bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defining the ATN framework using longitudinal biomarker trajectories reveals an emerging amyloid accumulation group
Authors: Boyle Rory Thomas , Coughlan Gillian T , Properzi Michael J , Archdeacon Claire , Chou Hsiang‐Chin Lori , Klinger Hannah , Jacobs Heidi I.L. , Papp Kathryn V. , Amariglio Rebecca E. , Farrell Michelle E. , Donohue Michael C. , Hohman Timothy J. , Mormino Elizabeth C. , Hanseeuw Bernard J , Chhatwal Jasmeer P. , Rentz Dorene M. , Price Julie C , Johnson Keith A. , Schultz Aaron P. , Sperling Reisa A. , Buckley Rachel F. ,   The Harvard Aging Brain Study
Published: December 2022

AbstractBackgroundThe ATN framework is defined by cross‐sectional biomarkers of β‐amyloid (Aβ), tau and neurodegeneration. Given that prevention trials, e.g., AHEAD 3‐45, are focused on individuals who have lower Aβ than established thresholds, we investigated whether defining the ATN framework using longitudinal biomarker trajectories might better identify an at‐risk sample within this boundary. Here, we applied a data‐driven method to re‐define the ATN with longitudinal biomarker data from the Harvard Aging Brain Study (HABS) and we then replicated this longitudinal framework in ADNI.Method157 HABS participants were clinically‐normal at baseline and underwent at least two Pittsburgh Compound‐B [PiB]‐PET, Flortaucipir‐PET, and T1‐weighted MRI scans. To define longitudinal ATN, we applied latent class mixture models (LCMM) to each biomarker (global Aβ DVR, entorhinal tau SUVr, ICV‐adjusted hippocampal volume) separately, adjusting for age, and including random intercept and slopes. Akaike information criteria (AIC) determined the best‐fitting models out of two‐group or three‐group solutions with linear or spline‐link functions. We compared longitudinal ATN profiles on demographics and an optimized estimate of cognitive change (derived from longitudinal Preclinical Alzheimer Cognitive Composite (PACC) data).ResultAβ trajectories (Fig.1a) were best categorized by one stable (A→) and two accumulating subgroups, a predominantly amyloid‐negative at baseline subgroup (A‐↑) and an entirely amyloid positive at baseline subgroup (A+↑). Tau (Fig.1b) and neurodegeneration (Fig.1c) were optimally defined by stable (T→/N→) vs accumulating/atrophying (T↑/N↑) groups, respectively. These groups were replicated in ADNI (Fig.2). The entire A‐↑ subgroup were stable on T and N (A‐↑/T→/N→) and were predominantly A‐/T‐/N‐ at baseline (86%; Table 1). By contrast, 38% of A+↑ individuals changed on T, or T&N. A‐↑/T→/N→ demographically most closely resembled the longitudinally‐stable ATN group (A→/T→/N→), but were older, more likely to carry e4+ and exhibited higher baseline Aβ (Table 2). Although demonstrating Aβ accumulation, A‐↑/T→/N→ did not exhibit greater cognitive decline versus the stable group (A→/T→/N→; Fig. 3).ConclusionOur findings suggest that a longitudinal biomarker run‐in of Aβ‐PET may be useful for the identification of early‐risk groups for prevention trials. Future work will establish whether other features (e.g. genetics, neuroinflammatory markers, functional imaging) can help to distinguish this cohort.
Prevalence and longitudinal clinical outcomes of negative, moderate, and advanced 18F‐flortaucipir PET visual patterns in aging and Alzheimer’s disease
Authors: Moscoso Alexis , Heeman Fiona , Camacho Valle , van Essen Martijn , Grothe Michel J. , Lin Li , Mainta Isminni , Ribaldi Federica , Devous Michael D. , Pontecorvo Michael J. , Frisoni Giovanni B , Garibotto Valentina , Schöll Michael 
Published: December 2022

AbstractBackgroundThe advent of positron emission tomography (PET) imaging with tracers such as [18F]flortaucipir (FTP) has allowed in‐vivo visualization of aggregated tau in Alzheimer’s disease (AD). Recently, a clinically applicable visual interpretation method for FTP PET yielding negative, moderate, and advanced AD visual patterns was developed, leading to its subsequent approval by the US Food and Drug Administration (FDA). Yet, the prevalence and longitudinal clinical outcomes of the different AD‐associated visual patterns, in particular the moderate AD pattern, have not been investigated systematically across the clinical spectrum of AD.MethodWe included cognitively normal individuals and patients with mild cognitive impairment and AD dementia from five observational cohort studies — Alzheimer’s Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain study (HABS), A4 study, AVID’s A05 study and Geneva Memory Clinic cohort — all of which had available FTP PET scans. Furthermore, Aβ status, established with Aβ PET, was available in 1924 participants (98%), and longitudinal clinical and cognitive data was obtained for 968 participants over an average follow‐up time of 2.2 years. Three readers, blinded to clinical and imaging information, will independently evaluate each FTP PET scan, and an individual’s FTP uptake pattern will be interpreted as negative, moderate, or advanced AD tau pattern, based on the majority read of the three readers. Multinomial generalized additive models (GAM) will be fitted to provide prevalence estimates of each FTP AD pattern. Mixed models for repeated measures (MMRM) will be used to estimate cognitive decline trajectories.ResultA total of 1963 participants had available FTP PET scans. We will investigate the prevalence of the different FTP AD patterns as a function of age per diagnostic group, stratifying participants by β‐amyloid status and APOE genotype. Further, in the subset of participants with available longitudinal clinical data, we will explore how the different FTP patterns associate with clinical decline across the aforementioned diagnostic groups.ConclusionOur large‐scale study will contribute significantly to elucidating the clinical relevance of FTP visual reads across the AD spectrum, potentially widening its applicability and promoting its use in patient assessment and in clinical prevention trials.
Utility of online cognitive test in cognitive neurology unit
Authors: Curnin Charlotte B , Hayashi Takuji , Smith Mauice A , Press Daniel Z. 
Published: December 2022

AbstractBackgroundDelirium is one of the most common complications in hospitalized elders and corresponds with a higher risk of cognitive decline and death. Numerous test batteries exist to assist clinicians in detecting delirium, but it continues to be undiagnosed in up to 88% of patients, particularly those with AD where “confusion” is mistakenly attributed to impaired baseline (1). This pilot study investigated the utility of a digital cognitive assessment (D‐Cog), in the form of an iPad game, which would allow for rapid and routine baseline testing in patients with AD so that delirium‐induced changes can be easily detected.MethodWhile collecting traditional vital signs, medical assistants in the Beth Israel Deaconess Center (BIDMC) Cognitive Neurology Unit (CNU) prompted 67 willing patients to complete the D‐Cog assessment, an adaptive visuospatial span task, on an iPad. We then retrospectively reviewed the medical records of each patient to collect diagnosis, demographics, and pen‐and‐paper neuropsychological scores (e.g., MoCA or MMSE). Of the 67 patients (mean age 67, 29 female), 22 were clinically diagnosed with mild cognitive impairment (MCI) or varying severities of AD.ResultThe assessment was successfully completed by 52 participants. 15 participants, including 5 participants with moderate AD, experienced great difficulty during the task and were subsequently excluded. The 17 included participants with AD (mean age 75, 6 female) averaged a D‐Cog score of 4.1 and a MMSE score of 23.1. In comparison, a control group with no cognitive concerns (n = 16, mean age 60, 9 female) garnered a 6.7 average D‐Cog score and 29.3 MMSE score. The difference in D‐Cog scores was significantly different at p = 0.001.ConclusionThe D‐Cog assessment is feasible in clinical practice for patients with a wide range of cognitive impairments. These scores can act as an attentional baseline to compare against later testing in the event of suspected delirium. While the D‐Cog is derived from traditional pen‐and‐paper testing, its digital framework offers new opportunities for adaptive and remote testing.ReferenceFong TG, Davis D, Grodon ME, Albuquerque A, Inouye SK. The interface between delirium and dementia in elderly adults. Lancet Neruol. 2015; 14(8): 823–32
Tau and amyloid PET imaging with 18F‐PI‐2620 and 18F‐Florbetaben in patients with early‐onset dementia and healthy controls
Authors: Santibanez Rodrigo A , Mendez‐Orellana Carolina , Escobar Sebastian , Bustamante Gabriel , Juri Carlos , Haeger Arlette , Amaral Horacio , Kramer Vasko 
Published: December 2022

AbstractBackgroundAbnormal deposits of tau protein and beta‐amyloid are the two fundamental pathological features of Alzheimer's disease (AD). The research framework for AD diagnosis proposes categorizing subjects based on biomarker evidence of pathology using the ATN classification system (amyloid, tau, neurodegeneration). In‐vivo detection of amyloid pathology using positron emission tomography (PET) is well established and new generation tau PET tracers like 18F‐PI‐2620 have shown a high binding affinity for aggregated tau without significant off‐target binding. The purpose of this study is to describe the ability of 18F‐PI‐2620 to detect tau pathology in patients with early‐onset dementia (EOD) with proven amyloid pathology.MethodTen patients with EOD and positive 18F‐Florbetaben amyloid PET (age range 54‐64y, 8 with suspected early‐onset AD (EOAD) and 2 with logopenic variant primary progressive aphasia (lvPPA)), along with 14 healthy controls (HC) (age range 54‐76y) underwent dynamic PET scans for 75 minutes after injection of 18F‐PI‐2620 to examine the presence of tau‐pathology in cortical and deep brain regions. Specific binding ratios were derived from averaged PET images from 45‐75 min post‐injection.ResultIn 9 out of 10 EOD patients, 18F‐PI‐2620 uptake was robust and extensive predominantly in cortical regions with relative sparing of deep brain regions. In the remaining EOD case, binding was low but with the same distribution pattern described for other EOD patients. In one HC, significant, specific uptake was observed predominantly in deep brain regions. 18F‐PI‐2620 administration was safe and well‐tolerated.ConclusionOur preliminary results suggest an excellent performance of the tracer 18F‐PI‐2620 to detect tau deposits in EOAD and lvPPA. Tau PET imaging with 18F‐PI‐2620, in conjunction with 18F‐Florbetaben amyloid PET, distinctly discriminates between early‐onset dementias due to AD pathology from HC. These results also support the usefulness of 18F‐PI‐2620 for visualizing tau aggregation in EOD. Finally, 18F‐Florbetaben and 18F‐PI‐2620 appear to be reliable tools for establishing the ATN biomarker status in EOD patients. Nevertheless, further studies are needed to confirm these preliminary results.
A telemedical interface for at‐home cognitive testing
Authors: Pebler Peter , Blank Michael , Geraci Kristin , Williams Garrett , Hall Kathleen , Baldo Juliana , Schendel Krista , Lwi Sandy J. , Chok Jas M. , Herron Tim , Wyma‐Hughes John , Woods David L. 
Published: December 2022

AbstractBackgroundThe COVID‐19 pandemic has limited in‐lab cognitive testing. While at‐home alternatives exist (testing over the phone), differences in test design and delivery complicate direct comparison of most in‐lab and at‐home tests.Here we describe the design, infrastructure, and implementation of the California Cognitive Assessment Battery (CCAB), a cognitive test battery and administration system. Using automated remote administration over cellular networks, identical computerized cognitive tests can be administered at‐home or in the lab.MethodThe CCAB comprises 30+ computerized cognitive tests. Test delivery is automated through text, text‐to‐speech, and graphical instructions; test scoring is also automated, using automatic speech recognition for verbal responses.The test delivery infrastructure consists of two components: the test kit (MS Surface Pro tablet computer with mouse, headset, and cellular dongle) , and a web‐browser application “CCAB Examiner,” used by the test administrator to control test delivery, view real‐time progress and scores, and monitor/chat with the participant via AV feeds.The system is coordinated by a cloud‐based server which also delivers the CCAB Examiner application to any browser. Once connected, the “CCAB Test Station” application and CCAB Examiner communicate over a commercial Communication as a Service (CAAS) provider, which transmits AV streams and a text messaging protocol. CCAB Test Station is designed to isolate control, communications, and testing functions for maximal fault tolerance. For example, test administration continues automatically even if Examiner and Test Station lose connection. Test data is uploaded to the server during sessions and re‐synced when the test kit returns.Result442 participants underwent three 90‐minute CCAB test sessions on successive days (72 total tests per participant). More than 98% of participants finished all three sessions, and >99% of tests were completed. Cellular connection failures occurred occasionally, but >98% resulted only in the loss of A/V feeds for the examiner, while tests continued automatically and examiners were able to monitor real‐time performance data.ConclusionThe CCAB permits identical tests to be administered at home or in the laboratory, while cellular‐network based remote administration allows for nationwide access for all socioeconomic groups, even for people in remote areas without Wi‐Fi, or those with limited technical expertise.
Characterization of tau PET according to amyloid chronicity
Authors: Cody Karly Alex , Koscik Rebecca Langhough , Christian Bradley T , Betthauser Tobey J , Johnson Sterling C. 
Published: December 2022

AbstractBackgroundThis work examined tau PET (MK‐6240 SUVR) relative to amyloid chronicity (duration of amyloid positivity (A+)) to better understand neurofibrillary tangle (NFT) spatial burden across the time course of Alzheimer’s disease (AD).MethodIndividuals (N=457, 68.3±7.1 years, 417 CU, 30 MCI, 10 dementia) from the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin AD Research Center underwent amyloid and tau PET and neuropsychological assessment. Cortical 11C‐PiB DVR and sampled iterative local approximation was used to estimate A+ onset age and years of A+ duration at tau PET. Tau burden was quantified using 18F‐MK‐6240 SUVR (70‐90 min, inferior cerebellar GM reference region). MK‐6240 SUVR was assessed for relationships with A+ duration (continuous and grouped by decade) and clinical diagnosis as well as spatial patterns corresponding to Braak NFT stages. Regional and voxelwise analyses were performed.ResultMK‐6240 SUVR was positively associated with A+ duration in regions associated with Braak NFT stages I‐VI while age was not associated after accounting for A+ duration (Figure 1A). In the CU subset, the MK‐6240/A+ duration association was spatially restricted to regions associated with NFT stages I‐IV(Figure 1B). Voxelwise MK‐6240 analyses revealed that with each decade of A+ duration, the spatial extent of measurable tau “spread”(ie .progressed) from regions associated with early to late Braak NFT stages (Figure 2A). Similar patterns were observed in the CU subset, but with lower SUVR and signal spatially restricted to the medial temporal lobe (MTL; Figure 2B). Regional analyses of MK‐6240 SUVR Z‐scores indicated significant stepwise increases across A+ duration groups (A‐ < A+ 0‐10 years < A+ 10‐20 years <A+ 20+ years; Figure 3A) and across clinical groups (CN A‐ < CN A+ < MCI A+ < AD A+; Figures 3B). Between group differences were largest in the entorhinal cortex and MTL Meta‐ROI for both A+ duration and clinical diagnosis groups (Figure 4A‐B).ConclusionResults suggest that entorhinal and MTL regions were most sensitive to early amyloid pathology and cognitive changes in AD. Applying the amyloid chronicity framework to tau PET data enables 'pseudo'spatiotemporal characterization of tau deposition patterns in the AD continuum. Longitudinal assessment of spatiotemporal tau deposition patterns is ongoing.
Associations of pathway‐specific polygenic risk scores with clinical status and Alzheimer’s‐related biomarkers
Authors: Elman Jeremy A. , Schork Nicholas J. , Kremen William S. 
Published: December 2022

AbstractBackgroundThe APOE gene represents the largest genetic risk factor in sporadic Alzheimer’s disease (AD), but there is a substantial polygenic component as well. Polygenic risk scores (PRS) represent a useful approach to summarize small effects across the genome but may obscure which pathways are affected. Variability across individuals at the genetic level may contribute to the extensive phenotypic heterogeneity of AD. Therefore, we calculated polygenic risk in multiple pathways associated with AD and examined its relationship with clinical status and AD biomarkers.MethodA total of 1,411 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with genotyping data were included. Top gene sets from a pathway analysis of AD GWAS summary statistics were combined into clusters based on proportion of overlapping genes. Pathway‐specific PRSs (ps‐PRS) were calculated for each participant by restricting to SNPs annotated to genes in each cluster. We tested associations of ps‐PRSs with diagnostic status (AD vs cognitively normal, MCI vs cognitively normal) and rate of progression to AD among those with no dementia at baseline. Additional analyses examined associations with amyloid and tau positivity, and hippocampal volume. The APOE region was excluded from all ps‐PRSs and the number of APOE‐ε4 alleles was included as a covariate along with age, gender, and the first 3 principal components. All analyses were FDR‐corrected.ResultThirteen pathway clusters were identified relating to categories such as immune response, amyloid precursor processing, protein localization, lipid transport and binding, tyrosine kinase, and endocytosis. Nine ps‐PRSs were significantly higher in AD and MCI compared to controls. A large subset of these were associated with both faster progression to AD and hippocampal volume. Amyloid and tau‐positivity were both related to endocytosis ps‐PRSs. Amyloid‐positivity was additionally related to microglial activation, lipid processing, fibril formation and amyloid precursor processing, whereas tau‐positivity was related to protein localization.ConclusionAlthough genetic risk for AD is widely distributed, AD‐phenotypes may be preferentially associated with risk in specific pathways. Defining genetic risk along multiple dimensions at the individual level may help clarify the etiology of heterogeneity in AD.
Brain morphometric and metabolic changes in Subjective Cognitive Decline individuals
Authors: Bieger Andrei , Souza Laura Willers , Borelli Wyllians Vendramini , Negrini Guilherme Bauer , Povala Guilherme , De Bastiani Marco Antônio , Tissot Cécile , Ferrari‐Souza João Pedro , Castilhos Raphael Machado , Souza Diogo O. , Rosa‐Neto Pedro , Pascoal Tharick A , Schumacher‐Schuh Artur Francisco , DuBois Jonathan M , Zimmer Eduardo R 
Published: December 2022

AbstractBackgroundSubjective cognitive decline (SCD) is defined as a memory complaint in individuals without an objective measure of cognitive impairment. In this study, we investigated the morphometric and metabolic brain changes in individuals presenting with SCD.MethodAge and sex matched structural MRI and [18F]FDG PET images from SCD and CU (n = 101, per group) were extracted from the ADNI database. We built general linear models corrected for multiple comparisons with 10,000 Monte‐Carlo simulations to verify differences in cortical thickness between groups, using age as a covariate (Freesurfer’s v7.1.1). Metabolic analysis was performed using voxel‐wise general linear models comparing the SUVR of the FDG signal, correcting for age and APOE4 allele carrying status, using the MINC toolkit and the R statistical program.ResultSCD and CU groups presented similar age, sex, years of education, CSF AD‐related protein levels (amyloid beta 1‐42, p‐tau and tau), and Clinical Dementia Rating – Sum of Boxes score (Table 1). Compared to CU individuals, SCD subjects showed increased cortical thickness in the right hemisphere rostral middle frontal gyrus (Figure 1), while glucose metabolism was increased in the right medial temporal lobe, including the hippocampus, and right occipital cortex (Figure 2).ConclusionIndividuals with SCD present cortical hypertrophy in the rostral middle frontal gyrus and glucose hypermetabolism in the medial temporal lobe and occipital cortex, all in the right hemisphere. Previous studies suggest that these areas play a role in personality and humor, and may be altering self‐perception of cognitive decline. At the biological level, given the high concentration of astrocytes in these areas, such changes may suggest a scenario of astrocyte reactivity. More specifically, astrocyte hypertrophy may account for increased cortical thickness and glucose uptake. In summary, we provide neuroimaging evidence of structural and functional changes in individuals with SCD, suggesting early astrocyte reactivity.
APOE3 Christchurch mutation carriers from the Colombian kindred with autosomal dominant Alzheimer’s disease due to PSEN1 E280A
Authors: Aguillon David , Lopera Francisco , Vasquez Daniel , Baena Ana Y. , Hincapie Liliana , Zuluaga‐Castaño Yesica , Vila‐Castelar Clara , Ramirez‐Gomez Liliana A. , Aduen Paula , Acosta‐Uribe Juliana , Kosik Kenneth S. , Reiman Eric M. , Arboleda‐Velasquez Joseph F , Quiroz Yakeel T. 
Published: December 2022

AbstractBackgroundOur understanding of the mechanisms of protection mediated by APOE has advanced significantly in the past years. Our group previously showed that APOE3 Christchurch (APOE3ch) homozygosity was associated with the protection against Alzheimer’s disease dementia in an individual who carried the Presenilin‐1 (PSEN1)‐E280A variant for autosomal dominant AD (ADAD) (Arboleda‐Velasquez et al., 2019). Here we present the initial characterization of individuals from the PSEN1‐E280A kindred with the APOE3ch variant.Methods1,000 PSEN1‐E280A variant carriers and 1,000 non‐carriers from the Colombian ADAD kindred were characterized in terms of their common APOE variants and the rare APOEch variant. Participants had previously completed a comprehensive neurological and neuropsychological evaluation. Those who were alive were re‐contacted in 2021 to undergo comprehensive clinical assessments, including the CERAD‐Colombia neuropsychological battery, and MRI and FDG PET imaging as part of the Resist Alzheimer’s Project.ResultsWe discovered 97 ADAD kindred members with the APOE3ch variant (95 heterozygotes), including 84 who are living and 13 who are deceased (7 who were brain donors). 29 of the APOE3ch carriers also had the PSEN1‐E280A variant, including 18 who are living and 11 who are deceased. The age range for all APOE3ch variant carriers was from 17 to 72 years, including 11 APOE3ch + PSEN1‐E280A carriers who were 50‐72 years old (i.e., older than the PSEN1‐E280A variant carriers’ median age at dementia onset). Overall, global cognition and memory performances of the first three APOE3ch + PSEN1‐E280A carriers (older than 50 years of age) assessed fell within the normal range, compared to age‐matched individuals from this kindred.ConclusionsThe prevalence rate of APOE3 Christchurch heterozygosity in the Colombian kindred with ADAD (4.85%) is very high compared to the general population (e.g., gnomAD database reports an allele frequency of 0.00001283; Karczewski et al., 2019). Preliminary clinical and cognitive data from APOE3ch variant carriers are consistent with the hypothesis that heterozygosity may have a mild‐to‐moderate protective effect against cognitive decline. We plan to compare longitudinal clinical, cognitive, biomarker, and post‐mortem neuropathological changes in PSEN1‐E280A carriers with and without the APOE3ch variant to clarify the role of APOE3ch heterozygosity in the protection from ADAD.