bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pre‐clinical dose ranging efficacy testing of ADx: A contrast agent for magnetic resonance imaging of amyloid burden in Alzheimer’s disease
Authors: Badachhape Andrew , Srivastava Mayank , Stupin Igor , Devkota Laxman , Tanifum Eric , Annapragada Ananth , Ghaghada Ketan 
Published: December 2020

AbstractBackgroundEarly detection of amyloid plaque deposits is crucial for identifying pre‐symptomatic Alzheimer’s disease (AD) patients. An amyloid imaging magnetic resonance imaging (MRI) contrast agent would have substantial utility in the clinic due to its ease of distribution and the standard use of MRI in AD patient workup. In this work, we describe dose‐ranging efficacy study of an amyloid‐targeted liposomal macrocyclic gadolinium (Gd) contrast agent, ADx‐001, for in vivo MRI of amyloid plaques.Method
In vivo studies were performed in an APPswe/PSEN1dE9 double transgenic mouse model of early‐onset Alzheimer’s disease that develop amyloid plaques starting at 6‐7 months of age. ADx‐001 was tested at three dose levels: 0.10, 0.15 and 0.20 (mmol Gd/kg). At each dose level, ADx‐001 was tested in transgenic (n=6) and age‐matched wild‐type (mice that lacked both mutations) mice (n=6). MRI was performed on a 1 Tesla permanent magnet MR scanner using a T1‐weighted spin‐echo (T1w‐SE) sequence and a fast‐spin echo inversion recovery (FSE‐IR) sequence that approximates a fluid‐attenuated inversion recovery (FLAIR) sequence. Images were acquired pre‐contrast and at 4 days after intravenous administration of ADx‐001. Animals were euthanized after post‐contrast imaging for post‐mortem histological evaluation of amyloid plaques. Pre‐contrast and delayed post‐contrast MR images were qualitatively and quantitatively analyzed to determine sensitivity, specificity and accuracy against post‐mortem histological identification of Aβ plaque.ResultADx‐001‐enhanced MRI showed significant brain signal enhancement (p < 0.05) in transgenic mice (amyloid‐positive) relative to wild‐type (amyloid‐negative) mice in T1w‐SE (Figure 1) and FSE‐IR (Figure 2) images at all dose levels (Figure 3). ADx‐001‐enhanced T1w‐SE imaging showed high sensitivity (>80%) at 0.2 and 0.1 mmol Gd/kg dose levels while FSE‐IR showed high sensitivity (>80%) at 0.2 and 0.15 mmol Gd/kg doses (Table 1). ADx‐001‐enhanced MRI showed excellent specificity (100%) at all dose levels. Microscopy confirmed co‐localization of ADx‐001 with amyloid plaque deposits in cortex and hippocampus regions of the brain in transgenic mice (Figure 4).ConclusionADx‐001 demonstrated high sensitivity and excellent specificity for in vivo MRI of amyloid plaques in transgenic mice even at moderate and low concentrations. An MRI‐based amyloid imaging agent holds great promise for early detection of AD and potential therapeutic studies.
Alzheimer’s disease biomarker roadmap 2020: Fluid biomarkers
Authors: Ashton Nicholas J , Leuzy Antoine , Karikari Thomas K , Dodich Alessandra , Boccardi Marina , Barthel Henryk , Bischof Gerard N , Carrillo Maria C , Chiotis Konstantinos , Corre Julie , Démonet Jean‐François , Drzezga Alexander , Gietl Anton F. , Johnson Karen C , Lorenzi Marco , Nordberg Agneta K , Ossenkoppele Rik , Rabinovici Gil D , Ratib Osman , Sabri Osama , Treyer Valerie , Unschuld Paul G. , Villemagne Victor LL , Winblad Bengt , Wolters Emma E , Frisoni Giovanni B , Garibotto Valentina , Mattsson Niklas , Zetterberg Henrik , Blennow Kaj , Hansson Oskar 
Published: December 2020

AbstractBackgroundThough cerebrospinal fluid (CSF) Aβ42, p‐tau181 and t‐tau have been shown to increase diagnostic accuracy for early Alzheimer’s disease (i.e. AD at the MCI stage), several challenges remain with respect to their routine clinical use. In order to address these and related issues, a multidisciplinary task force was formed (Geneva Biomarker Roadmap Initiative). Adapting a five‐phase framework for the development of cancer biomarkers (Pepe et al., 2001), this task force recently convened (2019) to provide an update on earlier publications (2017). We here provide an update for the core CSF AD biomarkers (Aβ42/Aβ40, p‐tau181 and t‐tau) and for the first time provide a review of the same measures in blood in context of the five‐phase framework.MethodIn a two‐day workshop (Geneva, November 2019), we convened a panel of experts in AD biomarkers. The level of maturity of CSF and blood biomarkers was assessed based on the Biomarker Roadmap (Frisoni et al., 2017). Biomarker maturity and research priorities were systemically assessed by subgroups before the meeting, and presented and discussed during the workshop.ResultCSF biomarkers continued to demonstrate the highest level of maturity according to the strategic roadmap. Significant improvements compared to the 2017 summary (Mattsson et al., 2017) included the development of fully‐automated assays and the introduction of standard operating procedures for the preanalytical handling of CSF. Despite being in their infancy, the data presented and discussed for certain blood biomarkers demonstrated promising results. While t‐tau in blood did not satisfy the criteria for phase 2 (diagnostic discrimination), p‐tau181 and Aβ in blood either fully or partially fulfilled the criteria for this phase. It was agreed that only preliminary, albeit encouraging, evidence was available for the ability of blood measures to predict AD dementia in subjects with MCI (phase 3). An overview of novel CSF and blood tau biomarkers will also be discussed.ConclusionThe core CSF AD biomarkers (t‐tau, p‐tau181 and Aβ) have the highest level of maturity for clinical utility. Blood biomarkers for p‐tau18, and to a lesser degree Aβ, show excellent discrimination for AD from controls and non‐AD neurodegenerative disorders.
Microglial activation in vivo is moderated by sex in response to amyloidosis but not to tau pathology in mouse models of Alzheimer’s disease
Authors: Biechele Gloria , Franzmeier Nicolai , Ewers Michael , Blume Tanja , Eckenweber Florian , Sacher Christian , Luque Jose Medina , Beyer Leonie , Ruch‐Rubinstein Francois , Lindner Simon , Gildehaus Franz Josef , von Ungern‐Sternberg Barbara , Bartenstein Peter , Rominger Axel , Höglinger Günter , Herms Jochen , Brendel Matthias 
Published: December 2020

AbstractBackgroundIn vivo assessment of neuroinflammation by 18 kDa translocator protein positron‐emission‐tomography (TSPO‐PET) ligands receives growing interest in preclinical and clinical research of neurodegenerative disorders. Higher TSPO expression in females has been reported for cognitively normal humans, but such effects have not yet been evaluated in rodent models of neurodegeneration and their controls. Thus, we aimed to investigate the impact of sex on TSPO expression in amyloid and tau mouse models and wild‐type (WT).MethodLongitudinal 18F‐GE‐180 TSPO‐PET (18F‐GE180) data of AppNL‐G‐F
(amyloid model), P301S (tau model) and C57Bl/6 (WT) mice were evaluated between two and twelve months of age. AppNL‐G‐F
received additional longitudinal amyloid‐PET (Aβ‐PET; 18F‐florbetaben). Immunohistochemistry also served for validation of microglial (Iba1, CD68) and tau (AT8) markers at the terminal time point. PET and immunohistochemistry were quantified in cortical regions and compared by linear mixed models (PET) and analysis of variance (immunohistochemistry) between male and female mice.ResultThe amyloid model AppNL‐G‐F
revealed a distinct cortical increase of TSPO‐PET values from 2.5 to 10 months in female mice (+31%), whereas male mice only increased slightly (+6%). The linear mixed model indicated a significant sex x time interaction (T=‐2.953, b/SE=‐0.011/0.004, p=0.0048, Figure 1A), validated by Iba1 and CD68 immunohistochemistry (Figure 2). Aβ‐PET values in the same AppNL‐G‐F
mice indicated no significant time x sex interaction (T=0.425, b/SE=0.001/0.003, p=0.673, Figure 3). The P301S tau model showed strong cortical increases of TSPO‐PET from 2 to 8.5 months of age (female: +32%, male: +36%) but no significant sex x time interaction (T=‐0.671, b/SE=‐0.003/0.005, p=0.504, Figure 1B) and no differences in Iba1, CD68 or AT8 were observed. TSPO‐PET values in WT mice indicated an increase with time (female: +23%, male +4%) and a significant time x sex interaction was found (T=‐4.171, b/SE=‐0.009/0.002, p<0.001, Figure 1C).ConclusionFemale mice indicate a sex dependent elevation of glial activation in response to amyloidosis but not to tau pathology which could be related to differences in sex dependency of microglial activation pathways in presence of both proteins. Sex requires attention when microglia activation is evaluated in mouse models of Alzheimer’s disease and requires detailed studies in human disease.
Supporting caregivers to increase confidence can delay functional decline in older adults
Authors: Tomita Machiko R 
Published: December 2020

AbstractBackgroundInformal caregivers of Alzheimer’s disease and other dementia (ADOD) have higher burden compared to caregivers of other illnesses, and caregivers’ well‐being affects their care recipients (CR). We hypothesized that with tangible support for caregivers' challenges related to daily activities, CR’s functional levels in the intervention group will be maintained while that in the control group will be declined.MethodThis randomized controlled trial involved a 3‐month intervention taking place in Caregiver's homes. Participants (21 intervention and 15 control) were caregivers of community‐dwelling older adults with ADOD who are members of the Programs of All‐inclusive Care for the Elderly (PACE). Challenges were described by caregivers, and solutions were derived from literature reviews, experiences and brain storming among geriatric occupational theorists, and delivered after a discussion with caregivers. Outcome measures were CR’s Activities of Daily Living (ADLs) and Instrumental ADLs, and caregivers’ burden, depression, physical fatigue, and confidence to continue care. T‐tests compared these group differences at baseline and 3 months due to much lower cognition of CR in the intervention group. All scores for the intervention group was much worse than those of the control group.ResultThe intervention group improved in confidence, depression, and physical fatigue, in contrast to the control group’s decline in all these measures. At baseline, CR’s functional levels of the intervention groups were much lower than those of the control group, and both groups declined further over 3 months. However, the decline of care recipients of the control group was much larger: 2.8 times for ADLs and 5.3 times for IADLs more than the intervention group.ConclusionEffective tangible support including working with caregivers to organize life and make schedules, training for transfer of CRs, use of a gait belt, and effective a communication method, and reviewing educational material with them improved their confidence, resulting in delaying CR's function decline. Even with CR's very low cognition, this type of support was effective to improve informal caregivers' confidence for continued care; therefore, we have to find a way to translate exiting knowledge of ADOD care to a practical support system.
Longitudinal assessment of amyloid‐beta deposition in initially amyloid‐negative individuals with [11C]‐PIB PET imaging
Authors: Hatashita Shizuo , Wakebe Daichi 
Published: December 2020

AbstractBackgroundThe earlier stage of amyloid‐beta (Aβ) deposition, before Aβ is widespread throughout cortex, remains poorly understood. The longitudinal change of Aβ deposition was evaluated with [11C]‐PIB PET in initially amyloid‐negative subjects.MethodSixteen cognitively normal (CN) and 7 mild cognitive impairment (MCI) subjects (age 60‐75 years) who were amyloid‐negative at baseline underwent cognitive assessment and 60‐min dynamic [11C]‐PIB PET at two or more over 5.0 to 9.4 years of a long follow‐up, and apolipoprotein‐E (APOE) genotype assessment. Regions of interest were defined in the bilateral cortex on co‐registered MRI. A quantitative analysis for [11C]‐PIB was used with the distribution value ratio (DVR). Longitudinal changes in PIB DVR values were evaluated in the same regions and an annual rate of change in PIB DVR was calculated.ResultSeven (30.4%) of 23 initially amyloid‐negative subjects converted to be globally amyloid‐positive (global DVR ≥1.40) over a follow‐up of 6.5±1.4 years (converter). A global DVR increased from 1.22±0.07 at baseline to 1.63±0.15 (n=7, p<0.01) at a last follow‐up. In contrast, in the 16 subjects, a global DVR was 1.15±0.07 at baseline and did not change over a follow‐up period (stable). An annual increase of global DVR in converters was 0.057±0.019 per year (n=7, p<0.01), larger than that in stable subjects (0.004 ± 0.013, n=16). An increase of global DVR was not correlated with baseline global DVR (r=0.26, n=23, p=0.22) or baseline age (r=0.15, n=23, p=0.47). Four (66.6%) of 6 APOE ε4 carriers converted to be amyloid‐positive while 3 (17.6%) of 17 APOE ε4 non‐carriers did (Fisher’s exact p<0.05). Among cortical regions, regional DVR in the lateral temporal cortex increased to 1.48±0.06 (n=6) above regional positivity threshold over 2.9±1.5 years of a follow‐up and its period was the shortest. Furthermore, an increase of regional DVR prior to reaching the globally positive threshold was 0.084±0.050 per year in the precuneus, which was the largest.ConclusionAmyloid‐negative individuals, especially with APOE ε4, could convert to be globally amyloid‐positive with extensive cortical spread of Aβ, based on an early Aβ deposition in lateral temporal cortex and a large increase of Aβ deposition in precuneus.
Mapping the contribution of clinical risk factors and MRI‐based imaging features to cognitive impairment in community elders
Authors: Zhao Lei , Yiu Brian , Lam Bonnie Y.K. , Biesbroek J. Matthijs , Luo Yishan , Shi Lin , Mok Vincent C.T. , Wong Adrian 
Published: December 2020

AbstractBackgroundIt is still not clear about the clinical risk factors of cognitive impairment in community elderlies. Although many studies have investigated the association of imaging features with cognitive impairment, none has applied location‐specific information for the prediction.MethodWe included 609 stroke‐ and dementia‐free elderlies with comprehensive clinical information collected (Table 1). T1‐weighted (T1W) images, T2‐weighted images, FLAIR and diffusion tensor imaging (DTI) were acquired. T1W images were processed with AccuBrain to quantify brain volumes of anatomical structures (Table 2). White matter hyperintensities (WMHs) were automatically segmented using AccuBrain and normalized to standard space for the quantification of regional burden. Other small vessel disease features, including lacunes, cerebral microbleed and enlarged perivascular spaces (EPVS) were visually rated (Table 2). Peak width of skeletonized mean diffusivity (PSMD) was calculated on DTI sequence. These vascular imaging features and clinical variables were used predict Montreal Cognitive Assessment (MoCA) and Symbol Digit Modalities Test (SDMT) with support vector regression (SVR). We compared three prediction models here: (1) with clinical variables as predictors, (2) imaging features as predictors, and (3) the combination of clinical and imaging features as predictors. Different feature selection methods were attempted. Further statistical inference was performed with permutations to investigate independent contributing factors.ResultParticipant characteristics were shown in Table 3. When predicting MoCA or SDMT (Figure 1), Model 3 performed no better than Model 2 or 1, and Model 1 performed better than Model 2 (p<0.001). In addition to age and education level, only average sitting systolic blood pressure presented significant independent contribution to MoCA, while for SDMT, no clinical variables had significant independent contribution (Table 4 and 5). The imaging features that had significant independent contribution included EPVS in basal ganglia, WMH volume in left superior corona radiata, and atrophy of right parietal lobe and insular for MoCA, and right insular atrophy for SDMT.ConclusionCombining clinical variables and MRI‐based features did not achieve better prediction of cognitive impairment than using either type of features alone. The highlighted predictors that presented independent contribution to MoCA or SDMT may help to understand the cognitive risk factors in community elderlies.
Stakeholder engagement in dementia care research: Identification of stakeholders and their perspectives on participatory research
Authors: Kowe Antonia , Köhler Stefanie , Klein Olga A , Lüthje Corinna , Teipel Stefan J 
Published: December 2020

AbstractBackgroundAlthough stakeholder engagement is increasingly being incorporated in research internationally, there is still a lack of participatory research in dementia care. Participatory research fosters the dialogue between different stakeholder groups, improves the quality and relevance of research, and supports efficiency of care. In the absence of a general definition for the term stakeholder, relevant groups must be identified for dementia care and analysed in terms of group commonalities and differences. In this study, we examined how stakeholder groups differed in terms of their preferences for participatory dementia care research to develop recommendations for optimal stakeholder engagement.MethodA group discussion was held in the format of a World Café. We identified stakeholders via two routes, with the help of dementia experts from local institutions and by using snowball sampling. The discussion session was attended by 16 people who were divided into two groups: (1) professional service providers (n = 8) and (2) patient representatives and informal caregivers (n = 8). A qualitative content analysis was carried out on the basis of protocols from the stakeholder responses, which were prepared by two researchers during the group discussion.ResultWith respect to preferred research areas where patients and the public should actively be involved, both groups were particularly interested in research on early detection of dementia. Digital media formats were seen as useful aid for recruitment of stakeholders and communication between scientists and non‐scientists. Both groups identified transparency in the research process as most important prerequisite for participatory dementia care research. The groups differed in their views on possible risks including data misuse, excessive demands on participants, and time expenditure for researchers.ConclusionWe conclude that stakeholders in dementia care represent a heterogeneous group whose different demands on stakeholder engagement in dementia care research must be taken into account for target group‐specific participation. The recommendations for the implementation of public involvement provide methodological clues for participation of patients with dementia in research.
Alzheimer’s disease and vascular disease: The clinical spectrum
Authors: Chen Christopher 
Published: December 2020

AbstractBackgroundThe terms Vascular Cognitive Impairment (VCI), Vascular Cognitive Disorder (VCD) and Vascular Contributions to Cognitive Impairment & Dementia (VCID) were introduced to emphasise the important contribution of vascular pathology to any severity of cognitive impairment, ranging from subjective cognitive decline and mild cognitive impairment (MCI) to dementia. Although vascular pathology and Alzheimer’s Disease (AD) is common in elderly individuals with and without cognitive impairment or dementia, pure vascular dementia (VaD) or AD is uncommon. Indeed, most patients with VaD or AD also have other types of pathology, the most common of which is a combination of AD (characterised by the diffuse accumulation of amyloid‐β plaques and neurofibrillary tangles composed of tau) and cerebrovascular disease (CeVD).MethodSeveral different VCI criteria have been proposed. The more recent VASCOG, DSM‐5 and the VICCCS criteria may have greater sensitivity, modest concurrent validity and better predictive validity than older criteria such as the NINDS‐AIREN and DSM‐4 criteria for VaD. Importantly, diagnoses for vascular MCI can now be made using the newer criteria which may be useful for clinical and research purposes which include establishing cognitive trajectories, prognostic biomarkers and better understanding of the underlying mechanisms.ResultAs vascular imaging biomarkers of small vessel disease of the brain are established, well characterized, and easy to recognize, it has been suggested that these vascular biomarkers should be incorporated into the AD Research “ATN” Framework for a biological definition of AD. This presentation will discuss ways in which the AD and VCI criteria can be bridged.ConclusionWhether this effort to bridge AD and VCI is achieved by integration or combination, it would enable a better understanding of both AD and VCI pathophysiology and aid in treatment efforts which is currently mainly through prevention by treating vascular diseases and other risk factors, such as hypertension and diabetes mellitus, until the much anticipated advent of disease‐modifying treatments.
Investigating the feasibility of using wearable technologies and machine learning techniques to recognise distress and agitation in people living with dementia
Authors: Steer Zeke , Pipe Anthony , Battle Steve , Cheston Richard 
Published: December 2020

AbstractBackgroundPeople in the later stages of dementia often express their needs and distress through their behaviour in ways that challenge care staff to respond appropriately. Technological solutions may help staff to recognise this distress at an early stage and take preventative action. The aim of this project is to develop and test the feasibility of using wearable technologies and machine learning algorithms to identify stress and agitation.MethodTwo laboratory‐based feasibility studies were undertaken with healthy adult volunteers. In study 1, 20 participants took part in a computer‐based exercise designed to elicit stress. In study 2, 20 participants completed eight different physical activities which a person living with dementia might undertake during a typical day, plus two additional activities which were designed to be positively‐ and negatively‐stimulating. In both studies, participants’ physiological responses were recorded using wearables – in study 1, using commercially‐available devices worn around the wrist and waist, and in study 2, using an additional device developed by the researcher, worn in a sock. Participants also provided information on their affective states – in study 1 they rated their stress, and in study 2 they completed the Positive and Negative Affect Schedule (PANAS) before and after each activity. Participants’ responses were used to train and evaluate different binary classifiers for their ability to recognise reported stress in the physiological data.ResultsIn study 1, the K‐nearest neighbours algorithm and an ensemble classifier called bagged trees recognised periods when participants reported feeling most stressed with accuracy rates exceeding 90% (98% sensitivity, >99% specificity), using five‐fold validation. However, in study 2 which used a different group of participants, the algorithms trained in study 1 failed to reliably identify the negatively‐stimulating activity from the other activities.ConclusionTechnological solutions can facilitate a proactive approach to the management of stress and agitation in dementia. However, for these kinds of solutions to be effective in practice, they must be able to generalise to new users and different environments including uncontrolled environments. These kinds of solutions also raise ethical considerations, such as privacy and data security, which are particularly important when users may lack capacity.