bluuebunny/crossref_metadata_2025_split huggingface dataset:
The influence of the ApoE genotype on regional amyloid beta progression and interregional correlations in nondemented elderly
Authors: Wybitul Maha , Langer Nicolas , Hock Christoph , Gietl Anton F. , Treyer Valerie 
Published: December 2023

AbstractBackgroundPrevious examinations have explored the spatiotemporal pattern of amyloid beta (Ab) deposition, one of the first pathogenic events in Alzheimer’s disease (AD). However, the literature presents with a limited characterization of early spatial Ab progression differences and interregional correlations related to the major genetic AD risk factor, the Apolipoprotein E (ApoE) genotype.MethodThe impact of ApoE genotype on dynamic spatiotemporal Ab patterns was investigated using longitudinal amyloid positron emission tomography (PET) imaging. A first analysis used data of 100 nondemented participants who were characterized as having an Ab increase over time. Standardized uptake value ratios (SUVRs) of 31 cortical and subcortical regions were extracted. Regional average SUVRs were clustered per genotype based on longitudinal trajectory shapes. A second analysis focused on the ApoE genotype impact on interregional correlations of annual change rates in 81 cognitively normal individuals. We explored the difference in the distribution of correlations and performed permutation statistics. All analyses were replicated and validated applying partial volume correction.ResultE4 carriers and noncarriers displayed different regional Ab trajectories. In general, noncarriers displayed a more homogeneous Ab increase over time in comparison to more diverse trajectories in carriers. Six regional clusters ranging from lowest Ab‐baseline values and none‐to‐small increases (cluster 1) to highest Ab‐baseline values and considerable increases (cluster 6) were identified for both carriers and noncarriers. Independent of genotype, cluster 1 contained the amygdala, the medial part of the anterior temporal lobe, the caudate nucleus, the parahippocampal gyrus, the anterior part of the superior temporal gyrus, and the hippocampus. Other clusters differed between genotypes with several regions being assigned to higher Ab‐baseline and higher increase clusters in carriers. The correlational analysis found a distinct pattern in noncarriers with most regions presenting significant positive intercorrelations except for the hippocampus, which demonstrated almost exclusively null‐to‐negative correlations. This pattern was not found in e4 carriers.ConclusionThe results suggested an ApoE genotype impact on the heterogeneity of the spatiotemporal Ab pattern and a dissociative hippocampal role.
The Pattern of Hippocampus and Entorhinal Cortex Subregion Atrophy in Early Alzheimer’s Disease
Authors: Laczó Jan , Lerch Ondrej , Martinkovic Lukas , Laczó Martina , Vyhnalek Martin , Hort Jakub 
Published: December 2023

AbstractBackgroundAtrophy of the hippocampus and entorhinal cortex (EC) develops early in Alzheimer’s disease (AD). The nature of atrophy along the anterior‐posterior longitudinal axis of the hippocampus and EC in individuals with amnestic mild cognitive impairment (aMCI) with positive AD biomarkers (AD aMCI) has been less researched. We aimed to reveal a possible different pattern of atrophy in longitudinal axis of the hippocampus and EC between AD aMCI individuals and those with AD biomarker negative aMCI (non‐AD aMCI).MethodIn total, 100 older adults with AD aMCI (n = 26), non‐AD aMCI (n = 23), mild AD dementia (n = 22) and cognitively normal (CN; n = 29) from the Czech Brain Aging Study (CBAS) underwent clinical and cognitive testing, and brain MRI with the 3‐dimensional T1‐weighted high‐resolution magnetization‐prepared rapid gradient echo sequences. An automated processing pipeline using the Advanced Normalization Tools based on the CBAS population template and a manual segmentation protocol were used to measure left and right subregional hippocampus and EC volumes including hippocampus head (HH), body (HB) and tail (HT), and anterolateral (alEC) and posteromedial (pmEC) entorhinal cortex volumes, respectively. Volumes were normalized to estimated total intracranial volume.ResultCompared to the CN group, the AD aMCI group had lower subregional hippocampus and EC volumes (p<0.05) except for right and left HH volumes. Compared to the non‐AD aMCI group, the AD aMCI group had lower right HB (p<0.05), right and left HT (p<0.01), right alEC (p<0.05), and right (p<0.01) and left (p<0.05) pmEC volumes. The mild AD dementia group had lower all subregional hippocampus and EC volumes compared to the CN group (p<0.05).ConclusionThese results are in line with previous research that demonstrated atrophy of the hippocampus and EC in early AD and indicate that atrophy of the posterior hippocampus and EC subregions may reflect AD pathology in aMCI individuals. Volumetric differences along the anterior‐posterior axis of the hippocampus and EC could serve as a potential biomarker to identify the underlying pathology in different neurodegenerative diseases.
Investigating epigenetic regulation of microglia in a human‐mouse chimera model of Alzheimer’s disease
Authors: Marzi Sarah 
Published: December 2023

AbstractBackgroundMicroglia, the resident macrophages of the brain, are implicated in Alzheimer’s disease (AD). The genetic risk for AD is significantly enriched near microglial genes and enhancers. In the human brain, APOE is the strongest genetic risk factor for late onset AD and is primarily expressed in microglia and astrocytes. The “disease associated microglia” (DAM) state, in which inflammatory pathways are upregulated in amyloid plaque‐associated microglia, is a characteristic pathological response in AD.MethodHere, we studied how amyloid pathology interacts with genetic risk for AD to regulate the DAM state.We profiled gene regulation in human iPS‐derived microglia. We xenotransplanted the microglia into the APPNL‐G‐F mouse model of AD using isogenic APOE2/3/4 and APOE knockout (KO) microglia (n = 5 animals per microglial APOE genotype). We characterized dissociated iPS‐derived microglia from each animal by RNA‐seq, CUT&Tag for H3K27ac, and ATAC‐seq. We performed quantitative analyses of the epigenetic landscapes of microglial populations across heterogeneous activation states. This allowed us to infer the regulatory pathways that are responsible for the differential microglia response to amyloid aggregation, depending on APOE.ResultWe observed widespread differences in gene regulation across microglia related to APOE genotype. While we observed upregulation of chemokine and interferon response signalling in AD‐risk variant e4, we observed corresponding downregulation in the AD‐protective variant e2. Additional analyses identified increased chromatin accessibility at vitamin D receptor binding motifs in e2 through motif analysis. Finally, we identified gene expression networks and modules underlying differential microglial activation states.ConclusionOur findings are important for understanding microglia and their activation in AD and neurodegenerative diseases. Here, we profiled comprehensive epigenetic landscapes in a human‐mouse chimera in the context of APOE genotype. This enabled us to leverage the realistic biological environment for the microglia offered by this model, and dissect genetic effects underlying microglial responses for the first time.
"Caregiving made me grateful:” The unexpected blessings of dementia caregiving for Alaska Natives when given a second chance to care for a family member
Authors: Kim Steffi M , Asquith‐Heinz Zayla , Lewis Jordan P. 
Published: December 2023

AbstractBackgroundThere is a cultural value among Alaska Natives to care for their Elders and this commitment applies to all Elders, regardless of health status or cognitive health. Caregiver duties can lead to stress, isolation, and depression that negatively impact their overall health and wellbeing. Despite the challenges, these caregivers emphasized the unexpected blessings, which served as coping mechanisms and providing meaning and purpose to their caregiver role.MethodInterviews were conducted with 22 Alaska Native caregivers for Alaska Natives with Alzheimer’s Disease and Related Disorders (ADRD) in rural and urban communities across Alaska. Interviews lasted approximately 60 min and were transcribed verbatim. We employed directed content analysis to examine the caregivers’ experiences of ADRD and the unexpected blessings associated with being a caregiver.ResultAlaska Native caregivers shared the challenges associated with caregiving duties, and the lack of education, awareness, and available resources exacerbated their stress and challenges. As their family member experienced changes related to the ADRD, the blessings took different forms and served different purposes. Spending more time with their family member, remembering family history, engaging in generative behaviors, and strengthening intergenerational relationships were the most frequently discussed blessings. Focusing on these blessings enabled caregivers to continue to find meaning in this role and carry on their cultural values and traditions.ConclusionThis study shifts the focus of caregiving research to highlight the unexpected blessings. The focus on strengths of caregiving and sharing these stories has the potential to provide current and future caregivers to step into this role with a different perspective, or at least not just hear of the challenges and barriers associated with ADRD caregiving.
Individualised prognostic models using plasma biomarkers for clinical progression to Alzheimer’s disease dementia in non‐demented elderly
Authors: Honey Madison I. J. , van Maurik Ingrid S. , van Harten Argonde C. , Gouda Mariam , Kroeze Lior A. , van Leeuwenstijn Mardou S. S. A. , Mank Arenda , Trieu Calvin , Pijnenburg Yolande A.L. , van der Flier Wiesje M. , Wilson David , Teunissen Charlotte E. , Verberk Inge M.W. 
Published: December 2023

AbstractBackgroundBlood‐based biomarkers can provide a low‐invasive and accessible way to identify neurodegenerative diseases before the clinical onset of dementia. We aimed to construct prognostic models for personalized risk of developing Alzheimer’s disease (AD) dementia in a memory clinic population of individuals with either subjective cognitive decline (SCD) or mild cognitive impairment (MCI), using plasma phosphorylated‐tau‐181 (pTau181), amyloid beta1‐42/1‐40 (Aβ42/40), glial fibrillary acidic protein (GFAP) and/or neurofilament light (NfL).MethodFrom the Amsterdam Dementia Cohort and SCIENCe project we included 303 individuals with SCD (age 61±9 years, n = 126(42%) female, MMSE 28±1) and 250 with MCI (age 65±7 years, n = 89(36%) female, MMSE 27±2), who had annual follow‐up visits for re‐evaluation of diagnosis (average follow‐up duration: 2.7±1.7 years.) Our outcome measure was progression to AD dementia. Plasma biomarkers were measured at baseline using SiMoa. Concentrations were then Z‐transformed for the statistical analysis and split into tertiles for risk chart visualisation. We evaluated adding the biomarkers individually, or as a panel, to a basic prognostic model including age, sex and baseline diagnosis. We selected a final model by its discrimination (Harrell’s C‐index, a value above 0.7 indicates a good model) and accuracy (Brier score, a value below 0.2 indicates a good model) and used it to calculate 5‐year risk scores for progression to AD dementia.ResultDuring follow‐up, 86 individuals developed AD dementia (8 with SCD, 78 with MCI at baseline, average time to progression: 2.8±1.7 years). Adding any of the biomarkers to the basic model improved the model discrimination (Table 1). The prognostic model with all four plasma biomarkers had the best discrimination and accuracy, followed by the model with GFAP only, and the model with pTau181 only (Table 1). Using the model with all four biomarkers, 5‐year individual progression risks to AD dementia varied from 1.9% (lowest tertiles for GFAP, pTau181 and NfL, highest tertile for Aβ42/40 ratio) to 40.6% (highest tertiles for GFAP, pTau181 and NfL, lowest tertile for Aβ42/40 ratio) (Figure 1).ConclusionPlasma biomarkers, particularly plasma GFAP, can be utilized to provide prognostic risk information about progression to AD dementia for individuals presenting at a memory clinic.
Development of Behavioural and Psychological Symptoms of Dementia(BPSD) App for use in a hospital setting
Authors: Soong Mei Min , Barrett Tomiko 
Published: December 2023

AbstractIntroductionPrevious quantitative audits at Wyong Hospital, a 300 bed regional and teaching hospital in the Central Coast Local Health District (CCLHD) showed that the majority of Clinical Aggression Response Team (CART) calls occurred in the geriatric population.Results suggested that often BPSD guidelines which were on the CCLHD intranet were not adhered to. It was suggested that medical officers need ready access to local guidelines and more education. Interviews with staff who were participating in CART calls found that medical staff were not confident in when to and what to prescribe and what was the most appropriate management.These audits, which involved interviewing participants of CART calls, plus evidence about implementing practice change, suggests that mobile phone apps are used more frequently and are more effective than intranet documents.ObjectiveDevelop a BPSD app with the potential to make evidence based recommendations and local guidelines accessible to the user at the bedside using a mobile device particularly during CART calls and enables the user to manage BPSD with ease.Methods1.	Content of the app is based on BPSD guidelines published on the CCLHD intranet geriatric medicine webpages.2.	A prototype of the app was developed on Marvel designs and provided to the IT and e‐health New South Wales department who provided suggestions, guidance on the app development and integration of the app onto the hospital IT system. Training sessions were provided via drop in sessions and online videos using Microsoft teams. Targeted education sessions on app usage was provided to medical personnel. Costs for the development of the app was funded by the Department of Geriatric medicine, Wyong and Gosford Hospital.3.	Ethics approval was obtained from the Central Coast Local Health District Human Research Ethics Committee.ResultsThere has been more than 100 downloads of the app with levels of usage ranging from 1 to 38 on a daily basis.ConclusionThe development of the app allows ease of access to concise evidenced based information and supports clinicians in their role in managing BPSD.
Angiotensin Receptor Blockers as an Alternative Strategy for Addressing Neurodegeneration in a LPS Mice Model
Authors: Gouveia Filipa , Fonseca Carla , Silva Ana , Camins Antonio , Cruz M. Teresa , Arriola Miren Ettcheto , Fortuna Ana 
Published: December 2023

AbstractBackgroundTo identify new therapeutic strategies that impair the development of Alzheimer’s disease (AD), angiotensin receptor blockers (ARB) were investigated as promising candidates to reduce the risk of developing AD in hypertensive patients. However, the mechanism by which they are able to induce this effect remains unclear. On the other hand, it has been described that neuroinflammation plays an important role in neurodegenerative diseases, including AD, being key in the cognitive decline process. Therefore, the aim of this study is to evaluate the neuroprotective effect of ARB in in vivo and in vitro models of neuroinflammation induced by Lipopolysaccharide (LPS) and to disclose their mechanism of action.MethodBV‐2 microglia cell line was exposed to LPS and treated with the ARB. Meanwhile, 7–8‐week‐old C57/BL6 male exposed to LPS were used as a neuroinflammation model. Animals were treated with saline or intranasal ARB (40 mg/kg/day) for 10 days and LPS (1 mg/kg) was injected in last day, 24h before sacrifice. Before euthanizing, long‐term memory was evaluated by Novel Object Recognition test (NORT). Afterwards, analysis of the dendritic spines, neuroinflammation and molecules related to neurodegeneration and cognitive decline was performed.ResultOur results show a beneficial effect of ARB in neuroinflammation by reverting the memory loss observed in mice that received a LPS injection. This beneficial effect is also correlated to an amelioration of the synapsis dysfunction by the activation of pathways involved in neuroprotection, namely the PI3K/AKT pathway and by differences in spine density. Moreover, molecular studies show that previous treatment with ARB is able to stimulate the anti‐oxidant defense system by increasing SOD2 and Gpx‐1. Also, LPS increased neuroinflammatory markers that were significantly reduced in the ARB group as well as apoptotic factors that were decreased with the treatment. Therefore, contributing to the maintenance of cognitive function avoiding the development of neurodegenerative processes.ConclusionIn conclusion, results demonstrate that intranasal administration of ARB prevents LPS‐induced cognitive decline, through the reduction of neuroinflammation and the activation of neuroprotective pathways, highlighting the potential of ARB in the prevention of AD and other neurodegenerative diseases.
Association between neutrophil to lymphocyte ratio and Alzheimer’s Disease in large biobank cohorts
Authors: Drzymalla Emily , Avery Christy , Raffield Laura 
Published: December 2023

AbstractBackgroundNeutrophil to lymphocyte ratio (NLR) is used as a marker for systematic inflammation and innate immune system activation; NLR has been associated with Alzheimer’s disease (AD) in previous literature, but mostly in relatively small case control studies. The goal of this study is to investigate the association between AD and NLR in two large biobanks, the UK Biobank and the United States based All of Us.MethodAD was defined using inpatient ICD10/9 codes and death certificates (UK Biobank) or inpatient ICD10/9 codes and Systematized Nomenclature of Medicine (All of Us). Cox proportional hazards models were used to estimate hazard ratios (HR) adjusting for age, sex, race, and recruitment center (UK Biobank). Because the UK Biobank had extensive covariate data available, we also estimated HRs further adjusting for hypertension, hypercholesterolemia, education, body mass index, and smoking.ResultWith complete covariate data, 233,173 UK Biobank (mean age = 58; 56% female; 2,049 incident AD cases) and 68,382 All of Us (mean age = 59; 65% female; 239 incident AD cases) participants were included. In the UK Biobank, every 1 standard deviation (SD) increase in NLR was associated with a 3% increase in AD risk (HR = 1.03, 95% CI = 1.01‐1.05, p‐value = 0.001) and this relationship was robust to lifestyle and clinical factor adjustment. NLR per 1 SD increase was not associated with AD (HR = 1.03, 95% CI = 0.81‐1.17, p‐value = 0.755) in All of Us.ConclusionNLR was associated with AD in UK Biobank but not in All of Us, however, we note that power is lower in All of Us due to fewer AD cases. We plan to repeat this analysis as more cases accrue in All of Us and explore the neutrophil‐associated Duffy null variant for potential modification of this AD/NLR association. These findings provide further evidence for the association between NLR and AD as well as the possible role of systemic inflammation in AD pathology.
External causes of death from death certificates in patients with dementia
Authors: Mo Minjia , Xu Hong , Hoang Minh Tuan , Jurado Pol Grau , Mostafaei Shayan , Kåreholt Ingemar , Johnell Kristina , Eriksdotter Maria , Garcia‐Ptacek Sara 
Published: December 2023

AbstractBackgroundThe external causes of death, including unintentional injuries, falls, suicide, and complications of medical and surgical care, in dementia are not well‐established, particularly in rare dementias. We compared risk of death from specific external causes in patients with dementia and control participants.MethodThis was a nationwide population‐based cohort study in Sweden integrating 6 national registers from May 1, 2007, through December 31, 2018. We included all dementia patients aged 40 years or older identified from the Swedish Dementia Register‐SveDem and the national patient registry during the period and up to four control participants who were matched on the year of birth (± 3 years), sex and region of residence. Causes of death were obtained from death certificates compiled in the death registry. Hazard ratios (HRs) and 95% confidence intervals (CIs) of dementia on external cause‐specific mortality were calculated using Cox proportional models, adjusted for sociodemographic variables, comorbidity, and psychiatric disorders.ResultThe study cohort included 241 569 patients with dementia (99 380 men [41.1%]; mean [SD] age, 81.5 [8.5] years) and 794 562 control participants (352 295 men [44.3%]; mean [SD] age, 79.9 [8.6] years), over 3 871 433 person‐years. People with dementia presented higher incident rates for unintentional injuries and falls during old age, and suicide in middle aged dementia patients, while the reverse trend for suicide in dementia was observed after 75 years. The association varied according to time since diagnosis. Compared with control participants, people diagnosed with dementia had an adjusted HR of 2.66 (95% CI, 2.58‐2.74) for unintentional injuries, 2.10 (95% CI, 2.01‐2.20) for falls, 0.48 (95%CI, 0.40‐0.58) for suicide, 0.94 (95%CI, 0.89‐1.00) for complications of medical and surgical care, and 2.61 (95%CI, 2.04‐3.34) for other external causes. Compared with control participants, patients with frontotemporal dementia had the highest risk of unintentional injuries and falls, while participants with mixed dementia were less likely to die from suicide and complications of medical and surgical care.ConclusionSuicide risk screening in early‐onset dementia and early interventions for unintentional injuries and falls prevention in older patients with dementia should be provided.
CSF ADAM10 levels in AD patients in relationship to ADAM10 gene variants
Authors: Agüero Pablo , Cremades‐Jimeno Lucía , García‐Ayllón María‐Salud , Gea‐González Adriana , Sainz María José , Téllez Raquel , Cárdaba Blanca , Sáez‐Valero Javier , Pérez‐Pérez Julián , Gómez‐Tortosa Estrella 
Published: December 2023

AbstractBackgroundThe disintegrin metalloproteinase 10 (ADAM10) is the main α‐secretase acting in the non‐amyloidogenic processing of APP. Some ADAM10 gene variants (Q170H, R181G) have been associated with higher susceptibility to develop late‐onset AD and have been shown to promote AD‐type changes in mice models. We tested the hypothesis that some ADAM10 rare variants could increase the risk for AD through conferring an earlier age‐related downregulation of a‐secretase activity.Method
ADAM10 gene was sequenced in 103 AD cases (78% with family history) with positive CSF biomarkers, and 96 cognitively preserved nonagenarians. ADAM10 in CSF of the AD cases was analyzed by means of ELISA (total levels) and western blot (segregated by isoforms of 50 kDa, 55 kDa, and 80 kDa) in comparison with controls and non‐AD dementia cases. We examined whether there was an increase of rare gene variants (MAF < 0.01) in the AD group and their potential association with lowers CSF protein levels.ResultRare variants were found in 15,5% of AD cases (in 23% of early‐onset versus 7,8% in late‐onset, p = 0.058) and in 12,5% of nonagenarians, and several of them were exclusive of the group. However, all were intronic variants except the Q170H change found in three AD cases and one nonagenarian. The SNP rs74016945 (3’UTR), with MAF close to 0.01, was found in 6% of the nonagenarians (OR 0.146, Fisher exact test p = 0.057). ELISA ADAM10 levels were not significantly different comparing AD cases with controls, carriers of rare variants versus non‐carriers, and did not differ consistently according to age at onset or APOE genotype. The three ADAM10 species were also similar in AD cases and controls, and did not differ according to genetic variants or age at onset.ConclusionRare ADAM10 exonic variants are uncommon in AD cases and the presence of rare intronic variants (more frequent in early versus late‐onset cases) is not associated with decreased ADAM10 levels in CSF.