bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of repetitive transcranial magnetic stimulation with computerized cognitive enhancement training on change in cognitive function of mild cognitive impairment patients: Existing, sham treatment‐controlled, pilot study
Authors: Lee Chang Uk , Kang Dong Woo 
Published: December 2020

AbstractBackgroundThis study aimed to investigate the effects of repetitive transcranial magnetic stimulation (rTMS) and computerized cognitive enhancement training combined treatment on cognitive function in mild cognitive impairment (MCI) patients, comparing to the application of the rTMS alone and the sham stimulation.MethodSix MCI patients received high‐frequency rTMS applied to the bilateral dorsolateral prefrontal cortex, followed by the computerized cognitive enhancement training. In addition, six MCI patients took high‐frequency rTMS alone. A sham stimulation was used as a control condition in 7 MCI patients. All stimuli were delivered at a frequency of two sessions per week for four weeks. Neuropsychological test was performed at each time points in each group.ResultAlthough there was the main effect of interaction between time and group on the score of the Korean version of Montreal Cognitive Assessment, only participants of the rTMS single treatment group showed significant improvement of this score.ConclusionIn order to overcome the weaknesses of previous studies confirming the efficacy of the combination therapy, this study included patients with MCI, which was the pre‐dementia stage, and included rTMS single treatment group, but did not confirm the clinical efficacy of the combination therapy. Small sample size, the baseline cognitive function score, and the ceiling effect of the group were considered to be the bias factor of this study and further studies supplementing these factors are needed.
Role of the lysosomal‐associated membrane protein 2 in the AD‐like neurodegeneration induced by HSV‐1
Authors: Aldudo Jesus , Mejias Victor , Sastre Isabel , Fuentes Maria , Aljama Sara , Bullido María J. 
Published: December 2020

AbstractBackgroundA growing number of studies have shown that herpes simplex virus type 1 (HSV‐1) infection could be involved in the pathogenesis of Alzheimer´s disease. Our group have developed a neuronal cell model of HSV‐1 infection showing the characteristic markers of Alzheimer‐type neurodegeneration. Gene expression studies of this cell model identified a set of oxidative stress‐regulated genes in infected cells. Analysis of these genes revealed that the main pathway altered was the lysosomal system (Neurobiol Aging. 2018 Aug;68:5‐17. doi:0.1016/j.neurobiolaging.2018.03.025). The lysosomal‐associated membrane protein 2 (LAMP2) gene was one of the most strongly modulated ones, pointing to LAMP2 as a strong candidate to mediate the lysosomal alterations induced by the virus. The objective of the present work is to study the involvement of LAMP2 in the neurodegeneration events induced by HSV‐1 infection.MethodsIn this work, we used murine neuroblastoma cell lines (N2a) with a stable knockdown for LAMP2. LAMP2 deficient and wild type N2a cells were infected by HSV‐1 for different times. Virus replication was assessed by quantitative PCR of viral genes. Levels of viral proteins were determined by western blot and infectious virus production was evaluated by titer plaque assays. Immunocytochemistry, western blot and ELISA assays were used to monitor AD neurodegeneration markers—tau hyperphosphorylation and Aβ accumulation.ResultsIn this project, we have focused on studying the role of LAMP2 in the neurodegeneration induced by HSV‐1 using a cellular model of neuroblastoma cells that expresses very low LAMP2 levels. The results show that LAMP2 deficiency deeply affects the efficiency of HSV‐1 infection reducing: i) the levels of viral DNA, ii) the amount of viral proteins and iii) the production of infectious viral particles. In addition, LAMP2 deficiency reduces tau hyperphosphorylation and increases Aβ secretion in HSV‐1‐infected cells. These findings indicate that LAMP2 deficiency partially blocks the neurodegeneration markers induced by the virus.ConclusionAll these findings suggest that the lysosomal gene LAMP2 could be a suitable candidate to mediate the AD‐like phenotype induced by HSV‐1.
Ongoing electroencephalographic rhythms related to exploratory movements in transgenic TASTPM mice
Authors: Tucci Federico , Percio Claudio Del , Drinkenburg Wilhelmus (Pim) , Lopez Susanna , Pascarelli Maria Teresa , Lizio Roberta , Noce Giuseppe , Soricelli Andrea , Ferri Raffaele , Bastlund Jesper F. , Clausen Bettina , Forloni Gianluigi , Frasca Angelisa , Fabene Paolo Francesco , Bertini Giuseppe , Colavito Valeria , Kelley Jonathan , Dix Sophie , Richardson Jill , Babiloni Claudio 
Published: December 2020

AbstractBackgroundThe European PharmaCog study (www.pharmacog.org) has reported a reduction in delta (1‐6 Hz) electroencephalographic (EEG) power (density) during cage exploration (active condition) compared with quiet wakefulness (passive condition) in PDAPP mice (hAPP Indiana V717F mutation) modeling Alzheimer’s disease (AD) amyloidosis and cognitive deficits. Here, we tested under similar conditions a cohort of TASTPM mice, in order to assess the reproducibility of the results, the studies were conducted in four different research centers of the PharmaCog consortium.MethodOngoing EEG rhythms were recorded from a frontoparietal bipolar channel in 29 TASTPM and 58 matched “wild type” C57 mice (range of age: 12‐24 months). Normalized EEG power was calculated. Frequency and amplitude of individual delta and theta frequency (IDF and ITF) peaks were considered during the passive and active conditions.ResultCompared with the “wild type” group, the TASTPM group showed a significantly lower reduction in IDF power during the active over the passive condition (p<0.05). This effect was observed in 3 out of 4 EEG recording centersConclusionTASTPM mice were characterized by “poor reactivity” of delta EEG rhythms during the cage exploration in line with previous evidence in PDAPP mice. The reliability of that result across the centers was moderate, thus motivating the use of EEG biomarkers in future multicenter preclinical trials performed in TASTPM mice.
The cerebrospinal fluid fractalkine as a biomarker in mild cognitive impairment (MCI)
Authors: Mroczko Barbara , Kulczynska‐Przybik Agnieszka , Klimkowicz‐Mrowiec Aleksandra , Pera Joanna , Borawska Renata , Muszynski Pawel , Mroczko Piotr , Dulewicz Maciej , Slowik Agnieszka 
Published: December 2020

AbstractBackgroundMild cognitive impairment (MCI) is a neurological disorder that occurs in older adults and could be a very early phase of AD dementia. It is not only medical but also socioeconomic and legal problem. Since the MCI symptoms are not yet associated with such serious memory problems as in dementia, it may be difficult to assess the patient's legal capacity. This is an extremely important issue, among others, from the point of view of the patient's decision about his/her treatment process. His ability to fully understand his health situation and the ability to make rational decisions, including being aware of its effects, can be difficult to assess, which has significant legal effects. Therefore, the biomarkers of early stage of dementia are critically important. Growing body of evidence indicated that overexpression of CX3CL‐1 may influence on tau pathology and modulate the dementia disorders development. In our investigation we aim to measure the cerebrospinal fluid concentration of fractalkine to assess the potential usefulness of this protein in the diagnosis of MCI patients. Moreover, the CSF CX3CL‐1 level was compared to the concentrations of classical AD biomarkers, including Aβ‐42, Aβ‐42/Aβ‐40, tau and pTau181.MethodThe study included 18 patients with MCI and 18 non‐demented controls. The cerebrospinal fluid levels of CX3CL‐1 and classical AD biomarkers, such as Aβ‐42, Aβ‐42/Aβ‐40, tau and pTau181, were assessed by immunoenzyme assays.ResultThe concentration of fractalkine was significantly higher in cerebrospinal fluid of MCI patients when compared to non‐demented controls. The increased CSF levels of CX3CL‐1 were observed to significantly correlate with amyloid beta 1‐42 (Aβ‐42) and phosphorylated tau protein (pTau181) in mild cognitive impairment MCI subjects. Moreover, similar association between CX3CL‐1 concentrations and Aβ‐42/Aβ‐40 ratio was revealed in the control group.ConclusionPresented findings indicate a potential role of CX3CL‐1 in the pathology of MCI and possible usefulness of this protein in the early diagnosis of patients with cognitive impairment. The study was conducted with the use of equipment purchased by Medical University of Białystok as part of the RPOWP 2007‐2013 funding, Priority I, Axis 1.1, contract No. UDA‐RPPD.01.01.00‐20‐001/15‐00 dated 26.06.2015.
Disease duration in autosomal dominant familial Alzheimer’s disease
Authors: Pavisic Ivanna M. , Nicholas Jennifer M. , O'Connor Antoinette , Lu Kirsty , Rice Helen , Khatun Ayesha , Fox Nick C. , Ryan Natalie S. 
Published: December 2020

AbstractBackgroundIn autosomal dominant Alzheimer’s disease (ADAD) an individual’s age at onset is significantly determined by causative mutation (Ryman et al. 2014). Determinants of disease duration are less well studied.MethodSymptomatic mutation carriers (N = 256: 201 PSEN1, 55 APP) from ADAD families referred to the Dementia Research Centre, UK, between 1987 and 2019 were included. Differences in disease duration were assessed using multilevel mixed effects Weibull survival model. We evaluated the effect of gene, sex, cognitive presentation and APOE ε4 status on disease duration and quantified the proportion of variance in disease duration and age at onset explained by mutation and family, using intra‐class correlation coefficients.ResultThere was no significant difference in survival time between genes (PSEN1: 9.7 years [SD 5.3] vs APP 11.2 [4.9], p = 0.474). In accordance with previous findings (Ryan et al., 2016), 67% of the variance in age at onset was explained by mutation and 72% by mutation and family together. In contrast, only 18% of the variability in disease duration was explained by family membership (p < 0.001) and 6% by mutation (p = 0.188). Irrespective of gene, individuals born in later generations had longer survival (p = 0.003). Within the PSEN1 cohort, APOE ε4 carriers (N = 35) had 24% longer survival time compared to non‐carriers (N = 61) (12.9 years [6.7] vs 9.4 [4.7], p = 0.046, Figure 1)). No significant difference between APOE ε4 status was observed (p = 0.738) within APP. Mutations in PSEN1 exon eight included a number of individuals with particularly long disease durations (Figure 2) and the greatest prevalence of atypical symptoms. Overall, individuals with atypical presentations (N = 19) had 43% longer survival than those with amnestic presentations (N = 120) (15.5 years [7.1], vs 10.9 [5.5]; p = 0.014). There was no significant difference in survival time between sexes (p = 0.895).ConclusionOur results suggest, survival in ADAD appears longer in atypical presentations, has increased over time and is influenced by mutation but to a much lesser extent than age at onset. A deeper understanding of this variability may inform disease‐modifying trials and potentially highlight new avenues for targeting the disease.
Hippocampal vascularization pattern exerts local and global effects on structural and functional brain integrity
Authors: Vockert Niklas , Perosa Valentina , Ziegler Gabriel , Schreiber Frank , Yakupov Renat , Spallazzi Marco , Düzel Emrah , Schreiber Stefanie , Maass Anne 
Published: December 2020

AbstractBackgroundThe main contributor to hippocampal blood supply is the posterior cerebral artery. Additional contribution of the anterior choroidal artery distinguishes potential dual from single hippocampal vascular supply. In a previous study on patients with cerebral small vessel disease (CSVD) and older controls by Perosa et al. (Brain, in press), dual hippocampal vascularization was functionally associated with better cognition and structurally associated with increased anterior hippocampal volumes. The CSVD patients showed declined cognitive abilities. However, dual supply was able to alleviate performance loss in CSVD patients, indicating resilience against pathology. We examined the effect of dual vascular supply on anterior/posterior hippocampal volume and global grey matter (GM) volume, which might mediate the beneficial effect on cognition, and whether it conveys resistance against CSVD.Methods47 subjects (71±8yrs) with/without CSVD (20/27) underwent 7T time‐of‐flight MRA for categorization of hippocampal vascularization pattern (HVP) and 3T T1‐weighted structural MRI. As measure of global cognitive function we focused on the MoCA. Automatic segmentations of the anterior and posterior hippocampus were obtained via the ASHS (Automatic Segmentation of Hippocampal Subfields) 3T T1 atlas. GM volumes were obtained by segmentation in SPM (Statistical Parametric Mapping). The effect of the HVP and CSVD on structural and cognitive measures was estimated using ANCOVAs. A mediation effect of GM volume on cognition was examined via bootstrapping. Fisher’s exact test assessed contingency of the observed pattern to both clinical groups to make inferences about resistance against CSVD.ResultsA region‐based approach revealed a greater bilateral anterior (but not posterior) HC volume and increased global GM volume in the dual supply group. In a mediation analysis, GM volume offset the effect of the HVP on the MoCA score, whereas bilateral anterior HC volume did not. While the HVP seems to convey some resilience against CSVD, no evidence for resistance against CSVD was found.ConclusionsPrevious findings of structural effects on anterior HC volume via VBM were confirmed. Besides its local effects, dual hippocampal vascular supply exerts global effects on brain structure. These effects partially account for better cognitive performance of the corresponding individuals. An int42708eraction with pathology might be restricted to resilience, but not resistance.
A novel method for integrating transcriptomics and neuroimaging
Authors: Povala Guilherme , Bastiani Marco Antônio , Bellaver Bruna , Ferreira Pamela C.L. , Souza Débora Guerini , Brum Wagner Scheeren , Zatt Bruno , Zimmer Eduardo R. 
Published: December 2020

AbstractBackgroundPositron emission tomography (PET) imaging has been playing a fundamental role in diagnosis of Alzheimer’s disease (AD). Also, in the context of AD, blood‐based biomarkers that are capable of predicting PET brain imaging findings are of high interest. Both PET imaging and transcriptomics are rich sources of different biological information. Hence, an interesting strategy to find potential novel blood biomarkers is by integrating PET imaging data with blood transcriptomics. We aim to develop a method for combining blood transcriptomics profile and PET imaging data, which may highlight novel AD biomarkers. Here, we hypothesize that by integrating blood transcriptomics and PET imaging data we will be able to identify clinically relevant novel peripheral biomarkers.MethodImaging and transcriptomics data were acquired from Alzheimer’s Disease Neuroimaging Initiative (ADNI). Microarray gene expression profiling from blood samples of 69 cognitively unimpaired (CU) individuals and 158 mild cognitively impaired (MCI) were submitted to differential expression (DE) analysis using the limma R package. The [F18]FDG‐PET standardized uptake ratio (SUVr), using cerebellum as the reference region, were calculated. Genes obtained from DE analysis were selected to undergo integration with [F18]FDG‐PET images using voxel‐wise generalized linear regressions (GLR) (RMINC package).ResultsThe DE analysis resulted in 1232 differentially expressed genes (DEGs) (p‐value < 0.05). The GLR computed the associations between gene expression and [F18]FDG for each voxel, resulting in t‐value maps. Afterwards, only gray matter voxels presenting absolute t‐values higher than 2.3 were retained. Then, we transformed t‐value maps into proportion maps. In brief, each volume of interest (VOI) shows the percentage of voxels statistically correlated with gene expression (see Figure 1). Finally, we ranked DEGs according to the amount of VOIs with a proportion higher than 30%.ConclusionWith the use of the proposed method, we were able to integrate blood transcriptomics with PET neuroimaging. The implementation of this method shows great potential in the search for new blood biomarkers, which can accelerate early diagnosis and provides a template for future research in the field.
Recessive missense variants in VWA2 increase risk of developing Alzheimer’s disease
Authors: Hoogmartens Julie , Hens Elisabeth , Engelborghs Sebastiaan , Vandenberghe Rik , De Deyn Peter Paul , Cacace Rita , Van Broeckhoven Christine ,   BELNEU Consortium
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is the most frequent cause of neurodegenerative dementia and presents at early (age at onset (AAO) ≤65 years, EOAD) or late age (LOAD). Only 5‐10% of EOAD patients are explained by dominant mutations in AD genes, APP, PSEN1 or PSEN2. We aimed at finding recessive mutations in patients that are not genetically explained.MethodsThe Flanders‐Belgian AD cohort (n = 1166) included 170 EOAD (AAO 57.96 ± 6.32 years; range 29‐65) and 996 LOAD (AAO 77.55 ± 6.30 years; range 66‐95) patients. Whole Genome Sequencing (WGS) was provided by Complete Genomics, BGI. The WGS data was searched for recessive variants, altering protein sequences and a minor allele frequencies ≤5%. Gene‐based resequencing was performed using target amplification assays.ResultsWe selected 18 EOAD patients with a well‐documented clinical or pathological diagnosis for WGS analysis. Mean AAO was 56.17 ± 6.90 years (range 37‐65) and 6 patients had pathological confirmed EOAD. One EOAD patient (AAO 64) was homozygous for p.V366M in the gene Von Willebrand Factor A Domain Containing 2 (VWA2). Resequencing of VWA2 in the AD patient cohort identified 1 additional EOAD (AAO 60) and 3 LOAD patients (AAO range 74‐90) with homozygous (p.R69M, p.V366M) or heterozygous (p.V366M/p.L715F) compound variants. Allele sharing analysis of the compound carriers identified common haplotypes flanking p.V366M and p.L715F, suggesting shared ancestors.ConclusionsWe identified 5 AD patients with trans compound variants in VWA2, 2 EOAD patients (2/170; 1.2%) and 3 LOAD patients (3/996; 0.3%). None of the compound carriers had first‐degree relatives with dementia, fitting autosomal recessive inheritance. The observed frequency of compound carriers in the AD patient groups was higher than expected based on the single allele frequencies calculated in our Flemish‐Belgian population. Overall, our genetic results suggest that compound variants in VWA2 might increase risk for AD. VWA2 is likely part of the extracellular exosomes, which are contributing to neuronal interaction and have a role in AD pathology. Genetic replication in independent AD patients cohorts and functional studies will be needed to understand the contribution of the biological function of VWA2 to AD.
Policy makers' perception on the potential of adoption of the Tailored Activity Program (TAP) in Chile
Authors: Moraga Carolina , Gajardo Jean , Fuentes‐García Alejandra , Gitlin Laura N 
Published: December 2020

AbstractBackgroundThe Tailored Activity Program (TAP) is an evidenced‐based program targeting behavioral and psychological symptoms of dementia and caregivers’ readiness, among other outcomes. TAP has been tested and implemented in different settings and countries. Evidence‐based interventions face the challenge of transference and adoption with a complexity of dimensions. This study explored the perception of key stakeholders and policy makers related to dementia care on the potential adoption of TAP in Chile, utilizing Roger’s Model of Innovation‐Decision Process (1983).MethodQualitative study. Key policy makers related to Chile’s Ministry of Health, Ministry of Social Development, and National Plan of Dementia, were introduced to TAP’s main features, process, and outcomes, and later interviewed to describe the following five attributes of TAP: relative advantage, compatibility, complexity, trialability, observability. These attributes were extracted from the Persuasion Phase of Rogers’ Model of Innovation‐Decision Process (1983). Interviews were recorded and transcribed, and narrative content analysis was used to produce content categories. Ethical approval was obtained from the Scientific Ethics Committee of Adults, Metropolitan Health Service, Santiago, 2019. Informed consent was completed by all participants.ResultSeven interviews were performed to policy makers at a national level part of Chile’s National Plan of Dementia. Participants described TAP in a low‐level of complexity, easy to understand, and highly feasible for implementation, as well as highly compatible with existing efforts on dementia care in Chile, highlighting its observable results, pertinence for local testing and its comparative advantage to existing interventions.ConclusionPolicy makers value positively TAP’s features and its adoption is highly feasible within current initiatives on dementia care in Chile.
Neuroinflammation imposes vulnerability to tau propagation
Authors: Rosa‐Neto Pedro , Pascoal Tharick A. , Benedet Andréa Lessa , Kang Min Su , Savard Melissa , Mathotaarachchi Sulantha , Edison Paul , Chamoun Mira , Stevenson Jenna , Therriault Joseph , Massarweh Gassan , Soucy Jean‐Paul , Gauthier Serge 
Published: December 2020

AbstractBackgroundTranslocator protein (TSPO) is an 18 kDa protein has been considered a target for neuroinflammation. Using multiparametric acquisitions, we tested in a large‐scale cohort the hypothetical framework proposing that neuroinflammation imposes vulnerability to neurofibrillary tangles (NFT) formation and propagation.MethodsWe studied cognitive unimpaired and impaired individuals from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort who had a complete baseline clinical and cognitive assessments, structural MRIs, [11C]PBR28, [18F]MK6240 and [18F]AZD4694 (PET proxies for TSPO, NFT and Αβ, respectively). The PET outcome measure was the SUVR. A fraction of these individuals also had CSF cytokines analysed using the Olink Platform. We conducted ROI path analysis and voxel‐based analysis to establish the associations between [11C]PBR28, [18F]MK6240 and [18F]AZD4694.ResultsA total of 138 (CN=90; MCI=30=; AD=18) individuals were included in this analysis. We found that brain [11C]PBR28 uptake was correlated with CSF biomarkers of neuroinflammation. We also found an age‐related increase of [11C]PBR28 uptake. [11C]PBR28 was increased brain in AD related areas across the its clinical spectrum. [11C]PBR28 was associated with cognitive deficits in these individuals. In regards to tau aggregates, we found that [18F]MK6240 uptake in the mesial temporal structures derives from local interactions between [18F]AZD4694 and [11C]PBR28. Importantly, path analysis revealed that [11C]PBR28 and [18F]AZD4694 uptake potentiated the propagation of [18F]MK6240 from early to late Braak stages (Figure 1).ConclusionsOur results reveal that TSPO upregulation is part of the repertoire of biomarker alterations in patients within the entire AD clinical spectrum. TSPO is critical for the early and late tangle formation on medial temporal structures as well in advanced Braak stages. Neuroinflammation imaging agents such as [11C]PBR28 provide critical information regarding inflammatory tissue responses amenable of pharmacological interventions.