Search

Abstract Background Leveraging Alzheimer’s disease (AD) imaging biomarkers and longitudinal cognitive data may allow us to establish evidence of cognitive resilience (CR) to AD pathology in-vivo. Here, we applied latent class mixture modeling, adjusting for sex, baseline age, and neuroimaging biomarkers of amyloid, tau and neurodegeneration, to a sample of cognitively unimpaired older adults to identify longitudinal trajectories of CR. Methods We identified 200 Harvard Aging Brain Study (HABS) participants (mean age = 71.89 years, SD = 9.41 years, 59% women) who were cognitively unimpaired at baseline with 2 or more timepoints of cognitive assessment following a single amyloid-PET, tau-PET and structural MRI. We examined latent class mixture models with longitudinal cognition as the dependent variable and time from baseline, baseline age, sex, neocortical Aβ, entorhinal tau, and adjusted hippocampal volume as independent variables. We then examined group differences in CR-related factors across the identified subgroups from a favored model. Finally, we applied our favored model to a dataset from the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 160, mean age = 73.9 years, SD = 7.6 years, 60% women). Results The favored model identified 3 latent subgroups, which we labelled as Normal (71% of HABS sample), Resilient (22.5%) and Declining (6.5%) subgroups. The Resilient subgroup exhibited higher baseline cognitive performance and a stable cognitive slope. They were differentiated from other groups by higher levels of verbal intelligence and past cognitive activity. In ADNI, this model identified a larger Normal subgroup (88.1%), a smaller Resilient subgroup (6.3%) and a Declining group (5.6%) with a lower cognitive baseline. Conclusion These findings demonstrate the value of data-driven approaches to identify longitudinal CR groups in preclinical AD. With such an approach, we identified a CR subgroup who reflected expected characteristics based on previous literature, higher levels of verbal intelligence and past cognitive activity.

Abstract Background Autopsy work indicates that the widely-projecting noradrenergic pontine locus coeruleus (LC) is among the earliest regions to accumulate hyperphosphorylated tau, a neuropathological Alzheimer’s disease (AD) hallmark. This early tau deposition is accompanied by a reduced density of LC projections and a reduction of norepinephrine’s neuroprotective effects, potentially compromising the neuronal integrity of LC’s cortical targets. Previous studies suggest that lower magnetic resonance imaging (MRI)-derived LC integrity may signal cortical tissue degeneration in cognitively healthy, older individuals. However, whether these observations are driven by underlying AD pathology remains unknown. To that end, we examined potential effect modifications by cortical beta-amyloid and tau pathology on the association between in vivo LC integrity, as quantified by LC MRI signal intensity, and cortical neurodegeneration, as indexed by cortical thickness. Methods A total of 165 older individuals (74.24 ± 9.72 years, ~ 60% female, 10% cognitively impaired) underwent whole-brain and dedicated LC 3T-MRI, Pittsburgh Compound-B (PiB, beta-amyloid) and Flortaucipir (FTP, tau) positron emission tomography. Linear regression analyses with bootstrapped standard errors (n = 2000) assessed associations between bilateral cortical thickness and i) LC MRI signal intensity and, ii) LC MRI signal intensity interacted with cortical FTP or PiB (i.e., EC FTP, IT FTP, neocortical PiB) in the entire sample and a low beta-amyloid subsample. Results Across the entire sample, we found a direct effect, where lower LC MRI signal intensity was associated with lower mediolateral temporal cortical thickness. Evaluation of potential effect modifications by FTP or PiB revealed that lower LC MRI signal intensity was related to lower cortical thickness, particularly in individuals with elevated (EC, IT) FTP or (neocortical) PiB. The latter result was present starting from subthreshold PiB values. In low PiB individuals, lower LC MRI signal intensity was related to lower EC cortical thickness in the context of elevated EC FTP. Conclusions Our findings suggest that LC-related cortical neurodegeneration patterns in older individuals correspond to regions representing early Braak stages and may reflect a combination of LC projection density loss and emergence of cortical AD pathology. This provides a novel understanding that LC-related cortical neurodegeneration may signal downstream consequences of AD-related pathology, rather than being exclusively a result of aging.

Abstract Background Evidence links lifestyle factors with Alzheimer’s disease (AD). We report the first randomized, controlled clinical trial to determine if intensive lifestyle changes may beneficially affect the progression of mild cognitive impairment (MCI) or early dementia due to AD. Methods A 1:1 multicenter randomized controlled phase 2 trial, ages 45-90 with MCI or early dementia due to AD and a Montreal Cognitive Assessment (MoCA) score of 18 or higher. The primary outcome measures were changes in cognition and function tests: Clinical Global Impression of Change (CGIC), Alzheimer’s Disease Assessment Scale (ADAS-Cog), Clinical Dementia Rating–Sum of Boxes (CDR-SB), and Clinical Dementia Rating Global (CDR-G) after 20 weeks of an intensive multidomain lifestyle intervention compared to a wait-list usual care control group. ADAS-Cog, CDR-SB, and CDR-Global scales were compared using a Mann-Whitney-Wilcoxon rank-sum test, and CGIC was compared using Fisher’s exact test. Secondary outcomes included plasma Aβ42/40 ratio, other biomarkers, and correlating lifestyle with the degree of change in these measures. Results Fifty-one AD patients enrolled, mean age 73.5. No significant differences in any measures at baseline. Only two patients withdrew. All patients had plasma Aβ42/40 ratios

Abstract Background Autopsy work reported that neuronal density in the locus coeruleus (LC) provides neural reserve against cognitive decline in dementia. Recent neuroimaging and pharmacological studies reported that left frontoparietal network functional connectivity (LFPN-FC) confers resilience against beta-amyloid (Aβ)-related cognitive decline in preclinical sporadic and autosomal dominant Alzheimer’s disease (AD), as well as against LC-related cognitive changes. Given that the LFPN and the LC play important roles in attention, and attention deficits have been observed early in the disease process, we examined whether LFPN-FC and LC structural health attenuate attentional decline in the context of AD pathology. Methods 142 participants from the Harvard Aging Brain Study who underwent resting-state functional MRI, LC structural imaging, PiB(Aβ)-PET, and up to 5 years of cognitive follow-ups were included (mean age = 74.5 ± 9.9 years, 89 women). Cross-sectional robust linear regression associated LC integrity (measured as the average of five continuous voxels with the highest intensities in the structural LC images) or LFPN-FC with Digit Symbol Substitution Test (DSST) performance at baseline. Longitudinal robust mixed effect analyses examined associations between DSST decline and (i) two-way interactions of baseline LC integrity (or LFPN-FC) and PiB or (ii) the three-way interaction of baseline LC integrity, LFPN-FC, and PiB. Baseline age, sex, and years of education were included as covariates. Results At baseline, lower LFPN-FC, but not LC integrity, was related to worse DSST performance. Longitudinally, lower baseline LC integrity was associated with a faster DSST decline, especially at PiB > 10.38 CL. Lower baseline LFPN-FC was associated with a steeper decline on the DSST but independent of PiB. At elevated PiB levels (> 46 CL), higher baseline LFPN-FC was associated with an attenuated decline on the DSST, despite the presence of lower LC integrity. Conclusions Our findings demonstrate that the LC can provide resilience against Aβ-related attention decline. However, when Aβ accumulates and the LC’s resources may be depleted, the functioning of cortical target regions of the LC, such as the LFPN-FC, can provide additional resilience to sustain attentional performance in preclinical AD. These results provide critical insights into the neural correlates contributing to individual variability at risk versus resilience against Aβ-related cognitive decline.

BackgroundChanges in everyday functioning constitute a clinically meaningful outcome, even in the early stages of Alzheimer's disease. Performance-based assessments of everyday functioning might help uncover these early changes. We aimed to investigate how changes over time in everyday functioning relate to tau and amyloid in cognitively unimpaired older adults.MethodsSeventy-six cognitively unimpaired participants (72 ± 6 years old, 61% female) completed multiple Harvard Automated Phone Task (APT) assessments over 2.0 ± 0.9 years. The Harvard APT consists of three tasks, performed through an automated phone system, in which participants refill a prescription (APT-Script), select a new primary care physician (APT-PCP), and transfer money to pay a bill (APT-Bank). Participants underwent Pittsburgh compound-B and flortaucipir positron emission tomography scans at baseline. We computed distribution volume ratios for a cortical amyloid aggregate and standardized uptake volume ratios for medial temporal and neocortical tau regions. In separate linear mixed models, baseline amyloid by time and tau by time interactions were used to predict longitudinal changes in performance on the Harvard APT tasks. Three-way amyloid by tau by time interactions were also investigated. Lastly, we examined associations between tau and change in Harvard APT scores in exploratory voxel-wise whole-brain analyses. All models were adjusted for age, sex, and education.ResultsAmyloid [unstandardized partial regression coefficient estimate (β) = −0.007, 95% confidence interval (95% CI) = (−0.013, −0.001)], and medial temporal tau [β = −0.013, 95% CI = (−0.022, −0.004)] were associated with change over time in years on APT-PCP only, i.e., higher baseline amyloid and higher baseline tau were associated with steeper rate of decline of APT-PCP. Voxel-wise analyses showed widespread associations between tau and change in APT-PCP scores over time.ConclusionEven among cognitively unimpaired older adults, changes over time in the performance of cognitively complex everyday activities relate to cortical amyloid and widespread cerebral tau burden at baseline. These findings support the link between Alzheimer's disease pathology and function and highlight the importance of measuring everyday functioning in preclinical disease stages.

Fin whale song is a ubiquitous low-frequency pulsing that has been recorded in every ocean basin. In recent years, the complexity of fin whale song has been realized. In the North Atlantic, this song is made up of two low-frequency note types (A and B notes) and one higher-frequency note type (upsweeps). The A and B notes are produced with both singlet and doublet inter-note intervals. These song patterns are interwoven throughout an individual’s song and have been observed to shift over time, both gradually and suddenly. Like many baleen whales, the population size of fin whales is poorly defined. Passive acoustic monitoring has been suggested as a way to estimate abundance if a cue rate or calling rate can be determined. In this study, we used recordings from 119 fin whale tracks from 2013–2023 generated from passive acoustic recorders in the North Atlantic to define fin whale song patterns in this ocean basin, identify changes in these song patterns over time, and calculate cue rates. The fin whales recorded sang in 4 distinct patterns. Inter-note intervals were 25 s for A-A singlets, 13 s for B-B singlets, 12/20 s for B-B doublets, and 10/11 s for A-B doublets. B-B doublet inter-note intervals significantly increased from May 2019–April 2023 and A-B inter-note intervals showed an intra-annual increasing trend that reset each summer. Fin whale song in the North Atlantic also often includes higher frequency upsweep notes immediately prior to B notes. While A and B note peak frequency was steady over these years, upsweep peak frequency significantly decreased, continuing a similar trend that has been observed over 30 years. Despite these changes, the dominant song pattern remained consistent and cue rate for actively singing whales was relatively stable, which is in contrast to patterns observed in the North Pacific. Many of these nuances in fin whale singing behavior are newly described herein, and these findings are vital for monitoring baseline behavior, behavioral trends over time, and ultimately estimating abundance of a poorly understood species.

Abstract Background There are ongoing efforts to eliminate juvenile detention in King County, WA. An essential element of this work is effectively addressing the health needs of youth who are currently detained to improve their wellbeing and reduce further contact with the criminal legal system. This formative study sought to inform adaptation and piloting of an evidence-based systems engineering strategy – the Systems Analysis and Improvement Approach (SAIA) – in a King County juvenile detention center clinic to improve quality and continuity of healthcare services. Our aims were to describe the priority health needs of young people who are involved in Washington’s criminal legal system and the current system of healthcare for young people who are detained. Methods We conducted nine individual interviews with providers serving youth. We also obtained de-identified quantitative summary reports of quality improvement discussions held between clinic staff and 13 young people who were detained at the time of data collection. Interview transcripts were analyzed using deductive and inductive coding and quantitative data were used to triangulate emergent themes. Results Providers identified three priority healthcare cascades for detention-based health services—mental health, substance use, and primary healthcare—and reported that care for these concerns is often introduced for the first time in detention. Interviewees classified incarceration itself as a health hazard, highlighting the paradox of resourcing healthcare quality improvement interventions in an inherently harmful setting. Fractured communication and collaboration across detention- and community-based entities drives systems-level inefficiencies, obstructs access to health and social services for marginalized youth, and fragments the continuum of care for young people establishing care plans while detained in King County. 31% of youth self-reported receiving episodic healthcare prior to detention, 15% reported never having medical care prior to entering detention, and 46% had concerns about finding healthcare services upon release to the community. Conclusions Systems engineering interventions such as the SAIA may be appropriate and feasible approaches to build systems thinking across and between services, remedy systemic challenges, and ensure necessary information sharing for care continuity. However, more information is needed directly from youth to draw conclusions about effective pathways for healthcare quality improvement.

Abstract INTRODUCTION To investigate the utility of a new digital tool for measuring everyday functioning in preclinical Alzheimer's disease, we piloted the Assessment of Smartphone Everyday Tasks (ASSET) application. METHODS Forty‐six participants (50.3 ± 27.1 years; 67% female; 20 young unimpaired, 17 old unimpaired, 9 mildly cognitively impaired) completed ASSET 7 times. ASSET comprises two main tasks, simulating a Patient Portal and a Calendar. We assessed ASSET's internal consistency, test–retest reliability, and user experience. RESULTS ASSET main tasks correlated with each other (r = 0.75, 95% confidence interval [CI] = [0.58, 0.86]). Performance on ASSET's Patient Portal related to cognition (r = 0.64, 95% CI = [0.42, 0.79]) and observer ratings of everyday functioning (r = 0.57, 95% CI = [0.24, 0.79]). Test–retest reliability was good (intraclass correlation coefficient = 0.87, 95% CI = [0.77, 0.93]). Most participants rated their experience with ASSET neutrally or positively. DISCUSSION ASSET is a promising smartphone‐based digital assessment of everyday functioning. Future studies may investigate its utility for early diagnosis and evaluation of treatment of Alzheimer's disease.

OBJECTIVES Pediatric residency trainees interface with electrocardiograms (EKG) as part of routine clinical care. Depending on workflow and availability of support staff, trainees may be required to obtain EKGs on patients, though training on this skill varies. Our intervention seeks to train incoming pediatric residents on obtaining EKGs from pediatric patients and identifying common problems that may result in acquisition of low-fidelity EKGs. METHODS A team of physicians, EKG technicians, and simulation educators designed a 30-min didactic and experiential learning opportunity for incoming pediatric trainees held prior to their start of clinical responsibilities. During the session, trainees were introduced to the basics of EKG acquisition and common quality issues that arise. Afterwards, they practiced placing EKG leads on a mannequin and a live model. A pre- and post-session survey was utilized to assess the session's utility and participant's learning. RESULTS The intervention was perceived as a valuable experience by participants over the course of 2 years. We found increased participant comfort with performing and troubleshooting EKGs ( P

Abstract The Face Name Associative Memory Exam (FNAME) was introduced into the NIH Toolbox as part of the ARMADA study and establishes normative data for diverse participants, ages 64 to 85+, and proposes cutoff scores between biomarker positive versus negative (+/−) groups. The FNAME was administered to 257 participants across the clinical spectrum with 122 having amyloid biomarkers. Linear regression explored the association between demographics and FNAME and between amyloid (+/−) groups. Receiver operating characteristic curves (ROC) identified performance thresholds that best discriminated between biomarker (+/−) individuals. Lower FNAME scores occurred in males, older ages, Black/African Americans, Hispanics, and biomarker‐positive participants. ROC analyses demonstrated acceptable accuracy (0.73 to 0.77) but only when combined with clinical status. The diagnostic discrimination of amyloid positivity was acceptable but not excellent, suggesting the FNAME may be a better screening indicator of clinical status rather than amyloid deposition in cognitively normal individuals. Normative data are provided.

Abstract Introduction GERAS‐US prospectively characterized clinical and economic outcomes of early symptomatic Alzheimer's disease (AD). Societal cost changes were examined in amyloid‐positive patients with mild cognitive impairment due to AD (MCI) and mild dementia due to AD (MILD). Methods Cognition, function, and caregiver burden were assessed using Mini‐Mental State Examination (MMSE), Cognitive Function Index (CFI), and Zarit Burden Interview, respectively. Costs are presented as least square mean for the overall population and for MCI versus MILD using mixed model repeated measures. Results MMSE score and CFI worsened. Total societal costs (dollars/month) for MCI and MILD, respectively, were higher at baseline ($2430 and $4063) but steady from 6 ($1977 and $3032) to 36 months ($2007 and $3392). Direct non‐medical costs rose significantly for MILD. Caregiver burden was higher for MILD versus MCI at 12, 18, and 24 months. Discussion Function and cognition declined in MILD. Non‐medical costs reflect the increasing impact of AD even in its early stages. HIGHLIGHTS In the GERAS‐US study, total societal costs for patients with mild cognitive impairment due to Alzheimer's disease (MCI) and mild dementia due to Alzheimer's disease (MILD) were higher at baseline but steady from 6 to 36 months. Mini‐Mental State Examination (MMSE) and Cognitive Function Index (CFI) worsened; the rate of decline was significant for patients with MILD but not for those with MCI. There was a rise in direct non‐medical costs at 36 months for patients with MILD. Caregiver burden was higher for MILD versus MCI at 12, 18, and 24 months. Slowing the rate of disease progression in this early symptomatic population may allow patients to maintain their ability to carry out everyday activities longer.

Abstract Introduction Subjective cognitive decline (SCD) has been associated with elevated amyloid levels and increased risk of future cognitive decline, as well as modifiable variables, including depression, anxiety, and physical inactivity. Participants generally endorse greater and earlier concerns than their close family and friends (study partners [SPs]), which may reflect subtle changes at the earliest stages of disease among participants with underlying neurodegenerative processes. However, many individuals with subjective concerns are not at risk of Alzheimer's disease (AD) pathology, suggesting that additional factors, such as lifestyle habits, may be contributory. Methods We examined the relation between SCD, amyloid status, lifestyle habits (exercise, sleep), mood/anxiety, and demographic variables among 4481 cognitively unimpaired older adults who are being screened for a multi‐site secondary prevention trial (A4 screen data; mean ±SD: age = 71.3 ±4.7, education = 16.6 ±2.8, 59% women, 96% non‐Hispanic or Latino, 92% White]. Results On the Cognitive Function Index (CFI) participants endorsed higher concerns compared to SPs. Participant concerns were associated with older age, positive amyloid status, worse mood/anxiety, lower education, and lower exercise, whereas SP concerns were associated with older participant age, male gender of participant, positive amyloid status of participant, and worse participant‐reported mood/anxiety. Discussion Findings suggest that modifiable/lifestyle factors (e.g., exercise, education) may be associated with participant concerns among cognitively unimpaired individuals and highlight the importance of further examining how modifiable factors impact participant‐ and SP‐reported concerns, which may inform trial recruitment and clinical interventions.

Abstract Background FACEmemory® is the first computerized, self-administered verbal episodic memory test with voice recognition. It can be conducted under minimal supervision and contains an automatic scoring system to avoid administrator errors. Moreover, it is suitable for discriminating between cognitively healthy and amnestic mild cognitive impairment (MCI) individuals, and it is associated with Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers. This study aimed to determine whether FACEmemory scoring is related to performance on classical memory tests and to AD biomarkers of brain magnetic resonance imaging (MRI) and CSF in patients with early-onset MCI (EOMCI). Methods Ninety-four patients with EOMCI from the BIOFACE study completed FACEmemory, classical memory tests (the Spanish version of the Word Free and Cued Selective Reminding Test -FCSRT-, the Word List from the Wechsler Memory Scale, third edition, and the Spanish version of the Rey–Osterrieth Complex Figure Test), and a brain MRI. Eighty-two individuals also underwent a lumbar puncture. Results FACEmemory scoring was moderately correlated with FCSRT scoring. With regard to neuroimaging MRI results, worse execution on FACEmemory was associated with lower cortical volume in the right prefrontal and inferior parietal areas, along with the left temporal and associative occipital areas. Moreover, the total FACEmemory score correlated with CSF AD biomarkers (Aβ1-42/Aβ1-40 ratio, p181-tau, and Aβ1-42/p181-tau ratio). When performance on FACEmemory was compared among the ATN classification groups, significant differences between the AD group and normal and SNAP groups were found. Conclusions FACEmemory is a promising tool for detecting memory deficits sensitive to early-onset AD, but it also allows the detection of memory-impaired cases due to other etiologies. Our findings suggest that FACEmemory scoring can detect the AD endophenotype and that it is also associated with AD-related changes in MRI and CSF in patients with EOMCI. The computerized FACEmemory tool might be an opportunity to facilitate early detection of MCI in younger people than 65, who have a growing interest in new technologies.

Older individuals exhibiting diminished function of the locus coeruleus while learning new information show faster cognitive decline that is typical for Alzheimer’s disease.

Abstract Background Little is known about using telehealth patient visits as an educational mode. Therefore, rapid implementation of telehealth during the COVID-19 pandemic had to be done without understanding how to optimize telehealth for education. With the likely sustained/post-pandemic use of telehealth in ambulatory patient care, filling gaps in our understanding of how telehealth can be used for instruction in this context is critical. This study sought to understand perceptions of pediatric postgraduate trainees and supervisors on the use of telehealth for instruction in ambulatory settings with the goal of identifying effective ways to enhance learning during telehealth visits. Methods In May–June of 2020, the authors purposefully sampled first- and third-year postgraduate trainees and supervising attendings from pediatric fellowship programs at one institution that implemented telehealth for instructional activities. They conducted semi-structured interviews; interviews lasted a median of 51 min (trainees) and 41 min (supervisors). They conducted interviews and data analysis iteratively until reaching saturation. Using thematic analysis, they created codes and constructed themes from coded data. They organized themes using the Replace-Amplify-Transform (RAT) model, which proposes that technology can replace in-person learning and/or amplify and transform learning. Results First-year trainees (n = 6), third-year trainees (n = 5) and supervisors (n = 6) initially used telehealth to replace in-person learning. However, skills that could be practiced in telehealth visits differed from in-person visits and instructional activities felt rushed or awkward. Trainees and supervisors adapted and used telehealth to amplify learning by enhancing observation and autonomy. They also transformed learning, using telehealth to develop novel skills. Conclusions To harness telehealth for instructional activities, our findings indicated that trainees and supervisors should shift from using it as a direct replacement for in-person education to taking advantage of novel opportunities to amplify and transform education in PGME. The authors provide data-driven recommendations to help PGME trainees, supervisors and educators capitalize on the educational advantages of telehealth.

Abstract Scalable cognitive paradigms that provide metrics such as the Computerized Cognitive Composite (C3) may be sensitive enough to relate to Alzheimer's disease biomarkers in the preclinical clinically unimpaired (CU) stage. We examined CU older adults (n = 3287) who completed alternate versions of the C3 approximately 51 days apart. A subset of CU with abnormal amyloid also completed tau positron emission tomography (PET) imaging. C3 initial performance and practice effects were examined in relation to amyloid status and continuous regional tau burden. Initial C3 performance was associated with amyloid status across all participants, and with tau burden in the medial temporal lobe and early cortical regions in CU with abnormal amyloid. Short‐term practice effects were associated with reduced tau in these regions in CU with abnormal amyloid, but were not associated with amyloid status. Thus, computerized cognitive testing repeated over a short follow‐up period provides additional insights into early Alzheimer's disease processes.

Summary: Background: The COVID-19 pandemic has disproportionately impacted the most vulnerable and widened the health disparity gap in both physical and mental well-being. Consequentially, it is vital to understand how to best support elderly individuals, particularly Black Americans and people of low socioeconomic status, in navigating stressful situations during the COVID-19 pandemic and beyond. The aim of this study was to investigate perceived levels of stress, posttraumatic growth, coping strategies, socioeconomic status, and mental health between Black and non-Hispanic, White older adults, the majority over the age of 70. Additionally, we investigated which variables, if any, were associated with posttraumatic growth in these populations. Methods: One hundred seventy-six community dwelling older adults (mean age = 76.30 ±8.94), part of two observational studies (The Harvard Aging Brain Study and Instrumental Activities of Daily Living Study) in Massachusetts, US, were included in this cross-sectional study. The survey, conducted from March 23, 2021 to May 13, 2021, measured perceived stress, behavioral coping strategies, posttraumatic growth, and mental health during the COVID-19 pandemic. We investigated associations with post-traumatic growth in a multiple linear regression model and examined their differences by race with t-tests, Wilcoxon rank-sum tests, and Fisher's exact tests. A second multiple linear regression model was used to examine which coping strategies were associated with posttraumatic growth. Findings: Our results indicated no significant difference between the groups in terms of mental health or stress. However, Black participants showed significantly greater posttraumatic growth compared to non-Hispanic, White participants. Additionally, the coping strategies of religion and positive reframing were found to be significantly associated with posttraumatic growth. Furthermore, even with the effects of stress and coping strategies controlled for, race remained significantly associated with posttraumatic growth. Interpretation: The COVID-19 pandemic has differentially impacted Black and non-Hispanic White older adults. These results may help encourage further analysis on geriatric psychiatry as well as understanding how cultural values and adaptations impact posttraumatic growth and mental health in diverse populations. Funding: The Harvard Aging Brain Study (HABS) has been funded by NIH-NIA P01 AG036694 (PI: Reisa Sperling). The IADL study is funded by the National Institute on Aging (R01 AG053184, PI: Gad A. Marshall).

Abstract Background Impairment in daily functioning is a clinical hallmark of dementia. Difficulties with “instrumental activities of daily living” (IADL) seem to increase gradually over the course of Alzheimer’s disease (AD), before dementia onset. However, it is currently not well established how difficulties develop along the preclinical and prodromal stages of AD. We aimed to investigate the trajectories of decline in IADL performance, as reported by a study partner, along the early stages of AD. Methods In a longitudinal multicenter study, combining data from community-based and memory clinic cohorts, we included 1555 individuals (mean age 72.5 ± 7.8 years; 50% female) based on availability of amyloid biomarkers, longitudinal IADL data, and clinical information at baseline. Median follow-up duration was 2.1 years. All amyloid-positive participants (n = 982) were classified into the National Institute on Aging–Alzheimer’s Association (NIA-AA) clinical stages ranging from preclinical AD (1) to overt dementia (4+). Cognitively normal amyloid-negative individuals (n = 573) served as a comparison group. The total scores of three study-partner reported IADL questionnaires were standardized. Results The rate of decline in cognitively normal (stage 1) individuals with and without abnormal amyloid did not differ (p = .453). However, from stage 2 onwards, decline was significantly faster in individuals on the AD continuum (B [95%CI] = − 0.32 [− 0.55, − 0.09], p = .007). The rate of decline increased with each successive stage: one standard deviation (SD) unit per year in stage 3 (− 1.06 [− 1.27, − 0.85], p

Abstract Background To determine whether performance on the Latin American Spanish version of the Face-Name Associative Memory Exam (LAS-FNAME) can differentiate between cognitively intact carriers of an autosomal dominant Alzheimer’s disease mutation (E280A) in Presenilin-1, who are genetically determined to develop early-onset dementia, from matched non-carriers. We also sought to examine whether LAS-FNAME performance is associated with amyloid-β and regional tau burden in mutation carriers. Methods A total of 35 cognitively intact mutation carriers (age range 26–41), 19 symptomatic carriers, and 48 matched non-carriers (age range 27–44) completed a neuropsychological assessment including the LAS-FNAME. A subset of participants (31 carriers [12 symptomatic] and 35 non-carriers) traveled from Colombia to Boston to undergo positron emission tomography (PET) using Pittsburgh compound B to measure mean cortical amyloid-β and flortaucipir for regional tau. ANOVA analyses and Spearman correlations were used to examine group differences and relationships among LAS-FNAME performance and amyloid-β and tau accumulation. Results Compared to non-carriers, cognitively intact mutation carriers had lower scores on the LAS-FNAME Total Scores (p = .040). Across all carriers (including symptomatic carriers), higher levels of amyloid-β (r = − .436, p = .018) and regional tau in the entorhinal (r = − .394, p = .031) and inferior temporal cortex (r = − .563, p = .001) were associated with lower LAS-FNAME Total Scores. Conclusions Performance on the LAS-FNAME differentiated between cognitively intact mutation carriers from non-carriers and was associated with greater amyloid and tau burden when examining all carriers. Findings suggest that the LAS-FNAME is sensitive to early clinical and pathological changes and can potentially help track disease progression in Spanish-speaking individuals.

Abstract Background Over the past decade, visual short-term memory (VSTM) binding tests have been shown to be one of the most sensitive behavioral indicators of Alzheimer’s disease (AD), especially when they require the binding of multiple features (e.g., color and shape). Recently, it has become possible to directly measure amyloid and tau levels in vivo via positron emission tomography (PET). To this point, these behavioral and neurochemical markers have not been compared in humans with AD or at risk for it. Methods In a cross-sectional study, we compared VSTM performance to tau and amyloid concentrations, measured by PET, in individuals certain to develop AD by virtue of their inheritance of the presenilin-1 E280A mutation. These included 21 clinically unimpaired subjects and 7 subjects with early mild cognitive impairment (MCI), as well as 30 family members who were not carriers of the mutation. Results We found that VSTM performance correlated strongly with tau in entorhinal cortex and inferior temporal lobe, and also with amyloid when examining asymptomatic carriers only. The condition requiring binding was not preferentially linked to tau—in fact, the non-binding “shape only” condition showed a stronger relationship. Conclusions The results confirm VSTM’s status as an early marker of AD pathology and raise interesting questions as to the course of binding-specific versus non-binding aspects of VSTM in early AD.

Abstract Background Computerized neuropsychological tests for early detection of Alzheimer’s disease (AD) have attracted increasing interest. Memory for faces and proper names is a complex task because its association is arbitrary. It implicates associative occipito-temporal cerebral regions, which are disrupted in AD. The short form of the Face-Name Associative Memory Exam (FNAME-12), developed to detect preclinical and prodromal AD, asks individuals to learn the names and occupations associated with 12 faces. The current work advances this field by using voice recognition and touchscreen response format. The purpose of this study is to create the first self-administered episodic memory test, FACEmemory®, by adapting the FNAME-12 for tablet use with voice recognition, touchscreen answers, and automatic scoring. The test was minimally supervised by a psychologist to avoid technological problems during execution and scored manually to assess the reliability of the automatic scoring. The aims of the present study were (1) to determine whether FACEmemory® is a sensitive tool for the detection of cognitive impairment, (2) to examine whether performances on FACEmemory® are correlated with those on the S-FNAME (paper-and-pencil version with 16 images), and (3) to determine whether performances on FACEmemory® are related to AD biomarkers in the cerebrospinal fluid (CSF) (Aβ42, p-tau, and Aβ42/p-tau ratio). Methods FACEmemory® was completed by 154 cognitively healthy (CH) individuals and 122 subjects with mild cognitive impairment, of whom 61 were non-amnestic (naMCI) and 61 amnestic (aMCI). A subsample of 65 individuals completed the S-FNAME, and 65 subjects received lumbar punctures. Results Performance on FACEmemory® was progressively worse from CH to the naMCI and aMCI groups. A cutoff of 31.5 in total FACEmemory® obtained 80.5% and 80.3% sensitivity and specificity values, respectively, for discriminating between CH and aMCI. Automatically corrected FACEmemory® scores were highly correlated with the manually corrected ones. FACEmemory® scores and AD CSF biomarker levels were significantly correlated as well, mainly in the aMCI group. Conclusions FACEmemory® may be a promising memory prescreening tool for detecting subtle memory deficits related to AD. Our findings suggest FACEmemory® performance provides a useful gradation of impairment from normal aging to aMCI, and it is related to CSF AD biomarkers.

Abstract Introduction The Integrated Alzheimer's Disease Rating Scale (iADRS) has been used to detect differences in disease progression in early Alzheimer's disease (AD). The objectives of this study were to enhance understanding of iADRS point changes within the context of clinical trials, and to establish a minimal clinically important difference (MCID) on the iADRS. Methods Data from AMARANTH and EXPEDITION3 were analyzed using various approaches, including anchor‐based, distribution‐based, regression analyses, and cumulative distribution function (CDF) plots. Three potential anchors were examined, including the Clinical Dementia Rating—Sum of Boxes, Mini‐Mental State Examination, and Functional Activities Questionnaire. Triangulation of all results was used to determine the MCID for participants with mild cognitive impairment (MCI) due to AD and AD with mild dementia. Results All three anchors met criteria for “sufficiently associated” (|r| = 0.4–0.7). Cumulatively, results from anchor‐based and distribution‐based results converged to suggest an iADRS MCID of 5 points for MCI due to AD and 9 points for AD with mild dementia. Regression analyses and CDF plots supported these values. Discussion These findings suggest the iADRS can be used in clinical trials to detect a clinically meaningful outcome of AD progression.

Introduction: We investigated whether monthly assessments of a computerized cognitive composite (C3) could aid in the detection of differences in practice effects (PE) in clinically unimpaired (CU) older adults, and whether diminished PE were associated with Alzheimer's disease (AD) biomarkers and annual cognitive decline.Materials and Methods:N = 114 CU participants (age 77.6 ± 5.0, 61% female, MMSE 29 ± 1.2) from the Harvard Aging Brain Study completed the self-administered C3 monthly, at-home, on an iPad for one year. At baseline, participants underwent in-clinic Preclinical Alzheimer's Cognitive Composite-5 (PACC5) testing, and a subsample (n = 72, age = 77.8 ± 4.9, 59% female, MMSE 29 ± 1.3) had 1-year follow-up in-clinic PACC5 testing available. Participants had undergone PIB-PET imaging (0.99 ± 1.6 years before at-home baseline) and Flortaucipir PET imaging (n = 105, 0.62 ± 1.1 years before at-home baseline). Linear mixed models were used to investigate change over months on the C3 adjusting for age, sex, and years of education, and to extract individual covariate-adjusted slopes over the first 3 months. We investigated the association of 3-month C3 slopes with global amyloid burden and tau deposition in eight predefined regions of interest, and conducted Receiver Operating Characteristic analyses to examine how accurately 3-month C3 slopes could identify individuals that showed >0.10 SD annual decline on the PACC-5.Results: Overall, individuals improved on all C3 measures over 12 months (β = 0.23, 95% CI [0.21–0.25], p < 0.001), but improvement over the first 3 months was greatest (β = 0.68, 95% CI [0.59–0.77], p < 0.001), suggesting stronger PE over initial repeated exposures. However, lower PE over 3 months were associated with more global amyloid burden (r = −0.20, 95% CI [−0.38 – −0.01], p = 0.049) and tau deposition in the entorhinal cortex (r = −0.38, 95% CI [−0.54 – −0.19], p < 0.001) and inferior-temporal lobe (r = −0.23, 95% CI [−0.41 – −0.02], p = 0.03). 3-month C3 slopes exhibited good discriminative ability to identify PACC-5 decliners (AUC 0.91, 95% CI [0.84–0.98]), which was better than baseline C3 (p < 0.001) and baseline PACC-5 scores (p = 0.02).Conclusion: While PE are commonly observed among CU adults, diminished PE over monthly cognitive testing are associated with greater AD biomarker burden and cognitive decline. Our findings imply that unsupervised computerized testing using monthly retest paradigms can provide rapid detection of diminished PE indicative of future cognitive decline in preclinical AD.

Whereas discrepancies between participant- and study partner-reported cognitive concerns on the Alzheimer’s disease (AD) continuum have been observed, more needs to be known regarding the longitudinal trajectories of participant- vs. study partner-reported concerns, particularly their relationship to AD biomarkers and mood symptomology. Additionally, it is unclear whether years of in-clinic data collection are needed to observe relationships with AD biomarkers, or whether more frequent, remote assessments over shorter periods of time would suffice. This study primarily sought to examine the relationships between longitudinal trajectories of participant- and study partner-rated cognitive decline and baseline biomarker levels [i.e., amyloid and tau positron emission tomography (PET)], in addition to how mood symptomatology may alter these trajectories of concerns over a 2-year period. Baseline mood was associated with longitudinal participant-rated concerns, such that participants with elevated depression and anxiety scores at baseline had decreasing concerns about cognitive decline over time (fixed estimate = −0.17, 95% CI [−0.29 to −0.05], t = −2.75, df = 457, adj. p = 0.012). A significant interaction between baseline amyloid (fixed estimate = 4.07, 95% CI [1.13–7.01], t = 2.72, df = 353, adj. p = 0.026) and tau (fixed estimate = 3.50, 95% CI [0.95–6.06], t = 2.70, df = 331, adj. p = 0.030) levels was associated with increasing study partner concerns, but not participant concerns, over time. The interaction between amyloid and study partner concerns remained significant when utilizing only the first year of concern-related data collection. Overall, these results suggest that frequent, remote assessment of study partner-reported concerns may offer additional insight into the AD clinical spectrum, as study partners appear to more accurately update their concerns over time with regard to pathology, with these concerns less influenced by participants’ mood symptomatology.

Abstract Introduction We aimed to examine the contribution of subjective cognitive decline (SCD) to reduce the number of β‐amyloid (Aβ) positron emission tomography scans required for recruiting Aβ+ clinically normal individuals in clinical trials. Methods Three independent cohorts (890 clinically normal: 72 yrs ± 6.7; Female: 43.4%; SCD+: 24%; apolipoprotein E [APOE] ε4+: 28.5%; Aβ+: 32%) were used. SCD was dichotomized from one question. Using logistic regression, we classified Aβ+ using the SCD dichotomy, APOEε4, sex, and age. Results SCD increased odds of Aβ+ by 1.58 relative to non‐SCD. Female APOEε4 carriers with SCD exhibited higher odds of Aβ+ (OR = 3.34), whereas male carriers with SCD showed a weaker, opposing effect (OR = 0.37). SCD endorsement reduces the number of Aβ positron emission tomography scans to recruit Aβ+ individuals by 13% and by 9% if APOEε4 status is known. Conclusion SCD helps to classify those with high Aβ, even beyond the substantial effect of APOE genotype. Collecting SCD is a feasible method for targeting recruitment for those likely on the AD trajectory.

Maintaining optimal cognitive functioning throughout the lifespan is a public health priority. Evaluation of cognitive outcomes following interventions to promote and preserve brain structure and function in older adults, and associated neural mechanisms, are therefore of critical importance. In this randomized controlled trial, we examined the behavioral and neural outcomes following mindfulness training (n = 72), compared to a cognitive fitness program (n = 74) in healthy, cognitively normal, older adults (65–80 years old). To assess cognitive functioning, we used the Preclinical Alzheimer Cognitive Composite (PACC), which combines measures of episodic memory, executive function, and global cognition. We hypothesized that mindfulness training would enhance cognition, increase intrinsic functional connectivity measured with magnetic resonance imaging (MRI) between the hippocampus and posteromedial cortex, as well as promote increased gray matter volume within those regions. Following the 8-week intervention, the mindfulness training group showed improved performance on the PACC, while the control group did not. Furthermore, following mindfulness training, greater improvement on the PACC was associated with a larger increase in intrinsic connectivity within the default mode network, particularly between the right hippocampus and posteromedial cortex and between the left hippocampus and lateral parietal cortex. The cognitive fitness training group did not show such effects. These findings demonstrate that mindfulness training improves cognitive performance in cognitively intact older individuals and strengthens connectivity within the default mode network, which is particularly vulnerable to aging affects.Clinical Trial Registration: [https://clinicaltrials.gov/ct2/show/NCT02628548], identifier [NCT02628548].

Abstract Background Diabetic retinopathy is the most common cause of blindness in working-age adults. Characteristics of patients with diabetes presenting to a retina subspecialty clinic have not been adequately studied, limiting our ability to risk stratify patients with diabetic retinopathy. Our goal is to describe an innovative program that collects structured, longitudinal data on patients with diabetes in a retina clinic, and identifies population characteristics to define patient risk stratification. Methods Demographics, body-mass index, blood pressure, hemoglobin A1c, smoking history, diabetes type, diabetes duration, kidney disease history, and diagnosis codes were collected on all patients with diabetes at the Kellogg Eye Center retina clinic. A mixed effects negative binomial regression was then performed to assess visit frequency as a function of these variables. Visit frequency was used as a marker for cost of care. A subgroup of patients was surveyed about knowledge of diabetes management goals and barriers to better self-management. Results There were 2916 patients in the cohort with 1014 in the subgroup. The cohort was predominantly Caucasian (74.5%), with a mean age of 64 years (range 13–99) and a relatively even distribution of sex (53.2% men). The mean maximum hemoglobin A1c was 8.0% (range 4.3–15.7%), and 57.1% had a diagnosis of diabetic retinopathy. Patients averaged 3.9 visits (range 1–27) during the 18-month study period. Blood pressure and duration of diabetes were positively associated with visit frequency (p

Abstract Background A decline in instrumental activities of daily living (IADL) correlates with the progression from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) dementia and has been associated with frontal and parietal hypometabolism, lower cerebrospinal fluid amyloid β 1–42, and inferior temporal cortical thinning. Identifying the underlying biomarkers of functional decline will allow for the early identification of individuals at risk of disease progression. Objective To investigate the association between IADL impairment and in vivo regional cerebral tau and cortical amyloid deposition across clinically normal (CN) elderly, MCI, and AD dementia. Methods Fifty-one CN elderly, 30 MCI, and 9 AD dementia participants of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) underwent assessment of regional tau deposition with flortaucipir (FTP) positron emission tomography (PET). An aggregate of cortical amyloid burden was assessed by florbetapir PET. IADL were assessed using the Functional Activities Questionnaire (FAQ). Tau regions with unadjusted correlations of p ≤ 0.006 (Bonferroni correction) with FAQ were used to evaluate the cross-sectional association between FAQ (dependent variable) and regional cerebral tau deposition, amyloid burden, and tau-amyloid interaction in separate general linear regression models with backward elimination. Covariates included age, American National Adult Reading Test (AMNART) intelligence quotient (IQ), and Rey Auditory Verbal Learning Test (RAVLT) total learning. Results Unadjusted correlations between FAQ and tau in the entorhinal cortex (EC) and inferior temporal cortex (IT) survived Bonferroni correction. FAQ was associated with the tau-amyloid interaction, such that in participants with greater amyloid burden, greater IADL impairment was associated with greater regional tau (EC tau × amyloid: partial r (pr) = 0.47, p

Abstract Background Impairment in instrumental activities of daily living (IADL) may occur in the earliest stages of mild cognitive impairment (MCI). However, there are few reliable measures of IADL in MCI or that have a sufficient range of scores in clinically normal (CN) elderly. The objective of this pilot study was to examine the convergent validity of a phone performance-based IADL instrument, the Harvard Automated Phone Task (APT), designed to measure the earliest IADL changes in Alzheimer’s disease (AD), with other sensitive performance-based and subjective measures of everyday functional capacity among CN and MCI participants. Methods Twenty-nine CN and 17 MCI participants were administered the Harvard APT, the computer performance-based Czaja Functional Assessment Battery (CFAB), and the AD Cooperative Study ADL prevention instrument (ADCS ADL-PI) participant and study partner versions; in addition, 52 different CN and 7 MCI participants were administered the Harvard APT and the Subjective Study Partner and Participant-reported (SSPP) IADL scale. The Harvard APT was compared with the three other IADL assessments. Results In both CN and MCI, better performance on the Harvard APT was associated with better performance on the CFAB. In CN, better performance on the Harvard APT was associated with better ADCS ADL-PI participant-reported IADL, while in MCI better performance on the Harvard APT was associated with better ADCS ADL-PI study partner-reported IADL. Furthermore, in CN better performance on the Harvard APT was associated with better SSPP-IADL participant and study partner-reported IADL. Conclusions In this small pilot study, the Harvard APT, a brief, self-administered, objective measure of IADL performance, appears to correlate well with other sensitive measures of everyday functioning, providing good preliminary convergent validity for this new measure. Moreover, it appears to perform well across both CN and MCI participants, which suggests that it is a promising measure of early, clinically meaningful functional change. This may not be the case as suggested in our small sample for subjective IADL scales that may perform differentially depending on the reporter (self vs. study partner) across the clinical spectrum possibly due to diminishing awareness of IADL difficulties in individuals who become cognitively impaired. Secondary prevention trials in AD have a great need for such ecologically valid and reliable measures of early IADL changes.

Background: In the COVID-19 pandemic, older adults from vulnerable ethnoracial groups are at high risk of infection, hospitalization, and death. We aimed to explore the pandemic's impact on the well-being and cognition of older adults living in the United States (US), Argentina, Chile, Mexico, and Peru. Methods: 1,608 (646 White, 852 Latino, 77 Black, 33 Asian; 72% female) individuals from the US and four Latin American countries aged ≥ 55 years completed an online survey regarding well-being and cognition during the pandemic between May and September 2020. Outcome variables (pandemic impact, discrimination, loneliness, purpose of life, subjective cognitive concerns) were compared across four US ethnoracial groups and older adults living in Argentina, Chile, Mexico, and Peru. Findings: Mean age for all participants was 66.7 (SD = 7.7) years and mean education was 15.4 (SD = 2.7) years. Compared to Whites, Latinos living in the US reported greater economic impact (p

Introduction Planning for and responding to happenstance is an important but rarely discussed part of the professional development of medical students. We noted this gap while conducting a study of career inflection points of 24 physicians who frequently mentioned how luck had shaped their unfolding careers. A review of the career counseling literature led us to a body of work known as Planned Happenstance Learning Theory (PHLT). PHLT focuses on the attitudes and skills to make happenstance a positive force in one's life. We found no reference to this work in the medical education literature and resolved to address this gap. Methods We created resources for an interactive, 90-minute faculty development workshop. In the workshop, the facilitator used a PowerPoint presentation, vignettes of happenstance, a student testimonial, and a reflection worksheet. We presented and formally evaluated the workshop at three national meetings for health science educators. Results Workshop participants, mostly faculty (N = 45), consistently expressed positive regard for the workshop content, organization, and instructional methods, especially the opportunity for guided reflection. A retrospective pre/postevaluation revealed a meaningful increase in knowledge about PHLT attitudes and skills, as well as a commitment to use these skills in promoting professional development. Discussion The skills and attitudes of PHLT are relevant to students' career development. A workshop designed to introduce PHLT skills and attitudes to faculty advisors and mentors can help prepare faculty to promote students' awareness and use of these attitudes and skills.

Abstract Demonstrating that treatments are clinically meaningful across the Alzheimer's disease (AD) continuum is critical for meeting our goals of accelerating a cure by 2025. While this topic has been a focus of several Alzheimer's Association Research Roundtable (AARR) meetings, there remains no consensus as to what constitutes a “clinically meaningful outcome” in the eyes of patients, clinicians, care partners, policymakers, payers, and regulatory bodies. Furthermore, the field has not come to agreement as to what constitutes a clinically meaningful treatment effect at each stage of disease severity. The AARR meeting on November 19–20, 2019, reviewed current approaches to defining clinical meaningfulness from various perspectives including those of patients and care partners, clinicians, regulators, health economists, and public policymakers. Participants discussed approaches that may confer clinical relevance at each stage of the disease continuum and fostered discussion about what should guide us in the future.

Abstract Introduction Unsupervised digital cognitive testing is an appealing means to capture subtle cognitive decline in preclinical Alzheimer's disease (AD). Here, we describe development, feasibility, and validity of the Boston Remote Assessment for Neurocognitive Health (BRANCH) against in‐person cognitive testing and amyloid/tau burden. Methods BRANCH is web‐based, self‐guided, and assesses memory processes vulnerable in AD. Clinically normal participants (n = 234; aged 50–89) completed BRANCH; a subset underwent in‐person cognitive testing and positron emission tomography imaging. Mean accuracy across BRANCH tests (Categories, Face‐Name‐Occupation, Groceries, Signs) was calculated. Results BRANCH was feasible to complete on participants’ own devices (primarily smartphones). Technical difficulties and invalid/unusable data were infrequent. BRANCH psychometric properties were sound, including good retest reliability. BRANCH was correlated with in‐person cognitive testing (r = 0.617, P

Abstract Introduction To assess the relationship between memory performance defined by the Stages of Objective Memory Impairment (SOMI) system and the Alzheimer's disease (AD) ATN (amyloid beta [A], pathologic tau [T], and neurodegeneration [N]) biomarker system. Methods We used data from the Harvard Aging Brain Study cohort to estimate the level of ATN biomarkers: amyloid beta (C‐Pittsburgh compound B‐positron emission tomography [PET]), tau (F‐18–flortaucipir [FTP] PET), and neurodegeneration (magnetic resonance imaging volumetrics). We assessed the cross‐sectional relationship of SOMI classification with global amyloid levels, entorhinal and inferior temporal tau deposition, and hippocampal atrophy. Results Participants with both memory storage and retrieval deficits (SOMI‐3, ‐4) had smaller hippocampal volumes and higher entorhinal and inferior temporal tau burden than participants with no memory impairment (SOMI‐0) or mild retrieval difficulty (SOMI‐1). Amyloid burden did not differ among SOMI stages. Discussion This pilot supports the close relationship between tau pathology and memory impairment across the AD continuum. SOMI may be useful to determine eligibility for randomized controlled trials prior to the assessment of biomarker status.

Context: Increasing federal requirements with no change in the Centers for Disease Control and Prevention budget creates an unsustainable delivery model between states and their local counterparts for programs like Vaccines for Children (VFC).Project: The Washington State Department of Health collaborated with the Washington Association of Local Public Health Officials to identify how best to improve the quality of the VFC program.Approach: Utilizing Quality improvement and Lean Six Sigma methods, the project team was able to adopt a new shared-service delivery model to improve the quality of the VFC program in Washington State.Discussion: Through utilization of quality improvement methods and Lean methodology Washington State Department of Health identified recommendations to adopt a shared-service delivery and implemented those changes.

Objective: To identify a parsimonious set of markers that optimally predicts subsequent clinical progression from normal to mild cognitive impairment (MCI). Methods: 250 clinically normal adults (mean age = 73.6 years, SD = 6.0) from the Harvard Aging Brain Study were assessed at baseline on a wide set of markers, including magnetic resonance imaging markers of gray matter thickness and volume, white matter lesions, fractional anisotropy, resting state functional connectivity, positron emission tomography markers of glucose metabolism and β-amyloid (Aβ) burden, and a measure of vascular risk. Participants were also tested annually on a battery of clinical and cognitive tests (median follow-up = 5.0 years, SD = 1.66). We applied least absolute shrinkage and selection operator (LASSO) Cox models to determine the minimum set of non-redundant markers that predicts subsequent clinical progression from normal to MCI, adjusting for age, sex, and education. Results: 23 participants (9.2%) progressed to MCI over the study period (mean years of follow-up to diagnosis = 3.96, SD = 1.89). Progression was predicted by several brain markers, including reduced entorhinal thickness (hazard ratio, HR = 1.73), greater Aβ burden (HR = 1.58), lower default network connectivity (HR = 1.42), and smaller hippocampal volume (HR = 1.30). When cognitive test scores were added to the model, the aforementioned neuroimaging markers remained significant and lower striatum volume as well as lower scores on baseline memory and processing speed tests additionally contributed to progression. Conclusion: Among a large set of brain, vascular and cognitive markers, a subset of markers independently predicted progression from normal to MCI. These markers may enhance risk stratification by identifying clinically normal individuals who are most likely to develop clinical symptoms and would likely benefit most from therapeutic intervention.

Abstract Introduction We examined the associations among instrumental activities of daily living (IADL), cortical amyloid, and cognition in cognitively normal (CN) older adults. Methods CN participants screening for the A4 Study (n = 4486) underwent florbetapir (amyloid) positron emission tomography. IADL were assessed using the Alzheimer's Disease Cooperative Study Activities of Daily Living Prevention Instrument. Separate logistic regression models were run with cortical amyloid or cognition as independent variable and IADL as dependent variable, adjusting for age and sex. Results IADL difficulties were endorsed infrequently (≤16%). Overall IADL and four select IADL item difficulties (“remembering appointments,” “finding belongings,” “following TV programs,” and “remembering current events”) reported by both participant and study partner were significantly associated with greater amyloid burden and worse cognition. Discussion Although IADL deficits were infrequent in this CN cohort, greater participant and study partner report of overall IADL deficits and subtle difficulties in specific IADL items were associated with mildly higher amyloid burden and worse cognition.