bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comorbidity to dementia: The contributions of focal subclinical ischemia to pathogenesis in a mouse model of Alzheimer’s disease
Authors: Liu Mingzhe , Beckett Tina , Dorr Adrienne , Stefanovic Bojana , McLaurin JoAnne 
Published: December 2020

AbstractBackgroundAlthough stroke and Alzheimer’s disease (AD) are distinctly different diseases, the risk for both substantially increase with aging, with stroke survivors being twice as likely to develop dementia. Although subclinical ischemic events do not present with outward symptoms, they share similar risk factors and outnumber overt ischemic events >9 to 1, with 31% of adults over the age of 65 experiencing at least one such event. The ischemic cascade may initiate neuropathological changes, leading to an increased susceptibility to develop AD. Hence, there is a need to elucidate the relationship between subclinical ischemia and AD pathogenesis.MethodThe endothelin‐1 (ET1) model of ischemia was utilized for subclinical focal stroke induction, while the inducible APPsi:tTA mouse was used to model AD, as it allows for temporal control of APP gene expression. To examine the impact of focal ischemia on AD, bigenic (tTA/APP) (DTg) and control (tTA) mice underwent unilateral stereotaxic ET1 or sham (vehicle) surgery in the medial prefrontal cortex and allowed to recover, before turning on APP gene expression. Structural MRI one week following surgery allowed for evaluation of the size and location of the stroke. Behavioral tests were performed to examine for changes as a result of subclinical focal ischemia and post‐APP expression. Immunohistochemistry and immunofluorescence were conducted for changes in amyloid load (6F/3D), astrocytes (GFAP), microglia (Iba1) 7 weeks post‐APP expression.ResultAnalysis of MRI confirmed the presence of subclinical ischemic events in ET1 DTg tTA mice. ET1 DTg animals showed significant behavioral deficits in marble burying, nest‐building, open field and Y‐maze, post expression of APP when compared to tTA controls. DTg animals also showed an increase in astrocyte and microglial activation post‐APP expression, but no differences were found in amyloid load between ET1 DTg and sham DTg animals.ConclusionThe APPsi‐tTA mouse model allowed for controlled APP transgene expression– where the AD pathogenesis occurs independently after the initial subclinical event. Results show that subclinical ischemic insult to the brain enhance AD pathogenesis and allow for better understanding of the impact of comorbidities to AD progression.
Association of multi‐domain cognitive performance, cortical thickness and amyloid levels in cognitively unimpaired elderly adults with sub‐threshold amyloid levels
Authors: Delrieu Julien , Udeh‐Momoh Chinedu T , Price Geraint J , Jager Celeste A , Robb Catherine , Giannakopoulou Parthenia , Middleton Lefkos T 
Published: December 2020

AbstractBackgroundAmyloid deposition assessed by Positron Emission Tomography (PET) is typically dichotomized to classify asymptomatic subjects as positive or negative, as part of the NIA‐AA Research Framework AT[N] biomarker‐based classification. Cerebral “amyloid negative” status represents a typically under‐studied group of individuals who may be on a trajectory for further amyloid and tau accumulation and associated cognitive decline, particularly when accounting in the presence of other AD risk factors. Thus, asymptomatic subjects excluded from AD observational and interventional prevention studies post amyloid status determination for being “amyloid negative”, present a unique opportunity to better evaluate them clinically and for MRI evidence of neurodegeneration.MethodCognitively normal participants aged 60‐85 years from the CHARIOT:PRO (Cognitive Health in Ageing Register: Investigational, Observational, and Trial studies in dementia research; Prospective Readiness Cohort Study) Sub‐study with negative amyloid PET (n=561) were included in our analysis. We separated a “sub‐threshold” group from the “clearly negative” and “extreme negative” individuals, defined respectively by intermediate, low and very low amyloid load on the centiloid scale and assess multi‐domain neurocognitive performance with RBANS (testing global cognition, memory, attention, visuospatial and language domains) and cortical thickness in AD‐pathology sensitive areas of the two groups, adjusting for confounders.ResultIn this cross‐sectional analysis, there were “within limits” discrete differences between “sub‐threshold” and “clearly negative” amyloid groups. On RBANS indices, the “sub‐threshold” group had modestly higher attention z‐score (0.68 vs 0.43, p=0.025) and index (112.46 vs 109.11, p=0.012) than the clearly negative group. There were no differences in RBANS memory or other domain indices, but trends noted in attention and visuospatial indices between subthreshold and extreme negatives (112.37 vs 109.65, p=088). Global cognition was correlated to AD‐related cortical thickness in the « sub‐threshold » group (r2=0.033, p=0.030) versus the « clearly negative » group (r2=0.002, p=0.384). APOE4 carrier status was noted in 28.30% of the “sub‐threshold” and 18.90% in the “negative” group.ConclusionOur results suggest that the association between AD‐related cortical thickness and global cognition may be driven by amyloid load in the “sub‐threshold” group. “Sub‐threshold” status in asymptomatic subjects could be a potential target for prevention trials, involving pharmacological and non‐pharmacological intervention.
Race modifies putamen connectivity in Alzheimer’s disease
Authors: Misiura Maria , Howell J Christina , Tannahill Amber , Parker Monica W , Turner Jessica , Hu William T 
Published: December 2020

AbstractBackgroundAfrican Americans (AAs) are twice as likely to develop Alzheimer’s Disease (AD) in their lifetime than Non‐Hispanic Whites (NHWs), but exhibit slower decline and lower tau in the presence of dementia. Increased prevalence of lifestyle risk factors for AD including of type 2 diabetes and vascular disease do not fully account for this disparity. To uncover biological mechanisms that contribute to these differences, we must continue to characterize the biomarker profile of AAs. Functional neuroimaging is a biomarker that warrants further characterization by race. Previous work identified increases in connectivity in AAs with dementia within the default mode network (DMN), an area that exhibits decreased connectivity in NHWs with dementia. This study investigated putamen functional connectivity differences between AAs and NHWs to determine whether they may be race‐specific regions vulnerable to disease. Previous research identified a relationship within AAs between putamen volumes and tau.MethodWe obtained structural and resting‐state functional MRI from 72 AAs and 65 NHWs. We defined regions in the left and right hemispheres in the putamen, as well as posterior cerebellum, superior frontal, and precentral gyri (as these regions are structurally connected to the putamen), and calculated connectivity between the putamen and each other region for both hemispheres. We constructed a multivariate model with connectivity values as outcome variables, and race, age, gender, and diagnosis as independent variables, and included a race x diagnosis interaction.ResultOf the functional connectivity pairs we investigated, connectivity patterns among diagnostic categories between the posterior cerebellum and anterior putamen were significantly different between races such that in AAs, connectivity was higher in mild cognitive impairment compared to controls (t(43)=2.44, p=0.02), and lower in individuals with AD compared to MCI (t(13)=2.39, p=0.03).ConclusionAAs exhibited disease‐related connectivity patterns, but in novel regions. Putamen to cerebellum connectivity patterns are consistent with studies that have identified increased DMN connectivity in individuals with mild cognitive impairment, followed by lower connectivity in Alzheimer’s disease. The race‐specific decreased putamen connectivity in AAs lends further support to the compensatory role of the DMN in previous studies indicated by an increase in connectivity as AD burden increased.
Verification of gas sensors to detect Alzheimer’s disease biomarkers with diabetic rats
Authors: Emam Shadi , Nasrollahpour Mehdi , Kulkarni Praveen , Ekenseair Adam , Ferris Craig , Sun Nian‐Xiang 
Published: December 2020

AbstractBackgroundEvidences prove that individuals with Type‐2 insulin resistant diabetes have a two‐three folder greater risk for Alzheimer’s disease (AD). The abnormal glucose metabolism leads to the increased production of reactive oxygen species (ROS) a hallmark of diabetes and AD. ROS‐induced lipid peroxidation can lead to neuronal damage and cell death and is thought to be a contributing factor to disease progression in AD.MethodRecently, we introduced an array of electrochemical gas sensor to detect volatile organic compounds (VOCs) biomarkers in the exhaled breath. The sensors were later tested with a rat model that combined the human ApoE4 gene with aging and the Western diet. Gas sensors fabricated from molecularly imprinted polymer‐graphene were engineered to react with alkanes and small fatty acids (butylated hydroxytoluene, pivalic acid and, 2,3 dimethyl heptane) associated with lipid peroxidation. With a detection sensitivity in parts per trillion, the sensors were sensitive against the breath of wild‐type and APOE4 male rats with 100% sensitivity, specificity and, accuracy. The results were matching with the resting state BOLD functional connectivity which is used to assess hippocampal function.ResultThe present study was designed to test the Alzheimer’s sensor on diabetic rats. Since diabetes and AD share the same vascular problem, the question was that whether they share the same biomarkers as well or not. So, six rats with diabetic symptoms were tested with AD sensors and the result was negative. None of the sensors was sensitive to the breath of diabetic rats.ConclusionThis result is confirming that the sensors are detecting biomarkers that are only specific to Alzheimer's disease, not to a very similar disease such as diabetes.
Exploration of the endo‐lysosomal pathway genes in frontotemporal dementia: The use of protein‐protein interaction networks to prioritize rare‐variant association analysis results
Authors: Kocoglu Cemile , Manzoni Claudia , Ferrari Raffaele , Van Broeckhoven Christine , van der Zee Julie 
Published: December 2020

AbstractBackgroundGenetic studies in frontotemporal dementia (FTD) have identified multiple genes linked to the disease, yet explain only 30% of the patients. Identification of genetic causes in the remaining inherited cases is needed to elucidate the molecular biology of disease development, and thereby to pinpoint novel targets for therapeutic applications. Multiple lines of evidence have demonstrated disruption of the endo‐lysosomal pathway (ELP) in dementia. Here, we aimed to search for novel FTD genes in the ELP through rare variant association analysis.MethodWe applied weighted protein‐protein interaction (PPI) network mapping using 66 dementia‐associated genes (FTD, Alzheimer disease and Lewy‐body dementia) as seed genes. From this ‘Dementia interactome’, we extracted brain expressed ELP associated genes consulting Gene Ontology, Reactome, GTEx and Braineac. Exome‐wide rare variant association was tested using SKAT‐O, CMC and Madsen‐Browning tests.ResultWe generated whole exome sequencing data on 238 Belgian FTD patients and extracted exonic variants from whole genome sequencing data of 176 Belgian controls, obtained through collaboration with Project MinE (van der Spek et al., 2019). No genes passed exome‐wide significance level in the rare‐variant burden tests. Mapping ELP‐associated genes on the PPI network resulted in a list of 2.486 genes to be prioritized in our gene burden test results. As a result of this prioritization, 31 genes reached nominal significance. We are presently investigating those genes by incorporating their weight in the network (i.e. distance to known gene products and network topology), as genes with a higher weight are more likely contributors to disease development. Preliminary results suggest a role for vesicle‐mediated transport (GO:0016192) genes in FTD risk.ConclusionApplying a tailored PPI network approach, we prioritized ELP‐associated genes as potential disease (risk/protective) genes for FTD. ELP candidate genes pointed towards a role for vesicle‐mediated transport in FTD pathogenesis. This prioritization approach increases the power needed for rare variant disease association. Furthermore, we present an accessible disease pathway‐based analysis pipeline that is applicable to different types of genetic studies (rare high‐penetrant vs common‐risk) and disease phenotypes and pathways of interest.
Preclinical development of PR006, a gene therapy for the treatment of frontotemporal dementia with progranulin mutations
Authors: Heckman Laura D. , Burstein Suzanne R. , Brandes Alissa , Wong Li Chin , Yang Zhaohui , Lin Hsuan‐Ni , Fenn Tim , Nelson Stuart , Aziz Zarah , Kamalakaran Sid , Garimalla Swetha , Haller Jorge , Daily Jenn , Politi Jason , Dai Yong , Hefti Franz , Abeliovich Asa 
Published: December 2020

AbstractBackgroundFrontotemporal dementia (FTD) caused by GRN haploinsufficiency (FTD‐GRN) represents 5‐10% of all FTD cases. GRN encodes progranulin, a glycoprotein that is essential for normal lysosomal function and neuronal survival. FTD‐GRN patients exhibit approximately 50‐70% reduction in progranulin levels. We are developing PR006, an AAV vector designed to deliver the GRN gene, for FTD‐GRN patients with a goal of slowing or stopping disease progression. We aimed to evaluate the efficacy of PR006 in preclinical models of FTD‐GRN.MethodWe evaluated the efficacy of PR006 in vitro using neurons differentiated from human induced pluripotent stem cells (iPSCs). iPSC‐derived neurons from individuals carrying GRN mutations exhibit reduced progranulin levels and decreased activation of the lysosomal enzyme cathepsin D. Additionally, we assessed the therapeutic effects of PR006 in vivo using a Grn knockout (KO) mouse model of FTD‐GRN. Grn KO mice exhibit progressive brain‐wide lipofuscinosis, ubiquitin accumulation, microgliosis, and neuroinflammation. PR006 was administered by intracerebroventricular (ICV) injection to Grn KO mice, and vector biodistribution, progranulin levels, lysosomal alterations, and neuroinflammation were assessed. Nonhuman primates (NHPs) were used to assess the safety and tolerability of PR006.ResultPR006 transduction in iPSC‐derived FTD‐GRN mutation carrier neurons resulted in robust, dose‐dependent secretion of progranulin and restored cathepsin D maturation. In the Grn KO mouse model, ICV PR006 treatment was well‐tolerated and resulted in broad vector biodistribution and increased progranulin expression in biofluids and tissues. PR006 treatment in the Grn KO mouse model decreased lipofuscinosis, ubiquitin accumulation, and expression of neuroinflammatory markers in the brains of these animals. PR006 treatment in NHPs was well‐tolerated and resulted in broad vector biodistribution and progranulin expression in the central nervous system and the periphery.ConclusionThese in vitro and in vivo preclinical studies demonstrated that PR006 effectively increased expression of progranulin and reduced pathological features of FTD‐GRN, supporting clinical development of PR006 for patients with this disease.
A qualitative review of areas of conflict within post‐diagnostic healthcare in dementia triads
Authors: Tuijt Remco , Rees Jessica , Frost Rachael , Wilcock Jane , Manthorpe Jill , Rait Greta , Walters Kate 
Published: December 2020

AbstractBackgroundThe functioning of a dementia healthcare triad, namely a person living with dementia, their (family) carer and their healthcare professional, is a recent focus of improving the understanding of relationships that are important in person‐centred care. Evidence was reviewed to synthesise qualitative research that included members of the triad to explore where triad members hold dissenting or discordant views on their dementia care.MethodsEnglish‐language Medline, PsycINFO, Embase and CINAHL were systematically searched up to January 2020 for qualitative research on healthcare experiences including all members of dementia healthcare triads: people living with dementia, carers and healthcare professionals. Data were coded and thematically synthesised. Relationships between members of the triad were explored by coding the views held by one or two members of the triad, where these were presented by the authors as unique or opposing the views of another.ResultsThe synthesis included 28 papers from 26 studies, including 243 people living with dementia, 433 carers, and 475 healthcare professionals. We identified areas where triad members held discordant or conflicting views. Professionals found it difficult to engage when people living with dementia did not accept their diagnosis, or when carers did not see a need for formal care. In addition to this, triad members commonly held different priorities for care, for example people living with dementia prioritised stability, whereas carers focused more on safety. People living with dementia were unlikely to initiate decision‐making discussions, which removed them from discussions carers and professionals were having. This also led to carers and professionals making decisions without input from the person living with dementia despite people living with dementia voicing their concern about being excluded. In order to re‐establish a working triad, conflict resolution was expected from the professionals.ConclusionBy exploring the differing viewpoints of members of a triad, we may increase understanding of how triads function and pre‐empt potential factions developing. Further research will examine how coalitions form that hinder or help wellbeing, as well as exploring further opportunities to work within dementia care triads that hold dissenting views.
The impact of patient and partner personality traits on learning success for a cognitive rehabilitation intervention for patients with MCI
Authors: Locke Dona E , Devick Katrina , Khayoun Renata , Cuc Andrea , Shandera‐Ochsner Anne , Francone Andrea , Smith Glenn E , Chandler Melanie 
Published: December 2020

AbstractBackgroundOne nonpharmacological intervention for persons with amnestic Mild Cognitive Impairment (MCI) is development of a compensatory memory notebook/planner system. De Wit et al. (2019) showed that global cognitive status is the primary predictor of learning success with training on a memory notebook system and that learning success predicts ongoing adherence to the tool. The purpose of our work is to validate their analysis in a new sample and evaluate whether or not patient or partner personality traits predict learning success over and above that explained by cognitive status.MethodTraining in the Memory Support System (MSS) is one component of the multi‐disciplinary behavioral intervention program called Healthy Action to Benefit Independence and Thinking (HABIT) offered at Mayo Clinic. 183 patient and partner dyads completed the HABIT program and enrolled in our IRB approved ongoing research registry to allow use of their clinical data for research purposes. Personality traits were measured with the self‐report Ten Item Personality Inventory (TIPI) based on the five‐factor model of personality (Agreeableness, Conscientiousness, Emotional Stability, Openness, and Extraversion) completed by both the patient and the partner. For our analyses, we fit logistic regression models to predict full MSS mastery at the end of the two‐week program and dichotomized TIPI into “high” or “low” for each trait based on its median (low was the reference group).ResultConsistent with De Wit et al. (2019), global cognitive status again was the only significant predictor of MSS learning mastery when considering age, education, baseline depression score and baseline global cognitive status (Table 2). When adding patient personality traits, only openness significantly added to the model with higher openness predicting learning success (Table 3). Adding both patient and partner personality traits resulted in a significant interaction between patient and partner openness (Table 4). The direction of this interaction indicates that learning success is highest when either the partner or patient is high in openness (but not both).ConclusionHigh openness to experience in the patient with MCI or their partner (but not both) significantly improves learning success for a cognitive rehabilitation memory support tool in patients with MCI.
Association of brain amyloid accumulation and glucose hypometabolism with memory loss
Authors: Wang Ying , Huang Qi , Ren Shuhua , Huang Lin , Jiang Donglang , Li Junpeng , Guan Yihui , Guo Qihao , Xie Fang 
Published: December 2020

AbstractBackgroundMemory loss is the main syndrome of Alzheimer’s disease (AD). Extracellular accumulation of amyloid‐β (Aβ) neuritic plaques and neurodegeneration such as glucose hypometabolismwere the main pathology of AD. In this study, we try to figure out the association of Aβ accumulation and glucose hypometabolism with memory loss.Methods91 normal cognition (NC) healthy volunteers, 37 subjective cognitive decline (SCD), 32 mild cognition impairment (MCI) and 34 AD patients were enrolled in this study from Chinese preclinical Alzheimer’s disease (C‐PAS), which is initiated by Shanghai Jiao Tong University Affiliated Sixth People’s Hospital and Huashan Hospital. 6 types of neuropsychological tests from 3 cognitive core, including Auditory verbal learning test (AVLT) 30‐minute delayed free recall and AVLT recognition for memory, MMSE, Moca B were performed. FDG and amyloid PET (18F‐Flortabetapir) were conducted in these participants. 18F‐FDG and 18F‐Flortabetapir PET images were coregistered to the individual structural MRI images and then spatially normalized into MNI space. The associations of FDG and Aβ with impairment of language were explored by performing multiple regression between the 18F‐FDG and neuropsychological scores, as well as 18F‐Flortabetapir PET images and neuropsychological scores with age, gender, educationalyears as covariates. The statistical level was set at p<0.05 with FDR correction and a minimum cluster extent Ke>20 voxels.ResultsNo relationship was found between memory loss and amyloid accumulation. Glucose metabolism in precuneus, middle frontal cortex, cuneus, posterior cingulate gyrus has association with AVLT 30‐minute delayed free recall. Association was observed between glucose metabolism in inferior frontal cortex, insula and AVLT recognition.ConclusionAssociations were observed between memory loss and glucose hypometabolism, but no association was found between amyloid and memory loss.