ORCID Profile
0000-0003-1687-4370
Current Organisations
Brigham and Women's Hospital
,
Harvard Medical School
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Publisher: American Psychological Association (APA)
Date: 05-2022
DOI: 10.1037/NEU0000833
Abstract: Studies are increasingly examining research questions across multiple cohorts using data from the preclinical Alzheimer cognitive composite (PACC). Our objective was to use modern psychometric approaches to develop a harmonized PACC. We used longitudinal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain Study (HABS), and Australian Imaging, Biomarker and Lifestyle Study of Ageing (AIBL) cohorts ( Baseline (BL) scores for the zPACC were centered on zero, by definition. The harmonized lPACC did not define a common mean of zero and demonstrated differences in baseline ability levels across the cohorts. Baseline lPACC slightly outperformed zPACC in the prediction of progression to dementia. Longitudinal change in the lPACC was more constrained and less variable relative to the zPACC. In combined-cohort analyses, longitudinal lPACC slightly outperformed longitudinal zPACC in its association with baseline β-amyloid status. This study proposes procedures for harmonizing the PACC that make fewer strong assumptions than the zPACC, facilitating robust multicohort analyses. This implementation of item response theory lends itself to adapting across future cohorts with similar composites. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-06-2017
DOI: 10.1212/WNL.0000000000004059
Abstract: To examine the utility of resting-state functional connectivity MRI (rs-fcMRI) measurements of network integrity as a predictor of future cognitive decline in preclinical Alzheimer disease (AD). A total of 237 clinically normal older adults (aged 63–90 years, Clinical Dementia Rating 0) underwent baseline β-amyloid (Aβ) imaging with Pittsburgh compound B PET and structural and rs-fcMRI. We identified 7 networks for analysis, including 4 cognitive networks (default, salience, dorsal attention, and frontoparietal control) and 3 noncognitive networks (primary visual, extrastriate visual, motor). Using linear and curvilinear mixed models, we used baseline connectivity in these networks to predict longitudinal changes in preclinical Alzheimer cognitive composite (PACC) performance, both alone and interacting with Aβ burden. Median neuropsychological follow-up was 3 years. Baseline connectivity in the default, salience, and control networks predicted longitudinal PACC decline, unlike connectivity in the dorsal attention and all noncognitive networks. Default, salience, and control network connectivity was also synergistic with Aβ burden in predicting decline, with combined higher Aβ and lower connectivity predicting the steepest curvilinear decline in PACC performance. In clinically normal older adults, lower functional connectivity predicted more rapid decline in PACC scores over time, particularly when coupled with increased Aβ burden. Among examined networks, default, salience, and control networks were the strongest predictors of rate of change in PACC scores, with the inflection point of greatest decline beyond the fourth year of follow-up. These results suggest that rs-fcMRI may be a useful predictor of early, AD-related cognitive decline in clinical research settings.
Publisher: Springer Science and Business Media LLC
Date: 23-03-2022
DOI: 10.1038/S41467-022-28986-2
Abstract: Animal and human imaging research reported that the presence of cortical Alzheimer’s Disease’s (AD) neuropathology, beta-amyloid and neurofibrillary tau, is associated with altered neuronal activity and circuitry failure, together facilitating clinical progression. The locus coeruleus (LC), one of the initial subcortical regions harboring pretangle hyperphosphorylated tau, has widespread connections to the cortex modulating cognition. Here we investigate whether LC’s in-vivo neuronal activity and functional connectivity (FC) are associated with cognitive decline in conjunction with beta-amyloid. We combined functional MRI of a novel versus repeated face-name paradigm, beta-amyloid-PET and longitudinal cognitive data of 128 cognitively unimpaired older in iduals. We show that LC activity and LC-FC with amygdala and hippoc us was higher during novelty. We also demonstrated that lower novelty-related LC activity and LC-FC with hippoc us and parahippoc us were associated with steeper beta-amyloid-related cognitive decline. Our results demonstrate the potential of LC’s functional properties as a gauge to identify in iduals at-risk for AD-related cognitive decline.
Publisher: American Medical Association (AMA)
Date: 08-2019
Publisher: Wiley
Date: 23-11-2017
Publisher: Wiley
Date: 04-01-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-04-2022
DOI: 10.1212/WNL.0000000000200137
Abstract: Alzheimer disease (AD) clinical trials are moving earlier in the disease process according to emerging signs of β-amyloid (Aβ) and tau pathology. If early treatment is the right time for intervention, it is critical to find the right test to optimize cognitive outcome measures for clinical trials. We sought to identify cognitive measures associated with the earliest detectable signs of emerging Aβ and tau pathology. One hundred twelve clinically normal adults with longitudinal Pittsburgh compound B (PiB)-PET, 18 F-flortaucipir (FTP)-PET, and cognitive data for ≥7 years were included from the Harvard Aging Brain Study (HABS). Analyses assessed those initially classified as PiB− (less than Centiloid [CL] 20) and then expanded to include PiB+ in iduals up to CL40, the approximate threshold beyond which neocortical tau proliferation begins. Separate linear mixed-effects models assessed the effects of emerging global Aβ (PiB slope) and tau (baseline FTP level and FTP slope) in the entorhinal and inferior temporal (IT) cortices on multiple cognitive tasks and the Preclinical Alzheimer's Cognitive Composite (PACC) over time. Steeper PiB slopes were associated with declining processing speed (Digit Symbol Substitution Test [DSST], Trail Making Test Part A) in those CL20 and expanded to include learning/memory retrieval (FCSRT-FR], Selective Reminding Test Total Recall [SRT-tr], Logical Memory Immediate Recall) in the CL40 group. FTP had limited effects under CL20, with only rising right IT FTP slope related to declining FCSRT-FR and SRT-tr learning/memory retrieval. When we expanded to include those initially CL40, rising FTP level or slope was related to declines across all tasks, and PiB slope effects on memory retrieval but not DSST score were reduced. A composite measure of processing speed and memory retrieval tasks provided the strongest prediction of decline under CL40, while PACC score remained optimal at high levels of Aβ ( CL40). Early, Aβ-mediated cognitive slowing was detected for processing speed measures, while early memory retrieval declines were associated with emerging Aβ and tau pathology. Composites of these measures may help determine whether anti-Aβ or anti-tau therapies administered at the first signs of pathology might preserve cognitive function. This study provides Class I evidence that in clinically normal older adults, emerging PET-detected AD pathology is associated with declining processing speeds and memory retrieval.
Publisher: Springer Science and Business Media LLC
Date: 29-10-2020
DOI: 10.1186/S13195-020-00706-2
Abstract: 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. In a longitudinal multicenter study, combining data from community-based and memory clinic cohorts, we included 1555 in iduals (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 in iduals ( n = 573) served as a comparison group. The total scores of three study-partner reported IADL questionnaires were standardized. The rate of decline in cognitively normal (stage 1) in iduals with and without abnormal amyloid did not differ ( p = .453). However, from stage 2 onwards, decline was significantly faster in in iduals 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 .001) and nearly two SD units per year in stage 4+ (1.93 [− 2.19, − 1.67], p .001). Overall, results were similar between community-based and memory clinic study cohorts. Our 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.
Publisher: Cambridge University Press (CUP)
Date: 13-10-2020
DOI: 10.1017/S1355617720000934
Abstract: 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. Amyloid-positive in iduals (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 in idual neuropsychological tests using linear mixed models. 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 ex le, 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). 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.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 22-09-2021
DOI: 10.1126/SCITRANSLMED.ABJ2511
Abstract: In vivo and autopsy evidence supports locus coeruleus MRI measures as proxy of initial TAU deposition and amyloid-related memory decline.
Publisher: Wiley
Date: 2020
DOI: 10.1002/DAD2.12132
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2012
Publisher: Elsevier BV
Date: 2020
Publisher: BMJ
Date: 26-03-2012
Publisher: Wiley
Date: 2021
DOI: 10.1002/DAD2.12243
Abstract: 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. 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. 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 .001). Lower BRANCH score was associated with greater amyloid ( r = –0.205, P = .007) and entorhinal tau ( r = –0.178, P = .026). BRANCH reliably captures meaningful cognitive information remotely, suggesting promise as a digital cognitive marker sensitive early in the AD trajectory.
Publisher: SERDI
Date: 2017
DOI: 10.14283/JPAD.2017.1
Abstract: Background: As prevention trials for Alzheimer’s disease move into asymptomatic populations, identifying older in iduals who manifest the earliest cognitive signs of Alzheimer’s disease is critical. Computerized cognitive testing has the potential to replace current gold standard paper and pencil measures and may be a more efficient means of assessing cognition. However, more empirical evidence about the comparability of novel computerized batteries to paper and pencil measures is required. Objectives: To determine whether two computerized IPad batteries, the NIH Toolbox Cognition Battery and Cogstate-C3, similarly predict subtle cognitive impairment identified using the Preclinical Alzheimer Cognitive Composite (PACC). Design, Setting, Participants: A pilot s le of 50 clinically normal older adults (Mage=68.5 years±7.6, 45% non-Caucasian) completed the PACC assessment, and the NIH Toolbox and Cogstate-C3 at research centers of Massachusetts General and Brigham and Women’s Hospitals. Participants made 3-4 in-clinic visits, receiving the PACC first, then the NIH Toolbox, and finally the Cogstate-C3. Measurements: Performance on the PACC was dichotomized by typical performance ( = 0.5SD), versus subtle cognitive impairment ( .5SD). Composites for each computerized battery were created using principle components analysis, and compared with the PACC using non-parametric Spearman correlations. Logistic regression analyses were used to determine which composite was best able to classify subtle cognitive impairment from typical performance. Results: The NIH Toolbox formed one composite and exhibited the strongest within-battery alignment, while the Cogstate-C3 formed two distinct composites (Learning-Memory and Processing Speed-Attention). The NIH Toolbox and C3 Learning-Memory composites exhibited positive correlations with the PACC (ρ=0.49, p .001 ρ=0.58, p .001, respectively), but not the C3 Processing Speed-Attention composite, ρ=-0.18, p=0.22. The C3 Learning-Memory was the only composite that classified subtle cognitive impairment, and demonstrated the greatest sensitivity (62%) and specificity (81%) for that subtle cognitive impairment. Conclusions: Preliminary findings suggest that the NIH Toolbox has the advantage of showing the strongest overall clustering and alignment with standardized paper-and-pencil tasks. By contrast, Learning-Memory tasks within the Cogstate-C3 battery have the greatest potential to identify cross-sectional, subtle cognitive impairment as defined by the PACC.
Publisher: Wiley
Date: 20-12-2012
DOI: 10.1002/HBM.22214
Publisher: Elsevier BV
Date: 06-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 26-01-2021
DOI: 10.1212/WNL.0000000000011214
Abstract: As clinical trials move toward earlier intervention, we sought to redefine the β-amyloid (Aβ)-PET threshold based on the lowest point in a baseline distribution that robustly predicts future Aβ accumulation and cognitive decline in 3 independent s les of clinically normal in iduals. Sequential Aβ cutoffs were tested to identify the lowest cutoff associated with future change in cognition (Preclinical Alzheimer Cognitive Composite [PACC]) and Aβ-PET in clinically normal participants from the Harvard Aging Brain Study (n = 342), Australian Imaging, Biomarker and Lifestyle study of aging (n = 157), and Alzheimer's Disease Neuroimaging Initiative (n = 356). Within s les, cutoffs derived from future Aβ-PET accumulation and PACC decline converged on the same inflection point, beyond which trajectories erged from normal. Across s les, optimal cutoffs fell within a short range (Centiloid 15–18.5). These optimized thresholds can help to inform future research and clinical trials targeting early Aβ. Threshold convergence raises the possibility of contemporaneous early changes in Aβ and cognition. This study provides Class II evidence that among clinically normal in iduals a specific Aβ-PET threshold is predictive of cognitive decline.
Publisher: Wiley
Date: 24-05-2018
DOI: 10.1016/J.JALZ.2018.04.010
Abstract: Our objective was to investigate the effect of sex on cognitive decline within the context of amyloid β (Aβ) burden and apolipoprotein E genotype. We analyzed sex‐specific effects on Aβ‐positron emission tomography, apolipoprotein, and rates of change on the Preclinical Alzheimer Cognitive Composite‐5 across three cohorts, such as the Alzheimer's Disease Neuroimaging Initiative, Australian Imaging, Biomarker and Lifestyle, and Harvard Aging Brain Study (n = 755 clinical dementia rating = 0 age (standard deviation) = 73.6 (6.5) female = 55%). Mixed‐effects models of cognitive change by sex, Aβ‐positron emission tomography, and apolipoprotein ε4 were examined with quadratic time effects over a median of 4 years of follow‐up. Apolipoprotein ε4 prevalence and Aβ burden did not differ by sex. Sex did not directly influence cognitive decline. Females with higher Aβ exhibited faster decline than males. Post hoc contrasts suggested that females who were Aβ and apolipoprotein ε4 positive declined faster than their male counterparts. Although Aβ did not differ by sex, cognitive decline was greater in females with higher Aβ. Our findings suggest that sex may play a modifying role on risk of Alzheimer's disease–related cognitive decline.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-06-2021
DOI: 10.1212/WNL.0000000000012108
Abstract: To 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. In 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, hippoc us, 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. Data 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. In 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. This study provides Class II evidence that in people with preclinical Alzheimer disease, entorhinal hypometabolism identified by FDG-PET is predictive of subsequent cognitive decline.
Publisher: Wiley
Date: 12-2019
Publisher: Wiley
Date: 21-01-2019
DOI: 10.1002/ANA.25395
No related grants have been discovered for Kate Papp.