bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fluid and imaging amyloid‐beta biomarkers discordant individuals present different blood transcriptomic phenotypes
Authors: Schlickmann Thomas Hugentobler , de Bastiani Marco Antônio , Bellaver Bruna , Zalzale Hussein , Souza Lara Angi , Machado Luiza Santos , da Rocha Andreia Silva , Da Ros Lucas Uglione , Ferrari‐Souza João Pedro , Carello‐Collar Giovanna , Lazzarotto Gabriela , Limberger Christian , de Carvalho Lavínia Perquim , Vidor Pedro , Borelli Wyllians Vendramini , Rohden Francieli , Pascoal Tharick A. , Zimmer Eduardo R. ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: December 2023

AbstractBackgroundCerebrospinal fluid (CSF) and Positron emission tomography (PET) amyloid‐β biomarkers are commonly used interchangeably to measure amyloid‐β deposition, an early event in the development of Alzheimer’s disease (AD). However, it is not uncommon to find individuals with discordant measurements of amyloid‐β CSF and PET. It has been hypothesized that this discordance may be an intermediate step between the CSF and brain amyloid deposition, and that discordant individuals might be in different disease stages or have different disease phenotypes. Here, we applied blood transcriptomic analysis to evaluate differences in amyloid‐β CSF and PET discordant and concordant individuals.MethodWe analyzed the blood transcriptome of 200 individuals from the ADNI cohort who had measurements of both CSF amyloid‐β42 and [18F]Florbetapir PET at baseline and at 2‐year follow‐up. The demographic characteristics of the sample are presented in table 1. Our analysis yielded four groups: CSF+/PET‐ (n = 18), CSF‐/PET+ (n = 19), CSF+/PET+ (n = 76), and CSF‐/PET‐ (n = 87). The latter was the control group for all analyses. Differentially expressed genes (DEGs, uncorrected p‐value < 0.01) were used for gene set enrichment analysis (GSEA) to identify group‐specific altered biological pathways.ResultCSF+/PET‐, CSF‐/PET+ and CSF+/PET+ individuals showed a great proportion of unshared DEGs (Figure 1). The CSF+/PET‐ group, which is thought to represent a very early stage in the disease, presented the highest number of unshared DEGs (273) with upregulated GO terms involved mainly in metabolic processes. The CSF‐/PET+ group possessed 113 unique DEGs, while the CSF+/PET+ possessed 47. Interestingly, these groups presented similar alterations in biological processes, representing mainly alterations in immune response and inflammation.ConclusionOur results highlight the differences in the blood transcriptomic phenotype between CSF and PET amyloid‐β concordant and discordant individuals. Importantly, individuals very early in the AD continuum (CSF+/PET‐) presented the most distinct phenotype. Our results suggest that blood transcriptomics are able to capture subtle changes in brain amyloid‐β and might help identify individuals in different stages of AD.
The effect of blood pressure on domain‐specific cognitive changes in older Black Americans: findings from the Baltimore Study of Aging – Patterns of Cognitive Aging
Authors: Byrd DeAnnah R. , Coon David W. , Thorpe Roland J. , Whitfield Keith E. 
Published: December 2023

AbstractBackgroundPrevious research suggests that hypertension shape cognitive health outcomes in older Blacks (Whitfield 2008). However, few studies have explored the relation between objective and subjective blood pressure (BP) measures and cognitive decline. This study examined whether systolic, diastolic, and self‐reported BP were associated with changes in cognition.MethodData are drawn from the Baltimore Study of Black Aging—Patterns of Cognitive Aging. At baseline, 602 Black participants (48‐95 years) were enrolled. At follow‐up, approximately 3 years later, 450 participants were re‐interviewed. Cognition included 5 domains: working memory, processing speed, verbal memory, vocabulary, and inductive reasoning. Using an oscillometer automated device (A&D model UA‐ 767), three readings of orthostatic BP were collected and mean systolic (SBP; range = 82‐230.3 mmHg) and diastolic BP (DBP; range = 51‐136.7 mmHg) values were calculated for each participant. BP was treated as a continuous variable. Participants were also asked “Have you ever been told by a doctor or nurse that you have high blood pressure? (yes/no response)” Data were analyzed using multiple linear regression, controlling for sociodemographic and health conditions.ResultMajority of the sample was female (25.4% male) and had at least a high school education (57.1%). Systolic BP was inversely associated with inductive reasoning at follow‐up (b = ‐0.208, p = 0.023; see Table 1), but was not related to any other cognitive domains, after adjusting for age, sex, education, depressive symptoms, comorbidities, diastolic BP, and baseline cognition. Diastolic BP and self‐reported hypertensive status were both unrelated to changes in each of the five cognitive domains (all models, p> 0.05).ConclusionThe present study adds to our understanding of cognitive aging among older Black Americans. Results support previous research, pointing to an independent effect of BP on domain‐specific cognitive changes (Buford 2016), but also extend the literature by highlighting a more pronounced negative effect of systolic BP. These findings suggest that the pathway to cognitive dysfunction is contributed to by BP. Several key mechanisms – including increased risk for stroke and “vascular dementia” (age‐ and hypertension‐related cerebral vasculature changes) – may explain the influence of hypertension on cognitive decline that warrant further study in Black Americans.
A Music Based Intervention: “Stay with Me” Results Reveal Challenges and Opportunities related to Burden in Family Caregivers of People with ADRD
Authors: Ray Kendra , Mittelman Mary S 
Published: December 2023

AbstractBackgroundFamily caregivers of home‐based people with ADRD took part in a 6‐week psychoeducational music‐based intervention, facilitated by a board‐certified music therapist. Caregivers identified care recipients’ strengths and needs related to symptoms of ADRD. In the following weeks, caregivers learned how to incorporate music‐based activities during their care. This included caregiver singing, adding background music to bath/shower routines, creating personalized playlists, the use of music for sundowning, etc. A concurrent, mixed methods approach was employed. The Short Zarit Burden Interview (12 item) was completed at baseline and follow‐up. During week 6, in small groups ranging from 2 – 6 persons, family caregivers (n = 20) rewrote the lyrics of Stand by Me, using a fill‐in‐the‐blank template.MethodA content analysis of rewritten lyrics revealed a focus on themes. A paired samples t‐test was performed to determine changes in burden. To merge the lyrics and burden scores, a joint display analysis was performed. A box plot of mild to high burden was created to demonstrate how the post‐test scores were distributed across levels of burden accompanied by a descriptive display of the most dominant lyrics that reflected each level.ResultFollowing the music‐based intervention, a paired samples t‐test found that caregiver burden reduced significantly from baseline (from M = 20.73 ± 6.72 to M = 16.1 ± 4.89; p = .000) indicating that caregiver participation in the 6‐week workshop contributed to perceived reduced burden. Post‐tests and box plot showed most caregivers (80%) scored with mild to moderate burden following the study. The results from content analysis of the lyrics described caregivers’ desire to persevere without fear, issues of falling or failing (a replica of the progression of ADRD) but indicate a desire to stay with the person for whom they are caring.ConclusionBurden decreased following participation in the psychoeducational, music‐based intervention. Nevertheless, caregivers cope with a range of emotions related to caring for a person with ADRD, revealing the facilitation of music‐based interventions at home is a useful tool for caregivers but also a need for continuous support. The study is ongoing.
Modulation of the p75 neurotrophin receptor in the PS19 tauopathy mouse model regulates transcription profiles and inter‐cellular communication across multiple populations of non‐neuronal cells
Authors: III Robert R. Butler , Yang Tao , Han Crystal , Guen Yann Le , Tran Kevin C , Lallani Shoeb , Liu Harry , Leng Song Albert , Massa Stephen M. , Longo Frank M. 
Published: December 2023

AbstractBackgroundTau pathologies contribute to neurodegeneration in Alzheimer’s Disease (AD) and other disorders via a variety of mechanisms. In tauopathy mouse models, administration of LM11A‐31 (C31), a small molecule modulator of the p75 neurotrophin receptor (p75NTR), reduced tau post‐translational modifications, accumulation of pathological tau species and microglial activation; restored synaptic plasticity, and reversed synaptic spine loss. We examined long‐term dosing with C31 at the single‐cell transcriptional level to further elucidate cell types and cellular mechanisms affected by treatment.MethodTauopathy model tauP301S mice (PS19) and age‐matched wildtype (Wt) mice were dosed by oral gavage with C31 or vehicle once daily for 3 months from 6 months of age, when tau pathology was well established. Whole cortex single‐nucleus RNA‐sequencing was analyzed using Seurat, with automated cell type annotation, followed by manual curation. Additional analyses compared AD‐associated biodomains and risk scored genes from TREAT‐AD with individual cell types. Finally, cell‐to‐cell communication was assessed via Liana ligand‐receptor (LR) interaction analysis.ResultSeveral neuronal, glial, and vascular cell types showed inverse correlations between C31 differential expression and both PS19 differential expression and TREAT‐AD biodomains (Figure 1), suggesting shifts in expression profiles in the opposite direction from those in human AD cohorts and mouse tauopathy models. In LR interaction analysis, vascular and leptomeningeal cells (VLMCs) were highly active as a signaling source to most other cells—particularly neurons—in the PS19 vehicle mice compared to all other groups (Figure 2). VLMC LR signals that were stronger in PS19 vehicle mice versus Wt vehicle were enriched for Focal Adhesion/PI3K‐Akt signaling, TGF‐beta signaling, AD‐presenilin pathways and regulation of synapse organization (Figure 3). VLMC LR signals that were stronger in PS19 C31 versus PS19 vehicle showed similar pathway enrichments and included several neuropilin‐semaphorin‐plexin complexes which may direct neuronal wiring and development.ConclusionThese findings demonstrate that broad patterns of expression and LR signaling in multiple cell types impacted by tauopathy show substantial reversion to wildtype‐like patterns when treated with C31. Further they indicate a possible role for VLMC signaling in the pathogenesis of tauopathies.
The human microglia response to amyloid plaques explains genetic risk of AD
Authors: De Strooper Bart 
Published: December 2023

AbstractBackgroundMany GWAS genes associated with risk of AD are expressed in microgliaMethodmicroglia in vitro have poor resemblance to microglia in vivo. On the other hand mouse microglia are not really suitable to catch human polygenic risk. We have created chimeric human‐mouse models to study the human microglia response to amyloid plaques.ResultWe have improved the chimeric model dramatically and have routinely 60% chimerism. We have performed single cell analysis and functional analysis to characterize the multipronged response of microglia to amyloid plaques. We are investigating how drugs modulate this response. We are using spatial transcriptomic approaches to see how microglia and astroglia react in the amyloid plaque nicheConclusionThe reaction of brain cells to amyloid pathology is complex and involves cell‐cell interactions that ultimately affect neuronal health. The simple linear interpretation of the amyloid hypothesis does not provide an explanation for this long cellular phase of the disease.
Single cell multi‐omics implicates immune and vascular cells in Alzheimer’s etiology
Authors: Yang Andrew 
Published: December 2023

AbstractBackgroundUnderstanding the genetic etiology of Alzheimer’s disease (AD) is critical to inform effective therapies but remains a challenge. Genetic heritability of late‐onset AD is ∼60‐80%, and genome‐wide association studies (GWAS) have uncovered dozens of noncoding single nucleotide polymorphisms (SNPs) that influence AD risk. Two challenges for the functional interpretation of AD genetic risk are (1) determining the cell types in which SNPs operate and (2) identifying the genes they dysregulate to drive AD pathogenesis. Single‐nucleus sequencing studies of human neurons, microglia, and other brain cell types have begun addressing these challenges. Yet, many AD risk SNPs remain unmapped. One possibility is that they are expressed in immunovascular brain cell types largely missed by current methods.MethodHere, we optimized Vessel Isolation and Nuclei Extraction for Sequencing (VINE‐seq) to capture multimodal gene expression and chromatin accessibility assays across all major brain cell types from 30 cognitively normal, MCI, and AD human prefrontal cortex samples.ResultWe discover early gene dysregulation in immune and vascular cell types along AD progression. We highlight the gene regulatory networks mediating this dysregulation and implicate processes associated with AD pathology and cognitive decline. Finally, we map noncoding AD risk variants to diverse immune and vascular cell types, thereby expanding our understanding of AD etiology.ConclusionDysfunction of diverse human brain immune and vascular cell types mediate the genetic risk for Alzheimer’s disease.
Delivery of cognition‐oriented treatments for older people with MCI in Australian Memory Clinics: A pilot implementation study
Authors: Bahar‐Fuchs Alex , Mowszowski Loren , Pike Kerryn E. , Lampit Amit , Lee Alessandra , Bentvelzen Adam , Mehrani Inga , Naismith Sharon L 
Published: December 2023

AbstractBackgroundThere is good evidence that cognition‐oriented treatments (COTs) including cognitive training and rehabilitation benefit older adults, including those with mild cognitive impairment or dementia. Despite this, there remains a research‐to‐practice gap where these interventions are not readily available in clinical practice. This paper will describe the protocol for a pilot/feasibility implementation study of rolling out COTs for people with MCI in the Australian Memory Clinic Network.MethodThe Australian Dementia Network (ADNeT) Working Group on Cognitive Interventions is tasked with bridging the evidence‐practice gap in Australian Memory Clinics. We have conducted a scoping review of COT implementation efforts around the world, a multi stakeholder survey to understand needs in gaps, have developed an online clinician‐training toolkit for choosing and delivering interventions, and are conducting an implementation study in 2023 using the RE‐AIM Implementation Framework (Glasgow et al. 2019; www.re‐aim.org), assessing Reach, Efficacy, Adoption, Implementation, and Maintenance of COTs in six participating clinics throughout Australia.ResultOur scoping review identified 29 eligible studies but only four have used formal implementation frameworks. Cognitive stimulation was the most frequent approach in these studies, and only a small proportion investigated cost‐effectiveness and maintenance parameters. The stakeholder survey confirmed that clinicians believe it is very important to offer interventions as part of routine clinical practice, and that more training was required. Progress of our implementation study to date will be described including the clinician training tool.ConclusionThis is the first study in Australia to address the evidence‐practice gap in COT research, and will inform the development of a larger implementation study to continue building the evidence base for the costs and benefits associated with incorporating these evidence‐based approaches in clinical practice.
Endo‐Lysosomal Dysfunction and Neuronal‐Glial Crosstalk in Niemann Pick Type C Disease
Authors: Tahirovic Sabina 
Published: December 2023

AbstractMicroglial activation is a neuropathological hallmark of the lysosomal storage disease Niemann‐Pick type C (NPC). Whole‐body knockout of NPC1 results in enhanced phagocytic uptake and impaired myelin turnover in microglia that precede neuronal death. Npc1‐ deficient microglia are characterized by accumulation of multivesicular bodies and impaired endo‐lysosomal trafficking of lipids while lysosomal degradation remains preserved. To study a cell‐autonomous function of NPC1 in microglia, we generated a conditional knock‐out of NPC1 in myeloid cells by crossing Npc1 flox/flox mice with Cx3cr1 +/Cre mice and characterized microglial, astrocytic and neuronal phenotypes at different pathological stages using mass spectrometry, immunohistochemistry and PET imaging. Microglial activation was the first pathological alteration detected in the brain upon loss of NPC1 in myeloid cells, reflected by altered lipidomic profiles and disease‐associated microglial signatures. Microgliosis was followed by astrogliosis as visualized by immunohistochemistry and TSPO‐ PET and Deprenyl‐D2‐PET imaging, respectively. Furthermore, the loss of microglial NPC1 resulted in neuronal injuries (axonal spheroids) and motor deficits that were detected at the age of 7 months.Our work reveals that a specific loss of NPC1 in myeloid cells is sufficient to trigger pathology in other brain cells, suggesting that a pathological cascade initiated by microglial dysfunction may propagate to astrocytes and neurons.
Graph Theory Analysis of Structural Connectivity in Limbic‐predominant Age‐related TDP‐43 Encephalopathy Neuropathological Change (LATE‐NC)
Authors: Tazwar Mahir , Evia Arnold M , Ridwan Abdur Raquib , Bennett David A. A , Schneider Julie A , Arfanakis Konstantinos 
Published: December 2023

AbstractBackgroundThe anatomical distribution of limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) typically involves the amygdala, hippocampus, and other subcortical, temporal and frontal lobe regions. But its impact on the structural integrity of this network of regions remains unknown. In this study, we tested the hypothesis that LATE‐NC is associated with abnormalities in graph theoretic measures of structural connectivity in the network of regions known to be involved in LATE‐NC.MethodThis study included 148 deceased older adults participating in Rush Memory and Aging Project and Religious Orders Study (Fig.1A). Ex‐vivo diffusion tensor imaging (DTI) scans were acquired on 3T scanners, followed by detailed neuropathologic examination by a board‐certified neuropathologist (Fig.1B). Fractional anisotropy (FA) maps derived from DTI scans were used to define region‐to‐region structural connectivity in a network of 19 regions known to be involved in LATE‐NC using graph theory‐based network measures (Fig.2). General linear models were used to investigate the association of global and local graph measures with LATE‐NC stages, controlling for other neuropathologies (Alzheimer’s disease, Lewy bodies, arteriolosclerosis, atherosclerosis, cerebral amyloid angiopathy, gross and microscopic infarcts), demographics (age at death, sex, education), total white matter hyperintensity volume, postmortem intervals and scanner variables. Statistical significance was set at p<0.05.ResultLinear regression revealed that greater LATE‐NC stage was associated with increased characteristic path length and with lower values of the remaining global network measures (p<0.05) (Fig.3A). LATE‐NC was also associated with lower local efficiency, increased path length, lower nodal strength, and lower clustering coefficient in 74%, 79%, 32%, and 63% of the nodes, respectively (p<0.05) (Fig.3B). Finally, LATE‐NC was associated with both greater (in 21% of nodes) and lower (in 16% of nodes) eigenvector centrality, and with both greater and lower betweenness centrality in 21% of nodes, respectively (p<0.05) (Fig.3B).ConclusionUsing graph theory and a hypothesis‐driven approach, we found significant degradation of structural integrity in white matter of the network of regions affected by LATE‐NC. These findings may shed light on the effects of LATE‐NC on brain connectivity, and in combination with other imaging and clinical information, may aid towards the development of tools for in‐vivo detection of this devastating neuropathology.
Evaluating brain age as a marker of autosomal dominant Alzheimer disease progression
Authors: Millar Peter R , Gordon Brian A. , Benzinger Tammie L.S. , Cruchaga Carlos , Fagan Anne M. , Goate Alison , Hassenstab Jason J. , Holtzman David M. , Llibre‐Guerra Jorge J , Morris John C , Perrin Richard J. , Supnet Charlene B , Xiong Chengjie , Bateman Randall J. , Ances Beau , McDade Eric 
Published: December 2023

AbstractBackgroundEstimates of “brain‐predicted age” quantify apparent brain age compared to normative trajectories of neuroimaging features. Brain‐predicted age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD). We used a previously‐trained model (DeepBrainNet [DBN], Bashyam et al., 2020), which requires minimal MRI pre‐processing, to predict brain age in the Dominantly Inherited Alzheimer Network (DIAN) and evaluated brain age as a marker of ADAD progression.MethodWe used DBN to predict brain age from minimally‐processed, whole‐brain T1 structural MRI scans in 265 ADAD mutation‐carriers (MCs) and 183 non‐carrier controls (NCs). We then tested whether the brain age gap (BAG; difference between predicted and true age) differed as a function of mutation and cognitive status, or estimated years until symptom onset (EYO), and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid‐ß‐42/40), phosphorylated tau (CSF and plasma pTau‐181), neurodegeneration (CSF and plasma neurofilament light [NFL]), and cognition (global neuropsychological composite and CDR‐sum of boxes). Finally, we compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of mutation variants (APP vs. PSEN1 before or after codon 200), APOE E4 carrier status, sex, and education.ResultDBN accurately predicted age in DIAN (Figure 1A). BAG was elevated in symptomatic and asymptomatic MCs, compared to NCs, beginning around ‐10 EYO (Figure 1B,C). BAG, hippocampal volume, and a cortical thickness summary followed similar trajectories across EYO (Figure 1D). BAG was positively associated with PiB PET, CSF and plasma pTau, and CSF and plasma NFL, and was associated with worse cognitive scores, especially in symptomatic MCs (Figure 2). BAG was most elevated in MCs with a PSEN1 mutation before codon 200, but did not differ as a function of APOE, sex, or education (Figure 3).ConclusionWe extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG tracks well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, DBN‐based BAG offers unique benefits in simplicity of data processing and interpretation.