bluuebunny/crossref_metadata_2025 huggingface dataset:
Amyloid Pattern Similarity Score (AMPSS): A reference region free measure of amyloid PET deposition in Alzheimer’s disease
Authors: Prosser Lloyd , Veale Thomas , Malone Ian B , Coath William , Fox Nick C , Cash David M
Published: December 2020

Background

Amyloid‐PET has high sensitivity for cerebral amyloid, a hallmark of Alzheimer’s disease (AD). Typically, a global measure of amyloid burden in used to classify individuals as amyloid positive or negative. Measures like the Standarised Uptake Value ratio (SUVr) rely on a reference region to normalise amyloid measures, but are non‐specific, sensitive to delineation errors, and reference region choice is debated. This study evaluates a summary measure based on the multivariate pattern of amyloid deposition without a reference region, named Amyloid Pattern Similarity Score (AMPSS).

Method

Alzheimer’s Disease Neuroimaging initiative (ADNI) individual and volumetric T1 MRI data were co‐registered. MRI data was then spatially normalised using DARTEL. Combined, these two transforms then map PET data into common space. A support vector machine (SVM) was trained using a) age‐matched normal controls with higher CSF Aβ42, and b) individuals with clinical diagnosis of AD and lower CSF Aβ42(Table 1). Normalised grey matter voxels were used as the SVM features. Rather than conventional binary classification, the SVM generated probabilistic scores based on logistic regression (i.e. AMPSS). Three evaluations were performed: (1) a validation set (Table 1), (2) comparison with CSF determined amyloid status, and (3) initial longitudinal trajectory evaluation (Table 2).

Result

The validation set AMPSS perfectly classified AD and controls. AMPSS results did not differ depending on specific reference region or global signal normalisation (between subjects ANOVA F(2,26) = 0.65, p = 0.526, r2 .99). AMPSS showed high concordance with CSF defined amyloid status. Figure 1 highlights the strong AMPSS and CSF relationship. There was a nominal, non‐significant improvement in accuracy for this method compared to SUVr (p=.176), Figure 2. Longitudinal data highlighted that individuals with baseline AMPSS >50% tended to show increased AMPSS at follow‐up, while most individuals <50% baseline AMPSS remained stable. However, there is evidence of some individuals with subthreshold amyloid accumulation. (Table 3, Figure 3.).

Conclusion

The Amyloid Pattern Similarity Score is a reference‐free summary metric of amyloid deposition that performs comparably with conventional SUVr measures. Initial validation shows high agreement with CSF and good sensitivity to increasing amyloid accumulation over time, even in early disease.
Pathways involved in the relationship between resilience and cognitive function: The Memento cohort
Authors: Grasset Leslie , Chêne Geneviève , Dubois Bruno , Vellas Bruno , Pasquier Florence , Blanc Frédéric , Paquet Claire , Hanon Olivier , Gabelle Audrey , Ceccaldi Mathieu , Annweiler Cedric , Salmon Pierre Krolak , Dufouil Carole ,   Memento Study Group
Published: December 2020

Background

Given the burden related to dementia, identifying prevention targets against cognitive aging and Alzheimer’s disease (AD) and related disorders is of high interest. While factors of resilience, i.e. education, physical or cognitive activity, or social network, are thought to mitigate the effect of cerebral damage on cognition, mechanisms involved are not well understood. This work thus aims to investigate the pathways involved in the association between resilience and cognition.

Method

Data were collected as part of the Memento study, a French nationwide cohort including patients from 28 memory clinics with either isolated cognitive complaints or mild cognitive impairment. Factors contributing to resilience, such as education level, salary, physical activity, leisure activities, or social network, as well as MRI markers of brain health were collected at baseline. AD cerebrospinal fluid (CSF) biomarkers were assessed in a subsample (n=410). Based on resilience factors, we established a global resilience score using a latent variable from a structural equation model. Structural equation models were also used to evaluate cross‐sectional pathways between resilience, brain ageing biomarkers in relation to cognition, taking into account potential confounders (Figure). Estimates from latent variables were standardized and results reported are for one SD of resilience.

Result

Participants’ mean age was 70.9 years old, 62% were women, 28% were APOE‐ε4 carriers, and 59% had a CDR score of 0.5. Resilience score obtained for each participants, ranged from ‐2.28 to 2.73. AD CSF biomarkers were all significantly associated with worse cognition. Higher resilience was significantly associated with higher cognitive performances (total βres_cog=0.569, p<.0001). In addition to a direct effect on cognition (direct βres_cog=0.519, p<.0001), this association was partly mediated by an indirect effect of resilience on cognition (indirect βres_cog=0.050, p<.0001) through lower neurodegeneration (direct βres_nd=‐0.128, p<.0001). White matter hyperintensities volume, CSF Aβ42/Aβ40 ratio, and CSF phosphorylated tau were not involved in the association between resilience and cognition.

Conclusion

Resilience preserves cognitive functions both directly and indirectly through an apparent protection against neurodegeneration. Beside, AD and small vessel disease markers are not associated with resilience and they do not mediate the protective effect of resilience on cognition.
Chimeric models to analyze human neuron and astroglia responses in Alzheimer's disease
Authors: Arranz Amaia M. , Preman Pranav , T.C.W. Julia , Snellinx An , Calafate Sara , Thal Dietmar Rudolf , Goate Alison M. , De Strooper Bart
Published: December 2020

Background

We have previously generated a chimeric model of Alzheimer´s disease (AD) by transplanting human pluripotent stem cell (PSC)‐derived neurons into the brain of a rodent model of AD. Remarkably, human neurons integrate efficiently into the mouse brain and show main pathological hallmarks of AD such as abnormal Tau phosphorylation, pathological Tau conformational changes and major degeneration and cell loss. However, PSC‐derived mouse neurons transplanted into the mouse brain are not able to recapitulate main AD hallmarks, which reveals a selective vulnerability of human neurons to the amyloid pathology and associated neuroinflammation.

Method

On follow‐up studies, we are generating a chimeric model of AD using a similar experimental approach and transplanting human PSC‐derived astrocytes into the brain of AD mice.

Result

Human astrocytes also integrate in the mouse host brain and mature in a cell‐autonomous way maintaining their human‐specific properties. Interestingly, human astrocytes interact with Aβ plaques showing differential morphological responses.

Conclusion

This novel data highlights the importance of studying both human neurons and glia cells on the context of AD.
Quantitative systems pharmacology model of Alzheimer’s disease to study efficacy of combinatorial therapy on multiple pathology components
Authors: Karelina Tatiana
Published: December 2020

Background

Immunotherapies 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.

Method

Predeveloped 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.

Result

Model 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.

Conclusion

QSP 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

Introduction

Cognitive 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.

Methods

Participants 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.

Results

After 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.

Conclusion

We 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

Background

Lewy 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.

Method

Nine 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.

Result

HC 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.

Conclusion

Our 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

Background

Medial 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.

Method

In 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.

Results

Different 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).

Conclusion

Our 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

Background

Neuro‐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).

Method

CSF 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.

Result

We 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).

Conclusion

Our 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

Background

Palliative 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.

Methods

Exemplar 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.

Conclusion

By 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

Background

White 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.

Method

We 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.

Result

Periventricular 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.

Conclusion

Sub‐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

Background

Assistive 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.

Method

Two 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.

Result

665 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.

Conclusion

Overall, 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

Background

Cholinesterase 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.

Method

Here, 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).

Result

We 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.

Conclusion

Our 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

Background

The 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.

Method

Fifty‐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.

Result

Roughly 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).

Conclusion

In 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.
‘Guttmann Cognitest®’, preliminary validation of an app to test cognitive performance
Authors: Cattaneo Gabriele , Solana Javier , García‐Zafra Edgar , Alviarez‐Schulze Vanessa , Opisso Eloy , Lopez‐Carballo Jaume , García‐Molina Alberto , Tormos‐Muñoz Josep Mª , Bartres‐Faz David , Pascual‐Leone Alvaro
Published: December 2020

Background

Thanks to technological advances the administration of cognitive assessments via computers, tablets or smartphones continues to increase, both in research and clinical practice. Several systems are commercially available and have been validated. However, there are limited tools that provide a baseline assessment and guide a personalized training program with the seamless integration of follow‐up evaluations. The “Guttmann Cognitest”® app has been specifically designed as a smartphone or tablet app to be eventually integrated as an assessment module of the “Guttmann, NeuroPersonalTrainer”® (Solana et al., 2014), a tele‐cognitive rehabilitation platform.

Method

In the context of the Barcelona Brain Health Initiative (BBHI, Cattaneo et al., 2018) 57 healthy subjects (28 women, mean age= 56.1±7, age range 42‐65, years of education= 16.1±3.6) underwent an extensive paper‐and‐pencil classical neuropsychological assessment and a cognitive assessment via the mobile app. The two cognitive assessments were completed on different days and their order was counterbalanced across subjects. The “Guttmann Cognitest”® app includes 6 tests designed to assess main cognitive functions and be completed in about 17 minutes (range 9‐30).

Results

Factorial analysis confirmed that the app measured the intended 6 different cognitive domains. Internal consistency was good (α=0.71) and convergent validity analysis demonstrated that performance in each of the 6 tests in the app correlated with the a priori defined correspondent gold standard paper and pencil test. We found no gender effects, and an expected correlation with age in 5 out of 7 tests.

Conclusions

Cognitive assessment with a mobile phone is feasible and useful. Preliminary results reveal that the “Guttmann Cognitest”® app has good psychometric properties and is suitable to test cognitive performance in large samples. Once integrated within the “Guttmann NeuroPersonalTrainer”® platform, it will enable automatically screening and effectively monitoring patient’s cognitive capacities over time while undergoing personalized cognitive training and allowing automatic adjustment of treatments in intensity and difficulty according to performance.
Mining gene expression omnibus metadata to unravel key genes entwined with pathogenesis and prognosis of Alzheimer’s disease: A comprehensive bioinformatics approach
Authors: Sree G.N.S Hema , Rajalekshmi Saraswathy Ganesan , Burri Raghunath R.
Published: December 2020

Background

Gene expression analysis has become a valuable resource to derive new hypotheses in exploring genetic background of neurodegenerative disorders. Dearth in break through Alzheimer’s disease research to unravel i) genetic predisposition, and ii) disease specific druggable targets, prompted us to initiate and frame this project.

Method

Gene Expression Omnibus (GEO) database was screened with a set of prescribed inclusion and exclusion criterion. Datasets evaluated in Homosapiens containing controls and patient samples describing the genetic source and diagnostic criteria were selected for the study. Datasets evaluated in cell lines, animals, mutational studies and methylation status were excluded. Shortlisted datasets were analysed individually to retrieve Differentially Expressed Genes (DEGs) by considering False Discovery Rate (FDR) and log Fold Change (FC) through GEO2R tool. Different permutation and combinations were tried between FDR p‐value and log FC (FDR p‐value < 0.05 and log FC >2; FDR p‐value < 0.05 and log FC >1.5; FDR p‐value < 0.05 and log FC >1; and FDR p‐value <0.01 and log FC >1) to retrieve common DEGs from 70% of the datasets satisfying any of the above criteria between control and disease groups. Protein‐Protein Interactions (PPI) of common DEGs with Literature Derived Genes (LDGs) (retrieved from NCBI) was constructed to identify potential AD specific target proteins.

Result

Around 32 datasets were identified from GEO database meeting the prescribed criteria. Each dataset was analysed individually and DEGs were retrieved. Amongst the different combinations applied between FDR p‐value and log FC, FDR p‐value <0.01 and log FC >1 was considered suitable and this ultimately resulted in 6 datasets which were found to satisfy the fixed criteria in up‐regulated and down‐regulated DEGs as well. Amid the 6 datasets, common DEGs were found in 4 datasets (about 70%) ‐ SLC5A3 and SERPINA3 from up‐regulated DEGs; SST, RGS4, CRYM, NPTX2, RTN3, BDNF and ENC1 from down‐regulated DEGs. PPI analysis revealed significant interactions of SERPINA3, SST, RGS4, BDNF and RTN3 with LDGs.

Conclusion

The above analysis identified the genetic potential of SERPINA3, SST, RGS4, BDNF and RTN3 to underpin AD pathogenesis.
The anti‐amyloid treatment in asymptomatic Alzheimer’s disease (A4) study: Report of screening and recruitment characteristics of the Melbourne composite site
Authors: Zisis Georgios , Mastwyk Maree , Huynh Andrew , Yates Paul A. , Langford Oliver , Raman Rema , Donohue Michael C. , Aisen Paul S. , Robertson Joanne S. , Fowler Christopher J. , Mitchell Natasha L. , Barac Alex M. , Rowe Christopher C. , Sperling Reisa A. , Masters Colin L.
Published: December 2020

Background

Secondary prevention trials in cognitively‐normal older people with brain amyloid beta (Aβ) accumulation are emerging as the next frontier in dementia therapy. The A4 Study is an international randomised placebo controlled trial of immunotherapy against Aβ, a hallmark contributing factor to Alzheimer’s disease (AD). Here we report the screening characteristics and common reasons for participation and screen failure for the Melbourne Composite Site (MCS).

Method

An advertising campaign was conducted over three years. Individuals who expressed interest were phone screened for initial eligibility and invited to the MCS for full assessment. Cognitively normal [CDR=0; Logical Memory Index II (LMII) score 6 to 18; MMSE ≥25] individuals underwent Aβ‐PET imaging using Florbetapir and were classified as Aβ+ (eligible), or Aβ‐ (not eligible) according to study protocol. Participants also provided responses to the Concerns about AD (CAD) and Views and Perceptions of Amyloid Imaging (VPAI) questionnaires.

Result

Science media was our main recruitment source (Mastwyk M et al, International Psychogeriatric Association 2019, DOI: https://doi.org/10.1017/S1041610219000474). 689 individuals were invited to be screened for eligibility and 674 were enrolled. 51% were female and median education level was 16 years (IQR: 12 – 18); 336/517 (65.0%) reported a family history of dementia. 446/524 (85%) wanted to know if they would develop AD (CAD). 452/523 (87%) desired to contribute to AD research (VPAI). The main screen fail reasons in 580 participants were: classified as Aβ‐ (56%); CDR and/or LMII (11%); unstable medical condition (8%); MMSE <25 (4%); PET scans were acquired in 431 participants; 94 Aβ+ participants were randomised [median age 70 (IQR: 67 – 73)]. Aβ‐ participants were more likely to be ≤70 years old.

Conclusion

Intervention trials in preclinical AD present a unique opportunity to reduce the impact of dementia for the future. Individual choice to participate in this sample was motivated by a desire to contribute to AD research and to find out their likelihood of developing AD.
Exploring the role of BIN1 in Alzheimer’s disease
Authors: Gabriele Rebecca , Glennon Elizabeth , Wray Selina , Lines Georgie
Published: December 2020

Background

Bridging integrator 1 (BIN1) is a major risk factor for Alzheimer’s disease (AD). In the brain BIN1 is expressed by neurons and glial cells with each cell type expressing specific isoforms. Interestingly, previous studies have shown that BIN1 expression is altered in AD brains. However, little is known on how each individual isoform is affected and how BIN1 contributes to AD pathogenesis. Our preliminary data suggests that the neuronal isoforms of BIN1 (nBIN1) may modulate the unfolded protein response (UPR), an endoplasmic reticulum stress triggered mechanism. The UPR consists of three different signalling pathways regulated by: PERK, IRE1 and the transcription factor ATF6, which is cleaved into an active form which translocates to the nucleus. Interestingly, the UPR is thought to play a role in AD pathogenesis. This study examines the role of BIN1 in AD as UPR modulator.

Method

Effects of BIN1 expression on UPR activation was investigated by means of western blot and immunocytochemistry in SH‐SY5Y cells expressing nBIN1 or an empty vector. To detect the ATF6 fragment, western blot was carried out on HEK cells expressing BIN1 or an empty vector co‐transfected with an ATF6‐GFP construct. Effects of BIN1 downregulation was explored by luciferase assay and immunocytochemistry in N2a cells transfected with BIN1 or control siRNA

Result

Increased expression of BIN1 showed a significant decrease in full‐length ATF6, an increase in the cleaved fragment of ATF6, an increase in the ATF6 target gene Bip and a significant increase in ATF6 nuclear translocation compared to control, suggesting a selective activation of the ATF6 arm of the UPR. Interestingly, downregulation of BIN1 in N2a shows a selective inhibition of the ATF6 pathway.

Conclusion

UPR dysregulation is a salient feature in AD; we explored the involvement of BIN1 in the regulation of the UPR and found that altered levels of BIN1 can selectively modulate the ATF6 pathway. Future studies to dissect the relationship between BIN1 and ATF6 and better understand the underlying mechanisms might offer an insight into future therapeutic targets.
Alteration of metabolic profile and potential biomarkers in the plasma of Alzheimer's disease
Authors: Le Weidong
Published: December 2020

Background

The expending of elderly population worldwide leads to a dramatical rising in the incidence of chronic diseases including Alzheimer’s Disease (AD) in the elderly. The inadequate understanding of the mechanisms underlying AD is deemed the greatest stumbling block against progress in definitive diagnosis and curative intervention of this disease. Efforts have been made towards the discovery of reliable AD biomarkers, but they are either invasive based on neuropathological markers in cerebrospinal fluid (CSF) or expensive using emission tomography scanning or magnetic resonance imaging techniques. With the emergence of high‐throughput technology that could detect and catalogue larger numbers of small metabolites, metabolomics offers hope for a better understanding of AD and subsequent identification of biomarkers.

Method

Herein, using untargeted ultra‐performance liquid chromatography‐mass spectrometry we firstly measured concentrations of plasma metabolites in a cohort of AD subjects (n=44) and cognitively normal controls (Ctrl, n=94).

Result

We found remarkable reductions of polyunsaturated fatty acids (PUFAs), acyl‐carnitines, tryptophan degradation related metabolites and elevated levels of bile acids in AD compared to Ctrl. Followed by repeated validation in an independent cohort including AD (n=30), mild cognitive impairment (MCI, n=13), Ctrl (n=43) and non‐AD neurological disease controls (NDC, n=31), we further identified a metabolite panel consisting of five metabolites including cholic acid, chenodeoxycholic acid, allocholic acid, indolelactic acid and tryptophan that can distinguish AD from both Ctrl and NDC with satisfactory sensitivity and specificity.

Conclusion

Notably, the concentrations of these metabolites are significantly correlated with disease severity. Our results also suggested the altered bile acid profiles in AD and MCI might provide clues for early risk of AD. Following further validation in larger cohorts, these findings are expected to provide new approaches for diagnosis of AD and offer novel insights into AD pathogenesis.
CLK inhibition alters tau splicing and has a neuroprotective effect in vitro
Authors: Alalwany Roaa H. , Donaldson Lucy F. , Morgan Kevin , Hawtrey Tom J. , Morris Jonathan C. , Bates David O.
Published: December 2020

Background

Microtubule‐associated protein tau (MAPT) undergoes alternative splicing at exon 10 which encodes one of its four microtubule‐binding repeats. Exon 10 inclusion gives rise to tau isoforms with all four repeats (4R) whilst exon 10 exclusion leads to isoforms with three repeats (3R). The 1:1 ratio between 3R and 4R isoforms is tightly regulated by splicing machinery and crucial to normal function. Kinases such as CLKs regulate the activity of splicing factors and their interaction with target transcripts, including MAPT. Disruption to this balance leads to the formation of neurofibrillary tangles (NFTs) and neurodegeneration but the mechanism of this is not yet wholly understood.

Methods

Differentiated Neuro2a and SH‐SY5Y cells were used as neuronal models as these cell lines show an imbalance of MAPT isoforms with bias towards 4R and 3R respectively. Splicing factor SRSF1 was transiently knocked down to confirm its role in MAPT splicing. Novel kinase inhibitors were used to reduce the activity of CLKs and determine the effect on MAPT splicing. The expression ratio of 4R and 3R isoforms was measured by RT‐PCR. Okadaic acid (OA) was used to produce a neurotoxic model and investigate the use of kinase inhibitors for neuronal protection. As a functional measure β3‐tubulin fluorescent marker was used to quantify OA dependent reduction in neurite outgrowth.

Results

4R:3R tau expression significantly decreased by 65% in Neuro2a cells with knockdown of SRSF1 (students t‐test, p<0.001). CLK inhibition increased 4R:3R by 50% in SH‐SY5Y cells compared to control (one‐way ANOVA, p<0.05). SHSY5Y cells neurite outgrowth was significantly reduced by 60% and 85% with 1nM and 5nM OA treatment respectively, demonstrating a concentration dependent effect (one‐way ANOVA, p<0.001). At 1nM OA, neurite outgrowth was rescued by co‐treatment with a novel CLK inhibitor (two‐way ANOVA, p<0.0001).

Conclusions

Novel CLK inhibitors can modulate the expression of MAPT splicing isoforms and exert a functional effect on neurite outgrowth. This suggests these compounds could have a therapeutic effect by rectifying the balance of 4R:3R tau expression.
Vafidemstat in mild to moderate Alzheimer’s disease: The ETHERAL study European cohort interim analysis
Authors: Bullock Roger Alan , Ropacki Michael T. , Gutierrez Sonia , Xaus Jordi , Maes Tamara , Buesa Carlos
Published: December 2020

Background

ETHERAL is a global, multicentre, 12‐month, randomized, Phase IIa safety study of vafidemstat in mild to moderate AD. The study includes a 6‐month, placebo‐controlled, 3‐arm period followed by a 6‐month, 2‐arm active treatment period where participants remain blinded to dose. Vafidemstat is the first epigenetic compound to be studied in clinical trials in CNS disorders. The primary endpoint is safety though data on cognition, behaviour and function and extensive CSF biomarker data was collected at 0, 6 and 12 months. The CSF biomarkers include amyloid and tau and the pro‐inflammatory biomarker S100A9, which is one of the top ten upregulated genes in late onset AD. This paper presents the first unblinded analysis of the data at the end of the first 6‐month period for the EU cohort.

Method

117 participants comprise the EU cohort recruited from sites in Spain, France and the UK. They were randomised to two doses of vafidemstat and placebo; with the placebo participants subsequently randomised to one of the two doses for the second half of the study. Unblinding will occur in February 2020 and randomised results will be presented on safety, cognition, behaviour and function, along with biomarker changes and correlations with clinical efficacy.

Result

Baseline data has shown that all participants meet the amyloid and tau requirements for a diagnosis of AD and S100A9 levels were elevated across groups, as expected. Safety data to‐date supports that vafidemstat has been safe and well‐tolerated, and there has been a low drop‐out rate.

Conclusion

This first analysis presentation will provide data analyses from the EU cohort of randomized, double‐blind 6‐month period of ETHERAL, examine safety data, and correlate clinical data with biomarker changes in CSF. While we may assume the sample size is likely not powered for the clinical efficacy outcomes, the study will demonstrate: a) that an epigenetic compound (vafidemstat, an LSD1 inhibitor) can be developed for CNS disorders, b) that vafidemstat is generally safe and well tolerated, especially in this frail population, and c) that initial efficacy of vafidemstat will provide further knowledge on how to design the confirmatory studies.