bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cluster analysis of the longitudinal progression of plasma biomarkers and amyloid imaging in the Wisconsin Registry for Alzheimer’s Prevention
Authors: Wells Michael , Bilgel Murat , Jonaitis Erin M. , Langhough Rebecca E , Du Lianlian , Betthauser Tobey J , Blennow Kaj , Ashton Nicholas J. , Zetterberg Henrik , Johnson Sterling C , Jedynak Bruno Michel 
Published: December 2023

AbstractBackgroundThe analysis of the longitudinal progression of plasma biomarkers and amyloid imaging might lead to new insights in the early pattern of biomarker changes.MethodPlasma Aβ42/Aβ40, pTau231/Aβ42, pTau181/Aβ42, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NFL) were measured for n = 223 subjects and 1673 total visits in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) using Quanterix Simoa assays at the University of Gothenburg. Global distribution volume ratio (DVR) was computed from 11C‐Pittsburgh compound B PET scans. Inclusion criteria included Amyloid or CSF Amyloid positive status, and at least one plasma serial value. Trajectories spanning age 46.9 to 80.3 years old for the DVR and plasma biomarkers were estimated by fitting a vector field to the longitudinal data (https://arxiv.org/abs/2206.15215). A Louvain community clustering analysis was performed. The time from Amyloid positivity (DVR = 1.19; centiloid of 22) was also computed for all individual trajectories that crossed this threshold.ResultThe Louvain community clustering algorithm resulted in three distinct communities (Fig 1): no increase in DVR or plasma biomarkers (Green, n = 88(39.5%)); increase in DVR and all plasma biomarkers except NFL (Red, 41(18.4%)); and mixed DVR plus GFAP and NFL increase (Blue, 94(42.2%)). Time since Amyloid positivity (TSAP) was computed for the subset of subjects (n = 84) expected to cross the Amyloid positivity threshold. The Louvain communities as a function of TSAP are shown in Fig 2.ConclusionWe identified three communities regarding the longitudinal progression of amyloid PET and plasma biomarker levels. Plasma biomarkers were dynamic up to 30 years before Amyloid positivity.
ApoE4 is associated with higher lipid peroxidation but not protein nitration in AD brains
Authors: Thorwald Max A , Godoy‐Lugo Jose A , Forman Henry Jay , Finch Caleb E 
Published: December 2023

AbstractBackgroundOxidative damage to proteins is associated with increased lipid peroxidation product hydroxynonenal (HNE) and nitrotyrosine (NT) during Alzheimer’s disease (AD). Because ApoE4 confers higher risk for AD, we assayed HNE and NT in AD and controls by ApoE allele. Oxidative damage was assayed in whole cell lysate and in lipid rafts (LR), where APP is enzymatically processed. Prefrontal cortex (Brodmann 8‐10) was compared with cerebellum, which has minimal AD pathology.MethodPostmortem samples were age‐and sex matched for Braak scores of NFT. Homogenates from full thickness prefrontal cortex (n = 52) or cerebellum (n = 58) in isotonic buffer and mild detergent (RIPA; 1% NP40) were centrifuged (10,000g/1h; for the supernate fraction’). The same brain samples were processed for the subcellular LR fraction (Invent Biotechnologies; LR‐039); LR isolations were validated by ultracentrifugal fractionation. Samples were assayed by dot blots with antibodies for HNE or NT (Millipore, Burlington, MA).ResultIn prefrontal cortex supernates, AD increased HNE (+60%) and NT (+40%) above cognitively normal, while in cerebellum, only HNE increased. For LR, HNE increased in both prefrontal cortex (+165%) and cerebellum (+45%), while NT increased in AD prefrontal cortex (+40%), but not cerebellum. ApoE alleles differed in oxidative damage by brain region: E4 carriers had higher HNE (+35%) only in prefrontal cortex, while LR HNE was higher in E4 carriers of both regions (prefrontal cortex, +80%; cerebellum, +35%). NT did not differ in prefrontal cortex supernatant or LR by ApoE allele.ConclusionThese findings extended prior findings on oxidative damage for HNE with AD by showing differences by brain region and by ApoE allele. HNE is formed from iron redox mediated lipid peroxidation, while protein nitration may be stimulated by aggregated amyloid independent of iron. AD was consistently associated with higher HNE and NT. The ApoE4 allele was more robustly associated with higher HNE in prefrontal cortex than cerebellum, while NT had no associations with E4, suggesting lipid peroxidation may be the predominant form of oxidative damage in the AD brain. The LR may be a hotspot for lipid peroxidation, with implications for APP processing which will be examined in future studies.
Imaging and quantifying microglial activation in vivo and ex vivo using diffusion MRI – with validation by immunohistochemistry
Authors: Sun Zhexian , Wu Wenjie , Xu Haonan , Flores Shaney , Hobbs Diana A. , Perrin Richard J. , Franklin Erin E. , Schindler Suzanne E. , Benzinger Tammie L.S. , Morris John C , Wang Yong , Wang Qing 
Published: December 2023

AbstractBackgroundAlzheimer disease (AD) is the most common type of dementia.There is growing evidence that the amyloid plaques in postmortem AD human brains are surrounded by activated microglia. Using diffusion basis spectrum imaging (DBSI), we have previously observed increased cellular diffusivity in AD patients, suggesting increased microglia activation as a key pathology in AD. To better understand the underlying mechanism and further establish the noninvasive and nonradioactive DBSI biomarkers of microglia activation, we conducted a realistic Monte Carlo (MC) simulation to model diffusion MRI signals associated with microglia in various activation states.MethodFirst, realistic microglia diffusion signals were generated using MC simulation with real 3D microglia geometry obtained from neuromorpho.org (Fig. 1A). We simulated different pathophysiological scenarios to validate DBSI’s capability in quantitatively detecting microglia activation (Fig. 1B). Second, we conducted and ex vivo MRI scans on human postmortem AD brain samples, followed by immunohistochemical (IHC) staining of microglia (Iba‐1) in aligned sections from the same tissue. DBSI cell apparent diffusion coefficients (ADC), reflecting microglia activation, were estimated and compared to quantitative histological assessments of microglia activation. Finally, in vivo DBSI was conducted on 200 participants who were classified into healthy control, preclinical AD, and early symptomatic AD groups based on cognitive assessments and measures of CSF amyloid (Aβ42) and pTau181.ResultTwo exemplary regions in grey matter (GM) and white matter (WM) of a postmortem AD brain were selected (Fig. 1C). We found that GM had significantly higher DBSI‐derived cell ADC than WM (Fig. 1D). Iba‐1 IHC revealed that WM had significantly larger average microglial area (p<0.005) and bigger max microglia larea (Fig. 1E‐F). MC Simulation was conducted on 700 microglia models. Microglial activation would result in an increased DBSI cell ADC (Fig. 1G). According to MC simulation, increased DBSI‐derived cell ADC in preclinical and early symptomatic AD indicated microglial activation in preclinical and early symptomatic AD (Fig. 1H).ConclusionDBSI‐derived cell ADC increases with microglial activation as assessed by quantitative Iba‐1 IHC. This finding is supported by MC simulation using real 3D microglia geometry. The study indicates that DBSI has the potential to provide non‐invasive MRI biomarkers of microglia activation.
Remote assessment of cognition with the unsupervised version of the Cogstate Brief Battery: Association of composite endpoints with Alzheimer’s disease biomarkers
Authors: Maruff Paul , Bransby Lisa , Yassi Nawaf , Buckley Rachel F. , Lim Yen Ying 
Published: December 2023

AbstractBackgroundIn people at risk of Alzheimer’s disease (AD), access to cognitive assessment can be increased through internet‐based registries, which can be linked to disease management clinics for comprehensive follow‐up. The Cogstate Brief Battery (CBB) has been optimized for unsupervised use in registries. This study aimed to determine relationships between performance on the unsupervised CBB, defined using conventional Cognigram and novel composite scores, and in‐clinic CSF AD biomarkers and cognition in middle‐aged adults at‐risk of AD.MethodSeventy‐six cognitively unimpaired (CU) adults (67% female; Mage (SD) 58.4(6.7)) enrolled in the Healthy Brain Project (healthybrainproject.org.au) completed unsupervised CBB assessments, and subsequent in‐clinic assessment of AD biomarkers and cognition. CBB tests included DET (psychomotor‐function), IDN (attention), OCL (learning) and OBK (working memory). The Cognigram Learning/Working Memory Composite, and the Cognigram Psychomotor/Attention composite were derived from these. Two novel composites were also computed: the OCL speed/accuracy composite, and OCL‐OBK speed/accuracy composite. In‐clinic assessments included the International Shopping List, Logical Memory, and Digit Symbol Substitution Tests, and Mini Mental Status Examination to provide a Preclinical Alzheimer’s Cognitive Composite (PACC) score. CSF Aβ42, total tau (t‐tau), and tau phosphorylated at threonine 181 (p‐tau181) were measured by immunoassay (Roche Elecsys®) and CSF neurofilament light (NfL) was measured using ELISA. Associations with CSF Aβ42, t‐tau, p‐tau181, NfL and PACC were determined for each CBB composite with age, sex, education, APOE4 and time difference between unsupervised and in‐clinic assessment controlled statistically.ResultThe Cognigram Learning/Working memory composite, the OCL speed/accuracy composite, and the OCL‐OBK speed/accuracy composite were associated with PACC scores and with t‐tau, p‐tau181, and NfL levels. Magnitude of relationships were similar across composites (Table 1). No cognitive composite was associated with CSF Aβ42. Performance on the Cognigram Psychomotor/Attention composite was unrelated to AD biomarkers or PACC scores.ConclusionIn CU adults, unsupervised performance on CBB composites containing learning and working memory measures were associated strongly with in‐clinic neuropsychological outcomes and AD biomarkers. Remote measurement of cognition can validly assess aspects of learning and working memory disrupted by early AD processes such as increases in tau, and could be useful for identification of individuals with early disease.
Functional connectivity trajectories in genetic frontotemporal dementia
Authors: Zhang Liwen , Flagan Taru M. , Staffaroni Adam M. , Häkkinen Suvi , Brown Jesse A. , Mandelli Maria Luisa , Rosen Howard J. , Kantarci Kejal , Ramos Eliana Marisa , Tempini Maria Luisa Gorno , Miller Bruce L , Seeley William W. , Lee Suzee E. ,   ARTFL/LEFFTDS/ALLFTD Consortia
Published: December 2023

AbstractBackgroundCharacterizing disease trajectories in frontotemporal lobar degeneration (FTLD) is essential to determine the optimal timing for initiating therapeutic interventions, and there is an urgent need for novel and sensitive disease biomarkers. Intrinsic connectivity network (ICN) mapping using task‐free fMRI is a promising biomarker which reveals early abnormalities even before symptomatic onset (Dopper et al. 2014; Lee et al. 2016). Yet, ICN trajectories from the presymptomatic to symptomatic stages in FTLD mutation carriers remain unclear.MethodIn this cross‐sectional study, we used UCSF and ALLFTD Consortia data to study 129 carriers with variants in MAPT (presymptomatic/prodromal/symptomatic: 34/4/7), C9orf72 (30/9/12) and GRN (22/4/7). Using cross‐sectional data to construct ICN trajectories by genotype, we built separate generalized additive models for each genetic group to estimate non‐linear relationships between standardized connectivity changes and disease age across clinical stages. ICN connectivity was based on seed‐based analyses for networks associated with common clinical syndromes for each genetic group (i.e., salience and default mode [MAPT/C9orf72/GRN], corticobasal syndrome [MAPT/GRN], progressive supranuclear palsy syndrome [MAPT], sensorimotor and medial pulvinar‐related [C9orf72], and non‐fluent variant primary progressive aphasia (nfvPPA) syndrome networks [GRN]). We included 127 healthy controls as a reference to calculate ICN z‐scores for each carrier. Each carrier’s disease age was defined as the difference between the carrier’s chronological age and estimated age of onset based on multimodal measures of structural imaging, fluid biomarker and clinical assessments (Staffaroni et al. 2022).ResultIn MAPT+, presymptomatic carriers showed declining salience network connectivity starting approximately 30 years before estimated onset, which plateaued about 20 years before onset. In C9orf72+, salience network hyperconnectivity emerged about 30 years before onset and declined throughout the presymptomatic and symptomatic stages. For GRN+, connectivity changes as a function of disease age were found within the salience and nfvPPA networks, with connectivity stable until around 10 years before estimated onset, followed by decline starting in the late presymptomatic phase and continuing through the prodromal and symptomatic stages.ConclusionThese findings demonstrate that FTLD genes show distinct ICN trajectories throughout the clinical spectrum. These results help pave the way for determining the optimal timing to initiate therapeutic interventions.
Chosen Family? Rethinking “Relationship Status” in LGB Cognitive Aging Research
Authors: Hanes Douglas William 
Published: December 2023

AbstractBackgroundExisting studies have shown the importance of marital status and quality on later‐life cognitive health, including dementia risk and likelihood of timely dementia diagnosis. Yet, much evidence comes from different‐sex couples’ experiences, for whom marriage remains the norm and unmarried persons face social and material costs. In contrast, where same‐same marriage is legal in North America and Europe, marriage has not yet become the norm: same‐sex couples (SSCs) have lower marriage rates than different‐sex couples. SSCs also tend to structure their relationships differently across a range of domains, from household labor to sexual nonmonogamy. Throughout Europe and North America, older lesbian and gay people are also more likely to be single, to live alone, and to have no living children than straight or bisexual people; as a result, the former tend to rely less on partners or biological family to meet their social needs. Unlike straight men, for example, gay and bisexual men tend to rely less on their partners or daughters to forge and maintain social and community connections, instead relying on “chosen families”.MethodGiven their unique prominence for sexual minorities, this paper uses population‐based surveys from the US (HRS) and Europe (ELSA and SHARE) to investigate measures of non‐biologically familial social bonds, including whether measures of friendship, social connectedness, and community involvement function similarly to marital status.ResultIn the US, which has the highest marriage rates and a deeply entrenched “marriage culture”, LGB participants in the HRS (1998‐2018; n = 23,035) who indicate having never been married perform better cognitively at baseline than married LGB people (β = 1.5; p = 0.05), while never‐married straights perform worse (β = ‐0.9; p <0.01).ConclusionRelationship factors have a different association with cognitive health for LGB people than straight people, yet these remain unexplored in their effects on cognitive aging and queerer pathways to good cognitive health.
Allostatic load measures in elderly subjects with mild cognitive impairment and subjective cognitive decline: a cross‐sectional analysis from the Brazilian Memory and Aging Study
Authors: Barbosa Breno José Alencar Pires , Jesus Maria Clara Ferreira , de Oliveira Maira Okada , Cassimiro Luciana , Avolio Isabella B , Trés Eduardo Sturzeneker , Borges Conrado Regis , Teixeira Thiago Bezerra Moraes , Souza‐Talarico Juliana Nery , Brucki Sonia Maria Dozzi 
Published: December 2023

AbstractBackgroundThere’s increasing evidence suggesting that chronic stress and persistently high levels of cortisol are related to cognitive dysfunction and neurodegeneration. The Brazilian Memory and Aging Study (BRAMS) is a research initiative for the longitudinal follow‐up of individuals in a tertiary center specialized memory outpatient clinic. The present study aimed to investigate the relationship between markers of chronic stress and cognitive status in BRAMS, making comparisons between participants classified as controls, subjective cognitive decline (SCD) and mild cognitive impairment (MCI)Methodcross‐sectional study with a subgroup analysis of the BRAMS cohort, in which individuals aged > 60 years had access to a comprehensive neuropsychological classification, clinical, imaging and laboratory measures. The allostatic load index (AL) was measured through anthropometric, endocrinological, cardiovascular, metabolic and inflammatory markers of chronic stress.Result77 participants were evaluated, of which 65 met the inclusion criteria. The mean age was 70.2 (+ 6.01) years, with 72% being female and 11 years of schooling (interquartile range 7 – 15). 42 subjects were classified as MCI, 15 as SCD and 8 as controls. There was a significant difference between waist/hip ratio (0.94 in the MCI group vs. 0, 88 in the SCD group, p = 0.03) and in the measurement of the weighted AL index considering individuals in the extremes values of cortisol (36.9% in the MCI group vs. 27.2% in the SCD group, p = 0.04). In the multivariate analysis, higher education was associated with reduced risk of MCI.Conclusiondespite a modest sample size, the present work probably represents one of the first research initiatives to address measures of chronic stress beyond cortisol in elderly participants diagnosed with SCD and MCI, with an increased AL in the MCI group. Due to the cross‐sectional nature of the study, the associations found do not allow inferring causality between the measures, which need further validation in the longitudinal follow‐up of the participants.
Socioenvironmental, Stigma, Risk, and Protective Factors Associated With the Health of Latino LGBTQ+ Dementia Caregivers
Authors: Kittle Krystal R. 
Published: December 2023

AbstractBackgroundCompared with caregivers of individuals with other chronic conditions, dementia caregivers experience worse emotional and physical health and are twice as likely to say their health has declined due to caregiving. Both Latino and LGBTQ+ populations are underrepresented in dementia caregiving research, though both populations report a higher prevalence of informal caregiving compared with their non‐Latino White and non‐LGBTQ+ counterparts. We aimed to examine associations between socioenvironmental, stigma, risk, and protective factors and global health among Latino LGBTQ+ caregivers of people with dementia.MethodData came from a cross‐sectional online survey using a non‐probabilistic sample of English‐proficient, Latino LGBTQ+ dementia caregivers recruited via social media (n = 103). We examined associations using bivariate analyses.ResultLatino bisexual respondents reported better global health than Latino gay and lesbian respondents. Females had better health than males and transgender respondents reported poorer health than cisgender respondents. Millennials had worse health than Generation X respondents. There were positive associations between global health and months providing care, lifetime discrimination, day‐to‐day discrimination, lifetime victimization, and microaggressions and negative associations between self‐efficacy for surrogate decision making and family quality of life. Respondents providing care to a spouse (versus a parent, another relative, or friend), those living with their care recipient, those who had been asked by a provider whether they needed help caring for themselves or their care recipient, and respondents who had requested information about financial help for their care recipient had better health. Respondents whose care recipients had advanced directives had poorer health than those who did not.ConclusionSeveral socioenvironmental, stigma, risk, and protective factors were associated with the global health of Latino LGBTQ+ dementia caregivers. Latino LGBTQ+ dementia caregivers may be exhibiting signs of resiliency, for example when it comes to discrimination and caregiving demand, and seeking help may be important for their health. Some associations may be confounded by other factors and more research is needed to understand the pathways by which these factors ultimately influence the health of Latino LGBTQ+ dementia caregivers.
Identifying the role of transcriptome in amyloid‐β and tau pathologies in Alzheimer’s disease
Authors: Yu Meichen , Risacher Shannon L , Nho Kwangsik , Saykin Andrew J. ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: December 2023

AbstractBackgroundAmyloid‐β and tau proteins accumulate at distinct neuronal systems in Alzheimer’s disease (AD). However, why specific brain regions are more vulnerable to amyloid‐β and tau pathologies than others remain unclear.MethodUsing two independent cohorts from the ADNI and the IADRC as discovery and replication samples, we studied the relationship between gene expression profiles and amyloid‐β and tau pathologies. In ADNI, we included 583 and 564 participants with amyloid‐β PET and tau PET data, respectively; in IADRC, we included 110 and 78 participants with amyloid‐β PET and tau PET data, respectively. In both cohorts, amyloid‐β pathology was measured by [18F]florbetapir (AV45) and [18F]florbetaben (FBB) PET; tau pathology was measured by [18F]flortaucipir (AV‐1451) PET. The regional vulnerability to amyloid‐β and tau pathologies were estimated by contrasting amyloid‐β and tau PET data between cognitively unimpaired (CU and/or SCD) and patients (MCI and AD). Regional expression profiles for 20,736 protein‐coding genes were derived from brain‐wide microarray‐based transcriptome data from the Allen Human Brain Atlas. We computed spatial associations between gene expression levels and amyloid‐β (gene‐to‐amyloid‐β associations) and tau (gene‐to‐tau associations) pathologies for 60 AD susceptibility genes selected from recent large‐scale GWAS studies.ResultIn both cohorts, AD and MCI showed the expected higher amyloid‐β loads than CU, particularly in the medial parietal cortex, temporal lobe, medial and inferior prefrontal cortices, and superior and middle frontal cortices. In both cohorts, AD and MCI showed higher tau deposits than CU, mainly in the medial temporal lobe, medial and inferior parietal cortices, and inferior and middle temporal cortices. In both cohorts, we identified consistent significant gene‐to‐amyloid‐β and gene‐to‐tau associations after multiple testing adjustment (PFDR < 0.05). Specifically, CNTNAP2 and CLU showed the strongest positive gene‐to‐amyloid‐β associations, whereas TNIP1 and INPP5D showed the strongest negative associations. APOE and BIN1 showed the strongest positive gene‐to‐tau associations, whereas SORL1 showed the strongest negative associations.ConclusionWe identified replicable regional vulnerability patterns of amyloid‐β and tau pathologies and their relationships to regional gene expression profiles. Better understanding of the regional association of gene expression and amyloid‐β and tau pathologies may foster identification of novel diagnostic and therapeutic targets.