bluuebunny/crossref_metadata_2025_split huggingface dataset:
PRESYNAPTIC AMYLOID PRECURSOR PROTEIN IS NECESSARY FOR THE IMPAIRMENT OF SYNAPTIC FUNCTION AND MEMORY CAUSED BY EXTRACELLULAR AMYLOID‐ΒETA AND TAU OLIGOMERS
Authors: Acquarone Erica , Costa Ana Paula , de Loo Jonathan Van , Williams Damian , Zhang Hong , Staniszewski Agnieszka , D'Adamio Luciano , Puzzo Daniela , McIntire Laura Beth , Teich Andrew F , Arancio Ottavio 
Published: December 2023

AbstractBackgroundAmyloid precursor protein (APP) is a transmembrane protein expressed at the synapse throughout life. In absence of APP, extracellular Aß‐ and tau‐oligomers no longer impair memory and its synaptic surrogate, long‐term potentiation (LTP). Synapses include pre‐ and post‐synaptic compartments. However, the relative role of pre‐ vs. post‐synaptic APP at the CA3‐CA1 hippocampal synapse in the Aß‐ and tau‐oligomer‐induced damage of memory and LTP is not know.MethodWe used a combination of gene editing, electrophysiological, behavioral and biochemical techniques to investigate the contribution of the pre‐ and post‐synaptic APP in oligomer induced impairment of memory and LTP.ResultSpecific ablation of APP expression in the post‐synaptic neuron did not alter the negative effects of Aß and tau oligomers on LTP and memory. In contrast, APP‐KO in the presynaptic neuron mimicked and occluded the negative effects of Aß and tau oligomers on LTP and memory, suggesting that presynaptic APP mediates the synapto‐toxic effect of Aß and tau. Further investigation demonstrated that pre‐synaptic APP deletion (but not post‐synaptic) mimicked and occluded the Aß and tau oligomer induced reduction of neurotransmitter vesicle availability during tetanic stimulation and increase of refilling rate after depletion of the readily‐releasable pool. Moreover, the increase in refilling rate after deletion of presynaptic APP was dependent upon intracellular calcium. Indeed, intracellular calcium homeostasis was affected both in basal conditions and after activity in full APP‐KO mice, likely due to decrease in the levels of inositol 1,4,5‐trisphosphate receptor, ryanodine receptor and the calcium pump, SERCA3.ConclusionThese data support the view that Aß and tau oligomers affect synaptic function and memory through pre‐synaptic APP.
Are sex differences in verbal memory related to sex differences in cognitive reserve?
Authors: O'Shea Deirdre , Camacho Simone , Ezzeddine Reem , Disla Shanell , Galvin James E 
Published: December 2023

AbstractBackgroundCognitive reserve (CR) is the capacity to maintain cognitive performances despite underlying brain pathology and a concept used in Alzheimer’s disease (AD) studies to explain clinical heterogeneity. Evidence for a female‐specific verbal memory reserve may contribute to sex disparities in AD incidence, via delayed diagnosis. However, whether sex differences in verbal memory relate to sex differences in CR, is unclear. The current study examined whether multiple measures of CR differed by sex and whether they mediated sex differences in verbal memory.MethodCross‐sectional data from 59 older adults (mean age = 68.1; SD = 10.7; Female = 62%; White = 70%), without a prior diagnosis of cognitive impairment, were included. Total recall from the immediate and delayed recall trials of the scores Hopkins Verbal Learning Test (HVLT) were used to assess verbal learning and memory. Years of education, self‐reported leisure activities, physical activity, mindfulness, and the MIND diet were used to assess CR. Sex differences in HVLT scores were tested with ANCOVAs, controlling for age and reran adjusting for education. A MANCOVA was used to assess sex differences on CR measures. A mediation analyses was used to test whether sex differences in CR measures mediated the association between sex differences and verbal memory.ResultWomen had higher scores on HVLT learning (M = 23.1, SD = 5.2; p<.01), delayed recall (M = 8.2; SD = 2.6; p<.01) and leisure activities (M = 35.93; SD = 7.9; p<.01) compared to men (learning: M = 19.5; SD = 5.2; delayed recall: M = 6.2; SD = 2.5; leisure: M = 28.5; SD = 10.9; p<.01). No other sex differences in CR measures were revealed. Leisure activities fully mediated sex and HVLT associations, such that women’s higher scores on leisure explained 39% and 35% of the variance between sex and HVLT learning and delayed recall, respectively.ConclusionWomen’s overall higher engagement in leisure activities accounted for their higher scores on HVLT learning and delayed recall relative to men. Increasing men’s engagement in leisure activities could attenuate sex differences in verbal learning/memory but warrants further investigation. Larger and more diverse samples are needed for follow‐up data analyses.
Integrated spatial and single‐cell transcriptomic analysis of genetic and sporadic forms of Alzheimer’s disease
Authors: Morabito Samuel , Miyoshi Emily , Henningfield Caden M , Shi Zechuan , Michael Neethu , Shabestari Sepideh Kiani , Das Sudeshna , Shahin Saba , Head Elizabeth , Green Kim N , Swarup Vivek 
Published: December 2023

AbstractBackgroundThe pathogenesis of Alzheimer’s disease (AD) varies greatly depending on environmental and heritable factors. Neuropathological scores aid in the understanding of disease severity in postmortem tissue, but fail to provide insights into disease onset and progression. Conversely, mouse models of AD like 5XFAD offer predictable timelines of amyloid accumulation due to specific human AD risk signals, but have limitations due to species differences. Studying AD in Down Syndrome (AD in DS) patients provides an opportunity to study the transcriptomics of AD progression due to overexpression of APP, which results in a more predictable disease time course compared to the more stochastic disease progression in the general population.MethodWe present a rigorous transcriptomic analysis of AD using single‐nucleus RNA‐seq (snRNA‐seq) and spatial transcriptomics (ST) in cortical samples from donors with early‐stage AD, late‐stage AD, AD in DS, and cognitively normal controls. We performed ST (10X Genomics Visium) in these groups, and additionally performed snRNA‐seq (Parse Biosciences) in tissue from AD in DS donors and controls. Finally, we profiled 5XFAD and wild type mice at four time points (4, 6, 8, and 12 months) using ST to facilitate cross‐species comparisons. We applied state‐of‐the‐art bioinformatic and statistical approaches to integrate these datasets with published AD snRNA‐seq data and to perform systematic analyses of gene expression and gene networks in these groups.ResultWe found shared and distinct differentially expressed genes (DEGs) between AD and AD in DS in the ST and snRNA‐seq datasets, with greater concordance in neuronal cell types compared to glia. Cell‐cell communication network analysis of integrated snRNA‐seq and ST data revealed vast network remodeling in disease, highlighting an increase in WNT and ANGPTL signaling and a decrease in CD99 signaling among other disrupted pathways. Using geospatial statistical analysis, we identified amyloid plaque proximal DEGs in human and mouse ST data, which were largely species‐specific with little overlap.ConclusionThe primary data generated here will be a valuable resource for the AD community, and our study provides new insights into the transcriptomics of AD and amyloid pathology by performing a holistic analysis considering sporadic and genetic forms of AD.
Butyrylcholinesterase Kalow variant reduces age‐of‐onset of Alzheimer Disease in apolipoprotein ɛ4 carriers
Authors: Lane Roger M , Junge Candice , Li Dan , Yang Qingqing M , Moore Katrina M , Edwards Amanda , Graham Danielle , Mummery Catherine J 
Published: December 2023

AbstractBackgroundPrevious investigations suggest carrier status for Karlow‐variant single‐nucleotide polymorphism (SNP) of butyrylcholinesterase (BCHE‐K) is associated with an earlier age‐at‐onset of AD in APOE4 carriers.MethodIn 45 mild AD patients, 50‐74 years, recruited into a clinical trial (NCT03186989), baseline characteristics were evaluated by BCHE‐K and APOE4 allelic status. Hypothesis tested that age‐at‐diagnosis of AD in APOE4 carriers was lowered in BCHE‐K carriers. Exploratory investigations conducted of associations of neuroimaging (ventricular and hippocampal volumes) and CSF biomarkers of amyloid (Aβ42), tau (p‐tau181), and neurodegenerative (NfL, Ng, PSD‐95) pathologies and glial activation (YKL‐40, GFAP, MCP‐1) across gender and genotype subgroups.ResultIn APOE4 carriers (N = 33), mean age‐at‐diagnosis of AD in BCHE‐K carriers (N = 11) was 6.4 years earlier than in BCHE‐K non‐carriers (N = 22, p < 0.001). In APOE4 non‐carriers (N = 12) there was no similar influence of BCHE‐K, but men (N = 8) had an age‐at‐diagnosis about 11 years earlier than women (N = 4). In APOE4 carriers, accumulation of amyloid and tau pathologies was slightly greater and ∼6 years earlier in BCHE‐K carriers versus non‐carriers. APOE4 allele frequency‐dependent increase in amyloid pathology observed with highest amyloid burden in APOE4 homozygotes that contrasted with lowest tau burden. Multiple regression analyses demonstrated that factors associated with amyloid accumulation included APOE4 carrier status (p < 0.05), larger total brain ventricle volume (p < 0.05), less synaptic injury (PSD‐95, p = 0.01; Ng, p < 0.001), and less tau (t‐tau and p‐tau181, p < 0.01). Factors associated with tau pathology included higher neuroaxonal damage (NfL, p = 0.002), higher synaptic injury (Ng, p <0.001; PSD‐95, p < 0.001), and higher glial activation (YKL‐40, p = 0.01). Phenotypic spectrum observed from predominant amyloid and limbic‐amnestic, exemplified by APOE4 homozygotes with BCHE‐K, to predominant tau, limbic‐sparing and multi‐domain cognitive impairment, exemplified in older women non‐carriers of APOE4 and BCHE‐K.ConclusionIn mild AD APOE4 carriers aged < 75 years, the mean age‐at‐diagnosis of AD was reduced by about 6 years in BCHE‐K carriers relative to non‐carriers. Relationships between biomarkers of amyloid and tau pathologies, neurodegeneration and glial activation, and putative cortical cholinergic denervation, suggested an age‐, gender‐ and genotype‐dependent phenotypic spectrum.
Title: Histochemical, immunohistochemical and behavioural demonstration of the potential of Zingerone to ameliorate cognitive decline in animal model
Authors: OVIOSUN AUGUSTINE , Anyanwu Emeka Godson , Oviosun Ezinne Chidinma , Memudu Adejoke Elizabeth 
Published: December 2023

AbstractBackgroundScientific evidence has revealed that dementia, cognitive impairment and Alzheimer’s disease (AD) is associated with increased oxidative stress and neuroinflammation leading to neurodegeneration. Zingerone has strong antioxidant and anti‐inflammatory potentials linked to possible neuroprotective effect.This study is to determine the modulatory mechanism of zingerone in cadmium induced cognitive decline by assessing memory using novel object recognition text, neuroinflammation biomaker‐ IL‐6, TNF‐alpha, Glial fibrillary acidic Protein (GFAP) in the PFC.MethodsThirty (30) adult male Wistar rats used were grouped into six (6) groups, n = 5 as follows; Control group (A), AD model was given 5mg/kg of cadmium for seven days (B), 100mg/kg of zingerone (C) for 14 days, the treatment study groups D‐F were given 5mg/kg of cadmium for seven days and treated using varying dose of zingerone for 14 days (50mg. 100mg and 200mg). Neurobehavioral test for memory and learning done using Novel object recognition. Left prefrontal cortices were homogenized for neuroinflammatory biomaker‐ (IL‐6) and (TNF‐alpha). Fixed prefrontal cortices were processed and stained using histological stain and immunohistochemical stain for astrocytes using glial fibrillary acidic protein (GFAP). Behavioral test data were analyzed using ANOVA, post hoc test and significance set at p<0.05.ResultsZingerone effectively reversed cadmium induced cognitive decline characterized by reduced discrimination index, a marked increase in neuro‐inflammatory biomaker (IL‐6 and TNF‐α). However 200mg/kg of zingerone had a significance effect as compare to the two doses. Zingerone significantly downregulated GFAP expression activities and reduced neuronal cell loss the PFC.ConclusionZingerone potential to repair cognitive impairment is associated with modulation of neuroinflammatory biomakers that result in improved cognitive function in the PFC.
Effect of Virgin Coconut Oil on Cognition of Mild‐to‐moderate Alzheimer’s Disease Patients with APOE ε4 Allele
Authors: Fernando Malika , Silva Renuka , Fernando Binosha , de Silva Asita , Wickremasinghe Rajitha , Dissanayake Asoka , Martins Ralph N , Williams Shehan 
Published: December 2023

AbstractBackgroundVirgin coconut oil (VCO) is an excellent source of medium chain fatty acids and thus, a potential natural ketogenic agent that can be used to substitute glucose in Alzheimer’s disease (AD) brain, in which the glucose metabolism is compromised. High content of polyphenols in VCO will also support to reduce inflammation and oxidative stress associated with AD. The aims of this double‐blind placebo‐controlled trial were to investigate the effect of VCO on cognition in mild‐to‐moderate AD patients and the association of apolipoprotein E (APOE) ε4 genotype on the outcome.MethodStudy participants were 120 mild‐to‐moderate AD patients [Mini‐Mental State Examination (MMSE) score = 15‐25, age ≥65 years], randomly allocated to either treatment or control groups and orally fed 30 mL/ day of VCO as the treatment and a same amount of canola oil as the placebo for 24 weeks. Cognition was assessed by MMSE, Montreal Cognitive Assessment (MOCA), and executive clock drawing task (CLOX) at the baseline and at the end of the intervention. APOE genotyping was conducted at the baseline. Fasting lipid profile and glycated hemoglobin (HbA1C) levels were analyzed at the baseline and at the end of the intervention.ResultThere was no significant difference in the post‐intervention changes of cognitive assessment scores, lipid profile and HbA1C levels between the treatment and control groups. The MMSE scores of the APOE ε4 carriers in the treatment group was improved compared to the non‐carriers (change of MMSE = 2.37, p = 0.021), whereas there was no difference in the control group. In both treatment and control groups, the lipid parameters were not compromised during the intervention.ConclusionOral supplementation of 30 mL/day of VCO for 24 weeks did not improve cognition of mild‐to‐moderate AD patients compared to canola oil. However, VCO improved the MMSE scores of APOE ε4 carriers compared to non‐carriers. Consumption of VCO was safe as it did not compromise lipid parameters.
Fukushimura Brain Bank ‐Nursing home based brainbank project in Japan‐
Authors: Kaneda Daita , Ogawa Norihiro , Kanesaka Takeshi , Hishida Chie , Sakurai Keita , Akatsu Hiroyasu , Yamamoto Takayuki , Yoshio Hashizume 
Published: December 2023

AbstractBackgroundThe Fukushimura (welfare village), located in Toyohashi city, Japan, is a unique complex of various nursing home facilities including dementia homes, Day‐care houses, homes for disabled and mentally retarded, and the Fukushimura Hospital. This village is totally managed by private sector, the Sawarabi Medical Cooperative. About 800 elderly people reside in this area. The hospital plays a pivotal role within the village and acts as the central facility for each nursing homes.Fukushimura BrainBank (FBB) was established in 1990. The neuropathological investigation of FBB was initially conducted by Kenji Kosaka, who reported cortical Lewy bodies first. Our research institute was approved in 2004 by the Ministry of Education, Culture, Sports, Science and Technology, as one of the non‐governmental institutes which is permitted to apply for governmental grants.MethodAll the medical records and radiological images from the nursing home to hospital are stored in the research institute and accessible for the researchers to evaluate the psychological symptoms observed by carers in the long duration of the disease. The brain MRI of 1.5 Tesla was used for evaluating 3D‐volumetric T1WI and diffusion tensor imaging.For collecting CNS specimens, the brains are separated into two hemispheres, one for neuropathological analyses with using several antibodies for beta‐amyloid, phosphorylated tau, alpha‐ synuclein, and TDP‐43. Modified gallyas‐silver staining is applied for evaluating argyrophilic grain disease. The other hemispheres are stored for frozen sections. Retinal tissue is collected with optional consent.ResultThe number of autopsy became over 30 cases per year. Most of the patients had dementia. Of note, geriatric residents with mentally retardation or cerebral palsy from childhood were included. At the end of 2022, more than 800 of frozen brains with detailed medical record are stored in FBB and readily available for research. The neuropathology database share the same coding system for Japanese Brain Bank Network for Neuroscience Research (JBBNNR).ConclusionThe challenge of FBB will play a unique and important role to clarify cliniconeuropathological correlation of the nursing home residential with various geriatric conditions with 3D(Disability, Dementia, and Developmental disorders).
Analysis of multi‐dimensional cognitive function of different sexes in the middle‐aged and elderly people at high altitude
Authors: Zhu Aiqin , Liu Wenzeng 
Published: December 2023

AbstractBackgroundTo explore the overall and multi‐dimensional cognitive function of middle‐aged and elderly people and gender difference analysis of its influencing factors under hypoxia environment.MethodFrom January 2018 to December 2021, using cross‐sectional study design, all participants from Xining, Qinghai Province (with an average altitude of 2,500m) who have lived for more than 20 years were selected.General data questionnaire survey, laboratory collection, overall and multi‐dimensional cognitive function assessment were conducted.ResultA total of 500 middle‐aged and elderly people were included in this study, 299 males and 201 females, with an average age of 64.17 ± 10.58 years. Compared with women, there were more men working in civil service, earning more than 5000 months, smoking and drinking, accompanied by hypertension and diabetes (P<0.01, P<0.001), but Geriatric Depression Scale(GDS)and Pittsburgh sleep quality index (PSQI) scores were significantly lower (P<0.01).Compared with women’s multiple cognitive domains, scores of Mini mental state examination(MMSE), Complex Figure Test Delay Recall(CFT‐DR), Digit Span Forward(DSF) and Digit Span Backward(DSB) in men were higher (P<0.05, P<0.01), while scores of Trail Making Test (TMT‐A and TMT‐B) were significantly lower (P<0.01, P<0.001).The neutrophil lymphocyte ratio (NLR) and homocysteine (HCY) in peripheral blood were higher than those in women (P<0.05, P<0.01). Covariance analysis showed after adjusting for education level that scores of MMSE and situational memory (CFT‐DR) of men in different age groups were higher than those of women, while scores of attention (TMT‐A) and executive ability (TMT‐B) were lower than those of women (P<0.05, P<0.01). After adjusting for age, scores of MMSE and CFT‐DR of men in primary school, middle school and high school were higher than those of women (P<0.05, P<0.01). With the influence of education level, men’s TMT‐A scores showed a trend of lower (P<0.05, P<0.01), while women’s TMT‐A scores changed little.TMT‐B score of men was lower than that of women in the four education stages (P<0.05), but there was no trend for men and women to optimize with the increase of education level.ConclusionMiddle‐aged and elderly people of different sexes living in high altitude hypoxic environment may have different multidimensional cognitive decline.
Language, Subjective Cognitive Decline and Help Seeking in Latinx
Authors: Chapman Silvia , Rentería Miguel Arce , Hokett Emily , Gonzalez Christopher , Seblova Dominika , Zahodne Laura B. , Marquine María J. , Brickman Adam M. , Manly Jennifer J. , Cosentino Stephanie 
Published: December 2023

AbstractBackgroundSubjective cognitive decline (SCD) is a marker of Alzheimer’s disease and related dementia (ADRD) risk, as well as a reason why older adults seek medical help. However, whether the concept of SCD has utility in Latinx populations has been questioned because SCD’s inconsistent associations with cognition in this population. Measurement factors, such as how we ask about SCD (e.g., age‐anchoring) and person factors (e.g., preferred language) may influence the reported level of measured SCD and/or its association with cognition and help‐seeking.MethodsParticipants included 699 (50 years and older) Latinx individuals enrolled in the Offspring study of Racial and Ethnic Disparities in Alzheimer’s Disease. Participants completed two independent SCD measures that queried if memory had become worse (general SCD) and if it had become worse compared to others their age (age‐anchored SCD). Memory was assessed via the Selective Reminding Test (SRT) total and delayed raw scores. Help‐seeking was assessed by one item that asked if individuals had talked to a nurse/doctor about their cognitive concerns. In a series of linear and logistic regressions, we evaluated the cross‐sectional relationship between 1) SCD (general and age‐anchored) and memory performance and 2) SCD and help‐seeking. Models were stratified by preferred language (English‐speakers/Spanish‐speakers) and adjusted for age, sex, education, and medical burden.ResultsSpanish‐speaking Latinx participants were on average older, had less educational attainment, had greater medical burden, and reported more general SCD, but not age‐anchored SCD, than English‐speaking Latinx participants. Memory scores did not differ across language groups. General SCD was associated with help‐seeking in Spanish‐speakers only. Greater age‐anchored SCD was associated with lower SRT total score in English‐ (R2 = 0.158, B = ‐4.289, CI = ‐8.342,‐0.236) and Spanish‐speakers (R2 = 0.178, B = ‐5.889, CI = ‐10.875,‐0.904), as well as greater help‐seeking in both groups (English‐speaking: R2 = 0.078, B = 0.842, CI = 0.056,1.740; Spanish‐speaking: R2 = 0.277, B = 2.202,CI = 1.571,2.833).ConclusionsAcross language groups, age‐anchored SCD was consistently associated with memory performance and help‐seeking among Latinx adults. In contrast, general SCD was associated with help‐seeking only in Spanish‐speakers, and not associated with memory performance. This study is the first to demonstrate the utility of age anchoring SCD assessments within both English‐ and Spanish‐speaking Latinx individuals.