clinical trials, including logistical and health issues that lessen adherence. The Alzheimer’s Association U.S. POINTER study is a multicenter trial (N=2,500) of individuals at increased risk for cognitive decline (60–79 years, sedentary lifestyle, poor diet, suboptimum cardiovascular and metabolic health status, parental history of significant memory impairment). It contrasts two lifestyle interventions, delivered at local YMCAs and Association chapters and differing in level of support, to encourage active lifestyles, healthy diets, social and intellectual engagement, and risk factor management. Recruitment through clinical trial networks begins with data-mining medical records to cull ineligible individuals and target those living proximal to intervention and data collection sites. Intervention protocols accommodate health events that compromise adherence. We report recruitment yields and describe data-mining algorithms tailored to enhance yields, protocols to enhance intervention adherence and heighten rigor, and approaches to trial design that promote dissemination and reproducibility.

Objectives Insulin resistance is a substantial health issue for American Indians, with type 2 diabetes overrepresented in this population as compared with non-Hispanic whites. Insulin resistance and its related conditions in turn increase risk for dementia and cognitive impairment. The aim of the current study was to determine whether type 2 diabetes and insulin resistance at midlife was associated with later-life cognitive testing in a large sample of older American Indians, aged 65 and older. Methods American Indian participants who underwent both fasting blood draw as part of the Strong Heart Study and had subsequent cognitive testing as part of the later adjunct Cerebrovascular Disease and its Consequences in American Indians study were included (n = 790). Regression models examined type 2 diabetes and impaired fasting glucose and subsequent cognitive test performance as part of a longitudinal study design. The relationship between a continuous measure of insulin resistance and later cognitive test performance was assessed using generalized estimating equations. Results Controlling for demographic and clinical factors, verbal fluency and processing speed/working memory were significantly negatively associated with having type 2 diabetes and with insulin resistance, but not with impaired fasting glucose. Conclusion In this sample of American Indians, type 2 diabetes at midlife was associated with subsequent lower performance on measures of executive function. These results may have important implications for future implementation of diagnostic and intervention services in this population.

Study Objectives To evaluate the associations between sedentary time, total (total-PA), light (light-PA), moderate (MOD-PA), and vigorous (VIG-PA) physical activity with indices of sleep in postmenopausal women. Methods Baseline self-reported data from the Women’s Health Initiative Observational Study (n = 75 074) were used in this cross-sectional analysis. Total-PA, light-PA, MOD-PA, and VIG-PA were categorized by metabolic equivalents of the activity (MET-hour [hr]/week [wk]) and were estimated using validated questionnaires. Sedentary time was categorized by hr/day and was estimated via questionnaire. Logistic regression was used to examine the associations between these variables and short sleep (≤6 hr/night), long sleep (≥10 hr/night), poor sleep quality, and insomnia symptoms after adjustment for age, race, socioeconomic status, body mass index, health status, depressive symptoms, smoking status, alcohol use, hormone therapy, and comorbidities. Results Higher sedentary time (>11 hr/day) was associated with higher odds of short sleep (odds ratio [OR] = 1.80, 95% confidence interval [CI]: 1.72–1.88), poor sleep quality (OR = 1.85, 95% CI: 1.74–1.97), and insomnia symptoms (OR = 1.56, 95% CI: 1.49–1.64). Light-PA (>0 MET-hr/wk) was associated with lower odds of short sleep (OR = 0.96, 95% CI: 0.92–1.00), and higher amounts of total-PA (OR = 0.90, 95% CI: 0.84–0.97), light-PA (OR = 0.94, 95% CI: 0.89–1.00), and MOD-PA (OR = 0.91, 95% CI: 0.86–0.97) were associated with lower odds of poor sleep quality. Conclusions Our findings suggest that higher levels of light and moderate intensity physical activity are associated with better sleep quality, whereas higher amounts of sedentary time are associated with short sleep and lower quality sleep. Future studies should investigate the directionality of these associations and potential causal pathways.

Background: Intensive lifestyle interventions (ILI) to reduce weight and increase physical activity may preserve higher-order cognition in overweight and obese adults with type 2 diabetes (T2D). Methods: Adults with T2D who enrolled in a randomized clinical trial of a 10-year ILI compared with diabetes support and education (DSE; N=5,084; mean age=58.7 years; mean BMI=35.9 kg/m2; 36.8% racial/ethnic minority) provided self-assessments of difficulty with memory, problem-solving, and decision-making abilities at baseline and over ≥10 years of follow-up. The Health Utilities Index assessed memory and problem-solving; the Beck Depression Inventory-II assessed decision-making. Analyses included the full sample and sub-groups based on baseline weight status and history of cardiovascular disease (CVD). Results: At baseline, 12%, 16%, and 23% of all participants reported some difficulty with problem-solving, decision-making, and memory, respectively. For those without baseline self-identified cognitive difficulties in a specific domain, ILI was associated with lower odds of decision-making difficulties at follow-up compared to DSE (odds ratio [OR]=0.85, [95% CI 0.75,0.97]). Among those who were not obese, ILI was associated with lower odds of problem-solving difficulties at follow-up (OR=0.69 [0.51,0.95]). For participants with self-identified cognitive difficulties at baseline who had a history of CVD, ILI may have worsened difficulties in problem-solving at follow-up visits (OR=2.95 [1.38,6.31]). Conclusions: A long-term ILI targeting weight loss and physical activity may protect self-reported higher-order cognitive abilities in adults with T2D without preexisting memory, problem-solving, or decision-making problems. However, among those with preexisting problems, ILI was not protective. Disclosure G.R. Dutton: None. M. Espeland: Consultant; Self; Boehringer Ingelheim GmbH, Janssen Pharmaceuticals, Inc.. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, National Heart, Lung, and Blood Institute. R.H. Neiberg: None. O. Carmichael: None. K.M. Hayden: None. K.C. Johnson: None. R.W. Jeffery: None. L.D. Baker: None. D. Cook: None. D. Kitzman: Advisory Panel; Self; AbbVie Inc.. Research Support; Self; AstraZeneca. S.R. Rapp: None.

Background Perioperative red blood cell (RBC) transfusion is associated with poor outcomes in liver surgery. Hypovolemic phlebotomy (HP) is a novel intervention hypothesized to decrease transfusion requirements. The objective of this study was to examine this hypothesis. Methods Consecutive patients who underwent liver resection at one institution (2010–2016) were included. Factors found to be predictive of transfusion on univariate analysis and those previously published were modeled using multivariate logistic regression. Results A total of 361 patients underwent liver resection (50% major). HP was performed in 45 patients. Phlebotomized patients had a greater proportion of primary malignancy (31% vs 18%) and major resection (84% vs 45%). Blood loss was significantly lower with phlebotomy in major resections (400 vs 700 mL). Nadir central venous pressure was significantly lower with HP (2.5 vs 5 cm H2O). On multivariate logistic regression, HP (OR 0.20, 95% CI 0.068–0.57, p = 0.0029), major liver resection (OR 2.91, 95% CI 1.64–5.18, p = 0.0003), preoperative hemoglobin Conclusion Hypovolemic phlebotomy appears to be strongly associated with a reduction in RBC transfusion requirements in liver resection, independent of other known risk factors.

BACKGROUND/OBJECTIVES: To examine whether trajectories of global cognitive function over time in studies that change assessment protocols may be modeled based on an individual’s performance relative to others in the study cohort. DESIGN: The Women’s Health Initiative Memory Study switched from an in-person interview with the Modified MiniMental State Exam (3MSE) to a telephone-based interview with the Telephone Interview for Cognitive Status (TICSm) for assessing global cognitive function during long term follow-up. Annual cognitive assessments from participants, ranked according to age- and race/ethnicity-adjusted performance levels, were used to identify distinct trajectories. Participants assigned to the resulting trajectories were compared for selected risk factor profiles. SETTING: Extended follow-up of a cohort originally enrolled in a clinical trial of postmenopausal hormone therapy PARTICIPANTS: Women (N=2,561) aged 75 to 92 years RESULTS: Our approach grouped participants into five trajectories according to relative cognitive performance over time. These groups differed significantly according to three known risk factors for cognitive decline -- education level, APOE-ε4 genotype, and type 2 diabetes – and a biomarker based on brain structure that has been linked to increased cognitive decline and Alzheimer’s disease. Participants with consistently low relative levels of cognitive function over time and those whose relative performance over time declined to these levels tended to have poorer risk factor profiles. CONCLUSION: Longitudinal measures of an individual’s relative performance across different assessment protocols for global cognitive function can be used to identify trajectories of change over time that appear to have internal validity with respect to known risk factors.

Objective Ankle-brachial index (ABI) and interartery systolic blood pressure differences, as markers of vascular disease, are plausible risk factors for deficits in cognitive function among overweight and obese adults with type 2 diabetes. Methods The ABI and maximum interartery differences (MIAD) in systolic blood pressures were assessed annually for five years among 479 participants assigned to the control condition in a randomized clinical trial of a behavioral weight loss intervention. A battery of standardized cognitive function tests was administered 4 to 5 years later. Analyses of covariance were used to assess relationships that ABI, MIAD, and progression of ABI and MIAD had with cognitive function. Results There was a curvilinear relationship between ABI and a composite index of cognitive function (p = 0.03), with lower ABI being associated with poorer function. In graded fashions, both greater MIAD and increases in MIAD over time also had modest relationships with poorer verbal memory (both p ≤ 0.05), processing speed (both p ≤ 0.05), and composite cognitive function (both p

Author(s): Baker, Laura D; Cotman, Carl; Morrison, Rosemary H; Kipperman, Sean A; Katula, Jeff; Lawson, Valerie; Johnson, Cara; Chmelo, Elizabeth; Nicklas, Barbara; Revta, Carolyn; Feldman, Howard H

Objective:To assess whether an average of 10 years of lifestyle intervention designed to reduce weight and increase physical activity lowers the prevalence of cognitive impairment among adults at increased risk due to type 2 diabetes and obesity or overweight.Methods:Central adjudication of mild cognitive impairment and probable dementia was based on standardized cognitive test battery scores administered to 3,802 individuals who had been randomly assigned, with equal probability, to either the lifestyle intervention or the diabetes support and education control. When scores fell below a prespecified threshold, functional information was obtained through proxy interview.Results:Compared with control, the intensive lifestyle intervention induced and maintained marked differences in weight loss and self-reported physical activity throughout follow-up. At an average (range) of 11.4 (9.5–13.5) years after enrollment, when participants' mean age was 69.6 (54.9–87.2) years, the prevalence of mild cognitive impairment and probable dementia was 6.4% and 1.8%, respectively, in the intervention group, compared with 6.6% and 1.8%, respectively, in the control group (p = 0.93). The lack of an intervention effect on the prevalence of cognitive impairment was consistent among individuals grouped by cardiovascular disease history, diabetes duration, sex, and APOE ε4 allele status (all p ≥ 0.50). However, there was evidence (p = 0.03) that the intervention effect ranged from benefit to harm across participants ordered from lowest to highest baseline BMI.Conclusions:Ten years of behavioral weight loss intervention did not result in an overall difference in the prevalence of cognitive impairment among overweight or obese adults with type 2 diabetes.Clinicaltrials.gov identifier:NCT00017953 (Action for Health in Diabetes).Level of evidence:This study provides Class II evidence that for overweight adults with type 2 diabetes, a lifestyle intervention designed to reduce weight and increase physical activity does not lower the risk of cognitive impairment.

Author(s): Craft, Suzanne; Claxton, Amy; Baker, Laura D; Hanson, Angela J; Cholerton, Brenna; Trittschuh, Emily H; Dahl, Deborah; Caulder, Erin; Neth, Bryan; Montine, Thomas J; Jung, Youngkyoo; Maldjian, Joseph; Whitlow, Christopher; Friedman, Seth | Abstract: BackgroundLong acting insulin detemir administered intranasally for three weeks enhanced memory for adults with Alzheimer's disease dementia (AD) or amnestic mild cognitive impairment (MCI). The investigation of longer-term administration is necessary to determine whether benefits persist, whether they are similar to benefits provided by regular insulin, and whether either form of insulin therapy affects AD biomarkers.ObjectiveThe present study aimed to determine whether four months of treatment with intranasal insulin detemir or regular insulin improves cognition, daily functioning, and AD biomarkers for adults with MCI or AD.MethodsThis randomized, double-blind, placebo-controlled trial included an intent-to-treat sample consisting of 36 adults diagnosed with MCI or mild to moderate AD. Participants received placebo (n = 12), 40 IU of insulin detemir (n = 12), or 40 IU of regular insulin (n = 12) daily for four months, administered with a nasal delivery device. A cognitive battery was administered at baseline and after two and four months of treatment. MRI was administered for all participants and lumbar puncture for a subset (n = 20) at baseline and four months. The primary outcome was change from baseline to four months on a memory composite (sum of Z scores for delayed list and story recall). Secondary outcomes included: global cognition (Alzheimer's Disease Assessment Scale-Cognition), daily functioning (Dementia Severity Rating Scale), MRI volume changes in AD-related regions of interest, and cerebrospinal fluid AD markers.ResultsThe regular insulin treated group had better memory after two and four months compared with placebo (p l 0.03). No significant effects were observed for the detemir-assigned group compared with the placebo group, or for daily functioning for either group. Regular insulin treatment was associated with preserved volume on MRI. Regular insulin treatment was also associated with reduction in the tau-P181/Aβ42 ratio.ConclusionFuture research is warranted to examine the mechanistic basis of treatment differences, and to further assess the efficacy and safety of intranasal insulin.

Objectives To assess whether randomization to 10 years of lifestyle intervention to induce and maintain weight loss improves cognitive function. Design Randomized controlled clinical trial. Setting Data obtained as part of the Action for Health in Diabetes (Look AHEAD) trial (NCT00017953) and Look AHEAD Continuation study (U01 DK057136-15). Participants Overweight and obese individuals with type 2 diabetes mellitus aged 45 to 76 (N = 3,751). Intervention Intensive lifestyle intervention (ILI) for weight loss through reduced caloric intake and increased physical activity compared with a control condition of diabetes support and education (DSE). Measurements Certified examiners who were masked to intervention assignment administered a standard battery of cognitive function tests (Modified Mini-Mental State Examination, Rey Auditory Verbal Learning Test, Digit Symbol Coding, Trail-Making Test, Modified Stroop Color-Word Test) to participants 10 to 13 years after enrollment. Results Assignment to lifestyle intervention was not associated with significantly different overall (P = .10) or domain-specific (all P > .10) cognitive function than assignment to diabetes support and education. Results were fairly consistent across prespecified groups, but there was some evidence of trends for differential intervention effects showing modest harm in ILI in participants with greater body mass index and in individuals with a history of cardiovascular disease. Cognitive function was not associated with changes in weight or fitness (all P > .05). Conclusion A long-term behavioral weight loss intervention for overweight and obese adults with diabetes mellitus was not associated with cognitive benefit. Trial Registration clinicaltrials.gov Identifier: NCT00017953.

Cerebellar dysplasia with cysts (CDC) is an imaging finding typically seen in combination with cobblestone cortex and congenital muscular dystrophy in individuals with dystroglycanopathies. More recently, CDC was reported in seven children without neuromuscular involvement (Poretti-Boltshauser syndrome). Using a combination of homozygosity mapping and whole-exome sequencing, we identified biallelic mutations in LAMA1 as the cause of CDC in seven affected individuals (from five families) independent from those included in the phenotypic description of Poretti-Boltshauser syndrome. Most of these individuals also have high myopia, and some have retinal dystrophy and patchy increased T2-weighted fluid-attenuated inversion recovery (T2/FLAIR) signal in cortical white matter. In one additional family, we identified two siblings who have truncating LAMA1 mutations in combination with retinal dystrophy and mild cerebellar dysplasia without cysts, indicating that cysts are not an obligate feature associated with loss of LAMA1 function. This work expands the phenotypic spectrum associated with the lamininopathy disorders and highlights the tissue-specific roles played by different laminin-encoding genes.

Identifying safe, affordable, and well-tolerated interventions that prevent or delay cognitive decline in older adults is of critical importance. There is growing evidence from basic science and small randomized trials that cocoa flavanols may provide protection against this decline. Funded by the NIA, COSMOS-Mind is an ancillary study of COSMOS and was designed to add cognitive outcomes to the parent study, a 2x2 factorial randomized controlled trial testing the effects of cocoa flavanols (600 mg/d) and a multivitamin with matching placebo on cardiovascular disease and cancer endpoints. A validated telephone-based protocol conducted at baseline and then annually for three years measures attention, memory, language, executive function, and global cognitive functioning in 2,262 women and men, ages 65 and older without insulin-dependent diabetes. Cases of mild cognitive impairment and Alzheimer’s and related dementias will be centrally adjudicated. For participants who score below a pre-specified threshold on a test of global cognition, a study partner is interviewed to obtain additional information regarding cognitive and functional status. With >5,000 interviews completed, this presentation will describe the cognitive battery, operational procedures used to ensure high data fidelity, and strategies employed that have maintained retention at >90%. Our experiences in COSMOS-Mind can inform the design and implementation of other large, multi-site RCTs and epidemiological studies. Telephone-based assessments of cognitive function are a cost-efficient method for assessing cognitive function.

Objectives: To assess whether older persons with osteoarthritis (OA) pain and insomnia receiving cognitive�behavioral therapy for pain and insomnia (CBT-PI), a cognitive�behavioral pain coping skills intervention (CBT-P), and an education-only control (EOC) differed in sleep and pain outcomes. Design: Double-blind, cluster-randomized controlled trial with 9-month follow-up. Setting: Group Health and University of Washington, 2009 to 2011. Participants: Three hundred sixty-seven older adults with OA pain and insomnia. Interventions: Six weekly group sessions of CBT-PI, CBT-P, or EOC delivered in participants' primary care clinics. Measurements: Primary outcomes were insomnia severity and pain severity. Secondary outcomes were actigraphically measured sleep efficiency and arthritis symptoms. Results: CBT-PI reduced insomnia severity (score range 0�28) more than EOC (adjusted mean difference = -1.89, 95% confidence interval = -2.83 to -0.96; P < .001) and CBT-P (adjusted mean difference = -2.03, 95% CI = -3.01 to -1.04; P < .001) and improved sleep efficiency (score range 0�100) more than EOC (adjusted mean difference = 2.64, 95% CI = 0.44�4.84; P = .02). CBT-P did not improve insomnia severity more than EOC, but improved sleep efficiency (adjusted mean difference = 2.91, 95% CI = 0.85�4.97; P = .006). Pain severity and arthritis symptoms did not differ between the three arms. A planned analysis in participants with severe baseline pain revealed similar results. Conclusion: Over 9 months, CBT of insomnia was effective for older adults with OA pain and insomnia. The addition of CBT for insomnia to CBT for pain alone improved outcomes.

The recognition of Alzheimer's disease (AD) as a heterogeneous disorder that results from incremental pathological changes in dynamic organismic systems is essential to move beyond the unidimensional approaches to prevention and therapy that have proven largely ineffective to date. Biological systems related to insulin metabolism are arguably the most critical regulators of longevity and corporeal aging. Our work has focused on identifying the relationship of the insulin network to brain aging, and determining the mechanisms through which insulin dysregulation promotes AD pathological processes. Candidate mechanisms include the effects of insulin on amyloid-β, cerebral glucose metabolism, vascular function, lipid metabolism, and inflammation/oxidative stress. It is likely that different nodes of the insulin network are perturbed for subgroups of AD patients, or that for some subgroups, pathways independent of insulin are critical pathogenetic factors. New methods from systems network analyses may help to identify these subgroups, which will be critical for devising tailored prevention and treatment strategies. In the following review, we will provide a brief description of the role of insulin in normal brain function, and then focus more closely on recent evidence regarding the mechanisms through which disruption of that role may promote AD pathological processes. Finally, we will discuss the implications of this area for AD therapeutics and prevention.