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IntroductionLate-onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long-Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique opportunity to investigate LOAD genetics.MethodsWe conducted a whole genome sequence analysis of 3475 LLFS members. Genetic associations were examined in six independent studies (N = 14,260) with a wide range of LOAD risk. Association analysis in a sub-sample of the LLFS cohort (N = 1739) evaluated the association of LOAD variants with beta amyloid (Aβ) levels.ResultsWe identified several single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium within the MTUS2 gene associated with LOAD (rs73154407, p = 7.6 × 10-9). Association of MTUS2 variants with LOAD was observed in the five independent studies and was significantly stronger within high levels of Aβ42/40 ratio compared to lower amyloid.DiscussionMTUS2 encodes a microtubule associated protein implicated in the development and function of the nervous system, making it a plausible candidate to investigate LOAD biology.HighlightsLong-Life Family Study (LLFS) families may harbor late onset Alzheimer's dementia (LOAD) variants. LLFS whole genome sequence analysis identified MTUS2 gene variants associated with LOAD. The observed LLFS variants generalized to cohorts with wide range of LOAD risk. The association of MTUS2 with LOAD was stronger within high levels of beta amyloid. Our results provide evidence for MTUS2 gene as a novel LOAD candidate locus.

Limbic-predominant age-related TDP-43 encephalopathy (LATE) affects approximately one-third of older individuals and is associated with cognitive impairment. However, there is a highly incomplete understanding of the genetic determinants of LATE neuropathologic changes (LATE-NC) in diverse populations. The defining neuropathologic feature of LATE-NC is TDP-43 proteinopathy, often with comorbid hippocampal sclerosis (HS). In terms of genetic risk factors, LATE-NC and/or HS are associated with single nucleotide variants (SNVs) in 3 genes-TMEM106B (rs1990622), GRN (rs5848), and ABCC9 (rs1914361 and rs701478). We evaluated these 3 genes in convenience samples of individuals of African ancestry. The allele frequencies of the LATE-associated alleles were significantly different between persons of primarily African (versus European) ancestry: In persons of African ancestry, the risk-associated alleles for TMEM106B and ABCC9 were less frequent, whereas the risk allele in GRN was more frequent. We performed an exploratory analysis of data from African-American subjects processed by the Alzheimer's Disease Genomics Consortium, with a subset of African-American participants (n = 166) having corroborating neuropathologic data through the National Alzheimer's Coordinating Center (NACC). In this limited-size sample, the ABCC9/rs1914361 SNV was associated with HS pathology. More work is required concerning the genetic factors influencing non-Alzheimer disease pathology such as LATE-NC in diverse cohorts.

BACKGROUND: Latinx family caregivers of individuals with dementia face many barriers to caregiver support access. Interventions to alleviate these barriers are urgently needed. OBJECTIVE: This study aimed to describe the development of CuidaTEXT, a tailored SMS text messaging intervention to support Latinx family caregivers of individuals with dementia. METHODS: CuidaTEXT is informed by the stress process framework and social cognitive theory. We developed and refined CuidaTEXT using a mixed methods approach that included thematic analysis and descriptive statistics. We followed 6 user-centered design stages, namely, the selection of design principles, software vendor collaboration, evidence-based foundation, caregiver and research and clinical advisory board guidance, sketching and prototyping, and usability testing of the prototype of CuidaTEXT among 5 Latinx caregivers. RESULTS: CuidaTEXT is a bilingual 6-month-long SMS text messaging-based intervention tailored to caregiver needs that includes 1-3 daily automatic messages (n=244) about logistics, dementia education, self-care, social support, end of life, care of the person with dementia, behavioral symptoms, and problem-solving strategies; 783 keyword-driven text messages for further help with the aforementioned topics; live chat interaction with a coach for further help; and a 19-page reference booklet summarizing the purpose and functions of the intervention. The 5 Latinx caregivers who used the prototype of CuidaTEXT scored an average of 97 out of 100 on the System Usability Scale. CONCLUSIONS: CuidaTEXTs prototype demonstrated high usability among Latinx caregivers. CuidaTEXTs feasibility is ready to be tested.

White matter pathologies are critically involved in the etiology of vascular cognitive impairment-dementia (VCID), Alzheimer's disease (AD), and Alzheimer's disease and related diseases (ADRD), and therefore need to be considered a treatable target ( Roseborough A, Hachinski V, Whitehead S. White matter degeneration - a treatable target? Roseborough et al. JAMA Neurol [Internet]. 2020 Apr 27;77(7):793-4, [1] . To help address this often-missed area of research, several workshops have been sponsored by the Leo and Anne Albert Charitable Trust since 2015, resulting in the incorporation of "The Albert Research Institute for White Matter and Cognition" in 2020. The first annual "Institute" meeting was held virtually on March 3-4, 2021. The Institute provides a forum and workspace for communication and support of the advancement of white matter science and research to better understand the evolution and prevention of dementia. It serves as a platform for young investigator development, to introduce new data and debate biology mechanisms and new ideas, and to encourage and support new research collaborations and directions to clarify how white matter changes, with other genetic and health risk factors, contribute to cognitive impairment. Similar to previous Albert Trust-sponsored workshops (Barone et al. in J Transl Med 14:1-14, [2]; Sorond et al. in GeroScience 42:81-96, [3]), established expert investigators were identified and invited to present. Opportunities to attend and present were also extended by invitation to talented research fellows and younger scientists. Also, updates on institute-funded research collaborations were provided and discussed. The summary that follows is a synopsis of topics and discussion covered in the workshop.

BackgroundOur goal was to investigate the role of physical exercise to protect brain health as we age, including the potential to mitigate Alzheimer's-related pathology. We assessed the effect of 52 weeks of a supervised aerobic exercise program on amyloid accumulation, cognitive performance, and brain volume in cognitively normal older adults with elevated and sub-threshold levels of cerebral amyloid as measured by amyloid PET imaging.Methods and findingsThis 52-week randomized controlled trial compared the effects of 150 minutes per week of aerobic exercise vs. education control intervention. A total of 117 underactive older adults (mean age 72.9 [7.7]) without evidence of cognitive impairment, with elevated (n = 79) or subthreshold (n = 38) levels of cerebral amyloid were randomized, and 110 participants completed the study. Exercise was conducted with supervision and monitoring by trained exercise specialists. We conducted 18F-AV45 PET imaging of cerebral amyloid and anatomical MRI for whole brain and hippocampal volume at baseline and Week 52 follow-up to index brain health. Neuropsychological tests were conducted at baseline, Week 26, and Week 52 to assess executive function, verbal memory, and visuospatial cognitive domains. Cardiorespiratory fitness testing was performed at baseline and Week 52 to assess response to exercise. The aerobic exercise group significantly improved cardiorespiratory fitness (11% vs. 1% in the control group) but there were no differences in change measures of amyloid, brain volume, or cognitive performance compared to control.ConclusionsAerobic exercise was not associated with reduced amyloid accumulation in cognitively normal older adults with cerebral amyloid. In spite of strong systemic cardiorespiratory effects of the intervention, the observed lack of cognitive or brain structure benefits suggests brain benefits of exercise reported in other studies are likely to be related to non-amyloid effects.Trial registrationNCT02000583; ClinicalTrials.gov.

IntroductionParticipant retention is important to maintaining statistical power, minimizing bias, and preventing scientific error in Alzheimer disease and related dementias research.MethodsWe surveyed representative investigators from NIH-funded Alzheimer's Disease Research Centers (ADRC), querying their use of retention tactics across 12 strategies. We compared survey results to data from the National Alzheimer's Coordinating Center for each center. We used a generalized estimating equation with independent working covariance model and empirical standard errors to assess relationships between survey results and rates of retention, controlling for participant characteristics.ResultsTwenty-five (83%) responding ADRCs employed an average 42 (SD=7) retention tactics. In a multivariable model that accounted for participant characteristics, the number of retention tactics used by a center was associated with participant retention (odds ratio=1.68, 95% confidence interval: 1.42, 1.98; P

UNLABELLED: ABSTRACTObjectives:To assess the association between cardiovascular health and cognitive function among Mexican older adults. DESIGN: Nationally representative cross-sectional survey. SETTING: Households in Mexico. PARTICIPANTS: Individuals aged 50 years and older (n = 1,492) from the Mexico-SAGE project Wave 1. MEASUREMENTS: A continuous and a categorical index of cardiovascular health was calculated based on exercise, smoking, body mass index, and blood pressure ranging from 0 to 4. Cognitive function was obtained by averaging the standardized scores (z scores) of five psychometric tests. Associations were conducted using linear regression. RESULTS: The continuous index of cardiovascular health was not associated with cognitive function. Using the categorical index, participants with the best levels of cardiovascular (score of 4) health performed better on global cognitive function than groups with lower cardiovascular health (scores of 0, 0.41 SD; 1, 0.39 SD; and 2, 0.56 SD). The association was moderated by age, reaching significance only among those 50-64 years old. CONCLUSIONS: If longitudinal research confirms these findings, results would suggest that dementia-related policies in Mexico need to focus on achieving optimal levels of cardiovascular health, especially in midlife.

INTRODUCTION: The Alzheimer's Prevention Initiative (API) Generation Studies evaluated the BACE inhibitor umibecestat for Alzheimer's disease (AD) prevention. The studies were terminated early, and the reversibility of umibecestat's side effects was assessed. METHODS: Cognitively unimpaired 60‐ to 75‐year‐old apolipoprotein E (APOE) ε4 homozygotes and heterozygotes (the latter with elevated brain amyloid deposition) (n = 1556) received umibecestat (50 or 15 mg daily) or placebo for 7 months on average and were followed for a median (interquartile range) of 4 (3 to 6) months after washout. RESULTS: Compared to placebo, umibecestat‐treated participants had small, non‐progressive, but statistically significant decline in performance on certain cognitive batteries including Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and API Preclinical Composite Cognitive test, but not Clinical Dementia Rating‐Sum of Boxes. RBANS differences were no longer significant at the end of follow‐up. DISCUSSION: In people at genetic risk for AD, high‐dose beta‐site amyloid precursor protein cleaving enzyme (BACE) inhibition was associated with early mild cognitive worsening, which reversed shortly after washout, suggesting a symptomatic side effect not associated with neurodegeneration. Fully anonymized data, images, and samples are available upon request for further research on BACE inhibition. Highlights: This is the first trial with blinded assessment of reversibility of BACE inhibitor side effects.Umibecestat was tested in cognitively unimpaired persons at genetic risk for AD.Umibecestat led to early mild cognitive decline that reversed shortly after washout.This suggests a potentially manageable effect not associated with neurodegeneration.Further research may determine the future of BACE inhibition in AD prevention. [ABSTRACT FROM AUTHOR]

BackgroundCognitive impairment is common in kidney transplant (KT) recipients and affects quality of life, graft survival, morbidity, and mortality. Failure to identify patients with cognitive impairment can withhold appropriate and timely intervention. This study determines whether measured cognition with standard screening tools offers any advantage over perceived cognition in screening transplant patients for cognitive impairment.MethodsCognition was assessed in 157 KT recipients using the Montreal Cognitive Assessment (MoCA; measured cognition). In addition, transplant physicians and nurse coordinators were asked to rate transplant recipients' level of cognition after routine clinical interactions (perceived cognition). Physicians and nurses were blind to MoCA scores. Perceived cognition scores were compared to MoCA scores.ResultsPerceived cognition scores fairly correlated with MOCA scores (γ = 0.24, p = 0.001 for physicians and γ = 0.33, p < 0.0001 for nurses). Physician scores moderately correlated with nurses scores (κ = 0.44, p < 0.0001). Clinical perception had a low accuracy for identifying patients with cognitive impairment (sensitivity 66% for physicians, 65% for nurses), and those without cognitive impairment (specificity 67% for physicians, 76% for nurses).ConclusionClinical perception is inaccurate at detecting cognitive impairment in KT recipients. Objective tests should be considered to screen KT recipients for cognitive impairment.

BackgroundMild cognitive impairment (MCI) has an uncertain etiology and prognosis and may be challenging for clinicians to discuss with patients and families. Amyloid imaging may aid specialists in determining MCI etiology and prognosis, but creates novel challenges related to disease labeling.MethodsWe convened a workgroup to formulate recommendations for clinicians providing care to MCI patients.ResultsClinicians should use the MCI diagnosis to validate patient and family concerns and educate them that the patient's cognitive impairment is not normal for his or her age and education level. The MCI diagnosis should not be used to avoid delivering a diagnosis of dementia. For patients who meet Appropriate Use Criteria after standard-of-care clinical workup, amyloid imaging may position specialists to offer more information about etiology and prognosis. Clinicians must set appropriate expectations, including ensuring that patients and families understand the limitations of amyloid imaging. Communication of negative results should include that patients remain at elevated risk for dementia and that negative scans do not indicate a specific diagnosis or signify brain health. Positive amyloid imaging results should elicit further monitoring and conversations about appropriate advance planning. Clinicians should offer written summaries, including referral to appropriate social services.ConclusionsIn patients with MCI, there is a need to devote considerable time and attention to patient education and shared decision-making. Amyloid imaging may be a tool to aid clinicians. Careful management of patient expectations and communication of scan results will be critical to the appropriate use of amyloid imaging information.

IntroductionDisclosing amyloid status to cognitively normal individuals remains controversial given our lack of understanding the test's clinical significance and unknown psychological risk.MethodsWe assessed the effect of amyloid status disclosure on anxiety and depression before disclosure, at disclosure, and 6 weeks and 6 months postdisclosure and test-related distress after disclosure.ResultsClinicians disclosed amyloid status to 97 cognitively normal older adults (27 had elevated cerebral amyloid). There was no difference in depressive symptoms across groups over time. There was a significant group by time interaction in anxiety, although post hoc analyses revealed no group differences at any time point, suggesting a minimal nonsustained increase in anxiety symptoms immediately postdisclosure in the elevated group. Slight but measureable increases in test-related distress were present after disclosure and were related to greater baseline levels of anxiety and depression.DiscussionDisclosing amyloid imaging results to cognitively normal adults in the clinical research setting with pre- and postdisclosure counseling has a low risk of psychological harm.

ObjectiveWe tested biweekly infusions of IV immunoglobulin (IVIg) as a possible treatment for mild to moderate Alzheimer disease (AD) dementia.MethodsIn a phase 3, double-blind, placebo-controlled trial, we randomly assigned 390 participants with mild to moderate AD to receive placebo (low-dose albumin) or IVIg (Gammagard Liquid; Baxalta, Bannockburn, IL) administered IV at doses of 0.2 or 0.4 g/kg every 2 weeks for 18 months. The primary cognitive outcome was change from baseline to 18 months on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale; the primary functional outcome was 18-month change on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory. Safety and tolerability data, as well as serial MRIs and plasma samples, were collected throughout the study from all enrolled participants.ResultsNo beneficial effects were observed in the dual primary outcome measures for the 2 IVIg doses tested. Significant decreases in plasma Aβ42 (but not Aβ40) levels were observed in IVIg-treated participants. Analysis of safety data showed no difference between IVIg and placebo in terms of the rate of occurrence of amyloid-related imaging abnormalities (brain edema or microhemorrhage). IVIg-treated participants had more systemic reactions (chills, rashes) but fewer respiratory infections than participants receiving placebo.ConclusionsParticipants with mild to moderate AD showed good tolerability of treatment with low-dose human IVIg for 18 months but did not show beneficial effects on cognition or function relative to participants who received placebo.Clinicaltrialsgov identifierNCT00818662.Classification of evidenceThis study provides Class II evidence that IVIg infusions performed every 2 weeks do not improve cognition or function at 18 months in patients with mild to moderate AD.

BackgroundThere is a high prevalence of cognitive impairment in dialysis patients. The prevalence of cognitive impairment after kidney transplantation is unknown.MethodsStudy Design: Cross-sectional study.Setting and participantsSingle center study of prevalent kidney transplant recipients from a transplant clinic in a large academic center.InterventionAssessment of cognition using the Montreal Cognitive Assessment (MoCA). Demographic and clinical variables associated with cognitive impairment were also examined. Outcomes and Measurements: a) Prevalence of cognitive impairment defined by a MoCA score of

BackgroundThere is increasing interest in the role of physical exercise as a therapeutic strategy for individuals with Alzheimer's disease (AD). We assessed the effect of 26 weeks (6 months) of a supervised aerobic exercise program on memory, executive function, functional ability and depression in early AD.Methods and findingsThis study was a 26-week randomized controlled trial comparing the effects of 150 minutes per week of aerobic exercise vs. non-aerobic stretching and toning control intervention in individuals with early AD. A total of 76 well-characterized older adults with probable AD (mean age 72.9 [7.7]) were enrolled and 68 participants completed the study. Exercise was conducted with supervision and monitoring by trained exercise specialists. Neuropsychological tests and surveys were conducted at baseline,13, and 26 weeks to assess memory and executive function composite scores, functional ability (Disability Assessment for Dementia), and depressive symptoms (Cornell Scale for Depression in Dementia). Cardiorespiratory fitness testing and brain MRI was performed at baseline and 26 weeks. Aerobic exercise was associated with a modest gain in functional ability (Disability Assessment for Dementia) compared to individuals in the ST group (X2 = 8.2, p = 0.02). There was no clear effect of intervention on other primary outcome measures of Memory, Executive Function, or depressive symptoms. However, secondary analyses revealed that change in cardiorespiratory fitness was positively correlated with change in memory performance and bilateral hippocampal volume.ConclusionsAerobic exercise in early AD is associated with benefits in functional ability. Exercise-related gains in cardiorespiratory fitness were associated with improved memory performance and reduced hippocampal atrophy, suggesting cardiorespiratory fitness gains may be important in driving brain benefits.Trial registrationClinicalTrials.gov NCT01128361.

ObjectiveTo identify a causative variant(s) that may contribute to Alzheimer disease (AD) in African Americans (AA) in the ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7) gene, a known risk factor for late-onset AD.MethodsCustom capture sequencing was performed on ∼150 kb encompassing ABCA7 in 40 AA cases and 37 AA controls carrying the AA risk allele (rs115550680). Association testing was performed for an ABCA7 deletion identified in large AA data sets (discovery n = 1,068; replication n = 1,749) and whole exome sequencing of Caribbean Hispanic (CH) AD families.ResultsA 44-base pair deletion (rs142076058) was identified in all 77 risk genotype carriers, which shows that the deletion is in high linkage disequilibrium with the risk allele. The deletion was assessed in a large data set (531 cases and 527 controls) and, after adjustments for age, sex, and APOE status, was significantly associated with disease (p = 0.0002, odds ratio [OR] = 2.13 [95% confidence interval (CI): 1.42-3.20]). An independent data set replicated the association (447 cases and 880 controls, p = 0.0117, OR = 1.65 [95% CI: 1.12-2.44]), and joint analysis increased the significance (p = 1.414 × 10(-5), OR = 1.81 [95% CI: 1.38-2.37]). The deletion is common in AA cases (15.2%) and AA controls (9.74%), but in only 0.12% of our non-Hispanic white cohort. Whole exome sequencing of multiplex, CH families identified the deletion cosegregating with disease in a large sibship. The deleted allele produces a stable, detectable RNA strand and is predicted to result in a frameshift mutation (p.Arg578Alafs) that could interfere with protein function.ConclusionsThis common ABCA7 deletion could represent an ethnic-specific pathogenic alteration in AD.

Alzheimer's disease (AD) is a complex genetic disorder with no effective treatments. More than 20 common markers have been identified, which are associated with AD. Recently, several rare variants have been identified in Amyloid Precursor Protein (APP), Triggering Receptor Expressed On Myeloid Cells 2 (TREM2) and Unc-5 Netrin Receptor C (UNC5C) that affect risk for AD. Despite the many successes, the genetic architecture of AD remains unsolved. We used Genome-wide Complex Trait Analysis to (1) estimate phenotypic variance explained by genetics; (2) calculate genetic variance explained by known AD single nucleotide polymorphisms (SNPs); and (3) identify the genomic locations of variation that explain the remaining unexplained genetic variance. In total, 53.24% of phenotypic variance is explained by genetics, but known AD SNPs only explain 30.62% of the genetic variance. Of the unexplained genetic variance, approximately 41% is explained by unknown SNPs in regions adjacent to known AD SNPs, and the remaining unexplained genetic variance outside these regions.

Insulin resistance is a risk factor for Alzheimer's disease (AD), although its role in AD etiology is unclear. We assessed insulin resistance using fasting and insulin-stimulated measures in 51 elderly subjects with no dementia (ND; n = 37) and with cognitive impairment (CI; n = 14). CI subjects exhibited either mild CI or AD. Fasting insulin resistance was measured using the homeostatic model assessment of insulin resistance (HOMA-IR). Insulin-stimulated glucose disposal was assessed using the hyperinsulinemic-euglycemic clamp to calculate glucose disposal rate into lean mass, the primary site of insulin-stimulated glucose disposal. Because insulin crosses the blood-brain barrier, we also assessed whether insulin infusion would improve verbal episodic memory compared to baseline. Different but equivalent versions of cognitive tests were administered in counterbalanced order in the basal and insulin-stimulated state. Groups did not differ in age or body mass index. Cognitively impaired subjects exhibited greater insulin resistance as measured at fasting (HOMA-IR; ND: 1.09 [1.1] vs. CI: 2.01 [2.3], p = 0.028) and during the hyperinsulinemic clamp (glucose disposal rate into lean mass; ND: 9.9 (4.5) vs. AD 7.2 (3.2), p = 0.040). Cognitively impaired subjects also exhibited higher fasting insulin compared to ND subjects, (CI: 8.7 [7.8] vs. ND: 4.2 [3.8] μU/mL; p = 0.023) and higher fasting amylin (CI: 24.1 [39.1] vs. 8.37 [14.2]; p = 0.050) with no difference in fasting glucose. Insulin infusion elicited a detrimental effect on one test of verbal episodic memory (Free and Cued Selective Reminding Test) in both groups (p < 0.0001) and no change in performance on an additional task (delayed logical memory). In this study, although insulin resistance was observed in cognitively impaired subjects compared to ND controls, insulin infusion did not improve memory. Furthermore, a significant correlation between HOMA-IR and glucose disposal rate was present only in ND (p = 0.0002) but not in cognitively impaired (p = 0.884) subjects, indicating potentially important physiological differences between these cohorts.

BackgroundEnd-stage renal disease (ESRD) is a disease with an aging population and a high prevalence of cognitive impairment affecting quality of life, health care costs and mortality. Structural changes in the brain with decreased white matter integrity have been observed in ESRD. Understanding the changes in cognition and associated changes in brain structure after renal transplantation can help define the mechanisms underlying cognitive impairment in ESRD.MethodsWe conducted a prospective, observational cohort study in ESRD patients listed for renal transplantation and followed them post-transplantation. We assessed their cognitive function with a battery of neuropsychological tests and brain white matter integrity with diffusion tensor imaging (DTI) both before transplant and 3 months after transplant.ResultsEleven patients, aged 56.5 ± 10.7 years, completed the study. Cognitive measures of memory and executive function improved after the transplant, specifically on tests of logical memory I (p = 0.004), logical memory II (p = 0.003) and digit symbol (p < 0.0001). DTI metrics also improved post the transplant with an increase in fractional anisotropy (p = 0.01) and decrease in mean diffusivity (p = 0.004). These changes were more prominent in tracts associated with memory and executive function.ConclusionsCognitive function, particularly memory and executive function, improve post the transplant with concurrent improvements in white matter integrity in tracts associated with memory and executive function. These data suggest that abnormalities in cognition and brain structure seen in the ESRD population are at least partially reversible.

UnlabelledEpidemiological studies suggest a dose-response relationship exists between physical activity and cognitive outcomes. However, no direct data from randomized trials exists to support these indirect observations. The purpose of this study was to explore the possible relationship of aerobic exercise dose on cognition. Underactive or sedentary participants without cognitive impairment were randomized to one of four groups: no-change control, 75, 150, and 225 minutes per week of moderate-intensity semi-supervised aerobic exercise for 26-weeks in a community setting. Cognitive outcomes were latent residual scores derived from a battery of 16 cognitive tests: Verbal Memory, Visuospatial Processing, Simple Attention, Set Maintenance and Shifting, and Reasoning. Other outcome measures were cardiorespiratory fitness (peak oxygen consumption) and measures of function functional health. In intent-to-treat (ITT) analyses (n = 101), cardiorespiratory fitness increased and perceived disability decreased in a dose-dependent manner across the 4 groups. No other exercise-related effects were observed in ITT analyses. Analyses restricted to individuals who exercised per-protocol (n = 77) demonstrated that Simple Attention improved equivalently across all exercise groups compared to controls and a dose-response relationship was present for Visuospatial Processing. A clear dose-response relationship exists between exercise and cardiorespiratory fitness. Cognitive benefits were apparent at low doses with possible increased benefits in visuospatial function at higher doses but only in those who adhered to the exercise protocol. An individual’s cardiorespiratory fitness response was a better predictor of cognitive gains than exercise dose (i.e., duration) and thus maximizing an individual’s cardiorespiratory fitness may be an important therapeutic target for achieving cognitive benefits.Trial registrationClinicalTrials.gov NCT01129115.

Objective:To investigate predictors of missing data in a longitudinal study of Alzheimer disease (AD).Methods:The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a clinic-based, multicenter, longitudinal study with blood, CSF, PET, and MRI scans repeatedly measured in 229 participants with normal cognition (NC), 397 with mild cognitive impairment (MCI), and 193 with mild AD during 2005–2007. We used univariate and multivariable logistic regression models to examine the associations between baseline demographic/clinical features and loss of biomarker follow-ups in ADNI.Results:CSF studies tended to recruit and retain patients with MCI with more AD-like features, including lower levels of baseline CSF Aβ42. Depression was the major predictor for MCI dropouts, while family history of AD kept more patients with AD enrolled in PET and MRI studies. Poor cognitive performance was associated with loss of follow-up in most biomarker studies, even among NC participants. The presence of vascular risk factors seemed more critical than cognitive function for predicting dropouts in AD.Conclusion:The missing data are not missing completely at random in ADNI and likely conditional on certain features in addition to cognitive function. Missing data predictors vary across biomarkers and even MCI and AD groups do not share the same missing data pattern. Understanding the missing data structure may help in the design of future longitudinal studies and clinical trials in AD.

The 1960s continue to fascinate historians and scholars, although their understandings of the decade's meaning differ dramatically. The same is true for the Catholic Sixties. To date, no comprehensive history exists of the Catholic Sixties, although much has been written. Catholic scholars, such as Donald Thorman, Daniel Callahan, and John Noonan, among others, wrote seminal works during the 1960s, establishing the initial lens through which scholars came to view the decade. In 1972, three important works were published by David J. O'Brien, James Hitchcock, and Garry Wills; all three provided decidedly different approaches and critiques of the decade and all have influenced contemporary understandings of the decade. Several scholars provided interpretive schemas through which future historians may organize the decade, with Mark Massa's work being the most important. Other historians focused on one aspect of the Sixties, which contributed to a deeper understanding. The many scholars and historians who have written to date provide much for future historians to consider. [ABSTRACT FROM AUTHOR]