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Introduction Early detection of cognitive decline in older adults is a public health priority. Advancing Reliable Measurement in Alzheimer's Disease and Cognitive Aging (ARMADA), a multisite study, is validating cognition, emotion, motor, and sensory modules of the National Institutes of Health Toolbox for Assessment of Neurological and Behavioral Function (NIHTB) in the aging spectrum from cognitively normal to dementia of the Alzheimer's type (DAT). Methods Participants 65 to 85 years old, in demographic groups racially proportional to the general US population, are recruited in one of three groups to validate the NIHTB: cognitively normal, amnestic mild cognitive impairment (aMCI), or mild DAT. Additional special emphasis cohorts include (1) Blacks in the three clinical groups; (2) Spanish-speakers in the three clinical groups; (3) cognitively normal, population-proportional, over age 85. Discussion Longitudinal study will determine whether NIHTB can predict cognitive decline and is associated with Alzheimer's disease biomarkers. Here, we detail the methods for the ARMADA study.

Neocortical Aβ-amyloid deposition, one of the hallmark pathologic features of Alzheimer's disease (AD), begins decades prior to the presence of clinical symptoms. As clinical trials move to secondary and even primary prevention, understanding the rates of neocortical Aβ-amyloid deposition and the age at which Aβ-amyloid deposition becomes abnormal is crucial for optimizing the timing of these trials. As APOE-ε4 carriage is thought to modulate the age of clinical onset, it is also important to understand the impact of APOE-ε4 carriage on the age at which the neocortical Aβ-amyloid deposition becomes abnormal. Here, we show that, for 455 participants with over 3 years of follow-up, abnormal levels of neocortical Aβ-amyloid were reached on average at age 72 (66.5-77.1). The APOE-ε4 carriers reached abnormal levels earlier at age 63 (59.6-70.3); however, noncarriers reached the threshold later at age 78 (76.1-84.4). No differences in the rates of deposition were observed between APOE-ε4 carriers and noncarriers after abnormal Aβ-amyloid levels had been reached. These results suggest that primary and secondary prevention trials, looking to recruit at the earliest stages of disease, should target APOE-ε4 carriers between the ages of 60 and 66 and noncarriers between the ages of 76 and 84.

In the present study, we tested the hypothesis that higher amyloid-beta (Aβ) burden at baseline is associated with greater longitudinal decline in body mass index (BMI) in clinically normal adults. Participants from the Harvard Aging Brain Study (n = 312) and the Alzheimer's Disease Neuroimaging Initiative (n = 336) underwent Aβ positron emission tomography at baseline. BMI was assessed longitudinally over a median of >4 years. Linear mixed models showed that higher baseline Aβ burden was significantly associated with greater decline in BMI in both the Harvard Aging Brain Study (t = −1.93; p = 0.05) and Alzheimer's Disease Neuroimaging Initiative cohorts (t = −2.54; p = 0.01), after adjusting for covariates, including cognitive performance and depressive symptoms. In addition, the association of Aβ burden with longitudinal decline in BMI persisted in both cohorts after excluding participants with diabetes/endocrine disturbances and participants classified as underweight or obese (BMI 30). These findings suggest that decline in BMI in clinically normal adults may be an early manifestation related to cerebral amyloidosis that precedes objective cognitive impairment. Therefore, unintentional BMI decline in otherwise healthy individuals might alert clinicians to increased risk of Alzheimer's disease.

The COVID-19 pandemic presents major challenges for mental health care providers. In particular, providers who treat posttraumatic stress disorder (PTSD) are now tasked with determining whether to initiate trauma-focused therapy during the pandemic and, if so, whether and how to adapt treatment. The purpose of this communication is to identify and organize key considerations for whether and how to deliver commonly used evidence-supported therapy protocols for trauma treatment-specifically, cognitive processing therapy (CPT) and prolonged exposure (PE) therapy-during the ongoing COVID-19 pandemic for adults who currently meet the criteria for PTSD. Based on relevant public health and clinical literature, we present a structured guide that can be used by treatment teams and individual providers to evaluate whether initiating CPT or PE is indicated given a particular patient-provider pair and system context amidst pandemic conditions. In addition, we suggest appropriate action steps, including problem-solving strategies, evidence-informed modifications to CPT and PE, and alternative intervention approaches.

ObjectiveTo determine whether performance on the Free and Cued Selective Reminding Test (FCSRT) is associated with PET in vivo markers of brain pathology and whether it can distinguish those who will develop dementia later in life due to autosomal-dominant Alzheimer disease (AD) from age-matched controls.MethodsTwenty-four cognitively unimpaired Presenilin-1 E280A carriers (mean age 36 years) and 28 noncarriers (mean age 37 years) underwent Pittsburg compound B-PET (amyloid), flortaucipir-PET (tau), and cognitive testing, including the FCSRT (immediate and delayed free and cued recall scores). Linear regressions were used to examine the relationships among FCSRT scores, age, mean cortical amyloid, and regional tau burden.ResultsFree and total recall scores did not differ between cognitively unimpaired mutation carriers and noncarriers. Greater age predicted lower free recall and delayed free and total recall scores in carriers. In cognitively impaired carriers, delayed free recall predicted greater amyloid burden and entorhinal tau, while worse immediate free recall scores predicted greater tau in the inferior temporal and entorhinal cortices. In turn, in all carriers, lower free and total recall scores predicted greater amyloid and regional tau pathology.ConclusionsFCSRT scores were associated with in vivo markers of AD–related pathology in cognitively unimpaired individuals genetically determined to develop dementia. Difficulties on free recall, particularly delayed recall, were evident earlier in the disease trajectory, while difficulties on cued recall were seen only as carriers neared the onset of dementia, consistent with the pathologic progression of the disease. Findings suggest that the FCSRT can be a useful measure to track disease progression in AD.

ObjectiveTo identify the hippocampal subregions linking initial amyloid and tau pathology to memory performance in clinically normal older individuals, reflecting preclinical Alzheimer disease (AD).MethodsA total of 127 individuals from the Harvard Aging Brain Study (mean age 76.22 ± 6.42 years, 68 women [53.5%]) with a Clinical Dementia Rating score of 0, a flortaucipir tau-PET scan, a Pittsburgh compound B amyloid-PET scan, a structural MRI scan, and cognitive testing were included. From these images, we calculated neocortical, hippocampal, and entorhinal amyloid pathology; entorhinal and hippocampal tau pathology; and the volumes of 6 hippocampal subregions and total hippocampal volume. Memory was assessed with the selective reminding test. Mediation and moderation analyses modeled associations between regional markers and memory. Analyses included covariates for age, sex, and education.ResultsNeocortical amyloid, entorhinal tau, and presubiculum volume univariately associated with memory performance. The relationship between neocortical amyloid and memory was mediated by entorhinal tau and presubiculum volume, which was modified by hippocampal amyloid burden. With other biomarkers held constant, presubiculum volume was the only marker predicting memory performance in the total sample and in individuals with elevated hippocampal amyloid burden.ConclusionsThe presubiculum captures unique AD-related biological variation that is not reflected in total hippocampal volume. Presubiculum volume may be a promising marker of imminent memory problems and can contribute to understanding the interaction between incipient AD-related pathologies and memory performance. The modulation by hippocampal amyloid suggests that amyloid is a necessary, but not sufficient, process to drive neurodegeneration in memory-related regions.

Background. For uncommon events in medicine, such as pediatric CPR, more frequent training is associated with improved performance among healthcare providers and physicians in training. Gamified learning may facilitate motivation to practice CPR, though studies to support this are lacking. Intervention. Residents were interviewed to understand motivating factors for CPR practice outside of a traditional classroom certification setting. Methods. We used a qualitative study design within a larger multinational study. Semi-structured, one-on-one interviews were completed with pediatric residents using a constructivist approach. Transcripts were reviewed independently by two authors (IHG, JLS). Results. The inductive framework gradually moved away from gamification and towards that of self-determination. Participating residents reported several types of intrinsic and extrinsic motivational drivers towards practicing CPR, such as practicing CPR to prepare, or as a connection to clinical practice. Some themes were amotivational, such as performance anxiety, and detracted from their drive to practice. Despite a gamification design to this curriculum, these components were rarely mentioned. These themes related to achieving Maslow’s three psychological needs of autonomy, relatedness and competence. Conclusion. The motivation to practice CPR among residents aligns with the self-determination theory. By stimulating intrinsic motivating factors, future curriculum design may better motivate residents to practice CPR.

Highlights • We examined the markers that optimally predict progression from normal to MCI. • A LASSO Cox model was used to determine the minimum set of markers. • Entorhinal thickness, Aβ burden, default network connectivity, and hippocampal volume predicted progression. • These markers may enhance risk stratification in clinically normal adults., 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.

Background: Computerized cognitive assessments may improve Alzheimer’s disease (AD) secondary prevention trial efficiency and accuracy. However, they require validation against standard outcomes and relevant biomarkers. Objective: To assess the feasibility and validity of the tablet-based Computerized Cognitive Composite (C3). Design: Cross-sectional analysis of cognitive screening data from the A4 study (Anti-Amyloid in Asymptomatic AD). Setting: Multi-center international study. Participants: Clinically normal (CN) older adults (65-85; n=4486). Measurements: Participants underwent florbetapir-Positron Emission Tomography for Aβ+/- classification. They completed the C3 and standard paper and pencil measures included in the Preclinical Alzheimer’s Cognitive Composite (PACC). The C3 combines memory measures sensitive to change over time (Cogstate Brief Battery-One Card Learning) and measures shown to be declining early in AD including pattern separation (Behavioral Pattern Separation Test- Object- Lure Discrimination Index) and associative memory (Face Name Associative Memory Exam- Face-Name Matching). C3 acceptability and completion rates were assessed using qualitative and quantitative methods. C3 performance was explored in relation to Aβ+/- groups (n=1323/3163) and PACC. Results: C3 was feasible for CN older adults to complete. Rates of incomplete or invalid administrations were extremely low, even in the bottom quartile of cognitive performers (PACC). C3 was moderately correlated with PACC (r=0.39). Aβ+ performed worse on C3 compared with Aβ- [unadjusted Cohen’s d=-0.22 (95%CI: -0.31,-0.13) p

Several autopsy studies recognize the locus coeruleus (LC) as the initial site of hyperphosphorylated TAU aggregation, and as the number of LC neurons harboring TAU increases, TAU pathology emerges throughout the cortex. By conjointly using dedicated MRI measures of LC integrity and TAU and amyloid PET-imaging, we aimed to address the question whether in vivo LC measures relate to initial cortical patterns of Alzheimer’s disease (AD) fibrillar proteinopathies or cognitive dysfunction in 174 cognitively unimpaired and impaired older individuals with longitudinal cognitive measures. To guide our interpretations, we verified these associations in autopsy data from 1524 Religious Orders Study and Rush Memory and Aging Project and 2145 National Alzheimer’s Coordinating Center cases providing three different LC measures (pigmentation, tangle density and neuronal density), Braak staging, beta-amyloid and longitudinal cognitive measures. Lower LC integrity was associated with elevated TAU deposition in the entorhinal cortex among unimpaired individuals, consistent with postmortem correlations between LC tangle density and successive Braak staging. LC pigmentation ratings correlated with LC neuronal density but not with LC tangle density, and were particularly worse at advanced Braak stages. In the context of elevated beta-amyloid, lower LC integrity and greater cortical tangle density were associated with greater TAU burden beyond the medial temporal lobe and retrospective memory decline. These findings support neuropathologic data in which early LC TAU accumulation relates to disease progression, and identify LC integrity as a promising indicator of initial AD-related processes and subtle changes in cognitive trajectories of preclinical AD.

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].

Background: Greater subjective cognitive changes on the Cognitive Function Index (CFI) was previously found to be associated with elevated amyloid (Aß) status in participants screening for the A4 Study, reported by study partners and the participants themselves. While the total score on the CFI related to amyloid for both sources respectively, potential differences in the specific types of cognitive changes reported by either participants or their study partners was not investigated. Objectives: To determine the specific types of subjective cognitive changes endorsed by participants and their study partners that are associated with amyloid status in individuals screening for an AD prevention trial. Design, Setting, Participants: Four thousand four hundred and eighty-six cognitively unimpaired (CDR=0; MMSE 25-30) participants (ages 65-85) screening for the A4 Study completed florbetapir (Aß) Positron Emission Tomography (PET) imaging. Participants were classified as elevated amyloid (Aß+; n=1323) or non-elevated amyloid (Aß-; n=3163). Measurements: Prior to amyloid PET imaging, subjective report of changes in cognitive functioning were measured using the CFI (15 item questionnaire; Yes/Maybe/No response options) and administered separately to both participants and their study partners (i.e., a family member or friend in regular contact with the participant). The impact of demographic factors on CFI report was investigated. For each item of the CFI, the relationship between Aß and CFI response was investigated using an ordinal mixed effects model for participant and study partner report. Results: Independent of Aß status, participants were more likely to report ‘Yes’ or ‘Maybe’ compared to the study partners for nearly all CFI items. Older age (r= 0.06, p

Introduction Immune dysregulation is implicated in neurodegeneration and altered cytokine levels are seen in people with dementia. However, whether cytokine levels are predictive of cognitive decline in cognitively unimpaired (CU) elderly, especially in the setting of elevated amyloid beta (Aβ), remains unclear. Methods We measured nine cytokines in the baseline plasma of 298 longitudinally followed CU elderly and assessed whether these measures were associated with cognitive decline, alone or synergistically with Aβ. We next examined associations between cytokine levels and neuroimaging biomarkers of Aβ/tau/neurodegeneration. Results Higher IL-12p70 was associated with slower cognitive decline in the setting of higher Aβ (false discovery rate [FDR] = 0.0023), whereas higher IFN-γ was associated with slower cognitive decline independent of Aβ (FDR = 0.013). Higher IL-12p70 was associated with less tau and neurodegeneration in participants with higher Aβ. Discussion Immune dysregulation is implicated in early-stage cognitive decline, and greater IL-12/IFN-γ axis activation may be protective against cognitive decline and early-stage AD progression.

ObjectiveTo compare how structural MRI, fluorodeoxyglucose (FDG), and flortaucipir (FTP) PET signals predict cognitive decline in high-amyloid vs low-amyloid participants with the goal of determining which biomarker combination would result in the highest increase of statistical power for prevention trials.MethodsIn this prospective cohort study, we analyzed data from clinically normal adults from the Harvard Aging Brain Study with MRI, FDG, FTP, and Pittsburgh compound B (PiB)-PET acquired within a year and prospective cognitive evaluations over a mean 3-year follow-up. We focused analyses on predefined regions of interest: inferior temporal, isthmus cingulate, hippocampus, and entorhinal cortex. Cognition was assessed with the Preclinical Alzheimer's Cognitive Composite. We evaluated the association between biomarkers and cognitive decline using linear mixed-effect models with random intercepts and slopes, adjusting for demographics. We generated power curves simulating prevention trials.ResultsData from 131 participants (52 women, age 73.98 ± 8.29 years) were analyzed in the study. In separate models, most biomarkers had a closer association with cognitive decline in the high-PiB compared to the low-PiB participants. A backward stepwise regression including all biomarkers demonstrated that only neocortical PiB, entorhinal FTP, and entorhinal FDG were independent predictors of subsequent cognitive decline. Power analyses revealed that using both high PiB and low entorhinal FDG as inclusion criteria reduced 3-fold the number of participants needed in a hypothetical trial compared to using only high PiB.DiscussionIn preclinical Alzheimer disease, entorhinal hypometabolism is a strong and independent predictor of subsequent cognitive decline, making FDG a potentially useful biomarker to increase power in clinical trials.Classification of EvidenceThis study provides Class II evidence that in people with preclinical Alzheimer disease, entorhinal hypometabolism identified by FDG-PET is predictive of subsequent cognitive decline.

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.

Objective: Public health recommendations promote social engagement to reduce risk of cognitive decline and dementia. The objective of this study was to evaluate the longitudinal associations of social engagement and cognition in cognitively normal older adults with varying levels of neocortical amyloid-beta, the Alzheimer's disease (AD) pathologic marker. Methods: Two hundred seventeen men and women, age 63-89 underwent assessments for social engagement and cognitive performance at baseline and 3 years later using the Community Healthy Activities Model Program for Seniors questionnaire and the Preclinical Alzheimer Cognitive Composite (PACC). Amyloid-beta was measured using Pittsburgh compound B-PET. Multivariable regression models estimated main and interactive effects of baseline social engagement and amyloid-beta on cognitive change. Reciprocal models estimated main and interactive effects of baseline cognitive performance and amyloid-beta on change in social engagement. Results: Baseline social engagement was associated with PACC change as a modifier but not as a main effect. Lower baseline social engagement was associated with greater amyloid-beta-related PACC decline, while higher baseline social engagement was associated with relative preservation of PACC scores (beta = 0.05, p = 0.03). Reciprocally, lower baseline PACC score was associated with decline in social engagement score (beta = 1.1, p = 0.02). This association was not modified by amyloid-beta, and there was no direct association of amyloid-beta with change in social engagement. Conclusions: Low social engagement may be a marker of neurocognitive vulnerability in older adults who are cognitively normal but have evidence of AD pathophysiologic change. Understanding changes in social engagement in older adults may lead to earlier diagnosis of AD and advances in evidence-based prevention and treatment.

From October 2015 to August 2018, tapeworm proglottids were obtained from 10 patients who were residents of Daegu and Gyeongbuk provinces and had a history of raw beef consumption. Most of them had no overseas travel experience. The gravid proglottids obtained from the 10 cases had 15-20 lateral uterine branches. A part of internal transcribed spacer 1 (ITS1) DNA of the 10 cases, amplified by polymerase chain reaction (PCR) and digested with AleI restriction enzyme, produced the same band pattern of Taenia saginata, which differentiated from T. asiatica and T. solium. Sequences of ITS1 and cytochrome c oxidase subunit 1 (cox1) showed higher homology to T. saginata than to T. asiatica and T. solium. Collectively, these 10 cases were identified as T. saginata human infections. As taeniasis is one of the important parasitic diseases in humans, it is necessary to maintain hygienic conditions during livestock farming to avoid public health concerns.

Purpose Intravitreal anti–vascular endothelial growth factor (VEGF) injections are used commonly in the treatment of diabetic retinopathy (DR), but the need for treatment and frequency of administration vary considerably among patients. There is no way to predict which patients will require treatment and how frequently injections will be needed. This study aimed to identify factors associated with receiving anti-VEGF injections and the number of treatments received in an 18-month period in patients with diabetes. Design Retrospective cohort study. Participants Two thousand nine hundred sixteen patients with diabetes treated at the Kellogg Eye Center Retina Clinic from June 1, 2016, through December 31, 2017. Methods Retrospective analysis was performed with institutional review board approval using data collected from diabetic patients treated at the retina clinic at the Kellogg Eye Center. Logistic regression was used to identify demographic and medical factors associated with receiving at least 1 injection. Negative binomial regression was used to model the number of anti-VEGF injections. Main Outcome Measures Receiving at least 1 anti-VEGF injection and the number of anti-VEGF injections received during the study period. Results Systolic blood pressure and a diagnosis of DR were associated significantly with receiving an injection. A history of kidney disease was associated positively with the number of injections received. Type 1 diabetes was associated negatively with receiving an injection and the number of injections. Current hemoglobin A1c level was not associated with either receiving an injection or the number of injections. Conclusions Elevated blood pressure is associated significantly with the need for treatment with anti-VEGF injections in patients with diabetes, and a diagnosis of type 1 diabetes is associated negatively with both receiving treatment and the number of injections. Of note, current glycemic control is not associated significantly with either outcome measure. To our knowledge, these associations have not been previously reported, and imply that factors that confer risk for DR development may not be the same that confer risk for treatment.

Background Hemodilution was introduced initially as a blood conservation technique to reduce allogeneic blood transfusion in patients undergoing surgical procedures. Although the technique has been approved by the National Institute of Health consensus panel, limits of hemodilution under anesthetic conditions have not been established as they have in animal models. Methods A novel multi-compartmental modeling approach has been proposed that includes the effect of anesthesia to quantify the effect of hemodilution on myocardial oxygen balance during myocardial ischemia. Results The results showed that isovolemic hemodilution would cause detrimental effects around a hematocrit of 15%. Even though the fall in oxygen content caused by the decrease in hemoglobin concentration was compensated by an increase in coronary blood flow induced by hypoxic vasodilation and decreased viscosity, the endocardial tissue received less oxygen compared to the epicardial regions, and this sub-endocardial ischemia eventually led to cardiac failure. Statistical analysis also showed that the type of acellular replacement fluid failed to affect the heart rate, the stroke index or the cardiac index during hemodilution, and supplemental oxygen improved the endocardial oxygen supply. Conclusion The model validates the clinical conclusions that sub-endocardial ischemia causes cardiac failure under extreme hemodilution conditions and the model can also be easily integrated into other human simulators.

Background Instrumental activities of daily living (IADL) impairment and apathy occur in early-stage Alzheimer's disease (AD) and are associated with regional atrophy and hypometabolism in vivo and greater tau burden at autopsy. Objective To explore the association between IADL impairment, apathy, and in vivo regional tau in mild cognitive impairment (MCI) and AD dementia. Methods Forty participants (24 MCI, 16 AD dementia) underwent assessments of IADL (Functional Activities Questionnaire, FAQ) and apathy (Apathy Evaluation Scale Informant report, AES-I). Regional tau was assessed using flortaucipir positron emission tomography (PET) and amyloid using Pittsburgh Compound B PET. Regions with unadjusted associations of p≤0.01 were entered into regression models assessing the relationship between tau and FAQ or AES-I, adjusting for age, sex, and cognition, with/without a tau by amyloid interaction. Results Unadjusted IADL impairment but not apathy was associated with greater tau in multiple regions. After adjusting for covariates, for medial orbitofrontal and entorhinal cortex the interaction between tau and amyloid was associated with IADL impairment and for anterior cingulate it was not but independent associations with both tau and amyloid were retained. With whole brain analyses, similar results were seen for IADL, while for apathy tau in small clusters within the right anterior cingulate and dorsolateral prefrontal cortices were seen, which were more pronounced in individuals with greater amyloid. Conclusions This exploratory study suggests that IADL impairment in AD is associated with medial temporal and frontal tau, especially in individuals with elevated amyloid, while apathy may be associated with right frontal tau.

OBJECTIVE: Neuropathological studies have demonstrated that cerebrovascular disease and Alzheimer disease (AD) pathology frequently co-occur in older adults. The extent to which cerebrovascular disease influences the progression of AD pathology remains unclear. Leveraging newly available positron emission tomography (PET) imaging, we examined whether a well-validated measure of systemic vascular risk and β-amyloid (Aβ) burden have an interactive association with regional tau burden. METHODS: Vascular risk was quantified at baseline in 152 clinically normal older adults (mean age = 73.5 ± 6.1 years) with the office-based Framingham Heart Study cardiovascular disease risk algorithm (FHS-CVD). We acquired Aβ (11 C-Pittsburgh compound B) and tau (18 F-flortaucipir) PET imaging on the same participants. Aβ PET was performed at baseline; tau PET was acquired on average 2.98 ± 1.1 years later. Tau was measured in the entorhinal cortex (EC), an early site of tau deposition, and in the inferior temporal cortex (ITC), an early site of neocortical tau accumulation associated with AD. Linear regression models examined FHS-CVD and Aβ as interactive predictors of tau deposition, adjusting for age, sex, APOE e4 status, and the time interval between baseline and the tau PET scan. RESULTS: We observed a significant interaction between FHS-CVD and Aβ burden on subsequently measured ITC tau (p < 0.001), whereby combined higher FHS-CVD and elevated Aβ burden was associated with increased tau. The interaction was not significant for EC tau (p = 0.16). INTERPRETATION: Elevated vascular risk may influence tau burden when coupled with high Aβ burden. These results suggest a potential link between vascular risk and tau pathology in preclinical AD. Ann Neurol 2019; 1-8 ANN NEUROL 2019;85:272-279.

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

Objective:Alzheimer’s disease (AD) studies are increasingly targeting earlier (pre)clinical populations, in which the expected degree of observable cognitive decline over a certain time interval is reduced as compared to the dementia stage. Consequently, endpoints to capture early cognitive changes require refinement. We aimed to determine the sensitivity to decline of widely applied neuropsychological tests at different clinical stages of AD as outlined in the National Institute on Aging – Alzheimer’s Association (NIA-AA) research framework.Method:Amyloid-positive individuals (as determined by positron emission tomography or cerebrospinal fluid) with longitudinal neuropsychological assessments available were included from four well-defined study cohorts and subsequently classified among the NIA-AA stages. For each stage, we investigated the sensitivity to decline of 17 individual neuropsychological tests using linear mixed models.Results:1103 participants (age = 70.54 ± 8.7, 47% female) were included: n = 120 Stage 1, n = 206 Stage 2, n = 467 Stage 3 and n = 309 Stage 4. Neuropsychological tests were differentially sensitive to decline across stages. For example, Category Fluency captured significant 1-year decline as early as Stage 1 (β = −.58, p < .001). Word List Delayed Recall (β = −.22, p < .05) and Trail Making Test (β = 6.2, p < .05) became sensitive to 1-year decline in Stage 2, whereas the Mini-Mental State Examination did not capture 1-year decline until Stage 3 (β = −1.13, p < .001) and 4 (β = −2.23, p < .001).Conclusions:We demonstrated that commonly used neuropsychological tests differ in their ability to capture decline depending on clinical stage within the AD continuum (preclinical to dementia). This implies that stage-specific cognitive endpoints are needed to accurately assess disease progression and increase the chance of successful treatment evaluation in AD.

Advances in molecular positron emission tomography (PET) have enabled anatomic tracking of brain pathology in longitudinal studies of normal aging and dementia, including assessment of the central model of Alzheimer's disease (AD) pathogenesis, according to which TAU pathology begins focally but expands catastrophically under the influence of amyloid-beta (A beta) pathology to mediate neurodegeneration and cognitive decline. Initial TAU deposition occurs many years before A beta in a specific area of the medial temporal lobe. Building on recent work that enabled focus of molecular PET measurements on specific TAU-vulnerable convolutional temporal lobe anatomy, we applied an automated anatomic sampling method to quantify TAU PET signal in 443 adult participants from several observational studies of aging and AD, spanning a wide range of ages, A beta burdens, and degrees of clinical impairment. We detected initial cortical emergence of tauopathy near the rhinal sulcus in clinically normal people and, in a subset with longitudinal 2-year follow-up data (n = 104), tracked A beta-associated spread of TAU from this site first to nearby neocortex of the temporal lobe and then to extratemporal regions. Greater rate of TAU spread was associated with baseline measures of both global A beta burden and medial temporal lobe TAU. These findings are consistent with clinicopathological correlation studies of Alzheimer's tauopathy and enable precise tracking of AD-related TAU progression for natural history studies and prevention therapeutic trials.

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

BackgroundImpairment 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.MethodsIn 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.ResultsThe 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 p ConclusionsOur results suggest that the rate of functional decline accelerates along the AD continuum, as shown by steeper rates of decline in each successive NIA-AA clinical stage. These results imply that incremental changes in function are a meaningful measure for early disease monitoring. Combined with the low-cost assessment, this advocates the use of these functional questionnaires for capturing the effects of early AD-related cognitive decline on daily life.

ObjectiveThe growing shortage of neurologists is in part due to suboptimal recruitment. Little is known about students' decision making regarding a career in neurology, particularly early in training. Using a longitudinal qualitative approach, we aimed to understand factors that influence first-year medical students' decisions about neurology.MethodsWe conducted 1-on-1 semistructured interviews with 15 first-year medical students at 1 institution before and after the preclinical neurology course (2018–2019). In the first interview, we asked about career intentions, factors likely to influence specialty choice, and perceptions of neurology. In the second interview, we asked about changes in students' views over the year. Using thematic analysis, we generated codes and clustered coded data into themes.ResultsThe 2 most prominent factors influencing career choice in general were lifestyle and personal interest. No students expressed concerns about lifestyle in neurology. Most students were neutral about neurology or had a positive personal interest, which typically increased after the neurology course. Students frequently worried about content difficulty and the curative potential of neurology.ConclusionsInterventions should include early education about the factors important to students in determining specialty choice, including lifestyle, and address potentially negative perceptions of neurology. Increasing time allotment to the preclinical neurology course may combat perception of the content as difficult.

Objectives To explore interrupters' and interruptees' experiences of interruptions occurring during morning rounds in a PICU in an attempt to understand better how to limit interruptions that threaten patient safety. Design Qualitative ethnographic study including observations, field interviews, and in-depth interviews. Setting A 55-bed PICU in a free-standing, quaternary-care children's hospital. Subjects participants Attending physicians, fellow physicians, frontline clinicians (resident physicians and nurse practitioners), and nurses working in the PICU. Interventions Data collection occurred in two parts: 1) field observations during morning rounds with brief field interviews conducted with participants involved in an observed interruption and 2) in-depth interviews conducted with selected participants from prior field observations. Measurements and main results Data were coded using a constant comparative method with thematic analysis, clustering codes into groups, and subsequently into themes. We observed 11 rounding encounters (17 hr of observation and 48 patient encounters), conducting 25 field interviews and eight in-depth interviews. Themes included culture of interruption triage, interruption triage criteria, and barriers to interruption triage. Interruptees desired forming a culture of triage, whereby less-urgent interruptions were deferred until later or addressed through an asynchronous method; this desire was misaligned with interrupters who described ongoing interruption triage based on clinical changes, time-sensitivity, and interrupter comfort, despite not having a formal triage algorithm. Barriers to interruption triage included a lack of situational awareness and experience among interrupters and interruptees. Conclusions Interrupters and interruptees did not have a shared understanding of the culture of triage within the PICU. Although interrupters attempted to triage interruptions, no formal triage algorithm existed and interruptees did not perceive a triaging culture. Using data from this study, we created a triage algorithm that could inform future studies, potentially decrease unnecessary interruptions, and optimize information sharing for essential interruptions.

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.

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.

Covid-19 has caused significant distress around the globe. Apart from the evident physical symptoms in infected cases, it has caused serious damage to public mental health. India, like other countries, implemented a nationwide lockdown to contain and curb the transmission of the virus. The current research is an attempt to explore psychological distress among people residing in India during the lockdown. Four hundred and three participants were asked to complete a questionnaire with questions around symptoms of depression, anxiety, stress, and family affluence. The results indicated that people who do not have enough supplies to sustain the lockdown were most affected, and family affluence was found to be negatively correlated with stress, anxiety, and depression. Among different professions, students and healthcare professionals were found to experience stress, anxiety, and depression more than others. Despite the current situation, stress, anxiety, and depression were found to be in normal ranges for mental health professionals highlighting their capabilities to remain normal in times of distress. Policymakers and other authorities may take the assistance of mental health professionals to help overcome psychological issues related to Covid-19.