bluuebunny/crossref_metadata_2025_split huggingface dataset:
A new de novo‐assisted mass spectrometry method for novel antimicrobial peptide expression profiling in cerebrospinal fluid (CSF) of demented subjects
Authors: Saxena Satya , Ye Yuanqing , Devanarayan Viswanath , Reyderman Larisa , Koyama Akihiko , Sachdev Pallavi 
Published: December 2023

AbstractBackgroundActivation of innate immunity is a pathological hallmark of Alzheimer’s disease (AD). Antimicrobial peptides (AMPs), small (12‐50 amino acid) peptides, are essential components of the innate immune system and provide the first line of defense against microbial infections in immune‐privileged tissues, like brain. Many proteins with antimicrobial activity have been shown to be involved in AD. We developed a new mass spectrometry (MS)‐based method to profile known and novel AMPs in CSF. Here we report differentially expressed AMPs in CSF of Ab+ (AD) and Ab‐ (non‐AD) dementia.MethodWe created a custom (Swiss‐Prot + human AMP) database for our de novo‐assisted proteomics platform. MS data (PRIDE archive PXD016278) from CSF of cognitively impaired subjects with or without amyloid positivity were analyzed. Peptide raw peak area intensities were quantile normalized and log2 transformed to reduce technical variation and ensure distribution symmetry. Differentially expressed peptides were identified via analysis of covariance after adjusting for age and gender, with the significant criteria based on 20% false discovery rate. Multiscale Embedded Gene Co‐expression Network Analysis (MEGENA) was used to identify AMPs with the potential to regulate the molecular changes in AD.ResultWe identified 24 differentially expressed AMPs in CSF of Ab‐driven dementia mapping to 6 proteins. These include the AMPs released by the chromaffin cells of the adrenal medulla (Chromogranin A and B, Ubiquitin), Beta‐2 macroglobulin, Amyloid‐beta A4, and Clustrin proteins. The antimicrobial activity containing sequence from Chromogranin A was represented in top two modules identified by MEGENA network analysis. These modules exhibited high correlation with peptides from a dementia‐linked neurosecretory protein VGF. The top 5 pathways enriched in MEGENA modules include cell adhesion, system development, nervous system development, regulation of nervous system development, and neurogenesis.ConclusionThis study reports the first unbiased analysis of dementia‐linked AMP diversity that can be monitored in CSF. Contribution of these AMPs and the associated pathways in the AD pathophysiology warrants further investigation.
Regulation of extracellular progranulin in the medial prefrontal cortex
Authors: Hall Justin A , Kaplelach Azariah K , Davis Skylar E. , Arrant Andrew E. 
Published: December 2023

AbstractBackgroundLoss‐of‐function mutations in progranulin (GRN) are a major genetic cause of frontotemporal dementia (FTD). Progranulin is a secreted protein that is trafficked to lysosomes, where it promotes lysosomal function. Progranulin also exerts neurotrophic and anti‐inflammatory effects, some of which may be mediated by extracellular signaling. Neurons and microglia express progranulin and loss of progranulin from either cell type induces FTD‐like deficits in mice. Both cell types secrete progranulin in culture, but their contribution to extracellular progranulin in the brain is unclear, as are the mechanisms regulating progranulin secretion from each cell type. In this study, we used microdialysis to gain insight into the contribution of neurons and microglia to extracellular progranulin in the medial prefrontal cortex (mPFC), a region that degenerates in FTD and develops impaired dendritic arborization in progranulin‐insufficient mice.MethodPolyethylene probes (2 mm, 1000 kDa cut‐off) were implanted in mouse mPFC and perfused with artificial cerebrospinal fluid containing 4% BSA using a push‐pull pump system (Atmos LM, Amuza). Progranulin levels in interstitial fluid (ISF) were measured by ELISA (Adipogen).ResultGrn+/– mice exhibited a roughly 50% decrease in ISF progranulin versus wild‐type, which was similar to the reduction of progranulin in mPFC tissue. In wild‐type mice, inducing cellular depolarization with KCl (100 mM) increased ISF progranulin, but stimulating synaptic activity with picrotoxin (100 μM) or NMDA (50 μM) did not. Inducing systemic inflammation with LPS (10 mg/kg i.p.) increased ISF progranulin to around 200% of baseline at eight hours after injection. Analysis of ISF progranulin from microglial progranulin knockout mice (Cx3Cr1‐Cre‐ER:Grnfl/fl) revealed a nearly 50% reduction in ISF progranulin compared to Cre– littermates, which was a larger reduction than observed in mPFC tissue. Ongoing studies are analyzing ISF progranulin in neuronal progranulin knockout mice (CamKII‐Cre:Grnfl/fl).ConclusionOur findings indicate that inflammation increases ISF progranulin in the mPFC and that nearly half of the extracellular progranulin in the mPFC may originate from microglia. In contrast, synaptic activity does not significantly increase ISF progranulin in the mPFC. Ongoing studies will investigate the contribution of neurons to extracellular progranulin in the mPFC.
The use of therapeutic lying in dementia care from the perspective of Brazilian caregivers
Authors: Alves Emily Viega , Beber Bárbara Costa 
Published: December 2023

AbstractBackgroundTherapeutic lying (TL) is a strategy that aims at the safety and well‐being of people with dementia (PwD), especially when they present behavioral changes. James et al. (2006) developed a protocol of guidelines on how to use the technique, demonstrating that its use requires trained professionals and caregivers. Considering that caregivers are the primary stakeholders in the daily life of PwD, it is critical to obtain their views on the use of TL in care practice. This study is part of a sequence of investigations into different public views on the use of TL with PwD, having already published the study with speech‐language pathologists. Thus, the purpose of this study was to verify the use and knowledge of TL among caregivers of PwD.MethodThis is a cross‐sectional study carried out through an online questionnaire. This is a cross‐sectional study carried out through an online questionnaire. The questionnaire was spread on social networks and collected sociodemographic data and information on knowledge, use and opinion regarding TL among PwD caregivers. The results were presented descriptively and the association between the frequency of the answers and the category of caregivers (formal or informal) was verified using the Chi‐square test with 5% significance.ResultsTwenty caregivers (17 informal and 3 formal), with a mean age of 48.6 years (±14.6), were included in the study. 90% of them had lied to PwD to benefit the patients and 25% had lied to benefit themselves. 20% had heard about TL, only 10% learned about the strategy in their training, and 75% would like to learn more about it. Also, 70.6% of caregivers think it is very valid to use TL, but 50% think it is very ethical. There was no significant difference for the responses when compared between formal or informal caregivers.ConclusionThe use of TL is widespread among caregivers, even without appropriate training to use this technique. Many caregivers question how ethical it can be to lie to PwD, even if it is to benefit them. Clearly, there is a need for education and training on TL in this population.
Baseline neuropsychological intra‐individual variability predicts cognitive impairment 8 years later in the Brazilian Longitudinal Study of Adult Health (ELSA‐Brasil)
Authors: Bertola Laiss , Gonçalves Natalia G , Bensenor Isabela M , Lotufo Paulo A , Suemoto Claudia Kimie 
Published: December 2023

AbstractBackgroundNeuropsychological assessment is still vastly based on a nomothetic approach. However, middle‐aged and older adults might start to reveal higher intra‐individual cognitive variability (IICV) as an early sign of cognitive impairment, even when still cognitively normal. IICV refers to inconsistency in function and has been related to an increased risk for dementia. Therefore, we aimed to verify if baseline IICV predicts the occurrence of cognitive impairment after eight years.MethodWe included 10,783 participants from the ELSA‐Brasil study, a multicenter, prospective cohort study with three waves, approximately four years apart each, starting in 2008. The ELSA‐Brasil baseline exclusion criteria included the presence of clinically observed severe cognitive or communication impairment. Participants' health status and cognitive performance were evaluated at baseline (W1) and Wave 3 (W3). Baseline neuropsychological assessment comprised measures of memory and executive function. We used regression corrected‐based norms, from a robust normative subsample, to generate the presence of baseline cognitive deficit (< ‐1.5 SD) (BCD) and the mean standard deviation across baseline cognitive scores (IICV). Mini‐Mental State Exam at W3 was corrected according to education‐based cutoff to verify the presence of cognitive impairment. Logistic regression, adjusted for sociodemographic (age, sex/gender, education, race/ethnicity) and clinical confounders (depressive symptoms, hypertension, diabetes, and alcohol consumption), was used to predict the odds ratios (OR) of being cognitively impaired after eight years of follow‐up when considering IICV, BCD and both.ResultParticipants had a mean age of 59.0±8.7 years old, 56% were women, 7% had less than high school level, and 42% were Black/Brown (Table 1). IICV within tasks ranged from 0.7 to 7.9 standard deviations, and only 1% of the sample had BCD. Higher IICV is associated with a higher occurrence of cognitive impairment after eight years, even after controlling for other risk factors (Table 2). IICV was associated with cognitive impairment even after controlling for BCD.ConclusionHigher cognitive intra‐individual variability among test scores at baseline was associated with a higher risk for cognitive impairment later in life. Cognitive heterogeneity should be considered during the neuropsychological assessment interpretation and can be a target for the detection of pre‐clinical cognitive impairment.
Amyloid and Tau Predominance Subtyping Identifies CI Patients With Different Clinical Phenotypes
Authors: Zalzale Hussein , Povala Guilherme , Ferreira Pamela C.L. , Bellaver Bruna , Ferrari‐Souza João Pedro , Soares Carolina , Lussier Firoza Z , Aguzzoli Cristiano Schaffer , Lemaire Peter Charles , Abbas Sarah , Rohden Francieli , Leffa Douglas Teixeira , Cabrera Arlec , Therriault Joseph , Stevenson Alyssa , Pallen Vanessa , Ashton Nicholas J. , Benedet Andrea Lessa , Blennow Kaj , Zetterberg Henrik , Karikari Thomas K , Rosa‐Neto Pedro , Pascoal Tharick A. 
Published: December 2023

AbstractBackgroundThe ATN classification system assumes a sequential model of disease progression. However, there are groups of individuals in the same ATN category that exhibit a predominance of abnormality (higher burden) of one of the biomarkers, creating heterogeneous ATN groups regarding pathological predominance. Thus, we tested the hypothesis that individuals clustered by ATN biomarker abnormality predominance may offer an alternative to groups defined using biomarkers cut‐offs.MethodWe assessed 103 cognitively impaired individuals(CDR> = 0.5) from the TRIAD cohort with available measures of plasma phosphorylated tau‐181, brain MRI, amyloid PET, and tau PET. We used the K‐means algorithm to stratify participants into three clusters. We compared the clusters on composite measures of memory, executive functioning, language, and visuospatial processing. To examine the utility of the discovered clusters, we compared them to traditional ATN categories in the prediction of neuropsychological measures. We did so by creating three categories: patients positive on all three ATN biomarkers, patients positive on two of the three biomarkers, and patients positive on either one or none. Additionally, we created an inflammation, amyloid and tau deposition probabilistic map anchored on young controls(n = 51, mean age = 23.74).ResultsWe uncovered 3 clusters: an amyloid predominant (AP) cluster, a tau/phosphor‐tau predominant cluster (TP), and a cluster showing no predominance with low levels on all biomarkers (CN)(figure 1). Notably, levels of neurodegeneration and inflammation were similar between the AP and TP clusters. The AP cluster significantly differed from the CN cluster in memory only. Participants in the TP cluster had significantly lower scores in memory, executive functioning, language, and visuospatial processing than the other two clusters. In comparison, using threshold‐based ATN groups showed milder differences in memory and executive functioning, and no differences in language and visuospatial processing(figure 2). Furthermore, cluster membership moderated the relationship between various biomarkers, to the point of reversing the direction of correlation(figure 3).ConclusionOur results highlight the biological heterogeneity present within the Alzheimer’s disease continuum and that the pathological predominance of amyloid and tau is associated with different disease phenotypes. Approaching dementia patients with an eye on the predominance of pathology rather than cutoffs for abnormality may provide a better understanding of AD pathological subtypes.
Longitudinal Quantification of Sub‐Regional Hippocampal Amyloid‐Beta Burden in Ex‐Vivo slices from the AppNL‐G‐F Mouse Model of Alzheimer’s Disease
Authors: Chen Yuqing , Turner Richard , Fuchsberger Tanja , Kelly Tommy L , Paulsen Ole 
Published: December 2023

AbstractBackgroundAmyloid‐beta (Aβ) pathology is suggested to precede the onset of clinical Alzheimer’s disease symptoms by up to two decades. The humanised AppNL‐G‐F knock‐in model of amyloidopathy has accelerated pathogenesis and can be used to study AD progression. Here we used it to quantify the temporal and spatial characteristics of Aβ plaque accumulation as they first appear in the hippocampus, and as pathology continues to develop.MethodAppNL‐G‐F knock‐in mice and wild‐type mice at 1, 3, 6, and 9 months of age were transcardially perfused with PBS followed by 4% paraformaldehyde (PFA), followed by preparation of coronal slices for immunohistochemistry analysis. Samples were stained with anti‐Aβ antibody (6E10) together with a neuronal marker, NeuN, and DAPI. Images were taken of sub‐hippocampal regions (CA1, CA3, DG), in left/right hemispheres, and ventral/dorsal segments using a confocal microscope (Leica SP8). Summation of intensity across Z‐stacks in Fiji was used to quantify Aβ plaques in regions of interest.ResultWe found age to be a statistically significant factor on determining area density, with hippocampal deposition observed by 3 months. Bin analysis showed a near‐exponential reduction in plaque number with increasing plaque size, increasing with age. Regionally, there was an increase in plaque density in CA3, with non‐linear regression analysis indicating area density for CA3 is most strongly correlated with age. Within the CA1 region, the densest plaque formation was in the pyramidal cell layer. Further analysis at the aged 9‐month time point suggested a differential pathology across the axial plane and greater left‐hemispheric lateralisation.ConclusionThis data provides further evidence for the protracted timeline to which AppNL‐G‐F knock‐in mice recapitulate key AD neuropathologies including insoluble amyloidosis beginning before 3 months in the hippocampus. It also indicates potentially novel differential sub‐regional Aβ accumulation patterns, axial variations, and hemispheric asymmetries, offering mechanistic insights for plaque localisation and differential susceptibility to Aβ. This could aid advancement of Αβ‐targeting therapies.
Workforce training through massive open online courses: can education generate collective hope for better dementia care?
Authors: Canty Alison Jane 
Published: December 2023

AbstractThe personal care workforce is generally poorly paid, often unregulated, minimally trained and unprepared for the challenges of working with people with dementia. When it comes to accredited healthcare degrees, established programs have little space to accommodate emerging health priorities, such as dementia, in an already crowded curriculum. This creates the perfect storm of a significantly unprepared healthcare workforce as we look towards an expected 139 million cases of dementia worldwide by 2050 (www.alzint.org).Could freely available, online, evidence‐based dementia care education be a solution, offering hope, knowledge and skills to carers across the globe? In 2013, the University of Tasmania launched an Understanding Dementia Massive Open Online Course (MOOC). Over 7 weeks participants increase their knowledge of dementia: its causes, symptoms and ways of responding to the needs of people living with the condition. This award‐winning MOOC has world‐leading completion rates, been rated amongst the top MOOCs of all time (Class Central), and reached over 330,000 people around the globe. As well as offering free MOOCS, there are low or no‐cost university level education options in a Diploma and Bachelor of Dementia Care. Targeted to the Australian Aged Care workforce, but open to any student, these fully online programs attract personal care workers, health professionals and family members of people living with dementia. Thousands of students have enrolled, primarily for professional and practice development reasons and to provide better care for family members or friends with dementia. These programs were created specifically for learners of all ages and from culturally and linguistically diverse backgrounds, and designed to facilitate success and progress. They are scalable and are being translated into a number of languages and cultures. With this approach, one click at a time, we offer hope through accessible education for those that need it most. In this sense, education is considered an intervention ‐ improving dementia care and awareness, decreasing stigma, and in driving a public health approach for dementia prevention.
Brain age gap, dementia risk factors and cognition in middle age
Authors: Stefaniak James D , Mak Elijah , Su Li , Carter Stephen F , Dounavi Maria‐Eleni , Muniz‐Terrera Graciela , Wells Katie , Ritchie Karen , Lawlor Brian , Naci Lorina , Koychev Ivan , Malhotra Paresh A , Ritchie Craig W , O'Brien John T 
Published: December 2023

AbstractBackgroundBrain Age Gap (BAG) represents the difference between an individual’s predicted age, derived from machine learning models trained on neuroimaging data, and their chronological age. BAG has been associated with dementia and cognition in old age. Less is known relating BAG to dementia risk‐factors or cognitive performance in middle‐age.MethodCognitively healthy, middle‐aged (40‐59 years) subjects from PREVENT‐Dementia had an array of neuropsychological, neuroimaging and genetic assessments. Brain Ages were predicted from T1‐weighted 3T MRI scans. Cognition was assessed using COGNITO. Multiple linear robust regression models tested hypotheses that: (i) BAG is positively associated with dementia risk‐factors; (ii) increased BAG is associated with worse cognition; (iii) longitudinal BAG change is positively associated with longitudinal cognitive deterioration. A range of machine learning algorithms with nested cross‐validation was used to assess whether BAG and cognition could predict each other.Result552 middle‐aged participants (median age 52.8 years) had all baseline assessments; 68 had amyloid PET data and 138 had longitudinal data. Median BAG was ‐2.0 years with a range from ‐21.2 to 18.4 years (Figure 1). BAG in middle‐age was associated with hypertension (p = 0.007) and alcohol intake (p = 0.008) but not APOE4 carrier status (p = 0.14) or amyloid centiloids (p = 0.53). BAG was not associated with cognitive performance either cross‐sectionally (p = 0.74) or longitudinally (p = 0.30), and there was no added predictive value between BAG and cognition. More education was associated with better cognition (p = 4.7×10−11) but not with BAG (p = 0.32).ConclusionEven in midlife, substantial inter‐individual heterogeneity exists in the extent to which brains have aged. BAG in middle‐age is associated with modifiable dementia risk‐factors, suggesting that lifestyle risk‐factor modification needs to start at, or before, midlife to optimise brain health. BAG in middle‐age was not associated with risk‐factors for Alzheimer’s disease (APOE4, amyloid deposition) or cognitive performance, despite there being a plausible and expected association between more education and better cognitive performance. These results are important for understanding brain‐age in middle‐aged populations who might be the target of future dementia‐preventing therapies.
The importance of study partners in Alzheimer’s clinical trials: An examination of the association between relationship type and protocol adherence
Authors: Parnitivithikul Tara , Abdulmumin Razyya L 
Published: December 2023

AbstractBackgroundClinical trials for Alzheimer’s Dementia (AD) often require the involvement of a study partner, or knowledgeable informant, who serves as a data source for outcomes related to participants’ cognition and function. Study partners are essential to the success of AD trials (Largent et al., 2018). Although participants are not required to be related to their study partners, research has found that those with spouses as study partners were more likely to qualify for trials compared to those with adult children as their study partners (Grill et al., 2012). Furthermore, those whose spouses served as their study partners were less likely to drop out than those whose study partners were neither spouses nor adult children (Grill et al., 2013; Nuno et al., 2022). The current study further contributes to these prior works by examining how study partner type relates to participants’ compliance while enrolled in a clinical trial.MethodSecondary data analyses of a Phase 3 Early AD clinical trial will be conducted to examine how relationship type relates to adherence to protocol visits. Specifically, one way analysis of variance will be conducted to test the effect of relationship type (i.e., spouse, other family, other/non‐family) on adherence to protocol visit windows (i.e., number of out of window and missed visits). Correlation analyses also will be conducted to assess whether the average number of hours participants spend with their study partners per week is related to their compliance with study visits.ResultResults from the study will provide insight on study partner types that can facilitate greater adherence to protocol‐related procedures. Findings also may indicate whether the number of hours participants spend with their study partners are an important component of protocol adherence. Findings would have implications for study partner requirements of future AD trials.ConclusionThe current study will provide greater understanding of the role of study partners, and how different relationship types and number of hours spent with participants may relate to overall study compliance.