bluuebunny/crossref_metadata_2025_split huggingface dataset:
Uncovering the Role of an ABCA7 Frameshift Deletion in African American Alzheimer’s Disease Cellular Pathology
Authors: DeRosa Brooke A. , Nam Younji , Golightly Charles G. , Simon Shaina A. , Arvizu Jamie , Adams Larry D. , Starks Takiyah D. , Laverde‐Paz Juliana , Cukier Holly N. , Vance Jeffery M. , Cuccaro Michael L. , Haines Jonathan L. , Byrd Goldie S. , Beecham Gary W. , Pericak‐Vance Margaret A. , Dykxhoorn Derek M. 
Published: December 2023

AbstractBackgroundThe ATP Binding Cassette Subfamily A Member 7 (ABCA7) gene is a risk factor for Alzheimer’s disease (AD). While ABCA7 has been implicated as a genetic determinant of AD across populations, the risk effect is the strongest in African Americans (AAs). We previously identified a common 44 base pair deletion in ABCA7 (p.Arg578Alafs) that is predicted to truncate the protein and is significantly associated with AD in AAs (frequency in cases = 15.2%, cognitively unimpaired (CU) = 9.74%, p = 1.41×10−5). Clinically, deletion homozygotes are similar to deletion heterozygotes, supporting dominant gain‐of‐function as a putative disease‐causing mechanism. We sought to determine if the deletion transcript is stable and if the truncated protein is expressed as steps to understanding the mechanism leading to AD risk.MethodRT‐PCR analysis of heterozygotes was conducted to assess the stability of the deletion transcript. FLAG‐tagged Arg578Alafs and wildtype ABCA7 vectors were constructed then overexpressed in HEK293APPsw cells. Western blot analysis of FLAG‐Arg578Alafs was performed to determine if the deletion produces a truncated protein. Induced pluripotent stem cell (iPSC) lines from six AA individuals with AD bearing the Arg578Alafs mutation (three heterozygous; three homozygous) were created in pair with isogenic CRISPR‐corrected control lines. These iPSC lines were validated for pluripotency, genomic stability, and lack of off‐target editing. The isogenic ABCA7 deletion and CRISPR‐corrected control iPSC lines will be differentiated into microglia and neurons and functionally assessed for cell type‐specific AD phenotypes.ResultInitial results comparing AD patients to CU individuals show that patient‐derived microglia have normal rates of phagocytosis but are impaired in the uptake and clearance of fibrillar Aβ. RT‐PCR analysis of the deletion in heterozygotes demonstrates that a stable RNA transcript is expressed from the ABCA7 deletion allele. Western blot analysis of overexpressed FLAG‐Arg578Alafs shows that the truncated protein is expressed, albeit at low levels compared to the wildtype protein.ConclusionThis ABCA7 deletion produces a stable transcript which appears to be translated into low levels of protein. This supports a potential gain of function as the disease risk mechanism. Studies in isogenic lines will further elucidate the functional effects of this ABCA7 deletion on AD pathology in AAs.
Do preclinical serum biomarker levels or their changes predict cognitive decline in clinical AD?
Authors: De Meyer Steffi , Blujdea Raluca E. , Vandenberghe Rik , Poesen Koen , Teunissen Charlotte E. 
Published: December 2023

AbstractBackgroundBlood‐based biomarkers have shown good prognostic performance to predict cognitive decline in well‐controlled asymptomatic cohorts. We now investigated whether preclinical serum levels (sampled on average five years prior to Alzheimer’s Disease (AD) diagnosis) or longitudinal changes in GFAP, a glial activation marker, or NfL, a marker of neurodegeneration could predict the rate of cognitive decline rate following initial memory clinic presentation.MethodPreclinical serum samples from 115 clinical AD patients (mean age at diagnosis = 74 years, 58% female, 40% biomarker‐proven) were retrospectively retrieved from the Leuven university hospital long‐term sample storage. All preclinical samples were collected during routine clinical visits on average 5 years (range: 2‐10 years) prior to AD diagnosis. GFAP and NfL were measured using Simoa at VUmc Amsterdam. For a subset of 51 AD patients, longitudinal serum biomarker data were available with follow‐up samples taken either before (N = 16), after (N = 16) or at the time of diagnosis (N = 40). Using linear mixed‐effects models, we assessed (i) the relationship between preclinical baseline biomarker levels and MMSE decline following memory clinic presentation, (ii) the annual rates in longitudinal serum biomarker change and (iii) the relationship between longitudinal serum biomarker changes and MMSE decline. Biomarker levels were natural log‐transformed for statistical analyses and reported p‐values were Bonferroni corrected.ResultHigh preclinical GFAP serum levels were predictive of faster MMSE decline after initial memory clinic presentation (βs = ‐0.97, p < 0.001). Preclinical NfL levels demonstrated no such predictive value (Figure 1). Across the total time period, serial NfL levels (βs = 0.091, 95% CI: 0.060‐0.13) increased more steeply than GFAP levels (βs = 0.052, 95% CI: 0.035‐0.072). However, within the preclinical time window, only serial GFAP levels (βs = 0.057, p = 0.03), and not NfL, displayed a significant time‐dependent rise (Figure 2). Not longitudinal GFAP nor NfL changes since preclinical sampling were associated with subsequent MMSE decline.ConclusionSerum GFAP levels measured on average five years prior to clinical diagnosis are informative of the rate of global cognitive decline once patients present at the memory clinic and serum GFAP levels increase towards diagnosis.
Longitudinal tau binding in tau‐PET negative patients with clinical Alzheimer’s disease
Authors: Rikken Roos M. , Coomans Emma M. , de Koning Lotte A. , Visser Denise , Verfaillie Sander C.J. , den Braber Anouk , Collij Lyduine E. , Golla Sandeep S.V. , Barkhof Frederik , Visser Pieter Jelle , Scheltens Philip , van der Flier Wiesje M. , Boellaard Ronald , Ossenkoppele Rik , van Berckel Bart N.M. , Vijverberg Everard G.B. , van de Giessen Elsmarieke 
Published: December 2023

AbstractBackgroundDifferent tau‐PET patterns have been observed in Alzheimer’s disease (AD) which may be associated with demographic factors, copathology and resilience. We and others previously found that not all Aβ‐positive AD patients are tau‐PET positive. It is currently not known whether tau pathology develops in these groups over time. Therefore, we aimed to examine longitudinal tau binding in tau‐PET negative individuals with symptomatic AD.MethodWe included 97 Aβ‐positive participants with clinical diagnosis of mild cognitive impairment or dementia due to AD (MCI/AD) of which 12 (13%) were tau‐PET negative. To compare, we included 131 tau‐PET negative cognitively unimpaired individuals (CU) of which 93 (71%) were Aβ‐negative and 38 (29%) Aβ‐positive. Tau‐status was defined by [18F]flortaucipir PET consensus visual read of two nuclear physicians according to US Food and Drug Administration‐approved guidelines. [18F]flortaucipir SUVr at baseline (N = 225) and after ±2 years (N = 81) was quantified in an early tau region reflecting Braak I (entorhinal cortex), the medial temporal lobe (MTL), and a combined visual read region of interest (ROI) (parietal, occipital, and posterior lateral temporal lobe). We used age‐and sex‐adjusted linear mixed models to compare tau accumulation.ResultDemographics are shown in table 1. Compared to MCI/AD A+T+, MCI/AD A+T‐ were older (p<0.001) and more often male (p = 0.015). MCI/AD A+T‐ did not differ from CU A‐T‐ in baseline tau‐PET SUVr, but had a slightly lower SUVr in Braak I compared to CU A+T‐ (p = 0.040) (figure 1). After ±2 years, all MCI/AD A+T‐ participants who underwent follow up remained visual read tau negative. However, MCI/AD A+T‐ showed a steeper increase in Braak I and MTL tau‐PET SUVr compared to CU A‐T‐ (figure 2A,B) and in Braak I compared to CU A+T‐ (β = 0.31, p = 0.036). Interestingly, MCI/AD A+T‐ showed a significantly steeper tau‐PET SUVr increase compared to MCI/AD A+T+ in Braak I (β = 0.29, p = 0.029) (figure 2A).ConclusionAlthough visual read tau‐PET status remains stable over time, our results indicate that tau‐negative MCI/AD patients do accumulate tau over time, most pronounced in early tau regions. This highlights the relevance of quantifying tau regionally over time in tau‐PET negative individuals with clinical AD diagnosis.
Updated Appropriate Use Criteria for Amyloid and Tau PET
Authors: Rabinovici Gil D. , Knopman David S. , Arbizu Javier , Benzinger Tammie L.S. , Donohoe Kevin , Hansson Oskar , Herscovitch Peter , Kuo Phillip , Lingler Jennifer H , Minoshima Satoshi , Murray Melissa E. , Price Julie C , Salloway Stephen , Weber Christopher J. , Carrillo Maria C. , Johnson Keith A. 
Published: December 2023

AbstractBackgroundThe Alzheimer’s Association and Society for Nuclear Medicine and Molecular Imaging convened a Workgroup to update previous Appropriate Use Criteria (AUC) for amyloid PET (Johnson 2013) and develop the first AUC for tau PET. The AUC represent general guidelines and should not be considered a substitute for clinical judgment exercised in the care of individual patients.MethodThe Workgroup included 14 researchers with multidisciplinary expertise. Meetings were held between June 2020 and August 2021. Key research questions were identified using the PICOTS framework, triggering an independent systematic literature review. Using established methods (Fitch 2001), the Workgroup identified 17 clinical scenarios in which amyloid/tau PET may be considered. Appropriateness of amyloid and tau PET as independent, stand‐alone modalities were ranked for each scenario using a 9‐point scale (Table 1). Consensus was achieved using a modified Delphi process. Online surveys were completed iteratively by Workgroup members, followed by discussion, until all votes for each scenario fell within one of the following categories: Appropriate/Uncertain/Rarely Appropriate.ResultAs an over‐arching principle, amyloid/tau PET should be considered in patients who: (1) have undergone a comprehensive assessment by a dementia expert; (2) Alzheimer’s disease (AD) is a diagnostic possibility but uncertainty remains; and (3) knowledge of amyloid/tau PET results is expected to help establish diagnosis and guide patient management. Consensus ratings for clinical scenarios are shown in Table 2. More evidence was available to inform recommendations for amyloid than tau PET. Amyloid PET was considered “Appropriate” to inform diagnosis of MCI or dementia due to suspected AD; clarify diagnosis when CSF biomarkers are equivocal; to inform prognosis in MCI; and to determine eligibility for amyloid‐targeting therapies. Tau PET was considered “Appropriate” to clarify diagnosis in patients with MCI/dementia under age 65 or those with atypical presentations; and to inform prognosis in MCI or dementia due to suspected AD.ConclusionThe updated AUC highlight a growing role for amyloid PET and an emerging role for tau PET in the clinical evaluation of cognitively impaired patients. AUC are expected to further evolve based on data from ongoing studies of clinical utility and a rapidly developing therapeutic landscape.
Cognitively healthy Indians with higher Framingham Cardiovascular Risk Scores have higher WMH burden with lesser grey matter, white matter and hippocampal volumes
Authors: Sundarakumar Jonas S. , Lingegodwa Abhishek Mensegere , Issac Thomas Gregor ,   SANSCOG and TLSA Study Teams
Published: December 2023

AbstractBackgroundIncreasing evidence indicates the important role of cardiovascular risk factors in dementia risk, particularly in Indians. It is known that cardiovascular risk factors tend to cluster together, and a widely used multivariable risk scoring is the Framingham Cardiovascular Risk Score (FRS). However, very little is known about the association between FRS and structural brain MRI parameters in cognitively healthy Indians.MethodBaseline clinical and brain MRI data of 487 cognitively healthy Indians (Clinical Dementia Rating score of ‘0’), who are part of two ongoing, large, aging cohort studies in India – Srinivaspura Aging, Neuro Senescence and COGnition study (SANSCOG) study (n = 200) and Tata Longitudinal Study of Aging (TLSA, n = 289) were utilized. FRS was calculated using clinical and blood biochemistry data, whereas brain MRI scans were performed on 3T MRI scanners. White matter hyperintensity (WMH) lesion segmentation was performed using Lesion Segmentation Toolbox (LST) and brain volumes (total grey matter, total white matter, 3rd ventricle, right and left hippocampus) were derived using FreeSurfer software and normalized according to total intracranial volumes of the respective subjects. Linear regression analysis was performed with FRS as independent variable and various structural MRI parameters as dependent variables. A p value of <0.05 was considered significant.ResultUrban subjects with higher FRS had significantly higher WMH volume (β = 0.00011, p<0.001, R2 = 0.130), lower grey matter (β = ‐0.00285, p<0.001, R2 = 0.206), white matter (β = ‐0.00180, p<0.001, R2 = 0.106), right hippocampal (β = ‐0.00004, p<0.001, R2 = 0.180), left hippocampal (β = ‐0.00003, p<0.001, R2 = 0.156) volumes and higher 3rd ventricle volumes (β = 0.00003, p<0.001, R2 = 0.150). Rural subjects higher FRS had lower grey matter (β = ‐0.00166, p<0.001, R2 = 0.118, white matter (β = ‐0.0011, p<0.001, R2 = 0.060), right hippocampal (β = ‐0.00002, p<0.001, R2 = 0.087), left hippocampal (β = ‐0.00002, p<0.001, R2 = 0.084) volumes and higher 3rd ventricle volumes (β = 0.00004, p<0.001, R2 = 0.264) but no significant association was seen with WMH volume.ConclusionThese findings indicate that cardiovascular risk is associated with structural brain changes in cognitively healthy Indians. Since cardiovascular risk can be reduced through cost‐effective community level strategies, such as lifestyle‐based interventions, promptly addressing this risk in Indians could be an important part of dementia prevention strategies.
Path integration deficits related to Alzheimer’s disease pathology in clinically normal older adults
Authors: Colmant Lise , Boyer Emilien , Gérard Thomas , Bierbrauer Anne , Kunz Lukas , Sleegers Kristel , Axmacher Nikolai , Lefèvre Philippe , Hanseeuw Bernard J 
Published: December 2023

AbstractBackgroundThe entorhinal cortex (EC) is the first cortical region affected by tauopathy in Alzheimer’s disease (AD) and is implicated in path integration. In early stages of AD, path integration deficits could be present, even before overt memory deficits. Furthermore, path integration deficits are found among older individuals at risk for AD, such as APOE ε4 carriers. We investigated whether this deficit was related to AD pathology or to APOE genotype using a pure path integration task, the “Apple Game” (Bierbrauer et al. 2020).MethodParticipants navigated through a virtual arena and were asked to drop a basket to its initial location after visiting one intermediate location. We recruited 175 clinically normal participants (MMSE>24/30, median age = 65). We genotyped the APOE gene and classified participants as ε4 carriers (n = 60) or non‐carriers (n = 115). We measured the plasma ratio of Aβ42 and Aβ40 using Simoa. We defined a threshold of Aβ42/Aβ40 with a gaussian mixture model to classify participants as Aβ+ (Aβ42/Aβ40<0.047, n = 54) or Aβ‐ (Aβ42/Aβ40> = 0.047, n = 121). We analyzed path integration performance depending on APOE genotype and amyloid status with a linear mixed model including age as covariate. A subset of participants (n = 49) underwent a second generation Tau‐PET (18F‐MK‐6240). Task performance was related to EC tauopathy using a linear mixed model.ResultsThe path integration performance was lower among older individuals Aβ+ compared to Aβ‐ (Fig.1, p = 0.04). There was no APOE effect after taking Aβ into account. This indicates that path integration performance was more related to Aβ pathology than to APOE genotype. In participants with Tau‐PET, we observed that the angular error, a component of the task performance, increased with the EC Tau signal (Fig.2, p = 0.05).ConclusionWe detected a path integration deficit among clinically normal older individuals that depended on Aβ. Furthermore, path integration performance was related to tauopathy in the EC, possibly reflecting impairment of grid cells. These observations suggest that path integration deficits observed in older individuals carrying an APOE ε4 allele are related to incipient AD pathology.
Identifying microglial CSF biomarkers specifically dysregulated in either the preclinical or the dementia stage of Alzheimer’s disease
Authors: Blujdea Elena Raluca , Vermunt Lisa , Irwin David J. , Chen‐Plotkin Alice , Boiten Walter , Pijnenburg Yolande A.L. , van der Flier Wiesje M. , del Campo Marta , Teunissen Charlotte E. 
Published: December 2023

AbstractBackgroundTranscriptomic and pathological studies indicate that microglia play a key role in the progression of Alzheimer’s disease (AD). Through the cellular theory of AD (De Strooper, Karran, 2016), microglia are shown to have dynamically heterogeneous states that could be both beneficial and detrimental. The states may present in time‐dependent waves of upregulation and/or downregulation of microglial‐specific proteins (Paolicelli et al., 2022), that could feature in the AD continuum. This study aims to find useful biomarkers to stage early versus late AD through CSF protein expression profiling of microglia.MethodProximity ligation‐based immunoassays panels were used to measure 637 proteins in 565 cerebrospinal fluid (CSF) samples from the Amsterdam Dementia Cohort and University of Pennsylvania from three groups: 1) subjective cognitive decline (SCD) with amyloid/tau ratio positivity (SCD(ratio+): n = 49, mean age = 58 years, 64% males), 2) AD‐dementia (n = 234, mean age = 66 years, 59% males), and, 3) non‐AD ratio negative controls (Controls(ratio‐): n = 282, mean age = 68 years, 66% males). In total, we selected 300 proteins for the comparisons, based on enrichment in microglia from human‐derived single‐cell RNA‐sequencing data. One‐way ANOVA with age, sex, and Tukey’s post‐hoc multiple comparison correction was performed to infer the group differences per protein and detect differing patterns between the three groups.ResultOut of 107 significantly dysregulated proteins compared to controls, only 5 had clear divergent effects in the two groups. IDUA, FURIN, and LGMN were lowered in AD‐dementia and elevated in SCD(ratio+), while IL18 and CTSC were elevated in AD‐dementia and lowered in SCD(ratio+), figure 1. IDUA is associated to lysosomal degradation, whereas FURIN and LGMN are both proteases that activate downstream pathways controlling cell growth and remodelling. IL18 is linked to macrophage activation and CTSC is involved in activation of inflammatory mediators.ConclusionOverall, this study shows preliminary patterns as a first step for precise biological staging of the AD continuum. Through identifying the microglial protein profiling at different stages of disease, we eventually aim to create biomarker panels to map the inflammatory profile and possibly find biomarkers for the hypothesized dual‐wave of inflammation response in AD.
The Association Between Levels of Plasma Biomarkers and Cognitive Performance in the Oldest Old
Authors: Lorenz Linda M.C. , Zhang Meng , Tesi Niccoló , van der Lee Sven J , Hulsman Marc , Gouda Mariam , Sikkes Sietske A.M. , Teunissen Charlotte E. , Holstege Henne 
Published: December 2023

AbstractBackgroundLower cognitive performance in Alzheimer’s Disease (AD) patients has been correlated with changes in blood‐based biomarkers Amyloid‐βeta‐40 (Aβ40), Amyloid‐βeta‐42 (Aβ42), phosphorylated Tau (pTau), neurofilament light (NfL) and glial fibrillary acidic protein (GFAP). However, it is still unclear whether there is an association between cognitive performance and plasma biomarkers in the oldest old. Here we investigate I) The association of plasma biomarkers with age across a wide age‐continuum until extreme age (≥100 years); II) To what extent plasma biomarkers associate with cognitive performance ≥100 years.MethodThe Dutch 100‐plus study cohort comprises of self‐reported cognitively healthy centenarians. Biomarkers were measured in 202 centenarians (137 females) on the Simoa platform. We also included centenarian siblings, offspring and their respective partners (N = 318), who were cognitively healthy. I) To investigate the relationship between age and biomarkers, we standardized all biomarkers and performed linear regression analyses. II) Cognitive performance in centenarians was determined using a comprehensive neuropsychological test battery assessing several cognitive domains. Biomarker concentrations were divided into tertiles. Cognitive performance was assessed adjusting for age, sex and education.ResultI) We observed an age‐related increase Aβ40 (rs = 0.70; range 46.5‐286.5 pg/mL), Aβ42 (rs = 0.53; range 1.4‐17.7 pg/mL), pTau‐181(rs = 0.68; range 0.5‐12.8 pg/mL), NfL (rs = 0.81; range 4.5‐378.7 pg/mL) and GFAP (rs = 0.76; range 24.4‐1085.1 pg/mL), or decrease in Aβ42/40 (rs = ‐0.43; range 0.01–0.10 pg/mL; P<0.001 for all biomarkers, Figure 1). II) Lower Aβ42/40 was associated with lower cognitive performance on global cognition (based on composite z‐score of all tests) β(95%CI) 0.26(0.00–0.51), P = 0.002) and domain executive functioning β(95%CI) 0.16(‐0.07–0.40), P = 0.039), but not with the Mini‐Mental State Examination (MMSE) or the other cognitive domains. Higher concentrations of NfL were associated with lower cognitive performance on MMSE β(95%CI) ‐0.22(‐1.48–1.04), P = 0.005), but not with the separate cognitive domains tested.ConclusionLevels of plasma biomarkers rise with age, also in cognitively healthy individuals. However, correlation with cognitive performance varies across biomarkers and cognitive tests, and deserves further evaluation.