bluuebunny/crossref_metadata_2025_split huggingface dataset:
Feasibility and evaluation of the Dementia Engagement Modelling Program (DEMP): a novel model of aged care during COVID‐19
Authors: Atee Mustafa , Morris Thomas , Cunningham Colm 
Published: December 2021

AbstractBackgroundThe COVID‐19 pandemic has a significant impact on the quality of life of aged care residents living with dementia (RLWD). Lockdown measures necessary to protect RLWD and caring staff from COVID‐19 have resulted in increased social isolation, loneliness, and behaviors and psychological symptoms of dementia (BPSD). In response, the Australian Government funded a pilot program, the Dementia Engagement Modelling Program (DEMP) as part of the Aged Care COVID‐19 Grief and Trauma support package for RLWD, their families and aged care staff. Operated by the Dementia Centre of HammondCare, the DEMP provides first‐line multimodal external support for RLWD at a greater risk of developing BPSD due to COVID‐19 restrictions. This study aims to describe the DEMP and evaluate its feasibility and outcomes for Australian RLWD.MethodsA team of 10 trained DEMP consultants was involved in delivering a consultancy service that modelled best practice and person‐centred activities of engagement to support staff in providing residents with meaningful purpose, comfort, and reassurance. Consultants also provided coaching and development opportunities for staff to enhance their knowledge regarding communication and engagement. Outcome measures included the regular administration of the Engagement in Preferred ActivitieS Scale (EPASS; ≥4‐9 moderate‐to‐high engagement). A phone evaluation survey for supported residential aged care homes (RACHs) was conducted to determine the feasibility of DEMP.ResultsA total of 60 residents (86.0 ± 7.8 y; 68% female) across 10 RACHs from three Australian states (VIC, NSW, QLD) was supported by DEMP between May and July 2021. More than half of the residents had Alzheimer’s disease (n = 24, 40%) and vascular dementia (n = 7, 12%). Completed EPASS assessments (n = 389) demonstrated that the vast majority (64%‐72%) of residents scored moderate‐to‐high engagement. All supported RACHs highly recommended the DEMP to other colleagues and rated the program highly for implementation feasibility including the recommended engagement activities/brokered items.ConclusionsThe DEMP is a novel, feasible and effective dementia‐specific engagement modelling program for Australian RLWD in the era of COVID‐19 pandemic.
Investigating isoform‐specific functions of Tau under healthy and pathological conditions using Tau‐deficient hiPSC‐derived cortical neurons
Authors: Bachmann Sarah , Bell Michael , Kabbani Mhd. Aghyad Al , Klimek Jennifer , Zempel Hans 
Published: December 2021

AbstractBackgroundOne hallmark of many neurodegenerative diseases, such as Alzheimer’s disease (AD), is the formation of neurofibrillary tangles by hyperphosphorylated Tau in the brain, resulting in neuronal death and cognitive decline. In the adult human brain, six Tau isoforms are expressed, originating from alternative splicing of exons 2, 3, and 10 of the MAPT gene. The isoforms differ in the number of N‐terminal inserts (0, 1, or 2N) and the C‐terminal repeat number (3 or 4R). Mutations affecting splicing of the MAPT gene can alter the Tau isoform ratio and ultimately cause neurodegeneration. Recent results from murine neurons highlight that the six human‐specific isoforms are differentially localized within neurons and influence microtubule dynamics in an isoform‐specific manner.MethodTo further investigate the Tau isoforms in a human neuronal model, we generated three Tau KO iPSC cell lines derived from Ngn2‐WTC11 cells using CRISPR/Cas9.ResultBasic characterization of the Tau KO cell lines showed no difference in the morphology or pluripotency of iPSCs, the capability of neuronal differentiation or neuronal morphology compared to WT iPSCs and induced neurons. Initial results from re‐expressed TAU isoforms in Tau KO human neurons support the differential localization of the isoforms observed previously. Further experiments will investigate the isoform‐specific role of Tau regarding microtubule dynamics, axonal branching, and synapse formation under basal and pathological conditions.ConclusionExpected results will provide a major understanding of basic biological functions of Tau and help to identify potential therapeutic targets for the treatment of AD and related neurodegenerative diseases.
Associations between iron deposition in the brain and grey matter volumes in cognitively unimpaired adults
Authors: Stankeviciute Laura , Falcon Carles , Operto Grégory , Rojas Santiago , Grau‐Rivera Oriol , Garcia Marina , Minguillón Carolina , Fauria Karine , Molinuevo Jose , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Cacciaglia Raffaele , Gispert Juan Domingo 
Published: December 2021

AbstractBackgroundIron dyshomeostasis is involved in the pathophysiology of Alzheimer’s disease (AD). Magnetic resonance imaging (MRI) is sensitive to iron in the brain as its concentration decreases the intensity of T2‐weighted images. However, there is little evidence on how iron affects structural changes in the brain of cognitively unimpaired individuals at the inception of the Alzheimer’s continuum. This research aimed to investigate the relationship between T2 MR hypointensities, as a proxy for iron content, and grey matter volume (GMv) in middle‐aged cognitively unimpaired (CU) individuals.MethodsThis cross‐sectional study included 302 CU adults from the ALFA+ cohort who underwent MRI, cerebrospinal fluid sampling (CSF) and neuropsychological assessment (Table 1). T2‐weighted images were used to calculate mean hypointensity values in a set of 18 subcortical nuclei (http://nist.mni.mcgill.ca/?p=1209). T1w scans were entered into voxel‐based morphometry (VBM) analysis to evaluate the relationship between regional T2 intensities and GM volumes. Due to the strong correlations between the T2 intensity of the subcortical regions, we performed principal component analysis (PCA) to reduce the dimensionality (Table 2). We created a general linear model where GMv was the dependent variable, the first principal component (PC1) was the independent variable and age, sex, APOE‐ε4 status, education level and total intracranial volume (TIV) were the covariates. In an additional model, CSF levels of amyloid‐beta (Aβ) ratio (CSF Aβ42/40) and phosphorylated tau (p‐tau) were entered as covariates. Statistical significance was set at p<0.001 uncorrected for multiple comparisons with a cluster‐level threshold of 100.ResultsPC1 explained 47.64% of the variance, and it was significantly and negatively associated with grey matter volumes in a highly symmetrical pattern which included the parahippocampal cortex (Table 3. Figure 1). These results remained largely unchanged when entering CSF AD biomarkers in the model.ConclusionsOur results indicate that, in cognitively unimpaired individuals, a higher content of iron deposition, as expressed by lower T2‐weighted MR intensities in subcortical regions, are associated with higher grey matter volumes in parahippocampus, independently of CSF AD biomarkers. These preliminary results may suggest that iron accumulation might be associated with neuroinflammatory mechanisms and render the brain more vulnerable to early AD pathology.
Assessing neuroinflammation and inflammasome activity in mouse models of Down syndrome
Authors: Farrell Clíona , Mumford Paige , Salih Dervis , Toomey Christina , Fisher Elizabeth , Wiseman Frances K 
Published: December 2021

AbstractBackgroundDown syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and is a leading genetic cause of Alzheimer’s disease. Neuroinflammation is altered in the post‐mortem brain of people with DS, with altered microglial morphology and upregulated proinflammatory cytokines, including IL‐1β. IL‐1β is produced by inflammasome activity activating caspase‐1 which cleaves and releases active IL‐1β. We hypothesize that IL‐1β levels are raised in the DS brain via upregulation of inflammasome activity, which persists when people with DS develop AD.MethodLevels of 10 cytokines IL‐1β, TNFα, IFNγ, IL‐6, IL‐2, IL‐4, IL‐5, IL‐10, IL‐12p70 and KC/GRO were measured (MSD) in the 3‐month hippocampus of a panel of segmental duplication models of DS, Dp1Tyb, Dp2Tyb, Dp3Tyb, Dp9Tyb and Dp17Yey. These models have a duplication on one chromosome of a number of orthologues for Hsa21 genes.ResultRaised IL‐1β abundance was identified in the hippocampus of the Dp1Tyb mouse, which has an additional copy of 148 mouse orthologues for Hsa21 genes. No difference in IL‐1β or any other cytokines measured were identified in the Dp3Tyb (39 genes duplicated), Dp9Tyb models (76 genes duplicated), Dp2Tyb (33 genes duplicated) or Dp17Yey (19 genes duplicated).ConclusionRaised IL‐1β in the Dp1Tyb brain is a multigenic phenotype, caused by having 3 copies of more than one gene/region of Hsa21. Next, we will prepare organotypic hippocampal slice cultures from the Dp1Tyb model and stimulate these with LPS, nigericin and amyloid‐β to understand how having three copies of Hsa21 orthologues modulates the neuroinflammatory and inflammasome response.
Brain regional volume analysis to differentiate Alzheimer’s disease (AD) and vascular dementia (VD) from healthy control (HC): Machine learning approach
Authors: Cheung Eva YW , Chiu Patrick Ka‐Chun , Kwan Joseph SK , Shea Yat Fung , Mak Henry 
Published: December 2021

AbstractBackgroundIn previous decades, structural MRI has been widely adopted in the diagnosis of AD, MCI and other forms of dementia[1]. Through quantitative measurement of volume of regions‐of‐interest (ROI), it is suggested that hippocampal volume reduction and the rate of reduction can be use in dementia diagnosis and predict the disease progression[2]. However, there is no such application to VD.Method81 participants (25 HC, 16AD, 28MCI, 12VD) were recruited to undergo structural MRI scanning. T1W Images MRI images were acquired using a Philips Achieva 3T. Volume of brain structures were assessed using Freesurfer (v. 7.1). MANCOVA test was adopted to determine the significant difference between diseased groups and HC, with GM volume, age and gender as covariates. R decision tree was adopted to identify major parameter and its threshold to classified AD, MCI, VD from HC.ResultsIn brain structural volume analysis, AD demonstrated significant atrophy in thalamus, hippocampus, amygdala, accumbens areas when compared to HC. VD showed similar results as AD, with ventral diencephalon as an addition region of atrophy when compared to HC group. For MCI, less severe atrophy was observed when compare to AD and VD toward HC. Furthermore, VD showed significantly enlarged in lateral ventricle, third ventricle, fourth ventricle, CSF, choroid plexus and white matter hypointenisty (WMH). While AD showed significantly enlarged lateral ventricle, inferior lateral ventricle and CSF when compared to HC. There is no statistically significant difference for MCI. In the decision tree model, WMH volume > 5826cm3 was used to classify VD from the rest. The left hippocampus volume < 3287cm3 was used to classify AD from HC. However, the MCI group could not be accurately identified. The accuracy of the model to predict AD, VD, HC from others were 87.5%, 99% and 96% respectively.ConclusionThe findings demonstrated that AD and VD had significant reduction in brain regional volume when compared to HC, but not MCI. The WMH and left hippocampus volume were included in the decision tree model as predictive parameters to classify AD and VD from HC. Though the sample size is small, further validation may be required.
HCN channelopathy couples disease‐associated tau to synaptic dysfunction
Authors: Goniotaki Despoina , Tamagnini Francesco , Biasetti Luca , Rumpf Svenja‐Lotta , Troakes Claire , Pollack Saskia J , Ukwesa Shalom , Sun Haoyue , Serpell Louise , Noble Wendy , Staras Kevin , Hanger Diane P 
Published: December 2021

AbstractBackgroundDeficits in synaptic function and neurite connectivity are early correlates of tauopathies. Altered tau processing and mis‐localization coincide with reductions in synapse density and synaptic function, suggesting a causal role for tau in disease pathogenesis. In parallel, altered activity of hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels, involved in synaptic integration, is implicated in disease progression in animal models of tauopathy. However, the mechanisms underlying these pathological events are not fully understood.MethodsWe performed histological and biochemical analyses of hippocampal tissues from Alzheimer’s disease (AD), age‐matched controls and Tau35 mice, in which a human tauopathy‐associated tau fragment is minimally expressed. Image analysis and quantification were performed on antibody‐labelled human and mouse hippocampal sections (Visiopharm). Brain tissue from Tau35 and wild‐type (WT) mice was also examined on western blots, by Golgi‐Cox staining and transmission electron microscopy. Primary hippocampal neurons from Tau35 and WT mice were transfected with a plasmid expressing enhanced green fluorescent protein (eGFP) and imaged up to 14 days in vitro. Three‐dimensional digital reconstruction of dendrites and spines enabled morphological analysis of eGFP‐expressing neurons. In parallel, patch‐clamp recordings were performed to assess functional changes and HCN channel activity in Tau35 neurons.ResultsHere we show that HCN channels are functionally linked to tau abnormalities. Alterations in HCN channel expression are detected in both Tau35 mouse and human post‐mortem AD brain. Tau35 neurons exhibit altered synaptic cytoarchitecture, including progressive reductions in dendritic branching, pre‐synaptic vesicles, spine density and synaptic markers, along with the development of tau pathology. These changes are accompanied by functional abnormalities in network activity, including increased HCN‐dependent sag voltage, reduced frequency and slower kinetics of spontaneous excitatory postsynaptic currents.ConclusionsOur findings are consistent with the hypothesis that disease‐associated tau species impact on HCN channels to drive network‐wide structural and functional synaptic deficits, with significant therapeutic relevance for tauopathies.
Identification of cis‐regulatory elements associated with MAPT expression in human induced pluripotent stem cell derived neural cells
Authors: Rogers Brianne B. , Lauzon Shelby N. , Davis M. Natalie , Rizzardi Lindsay F. , Cooper Sara J. , Myers Richard M. , Cochran J. Nicholas 
Published: December 2021

AbstractBackgroundTau is encoded by MAPT and abnormal aggregates of tau are a hallmark of many neurodegenerative diseases. MAPT is highly expressed in neurons but much more lowly expressed in other cell types, including neural precursor cells (NPCs), suggesting that its expression may be controlled by neuron‐specific transcription factors and cis‐regulatory elements. Tau reduction, even of endogenous tau, is a current therapeutic strategy in both model systems and humans; therefore, understanding MAPT regulation may point to new strategies to achieve tau reduction. Additionally, genome sequencing studies continue to identify disease‐associated variants in non‐coding regions of the genome. These variants are likely located in regulatory regions and affect the expression of target genes whose function contributes to neurodegeneration. Therefore, an additional benefit of this study is that high confidence regulatory regions for MAPT may provide a way to identify important non‐coding variants associated with disease.MethodsThree‐dimensional chromatin conformation capture (Capture‐C), single‐cell multiomics (RNAseq + ATACseq), and chromatin marks including H3K27ac, H3K4me1, and DNase hypersensitivity were used to identify candidate enhancers of MAPT in human NPCs, NPCs differentiated to neurons, and pure inhibitory or excitatory neuron cultures (all lines were H1/H1). Approaches included nomination of elements with signals specific to neurons or neuronal subtypes. The nominated regions were then assessed using luciferase assays to test sufficiency for regulatory activity as well as CRISPR‐dCas9‐KRAB to assess the effect of nominated elements on MAPT expression.ResultsWe identified both proximal and distal regulatory elements for MAPT with function confirmed by up to four orthogonal approaches (chromatin capture, single cell multiomics, a reporter assay, and element inhibition using dCas9‐KRAB). Several of these elements were specific to neurons. One particularly important region was centromeric to MAPT beyond the H2 inversion breakpoint.ConclusionsOverall, these results indicate that MAPT regulation is likely controlled by neuron‐specific cis‐regulatory elements, including both proximal and distal elements. Next steps include study of the effect of trans‐regulatory elements (i.e., transcription factors) that may control recruitment of these cis‐regulatory elements for expression of MAPT and assessment of the effects of the disease‐associated genetic variation on cis‐regulatory element function and expression of MAPT.
DNA methylation "GrimAge" acceleration mediates sex differences in verbal learning and memory: Findings from the health and retirement study
Authors: O'Shea Deirdre , Tremont Geoffrey , Drake Jonathan D 
Published: December 2021

AbstractBackgroundEvidence from cognitive science support sex differences in verbal memory, that tend to favor women. Epigenetic research has also shown slower rates of biological aging in women compared to men. The aim of the current study examined whether sex differences in biological aging mediate sex differences in verbal learning/memory in older adults.MethodData was obtained from the Harmonized Cognitive Assessment Protocol and the 2016 Venous Blood Study, sub‐studies of the 2016 wave of the Health and Retirement Study (HRS). Thirteen epigenetic “clocks” were constructed from these data and made publicly available by HRS staff. DNA methylation “GrimAge” clock was used as the indicator of biological aging, given evidence relating it to cognition in prior studies. A sample of 1,505 participants (mean age =75, SD= 6.8, male= 42%, White= 81%, Black=13%, Hispanic= 6%), with full data were included in the analyses. The residual from age adjusted GrimAge (AgeAccelGrim) was used as the measure of age acceleration. Cognitive composites were constructed from the learning and delayed recall trials of the Consortium to Establish a Registry for Alzheimer's Disease Word List Memory Task and the Wechsler Memory Scale‐IV, Logical Memory subtest and used as the outcome measures. Mediation analysis tested whether AgeAccelGrim mediated (5,000 resamples) the association between sex and learning/recall composites. Chronological age, years of education, smoking status, white blood cell count, and race/ethnicity were included as covariates.ResultMediation analyses revealed a total direct effect of sex on learning (β=.32, 95% CI [.26, .37]), with a significant indirect effect of AgeAccelGrim, that explained 12.5% of the total effect of sex (CI [.02, .06]). A similar pattern was revealed for delayed recall (total effect of sex β= .26, 95% CI [.20, .32]), with AgeAccelGrim accounting for 11.5% of the total effect (95% CI [.01, .04]).ConclusionWomen performed better on verbal learning/recall measures compared to men, and this association was partially explained by slower biological aging in women. These findings demonstrate the potential for epigenetic markers of aging to increase understanding of sex differences in verbal learning and memory in older adults.
White matter lesion burden correlates with the free water distribution surrounding the lateral ventricle
Authors: Zhou Liangdong , Nguyen Thanh D , Li Yi 
Published: December 2021

AbstractBackgroundThe clearance function is considered playing significant role in the neurodegeneration and neuroinflammation diseases, such as Alzheimer's disease (AD), Parkinson disease (PD) and multiple sclerosis (MS), etc. The enlarged perivascular space (EPVS) is believed to be a main pathway for the clearance of metabolic wastes. The free water in the PVS helps to clear the waste. The dysfunction of clearance function may accelerate the progression of diseases. We propose to use a T2 relaxometry based free water mapping to investigate the free water distribution in MS subjects. We call the free water mapping as cerebrospinal fluid water fraction (CSFF).MethodMulti‐echo T2 image was acquired with 7 echoes (TE = 0, 7.5, 17.5, 67.5, 147.5, 307.5, 1000 ms). Then the T2 data was fitted to three‐compartment water model (myelin water, intro‐extracellular water, and free water) by the T2 relaxometry of different tissue type. The CSFF in the white matter region is extracted from the FreeSurfer processed white matter mask. For each subject, the extracted WM CSFF was organized into a column vector and then fed in the k‐means algorithm. The number of categories is set to k = 8, which is sufficient to categorize the WM CSFF pattern into detailed tissue structure. We are interested in the distribution pattern of smallest CSFF values in WM, i.e., the category that has smallest mean CSFF.We then check the correspondence between the smallest CSFF pattern with the anatomic structure. If the distribution of the smallest CSFF is continuous region near the posterior of ventricle CSF, then we call the subject CSFF‐negative (Fig. 1a), otherwise it’s CSF‐positive (Fig. 1b).ResultThe distribution of the smallest WM CSFF in the MS cohort is significantly related to the severity of the disease. CSFF‐positive subjects have light MS lesion load, while the CSFF‐negative subjects have heavy MS lesion load (Fig.2).ConclusionThe results show that the T2 relaxometry based free water mapping could be treated as a biomarker of MS load. This finding might be helpful for the understanding of development of MS disease.
Mitochondrial changes caused by LDL in hippocampal neurons
Authors: Farias Hemelin Resende , Martins Leo , Beber Lílian Corrêa Costa , Rodrigues Matheus Scarpatto , Guma Fátima , de Oliveira Jade 
Published: December 2021

AbstractBackgroundFamilial hypercholesterolemia (FH) is characterized by high plasma accumulation of low‐density lipoproteins (LDL) due to mutations in the LDL receptor gene (Hobbs et al., Hum. Mutat., 1: 445‐466, 1992). Furthermore, FH patients present a high incidence of cognitive impairments (Zambón et al., Am J ed, 123:267‐274, 2010; Ariza et al., Eur J Intern Med., 34:e29‐e31, 2016). Experimental studies also demonstrated that FH leads to an increase in blood‐brain‐barrier permeability (De Oliveira et al., J Alzheimers Dis, 78:97‐115, 2020), which could allow the LDL to pass from the peripheral system to the central nervous system. Importantly, the cellular mechanisms responsible for neurotoxicity induced by LDL are unclear. Herein, we aimed to investigate whether LDL causes mitochondrial alterations in neurons.MethodWe exposed HT‐22 cells (Mouse Hippocampal Neuronal Cell) to human isolated LDL (50 and 300 ug/mL) for 24 hours. Furthermore, mass and potential mitochondrial were evaluated by Mitotracker green (MTG) and red (MTR), respectively, and the reactive species generation was evaluated by DCF.ResultNotably, when HT‐22 cells were incubated with LDL (50 ug/mL), MTR fluorescence was decreased compared with control cells. The ratio between MTG and MTR fluorescence showed increased mitochondria mass compared to their activity, suggesting an increase of swollen and non‐functional mitochondria. We observed in HT‐22 cells exposed to LDL (300 ug/mL) that both MTG, MTR, and ratio MTR/MTG were decreased, suggesting mitochondrial dysfunction. It is known that mitochondrial dysfunction leads to the excessive production of reactive species, and this may cause damage to essential cell components. In this regard, next, we evaluated the reactive species formation using DCF. The reactive species formation was significantly increased in cells exposed to both concentrations of LDL (50 and 300 ug/mL) in two times of exposure (1 and 24 hours) compared with the control cells.ConclusionThese findings indicate that LDL causes mitochondrial dysfunction, which appears to be a relevant event in hypercholesterolemia‐induced cerebral dysfunction.