bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overview of immune system in AD
Authors: Heneka Michael T. 
Published: December 2020

AbstractBackgroundThe accumulation of neurotoxic amyloid beta peptides along with neurofibrillary tangle formation are key pathological hallmarks of Alzheimer’s disease. The brain has been considered as an immune‐privileged organ, however, increasing evidence from translational, genetic, and pathological studies suggests that activation of distinct innate immune pathways are a third important disease hallmark which, once initiated, actively contributes to disease progression and chronicity.MethodRepresenting the innate immune system, microglial cells play a pivotal role in this immune response and are activated by binding of aggregated proteins or aberrant nucleic acids to pattern recognition receptors. This immune activation leads to the release of inflammatory mediators, but also distracts microglia cells from their physiological functions and tasks, including debris clearance and trophic factor support. Likewise, the adaptive immune system shows changes that suggest that it actively contributes to the immune processes that are ongoing in the brain during the entire disease trajectory.ResultSeveral lines of evidence suggest that immune processes may have protective as well as detrimental consequences. The precise molecular, spatial and temporal characterization of these immune processes will be necessary in order to develop new diagnostics as well as therapeutic interventions.ConclusionAn overview of the current understanding of immune mechanisms in AD, their link to the microbiome, as well as open questions will be outlined and discussed.
Cell‐type specific eQTLs (ct‐eQTLs) associated with Alzheimer disease in blood and brain tissue
Authors: Patel Devanshi , Zhang Xiaoling , Farrer Lindsay A. 
Published: December 2020

AbstractBackgroundExpression quantitative trait locus(eQTL) analysis has demonstrated that changes in gene expression play a role in Alzheimer disease(AD) pathogenesis. Regulation of gene expression is dependent on context such as tissue and cell‐type. Previous studies found monocyte‐specific eQTLs among AD variants.MethodCis‐eQTL mapping was performed for 723 genes located within 1 Mb of 79 AD‐associated loci in RNA‐seq data in blood from Framingham Heart Study (FHS) participants and in brain tissue from Religious Orders Study/Memory & Aging Project(ROSMAP) participants. The association of gene expression with genotypes for all cis SNPs within these genes was evaluated using linear regression models for ROSMAP and linear mixed models adjusting for family structure in FHS. Models testing associations with cell type‐specific eQTLs (ct‐eQTLs) included an interaction term for expression of “proxy” genes that discriminate the particular cell type.ResultA total of 10,970 eQTLs and 1,324 ct‐eQTLs in brain, and 29,508 eQTLs and 2,313 ct‐eQTLs in blood were nominally significant after Bonferroni correction. Ct‐eQTL analysis identified 964 and 44 significant gene‐SNP eQTL pairs in brain and blood, respectively, that were not detected in generic eQTL analysis. Of note, 760 gene‐SNP eQTL pairs were shared between blood and brain and are enriched in AD‐related immune pathways. Among the significant ct‐eQTLs, the most frequent cell types were interferon response/antibacterial cells in blood(70.6%) and endothelial cells in brain(35.5%). Established AD genes CD2AP and NCR2 had a large number of significant eQTLs in NK/ CD8+T cells in blood and brain endothelial cells respectively. In addition, several significant eSNPs were observed for novel genes under linkage analysis peaks spanning multiple genes. The eGene target for one of these AD peak eSNPs, rs2985987, is COG3 is involved in ER‐Golgi transport, a key AD‐related pathway. Furthermore, many novel variants and genes were identified among the significant eQTLs that target previously associated AD genes or associate with AD peak SNPs. Target eGenes associated with AD peak eSNPs include TAS2R60, PILRB, CNN2‐ previously implicated in AD in a targeted gene sequencing study in African Americans, HLA‐DQA2, and MS4A5.ConclusionWe identified novel AD‐related ct‐eQTLs that highlight the importance of cell‐type specific analysis and cell‐type dependent context.
A scoping review of dementia caregiving for Korean Americans and recommendations for future research
Authors: Park Van Ta , Ly Quyen , von Oppenfeld Julia , Joo Yoonmee , Shin Hye‐Won , Rhee YongJoo , Park Linda G 
Published: December 2020

AbstractBackgroundAlzheimer’s disease and related dementias (ADRD) unpaid caregivers experience significant caregiver burden with physical/mental health and financial issues. In the United States (U.S.), there is limited ADRD research among Asian Americans, who are the fastest growing racial group of older persons. Older Korean Americans (KA), specifically have unique additional dementia caregiving needs with language and cultural barriers. We conducted a scoping review of the published literature on dementia caregiving among KA, and provide recommendations on potential future intervention research to help address this research gap for an underserved U.S. population.MethodA comprehensive electronic search was conducted within multiple databases (PubMed, CINAHL, Web of Science, Embase, PsycINFO, and Proquest) by two independent reviewers for qualitative and quantitative papers that were published from 01/01/00‐06/30/19. The review’s inclusion criteria included: focus/inclusion of KA ADRD caregivers; caregiving interventions/programs; qualitative and/or quantitative primary research papers; study outcomes focused on caregivers’ health/burden/use of services; and published in English. Two additional reviewers confirmed the inclusion of the selected papers.ResultsThe search yielded 843 publications; data were extracted from 17 eligible studies (8 quantitative and 9 qualitative) following the Arksey and O’Malley framework. Quantitative studies included cross‐sectional surveys. Qualitative studies included focus groups and interviews. The scoping review revealed that the majority of KA caregivers were wives, daughters, and daughters‐in‐law. KA caregivers often experience stress, anxiety, depression, and burden outcomes associated with caregiving. Social support and familism were found to be two of the most important factors that determine KA caregivers’ attitudes toward caregiving. The most commonly reported barriers to utilizing public services including limited ADRD knowledge, language barriers, stigma, and desire to care for their family at home. Challenges in finding culturally relevant resources are common among KA caregivers.ConclusionSome research about KA dementia caregiving exist, but none that were intervention‐based for caregivers. Future intervention research for KA dementia caregivers should focus on culturally appropriate resources in health, social services, and education. Dementia caregiving is a significant public health problem facing our diverse nation that warrants the development and provision of targeted culturally appropriate programs for underserved populations such as KA.
Identification and characterization of immune‐focused therapeutic targets in the MODEL‐AD and TREAT‐AD consortia
Authors: Lamb Bruce T. , Palkowitz Alan David , Howell Gareth , Carter Gregory W. , Territo Paul R. , Oblak Adrian L. , Rizzo Stacey J. Sukoff , Sasner Michael 
Published: December 2020

AbstractBackgroundDespite considerable efforts, the development of amyloid and tau focused therapies has thus far not yielded compelling positive results in Alzheimer’s disease (AD) clinical trials. In an effort to identify and characterize additional, novel animal models and therapeutic targets for AD, the NIA has funded the Model Organism and Development and Evaluation for Late onset AD (MODEL‐AD) and the Target Enablement to Accelerate Therapy Development for AD (TREAT‐AD) consortia and many of the animal models and therapeutic targets are focused on immune pathwaysMethodThe MODEL‐AD consortium has been generating and characterizing novel animal models of late‐onset AD and performing pre‐clinical testing in a subset of models. The recently funded TREAT‐AD consortium seeks to identify and characterize novel therapeutic targets initially focusing on targets nominated by the Accelerating Medicines Partnership for AD (AMP‐AD). The IU/JAX/Pitt AD Precision Models Center (ADPMC) and the IUSM/Purdue AD Drug Discovery Center (ADDDC) part of the MODEL‐AD and TREAT‐AD consortia, respectively, have focused on immune models and targets to accelerate their development as potential therapies for AD.ResultThe IU/JAX/PITT ADPMC has utilized genetic and systems biology data from many of the large AD consortia to prioritize genes and variants to model in animals. This has included a large number of genes/variants in immune pathways including APOE, TREM2, PLCG2, ABCA7, CR1 and others. A subset of the resulting animals have undergone deep phenotyping including histology, fluid biomarkers, brain imaging, behavior, ‐omics and also analysis of the microbiome. The IUSM/Purdue ADDDC has multiple components including a bioinformatics and structural biology core, a structural biology and biophysics core, an assay development and high throughput screening core and a medicinal chemistry and chemical biology core. While the overall strategy and prioritization scheme is still under development, the initial IUSM/Purdue targets will be immune‐focused including INPP5D (SHIP1).ConclusionThrough the coordinated efforts of the NIA‐funded MODEL‐AD and TREAT‐AD consortia, novel AD models and targets will be developed, characterized and made widely available to the scientific community, including a number targeting immune pathways. These efforts are geared to accelerate the development of novel therapeutic targets for AD.
APOE alleles' association with neurocognitive function differ across Hispanic background groups
Authors: Granot‐Hershkovitz Einat , Tarraf Wassim , Kurniansyah Nuzulul , Daviglus Martha , Isasi Carmen R , Kaplan Robert , Lamar Melissa , Perreira Krista , Smoller Sylvia , Stickel Ariana , Thyagarajan Bharat , Zeng Donglin , Fornage Myriam , DeCarli Charles , Gonzalez Hector M. , Sofer Tamar 
Published: December 2020

AbstractBackgroundCognitive impairment, dementia, and Alzheimer's disease (AD) have higher rates in the Hispanic population compared to non‐Hispanic Whites. APOE alleles are the strongest known genetic predictors for AD, however, in the Hispanic population, the effect appears to be weaker, and inconsistent between studies. We hypothesized that this heterogeneity is due, in part, to ancestry‐specific genetic effects.MethodWe investigated the associations of APOE alleles with cognitive decline and mild cognitive impairment (MCI), determined by longitudinal cognitive assessment 1. The study population included 4,250 individuals from the SOL‐INCA study, a subset of middle‐aged and older adults’ from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We further stratified and explored these associations within six different Hispanic background groups: Cuban, Dominican, Mexican, Puerto‐Rican, South‐American, and Central‐American. Finally, we performed interaction analysis to study the hypothesis that proportion genetic ancestry (European, African and Amerindian) modifies the effect of the APOE alleles on the neurocognitive functions.ResultThe APOE ε4 allele was associated with both global cognitive decline (Beta=‐0.11, p‐value= 0.01) and a status of ‘cognitive decliner’, defined when global cognitive decline is higher than expected in normal cognitive aging, (OR=1.15, p‐value=0.03). After stratification by background groups, these associations remained significant only for Cubans showing a stronger effect relative to the effect in the total population (Decliners: OR= 1.46, p‐value= 0.007, global cognitive decline: Beta= ‐0.25, p‐value= 0.01). Stratification analysis also revealed new associations showing protective effects on MCI and cognitive decline by the APOE ε2 allele in two of the Hispanic background groups: Dominican and Puerto‐Rican. Heterogeneity tests suggest a significant differential effect for global cognitive decline for both APOE ε2 (p‐value <0.001) and APOE ε4 (p‐value <0.05). Interaction analysis suggests that increased proportion of African genetic ancestry was associated with a more protective effect conferred by APOE ε2 on global cognitive decline. Also, an increased proportion of Amerindian genetic ancestry was associated with lower risk effects conferred by APOE ε4 on both decline phentoypes.ConclusionThese results suggest that APOE alleles' effects on neurocognitive functions differ across the six Hispanic genetic backgrounds and are modified by ancestry‐specific genetic effects.
Physical activity levels are associated with sleep efficiency and cerebral blood flow in healthy older adults
Authors: Fenton Laura E , Albrecht Daniel , Isenberg Lisette , Aslayan Vahan , Stradford Joy , Monreal Teresa , Pa Judy 
Published: December 2020

AbstractBackgroundIdentifying modifiable risk factors that prevent or delay the onset of dementia remains a priority. While there is evidence that physical activity (PA) can improve cognition (Hillman et al., 2008; Kramer & Colcombe 2018) and prevent cognitive decline (Sofi et al., 2011; Hamer & Chida, 2009), our understanding of the mechanisms through which PA exerts these effects remains unclear. Two recently proposed mechanisms which warrant further investigation are cerebral blood flow (CBF) and sleep efficiency (Stillman et al., 2016).MethodWe examined relationships between PA, sleep efficiency, CBF, and performance on neuropsychological assessments (MoCA, Flanker, CVLT) in a sample of non‐demented, older adults (N=43, 67% female, age=66.67+6.83). An average of 36.97 days of objective PA and sleep efficiency were recorded using the GENEActiv tri‐axis accelerometer prior to participants’ in‐person visits. CBF was quantified using a pseudo‐continuous arterial spin labeling MRI scan. Linear regression analyses adjusting for age, sex, and education were conducted to examine the relationships between PA, sleep efficiency, CBF, and cognition. As an exploratory analysis we examined the moderating effect of APOE4 status.ResultHigher levels of light PA were associated with greater levels of global CBF (p=0.03) which was in turn associated with higher MoCA scores (p=0.03). In APOE4 non‐carriers (n=32), higher levels of vigorous PA were associated with greater sleep efficiency (p=0.03). No significant relationships between PA and cognition or between sleep efficiency and cognition were observed. Additionally, CBF was not a significant mediator of the relationship between PA and cognition. Exploratory analyses revealed a significant moderating effect of APOE4, such that elevated right hippocampal CBF was associated with poorer sleep efficiency in APOE4 carriers only (p<0.01).ConclusionThese results provide evidence that baseline levels of light PA are associated with greater CBF throughout the brain. However, more intense levels of PA are necessary to influence sleep efficiency and differ based on APOE4 status. The lack of relationship between PA and cognition may be due to the fact that participants did not meet a necessary PA threshold to elicit a relationship. Future intervention studies assessing whether increasing levels of PA impacts sleep efficiency, CBF, and cognition are needed.
Internet based multicomponent interventions to prevent cognitive decline: The Maintain Your Brain trial
Authors: Brodaty Henry , Heffernan Megan , Andrews Gavin , Anstey Kaarin J , Singh Maria A Fiatarone , Jorm Louisa , Lautenschlager Nicola T , Maeder Anthony , McNeil John , Sachdev Perminder S , Valenzuela Michael 
Published: December 2020

AbstractBackgroundFollowing unsuccessful pharmacological interventions, momentum is increasing for prevention of cognitive decline and dementia strategies for which technology and web‐based non‐pharmacological applications provide a scalable population‐based approach1. We describe feasibility of a pilot study of an internet based randomised controlled trial targeting modifiable dementia risk factors.MethodInvitations to participate in the Maintain Your Brain (MYB) Pilot were emailed to 2,000 people aged 55‐77 years recruited from the 45 and Up study, a population‐based cohort study of one‐in‐ten people aged 45 years and older in NSW, Australia (n = 267,000). Modules were designed to address physical inactivity and inactivity‐associated health risks (Physical Activity), Mediterranean‐type diet adherence and poor nutrition associated health risks (Nutrition), cognitive activity (Brain Training) and mental wellbeing (Peace of Mind)2. The 10‐week Pilot aimed to test the procedures of the planned intervention including online system stability. Based on risk factors, participants were randomly allocated to one of four modules (coaching) or information, all delivered digitally. Active coaching participants received weekly module‐specific activities; information participants received static information. Online cognitive testing covered learning and memory, attention and executive function. Linear mixed models, including age, education and sex, were used to test interaction effects (time by group) on each domain.ResultOf 2,000 invitees, 425 (21%) consented of whom 271 (14%) started baseline and 144 (7%) were ultimately enrolled into the study. Participants were aged 55‐77 years (M = 65.9, SD = 5.2), and educated for 9‐29 years (M = 16.6, SD = 3.6); 56% were women (56%). Eighty‐seven (60%) participants were allocated to one of the coaching modules; 57 (40%) to information only. Of participants who completed baseline testing; 69% (n = 99) had a full dataset at follow‐up, (63% of coaching; 77% of information participants).ConclusionThe pilot tested the feasibility of the intervention in recruitment and retention of participants. Internet based interventions, while theoretically appealing, offer challenges eg user friendliness3, technology interface. We describe how these were met in recruitment of 6236 persons for the substantive MYB trial2, currently underway.
A comparison of clinician assessment of speech versus automated speech analysis in mild cognitive impairment and Alzheimer’s dementia
Authors: Yeung Anthony , Iaboni Andrea , Rochon Elizabeth , Lavoie Monica , Santiago Calvin , Yancheva Maria , Novikova Jekaterina , Kaufman Liam D. , Mostafa Fariya 
Published: December 2020

AbstractBackgroundLanguage impairment is an important marker of neurocognitive disorders. Despite this, there is no universal system of terminology used to describe speech impairment and large inter‐rater variability can exist between clinicians assessing speech. The role of automated speech analysis is emerging as a novel and potentially more objective method to assess speech in individuals with mild cognitive impairment (MCI) and Alzheimer’s dementia (AD). No studies have analyzed whether variables extracted through automated speech analysis can also be correlated to speech characteristics identified by a clinician. We sought to: (1) investigate whether clinician‐identified speech characteristics could be correlated with acoustic and linguistic variables identified through automated speech analysis, and (2) through automated speech analysis, identify novel acoustic and linguistic variables that may be associated with MCI or AD.MethodUsing the DementiaBank speech corpus (Cookie Theft picture description task), audio recordings from patients with possible/probable AD (n=10), MCI (n=10), and controls (n=10) were rated by clinicians. Four characteristics of speech were rated by clinicians, including: word‐finding difficulty, coherence, perseveration, and speech errors. Clinicians were blinded to each other’s scoring. Where scores differed, a consensus rating was established. The speech recordings were then transcribed, and linguistic and acoustic variables were extracted through automated speech analysis. The correlation between clinician‐identified speech characteristics and the acoustic and linguistic variables were then compared.ResultA significant correlation (p < 0.05) was found between clinician‐identified speech characteristics and variables extracted through automated analysis. Average word length was correlated with word‐finding difficulty (ρ = 0.74); changes in syntactic construction (use of past tense, third person singular verbs, and subordinate clauses) were correlated with coherence (ρ = 0.51) and errors in speech (ρ = 0.58); similarity between consecutive utterances was correlated to perseveration (ρ = 0.68).ConclusionIn this exploratory study, variables extracted through automated acoustic and linguistic analysis of MCI and AD speech were strongly correlated to clinician‐identified speech characteristics. Our results suggest further investigation for using an automated, data‐driven approach to define and monitor subjective clinical speech descriptors in neurocognitive disorders.
Quality of connections counts: Social relationships and global cognition in the Sydney Memory and Ageing Study
Authors: Casey Anne‐Nicole S , Kochan Nicole A , Crawford John D , Sachdev Perminder S , Brodaty Henry 
Published: December 2020

AbstractBackgroundSocial relationships create and emerge from social networks, which in turn promote social engagement and support (Berkman et al., 2000). Adults may focus on fewer and better relationships in older age (Carstensen and Scheibe, 2009). Yet meta‐analyses report that larger, supportive networks are protective for cognitive health (Penninkilampi et al., 2018). Health‐related Quality of Life (HRQoL) includes perceptions of social relationship quality and is positively associated with cognitive function (Wlodarczyk et al., 2004). We examined longitudinal association of perceived quality of social relationships with global cognition, controlling for common demographic and health factors.MethodData were collected at 2‐year intervals across six years in the Sydney Memory and Ageing Study, an ongoing prospective longitudinal cohort study (Sachdev et al., 2010). Participants enrolled at baseline were 1037 cognitively healthy community volunteers recruited from the Electoral Roll. Comprehensive neuropsychological assessment included 10 tests from 5 cognitive domains (Attention/ Processing Speed, Executive, Visuospatial, Verbal Memory, Memory). Global cognition scores for each wave were calculated as the average of cognitive domain scores. Perceived relationship quality was assessed using relationship dimension scores from the Assessment of Quality of Life (AQoL‐6D: Richardson et al, 2012). The association of social relationship quality with global cognition was examined using mixed linear regression models. Covariates were age, sex, years of education, ApoE4 status, NEO‐FFI Neuroticism score (Costa and McCrae, 1992), Geriatric Depression Scale (GDS) score (Sheikh and Yesavage, 1986), number of medical conditions, number of mental activities, social network size as number of friends/relatives contacted at least monthly, and minutes of weekly vigorous physical exercise.ResultWithout covariates included, the association of relationship quality with global cognition was highly significant (B=0.08, p<0.0005). With covariates included, the strength of association approximately halved (B=0.04, p=0.037) indicating that these factors were influential. Social network size and number of medical conditions were not associated with cognition in the model.ConclusionBetter perceived quality of social relationships, not network size, was associated with better cognition across six years in this study. The connections between social relationships and brain ageing are complex. Meaningful interpretation of these connections may require more nuanced measures of socialisation.