bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex‐ or depression‐specific relationships with CSF sAPPα, sAPPβ and their associations with CSF sTREM2 in older adults
Authors: Nunzio Pomara , Plaska Chelsea Reichert , Bruno Davide , Ramos‐Cejudo Jaime , Osorio Ricardo S , Heslegrave Amanda , Pillai Anilkumar , Imbimbo Bruno P , Zetterberg Henrik , Blennow Kaj 
Published: December 2023

AbstractBackgroundFemale sex and depression are associated with increased risk for Alzheimer’s disease (AD) but the mechanisms for the increased risk remain poorly understood. Increased brain amyloid deposition and microglial activation have both been implicated; however, the role of sex‐ and depression‐related effects on microglial activation remain understudied.Both sAPPα and sAPPβ, cleavage products of non‐amyloidogenic and amyloidogenic APP cleavage, respectively, have been reported to induce microglial activation. These observations prompted us to examine the relationships between sex, depression, and levels of sAPPα and sAPPβ. CSF levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2), which is a possible proxy for phagocytic anti‐inflammatory TREM2‐dependent microglial activation, was also examined.MethodFifty‐one cognitively intact subjects (31 subjects with late‐life major depression (LLMD) and 20 controls) aged 60 years and older, completed a 3‐year longitudinal study. Independent‐samples Mann‐Whitney‐U tests were used to examine group differences by diagnosis, sex, and APOE genotype for sAPPα and sAPPβ.ResultThere were no significant differences between subjects with LLMD and Controls in CSF sAPPα or sAPPβ levels. Irrespective of diagnosis, females had significantly higher levels of both sAPPα (p = 0.016) and sAPPβ (p = 0.010) compared to males. sAPPα and sAPPβ were significantly correlated with each other (rho = 0.930, p<0.001). In the whole sample, sTREM2 correlated with both sAPPα (rho = 0.462, p = 0.001) and sAPPβ (rho = 0.504, p<0.001). When examining the relationships as a function of diagnosis, sAPPα was found to be associated with sTREM2 in Controls only (rho = 0.474, p = 0.035) while sAPPβ correlated with sTREM2 in LLMD only (rho = 0.370, p = 0.048). When examining the relationship as a function of sex, we found that sTREM2 significantly correlated with both sAPPα (rho = 0.629, p = 0.002) and sAPPβ (rho = 0.673, p = 0.001) in females but not in males (sAPPα: rho = 0.310, p = 0.109; sAPPβ: rho = 0.341, p = 0.076).ConclusionMean CSF sAPPα and sAPPβ levels between Controls and LLMD showed no group differences but were significantly increased in females compared to males. Females but not males showed significant positive associations between CSF sTREM2, sAPPα and sAPPβ. Future studies should determine if these results are associated with differences in microglial activation and to the increased risk for AD and depression in females.
Role of peripheral inflammation in driving central nervous system inflammatory signature in pathogenesis of Alzheimer’s disease
Authors: Sanchez‐Molina Paula , Bogachuk Alina , Soto‐Faguás Carlos M , Woltjer Randy L , Cowley Sally A , Quinn Joseph F , Ajami Bahareh 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) impacts an estimated 6.5 million people in the United States, however, it cannot yet be prevented, slowed or cured. Although the sporadic AD form comprises around 95% of cases, animal models of familial AD are the ones used for basic and translational research. Most of these models are based on human mutations that cause amyloid‐β (Aβ) pathological accumulation. However, the failure of the majority of Aβ‐related clinical trials, has begged the necessity of an alternative approach to address AD. Interestingly, most of the genetic and non‐genetic risk factors for developing sporadic AD are associated with inflammation. Thus, it has been suggested that microglia, the immune cells in the central nervous system, play a key role in the pathogenesis of AD, and that people with systemic inflammatory diseases have a higher incidence of developing AD. In this context, we hypothesize that a specific subset of cells in peripheral blood contributes to AD development through its communication with microglial cells in the brain parenchyma.MethodTo address this hypothesis, we analyzed peripheral blood mononuclear cells (PBMCs) from sex‐ and age‐matched healthy and AD subjects using mass cytometry (CyTOF) and cellular indexing of transcriptomes and epitopes by sequencing (CITE‐seq) technologies. Moreover, we used in vitro and histological approaches to study interactions between PBMCs and human microglial cells.ResultOur preliminary data show a different proportion of peripheral blood immune cell types between healthy controls and AD patients. Remarkably, a specific inflammatory subset of immune cells characterized by the upregulation of pro‐inflammatory signaling pathways and cytokines was detected in blood of AD patients. In addition, T cells in contact with microglia were detected in the parenchyma of AD brains by histological analysis, suggesting adrive of microglial cells towards an inflammatory phenotype that could contribute to AD pathology. We corroborated the pathogenic component of AD blood as healthy PBMCs developed an inflammatory phenotype after stimulation with AD plasma.ConclusionTogether, our data demonstrate the importance of peripheral immune cells in AD disease and reinforce that studying AD as a multifactorial disease could be key to its prevention and treatment.
Comparison of Vascular Health in Super‐Agers and Cognitively Normal Adults 80 Years and Older
Authors: Trammell Antoine R , Parker Monica W , Wingo Aliza P. , Wingo Thomas S. , Johnson Kirstin M , Binford Bill , Hajjar Ihab , Goldstein Felicia C 
Published: December 2023

AbstractBackgroundUnraveling factors associated with cognitive resilience and super‐agers might reduce expected increases in Alzheimer’s disease and related dementia (ADRD). Vascular disease can impair the cerebral circulation and increase risk for cognitive decline and ADRD. However, data in persons aged 80+ suggests that maintained vascular health can preserve key brain regions for normal cognition.MethodUsing National Alzheimer’s Coordinating Center (NACC) data from January 2005 ‐ December 2020, we found 9,581 participants age 80+ (white: 8,296 vs. AA: 1,285,p<.0001) at the baseline visit. We defined cognitive groups per global Clinical Dementia Rating (CDR) and Memory subscale scores. Normal cognition (NC) was defined as a global CDR and memory subscale score = 0. To identify super‐agers (SA), we utilized data‐derived cutoffs from cognitive test performances consistent with prior reports. The operationalized definition was created from: 1) Mean Craft delayed recall scores in 50–60‐year‐olds with NC; 2) Craft scores among age 80+ with NC group were standardized to the mean score for age 50‐60 with NC; and 3) Standardized mean scores for non‐memory measures (trail making test‐B, phonemic fluency, and multilingual naming test) for age 80+ with NC. SA were defined as age 80+ with episodic memory performance (Craft scores) ≥ 1 standard deviation (SD) of the standardized mean for the age 50‐60 group and non‐memory scores ≥ 1 SD of the standardized mean for the 80+ age group.ResultWe identified 4.5% (n = 431) SA and 27.7% (n = 2,654) NC (p<.01) to compare vascular variables. Compared to NC, SA were younger (83.5±3.4 vs. 84.7±4.0, p<.01), had more education (16.5±2.8 vs. 15.2±3.1, p<.01), higher diastolic blood pressure (DBP) (73.9±10.5 vs. 71.9±10.5, p<.01), and mean arterial pressure (MAP) (95.5±11.8 vs. 93.5±11.5, p<.01). Pulse pressure (PP) was similar for both groups (67.5±17.1 vs. 68.1±10.5, p = .33).ConclusionOur results suggest that vascular health could impact cognition in aged 80+ adults. SA may have higher cerebral perfusion (CP) per MAP. Although DBP can decrease with aging, higher values in our sample may contribute to CP. The PP in our sample is similar to reported values for healthy 70‐year‐old adults. Further study of vascular health and super‐aging is needed.
Plasma glucose does not influence performance on standard cognitive screening tests in a mixed memory clinic cohort
Authors: Gramkow Mathias H. , Simonsen Anja Hviid , Hasselbalch Steen G. , Waldemar Gunhild , Frederiksen Kristian Steen 
Published: December 2023

AbstractBackgroundIt has been shown under experimental conditions that cognitive performance, especially working memory, is impaired in type I and type II diabetes during hyperglycemic and hypoglycemic conditions, perhaps due to altered cerebral glucose metabolism. It is not known if patients with neurodegenerative diseases, who also exhibit pathological cerebral glucose metabolism, are affected in a similar manner by their intrinsic plasma glucose levels. We aimed to test if performance on two standard cognitive screening tests is influenced by intrinsic plasma glucose levels in a memory clinic cohort.MethodIn this retrospective study, we included patients from the Copenhagen Memory Clinic Cohort (CMCC) with an available Mini Mental‐State Examination (MMSE) test score and a plasma glucose measurement performed in conjunction with cognitive testing. Patients were included from the inception of the cohort in 2008 till September 2021. We built linear regression models with MMSE and Addenbrooke’s Cognitive Examination (ACE) test scores as the outcome and plasma glucose as the explaining variable and adjusted models for age, sex and diabetes (plasma glucose measurement > 11.1 mmol/L). We explored non‐linear relationships by adding squared terms to the models and by fitting cubic spline regression models.ResultIn total, 2714 patients had an available MMSE score and a plasma glucose measurement. Patients had a mean age of 71.6 years [range 19‐99] and a baseline plasma glucose level of 5.8 mmol/L [range 2.7‐28.1]. A total of 581 of patients had a plasma glucose level outside normal range (<4.2 or >6.3 mmol/L). A total of 31.2% of the cohort studied had a diagnosis of Alzheimer’s disease (AD). MMSE and ACE total scores were not influenced by plasma glucose in a linear nor in a non‐linear fashion, when we adjusted for age, sex and diabetes. Sub‐group analyses in patients with AD and in patients with cerebrovascular disease showed similar results.ConclusionPlasma glucose levels inside normal range were not shown to influence performance on routinely applied cognitive tests and do not need be taken into consideration when interpreting test results from memory clinic patients.
Amyloid and tau fibrils induce different microglial phenotypes but converge to similar altered molecular processes
Authors: da Rocha Andreia Silva , Bastiani Marco Antônio De , Zimmer Eduardo R. 
Published: December 2023

AbstractBackgroundMultiple studies in the past years have supported the idea that microglial cells play a crucial role in the pathophysiology of Alzheimer’s disease (AD) and that their response might be quite heterogeneous. However, whether these cells react differently to Amyloid‐β (Aβ) and Tau pathology, as well as, the molecular mechanisms and distinct pathways underlying these responses remains elusive. In this work, we aimed to investigate the response of microglia to Aβ and Tau fibrils, which are being recognized as one of their most toxic forms. We hypothesize that microglia will present a unique response for Aβ and Tau fibrils.MethodTranscriptomic analysis of mice primary microglial cultures exposed to Aβ or Tau fibrils (5µM, 12‐24hs) was performed. Differentially expressed genes (DEGs) between control and Aβ or Tau fibrils were identified using the DESeq2 method. Functional enrichment (FEA), semantic similarities and protein‐protein interaction networks were conducted. Differences were statistically significant with FDR‐adjusted p‐value < 0.05 and logFC > 1.ResultsCompared to controls, microglia exposed to Aβ fibrils presented 917 DEGs, while the ones exposed to Tau fibrils presented 672 DEGs, of which, only 275 were shared. In contrast, the FEA indicated that more than 69% (736 BP, 50 MF and 32 CC) of the enriched terms were shared between Aβ and Tau. Among the not shared terms, the semantic similarities analysis identified 16 clusters specific for each treatment: Aβ clusters included “regulation of lipids, carbohydrate and ATP metabolic process”, “response to starvation” and “autophagy”, while Tau clusters included “regulation of transmembrane transport of ions”, “gliogenesis” and “neural cells proliferation”.ConclusionThis work corroborates the idea that microglia react differently to Aβ or Tau pathology but reveals that this response might not be unique as we hypothesized. Although different at the gene level, a big portion of the microglial response to Aβ and Tau converged to the same mechanisms. Despite that, there is still a smaller quantity of adaptations that are specific, such as substrates handling for Aβ and ions transport for Tau. Further validation of these unique phenotypes is being conducted in additional Aβ and Tau pathology models.
Both clinically informed and brain region agnostic approaches identify neuroimaging derived phenotypes associated with genetically regulated gene expression of late‐onset Alzheimer’s disease genes
Authors: Wang Ting‐Chen , Bledsoe Xavier , Shaw Douglas , Chen Hung‐Hsin ,   International Genomics of Alzheimer’s Project (IGAP), Naj Adam C. , Bush William S. , Gamazon Eric J , Below Jennifer E. 
Published: December 2023

AbstractBackgroundGenetically regulated gene expression (GReX) data leverages expression quantitative trait loci to investigate the genetic mechanism of Alzheimer’s disease (AD). This study utilized the GReX‐mediated neuro‐imaging derived phenotypes (NIDPs), summary features derived from brain imaging modalities, as an endophenotype to identify brain regions associated with late‐onset AD (LOAD) via gene expression.MethodThis study contained brain region‐agnostic and region‐informed approaches. Both approaches utilized a set of 25 genes causally associated with LOAD in our previous cross‐tissue transcriptome‐wide association studies (TWAS) (Chen et al., 2021) to identify LOAD‐associated GReX‐mediated NIDPs. We leveraged the UK Biobank (UKBB) neuroimaging TWAS resource to provide GReX‐mediated NIDP information.
Region‐agnostic: We assessed associations between GReX of LOAD genes and T1‐derived cortical and subcortical grey matter NIDPs from the UKBB neuroimaging TWAS.
Region‐informed: We identified a set of AD‐associated cortical grey matter NIDPs from diagnosed AD patients (Westman et al., 2013). Next, we subset the UKBB neuroimaging TWAS data to those describing associations between GReX of LOAD genes and the selected AD NIDPs.A Benjamini‐Hochberg FDR p‐value threshold of 0.05 was used to establish statistical significance, and causal inference testing on associations between GReX of LOAD genes and NIDPs was conducted by implementing MR‐JTI in both approaches.Result
Region‐agnostic: This approach found associations between GReX of 8 LOAD‐associated genes and 14 NIDPs (Figure 1). The most significant association is the GreX of ZNF296 and the right pars opercularis of the inferior frontal cortex, which replicated across 16 different tissues.
Region‐informed: A single highly significant causal association between the GReX of PSMC3 and the ventral diencephalon was identified and replicated in gene expression models of 3 different bansal ganglia‐derived tissue models.ConclusionOur study shows the highly significant causal association between the GReX of ZNF296 and the right pars opercularis on LOAD through the region‐agnostic approach and the strong causal association between the GReX of PSMC3 and the ventral diencephalon on LOAD in AD‐associated region‐informed analyses. Our methodologies provide opportunities to explore brain regions associated with LOAD that are mediated by GReX of AD‐associated genes illuminating the impact of LOAD‐associated genes on gene expression and brain physiology.
Investigating the role of ketogenic conditions on cholesterol metabolism and neuroinflammation in APOE4 carriers
Authors: Suhy Natalie , Mesentier‐Louro Louise A. , Goldman Camille , Forton‐Juarez Ana , Rooklin Rikki , Blanchard Joel 
Published: December 2023

AbstractBackgroundThe study of genetic risk factors in Alzheimer’s Disease (AD) in conjunction with lifestyle factors is critical in order to fully understand manifestations of disease phenotypes. APOE4, the primary genetic risk factor for AD, is a mutant implicated in dysfunctional lipid and cholesterol transport. We have demonstrated that APOE4‐expressing oligodendrocytes produce a multitude of dysfunctional cholesterol synthesis conditions including decreased cholesterol transport, increased cholesterol accumulation, and reduced levels of myelination (Blanchard et al. 2022). One avenue to study the intersection of genetic and lifestyle factors is to explore APOE mutants with particular dietary conditions that may implicate neuro‐inflammatory phenotypes. The role of cholesterol metabolic dysfunctionality in APOE4 carriers, taking into account the diverse diets that humans consume, has yet to be studied.MethodIn order to investigate this, we developed a 3D multi‐cellular integrated brain tissue (miBrain) technology that contains iPSC‐derived neurons, endothelial cells, astrocytes, pericytes, microglia, and oligodendrocytes. This model has the ability to recapitulate physiological conditions of disease with great accuracy. To study different dietary conditions with our miBrain technology, we employed ketogenic vs. glucose media conditions on APOE4‐carrying cell types within the miBrain model.ResultWe have found that ketogenic conditions promote a neuro‐inflammatory phenotype in APOE4 carriers. This is shown by our observed differences in cholesterol accumulation, levels of myelination, and transcriptomics, between APOE3 and APOE4 miBrain models treated with ketogenic energy sources. We are confirming these findings using in vivo models.ConclusionKetogenic conditions may exacerbate the cholesterol abnormalities in APOE4 carriers, through promoting neuro‐inflammatory conditions that give rise to AD pathogenesis. Findings from these studies highlight therapeutic and diagnostic strategies to reduce the risk of developing AD in APOE4 carriers.
References: Blanchard, J.W., Akay, L.A., Davila‐Velderrain, J. et al. APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes. Nature
611, 769‐779 (2022). https://doi.org/10.1038/s41586-022-05439-w
Utility of Cortical Atrophy in Functional Networks as a Predictor of Progression in bvFTD
Authors: Krahn Erin , Katsumi Yuta , Brickhouse Michael , Rosen Howard J. , Touroutoglou Alexandra , Dickerson Brad C. , Eldaief Mark C. 
Published: December 2023

AbstractBackgroundBehavioral variant frontotemporal dementia (bvFTD) is a clinically heterogeneous neurodegenerative disorder with variable rates of disease progression. Predictors of disease progression in bvFTD are significantly lacking, limiting the ability of clinical care planning. We recently showed that cortical atrophy in the frontoparietal control network (FPN) at baseline predicts the conversion to dementia in patients with Primary Progressive Aphasia (PPA). Leveraging this methodology, we hypothesized that FPN atrophy would predict progression of dementia in patients diagnosed with bvFTD.MethodWe analyzed data from 48 bvFTD patients (mean age 59.9 years, 20 Female) with very mild or mild dementia from our Frontotemporal Disorders Unit cohort and the Frontotemporal Lobar Degeneration Neuroimaging Initiative. Our primary outcome measure was change in the Clinical Dementia Rating‐FTLD Sum‐of‐Boxes (SoB) at baseline and at least one year later. Each participant underwent baseline MRI scanning for cortical thickness estimates. We ran a Pearson correlation analysis between the annualized change of CDR‐FTLD SoB from baseline to last observation, and baseline cortical network atrophy (quantified as network‐wise W scores). Vertex‐wise GLM analyses and network‐wise bivariate correlation analyses were also used to assess the relationship between network cortical atrophy and annualized CDR changes.ResultOf the 7 networks investigated, only FPN atrophy predicted annualized change in CDR‐FTLD SoB scores (r = ‐0.31, p = 0.03). That is, in bvFTD patients at the very mild/mild dementia stage, the greater the baseline FPN atrophy, the more rapid the clinical decline. Vertex‐wise GLM maps did not show that atrophy across the entire FPN predicted clinical decline. Rather, baseline atrophy in the dorsal precuneus and supramarginal gyrus nodes of the FPN was most predictive of clinical disease progression.ConclusionCortical atrophy in the FPN, and particularly in posterior regions of this network, is predictive of the rate of clinical decline in bvFTD patients, possibly due to the critical roles this network serves in executive function and affective regulation. This work could promote the use of structural imaging biomarkers to guide prognostication for bvFTD patients and their families, and to inform the design of clinical trials.
“It’s my life, it’s my choice and I want to say when” vs “A good death is to be on good terms with God”. Comparing the views of people with dementia in the UK and Brazil about a good death: Qualitative study
Authors: de Oliveira Vidal Edison Iglesias , Harrison‐Dening Karen , Vanelli Julia Maria , Neves Adriele Ferreira , Dekker Natashe Lemos , Oliveira Déborah , Roque Francelise Pivetta , Mikelyte Rasa 
Published: December 2023

AbstractBackgroundFew studies have directly asked people living with dementia (PLwD) about their views regarding a good death taking into account their diagnosis or compared their perspectives cross‐culturally. We aimed to compare the meaning of a good death for PLwD in Brazil and the UK.MethodIn this qualitative study, a convenience sample of 32 PLwD (16 each in Brazil and the UK) took part in semi‐structured interviews between Jul 2019 and Aug 2021. A co‐developed topic guide was used in both countries. We assessed all participants for cognitive capacity to give informed consent. Two teams of interdisciplinary researchers independently analysed transcripts for their country using inductive thematic analysis, followed by jointly developing overarching themes on the contrasts and similarities across the two countries.ResultWe identified 3 main themes: Choice and Control; Spirituality and Religious Beliefs; and Fears and Wishes. Choice and Control permeated all aspects of what a good death meant to PLwD in the UK, but was largely absent from Brazillian narratives. The opposite was true for Spirituality, which was central to the meaning of a good death in Brazil, while far less prominent in the UK, even among religious participants. Fears and Wishes was the only theme showing substantial similarities between the two countries. Exploring relationships between the themes demonstrated that how participants experienced and assuaged Fears was predominantly related to Spirituality in Brazil, and Choice and Control in the UK.ConclusionDesigning culturally‐sensitive approaches in palliative dementia care has to take into account how PLwD define both what a good death is and what helps to achieve it. Our findings also raise caution around replicating palliative care initiatives (e.g., on advance care planning) between countries without adapting its goals and means to achieve them so they are culturally meaningful.