bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cortical thickness and mean diffusivity AD signatures at average age 56 predict 12‐year progression to mild cognitive impairment
Authors: Williams McKenna E. , Elman Jeremy A. , McEvoy Linda K. , Dale Anders M. , Fennema‐Notestine Christine , Franz Carol E. , Gillespie Nathan A. , Hagler Donald J. , Lyons Michael J. , Neale Michael C. , Panizzon Matthew S. , Puckett Olivia K. , Kremen William S. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) brain signatures based on cortical thickness, with or without hippocampal volume, predict progression from mild cognitive impairment (MCI) to AD. It would be advantageous if AD signatures could predict earlier progression to MCI. Toward that end, a signature sensitive to microstructural changes that may predate macrostructural atrophy should be useful. We hypothesized that: 1) AD signatures in cognitively normal middle‐aged adults can predict progression to MCI; and 2) Gray matter mean diffusivity (MD) may capture earlier microstructural changes associated with AD.MethodWe investigated the ability of a published cortical thickness/volume signature and a novel MD signature to predict incident MCI in 261 cognitively normal middle‐aged men from the Vietnam Era Twin Study of Aging (VETSA) (baseline age=56.28±2.56; follow‐up age=67.50±2.61). The thickness/volume signature was a weighted average of 8 bilateral regions found to maximally discriminate AD from healthy controls. The same weights were applied to MD in these regions to create an MD signature in 206 subjects with diffusion‐weighted MRI data at baseline. Logistic regression and ROC curves were used to compare models with baseline thickness/volume signature, MD signature, age, and an AD polygenic risk score (ADPRS) predicting MCI at follow‐up.ResultThickness/volume signature, MD signature, age, and ADPRS together predicted progression to MCI an average of 12 years later with 77.85% specificity, 80% sensitivity, and area‐under‐the‐curve (AUC) of 0.822 (95% CI=0.729‐0.914) (Figure 1). Age and ADPRS alone yielded a significantly lower AUC of 0.633 (95% CI=0.561‐0.705; n=601). Adding the MD signature significantly improved prediction over age and ADPRS (AUC=0.811 vs. 0.633; p=.002) but adding the thickness/volume signature did not (AUC=0.746; p=.069).ConclusionAD brain signatures can predict 12‐year progression to MCI among cognitively normal adults who are only in their 50s, but our novel MD signature may be more sensitive to AD‐related changes than traditional thickness/volume signatures. Notably, the MD signature was limited by being yoked to the thickness/volume signature weightings. An independently derived MD signature may provide even stronger prediction. The results are thus promising with respect to early identification of AD and the potential value of MD‐ and/or multimodal AD brain signatures.
Three plasma metabolites in elderly patients differentiate mild cognitive impairment and Alzheimer’s disease: A mass spectrometry study
Authors: Talib Leda Leme , Costa Alana Caroline , Joaquim Helena Passarelli Giroud , Forlenza Orestes Vicente , Gattaz Wagner Farid 
Published: December 2020

AbstractBackgroundMembrane metabolites are important mediators of neuronal function. The metabolomic profile of patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) may suggest potential diagnostic biomarkers and provide information on the pathophysiology of dementia.MethodWe investigated the metabolomic profile of 79 older adults with primary cognitive impairment (34 patients with AD and 20 with MCI) and 25 physically and cognitively healthy elders (controls). We quantified plasma metabolites including membrane phospholipids, sphingomyelins, and acylcarnitines using the AbsoluteIDQ® p180 followed by flow injection analysis coupled with mass spectrometry.ResultA cluster analysis revealed that a combination of acylcarnitines (C12‐DC, C12) and phosphatidylcholine (PC aa C26:0) could differentiate the patients according to diagnostic groups. As a general trend, phosphatidylcholines, acylcarnitines and sphingomyelins levels were lower in AD and MCI subjects compared to healthy controls, and this decrease was even more significant in MCI. The concentration of lysophospholipids was higher in AD and decreased in MCI, as compared to controls.ConclusionFuture studies should combine metabolomic profiles with other biomarkers to identify diagnostic groups.
The development of a multi‐sensory intervention for people with dementia living in care homes
Authors: D'Andrea Federica , Tischler Victoria , Dening Tom 
Published: December 2020

AbstractBackgroundMulti‐sensory intervention is a sensory stimulate approach that has received great interest within the field of dementia treatment, particularly for the management of responsive behaviours (Strøm, et al., 2016). The encouraging results on handling objects activities (Camic et al., 2019) and the unique relationship between olfaction, memory and emotion (Herz, 2016), prompts the interest to develop a multi‐sensory intervention (MSI), using olfactory, tactile and visual stimulation for people with dementia living in care homes, based on the Medical Research Council framework (2008).MethodA background literature on multi‐sensory interventions and olfactory stimulations as well as a scoping review on object handling interventions were conducted to identify evidence and theories. To inform the MSI development, interviews with archivists and experts on olfaction (smell) took place prior to design the intervention and drafting the materials. In addition, a series of taster sessions with stakeholders and people with dementia were conducted to identify areas for refinement and to ensure MSI was appropriately tailored to the needs of people with dementia.ResultsThe results of the scoping review and background literature form an evidence base from which the multi‐sensory intervention was developed. Interviews with experts helped to answer a number of questions in relation to the identification of intervention materials and procedure, which helped to create the first version of the intervention (MSI‐1). The results of the taster session will inform the development of the final version of the MSI.ConclusionThe present study describes the development of an evidence‐based intervention, offering an important contribution to the literature supporting the need for developing intervention through a rigorous approach in order to establish clear evidence of the effectiveness of interventions that can help decision makers and budget holders to consider using those treatments.
Hippocampal volumetric variability is associated with memory in subjective cognitive decline
Authors: Ziegler Gabriel , Heinzinger Nils , Metzger Coraline D. , Yakupov Renat , Bittner Daniel , Glanz Wenzel , Spottke Annika , Brosseron Frederic , Bürger Katharina , Fließbach Klaus , Heneka Michael T. , Laske Christoph , Nestor Peter J. , Peters Oliver , Priller Josef , Ramirez Alfredo , Schneider Anja , Speck Oliver , Teipel Stefan J. , Wiltfang Jens , Wagner Michael , Düzel Emrah , Jessen Frank 
Published: December 2020

AbstractBackgroundSubjective cognitive decline (SCD) has been proposed as an early symptomatic representation of Alzheimer’s disease (AD). Per definition SCD implies patient’s memory being subjectively impaired while broad neuropsychological indicators are still in normal range (Fig.1A). SCD might show early signs of atrophy in networks typically affected during AD disease progression. Among individuals with SCD, the prevalence of older adults who are on a declining AD trajectory are more frequent than in cognitively normal (CN) elderly. The key distinction between SCD and MCI would be a higher offset in memory ability in SCD and a larger proportion of individuals who have progressed further along the AD spectrum. This predicts that brain volume variability would be higher in SCD than in CN and non‐complaining older adults.MethodsWe used sMRI at 3T to quantify anatomical differences using VBM in the DELCODE cohort in a subsample of 755 nondemented elderly (including 221 CN, 376 SCD & 158 MCI). We characterise memory ability using a composite score based on factor modelling (Wolfsgruber et al., under review) of neuropsychological tests. We explore group differences and the association of memory to local brain morphometry using GLM and SPM. We further analyze variability of local volumes across groups using voxel‐based Brown‐Forsythe‐Tests.ResultsWhile there were significant volumetric differences of MCI but not in SCD as compared to healthy controls (Fig1 C left & right panel), volumetric variability (across subjects) was higher within the SCD (and MCI) as compared to CN in hippocampus (Fig. 2A). Individual differences in memory‐ability were positively associated with posterior hippocampal volume in SCD, but showed no association with brain volume in CN (Fig. 2B‐C). In MCI, variability in memory‐ability was also related to posterior hippocampal volume and in addition also to the volume of the anterior hippocampus and entorhinal cortex.ConclusionsIn terms of morphometric variability and the association between morphometric measures and memory ability, the SCD group shows partial overlap with MCI and is distinct to cognitively normal, non‐complaining older adults. The posterior hippocampal region could be an area that explains interindividual memory variability in early stages of the Alzheimer’s disease spectrum.
Automatic early detection of cognitive decline
Authors: Maimon Neta , Molcho Lior , Loterrman Tomer , Pressburger Narkiss , Sasson Ady , Intrator Nathan 
Published: December 2020

AbstractBackgroundWhile it is agreed that cognitive decline is underdiagnosed, there is still no single universally accepted and affordable screening method that satisfies all needs in the detection of cognitive impairment. The goal of this presentation is to demonstrate an automatic cognitive decline assessment with Neurosteer Aurora, utilizing a novel EEG analysis as a method for characterization of cognitive activity and detection of early cognitive impairment.MethodNeurosteer has developed a miniature wearable neurological sensor combined with an automatic assessment tool for a wide range of brain monitoring and treatment needs. It is based on a single EEG channel and relies on advanced mathematical analysis for a decomposition of the EEG signal into multiple components. These components are then processed with machine learning algorithms to create high level biomarkers for real‐time brain activity interpretation. Additionally, Neurosteer has developed a fully automatic assessment and biomarkers for cognitive decline. It is based on a verbal and musical cognitive assessment during brain activity recording. Machine learning algorithms analyze the combined data to produce a simple‐to‐read report indicating the level of different aspects of cognitive decline. We applied this technology on three different healthy population (N=14, 40, 215) and cognitively impaired (N=24, 10, 9, 8) undergoing several automatically administered cognitive tasks.ResultA few biomarkers were extracted using machine learning tools on the collected data. The biomarkers distinguished between different levels of cognitive load as well as resting state patterns. The new groups of cognitively impaired populations were examined with Neurosteer Aurora, completing short and automatic auditory assessments. The patterns of the predefined biomarkers were significantly different for each population, differentiating between clinical populations and negatively correlated with the severity of cognitive decline.ConclusionUsing the novel brain activity interpretation and biomarkers enables an automatic and easy‐to‐administer cognitive decline assessment in the clinical population. Such assessment is a step forward towards a wide‐spread screening, allowing early and personalized intervention to slow down cognitive decline, improving health and quality of life outcomes.
Two APOE splice sQTLs reduce Alzheimer’s disease risk in APOE 4/4 carriers
Authors: Belloy Michael E. , Eger Sarah J. , Guen Yann Le , Napolioni Valerio , Greicius Michael D. ,   Alzheimer's Disease Neuroimaging Initiative
Published: December 2020

AbstractBackgroundAre there genetic variants in the APOE locus that alter APOE4‐related risk for AD? Do these putative variants exert their effect through altering availability of the APOE protein? With these questions in mind, we investigated whether the APOE splice quantitative trait loci (sQTL; variants that alter post‐transcriptional splicing) affect risk for AD, age‐at‐AD‐onset, and APOE protein levels, in analyses stratified to APOE 2/4, 3/4 and 4/4 carriers, respectively.MethodGenetic and phenotypic data was available from 35,760 eligible participants across twenty‐two independent AD‐related studies. Genetic data underwent standard quality control (Plink v1.9) and ancestry determination (SNPweights v.2.1). Included participants were ages 60+, non‐Hispanic, of European ancestry, had APOE genotype available, and were diagnosed as cases or controls (Table 1). From 17 APOE sQTL variants reported in GTEx, only rs157580 and rs439401 were genotyped in >80% of the available sample and further investigated (Figure 1). The role of APOE sQTL SNPs on AD risk was evaluated through logistic regression analyses under a case‐control design, and on age‐at‐onset through multiple linear regression. Associations with APOE protein levels were evaluated in post‐mortem tissue from the dorsolateral prefrontal cortex (dlPFC, n = 655), in which rs157580 alters excision rates of an intron on the APOE‐203 transcript variant. Given the relative paucity of subjects carrying APOE 2/4‐4/4 (n = 11‐11), protein level analyses were restricted to APOE 3/4 carriers (n = 161). Study design and model details/covariates are shown in Figure 1.Resultrs157580 and rs439401 reduced AD risk in APOE 4/4 carriers (Table 2). rs157580 also showed a trending effect to increase age‐at‐AD‐onset in both APOE 4/4 and APOE 3/4 carriers (Table 3). Finally, rs157580 increased APOE protein levels in the dlPFC of APOE 3/4 carriers (Figure 2). Supplemental analyses suggest that the sQTLs and APOE4 must be in phase in order to confer protection.ConclusionOur results bring new insights into (genetic) mechanisms that alter APOE expression and how this affects APOE4‐related AD risk. This is crucially relevant for the development of AD drug therapies aimed at APOE4 and genetic risk counseling. Future work is needed to more precisely evaluate how haplotypes of the common APOE*2/3/4 polymorphisms and sQTLs affect AD risk.
Validation of circadian rhythm parameters derived from a user‐friendly activity monitor for long‐term continuous monitoring of brain health
Authors: Reynolds Christina L , Beattie Zachary , Au‐Yeung Wan‐Tai M , Kaye Jeffrey 
Published: December 2020

AbstractBackgroundFragmentation of sleep patterns is one of the earliest symptoms of Alzheimer’s disease and related dementias (ADRD) and is debilitating to both patients and caregivers. Interdaily stability and intradaily variability can be used to characterize the strength of an individual’s circadian rhythms. The utility of these parameters could be increased by applying this analysis to activity data collected over long periods, enabling longitudinal studies of changes in circadian rhythms as ADRD progresses.MethodActivity data was collected for seven study participants (mean age = 73 years; 2 men, 5 women) for two weeks each. Over the two week period, participants simultaneously wore an ActiGraph wGT3X‐BT actigraph at the waist and on the nondominant wrist and a Withings Activite watch also on the nondominant wrist. The Withings watch was chosen for our study because of its watch‐like form factor, low cost and long battery life (up to six months). MATLAB functions were written to calculate interdaily stability and intradaily variability from the data collected from all three devices for each participant. Interdaily stability and intradaily variability calculated from the Withings watch data were compared with the same parameters calculated using both data from the actigraph worn on the wrist and the actigraph worn on the waist.ResultEach participant contributed 144 hours of device data. High correlations were found in each of the comparison cases. For interdaily stability, the KS p‐value of correlation between the data produced by the watch and the actigraph was 0.68 for the actigraph at the waist and 0.65 at the wrist. In the case of intradaily variability, the KS p‐value was 0.86 at the waist and 0.92 at the wrist.ConclusionThese results demonstrate the validity of a user‐friendly, low cost, consumer grade activity monitor to generate standard metrics of circadian function (interdaily stability and intradaily variability) in longitudinal studies of circadian rhythms. Low cost mass‐market activity monitors can be a valuable addition to studies of life patterns because they facilitate data collection both over long periods of time and from large numbers of study participants.
Hormetic effects of galactose could be explained by rapid metabolic network disinhibition of the protective oxidative pentose phosphate pathway flux
Authors: Homolak Jan , Perhoc Ana Babic , Knezovic Ana , Barilar Jelena Osmanovic , Salkovic‐Petrisic Melita 
Published: December 2020

AbstractBackgroundLong‐term oral galactose treatment prevents and rescues cognitive deficits in rat model of Alzheimer's disease. In contrast, long‐term parenteral galactose treatment‐induced oxidative stress is used to model aging in rodents. The aim of this study was to provide new information on the effects of single acute oral galactose treatment, elucidate mechanisms responsible for both detrimental and protective effects, and explore their association with oxidative stress.MethodMale Wistar rats were acutely treated with D‐galactose (200mg/kg) by orogastric gavage and sacrificed 30, 60 or 120 minutes after the treatment. Oxidative stress, metabolic parameters and proteins of interest were analyzed by spectrophotometry, electrochemistry, western blotting, ELISA and novel method for spatiotemporal reductive analysis. Data was tested for normality and analyzed by exploratory factor analysis of mixed data. Most significant determinators of two primary components were identified and tested for group and intraexperimental differences by Wilcoxon test, intragroup and combined Pearson correlation coefficient.ResultContribution analysis identified hippocampal NADP and NADPH, oxidative stress (superoxide dismutase (SOD) activity and redox couple oxidation‐reduction potential (rcORP)) and hippocampal expression of c‐fos and cytochrome c oxidase as primary determinants of the first component, and GLP‐1 total and active fractions as determinants of the second component. Acute oral galactose treatment increased hippocampal NADP, NADPH, cytochrome c oxidase, catalase activity and lipid peroxidation. Protein sulfhydryl content, SOD activity, and c‐fos were decreased by the treatment. Total amount of reduced glutathione and rcORP remained unchanged.ConclusionAcute oral galactose treatment induced increase in oxidative stress markers with no effect on net tissue reductive potential suggests endogenous compensation of oxidative challenge. Rapid metabolic shift towards phosphorylation of nicotinamide adenine dinucleotides and decreased cellular activity points to oxidative pentose phosphate pathway disinhibition‐mediated activation of conserved protective reactive oxygen species detoxification mechanism as a potential mediator of galactose‐associated hormetic effects. This work was funded by the Croatian Science Foundation (IP‐2018‐01‐8938). Research was co‐financed by the Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience (project “Experimental and clinical research of hypoxic‐ischemic damage in perinatal and adult brain”; GA KK01.1.1.01.0007 funded by the European Union through the European Regional Development Fund).
Time from symptom onset to specialist consultation and associated factors in the assessment of dementia in a dementia clinic in Southern Brazil
Authors: Chaves Marcia L Fagundes , Tello Brunna Jaeger , Castilhos Raphael Machado 
Published: December 2020

AbstractBackgroundIn the Brazilian unified health system (SUS) most dementia cases are referred by the general practitioner to the specialist for diagnosis, which may increase complexity of the process and can cause delay for diagnosis.MethodA cross‐sectional database study with 245 dementia patients from an outpatient clinic in a tertiary university hospital in Southern Brazil was carried out to evaluate time from onset of symptoms to specialist consultation and associated factors in the assessment of dementia. The outcome variable was time from symptom onset to specialist assessment, reported by informants in the first consultation. For the analysis, participants were classified into two groups according to time for diagnostic evaluation (≤ and > 1 year; 20% x 80%). An univariate analysis was used to test the potential related factors associated with the delayed specialist assessment, and a multivariate logistic regression model was used to test association with the outcome.ResultThe mean time to theh specialist assessment was 3.3 ± 3.3 years. In the unadjusted analysis, individuals who were assessed after 1 year were diagnosed with Alzheimer’s isease, while who came before 1 year were most likely diagnosed with vascular dementia and other dementia types, had more sudden and subacute onset, neuropsychiatric symptoms at presentation, rapid progression, alcohol and antipsychotics use (p < 0.05). In the multivariate analysis, the effects of personality changes and onset presentation persisted, even controlling for other significant characteristics. The mean time to the specialist assessment was 3.3 ± 3.3 years. In the unadjusted analysis, individuals who were assessed after 1 year were mostly diagnosed with Alzheimer’s disease, while those who came before 1 year were most likely diagnosed with vascular dementia and other dementia types, had more sudden and subacute onset, more personality changes at presentation, rapid progression, and alcohol and antipsychotics use (p < 0.05). In the multivariate logistic regression, personality changes and onset presentation kept the association with time for assessment.ConclusionWe found a long time from symptoms onset to specialist assessment in the public system. Individuals with more disrupting presentations such as personality changes and a faster presentation were referred earlier.