bluuebunny/crossref_metadata_2025_split huggingface dataset:
A pilot study on Alzheimer’s disease‐related biological and cognitive markers in dementia and history of mild traumatic brain injury
Authors: LoBue Christian , Champagne Patricia , Munro Catherine E , Womack Kyle B , Kelley Brendan , Abdullah Kalil , Cullum Munro 
Published: December 2020

AbstractBackgroundMild traumatic brain injury (mTBI) has been associated with a higher risk for developing dementia later in life. Several mechanisms have been proposed, with most relating to TBI accelerating AD‐linked pathological changes or decreasing neuronal and/or cognitive reserve. The purpose of this study was to compare AD‐linked biomarkers and measures of neuronal and cognitive functioning in AD participants with and without a history of mTBI.MethodThe Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset was used to identify participants with dementia due to AD and a history of mTBI (n = 10),compared with a group of AD patients without TBI (n = 20) similar in gender, age (±5 years), education (± 3 years), and apolipoprotein ε4 status. Baseline cerebrospinal fluid (CSF)‐derived markers of amyloid and tau, and FDG PET glucose metabolism for three regions of interest (angular, temporal, and posterior cingulate), along with neuropsychological measures (i.e., Alzheimer’s Disease Assessment Scale–Cognitive Subscale 13 items, Rey Verbal Learning Test, Wechsler Memory Scale Logical Memory, Trail Making Test), were compared between groups.ResultAD mTBI and control groups did not significantly differ in glucose metabolism using PET across regions often reduced in AD (p=0.53). CSF‐derived markers of amyloid formation also did not differ between the groups (p=0.76), though interestingly, there was a trend for higher phosphorylated tau (p=0.07) and total tau (0.08) markers in the mTBI group (Mptau=41.0, SD=15.0; Mttau=409.9, SD=133.7) relative to the control group (Mptau=31.5, SD=9.8; Mttau=319.5, SD=93.4). The groups were similar across neuropsychological measures (p’s=0.16 – 0.90).ConclusionA history of mTBI was not associated with greater markers of amyloid formation, lower cerebral glucose metabolism, or worse cognitive functioning in those with AD dementia. While not statistically significant, AD participants with mTBI did have a trend for higher tau levels compared to those with no history of TBI in this preliminary study. The findings may indicate a link between mTBI and greater accumulation of tau in some individuals that needs further evaluation in future studies with larger samples.
Amyloid BETA‐42 peptides facilitate the entry of gastrointestinal tract microbiome‐derived lipopolysaccharide into human neurons
Authors: Lukiw Walter J. , Li Wenhong , Bond Taylor , Zhao Yuhai 
Published: December 2020

AbstractBackgroundLipopolysaccharide (LPS) derived from the human gastrointestinal (GI)‐tract microbiome: (i) has been recently shown to target, accumulate within, and eventually encapsulate neuronal nuclei of the human central nervous system (CNS) in Alzheimer’s disease (AD) brain; and (ii) recent evidence indicates that this action appears to restrict the outward flow of genetic information from neuronal nuclei. It has previously been shown that in LPS‐encased neuronal nuclei in AD brain there is a specific disruption in the output and expression of two AD‐relevant, neuron‐specific markers encoding the cytoskeletal neurofilament light (NF‐L) chain protein and the synaptic phosphoprotein synapsin‐1 (SYN1) involved in the regulation of neurotransmitter release. The biophysical mechanisms involved in the facilitation of the targeting of LPS to neuronal cells and nuclei, and eventual nuclear envelopment and functional disruption are not entirely clear.MethodIsolation of lipopolysaccharide (LPS), bacterial amyloid(s), enterotoxin(s) and small non‐coding RNAs (sncRNAs) from Gram‐negative anaerobic bacilli of the human gastrointestinal (GI) tract; isolation of human temporal lobe neocortical, hippocampal and retinal tissues; aging 5xFAD (amyloid over‐expressing; C57BL6 background); RNA sequencing; LED Northern dot blots; Western analysis, immunocytochemistry; biostatistics, bioinformaticsResultIn this presentation we will (i) provide novel evidence in human neuronal‐glial (HNG) cells in primary co‐culture that the incubation of LPS with amyloid‐beta 42 (Aβ42) peptides facilitates the association of lipoglycans such as LPS with neuronal cells; and (ii) that a similar phenomenon is observed in the brains of 5xFAD transgenic mice, an amyloid over‐expressing transgenic model of AD as well as in AD‐affected neocortex and hippocampal CA1.ConclusionThese novel findings: (i) support a novel pathogenic role for Aβ42 peptides in neurons via the formation of pores across the nuclear membrane and/or a significant biophysical disruption of the neuronal nuclear envelope; and (ii) advance the concept that the Aβ42 peptide‐facilitated entry of LPS into brain neurons, accession of neuronal nuclei, and down‐regulation of neuron‐specific components such as NF‐L and SYN1 may contribute significantly to neuropathological deficits as are characteristically observed in AD‐affected brain.
Gene‐ and age‐informed enrichment method for preclinical Alzheimer’s disease trials: Approach and estimated cost savings
Authors: Spencer Barbara E. , Digma Leonardino A. , Jennings Robin G. , Brewer James B. 
Published: December 2020

AbstractBackgroundElevated β‐amyloid (Aβ) is used to enroll clinically normal (CN) individuals in preclinical Alzheimer’s disease (AD) trials, but the screening process is inefficient and expensive. Novel enrichment methods are needed to improve efficiency of enrollment of these individuals while reducing costs. We hypothesized that by combining a polygenic hazard score (PHS) and age‐specific risk for AD we could predict elevated Aβ in CN individuals.MethodAD incidence rates and each participant’s PHS were used to adjust the participant’s chronological age based on protective or deleterious genetic factors, thus creating an ADAge. An individual’s ADAge is defined as the chronological age at which there is equivalent AD risk in the population. Meng’s test was used in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort to assess whether the ADAge was more correlated with Aβ than was chronological age. An ADAge cutpoint was chosen to optimally predict Aβ positivity among 306 CN participants from the ADNI and applied to 1000 bootstrap samples of an independent validation cohort of 80 CN participants from the UC San Diego Shiley‐Marcos Alzheimer’s Disease Research Center. The differences in means between samples enrolled by each strategy (ADAge enrichment vs no enrichment) were calculated to determine the efficiency of ADAge‐informed Aβ screening for preclinical AD trials as well as to determine the impact of ADAge enrichment on trial population demographics. The screening cost for enrolling 1000 Aβ+ CN participants in a clinical trial using each enrollment strategy was compared.ResultCompared to chronological age, ADAge was more correlated with Florbetapir SUVR in the ADNI cohort (p < .001). In the validation cohort, the ADAge‐enriched sample had a higher proportion of individuals with elevated Aβ (difference[95% CI] 0.19[0.07–0.33]) than the unenriched sample. The ADAge‐enriched sample was older than the unenriched sample (difference 3.00[0.94 – 5.22]). However, the samples were similar in the proportion of APOE ε4 carriers, the dementia rating scale score, and the proportion of female participants. ADAge enrichment lowered screening costs by $5.3 million (34%) in a clinical trial scenario.ConclusionADAge enrichment provides for a more efficient and cost‐effective means to enroll CN individuals with elevated Aβ in clinical trials.
A systematic overview of evidence for cognition‐oriented treatments in older persons
Authors: Gavelin Hanna Malmberg , Lampit Amit , Hallock Harry , Sabatés Julieta , Bahar‐Fuchs Alex 
Published: December 2020

AbstractBackgroundCognition‐oriented treatments (COTs) – commonly categorized as cognitive training, cognitive rehabilitation and cognitive stimulation – are promising approaches for the prevention of cognitive and functional decline in older people. We conducted the first systematic overview of meta‐analyses investigating the efficacy of COTs on cognitive and non‐cognitive outcomes in older people with or without cognitive impairment. This presentation will describe the methodology, main findings, and implications from this overview and provide future directions for research and research synthesis in the field.MethodWe conducted a systematic search to identify eligible reviews. Study characteristics, methodology and reported effect estimates were extracted and review quality assessed by two independent reviewers using AMSTAR 2. The effect estimates were summarized graphically to provide an overview of the available evidence across the different populations, interventions and outcomes. Meta‐regression was used to investigate the moderating effect of methodological variables on the overall effect estimate of cognitive outcomes.ResultThe search yielded 51 eligible reviews, 46 of which were included in the quantitative synthesis. The confidence ratings were “moderate” for 9 (20%), “low” for 13 (28%) and “critically low” for 24 (52%) of the 46 reviews. While most studies provided pooled effect estimates for objectively measured cognition, non‐cognitive outcomes of potential relevance to patients and caregivers, such as clinical or functional status and caregiver burden, were more sparsely reported. The mean effect estimate on cognition was small for cognitive training in healthy older adults (Hedge’s g 0.32, range 0.13‐0.64, 19 reviews), mild cognitive impairment (Hedge’s g 0.40, range 0.32‐0.60, five reviews), and dementia (Hedge’s g 0.38, range 0.09‐1.16, seven reviews), and small for cognitive stimulation in dementia (Hedge’s g 0.36, range 0.26‐0.44, five reviews). Meta‐regression revealed that higher AMSTAR score was associated with larger effect estimates for cognitive outcomes.ConclusionThe available evidence supports the efficacy of COTs in improving cognitive performance in older people with and without cognitive decline. The extent to which such effects are of clinical value remains unclear, due to the scarcity of high‐quality evidence and heterogeneity in reported findings. For meta‐analyses in the field, there is a need for better adherence to methodological standards.
Novel mechanism underlying the APOE ε2 protective effect for Alzheimer disease implicated by integrative genome and transcriptome analysis
Authors: Panitch Rebecca , Zhu Congcong , Hu Junming , Chung Jaeyoon , Stein Thor D. , Farrer Lindsay A. , Jun Gyungah R. 
Published: December 2020

AbstractBackgroundThe APOE ε4 allele is the strongest genetic risk factor for late onset Alzheimer disease (AD) and the ε2 allele is known to mitigate risk of AD. While potential mechanisms accounting for AD risk associated with ε4 have been extensively studied, the mechanism underlying the protective effect of ε2 is largely unknown.MethodsWe evaluated transcriptome‐wide (TW) differential gene expression (DGE) analysis in autopsied brains from 568 participants (339 AD, 229 controls) of the Religious Orders Study and Memory and Aging Project (ROSMAP), 162 subjects (82 AD, 80 controls) in the Mayo Clinic Study of Aging (MAYO), and 193 participants combined from the Framingham Heart Study and Boston University Alzheimer’s Disease Center (FHS/BUADC:64 AD, 129 controls). Results were combined across datasets by meta‐analysis. Analyses were focused on APOE 2/3 (E23) persons including 42 AD cases and 72 controls. The TW significance level was set at p < 10−6. Co‐expressed gene‐networks were created separately in AD cases and controls using Weighted Co‐expression Network Analysis. To validate AD enriched networks, we conducted gene enrichment analysis using lists from our top ranked DEGs and AD genes from a recent genome‐wide association study by Kunkle et al. In addition, we tested association of expression profiles from the top‐ranked DEGs with neuropathological traits in ROSMAP and FHS/BUADC.Results
C4A (P = 1.9 × 10−5), GFAP (P = 3.8 × 10−5), and C4B (P = 4.8 × 10−5) were the most significant DEGs in the E23 group and TW significant in the total sample. The top‐ranked co‐expressed gene‐network in the E23 AD cases contained complement pathway genes such as C4A, C4B, and CR1, with significant enrichment for DEGs from the E23 subgroup (P = 0.05), DEGs from the total sample (P = 4.3 × 10−32), and known AD risk genes (P = 1.2 × 10−5). In FHS/BUADC, C4A expression was significantly associated with increased pTau181/tTau ratio (P = 0.01) and pTau231/tTau ratio (P = 1.0 × 10−5).ConclusionThe complement pathway was previously implicated in AD, but to our knowledge this is the first biological link between APOE ε2 and the complement pathway. Together with a recent study showing direct binding between ApoE and C1q, our findings suggest that further studies of the interaction of APOE ε2 with complement pathway genes may lead to novel therapeutic targets for AD.
Quantifying what matters most to patients and care partners in Alzheimer's disease
Authors: Hauber Brett , Paulsen Russ , Callahan Leigh F. , Potashman Michele , Lee Daniel , Hartry Ann , Wunderlich Glen , Hoffman Deborah , Wieberg Dan , Kremer Ian N. , DiBenedetti Dana B. 
Published: December 2020

AbstractBackgroundThe Alzheimer's Disease Patient and Caregiver Engagement (AD PACE) Initiative works to identify and measure treatment‐related needs, preferences, and priorities of individuals across the continuum of AD. In the What Matters Most (WMM) study, we identified concepts of interest among patients and care partners and derived 42 items from these concepts.MethodRespondents were recruited primarily from US clinical sites and assigned by a clinician to one of five groups: (1) AD risk factors without subjective memory complaints (SMC), (2) AD risk factors and SMC, and (3) mild AD, and care partners of patients with (4) moderate AD or (5) severe AD. Survey was administered online. Items were individually rated using a 5‐point verbal rating scale from 1 (Not at all important) to 5 (Extremely important). Responses were analyzed by group. Care partners (groups 4 and 5) rated item importance for themselves, not as patient proxies.ResultTwo hundred seventy‐four respondents (50‐65 in each group) completed the survey. Among all respondents, 193 (70.4%) were female, 173 (63.1%) identified as white, and 221 (80.7%) had education beyond high school. Among the three patient groups, the minimum (maximum) mean importance rating for any item was 3.4 (4.6) indicating all items were at least moderately to very important. Among care partners of patients with more severe AD, the minimum (maximum) mean importance rating was 2.1 (4.4); most items were rated as at least moderately important. One item (driving) was rated as less than a little important in group 5. Five items were among the most important for all groups: taking medications correctly, not feeling down or depressed, not feeling anxious, worried or stressed, being able to stay safe, not feeling like a burden to others.ConclusionFor SMC and mild AD patients and those at risk for AD, all items were important. Among care partners of more severe patients, most items were important, and one was unimportant. These results may indicate that the 42 items in the WMM survey capture symptoms and behaviors that are meaningful to patients and care partners and should be considered when evaluating impacts of potential AD treatments.
Māori Assessment of Neuropsychological Abilities (MANA): A cognitive, functional and wellbeing screening tool for dementia in older Māori
Authors: Dudley Makarena Diana 
Published: December 2020

AbstractBackgroundIn New Zealand (NZ) in 2013, 5.4% of Māori (the Indigenous people of NZ) were over the age of 65 years and in the last decade the number of Māori kaumātua (elderly) living beyond the age of 80 years has more than doubled. This increase is likely to be accompanied by increases in the prevalence of dementia for Māori. In 2011, 1,928 Māori were estimated to have dementia and is expected to increase to 4,493 by 2026, although numbers are likely to be much higher because many with dementia remain undiagnosed. Cognitive screening and assessment tools commonly used in the diagnosis of dementia in NZ have not been validated on Māori despite these tools having poor specificity and sensitivity when applied to people from culturally and linguistically diverse backgrounds. Cultural bias in cognitive testing has been well established in the international literature and reiterated in studies conducted with Māori. The authors therefore developed the Māori Assessment of Neuropsychological Abilities (MANA) to address this disparity.MethodTwo hundred and fifty kaumātua representing all the major Māori tribes were interviewed in focus‐group settings about their understandings and experiences of dementia. A team, comprised of Māori and non‐Māori specialists in dementia, neuropsychology, and biostatistics in collaboration with Māori health researchers, Māori elders, and Māori dementia health workers, identified information from the data that paired with those domains commonly assessed for dementia in NZ. This data was then applied to develop a dementia screening tool for Māori consisting of a cognitive, functional and wellbeing interview schedule. We are conducting a Pilot study, N=40 in 2020 to test item content and relevance, scoring criteria, adequacy of floor and ceiling effects, clarity of instructions, and administration procedures. Receiver‐operating characteristic (ROC) curve analysis will also be used to determine the predictive accuracy of the assessment tools and to identify the best cut‐ off points for detecting cognitive and functional impairments.ResultWe will present preliminary results of the pilot study.ConclusionWe hypothesise that a culturally validated and appropriate screening tool will provide improved accuracy in the diagnosis of dementia in Māori.
Functional characterizations of APP VAL604MET by CRISPR/CAS9
Authors: Kim Danyeong , Shim KyuHwan , Van Vo Giau , Bagyinszky Eva , An Seong Soo 
Published: December 2020

AbstractBackgroundMany variants near the amyloid‐beta peptide (Aβ) of Amyloid Precursor Protein (APP) gene were reported major pathogenic mutations in Alzheimer's disease (AD), especially in early‐onset Alzheimer's disease (EOAD). Even though several mutations were investigated for the functional studies with cell and animal models, larger number of mutations were not investigated for the verification of the AD pathology. Previously, APP V604M was found from a EOAD patient with family history from Thailand. Since APP V604M was located outside of the Ab region, its causal pathogenic relationship could be questioned. In this study, APP V604M was introduced to a HEK293 cell line with CRISPR/Cas9 technology for the clarification of the functional pathogenicity.MethodThe guide RNA (gRNA) of APP V604M was introduced to a HEK293 cell line with CRISPR/Cas9 technology as previously reported. In CRISPR/Cas9, gRNA and donor DNA were designed for the APP V604M mutation and used to transfect HEK293 cells with Cas9 protein. The functional study of APP V604M was conducted using Aβ ELISA test. Aβ oligomers were measured by the Multimer Detection System (MDS).ResultTransfection of APP V604M was confirmed using restriction enzymes. The mutation was identified by Sanger sequencing after single cell isolation. Next, the effects of the mutation were examined with gamma‐secretase activity, Aβ 42 productions and the presence of Aβ oligomers. MDS result showed the elevated levels of Aβ oligomers in APP V604M cells than the control, suggesting the mutation could be pathogenic. Additional biomarker results of gamma‐secretase activity and Aβ42 productions will be presented.ConclusionTransfection with CRISPR/Cas9 technology could help in understanding the pathogenicity of a mutation. APP V604M in HEK 293 was produced and biomarker study supported the pathogenicity.
Detecting cortical signatures of suspected non‐amyloid pathology using large harmonized datasets
Authors: Rane Swati 
Published: December 2020

AbstractBackgroundSuspected non‐amyloid pathology (SNAP) MCI individuals constitute 7‐25% of the total MCI group and have a high risk of progression to AD. They are categorized by low amyloid accumulation but significant neurodegeneration as A‐T+[N] as opposed to A‐T‐[N] MCI individuals who have neither a high amyloid burden nor neurodegeneration. The low prevalence of SNAP makes it difficult to evaluate robust biomarkers for this group. In this work we leverage the GAAIN platform to harmonize anatomical imaging data from multiple repositories across the world to determine and compare cortical thickness differences and longitudinal rates of atrophy in SNAP‐MCI and A+T+[N] MCI groups.MethodADNI, EDSD, ARWiBo, and PharmaCog databases were queried using the GAAIN platform for individuals with T1 imaging and AD biomarker status. A total of 218 A+T+[N] MCI individuals, and 107 A‐T+[N] SNAP MCI individuals were identified. Cross‐ sectional differences in cortical thickness was evaluated using FreeSurfer. The differences were re‐evaluated following harmonization to remove any site related systematic differences. Next, longitudinal rates of atrophy were computed using FreeSurfer using the 2‐step model and a cluster wise threshold of p=0.05 with multiple comparisons correction using family‐wise error. Longitudinal data was available in 18 NC, 137 MCI, and 34 SNAP subjects. All comparisons were adjusted for age and gender.ResultBefore harmonizing across site‐related differences, cross‐sectionally, MCI individuals have lower cortical thickness with age in the superior frontal gyrus, caudal middle frontal gyrus, rostral middle frontal gyrus, precentral gyrus, and postcentral gyrus (Figure 1). The SNAP‐MCI individuals only had lower cortical thickness with age in the superior temporal gyrus and precentral gyrus. No group differences were observed. After harmonization, there was minimal difference in outcome. Comparing longitudinal rate of atrophy SNAP‐MCI individuals had a faster rate of atrophy in the superior and medial frontal gyri (Figure 2).ConclusionWe did not find cortical thickness differences between MCI and SNAP individuals. We however show that MCI subjects have more widespread cortical thinning with age compared to SNAP‐MCI subjects. Comparing longitudinal rates of cortical atrophy, SNAP‐MCI individuals have faster rates of atrophy than MCI individuals in the frontal cortex.