bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of amyloid load uptake and cerebral blood flow in non‐Alzheimer's disease dementia and mild cognitive impairment
Authors: Chau Anson CM , Cheung Eva YW , Shea Yat Fung , Chiu Patrick Ka‐Chun , Mak Henry , Bao Yiwen 
Published: December 2020

AbstractBackgroundFibrillary beta amyloid deposits and cerebral hypoperfusion are upstream and downstream pathological features in demented individuals respectively. Asymptomatic amyloid plaque deposition begins and becomes saturated way before cerebral structural and metabolic changes in the course of Alzheimer’s disease dementia, and their relationships been vigorously studied. However, the relationship of amyloid load and cerebral functions in non‐AD dementia is under‐investigated. This study aims to investigate the correlation between plaque deposition and cerebral blood flow (CBF) in non‐AD demented individuals.MethodThirty‐three non‐AD demented subjects recruited for PET amyloid/MRI study in a University hospital. Each subject underwent a multiparametric MRI brain scanning which included 3D T1W and 2D pseudo‐continuous ASL sequence, and 18F‐Flutametamol Positron Emission Tomography Computed Tomography (PET‐CT). Standardized uptake value ratio (SUVR) of 18F‐flutametamol in eight bilateral cortical regions and absolute CBF of the same regions recorded for each subject. Partial correlation controlling for age between CBF and flutametamol uptake of each brain region computed.ResultSix non‐amnesic mild cognitive decline (MCI), 14 MCI with vascular pathologies and 13 vascular dementia had SUVR uptake ranged from 0.42 to 0.54, with the most deposition in the occipital, precuneus posterior cingulate (PCC), anterior cingulate, and the least in the prefrontal. Significant mild positive correlations (r=0.3) between SUVR uptake and CBF were found in occipital, anterior cingulate, sensorimotor and prefrontal. Significant moderate positive correlations (r=0.4) were found in temporal lateral and parietal. No significant correlation was found in PCC and temporal mesial.ConclusionIncreased amyloid deposition in non‐AD dementia and MCI has positive correlation with cerebral blood flow, possibly indicating a different pathophysiological mechanism from AD.
Identification of abnormal astrocyte subpopulation in Alzheimer’s disease
Authors: Jung Yeon‐Joo , Lee Eunbeol , Chung Won‐Suk 
Published: December 2020

AbstractBackgroundIn Alzheimer’s disease (AD), where amyloid beta (Aβ) plaques accumulate in the brain with surrounding reactive glial cells, synapses are weakened and eliminated. Previously, it was thought that synapse elimination and subsequent neuronal death were mainly due to the direct effects of Aβ oligomers and fibrils on neurons. However, recent studies have revealed that abnormal glial function can be an active inducer of the initiation and progression of AD. Reactive astrocytes are found around Aβ plaques and can internalize Aβ in vitro and in vivo, although the molecular mechanism and biological impact of this clearance are unclear.MethodWe have performed RNA‐seq analysis to reveal the changes of astrocytic gene expression upon oligomeric Aβ exposure. Through this analysis, we have isolated specific genes that are highly upregulated and downregulated in astrocytes during the progression of AD. The expression and function of one of the upregulated genes, KAGS1, are under investigation using APP/PS1 mice.ResultKAGS1 was detected in APP/PS1 mouse hippocampus starting from 6‐month‐old APP/PS1 mice and its expression was increased in astrocytes along with the progression of AD. We found that KAGS1 was dramatically accumulated in a subset of astrocytes in the hippocampus. Interestingly, organelles with accumulated KAGS1 were co‐localized with p62 and LC3B, indicating that KAGS1 accumulation was associated with autophagy in astrocytes. This dramatic autophagosome accumulation in the aged AD astrocytes appears to be due to the AD related proteasomal as well as lysosomal dysfunctions in astrocytes. Importantly, we found that many critical membrane receptors in astrocytes, such as MEGF10 and LDLR, get trapped inside of the accumulated autophagosomes, instead of localizing in astrocytic membranes.ConclusionThis finding suggests that the AD astrocytes with accumulated autophagosomes may lose their normal ability for regulating synaptic homeostasis/function and may contribute to AD‐related learning and memory loss.
Multimodal imaging correlates of the protective APOE2 allele
Authors: Groot Colin 
Published: December 2020

AbstractBackgroundThe protective effect of APOEε2 against Alzheimer’s disease (AD) is relatively well‐established, but the mechanisms conferring this effect are incompletely known.MethodStudies have tried to assess these mechanisms through studying the physiological functions of the APOE protein, the most promising being clearance and degradation of amyloid.ResultsIt has been consistently observed in post‐mortem studies that APOEε2‐carriers have decreased amyloid‐pathology and a large meta‐analytic investigation assessing amyloid‐status on PET or CSF across APOE genotypes also revealed that amyloid‐positivity, and age‐related increases in amyloid‐positivity, were lowest in APOEε2‐carriers. Some post‐mortem studies have also reported a protective effect of APOEε2 on tau pathology, but these results could not be replicated in all examinations. Recently, efforts have been undertaken to assess the effect of APOEε2 on amyloid and tau pathology using in‐vivo PET imaging. These studies indicate that APOEε2‐carriers have decreased cortical amyloid load while no effects were observed on cortical tau, nor on hypometabolism (FGD‐PET) or hippocampal and entorhinal gray matter (MRI). This suggests that the protective effect of APOEε2 might be selective for amyloid. However, amyloid‐independent effects on cognitive decline have been reported and it is postulated that the APOEε2 allele increases synaptic density and protects against neuroinflammation. More in‐vivo imaging studies are needed to elucidate these amyloid‐independent protective effects of APOEε2, and with recent developments in novel imaging methodologies this might soon be possible. For instance, UCB‐J PET imaging might be implemented to assess synaptic density in APOEε2‐carriers, and TSPO‐PET might be used to detect neuroinflammatory markers.ConclusionStudying the protective mechanisms of APOEε2 using neuroimaging studies are essential as they might inform future disease‐modifying treatments, such as using gene‐editing techniques to convert APOEε4 to APOEε2, and delivering APOEε2 into APOEε4 carriers through the use of adeno‐associated viruses. Paradoxically, it has been shown that APOEε2, while protective against AD, has a detrimental effect on markers of cerebrovascular disease and subjects who do develop AD despite being an APOEε2‐carrier display a distinct phenotype with increased small vessel disease and non‐amnestic cognitive impairments. These factors need to be considered in any future neuroimaging examinations into the protective effects of APOEε2.
Out of the shadows: Addressing resident‐to‐resident aggression in long‐term care
Authors: Malvern Riley 
Published: December 2020

AbstractBackgroundResident‐to‐resident aggression is a behaviour concern in long‐term care (LTC). Incidents of resident‐to‐resident aggression can have serious consequences and may result in poorer quality of life for residents, increased staff turnover, harmful psychological and physical effects, or death. Many people shy away from talking about resident‐to‐resident aggression because it can be a sensitive topic. This silence can result in missed opportunities to reduce the risk. Discussing it openly is an important step in working towards solutions.MethodRecognizing resident‐to‐resident aggression as an urgent public health issue, the Alzheimer Society of Canada (ASC) has embarked on a multiyear project to understand the underlying needs that can trigger this behaviour, and what LTC staff need to address it. The outcome for the first phase of this project was the creation of an information booklet for LTC staff. To create the booklet an environmental scan was conducted that examined existing literature and tools on resident‐to‐resident aggression, subject‐matter experts were consulted, and focus groups were conducted with staff and families at a Canadian LTC home.ResultThe information booklet that has been developed addresses three main topic areas. First, it provides an overview of the issue of resident‐to‐resident aggression and outlines the potentially harmful consequences this can have on residents, families, staff and management if not dealt with appropriately and openly. Second, it outlines the importance of talking openly about resident‐to‐resident aggression as a first step in addressing this issue. Finally, the resource provides practical, person‐centred strategies for reducing incidents of resident‐to‐resident aggression; including structural and environmental approaches. In particular, it includes practical tips and strategies for how to respond to incidents when they do occur and how to reduce the risk of them happening again in the future.ConclusionEducating LTC staff about resident‐to‐resident aggression can support them to think creatively and apply effective strategies to reduce the number of incidents. Doing so can improve quality of life for residents, staff, management and families. ASC’s next steps will involve creating practical tools for staff to help them address the issue of resident‐to‐resident aggression in their own LTC home.
Interactions between insulin, the blood‐brain barrier, and beta‐amyloid in Alzheimer's disease
Authors: Leclerc Manon , Bourassa Philippe , Vandal Milene , Caron Vicky , Virgili Jessica , Tremblay Cyntia , Emond Vincent , Bennett David A. , Calon Frederic 
Published: December 2020

AbstractBackgroundDefects in central response to insulin is suspected to play a role in AD. However, to act on the brain, pancreas‐secreted insulin must interact first with the blood‐brain barrier (BBB). The aim of the present study was to better understand mechanisms underlying transport and cell‐signaling of insulin at the BBB, and how they are altered in AD.MethodWe used microvessel‐enriched brain samples from individual classified as Controls, MCI or AD and from 3xTg‐AD mice from different ages, exposed or not to a high fat diet. In situ cerebral perfusion was used to quantify the transport of [125I] insulin across the BBB.ResultsWe first show that insulin receptors (INSR) in human and mouse brains are concentrated in blood microvessels. We observed lower concentrations of INSRα in microvessel extracts from the parietal cortex of AD patients, associated with cognitive symptoms. We also observed a shift toward a higher INSRα‐A: INSRα‐B ratio in AD, which is consistent with insulin resistance. We next looked at insulin‐activated cell‐signaling pathways within microvessels and found that activation was reduced in 3xTg‐AD mice, following a high‐fat diet. Although it is assumed that insulin crosses the BBB, we found that its transport rate remained very low and was not antagonized by INSR blockers. Finally, we provide some insights on the regulation of brain beta‐amyloid levels following the activation of BBB INSR.ConclusionOverall, our data support the hypothesis of brain insulin resistance in AD, but at the level of INSR localized in microvessels. This also suggests that the INSR and its downstream signaling within endothelial cells of the BBB may be a systemically accessible drug target in AD.
Alzheimer’s disease biomarker roadmap 2020: [18F]flortaucipir
Authors: Wolters Emma E. , Chiotis Konstantinos , Dodich Alessandra , Ashton Nicholas J. , Barthel Henryk , Bischof Gerard N. , Boccardi Marina , Carrillo Maria C. , Corre Julie , Démonet Jean‐François , Drzezga Alexander , Gietl Anton F. , Hansson Oskar , Johnson Keith A. , Leuzy Antoine , Lorenzi Marco , Rabinovici Gil D. , Ratib Osman , Sabri Osama , Treyer Valerie , Unschuld Paul G. , Villemagne Victor L.L. , Winblad Bengt , Frisoni Giovanni B. , Garibotto Valentina , Nordberg Agneta K. , Ossenkoppele Rik 
Published: December 2020

AbstractBackgroundIn the last decade, the research community focused on defining reliable biomarkers for the early detection of the pathological hallmarks of Alzheimer’s Disease (AD). In 2017, the Geneva AD Biomarker Roadmap Initiative adapted the framework for the systematic validation of oncological diagnostic biomarkers to AD, with the aim to accelerate their development and implementation in clinical practice. With this work we assess the maturity of [18F]flortaucipir and we define the research priorities.MethodIn a two‐day workshop (Geneva, November 2019), we convened a panel of experts in AD biomarkers. The level of maturity of [18F]flortaucipir has been assessed based on the Biomarker Roadmap (Frisoni et al., 2017). Biomarker maturity and research priorities were processed by thematic subgroups before the meeting, and presented and discussed during the workshopResult[18F]flortaucipir binds with high affinity to paired helical filaments of tau and has favorable kinetic properties. It accurately discriminates between AD and patients with non‐AD neurodegenerative disorders as well as healthy controls. Initial studies showed high correlations between ante mortem and post‐mortem tau pathology. Further research is needed to investigate the effects of covariates on tracer binding and its ability to detect tau pathology in the early phase of AD.Conclusion[18F]flortaucipir provide partial evidence for clinical utility. In vivo [18F]flortaucipir PET shows excellent discrimination for AD from controls and non‐AD neurodegenerative disorders and promising results for the validation with autopsy. However, completion of studies on analytical validity is a requirement to investigate clinical utility properly.
Hippocampal subfield microstructure abnormalities mediate associations between tau burden and memory performance
Authors: Nir Talia M , Salminen Lauren , Reina Julio E Villalon , Tubi Meral A , Thomopoulos Sophia I , Maiti Piyush , Braskie Meredith N , Thompson Paul M , Jahanshad Neda 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) pathology in the medial temporal lobes, including tau accumulation, is associated with memory impairment. This relationship may be mediated by microstructural changes in hippocampal tissue, particularly in subregions with prominent tau deposition and neuronal loss such as the CA1 and subiculum. Multi‐shell diffusion MRI (dMRI) can be used to fit biophysical models, such as Neurite Orientation Dispersion and Density Imaging (NODDI), which estimate intracellular (ICVF) and CSF (ISOVF) volume fractions in brain microstructure; these measures may offer enhanced specificity and sensitivity to disease processes such as neuronal loss and inflammation. Here, we evaluated the relationships between hippocampal subfield PET tau accumulation (F‐AV1451), NODDI microstructure, and a composite measure of memory performance (ADNI‐Mem) in the ADNI‐3 database.MethodsData were available for 70 ADNI‐3 participants (age: 73.6±6.7yrs; 40F; 48 CN, 18 MCI, 4 with dementia). NODDI measures (ICVF, ISOVF) were estimated using a novel multi‐tissue approach (MT‐NODDI); a gray matter specific response function was used to improve estimates in the hippocampus. Hippocampal subfields were parcellated from T1w images using FreeSurfer, and mean dMRI‐NODDI and PET‐AV1451 measures were extracted from 11 individual subfields and 9 composite subregions (Fig 1a). For each ROI, linear regressions tested associations between (1) MT‐NODDIROI and TauROI,(2) ADNI‐Mem and TauROI, and (3) ADNI‐Mem and TauROI while adjusting for MT‐NODDIROI (Fig 1b). We used FDR (q=0.05) to adjust for multiple tests. Mediation analyses were performed for regions showing significant associations in models 1 and 2.ResultsHigher regional tau was associated with lower ADNI‐Mem (Fig 2a). Higher tau depositions were also associated with lower ICVF and higher ISOVF (Fig 2b); MT‐NODDI measures detected significant associations with tau where standard NODDI did not (Fig 3). Excluding subfields comprising the subiculum‐complex, the negative effects of tau on memory scores were mediated by lower ICVF and higher ISOVF (Fig 4).ConclusionsTau pathology may lead to memory deficits through a variety of mechanisms, including hippocampal microstructural changes such as neuronal loss or increased inflammatory processes (lower ICVF and increased ISOVF) in subfields downstream from the subiculum‐complex.
AmyQ: An index to accurately measure cerebral amyloid load
Authors: Pegueroles Jordi , Montal Victor , Vilaplana Eduard , Bejanin Alexandre , Santos‐Santos Miguel A , Aranha Mateus Rozalem , Carrió Ignasi , Camacho Valle , Lleó Alberto , Fortea Juan 
Published: December 2020

AbstractBackgroundQuantification of amyloid‐β (Aβ) PET images is a surrogate marker of amyloid deposition in the brain. MRI‐independent approaches have been developed and have reported accurate quantification without the use of MRI but they still require a reference region to compute a SUVr value. The goal of this work was to design a new measure of amyloid deposition (AmyQ) that does not require the use of an MRI or a reference region and compare it to other commonly used measures (SUVR and Centiloid units) using two different samples of Flutemetamol (FMT) and Florbetaben (FBB) data.MethodsWe selected 198 subjects from the AIBL dataset (aibl.csiro.au) and 215 from the ADNI dataset (http://adni.loni.usc.edu/) in the Alzheimer’s Disease continuum with available amyloid PET and a T1‐weighted MRI. FMT and FBB PET images were first coregistred to its corresponding MRI and then normalized to the MNI space. Using the combination of the two first components of principal component analysis (PCA) we created a PET adaptive template (Figure1). Betas for the PCA components were optimized by maximizing the similarity between the MRI‐based spatially normalized PET images and the generated adaptive template. The AmyQ was determined using the beta of the second component (β2). Correlation analysis was used to evaluate the relationship between the AmyQ with the SUVr for each tracer, and with Centiloid units of both tracers. Finally, ROC curves were used to assess the power of the AmyQ to discriminate between positive and negative PET scans using global SUVr as the gold standard.ResultsFor both tracers, the AmyQ presented high relationship with both the global SUVr (Figure2A and B; rFMT=0.88 and rFBB=0.85) and centiloid (Figure2C). The ROC curve using AmyQ to discriminate PET‐positivity (as determined by the global SUVr) showed an AUC of 0.96 and 0.92 for FMT and FBB respectively.ConclusionsAmyQ may serve as a new index of global amyloid load, computed without MRI and independent of a reference region and tracer, which could prove highly useful for inter‐tracer studies. Additional studies are needed to confirm the relevance and potential clinical application of this new brain amyloid measure.
Dementia diagnosis affects pharmacological management of diabetes mellitus: A matched analysis of ∼20,000 patients from the Swedish registries
Authors: Secnik Juraj , Xu Hong , Schwertner Emilia , Hammar Niklas , Alvarsson Michael , Winblad Bengt , Eriksdotter Maria , Garcia‐Ptacek Sara , Religa Dorota 
Published: December 2020

AbstractBackgroundCurrently, there is no evidence‐based approach to treatment of diabetes mellitus (DM) when dementia is present. To reflect current clinical practice, we aimed to determine the differences in antidiabetic drug usage among DM patients with and without dementia.MethodIn this open‐cohort study we used five national Swedish registers to extract patients with DM & dementia and compared them to patients with DM who were dementia‐free. Overall, 10,470 DM & dementia patients registered to the Swedish Dementia Registry (until October 2018) were propensity‐score matched to 10,470 DM & dementia‐free controls originating from the Total Population Register. Information on comorbidities, antidiabetic and other medication and mortality originated from the Patient Register, Prescribed Drug Register and Cause of Death Register, respectively. Matching characteristics included index date (date of dementia diagnosis), age, sex, comorbidity score, education, DM type (excluding type 1 DM), DM duration and cardiovascular, psychotropic and dementia medication. Competing‐risk regression models (death as competing risk) were used to evaluate whether dementia status may alter the probability of antidiabetic drug usage defined using the date of first dispensation after dementia diagnosis (or index date) in patients without history of usage. Medications of interest were insulin, metformin, sulfonylurea derivates (SU), thiazolidinediones and more modern medication like dipeptidyl‐peptidase‐4 inhibitors (DPP‐4i), glucagon‐like peptid‐1 agonists (GLP‐1a) and sodium‐glucose cotransporter‐2 inhibitors (SGLT‐2i). We also assessed the likelihood of treatment with other antidiabetic drugs in addition to metformin as a proxy for treatment intensification.ResultThe dementia and DM group was significantly more likely to be treated with insulin (sHR 1.31 [95% CI 1.21‐1.43]) and less likely to receive DPP‐4i (0.79 [0.72‐0.88]), GLP‐1a (0.50 [0.40‐0.63]) and SGLT‐2i (0.42 [0.34‐0.52]). Dementia patients were also more likely to receive further medication in addition to metformin (1.08 [1.01‐1.15]).ConclusionsIn comparison to dementia‐free controls, dementia patients were less likely to receive modern antidiabetic drugs, with simultaneous higher likelihood of being prescribed insulin.
Premature neuronal differentiation in familial Alzheimer’s disease human stem cells in vitro and in postmortem brain tissue
Authors: Arber Charles , Lovejoy Christopher E.J. , Willumsen Nanet , Alatza Argyro , Casey Jackie M. , Lines Georgie , Kerins Caoimhe , Zetterberg Henrik , Hardy John , Ryan Natalie S. , Fox Nick C. , Lashley Tammaryn , Wray Selina 
Published: December 2020

AbstractBackgroundFamilial Alzheimer’s disease (fAD) is caused by mutations inPSEN1, PSEN2and APP. PSEN1forms the catalytic core of g‐secretase, a membrane protease which cleaves numerous substrates including APP and Notch. We have previously shown that our panel of fAD patient‐derived iPSCs show altered APP processing and Abgeneration. Here we investigated whether mutations led to altered Notch cleavage in neural precursors. We hypothesised that reduced Notch cleavage in fAD lines would promote premature differentiation during iPSC neuronal differentiation and during adult hippocampal neurogenesis.MethodsWe generated 2D cortical neurons and 3D cerebral organoids from a panel of 14 donor‐derived iPSC lines (5 controls, 2 APPmutation lines and 7 PSEN1mutation lines). Neurogenesis was quantified via the proportion of neural precursors versus the number of post‐mitotic neurons at timepoints of neural commitment. In addition, we quantified newly generated neurons in the post‐mortem hippocampus of 3 control brains and 7 brains derived from fAD mutation carriers.ResultsWe describe a small, yet reproducible premature differentiation phenotype in lines containing mutations in PSEN1during in vitro neurogenesis. This is, at least in part, due to reduced Notch signalling; which drives terminal differentiation. These findings are corroborated in independent orthogonal iPSC systems, namely 2D neurogenesis and 3D organoid differentiation. Using immunohistochemistry against b‐III‐tubulin, we describe robust, quantifiable neurogenesis in post‐mortem tissue. Results are suggestive of mutation‐specific effects and also a premature ageing phenotype in fAD tissue.ConclusionThese findings reveal insights into the functional outcomes of fAD mutations. Mutations in PSEN1, but not APP, alter Notch signalling in neural precursors, which in turn drives premature terminal differentiation. Premature differentiation and mutation‐specific differences both necessitate careful consideration for drug design and patient stratification.