bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detecting MCI using real‐time, ecologically valid data capture methodology: How to improve scientific rigor in digital biomarker analyses
Authors: Hong Junyuan , Kaye Jeffrey , Dodge Hiroko H , Zhou Jiayu ,   ORCATECH
Published: December 2020

AbstractBackgroundEarly identification and accurate assessment of Mild Cognitive Impairment (MCI) is critical for clinical‐trial enrichment as well as the early intervention of the neurodegenerative disease. Continuous home‐based measurements of functions using simple embedded sensors and devices could provide an opportunity to improve the sensitivity and specificity in identifying MCI subjects in the community. However, a large number of assessment data points from each individual might increase the possibility of a chance finding. Careful and creative approaches are required to confirm robustness of the findings.MethodsA total of 152 participants enrolled in the Intelligent Systems for Assessing Aging Changes Study (ISAAC) from the Oregon Center for Aging and Technology (ORCATECH) were used in the current project. In‐home monitored functional measurements including daily average walking speed, walking variability, computer usage and other functional measures were used. Each subject contributed 1372 days of data on average (SD = 662.3). In order to reflect the fact that various stages of MCI and NC are enrolled into trials in real‐world, longitudinal trajectories from each participant was sliced into small pieces, i.e., slicing windows of different sizes and used for cross‐validation. The cross‐validation was conducted on randomly permutated left‐out validation data to evaluate the performance. We also examined proportion of missingness during each slicing window and examined its impact on the ability in identifying MCI. We used various feature selection methods including F1‐score, mutual information, and chi2 to rank the effectiveness of variables. From the selected variables, we constructed different machine learning models, including logistic regression and support vector machines.ResultsModels using top‐4 features gave the best ability in differentiating MCI from NC, indicated by Receiver Operating Characteristics Area under Curve. Using slicing windows with a missing ratio higher than 30% was found to compromise the model performance. Longer subsequences have more information for modeling, but subsequences longer than a 2‐month window did not further help the performance.ConclusionsThis study proposed an approach that effectively detects MCI from in‐home monitoring measurement, which could benefit study enrichment in preclinical trails. The approaches presented could aid in improving scientific rigor of digital biomarker analyses.
Social isolation and incident dementia in Mexican elders
Authors: Sánchez Brenda Sarai Miranda , Acosta‐Castillo Gilberto Isaac , Ortiz Ana Luisa Sosa 
Published: December 2020

AbstractBackgroundSocial isolation (SI) (defined as infrequent social contact or people with limited social networks) has been association with cognitive impairment, however, some authors has argued there is not a relationship between both. In line with the World Health Organization (WHO). Dementia is a syndrome affecting memory, thinking, orientation, comprehension, judgement and so on that interfere significantly in the person’s activities of daily living and it is not a normal part of ageing. WHO, points out two in three people with dementia live in low‐and middle‐income countries like Mexico. Indeed, Dementia has a physical, psychological, social, and economic impact on people with it, but also on their families and society.MethodWe analyzed data from 1,355 adults aged 65 or over, evaluated in incidence phase of Dementia Research Group 10/66 protocols in Mexico. Dementia was evaluated according to 10/66 algorithm. Statistical analysis consisted in to compare incident dementia in both groups with and without SI considering: sex, age, education, marital status, home services, disability, depressive symptoms and feelings of loneliness as possible confounding.ResultThe incidence rate in whole sample was 32.5 cases per 1000 person‐years, in presence of SI the incidence was 36.8 cases and in absence of SI was 28.2. When we estimate the association between SI and incident dementia the incidence cumulative ratio was 1.28 and the 95% confidence interval was from 0.92 to 1.79. Also, non‐significance was shown when we adjusted for other variables of interest that previously have been reported as risk factors or predictors for dementia (e.g. age, mild cognitive impairment, neuropsychiatric symptoms, diabetes and feelings of loneliness).ConclusionThe present study didn’t find a significant relationship between SI and incident dementia. Is important to consider other conditions to improve quality of life in elders, include the social sphere such as loneliness or social support (not analyzed here). Also is important to generate new research about SI independently to know more about this phenomenal and its consequences on elders’ health.
Plasma alpha synuclein (a‐syn) as a potential biomarker of diseases with synucleinopathy
Authors: Senanarong Vorapun , Wachirutmangur Lertchai , Rattanabunnakit Chatchawan , Srivanitchapoom Prachaya , Udomphanthurak Suthipol 
Published: December 2020

AbstractBackgroundAlpha‐synuclein (a‐syn) is present in red blood cells, cerebrospinal fluid (CSF), plasma and saliva, in both monomeric and oligomeric forms. Alterations in a‐syn levels in CSF and plasma of Parkinson disease (PD) patients have claimed to be potential PD biomarkers. We explored that a‐syn in plasma was a potential biomarker for synucleinopathy diseasesMethoda‐syn levels in plasma from 54 Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) patients (28 men), 31 Alzheimer disease dementia (AD) (16 men), and 28 controls (3 men) were measured by enzyme‐linked immunosorbent assay (ELISA).ResultThe mean(SD) age of synucleinopathy group, AD group, and normal controls was 72.70(7.72), 74.26(10.37), 62(10.68) (ANOVA test, p<0.001) We showed that the 50th percentile levels of a‐syn were 9.72 ng/ml, 16.78 ng/ml, 16.75 ng/ml in synucleinopathy group, AD group, and normal controls respectively (p<0.001 by Shapiro‐Wilk test of normality in each group). Pairwise comparisons of group diagnosis revealed that between PDD+DLB vs controls: test statistic ‐16.67, SE 7.63, SD ‐2.19, p=0.03; between PDD+DLB vs AD: test statistic 17.21, SE 7.38, SD 2.33, p=0.02; and between controls vs AD: test statistic 0.63, SE 8.54, SD 0.06, p=0.95. The means plasma a‐syn levels in synucleinopathy group (n=54), AD (n=31) group, and controls (n=29) were 21.89(38.84), 38.45(47.79), 34.02(43.97) ng/ml accordingly (ANOVA test, p=0.18). The levels in synucleinopathy group were lower than those in AD and controls. There was a fair correlation between levels of plasma a‐syn and sum of UPDRS part3 (spearman correlation coefficience r=‐0.32, p=0.008) but not with cognition measured by Addenbrook scale. When eliminating the outliers, the area under the receiver operating characteristic curve (ROCwas 0.710 between PDD+DLB vs non synucleinopathy group (AD+NC) (SE=0.052, p=<0.001). At the cut off levels of 11.4 ng/ml indicated sensitivity of 58%(95%CI 43.21%‐71.81%), specificity of 84.78%(95%CI 71.13%‐93.66%), positive predictive value (PPV) of 80.56%, negative predictive value(NPV) of 65%, and accuracy of 70.83%.ConclusionThe present results suggested that plasma a‐syn could be a potential biomarker for synuclienopathy diseases.
Amyloid‐β, tau, synaptic dysfunction, neurodegeneration, glial and vascular biomarkers in the preclinical stage of the Alzheimer’s continuum
Authors: Suárez‐Calvet Marc , Milà‐Alomà Marta , Salvadó Gemma , Gispert Juan Domingo , Vilor‐Tejedor Natalia , Grau‐Rivera Oriol , Sala‐Vila Aleix , Sanchez‐Benavides Gonzalo , Arenaza‐Urquijo Eider M , Crous‐Bou Marta , González‐de‐Echávarri José Maria , Minguillón Carolina , Fauria Karine , Simon Maryline , Kollmorgen Gwen , Rodríguez‐Lantero Juan , Ashton Nicholas J , Zetterberg Henrik , Blennow Kaj , Molinuevo Jose Luis ,   the ALFA study
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) comprises a preclinical stage characterized by pathophysiological changes that occur decades before symptoms arise. Despite the importance of this stage, the biological pathways involved are not yet well understood. The main aim of this study is to define the pathophysiological processes, as measured by CSF biomarkers changes, that occur in the preclinical stage of the Alzheimer’s continuum in a finely‐characterized cohort of cognitively unimpaired individuals.MethodsWe measured a comprehensive set of CSF biomarkers that reflect different pathophysiological processes in 381 cognitively unimpaired participants aged between 49 and 73 years of the ALFA+ study (61% women; 53% APOE‐ε4 carriers; 34% Aβ positive). Specifically, we measured CSF biomarkers related to amyloid‐β (Aβ42, Aβ40) or tau (p‐tau, t‐tau) metabolism, neuronal and axonal damage (NfL), synaptic dysfunction (neurogranin), neuroinflammation (IL6, MCP1), micro‐ and astroglial markers (sTREM2, YKL40, GFAP, S100), vascular injury (sVCAM1, sICAM1), and total α‐synuclein. Measurements were performed using MSD, NeuroToolKit and Elecsys® immunoassays.ResultsWe found that CSF tau‐related (p‐tau and t‐tau) and synaptic dysfunction (neurogranin) biomarkers increase throughout ageing only in Aβ‐positive individuals. In contrast, neuronal injury (NfL), micro‐ and astroglial (sTREM2, YKL40, GFAP) and vascular (sVCAM1, sICAM1) CSF biomarkers increase with ageing both in Aβ‐positive and ‐negative individuals (Fig.1). We modelled the changes in CSF biomarkers as a function of CSF Aβ42/40 ratio, p‐tau and p‐tau/Aβ42, which were used as proxies of disease progression. We observed that the first change that occurs in the Alzheimer’s continuum is a decrease in the Aβ42/40 ratio. Shortly after this ratio becomes positive, there is a steep increase in CSF p‐tau, t‐tau, neurogranin and, to lesser extent, in CSF NfL and glial biomarkers (Fig. 2).ConclusionOur results show that multiple biological pathways are altered very early in the Alzheimer’s continuum, but differ in their association with Aβ pathology. Whereas CSF tau‐related and synaptic dysfunction biomarkers change promptly and specifically when there is underlying Aβ pathology, CSF NfL and glial biomarkers have a less pronounced and specific increase. Altogether, our results suggest that different biological pathways could be targeted during the preclinical stage of the Alzheimer’s continuum.
Cross‐cultural neuropsychological assessment in Europe: A Delphi expert study
Authors: Franzen Sanne , Nielsen Rune , van den Berg Esther , Papma Janne M. 
Published: December 2020

AbstractBackgroundPerformance on traditional neuropsychological tests is influenced by factors such as culture, language, (quality of) education, and literacy. As Europe is becoming increasingly diverse, neuropsychological assessment practices need to be adapted to these diverse populations. The aims of this study were to examine the current state of cross‐cultural neuropsychological assessment in Europe and to provide recommendations for researchers and policy makers on this topic.MethodTwelve experts from nine European countries participated in a Delphi study involving two survey rounds and a group discussion stage. The surveys consisted of open‐ended questions and importance ratings (score out of 10).ResultAcross Europe, several cross‐cultural (adaptations of) neuropsychological tests are available, as well as a limited number of initiatives for training. The main priorities that were identified were the development of tests (median importance rating 10, Q1‐Q3: 9‐10) and norms (median importance rating 9, Q1‐Q3: 8‐10), as well as training, awareness and knowledge among European neuropsychologists (median importance rating 9, Q1‐Q3: 8‐10). According to the Delphi panelists, future focus should be on tests of social cognition (median 9, Q1‐Q3: 8‐10) and language (median 9, Q1‐Q3: 7‐10), closely followed by other domains, such as executive functioning (median 8, Q1‐Q3: 8‐10).ConclusionEuropean experts agree that developing tests should be a priority, in particular tests of social cognition and language. European guidelines should be established for working with interpreters in a neuropsychological assessment. Furthermore, training needs to be improved across Europe. A list of recommendations was generated describing essential skills and knowledge necessary for cross‐cultural neuropsychological assessment.
SORL1‐variant carriers in ADES‐ADSP: A higher level of variant pathogenicity associates with earlier age at onset of Alzheimer's disease
Authors: Holstege Henne , Hulsman Marc , Charbonnier Camille , Grenier‐Boley Benjamin , Quenez Olivier , Ahmad Shahzad , Amin Najaf , van Rooij Jeroen G.J. , Grozeva Detelina , Norsworthy Penny , Hummerich Holger , Kawalia Amit , Mok Kin Y. , Shoai Maryam , Dols‐Icardo Oriol , van Der Flier Wiesje , Sims Rebecca , Amouyel Philippe , Hardy John , Clarimon Jordi , Mead Simon , van Swieten John C. , Ramirez Alfredo , van Duijn Cornelia M. , Williams Julie , Nicolas Gaël , Bellenguez Céline , Lambert Jean‐Charles ,   ADSP Consortium
Published: December 2020

AbstractBackgroundRecent reports indicated that extremely rare protein truncating or missense variants in the SORL1 gene are associated with an increased risk and possibly a causative effect on developing Alzheimer’s Disease (AD). Here, we investigated the relationship between the predicted variant pathogenicity and the age at AD onset (a.a.o.) in the largest whole exome sequencing (WES) dataset of AD cases and controls world‐wide.MethodWe combined sequencing data from the ADES and ADSP consortia on a single server. After quality control and exclusion of carriers of pathogenic variants in genes associated with Mendelian inheritance of AD, 12,675 AD cases and 8,693 controls were available for analysis. Non‐synonymous variants were scored using the REVEL algorithm, and loss‐of‐function (LOF) variants were predicted using LOFTEE. The variant‐burden was determined across all genes and odds ratios (OR) for AD‐status were calculated using a multinomial logistic test across age groups.ResultOf all genes in the genome, rare variants in the SORL1 gene had the strongest association with AD (p = 6.4 × 10−14). We identified 320 rare nonsynonymous missense and loss‐of‐function SORL1 variants (MAF<1 × 10−4). The carrier frequency in AD cases with a.a.o. <65, a.a.o. >65 and cognitively healthy controls was respectively 1.9%, 1.3%, 0.7%. Carrying a SORL1 variant associated with an increased risk of early onset AD (Figure A). Specifically, carriers of LOF variants had a median a.a.o. of 63 years (Figure C), and this associated with a 24.8‐fold increased chance of developing AD before 65 years compared to non‐carriers (Figure B). The median a.a.o. for carriers of nonsynonymous variants with REVEL>75 was 70 years, and such variants associated with estimated 7.6‐fold increased risk of developing AD between 65‐70 years (Figure B). Variants with lower REVEL scores associated with a lower AD‐risk.ConclusionThe abundance of predicted pathogenic SORL1 genetic variants and the profound effect on AD risk makes the SORL1 protein product a promising target for the design of selective treatment strategies for affected individuals. Further, our results open the discussion of whether and how AD‐affected SORL1‐variant carriers and their (presymptomatic) family‐members should be clinically counselled. For this, pathogenicity screens that distinguish between pathogenic and non‐pathogenic non‐synonymous variants are warranted.
AHEAD 3‐45 study design: A global study to evaluate the efficacy and safety of treatment with BAN2401 for 216 weeks in preclinical Alzheimer’s disease with intermediate amyloid (A3 trial) and elevated amyloid (A45 trial)
Authors: Aisen Paul S. , Zhou Jin , Irizarry Michael C. , Kramer Lynn D , Swanson Chad J. , Dhadda Shobha , Rabe Martin , Krause Stephen , Li David JianJun , Raman Rema , Donohue Michael C. , Sethuraman Gopalan , Johnson Keith A. , Sperling Reisa A. 
Published: December 2020

AbstractBackgroundAβ pathologies occur years prior to cortical tauopathy, neurodegeneration, and clinical symptoms. BAN2401 is a humanized immunoglobulin G1 monoclonal antibody that selectively binds to soluble Aβ aggregated species (oligomers, protofibrils). BAN2401 reduced amyloid on PET and slowed cognitive decline in a Phase 2 study in early symptomatic AD. The AHEAD 3‐45 study will test the safety and efficacy of BAN2401 even earlier in the AD continuum.MethodAHEAD 3‐45 consists of two trials (A3 Trial and A45 Trial) under a single protocol and screening process, common schedule of assessments, and distinct dosing regimens tailored to the baseline amyloid level. The study is a Public‐Private Partnership of the Alzheimer’s Clinical Trial Consortium (ACTC), National Institutes of Health (NIH), and Eisai, Inc. The A3 Trial will enroll cognitively normal individuals (CN) with intermediate amyloid (approximately 20‐40 centiloids), at risk for further amyloid accumulation and development of neurofibrillary tangles on tau PET over four years. Approximately 400 participants will be randomized 1:1 to placebo or BAN2401 infusion—8 weeks of titration followed by 10 mg/kg every four weeks for 216 weeks. The A45 Trial will enroll CN individuals with elevated amyloid, defined as amyloid PET approximately >40 centiloids, at risk for cognitive decline over four years. Approximately 1000 participants will be randomized 1:1 to placebo or BAN2401 infusion—8 weeks of biweekly titration dosing, then 10 mg/kg biweekly induction dosing through 96 weeks to clear aggregated Ab, followed by 10 mg/kg every four weeks maintenance dosing through 216 weeks to prevent reaccumulation of Aβ.ResultLongitudinal cognitive, safety, amyloid and tau PET, MRI and fluid biomarker assessments will be performed. The primary outcome of the A3 Trial is prevention of brain amyloid accumulation by amyloid PET at 216 weeks, with delay of tau PET accumulation as a key secondary outcome. The primary outcome measure of the A45 Trial is the Preclinical Alzheimer’s Disease Cognitive Composite 5 (PACC5) scale at 216 weeks.ConclusionThe AHEAD 3‐45 Study will test whether BAN2401 can prevent the accumulation and spread of Aβ deposition, downstream tau pathology, and cognitive decline in at‐risk cognitively normal individuals prior to significant irreversible neurodegeneration.
Impact of mild head injury on diffusion MRI brain characteristics in midlife: Data from the PREVENT Dementia Study
Authors: Raymont Vanessa , O'Donoghue M Clare , Mak Elijah , Dounavi Maria‐Eleni , Su Li , MacKay Clare , O'Brien John T , Ritchie Craig W 
Published: December 2020

AbstractBackgroundTraumatic brain injury (TBI) has been associated with an increased risk of dementia, but the link between mild TBI across the life‐course remains unclear. The PREVENT Dementia study is recruiting healthy volunteers in middle age (aged 40 – 59) to identify factors that may increase their risk of dementia. This analysis assessed white matter integrity and its association with the incidence, frequency and severity of TBIs.Methods140 subjects (mean age=51.9 years) from the PREVENT Dementia study West London site underwent a 3T MRI scan, including diffusion‐weighted (DW) imaging, and completed the self‐report Brain Injury Screening Questionnaire (BISQ). DW images were processed using FSL tools (EDDY, DTIFIT, TBSS) and resulting fractional anisotropy (FA) and mean diffusivity (MD) spatial maps were fed into voxelwise cross‐subject analysis (FWE‐corrected at p<0.05). BISQ summary scores were used as regressors in cross‐subject analyses to test the effect on WM integrity of a) no TBI (N=29) vs. any TBI (N=107), b) number of TBIs, and c) severity of TBIs. Gender, years of education, NART score, presence of psychiatric diagnoses and substance abuse were included as covariates. One participant with severe TBI (BISQ severity=6) and three participants with moderate TBI (BISQ severity=4) were excluded from analyses.ResultsHigher FA was observed in bilateral body of the corpus callosum, superior corona radiata and forceps minor in those that reported at least one TBI compared to those that had none. There was no effect of this on MD. There was no significant association of the number of TBIs with either FA or MD. However, increased severity of TBI was significantly associated with higher FA in similar regions showing an effect of any vs. no TBI. Increased severity of TBI was also significantly associated with lower MD in the same regions.ConclusionsIt is unclear if higher FA reflects a mechanism of recovery post‐TBI or the injury itself. We plan to analyse a larger sample, as this sub‐group may not be representative, and include other possible confounders, such as cognition and age of and time since injury, to explore what these results may infer about mild TBI and dementia risk.
Assessment of intracranial vascular flow oscillations in Alzheimer’s disease using real time 4D flow MRI
Authors: Rivera Leonardo A , Eisenmenger Laura , Cary Paul , Johnson Sterling C. , Johnson Kevin M 
Published: December 2020

AbstractBackgroundRecent models suggest clearance of soluble metabolites from the brain can be driven by low frequency flow oscillations (LFO) of vascular smooth muscle cells through the intramural periarterial drainage (IPAD) pathway. This work derives LFO from measures of blood flow variance using real time 4D flow MRI in the intracranial arteries of clinically diagnosed Alzheimer’s disease (AD) subjects.MethodsSubjects: Study groups are summarized in Figure 1. The APOE4+,FH+ group consisted of healthy late middle‐aged subjects with both APOE ε4 allele and parental family history of AD dementia positive. MRI: Volumetric, time‐resolved 4D flow MRI data were acquired on a 3.0T system (MR750, GE Healthcare) using a 32‐channel head coil (GE Healthcare). Images were reconstructed to a spatial resolution of 1.38mm isotropic and a temporal resolution of 4.3sec (scan time=7.1min). To evaluate the ability of 4D flow to distinguish physiologic flow changes from noise, healthy volunteers were scanned during a scan with breath‐holds (BH). LFO analysis: Flow waveforms in the internal carotid artery (ICA) and superior sagittal sinus (SSS) were recorded from the dynamic data. To quantify LFO demeaned temporal flow changes and standard deviations were calculated. Global atrophy was estimated as the ratio of CSF volume to brain volume. Group differences were assessed using ANOVA followed by Tukey‐Kramer method for pairwise comparison for adjusted means (P<0.05).ResultsFigure 2 shows an example of flow curves from a young volunteer during free breathing and a scan with BHs. Flow variance increased during the BH scan. The ICA flow variance normalized to the intracranial volume (ICV) and global atrophy, and ICA blood flow ranges were significantly larger in age‐matched controls compared to AD (P=0.025, P=0.024, P=0.004) (Figures 3&4). LFO from demeaned flow profiles are shown in Figure 5 for all subjects. The LFO in age‐matched controls were noticeable larger than in AD subjects. Finally, average flow rates in age‐matched controls were significantly larger than in AD subjects in the ICA (P=0.034) (Figure 6).ConclusionsSignificantly higher LFO, as measured by standard deviations, are measurable in age‐matched controls when compared to AD subjects suggesting decreased vascular compliance and vasomotion in AD.