bluuebunny/crossref_metadata_2025_split huggingface dataset:
Testing bidirectional relationships between functional brain networks and preclinical Alzheimer disease biomarkers
Authors: Millar Peter R , Singhe Nawang , Macharia Kiana Angela , Metcalf Nicholas V , Roman June , Morris John C , Benzinger Tammie L.S. , Ances Beau 
Published: December 2023

AbstractBackgroundResting‐state functional connectivity (RSFC) provides estimates of brain networks using fMRI. There are conflicting reports regarding the effects of amyloid‐β (Aβ) and tau on RSFC networks in cognitively normal participants. These inconsistencies might be explained by a recently‐proposed theoretical model that Aβ and tau have an interactive effect on RSFC, marked first by hyper‐connectivity in association with Aβ, then by hypo‐connectivity in association with tau. Although there is preliminary support for this model, independent validations and further characterizations of the effects of Aβ and tau on RSFC are needed.MethodWe analyzed RSFC, Aβ PET, and tau PET data from the Knight Alzheimer Disease Research Center (ADRC). All participants were cognitively normal (Clinical Dementia Rating®: 0). RSFC was collected on two scanners in partly‐overlapping samples (PETMR N: 190, TRIO N: 149). RSFC data were processed with framewise censoring and global signal regression. RSFC networks were defined using 298 regions of interest. Aβ was measured with PET PiB and AV‐45 tracers, which were harmonized using a Centiloid conversion. Tau was measured with a PET AV‐1451 tracer and was summarized in pre‐defined regions. Main effect and interaction relationships between Aβ, tau PET, and RSFC were tested with linear regression models, controlling for age, sex, education, and head motion as covariates, with a false discovery rate correction.ResultWe did not observe a bidirectional interaction effect in any of the hypothesized networks (default mode [DMN], salience [SAL], frontoparietal [FPN]). Aβ was positively associated with RSFC, independent of tau, in the DMN and SAL, while tau was negatively associated with RSFC, independent of Aβ, in the SAL only. Exploratory analyses of FC within and between all networks did not identify clear patterns of interactive biomarker effects, nor consistent patterns of main effect relationships within any of the other networks.ConclusionThese results do not support an interactive model of RSFC in preclinical AD. Inconsistencies with previous interactions may be driven by sample‐specific or methodological differences, or the low reliability of FC and brain‐behavior relationships. Prominent biomarker relationships in the DMN and SAL are consistent with regional overlap with Aβ deposition in early AD.
The role of capillary and pericyte associated microglia in health and Alzheimer’s disease
Authors: Morris Gary P , Foster Catherine G , Courtney Jo‐Maree , Collins Jessica M , Cashion Jake M , Brown Lachlan S , Howells David W , Deluca Gabriele C , Canty Alison J , King Anna E , Ziebell Jenna M , Sutherland Brad A 
Published: December 2023

AbstractBackgroundThe majority of individuals with Alzheimer’s disease (AD) exhibit vascular damage in the brain including reduced cerebral blood flow (CBF) and blood‐brain‐barrier (BBB) breakdown. Growing evidence suggests pericytes, a vessel‐residing cell able to modulate CBF and BBB integrity, are a major contributor to vascular dysfunction in AD. The close spatial relationship between microglia and capillaries led us to explore the hypothesis that microglia and pericytes functionally interact to influence vessel function in the healthy brain and that this interaction may become pathological in AD.MethodsWe first characterized the spatial and functional relationship between microglia, capillaries and pericytes in the healthy central nervous system (CNS) in fixed tissue and using in vivo two‐photon microscopy through cranial windows in adult NG2DsRed x CX3CR1+/GFP mice. We then assessed the spatial relationship between microglia, capillaries and pericytes in the human superior frontal gyrus (SFG) of 12 control and 11 AD cases.ResultsWe discovered a subset of microglia dynamically interacting with pericytes in the healthy CNS, which we termed pericyte‐associated microglia (PEM). PEM are present throughout the capillary tree, often maintain their position for at least 28 days and frequently were found to associate with pericytes lacking astroglial endfeet coverage. The loss of PEM alters capillary width beneath pericytes, but deletion of the microglial fractalkine receptor (CX3CR1), which regulates the recruitment of microglia to sites of neuroinflammation, does not reduce the proportion of microglia that are PEM. In AD, we found the proportion of microglia associated with capillaries and pericytes declines in the superior frontal gyrus (SFG) and that this decline is exacerbated by the APOE ε3/ε4 genotype. This reduction occurs despite an overall increase in pericyte numbers in AD cases.ConclusionWe identify microglia specifically associating with pericytes in the healthy CNS and find these associations are reduced in AD. The changing relationship between microglia, capillaries and pericytes may be a novel mechanism contributing to vascular dysfunction in AD.
Association between childhood experiences and mental health in later‐life: Findings from the National Social life, Health, and Aging Project
Authors: Lim Seungju , Park Sang‐Mi , Han Yebin , Kim Kiwoong , Jee Sujeong , Hong Ickpyo , Park Ji‐Hyuk 
Published: December 2023

AbstractBackgroundMiddle age is the central period of life, and it is a time when people face various mental health problems. It has been reported that the experience of childhood has a lifelong effect on mental health in middle age. However, research on positive childhood effects is insufficient, compared to negative childhood.ObjectivesTo investigate associations between childhood experiences and a latent construct of mental health in midlife adults.MethodsThe participants included 770 adults aged 50‐64 who retrospectively reported childhood events, including family life happiness, parent’s education, family’s financial status, childhood health status, family structure, experience of violence, and witness of violence. Second‐order structural equation modelling was used with mental health modelled as a second‐order latent variable with depression, anxiety, loneliness, and stress as first‐order components.ResultsThe study found that family life happiness and healthy childhood were associated with better mental health of midlife, in both the crude (β = −.221, p < 0.001; β = −.201, p < 0.01) and adjusted models (β = −0.128, p < 0.001; β = −0.095, p < 0.05).ConclusionThis is the first study confirming the associations of family life happiness and childhood health with mental health of midlife using second‐order structural equation modeling. Future work would benefit from a prospective investigation of these associations.
Keywords:Mental health, Midlife, Childhood, Second‐order structural equation model
Biomarker Profiling for Alzheimer‐like Dementia in Aged Non‐human Primates
Authors: Yu Ying , Wang Mingyue , Tan Maoyun , Jiang Zhichao , Xu Gaorui , Zhou Jiawen , Gan Xue , Peng Yanlai , Zhong Qian , Wen Rongchen , Fan Yuqing , Zhang Guodong , Xu Deming 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) places increasingly burdens on global healthcare. Non‐human primates (NHPs) have been used in preclinical pharmacology for AD drug discovery and they were mainly based on induction by amyloid plaque. However, previous strategies focused on clearance and prevention of amyloid plaques and neurofibrillary inclusions have mostly yielded discouraging results in clinical trials for AD. More fitting NHP models reflective of natural ageing of brain with an AD‐related clinical profile would be most desirable for translational pharmacology. To address this, the pilot study herein profiled a group of aged NHPs for biomarkers characteristic of AD‐like dementia, including cognitive behavior, diagnostic neuroimaging, EEG, and amyloid beta 42 (Aβ42) in cerebrospinal fluid (CSF).MethodTwo groups of male Macaca fascicularis (adult: 9‐11 years, n = 4; aged: 20‐25 years, n = 10) were trained to perform a delayed response task (DRT) to assess their short term memory. Meanwhile, their CSF levels of Aβ42 were determined. EEG signals at rest were captured with Neuroscan EEG System and data processed with customized Matlab code. The volume of hippocampus in eight selected animals were analyzed through a 3‐D reconstruction with MRI imaging.ResultSix (6) out of 10 aged animals showed lower DRT performance (successful rate < 80%) than the remaining 4 and those in the adult group. The overall DRT performance was positively correlated with the CSF levels of Aβ42 in all animals. Moreover, we observed the slowing of EEG activity (increased δ & θ activity and decreased β activity) in the frontal lobe and smaller average volume of hippocampus in the low DRT performers vis‐à‐vis the rest of the animals.ConclusionWe identified a group of aged NHPs with spontaneous dementia, with cognitive, electrophysiological and brain structural characteristic of mild cognitive impairment in the humans. Their CSF levels of Aβ42 inversely correlated with the memory function. Most notably, EEG and neuroimaging showed promising potential as non‐invasive approaches for the evaluation of aging‐related dementia of NHP in the longitudinal studies. The translational value of such animals could provide important insight to the disease progress and the therapeutic efficacy of AD treatment in the preclinical stages.
A community‐based program for older women living alone: a systematic review
Authors: Kim Inhye , Lee Hamin , Kim Mi Kyeong , Yun Sohyeon , An Hyun Seo , Park Hae Yean 
Published: December 2023

AbstractBackgroundLife expectancy has been increasing over the decades, while there is a gap between the genders. Women are more likely to live longer than men, resulting in older women living alone. Older adults living alone could be at risk of physical or mental health and well‐being. Therefore, this systematic review aimed to identify which interventions affected older women living alone and suggest community programs to improve their health and well‐being.MethodThis study was conducted using three databases, including PubMed, Archives of Physical Medicine and Rehabilitation, and Scopus. This review followed Preferred Reporting Items for Systematic Reviews and Meta‐Analysis (PRiSMA) guidelines, and studies were assessed based on inclusion and exclusion criteria. The Standardised Critical Appraisal Tool from Joanna Briggs Institute Meta‐Analysis of Statistics Assessment and Review Instrument (JBI‐MAStARI) was used to appraise the methodological quality of these studies.ResultOf the 2003 articles, three of them met inclusion and exclusion criteria and were reviewed. The articles are clinical trials, and the interventions were psychosocial support, reminiscence therapy, and a well‐being enhancement program. As a result of the interventions, self‐efficacy, cognitive function, and quality of life were improved, and the level of loneliness was decreased in older women living alone.ConclusionThe findings indicated that a community intervention such as psychosocial support, reminiscence therapy, and a well‐being enhancement program positively affected self‐efficacy, cognitive function, quality of life, and the level of loneliness for older women living alone. However, further studies are required with sufficient sample sizes and diverse intervention programs.
Admixture mapping of cognitive function in diverse Hispanic and Latino adults
Authors: Fornage Myriam , Sofer Tamar , Satizabal Claudia L. , Seshadri Sudha , Mosley Thomas H. , Decarli Charles , Tarraf Wassim , Thornton Timothy A , González Hector M 
Published: December 2023

AbstractBackgroundGenome‐wide association studies (GWAS) conducted primarily in populations of European ancestry have revealed the polygenic nature of cognitive abilities [1, 2] but genetic discoveries in other populations, including Hispanics/Latinos, are lagging. Genetically, US Hispanics/Latinos have uniquely admixed genomes, encompassing African, Amerindian, and European ancestries.[3] Admixture patterns in genomic regions (local ancestry) can be leveraged in gene mapping when frequencies of trait‐associated genetic variants located within these regions differ between ancestries.MethodWe conducted genome‐wide admixture mapping analyses followed by fine mapping to identify genetic variants associated with cognitive function in 7,140 Hispanic and Latino adults (mean age 55 years; 60.5% women) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Five measures of cognitive function were investigated: Six‐Item Screener (SIS), Brief Spanish English Verbal Learning Test (SEVLT), Word Fluency Test (WFT), Digit Symbol Substitution Test (DSST), and a measure of general cognitive function (PC1). We tested the identified variants for replication in independent samples with similar neurocognitive measures.ResultWe identified 9 significant local ancestry‐associated regions for the 5 cognitive tests. Counts of African ancestry on at 13q12.11, 4q14, 10p12.2 and 9p22.1 were associated with DSST, PC1, SIS, and WFT, respectively. Counts of Amerindian ancestry at 1q25.2 were associated with DSST; and at 12q14.2 and 12q15 with SIS. Counts of European ancestry at 8p22 were associated with SEVLT; and at 13q12.13 with, both, DSST and PC1. Fine mapping via SNP association testing in each region identified genetic variants that partially or totally explained the admixture signal. While statistical evidence of independent replication of the prioritized variants was generally weak, with only two replicated associations at chr8p22 and chr13q12.13, there was strong biological support for the observed associations to cognitive function. For example, the prioritized variant at 8q22 is an eQTL for CNOT7, which regulates synaptic plasticity and is essential for hippocampal‐dependent learning and memory [4].ConclusionOur admixture mapping analyses identified multiple novel loci associated with measures of cognitive function. This demonstrates the effectiveness of admixture mapping in complementing GWAS [5] and provides an opportunity to identify genetic loci that may be particularly relevant in underrepresented populations.
B cell and T cell populations are altered in the brain‐draining lymph nodes of the senescence accelerated mouse prone 8 (SAMP8)
Authors: Sun Jiaqi , Huang Xin , Ma Liwei , Chu Chenyin , Takechi Ryu , Mamo John CL , Trevaskis Natalie , Masters Colin L , Jin Liang , Pan Yijun 
Published: December 2023

AbstractBackgroundRecent studies have (re)‐discovered lymphatic vessels in the meninges and other sites that flow from the brain to deep cervical lymph nodes (dcLNs). Like elsewhere in the body, these lymphatic vessels play a critical role in the clearance of fluid and macromolecules from the brain including Aβ (a toxic protein that accumulates in the brain in Alzheimer’s disease) and in trafficking immune cells to the dcLNs, where immune activation occurs. The current study examined whether the immune cell populations are altered in the dcLNs of SAMP8 mice (a mouse model of accelerated aging with spontaneous overproduction of amyloid precursor protein in the brain) compared to the healthy control mice (SAMR1).MethodIn this study, dcLNs were collected from 12‐month‐old SAMP8 and SAMR1 mice (n = 6). Cells were isolated from the dcLNs, and the B cell and T cell populations (CD19 for B cells, PNA for germinal centre B cells, CD93 for early B cells, CD138 for antibody secreting B cells; CD3 for T cells, CD8a for cytotoxic T cells, CD4 for helper T cell) were studied using flow cytometry.ResultA significant 1.4‐fold increase in CD3+ T cells (p = 0.04) and a trend toward a decrease in CD19+ B cells (p = 0.06) was observed in the SAMP8 dcLNs compared with SAMR1 dcLNs. For B cell sub‐populations, a 77.9 ± 26.9% decrease (p = 0.0078) in geminal center B cells was observed in SAMP8 dcLNs. The T/B cell ratio was significantly increased in SAMP8 dcLNs (2.74 ± 0.14) comparing to SAMR1 dcLNs (2.10 ± 0.16). Such alteration was not observed in mesenteric lymph nodes.ConclusionThe B cell and T cell populations were altered in the brain‐draining dcLNs of SAMP8 mice, suggesting that the dcLNs responded to pathological changes in the brain. The reduced B cells, especially the germinal centre B cells, indicate a possible impairment in the production of antibody‐secreting B cells in SAMP8 mice. We will confirm these observations in APP/PS1 and 5xFAD mice in future studies, and investigate whether such alteration in B cells contributes to Alzheimer’s disease pathology.
INPP5D modulates TREM2 loss‐of‐function phenotypes in a β‐amyloidosis mouse model
Authors: Tomita Taisuke 
Published: December 2023

AbstractBackgroundThe genetic associations of TREM2 loss‐of‐function variants with Alzheimer disease (AD) indicate the protective roles of microglia in AD pathogenesis. Functional deficiencies of TREM2 disrupt microglial clustering around amyloid β (Aβ) plaques, impair their transcriptional response to Aβ, and worsen neuritic dystrophy. However, the molecular mechanism underlying these phenotypes remains unclear.MethodsIn this study, we investigated the pathological role of another AD risk gene, INPP5D, encoding a phosphoinositide PI(3,4,5)P3 phosphatase expressed in microglia by crossing Tyrobp knockout, Inpp5d knockout and human mutant APP knockin mice.ResultIn a Tyrobp‐deficient TREM2 loss‐of‐function mouse model, Inpp5d haplodeficiency restored the association of microglia with Aβ plaques, partially restored plaque compaction and astrogliosis, and reduced phosphorylated tau+ dystrophic neurites. RNA‐sequencing of isolated microglia demonstrated that the expression of “disease‐associated microglia” genes is not responsible for these beneficial effects.ConclusionOur results suggest that INPP5D acts downstream of TREM2/TYROBP to regulate the microglial barrier against Aβ toxicity, thereby modulates Aβ‐dependent pathological conversion of tau.
INPP5D inhibition attenuates amyloid pathology through the regulation of microglial functions
Authors: Oblak Adrian L 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by accumulated beta‐amyloid (Aβ) deposits and robust microgliosis. Recent genome‐wide association studies have identified genetic risk factors in late‐onset AD (LOAD) which are largely microglia. Among the risk factors, Inositol polyphosphate‐5‐phosphatase D (INPP5D) confers an increased risk of developing AD and is associated with increased plaque deposition. As a microglia‐specific lipid phosphatase, INPP5D negatively regulates signaling via several microglial cell surface receptors, including TREM2; however, the impact of INPP5D inhibition on AD pathology remains unclear.MethodsTo determine the impact of Inpp5d on disease pathogenesis and microglial phenotypes, we utilized the 5xFAD model expressing Inpp5d haplodeficiency.ResultsInpp5d deficiency perturbs microglial intracellular signaling pathways that regulate the immune response, including phagocytosis, microglia‐plaque engagement, and Aβ clearance. Importantly, Inpp5d haploinsufficiency leads to the preservation of cognitive function in 5xFAD mice. Furthermore, a novel spatial transcriptomic analysis revealed genetic profiles altered by Inpp5d haploinsufficiency are related to microglial functions, synaptic regulation, and immune cell activation.ConclusionThese data demonstrate that Inpp5d deficiency enhances microglial functions by increasing plaque clearance and preserves cognitive abilities in 5xFAD mice. Inhibition of INPP5D may serve as a potential therapeutic strategy targeting microglia for AD.
Voice Analysis of People with Dementia:Toward to AI‐based Emotion Detection for People with Dementia
Authors: Kim Dongseon , Lee Bongwon 
Published: December 2023

AbstractBackgroundThere is lack of evidence‐based research concerning the emotion expression of people with dementia even though it is important to detect their emotional state because emotion plays an important influence on the quality of life and communication in dementia care. Emotion detection is further important in developing AI conversation intervention programs as emotion detection could be a mediator for better Human‐machine interface.MethodResearchers interview people with dementia on their emotion‐related topic (good and bad memories, their wishes, and other everyday topics) and record the dialogue. Besides, their caregivers record the dialogue with them when they show psychological and behavioral symptoms. Participants vary in gender, location of living(dialects), seriousness of the disease from mild cognitive impairment (MCI) to severe dementia. Recording is done for months long enough to collect various emotions from a person who has his or her individual voice characteristics. Researchers extract and classify the emotion into 5 categories of anger, sadness, agitation (expressed as BPSD), happiness and neutral based on the content and mood of PWD during the interview. Analysis will be done with Praat program, voice analysis program, on changes of pitch, shimmer, jitter. formant, intensity, HNR(harmony and noise ratio), and other characteristics. Verification of differences by emotions is confirmed by ANOVA, SPSS23.0.ResultStatistically significant speech parameters for classifying the emotional groups are mainly related to speech characteristics such as jitter, shimmer, basic formant, intensity and HNR. For agitation and anxiety expressed by shouting, swearing, and repetition, voice features have different characteristics of intensity and HNR from ones of other emotions.ConclusionThis research is useful in establishing labeling systems for future artificial intelligence modeling. At the same time, it has humanistic implications. Emotions expressed by people with dementia are various against the prejudice which their emotions are monotonous. Thus, emotion expression of people with dementia needs further analysis based on the understanding of context‐ and care method‐dependent changes. On the other hand, this data is collected in the natural settings while most data for voice‐emotion study is collected in the experimental setting. Accordingly, both limitations and merits of this unstructured data should be discussed.
Efficacy of Common Ingredients in Over‐the‐Counter Memory Supplements
Authors: Hersant Haley , He Sean , Maliha Peter , Grossberg George T 
Published: December 2023

AbstractBackgroundThe Global Brain Health Supplement Industry Market size was valued at 7.6 billion U.S. dollars. It is predicted to increase to 15.59 billion U.S. dollars by 2030. Memory and enhancement is a segment of the market that comprised the highest global revenue share in 2021.MethodAn extensive review of current supplements on the market was performed by surveying products for sale at local and national pharmacies and grocery stores. A list of 103 supplements was compiled and the most common ingredients in these supplements were identified. Scientific data relative to these ingredients was searched using PubMed and Cochrane library databases.ResultThere is not currently strong evidence that supports the clinical use of apoaequorin, ashwagandha, carnitine, choline, coenzyme q10, coffee extract, ginger, ginkgo biloba, Huperzine A, lion’s mane, l‐theanine, omega‐3 fatty acids, phosphatidylserine, polyphenol, turmeric, vitamin B9, vitamin B12, vitamin D, or vitamin E supplementation for memory improvement.ConclusionDietary supplements geared toward improving cognition are a billion‐dollar industry that continues to grow despite lacking a solid scientific foundation for their marketing claims. More rigorous studies are needed relative to the long‐term use of these supplements in homogenous populations with standardized measurements of cognition.