bluuebunny/crossref_metadata_2025_split huggingface dataset:
Knowledge, beliefs and attitudes towards dementia risk assessment and reduction among individuals with a parental family history of dementia
Authors: Vrijsen Joyce , Maeckelberghe Els , de Vries Jeroen , Abu‐Hanna Ameen , De Deyn Peter Paul , de Winter Andrea , Reesink Fransje E , Voshaar Richard C Oude , Buskens Erik , De Rooij Sophia , Smidt Nynke 
Published: December 2020

AbstractBackgroundIndividuals with a parental family history (PFH) of dementia have an increased risk to develop dementia, as they do not only share their genes but also their psychosocial behavior (Borenstein et al., 2016). This study will explore the knowledge, beliefs and attitudes towards dementia‐risk‐assessment and dementia‐risk‐reduction by changing health behavior among middle‐aged descendants of people with recently diagnosed late‐onset dementia.MethodThe study population consists of middle‐aged descendants of individuals who are recently (last 6 months) diagnosed with late‐onset dementia (Alzheimer’s Disease, Vascular Dementia) at a hospital memory clinic in the Netherlands. Eligible participants are invited by the medical specialist of their parent to participate in a focus group discussion. Focus group discussions are audio recorded and transcribed. Transcripts are analyzed thematically using Atlas‐Ti 8.1 by two independent researchers. The results are categorized into the following five themes derived from the Health Belief Model: (1) dementia and dementia risk factor literacy; (2) perceived severity; (3) perceived susceptibility; (4) perception towards dementia‐risk‐assessment and reduction; (5) benefits and barriers.ResultThree focus group discussions were conducted, each with 4‐6 participants, until saturation of information was achieved. The study population (n=15) consisted of 12 females and had a mean age of 47 years (range 26 to 65 years). The majority (80%) of the participants had a high socioeconomic status. Participants had poor knowledge of the risk and protective factors for dementia. The majority of the participants perceived the threat (i.e. perceived severity and susceptibility) of the disease as high, as participants were anxious about the heritability of dementia. Due to their unawareness of the potential for risk reduction by lifestyle improvement they did not see the need to assess their dementia risk. After gaining this knowledge, participants’ beliefs and attitudes became more positive towards dementia‐risk‐assessment and reduction.ConclusionIndividuals with a positive PFH of dementia have insufficient knowledge about the risk factors of dementia and how they can reduce their risk. The public, especially those with a PFH of dementia, should be informed about dementia, the advantages and disadvantages of dementia‐risk‐assessment and how they can reduce their dementia risk.
Validation of the Oxford Cognitive Screen‐Plus: Tablet‐based cognitive testing in patients with amnestic mild cognitive impairment
Authors: Hübner Clara Margarethe , Demeyere Nele , Preul Christoph , Finke Kathrin 
Published: December 2020

AbstractBackgroundThe Oxford Cognitive Screen ‐ Plus (OCS‐Plus) is a tablet‐based cognitive screen developed for detection of mild cognitive impairment in various settings. We validated it in the target group of aMCI/dementia patients.MethodsPatients with aMCI (N=57) and mild dementia (N=13) were assessed with OCS‐Plus at the Jena University Hospital Memory Center. Comparison of their data with a) those of established dementia testing, third part interview and depression and anxiety questionnaire and b) with those of a demographically matched control group (N = 67) were conducted to explore construct validity and discriminatory power.ResultsSignificant correlations of the OCS‐Plus scores with those of established assessments indicated good convergent validity, divergent validity was indicated by a lack of significant correlations with depression and anxiety scores. Among different scores, the delayed memory score demonstrated the best discriminatory power with sensitivity of .74 and specificity of .75.ConclusionThe OCS‐Plus is able validly to differentiate between healthy control participants and aMCI patients and potentially to differentiate aMCI from mild dementia.
The cerebrospinal fluid stromal cell‐derived factor 1 (CXCL12) concentration in Alzheimer’s disease
Authors: Dulewicz Maciej , Kulczynska‐Przybik Agnieszka , Borawski Bartlomiej , Klimkowicz‐Mrowiec Aleksandra , Pera Joanna , Slowik Agnieszka , Mroczko Barbara 
Published: December 2020

AbstractBackgroundAlzheimer’s Disease (AD) is one of the most common age‐related neurodegenerative diseases. Many molecular mechanisms are underlying in the foundations of AD, e.g. inflammation, tauopathy, amyloid Beta cascade pathology or imbalance of calcium. Neuroinflammation is highly related to proinflammatory proteins and chemokines, widely distributed in the central nervous system (CNS). Interestingly, in AD pathology chemokines with CXC motif were detected in human fluids. The stromal cell‐derived factor 1 (SDF1), known as chemokine CXCL12, was a proinflammatory chemokine, highly expressed in the CNS. Their role is not clearly defined and still not fully understood, but they may regulate synaptic transmission in excitability neurons and modulate neuroglial communication. CXCL12 was detected in plasma and hippocampus AD patients. Levels of this chemokine were considerably decreased compared to the control group. In our investigation, the purposes were the quantitative assessment of CXCL12 levels in the cerebrospinal fluid and evaluation of the potential usefulness of this protein in the diagnosis of AD patients.MethodThe cerebrospinal fluid levels of CXCL12 and classical AD biomarkers, such as Aβ‐42, Aβ‐42/Aβ‐40, hTau and pTau181 were assessed by immunoenzyme assays. The study included 15 patients with AD and 15 non‐demented controls.ResultIn our research, we showed that the concentration of CXCL12 was significantly higher in cerebrospinal fluid of AD patients compared to non‐demented controls. The increased CSF levels of CXCL12 were significantly correlated with Aβ‐42, Aβ‐42/Aβ‐40 ratio and pTau181 in AD subjects.ConclusionThese results point at the CXCL12 is a promising indicator of the inflammatory AD pathology. Furthermore, it seems to be an essential factor for future investigation and may prove to be useful for differential diagnostics.
The ANeED study: Ambroxol in new and early dementia with Lewy bodies
Authors: Rongve Arvid , Holst‐Larsen Elin , Steingildra Stina , Tzoulis Charalampos , Haugarvoll Kristoffer , Myhr Kjell‐Morten , Aarsland Dag 
Published: December 2020

AbstractBackgroundThe mechanisms by which GBA and APOE mutations result in PD or DLB are not fully understood, however there is evidence that it may be connected to reduced levels of GCase enzyme activity. CNS penetration has been confirmed for Ambroxol, and has been shown to increase glucocerebrosidase activity and protein levels in animal and human studies. One small open study with Ambroxol 420mg TID in PD for 186 days found excellent target engagement and improved motor symptoms, and a RCT with 50 PDD patients is ongoing in London, Canada.MethodWe will execute a national multicenter phase III RCT clinical intervention study with Ambroxol in prodromal and mild DLB in Memory Clinics in Norway. We will include persons living with prodromal (DLB‐MCI) or mild DLB with MMSE >=15 to Ambroxol or placebo. We will stratify participants based on genotypes for APOE and GBA and the CSF biomarkers A‐beta, total and phosphorylated tau protein. We will build a national trial platform for drug trials in neurodegenerative disorders in Norway and aim to include more centers in Europe for next phase studies via the European DLB Consortium (E‐DLB). We will execute a PPI program to raise awareness and reduce stigma for people living with DLB and their families.ResultThe ANeED‐study has received funding from the national Norwegian health authorities. Formal approvals for ethics, data protection and Medicine Agency are ongoing. We are planning a national start‐up meeting in Norway in September 2020, and we are currently building a national platform in Norway to be able to run clinical intervention studies in neurodegenerative disorders. We are building a PPI program to recruit patients and caregivers to clinical studies.ConclusionPhase III studies with Ambroxol in PD, PDD and DLB are currently being planned. APOE, GBA and GCase are central to the disease process in both PD, PDD and in DLB. Patients, carers and health providers now need to be offered participation in clinical studies also when diagnosed with one of the α‐synucleinopathies. Preliminary data find Ambroxol to be potentially disease modifying in these disorders.
Immune response and endocytosis pathways are associated with the resilience against Alzheimer’s disease
Authors: Tesi Niccoló , Van Der Lee Sven J. , Hulsman Marc , Jansen Iris E. , Stringa Najada , van Schoor Natasja , Scheltens Philip , van Der Flier Wiesje , Huisman Martijn , Reinders Marcel J.T. , Holstege Henne 
Published: December 2020

AbstractBackgroundDeveloping Alzheimer’s disease (AD) is influenced by multiple genetic variants that are involved in five major AD‐pathways: immune response, β‐amyloid metabolism, endocytosis, cholesterol/lipid metabolism and angiogenesis. The extent to which these pathways are involved in the resilience against AD have thus far been poorly addressed. Here, we investigated the association of each molecular mechanism with (i) the increased risk of AD, and (ii) the resilience against AD until extreme old age, by comparing pathway‐specific polygenic risk scores (pathway‐PRS).MethodWe focused on 29 genetic variants identified in GWAS studies of AD to calculate a pathway‐PRS for the five major pathways involved in AD. For our pathway‐PRS, we developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied the pathway‐PRSs in the Amsterdam Dementia Cohort of well‐phenotyped AD patients (N = 1,909), Dutch population controls from the Longitudinal Aging Study Amsterdam (N = 1,654), and our unique 100‐plus Study cohort of cognitively healthy centenarians who avoided AD (N = 293). Moreover, we estimated the contribution of each pathway to the genetic risk of AD in the general population.ResultAll pathway‐PRSs (except for angiogenesis) significantly associated with increased AD‐risk and, in the opposite direction, with resilience against AD (p < 0.05). The pathway that contributed the most to the overall modulation of AD‐risk was β‐amyloid metabolism (29.6%), which was driven mainly by APOE‐variants. After excluding APOE variants, all pathway‐PRSs (except for angiogenesis) associated with increased AD‐risk (p < 0.05), while specifically immune response (p = 0.003) and endocytosis (p = 2.2 × 10−4) significantly associated, in the opposite direction, with resilience against AD. Indeed, the variants in these pathways were the main contributors to the overall modulation of genetic risk of AD in the general population (45.5% and 19.2%, respectively).ConclusionThe genetic variants associated with the resilience against AD indicate which pathways are involved with maintained cognitive functioning until extreme ages. Our work suggests that a favorable immune response and a maintained endocytosis pathway might be involved in neuro‐protection mechanisms of AD, which highlight the need to investigate these pathways, next to β‐amyloid metabolism.
Predictors of preclinical Alzheimer’s disease in persons with subjective cognitive decline
Authors: Janssen Olin , Jansen Willemijn J. , Vos Stephanie J.B. , Maserejian Nancy Nairi , Ossenkoppele Rik , Verhey Frans R.J. , Jessen Frank , Visser Pieter Jelle ,   the Amyloid Biomarker Study Group
Published: December 2020

AbstractBackgroundTo identify at‐risk individuals that will likely benefit from disease‐modifying treatment and improve selection for clinical trials, the role of unobjectified cognitive complaints (subjective cognitive decline, SCD) in preclinical Alzheimer’s Disease (AD) needs to be refined. Although persons with SCD are at increased risk of developing dementia, it is unclear whether SCD is a symptomatic indicator of preclinical AD. We aim to identify SCD characteristics that are associative of amyloid positivity and are thus indicative of preclinical AD.MethodsWe included 1,336 persons with SCD from 14 centers included in the Amyloid Biomarker Study. Amyloid‐ß deposition was measured with positron emission tomography or cerebrospinal‐fluid biomarkers and dichotomized as normal or abnormal according to study‐specific cut‐offs. SCD characteristics included were subjective decline in memory, informant confirmation of SCD, concerns about complaints, feelings of worse performance, subjective decline in attention and concentration, depression, anxiety, and setting. Generalized‐estimating‐equations adjusting for center were used to examine the association between SCD characteristics and amyloid positivity.ResultsAverage age was 66.5 years, 52% were female, mean education was 14.2 years, 33% was APOE‐ε4 positive, 19% was amyloid positive, 21% was t‐tau positive, and 30% was p‐tau positive. Increased age (p<0.001) and APOE‐ε4 carriership (p<0.001) were associated with a higher probability of amyloid positivity. Subjective decline in memory was associated with an increased probability of amyloid positivity (25% vs. 19% for persons without subjective decline specific to memory, mean difference 9%, p=0.036). The probability of amyloid positivity differed according to setting and was higher in a memory clinic setting (29%) compared to research setting (15%) and population setting (5%). The other SCD characteristics were not associated with amyloid positivity. Age, APOE‐ε4 carriership, subjective decline in memory, and setting remained independent predictors of amyloid positivity when analysed combined.ConclusionBased on these analyses, age, APOE‐ε4 carriership, subjective decline in memory, and setting are characteristcs that may help identify preclinical AD in persons with SCD.
Integration of demographics, genetics, imaging and metabolomics data to identify Alzheimer’s disease patients
Authors: Damotte Vincent , Marot Guillemette , Meirhaeghe Aline , Amouyel Philippe , Bellenguez Céline , Chouraki Vincent ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

AbstractBackgroundAvailability of omics data offers new opportunities to improve diagnosis of Alzheimer Disease (AD). Most of existing efforts have focused on one dimension at a time (genetics, metabolomics, imaging...) without considering them simultaneously. We integrated clinical, genetic, metabolomics and imaging data of individuals from the Alzheimer Disease Neuroimaging Initiative (ADNI) dataset in order to build models to accurately classify AD and cognitively normal (CN) individuals.MethodSamples were divided into training (65 AD and 82 CN samples) and validation datasets (33 AD and 41 CN samples). Three modalities were considered in this analysis: metabolomics, imaging and a third modality containing known demographic and genetic AD risk factors. After quality control, 6 known risk factors, 119 metabolomic variables and 283 imaging variables were included. Sparse Partial Least Squares‐Discriminant Analysis (sPLS‐DA) was performed in order to classify individuals into AD and CN categories, based on a small number of variables. This method was used to build three models, one for each of the three modalities separately. We then built two additional models with the three modalities considered as (1) one super modality (i.e. combining the three modalities into one modality), or (2) independent modalities. For each model including the genetics modality, we built three different models, including as the genetic variable(s) either Apolipoprotein E4 (APOE4) status only, or the Desikan’s polygenic hazard score (PHS) only, or the two genetic variables: APOE4 genotype and the PHS but computed without APOE4. Classification performance of each model was assessed on the validation dataset, using Area Under the Curve (AUC), sensitivity, specificity, negative and positive predictive values (NPV and PPV).ResultsSeven models out of eleven had an AUC above 0.8. The best model was built using the super modality and including the PHS as the genetic variable, with an AUC of 0.89 [0.82‐0.96]. Sensitivity, specificity, NPV and PPV were 79%, 100%, 85% and 100%, respectively.ConclusionWe built diagnostic models in order to classify AD and CN individuals. The best model was highly efficient, with an AUC of 0.89 and needs to be further validated in an independent cohort.
Inflammasome activation and reduced sTREM2 release in LPS stimulated organotypic brain slices
Authors: Schilcher Irene , Loeffler Tina , Flunkert Stefanie , Hutter‐Paier Birgit 
Published: December 2020

AbstractBackgroundImmune activation in the CNS and production of neurotoxic mediators are linked to various neurodegenerative diseases, especially to Alzheimer’s disease (AD). On the one hand, the finding of TREM2 variants as genetic risk factor for AD and on the other hand, the current focus of research on the inflammasome activation are giving evidence for the importance of glial cells in AD. The further characterization of glial cells, ideally in co‐culture with neurons, during inflammatory processes are necessary to better understand the disease. Also screening of anti‐inflamamtory drug candidates in an in vitro system maintaining the interplay of different cell types is highly relevant to provide results of translational value. To assess whether organotypic slices are a suitable tool to investigate inflammasome activation and involvement of TREM2 we tested several LPS stimulation paradigms in this system.MethodTo study neuroinflammation in an intact neuronal system, organotypic slices from the hippocampus were prepared from early postnatal wild type mouse pups. To stimulate inflammation, slices were incubated with lipopolysaccharide at numerous concentrations and cytokine and sTREM2 release into the supernatant was measured by multiplex Mesoscale Discovery (MSD) immunosorbent assay at several time points. NLRP3 and Caspase 1 expression were examined with protein simple WES technology. Dexamethasone or MCC950 served as reference items to counteract the inflammatory response.ResultLipopolysaccharide stimulation at numerous concentrations and durations differently changed cytokine and sTREM2 release into the supernantant as wells as NLRP3 and caspase1 expression within the slices. Reference items like dexamethason or MCC950 can downregulate the inflammatory response to various degrees.ConclusionOrganotypic brain slices are a perfect tool to study neuroinflammatory pathways ex vivo. Disease‐relevant pathways are activated by LPS stimulation and this process can be reversed by some reference compounds. By maintaining the three‐dimensional structure and interplay of different cell types of the postnatal brain, this system closely resembles the in vivo situation while offering several advantages for early screenings, like sampling of supernatant at various time points and higher throughput.
Alzheimer's disease patients getting lost in the community: Is road network structure a significant risk factor?
Authors: Puthusseryppady Vaisakh , Manley Ed , Hane Aung Min , Patel Martyn , Hornberger Michael 
Published: December 2020

AbstractBackgroundGetting lost is one of the earliest and most distressing symptoms seen in Alzheimer’s disease (AD). Despite being a prevalent problem in the community worldwide, very few studies have explored real‐world environmental factors that may potentially contribute to patients getting lost. In this study, we aim to investigate whether road network structure plays a contributory role to AD patients getting lost in the community using retrospective and prospective data.MethodRetrospective data of police case records of a large sample of missing dementia patients in the Norfolk county (n = 210), over a three year period, was used first to test our aim. Here, for each missing patient location, we measured the road intersection density, intersection complexity, as well as orientation entropy at a 1 km radius buffer zone around these locations; these measures were then compared to that of a set of random but matched locations. We then collected data prospectively to test the performance of 18 community‐dwelling patients with AD (aged 50‐80 years) on their ability to find their way in their own neighbourhood using a novel ‘Detour Navigation Task’. Here, we will measure the road intersection density, complexity, and orientation entropy at the locations in their neighbourhood where patients exhibited spatial disorientation.ResultThe 210 patients in the police data went missing from a total of 168 locations in the Norfolk county. Our results show that the locations patients went missing from had significantly increased road intersection density, complexity, and orientation entropy when compared to that of the matched locations. Meanwhile, the performance of the sample of 18 AD patients on the Detour Navigation Task will then be analysed to see whether the neighbourhood locations where the patients felt disoriented exhibited higher road intersection density, complexity, and orientation entropy when compared to locations where they did not feel disoriented.ConclusionThe results of this study will provide evidence for road network structure as being a significant factor contributing to AD patients getting lost. This can in future help to potentially identify patients at high risk for getting lost as well as inform safeguarding guidelines.