bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative systems pharmacology model of Alzheimer’s disease to study efficacy of combinatorial therapy on multiple pathology components
Authors: Karelina Tatiana 
Published: December 2020

AbstractBackgroundImmunotherapies targeting tau or Aβ remain the key focus for neurologists. But low brain penetration and limited scope of targeting may restrict efficacy. This restriction may be overcome by combinations with other treatments targeting protein degradation systems. Quantitative systems pharmacology model allows for integration of available information from multiple preclinical studies to simulate clinical studies. The goal was to develop the translational model of key AD markers, verified and validated on the literature data and to simulate effects of combinations.MethodPredeveloped Ab and tau pathology submodels have been merged through the model of intracellular protein degradation systems (proteasome, autophagy), which is known to fail progressively in AD. Literature data (concentration baselines and dynamics, SUVR) from mice and human have been used for calibration. Multiple in vitro data for intracellular dynamics perturbations (rapamycin, proteasome inhibitors, vinblastine) available from the literature were used to estimate the intracellular regulation parameters. Immunotherapy mechanism is described through 1) binding of antibodies and prevention of seeding and growth of aggregates, 2) activation of microglia for Ab degradation. Data from clinical studies for immunotherapy (BAN2401) and BACE inhibitor (verubecestat) have been used for retrospective model validation, together with data for treatment by rapamycin, calpain inhibitors, proteasome activation in mouse AD models.ResultModel correctly describes the Aβ and tau accumulation and mutual exacerbation in mice and humans. It correctly predicts effect of rapamycin, calpain inhibitors, proteasome activation on tau tangles in tau‐transgenic mouse and absence of effect of Aβ targeting on tau pathology markers in humans. Simulation of Aβ immunotherapy starting from 65 years (Braak stage 3‐4), predicts 80% Aβ plaque difference vs placebo within 2 years, without effect on tau markers. Rapamycin is predicted to clear tau pathology, with modest efficacy (up to 30‐40%) of Aβ clearing. An example of combination, anti‐Aβ immunotherapy with rapamycin is most effective in retarding both pathologies (up to 80‐90%) in hippocampus.ConclusionQSP modeling allows for choice of combinations of newly emerging biologics combined with targeting cell metabolism, to lead optimization and increase of treatment efficacy.
Improvements of visuospatial function and frontal‐occipital connectivity after cognitive training using virtual reality in old adults with subjective cognitive decline and mild cognitive impairment
Authors: Kang Jae Myeong , Lee Sook Young , Kim Nambeom , Woo Soo Kyun , Yeon Byeong Kil , Cho Seong‐jin 
Published: December 2020

AbstractIntroductionCognitive intervention is believed as a potential therapy to prevent incident dementia. Previous studies using virtual reality (VR)‐assisted cognitive training have shown inconsistent results with minimal effect for patients with mild cognitive impairment (MCI). We investigated the hypothesis that fully immersive VR‐assisted cognitive training would be effective in multidomain cognition, psychological symptoms, and brain connectivity in old adults with subjective cognitive decline (SCD) and MCI.MethodsParticipants were randomly assigned as VR group (n=23; SCD=13 and MCI=10) and control group (n=18; SCD=13 and MCI=5). VR group participants conducted a multi‐domain cognitive training program using fully immersive 3D VR twice a week for a month. Both groups were evaluated of their cognitive function, psychological states, and resting‐state functional magnetic resonance imaging (fMRI) before and after the program.ResultsAfter the VR cognitive training, the VR group showed improvements in the Rey‐Osterrieth complex figure test (RCFT) copy (p<0.001), positive and negative affect schedule‐positive affect (p<0.001), and apathy evaluation scale (p=0.006) compared to control group. Seed‐based correlation analyses on fMRI results showed that improvement in RCFT copy was associated with activation in the frontal‐occipital connectivity in the VR group compared to the control group.ConclusionWe found that the fully immersive 3D VR program had positive effects on visuospatial function, positive affect, apathy, and the frontal‐occipital connectivity in old adults with SCD and MCI. Future trials using VR cognitive training with larger sample sizes, selected participants, and longer duration may find extended improvements in multidomain cognition, psychological aspects, and evidence in the brain activation.
Increased electromagnetic variability in Lewy body dementia: A MILOS study
Authors: Huang Yujing , Prats‐Sedano Maria , O'Brien John T , Kocagoncu Ece , Henson Rik , Rowe James B , Su Li 
Published: December 2020

AbstractBackgroundLewy body dementia (LBD) includes dementia with Lewy bodies and Parkinson’s disease dementia, which shared a common pathological core feature of cognitive fluctuations. However, the clinical identification of fluctuations is still controversial. With Electroencephalogram (EEG) and Magnetoencephalography (MEG), it becomes possible to observe the neural correlates of fluctuations with a high temporal resolution in LBD. In this multimodel imaging and computational modelling of dementia with lewy bodies (MILOS) study, we combined EEG/MEG to explore the electro‐magnetic biomarkers of fluctuations in LBD. We hypothesized that LBD would show an increased variation in EEG/MEG compared with controls, indicating a potential underlying mechanism for fluctuations in LBD.MethodNine patients with LBD (mean age=72) and twelve healthy controls (mean age=67) were recruited and an animal/non‐animal object recognition task was conducted. 64‐channel EEG and 306‐channel MEG (including gradiometer (GRM) and magnetometer (MAG)) were simultaneously recorded during this task. Subsequently participants had MRI with T1‐weighted images for EEG/MEG source coregistration. Forward models for EEG/MEG were 3‐Shell Sphere and Single Shell respectively and minimum norm Least‐Squares as the inversion method. The variations of source post‐stimulus in object recognition was assessed. We used standardized clinical batteries to test cognitive functions and overall scalp sensors for EEG/MEG sensor‐level analyses.ResultHC had shorter reaction time and higher accuracy rate than LBD in object recognition. The variations of reaction time across trials in object recognition was significantly higher in LBD than HC. LBD had weaker overall EEG amplitudes and stronger MEG variations across trials for post stimulus than HC. Phase lock value (PLV) indicated different EEG synchronization patterns between groups with higher theta and lower beta synchronization in LBD than HC. The MEG variations across trials in LBD were involved with theta, alpha and beta bands. The MEG variations were negatively correlated with MMSE, ACER, ACE‐III but positively correlated with UPDRS scores. Source variations in LBD involved a network of parietal areas, including postcentral gyrus and superial parietal areas.ConclusionOur study revealed the possible biomarkers of fluctuations in LBD by using EEG/MEG. It highlighted the importance of electrophysiological correlates of fluctuations in understanding the etiology of LBD.
Medial temporal lobe atrophy in preclinical dementia: Visual and automated rating during six‐year follow‐up
Authors: Mårtensson Gustav , Håkansson Claes , Pereira Joana B. , Palmqvist Sebastian , Hansson Oskar , van Westen Danielle , Westman Eric 
Published: December 2020

AbstractBackgroundMedial temporal lobe atrophy (MTA), a morphological hallmark of neurodegenerative diseases, especially Alzheimer’s disease, is assessed through visual ratings in the clinic. Here, we study the potential of detecting longitudinal changes in medial temporal atrophy in preclinical dementia with Scheltens' MTA scale (ranging from 0‐4) with ratings from two radiologists and AVRA―our newly developed software providing continuous MTA ratings.MethodIn this study 93 individuals, followed up three times over six years with subjective cognitive decline (SCD, N = 61) or mild cognitive impairment (MCI, N = 32) from the Swedish BioFINDER cohort, were included. Two blinded raters visually assessed MTA according to Scheltens' scale. These ratings were compared to those from AVRA, MMSE, ADAS‐delayed word recall test, as well as hippocampal (HC) and inferior lateral ventricle (ILV) volumes segmented with FreeSurfer.ResultsDifferent rating styles, with one rater being more conservative, resulted in relatively low inter‐rater agreement for visual MTA assessment between radiologists (weighted kappa of 0.33). However, both sets of ratings showed strong Spearman correlations between raters (rs = 0.76) and to AVRA (mean rs = {0.75, 0.84}). Both visual and automated ratings were strongly associated with HC (rs = {−0.55, −0.50, −0.54}, for rater 1, rater 2 and AVRA, respectively) and ILV (rs = {0.79, 0.83, 0.87}) volumes as well as MMSE (rs = {−0.37, −0.34, −0.31}) and ADAS (rs = {0.42, −0.44, 0.40}). AVRA provided average annual progression rates of MTA points for SCD individuals (0.05/year) and MCI patients (0.09/year), with similar rates for the radiologists' ratings. These changes were comparable to the average changes in HC (−2.9%/year and −4.9%/year, for SCD and MCI respectively) and ILV volumes (10.5%/year and 13.0%/year).ConclusionOur results suggest that visual MTA ratings are sensitive to detect longitudinal changes in HC and ILV volumes in SCD and MCI individuals. The main limitation of quantifying atrophy with visual ratings in clinics is the subjectiveness of the assessment.
Neuroleukin: A potential cerebrospinal fluid biomarker for Alzheimer's disease
Authors: de Kort Anna M. , Kuiperij H. Bea , Kersten Iris , Versleijen Alexandra A.M. , Schreuder Floris H.B.M. , Klijn Catharina J.M. , Claassen Jurgen A.H.R. , Verbeek Marcel M. 
Published: December 2020

AbstractBackgroundNeuro‐inflammation is an important mechanism that occurs during the early stages of AD, and this can be studied indirectly via the CSF. Neuroleukin (NLK) can serve as an interesting new inflammatory marker. NLK is a lymphokine product of lectin‐stimulated T‐cells and induces immunoglobulin secretion by human mononuclear cells.1 Moreover, it can serve as a neurotrophic factor for spinal and sensory neurons. Furthermore, It has previously been shown that neuroleukin is expressed in neurons, microglia, oligodendroglia, and in cerebrovascular cells such as smooth muscle cells. In addition, expression of neuroleukin was found in senile plaques and in Aβ‐laden vessels.2 Thus, the aim of our study was to investigate the diagnostic and discriminative value of NLK cerebrospinal fluid (CSF) in patients at various clinical stages of Alzheimer’s disease (AD) and in patients with cerebral amyloid angiopathy (CAA).MethodCSF NLK were quantified by ELISA. Cohorts of controls (n=47), patients with AD (n=59; consisting of 19 patients with mild cognitive impairment (clinical dementia rating (CDR) = 0.5), 28 patients with CDR 1.0 and 12 patients with a CDR of ≥ 2.0.) and patients with CAA (n=28) were used to evaluate the diagnostic value of CSF NLK levels.ResultWe found that NLK levels were significantly elevated in the CSF of AD patients (4.64 ng/ml (IQR: 3.69‐5.57) compared to controls (3.29 ng/ml (IQR: 2.39‐3.94); p<0.0001) and levels were also significantly elevated in patients with mild cognitive impairment. In CAA patients, NLK was not elevated (3.39 ng/ml, IQR 2.94‐4.17). NLK correlated with total tau levels (rSP = 0.653, p < 0.0001), phosphorylated tau levels (rSP = 0.604 p < 0.0001) and to a lesser extent with amyloid β42 levels (rSP = ‐0.294, p < 0.0001).ConclusionOur findings indicate that CSF NLK levels are elevated in AD patients compared to controls and support an increased neuroinflammatory state in the various stages of AD. In addition, NLK appears to be associated with neurodegeneration as measured by total tau and phosphorylated tau. References: 1. Chaput et al. Nature, 1988. 332(6163): p. 454‐455, 2. Rensink et al. Neuropathology and Applied Neurobiology, 2004. 30(3): p. 279.
Using the RE‐AIM framework to evaluate existing services and inform the development of a new model of dementia palliative care
Authors: O'Connor Niamh , Timmons Suzanne , Kernohan George , Guerin Suzanne , Drennan Jonathan , Murphy Aileen , Fox Siobhan 
Published: December 2020

AbstractBackgroundPalliative care is suitable for anyone with a life‐limiting illness, and addresses their physical, psychological, spiritual and social needs. People with dementia and their families can greatly benefit from a palliative approach to their care. The Model for Dementia Palliative Care Project is developing a new service delivery model for dementia palliative care for the Irish healthcare system. In this project, in‐depth examination of a purposive sample of existing services across Ireland and the UK has been carried out, using robust evaluation methods.MethodsExemplar services were identified across Ireland, Northern Ireland, and England. Existing data was collected at each service, along with primary data from interviews, focus‐groups, and questionnaires with service providers, and questionnaires of service‐users. Logic models were used to describe each service. Services were then compared using the RE‐AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework, with the domain of ‘context’ added for completeness.Results‘Reach’ data included service users’ demographics and geographical coverage of the service, used to estimate the size of a service needed for a certain location. ‘Effectiveness’ data pertained to service users’ satisfaction, for example a good service was associated with flexibility and good communication. ‘Adoption’ and ‘Implementation’ data assessed how well staff ‘bought into’ dementia palliative care practices, as well as barriers to certain components being implemented such as under‐funded homecare services blocking the goal of living and dying at home. ‘Context’ data helped to identify the local driving forces underpinning each service, e.g. an effective volunteer programme, or the local context of a hospice being located on hospital grounds encouraging transfers of non‐cancer patients, through awareness of the service.ConclusionBy using this summative evaluation technique to identify components/activities at each service, it aided the research team to make decisions on the core components to include in the proposed model of palliative care. The novel model of dementia palliative care will have to be flexible, will have a strong multidisciplinary team aspect, support for people with dementia and their families in the community, and education and training for both staff and loved ones of people with dementia.
Classifying white matter hyperintensities according to intensity and spatial localisation reveals specific association with cognition
Authors: Melazzini Luca , Bordin Valentina , Suri Sana , Zsoldos Enikő , Ebmeier Klaus P , Jenkinson Mark , Mackay Clare , Sardanelli Francesco , Griffanti Ludovica 
Published: December 2020

AbstractBackgroundWhite matter hyperintensities (WMH) on T2‐weighted images are imaging biomarkers of brain small vessel disease. When classified according to location (periventricular/deep), they have shown different associations with cognition. WMH can also appear hypointense on T1‐weighted (T1w) images as a possible sign of irreversible tissue damage. We hypothesise that sub‐classifying WMH combining intensity information and spatial localisation may provide better insight into the association with cognition, not detectable for the total WMH burden.MethodWe analysed data from 684 subjects of the Whitehall II imaging sub‐study. A supervised machine learning method (BIANCA) was used to segment WMH. An automatic method based on cluster localisation and image intensity was then applied to classify WMH into 4 categories according to adjacency to the ventricles (periventricular/deep) and appearance on T1w images (either T1w‐hypointense or not) (Figure 1). Derived volumes were entered into a general linear model as predictors of the participants’ cognitive scores on neuropsychological tests.ResultPeriventricular T1w‐hypointense WMH were significantly related to worse performance in the trail‐making test A (p = 0.011), digit‐symbol (p = 0.028), and digit‐coding (p = 0.009) tests. When including only the total WMH burden in the model, we could not find any associations between WMH and cognition. Age, gender, years of education, systolic and diastolic blood pressure were used as covarietes in the statistical models.ConclusionSub‐classifying WMH according to both location and appearance on T1w images provided added value compared to total WMH burden alone. These are promising findings for WMH interpretation in the clinical practice and for the development of methods for analysing imaging biomarkers related to cognition.
Current memory service professional practice surrounding assistive technology in England: What do memory service professionals need in order to provide information on, and support access to, assistive technology for people living with dementia?
Authors: Newton Lisa Anne , Brittain Katie , Taylor John‐Paul , Robinson Louise 
Published: December 2020

AbstractBackgroundAssistive Technology (AT) has the potential to support people with dementia to remain independently at home for longer. Unfortunately, to date AT is not fully integrated into Dementia care. A recent European position paper(2) called for better education and training of stakeholders and a central information source in order to successfully deploy AT. Key stakeholders involved in deployment of AT in England are Memory Service (MS) professionals who are the first professionals to give information to people with dementia after diagnosis. This study aims to explore current MS practice surrounding AT.MethodTwo surveys were designed and piloted with MS professionals in England. One survey targeted MS managers/lead clinicians to explore MS characteristics and the other looked an individual professionals practice. Questions included fixed and open‐ended responses. They were distributed by the Royal College of Psychiatrists and the National Institute for Health Research to more than 117 MS. Quantitative data was analysed using descriptive statistics and qualitative data using thematic analysis.Result665 professionals completed a survey. Professionals lack key resources to provide information and support access to AT; only 7% have access to a protocol and 12% to a demonstrator site, 31% receive training, and 38% have a named professional responsible for AT. Professionals are positive about AT and view AT as a solution to a problem. However, they describe assessing risk, were risk was viewed negatively. Professionals were aware of a range of AT available but concerns were raised about potential knowledge gaps and challenges of keeping abreast with technological advances. Information and access pathways were tailored to the individual resulting in no one pathway to AT.ConclusionOverall, professionals provided an insight into current practice and challenges of giving information and supporting people with dementia to access AT. They also suggested ways to improve the current provision and thus deployment of AT.1. Meiland F, Innes A, Mountain G, Robinson L, van der Roest H, García‐Casal JA, et al. Technologies to support community‐dwelling persons with dementia: a position paper on issues regarding development, usability, effectiveness and cost‐effectiveness, deployment, and ethics. JMIR Rehabilitation and Assistive Technologies. 2017;4(1).
Structural MRI of the basal forebrain as predictor of cognitive response to galantamine in healthy older adults: A randomized controlled double‐blinded crossover study
Authors: Müller Patrick , Vellage Anne Katrin , Müller Notger 
Published: December 2020

AbstractBackgroundCholinesterase inhibitors (e.g. galantamine) can enhance cognitive functions in healthy elderly and delay cognitive decline in patients with Alzheimer`s diseases (AD). However, not everyone benefits from this treatment (non‐responders). Current studies show clinical meaningful improvements only in one third of AD patients treated with cholinesterase inhibitors. In this context, predictors of drug response could optimize AD treatment by identifying non‐responders and protect these patients from common adverse side effects.MethodHere, we investigate structural MRI of the basal forebrain cholinergic system volume (BFvol) as a potential predictor of cognitive response to a single dose of galantamine in healthy adults (n=18; 59‐75 years).ResultWe observed that the cognitive response to galantamine, more specifically the attention‐dependent filtering performance in a delayed match‐to‐sample working memory task, correlated with BFvol: Only participants with high BFvol showed a significant positive effect of galantamine on the ability to filter out distracting information during the working memory encoding process.ConclusionOur results indicate that BFvol could be a predictor of galantamine response in healthy elderly. Future studies need to assess whether BFvol may serve as a predictor of the galantamine response in AD patients, too.
Amyloid‐β deposition in cognitively normal oldest‐old is associated with cortical thinning and faster memory decline
Authors: Pelkmans Wiesje , Legdeur Nienke , ten Kate Mara , Yaqub Maqsood , Barkhof Frederik , Van Berckel Bart N.M. , van Der Flier Wiesje , Visser Pieter Jelle , Tijms Betty M. 
Published: December 2020

AbstractBackgroundThe Alzheimer’s disease (AD) pathological cascade is hypothesized to start with the accumulation of amyloid‐β (Aβ). However, the precise effect of Aβ deposition on cognitive decline in the oldest‐old remains controversial, since very old individuals can have intact cognition despite abnormal AD biomarkers. Here we studied, in cognitively normal individuals of 90 years and older, the impact of Aβ on structural brain integrity and the association of Aβ and structural brain integrity on decline over time in memory functioning.MethodFifty‐seven cognitively normal individuals (age mean ± sd = 92.7 ± 2.9) were selected from the EMIF‐AD 90+ study. Aβ status was determined by visual reads on [18F]‐flutemetamol PET (normal = Aβ‐, abnormal = Aβ+); cortical thickness and hippocampal volume were quantified on structural MRI with FreeSurfer and FSL, respectively. Cortical thickness was computed according to the Desikan‐Killany atlas and averaged across hemispheres. Hippocampal volume was normalized for intracranial volume. Memory performance was evaluated using a composite score of the CERAD (delayed recall), Logical Memory (delayed recall), Rey Complex Figure (delayed copy), and the Visual Association Test, that were repeated after 20 months (n = 43). Effects of Aβ status, regional cortical thickness, hippocampal volume, time, and their interactions on memory function were assessed with linear mixed models, adjusted for age and sex.ResultRoughly one out of three (n = 19; 33%) individuals had an abnormal amyloid PET (Table 1). Compared to Aβ‐, those with Aβ+ showed at baseline a thinner parahippocampal and medial orbitofrontal cortex (p<.05; Figure 1), while hippocampal volume did not differ. Over time, Aβ+ individuals showed a steeper decline (β ± SE = ‐.27 ± .09; p<.01;) on memory performance than Aβ‐ (Figure 1). Faster memory decline was also predicted by cortical thinning in predominantly temporal regions in the whole group (Figure 1).ConclusionIn the oldest‐old with initially intact cognition, Aβ pathology was associated with a thinner cortex and faster decline in memory performance. These results suggest that Aβ abnormality, even in the oldest old with apparent high reserve and maintenance mechanisms, is indicative of active neurodegeneration. Other pathologies may also contribute to decline in the oldest old as a thinner temporal lobe predicted decline in memory irrespective of Aβ pathology.