bluuebunny/crossref_metadata_2025_split huggingface dataset:
Attenuation of translational repression rescues memory impairment in Alzheimer`s disease mice
Authors: Ribeiro Felipe Campos , Ferreira Danielle Cozachenco , De Felice Fernanda G. , Lourenco Mychael V. , Aguilar‐Valles Argel , Sonenberg Nahum , Ferreira Sergio T. 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is characterized by impaired synaptic plasticity and progressive memory deficits. Converging evidence indicates that hippocampal mRNA translation, required for memory consolidation, is defective in AD. Eukaryotic initiation factor 4E (eIF4E)‐binding protein 2 (4E‐BP2) and Fragile X mental retardation protein (FMRP) act as translational brakes at different stages of protein synthesis. While 4E‐BP2 represses protein synthesis at the initiation step through inhibition of ribosome‐mRNA complex formation, FMRP blocks translation at the mRNA elongation step through ribosome stallingMethodAβ oligomers were injected in 3‐month old mice lacking one allele of 4E‐BP2 and one or two alleles of Fmr1. Protein synthesis was assessed by non‐radioactive incorporation of puromycin (SuNSET) in hippocampal slices. Memory performance was assessed by contextual fear conditioning (CFC). Moreover, mice lacking one allele of 4E‐BP2 were crossed with APP/PS1 mice and memory was assessed by CFC at 12 month old.ResultGenetic reduction of the translational repressors FMRP or 4E‐BP2, prevented the inhibition of hippocampal protein synthesis and memory impairment induced by Alzheimer’s‐linked amyloid‐β oligomers (AβOs) in mice. Moreover, 4E‐BP2 deletion rescued memory deficits in the APPswe/PS1dE9 (APP/PS1) transgenic mouse model of ADConclusionOur findings demonstrate that strategies targeting translational repression correct hippocampal protein synthesis and memory deficits in AD models.
Markers of vitamin B12 status in relation to CSF biomarkers and cognitive performance
Authors: Hooshmand Babak , Koch Franziska , Fissler Patrick , Otto Markus , Tumani Hayrettin , Kivipelto Miia , von Arnim Christine 
Published: December 2022

AbstractBackgroundThe association between markers of vitamin B12 status and cerebrospinal fluid (CSF) biomarkers of Alzheimer’s type dementia which precede cognitive impairment has been investigated by only a few small studies and the results have been inconsistent.MethodData included 462 patients aged 40‐94 years referred to the Memory Clinic at the Ulm University Hospital, Ulm, Germany between December 2009 and August 2015. Vitamin B12 and HoloTC were measured via chemiluminescence microparticle immunoassay, tHcy via chemiluminescence immunoassay and MMA via liquid chromatography mass specterometry. High performance liquid chromatography with fluorescence detection was used for measuring vitamin B1 and vitamin B6 whereas electrochemiluminescence immunoassay was used tomeasure folate. CSF Aβ42 and total tau were measured using conventional methods. CERAD battery was used to examine the cognitive status, and different domains were derived. Regression models were used to investigate the associations.ResultAfter adjusting for age, sex, creatinine levels and APOEε4 status, higher values of vitamin B12 and lower values of MMA were associated with lower concentrations of CSF total‐tau: the odds ratios (ORs) (95% confidence intervals (CI)) in a binary logistic regression analysis investigating the associations with total tau cut‐off of 400 pg/ml were 0.39 (0.15 ‐ 0.99) and 5.60 (1.93 ‐ 16.26) for the highest quartile of B12 and MMA compared to the lowest, respectively. In addition, vitamin B1 was significantly associated with t‐tau status. Furthermore, HoloTC, MMA, tHcy, vitamin B1, and vitamin B6 were associated with several cognitive domains such as episodic memory and executive functioning. No relationships were found with Aβ42.ConclusionVitamin B12 and vitamin B1 may be independent predictors of CSF biomarkers of Alzheimer’s disease and cognitive status. Randomized controlled trials are needed to determine the importance of supplementing with these vitamins on slowing structural brain changes and cognitive decline in older adults.
FOXO3 longevity genotype protects elderly men with late‐life hypertension from Alzheimer’s disease – Kuakini Honolulu Heart Program
Authors: Chen Randi , Morris Brian J , Donlon Timothy A , Ross G Webster , Willcox Bradley J , Allsopp Richard C , Nakagawa Kazuma , Masaki Kamal H 
Published: December 2022

AbstractBackgroundWhile studies have found that mid‐life hypertension increases risk of Alzheimer’s disease (AD), the association of late‐life hypertension with AD is still unclear, FOXO3 genotype influences mortality risk from cardio‐metabolic diseases (CHD, diabetes, and hypertension). We hypothesize that FOXO3 genotype affects the risk that late‐life hypertension poses to development of AD.MethodThe study involved 2,688 Japanese‐American men (mean age: 77.0 ± 4.1, range 71‐92) from the Kuakini Honolulu Heart Program with FOXO3 rs2802292 genotype, and information on incident AD from 1991 to 2012. Late‐life hypertension was defined as SBP/DBP ≥ 160/95 or taking anti‐hypertensive medication. Here, FOXO3 longevity haplotype (FOXO3‐LH) comprised minor allele frequencies of rs2802292 (G), rs2253310 (C), rs2802288 (A), rs2764264 (C), rs9398171 (C), rs12212067 (G), and rs3800230 (G). The association of FOXO3 genotype with late‐life hypertension and incident AD was assessed using a Cox proportional hazard model.ResultDuring 21 years of follow‐up, 513 people were diagnosed with incident AD. Age‐adjusted incidence rates of AD among late‐life hypertensive subjects showed that those with the rs2802292 longevity genotype TG/GG had a lower incidence than those with genotype TT (21.58 vs 24.49 per 1,000 person‐years; p = 0.038). A multivariable Cox model, adjusting for age, education, APOE‐ε4 and other CVD risk factors, showed late‐life hypertension protects men from AD only for those with a longevity genotype such as rs2802292 TG/GG (HR = 0.68, 95% CI 0.52–0.89; p = 0.0052), and with the FOXO3‐LH (HR = 0.59, 95% CI 0.39–0.91; p = 0.016), but this was not seen for the rs2802292 genotype TT (HR = 1.15, 95% CI 0.89–1.49; p = 0.28), nor in the absence of the FOXO3‐LH (HR = 1.14, 95% CI 0.88–1.49; p = 0.31).ConclusionThis study provides the first evidence that FOXO3 genotype influences the risk that late‐life hypertension has on developing Alzheimer’s disease. Only with the FOXO3 longevity genotype was there protection against a late‐life hypertension‐mediated increase in incident AD risk. The findings have implications for the effect of the FOXO3 longevity genotype on late‐life hypertension‐associated risk of AD. Without considering the effect of FOXO3 longevity genotype, one should be cautious about generalizations concerning the protective effect of late‐life hypertension on AD in the population.
Angiotensin‐(1‐7)/Mas receptor agonist: a disease modifying therapeutic for VCID protects cognitive function and inhibits serum neurofilament light protein
Authors: Hoyer‐Kimura Christina , Konhilas John , Sweitzer Nancy , Ryan Lee , Hay Meredith 
Published: December 2022

AbstractBackgroundVascular contributions to cognitive impairment and dementia (VCID) and Alzheimer’s disease related dementias (ADRD) are associated with increases in systemic and brain inflammatory cytokines, increased reactive oxygen species (ROS) and decreased brain blood flow. We have completed preclinical development of novel synthetic glycopeptide derivatives of Angiotensin‐(1‐7) (Ang‐1‐7) MasR agonists that have outstanding brain penetration, improved half‐life, reverse cognitive impairment and decreases plasma neurofilament light protein (NfL) in our preclinical model of VCID. Ang‐(1‐7)/MasR mechanisms of action include inhibition of 1) microglia activation, 2) brain cytokines activation and, 3) vascular endothelial ROS production. The purpose of this pilot study was to 1) determine if plasma NfL is increased in coronary artery bypass graft (CABG) surgery patients at‐risk for VCID and 2) determine if treatment with an Ang‐(1‐7)/MasR agonist protects cognitive function post‐surgy and modifies NfL.MethodSubjects were randomly assigned to receive either 200 micrograms/kg/day s.c. (n = 3) or saline‐placebo (n = 2). Injections were begun 2 hours prior to surgery and then daily for 21 days. Cognitive function was measured prior to surgery and at 21‐ and 90‐days post‐surgery. Serum NfL was measured via Quanterix Simoa assay. Statistical analysis was performed using GraphPad and significance tested using Welch’s ANOVA, Dunnett’s post. Memory function was measured using a composite score comprised of memory, executive functioning, language, and processing speed.ResultPlasma levels of NfL prior to surgery were significantly increased by 176% in CABG patients (n = 5) as compared to age‐matched healthy controls (n = 8, p = .003). Treatment with Ang‐(1‐7) for 21‐days via subcutaneous injections protected memory function as measured by both the Face‐Name and Cured Name Retrieval associative memory tests at both 21‐ and 90‐days post ‐surgery and significantly attenuated CABG induced increases in NfL as compared to placebo‐saline treatment (p = .004).ConclusionThese preliminary data suggest that NfL may serve as a biomarker of VCID in CABG surgery patients and for MasR target engagement for VCID‐modifying treatments with Ang‐(1‐7) analogs. We have begun studies to develop NfL as a biomarker for Ang‐(1‐7)/MasR target activation and for patient stratification for treatment of VCID (Supported by NIH U01HL131014, U01AG066623).
Longitudinal tau accumulation interacts with cortical thinning to predict steeper memory decline in cognitively normal older adults
Authors: Fonseca Corrina S. , Chen Xi , Baker Suzanne L. , Jagust William J. , Harrison Theresa M. 
Published: December 2022

AbstractBackgroundCross‐sectional measures of tau pathology, a hallmark of Alzheimer’s disease (AD), have been associated with brain structure and memory performance in cognitively normal older adults (OA). Fewer studies have explored the downstream effects of longitudinal tau accumulation in OA. Here, we investigated relationships between tau accumulation, atrophy, and memory performance change over time.MethodSeventy cognitively normal OA (age = 77 ± 5 years; Table1) underwent longitudinal flortaucipir (FTP) PET, structural MRI scanning, and neuropsychological assessment. Annual change slopes for entorhinal cortex (EC) and a temporal meta‐ROI partial‐volume corrected FTP, cortical thickness, and an episodic memory (EM) composite were estimated using linear mixed effects models. Linear methods (Pearson correlation, multiple regression, mixed effects models) were used to relate regional tau slopes to atrophy and EM change. We used elastic net regression to select the best predictors of EM slope, including all FTP and structural ROIs, age, education, beta‐amyloid burden, and sex. Voxel‐wise FTP slope images were also generated to explore associations with atrophy and EM slope across the cortex.ResultHigher FTP slope in EC and meta‐ROI significantly predicted EM decline (β= ‐.26 p=.03 & β= ‐.38 p=.001, respectively; Fig.1). FTP slope did not significantly predict longitudinal atrophy in EC or meta‐ROI (ps>.10). A multiple regression with predictors selected via an elastic net model (Table2) showed a significant interaction between meta‐ROI FTP slope and EC cortical thickness slope such that tau accumulation and EM decline were more strongly related in OA with a higher rate of entorhinal cortical thinning (β=.23 p=.02; Fig.2). Voxel‐wise models with tau slope and memory showed interesting findings in the temporal lobe but clusters did not reach statistical significance. A one‐sample t‐test showed significant tau accumulation in frontal, parietal, and temporal lobe regions (Fig.3).ConclusionEC and meta‐ROI tau accumulation predicts memory decline in cognitively normal OA. EC atrophy moderated the effect of meta‐ROI tau accumulation on memory decline, suggesting a synergic effect of tau pathology and structural atrophy on memory decline in early AD. These novel findings provide insights into mechanisms of memory decline in typical aging and early AD.
Is blood‐based kallikrein‐8 increased in participants with subjective cognitive decline compared to cognitively healthy controls? Results of the Heinz Nixdorf Recall Study
Authors: Jokisch Martha , Krizanovic Nela , Jöckel Karl‐Heinz , Herring Arne , Keyvani Kathy , Weimar Christian , Schramm Sara ,   the Heinz Nixdorf Recall Study Investigative Group
Published: December 2022

AbstractBackgroundWhile there is rising evidence of blood kallikrein‐8 (KLK8) as a new blood‐based biomarker for mild cognitive impairment due to Alzheimer’s disease (AD) and for AD, little is known about the role of blood KLK8 in earlier prodromal stages of disease. Therefore, the aim of the present study was to examine whether blood KLK8 is elevated in participants with subjective cognitive decline (SCD) compared to cognitively unimpaired controls.MethodWe included 80 participants with incident SCD and 80 controls (matched by sex and age (+/‐ 3 years)) from the population‐based, longitudinal Heinz Nixdorf Recall Study (t0: 2000‐2003, n=4814, ø 57.8 years, 48.3% men; t1: 2005‐2008, n=4157, ø 62.9 years; t2: 2010‐2015, n=3087, ø 68.1 years). A cognitive assessment was conducted at t1 and t2. The cognitive performance of cases and controls was in the normal age and education range at both visits. Cases with incident SCD at t2 did not report SCD at t1. Controls never reported SCD. KLK8 levels at t2 were measured in defrosted serum samples. Using multiple logistic regression the association between KLK8 in cases vs. controls was investigated by estimating odds ratios (OR) and 95%‐confidence intervals (95%CI), adjusted for inter‐experimenter assay variability, freezing duration and depressive symptoms. Using receiver operating characteristic (ROC) analysis the diagnostic accuracy of KLK8 was determined by estimating the area under the curve (AUC) and 95%CI (adjusted for inter‐experimenter assay variability, freezing duration, age, sex, depression).ResultN=141 participants (50% cases, 36.9% women, 69.5±7.4 years) had valid KLK8 measurements. Mean KLK8 was higher in cases than in controls (1050.1±918.9 pg/ml vs. 834.7±711.6 pg/ml). Fully adjusted, a KLK8 increase of 500pg/ml was associated with a 1.18 (0.92‐1.52) higher chance of having SCD compared to being cognitively unimpaired at t2. With an AUC of 0.71 (0.62‐0.80)) blood KLK8 was a rather weak discriminator for SCD and cognitively unimpaired controls.ConclusionThis is the first study to show increased KLK8 levels in participants with SCD compared to cognitively healthy controls. However, the diagnostic utility of KLK8 in participants with only SCD seems limited. These results have to be replicated in larger samples.
REMOTE COGNITIVE STIMULATION THERAPY: CONTINUITY IN THE CONTEXT OF COVID‐19 PANDEMIC IN BUENOS AIRES, ARGENTINA.
Authors: Fernandez Maria Cecilia , Murphy Georgina , Melnitzky Agustina , Golimstok Angel , Berrios Waleska , Campora Nuria , Basalo Maria Jose Garcia , Basalo Maria Mercedes Garcia , Quintana Marcos Ojea ,   Memory and Behavior Disorders Research Group of Hospital Italiano of Buenos Aires
Published: December 2022

AbstractBackgroundDue to the COVID‐19 pandemic, clinical practice of neuropsychology has been substantially modified keeping the remote attention since then. In this work our experience in remote cognitive stimulation (RCS) for the past fifteen months and the user satisfaction during the second year of the pandemic is described.Materials and methodsSurveys were conducted using Google Forms sent via email to patients, relatives or caregivers of patients who agreed to the RCS practice. The degree of difficulty to handle virtual platforms, and the level of satisfaction with the RCS practice were assessed through subjective report of the respondents.ResultsThe survey was completed by 121 individuals (67.8% patients and 32.2% relatives). The mean age of the patients who accessed RCS was 75.3, 66.9% were women, 2.6% had incomplete primary school, 34.2% had completed primary school, 42.6% had completed secondary school, 20.6% had completed university and higher degrees.Regarding the ease of accessing the platform, 56.2.3% referred that it was easy for them. About the degree of satisfaction with the RCS, 65.3% conveyed being very pleased, and 33.1% pleased. 96.7% of those surveyed held that the practice was in accordance with their expectations and 94.2% stated that they would carry out RCS again in the future. Regarding the advantages identified, 52.1.6% recognized as an advantage avoiding the transfer, and 42.1.9% referred a greater use of time.ConclusionDuring the second year of the pandemic we have observed that the satisfaction level regarding remote practice held the same. Patients stood out as principal benefits of it avoiding traveling and the better use of time preferring to continue with this modality. This data allows us to take a glimpse at the benefits of this modality to continue using it in the future regardless of the epidemiological situation.
Glycolysis‐derived L‐serine in hippocampal astrocytes rescues synaptic plasticity and memory loss in a mouse model of Alzheimer’s disease
Authors: Bonvento Gilles 
Published: December 2022

AbstractBackgroundImpairment of glycolysis has often been observed early in the course of Alzheimer’s disease, although it is not known whether this deregulation contributes to the cognitive deficits observed in the disease. Aside from ATP production, a major function of glycolysis is to provide precursors, such as L‐serine, to support macromolecular synthesis. L‐serine is a metabolic hub and plays pivotal role in the brain. It is the precursor of D‐serine, the principal co‐agonist of synaptic N‐methyl D‐aspartate receptors (NMDARs) required for the induction of long‐term synaptic plasticity in the hippocampus. It also contributes to the homeostasis of synapses and of mitochondrial function by providing lipids.MethodWe used young female 3xTG‐AD mice to determine whether a shortage in the synthesis of L‐serine produced by hippocampal astrocytes from a glycolytic intermediate is responsible for the impairment of synaptic plasticity and spatial memory.ResultWe found that 3xTG‐AD mice in the early stage of the disease have reduced extracellular L‐serine levels in the hippocampus where in vivo glucose metabolism is reduced, but not in the frontal cortex that does not present metabolic alterations. Acute application of D‐serine or L‐serine rescues long‐term synaptic plasticity and chronic oral L‐serine supplementation restores memory deficits in AD mice. Such chronic treatment also restores the atrophy of hippocampal astrocytes in these AD‐mice.ConclusionThese results indicate that a metabolic deficit of L‐serine synthesis by astrocytes contributes to cognitive deficits in AD.
Cell sorting after tracer injection to elucidate allocation of cellular FDG uptake in different cell types and different microglial activation states
Authors: Brendel Matthias 
Published: December 2022

AbstractBackground2‐deoxy‐2‐[18F]fluoro‐d‐glucose positron‐emission‐tomography (FDG‐PET) is widely used to study cerebral glucose metabolism. Radiosorting revealed that the FDG‐PET signal is directly influenced by microglial glucose uptake in mouse models and we found similar associations in patients with neurodegenerative diseases. Now, we questioned the allocation of cellular FDG uptake in the rodent brain.MethodSingle cell [18F]FDG uptake as assessed by magnetic activated cell sorting (MACS) was multiplied with published total cell numbers in the mouse brain, i.e. 71e+6 neurons or 7% (≈ 7.6e+6) microglia cells to estimate the overall uptake per cell fraction. Estimated cellular microglial [18F]FDG uptake as assessed by MACS was cross‐validated with observed %‐FDG‐PET reductions after microglia depletion. Interstitial and vessel [18F]FDG was estimated by interstitial compartment volume and assumed equilibrium of non‐phosphorylated extra‐ and intracellular [14C]Deoxyglucose. Synaptic [18F]FDG uptake was estimated via an enriched synaptosome fraction relative to [18F]FDG uptake of whole‐brain homogenate. A microglia proliferation index of 1.3 was assumed for the whole brain in the Aβ mouse model.ResultMicroglia cells accounted for 8.6% of the overall brain [18F]FDG uptake in wild‐type mice and for 29.9% of the overall brain [18F]FDG uptake in PS2APP mice, confirmed by similar alterations after microglia depletion in PET. Synapses contributed to 13.2‐17.1% of the overall brain [18F]FDG uptake whereas interstitial (5.9‐7.7%) and vessel (2.6‐3.4%) [18F]FDG uptake was of minor magnitude. Neuronal and astrocyte cell bodies accounted for <10% of the overall brain [18F]FDG uptake, but a proportion of 42‐55% was not recovered and likely allocated in lost cell processes, oligodendrocytes and other cell types.ConclusionMicroglial FDG uptake alterations are the source of FDG‐PET changes in models of neurodegenerative diseases. Our data should increase the awareness to consider glia cells as key contributors of FDG uptake and the detailed proportions of these cellular contributions in healthy brains and under disease conditions deserve deeper investigation.
Identifying relevant psychosocial factors in the Care of People with Dementia: findings of a focus group study with informal caregivers and health professionals
Authors: Ross Sabrina D , Ziegert Nadja , Rodriguez Francisca S 
Published: December 2022

AbstractBackgroundPsychosocial factors offer promising possibilities for preventing dementia and slowing its progression. The extent to which psychosocial factors are taken into account in the treatment and care of people with dementia is not well known. The aim of this study was therefore to examine personal experiences and knowledge of psychosocial factors in dementia care structures. Particularly, their influence on dementia symptoms, on coping with daily life as well as on interpersonal relationships and the role of dementia in society.MethodTo identify which psychosocial factors play a role in the treatment and care of people with dementia, three focus groups were held with informal caregivers (1) and health professionals (2) involved in the daily lives of people with dementia. The focus group discussions were transcribed verbatim and analyzed using qualitative content analysis.ResultIt emerges that psychosocial factors have a beneficial effect on daily life performance and general wellbeing, especially social contact. Further, psychosocial factors aid people with dementia in perceiving their general competency and specific abilities. Needs, interests and preserved abilities of people with dementia should be in focus when deciding on psychosocial applications. Perceived barriers to the implementation of psychosocial factors in daily life are bureaucracy, inadequate staffing, cost, and limited offers of and assistance in using psychosocial services. Educating the population about dementia was identified as an important societal challenge in order to counteract a lack of social participation and stigmatization.ConclusionThe results of our study contribute to a better understanding of the needs psychosocial factors can address successfully. Yet, we also find a number of obstacles to implementing psychosocial factors in the daily life of people with dementia. Many barriers may be overcome by reducing bureaucracy, expanding infrastructure, and increasing dementia awareness as well as time for care activities.