bluuebunny/crossref_metadata_2025 huggingface dataset:
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

Background

Expression 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.

Method

Cis‐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.

Result

A 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.

Conclusion

We 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

Background

Alzheimer’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.

Method

A 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.

Results

The 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.

Conclusion

Some 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

Background

Despite 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 pathways

Method

The 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.

Result

The 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).

Conclusion

Through 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

Background

Cognitive 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.

Method

We 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.

Result

The 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.

Conclusion

These 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

Background

Identifying 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).

Method

We 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.

Result

Higher 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).

Conclusion

These 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

Background

Following 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.

Method

Invitations 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.

Result

Of 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).

Conclusion

The 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

Background

Language 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.

Method

Using 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.

Result

A 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).

Conclusion

In 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

Background

Social 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.

Method

Data 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.

Result

Without 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.

Conclusion

Better 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.
Improvements in memory and brain functional connectivity in older adults with subjective cognitive complaints following multiple‐modality exercise and mind‐motor training: An exploratory sub‐study
Authors: Silva Narlon Cassio Boa Sorte , Gill Dawn P , Nagamatsu Lindsay , Owen Adrian M , Petrella Robert J
Published: December 2020

Background

Whether task‐based brain functional connectivity (FC) following exercise suggests adaptations in preferential brain regions is unclear. The objective of this study was to explore cognitive function and FC changes following multiple‐modality exercise and mind‐motor training in older adults with subjective cognitive complaints.

Methods

We included older adults (n=127, mean age 67.5 [7.3] years, 71% women) randomized to 45 minutes of multiple‐modality exercise with 15 minutes of mind‐motor training (M4 group, n = 63) or an active control group (M2 group, n = 64). Both groups exercised 60 minutes/day, 3 days/week, for 24 weeks. Participants completed twelve cognitive tasks from the Cambridge Brain Sciences (CBS) battery at baseline and follow‐up (memory, reasoning, concentration and planning tasks). A subsample of participants from the M4 group (n = 9, mean age 67.8 [8.8] years, 8 women) also underwent 5 minutes of continuous fMRI data collection while completing four CBS memory tasks. Behavioural data were analyzed using linear mixed models for repeated measures, and paired samples t‐test. All fMRI data were analyzed using group‐level independent component denoising and dual regression procedures, correcting for voxel‐wise comparisons.

Results

The M4 group showed greater improvements in the Paired Associates tasks compared to the M2 group at 24 weeks (mean difference: 0.47, 95% confidence interval: .08 to .86, p = 0.019). No other results were found to be significant. For our fMRI analysis, dual regression revealed significant decreased FC co‐activation in the right precentral/postcentral gyri after the exercise program during the Spatial Span task (corrected p = 0.008) with no change in the behavioural task performance. Only trends for changes in FC were found for the other tasks (all corrected p < 0.09). For the Paired Associates task, there was a trend for increased co‐activation in the right temporal lobe (Brodmann Area = 38, corrected p = 0.07), and left middle frontal temporal gyrus (corrected p = 0.06).

Conclusions

Our findings provide insight into the potential of our multiple‐modality exercise and mind‐motor training intervention to promote improvements in behavioural measures of visuospatial memory, as well as, impart FC adaptations in brain regions relevant to Alzheimer’s disease risk.
Metabolite differences in TDP‐43 proteinopathy and control human brain tissue
Authors: Hammond Tyler C. , Xing Xin , Nelson Peter T. , Ham Stephanie , Lin Ai‐Ling
Published: December 2020

Background

Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) is a newly recognized neurodegenerative disease that presents as an amnestic dementia syndrome that mimics Alzheimer’s‐type dementia. The hallmark neurodegenerative feature of LATE is a TDP‐43 proteinopathy distributed throughout the frontotemporal lobe. The main neuropathological and clinical features for LATE have been described elsewhere, but little is understood about the underlying metabolic processes that may contribute to TDP‐43 pathology in LATE. Here we measure the metabolites of control brains and brains with TDP‐43 to understand how they differ.

Method

The global biochemical profiles of post‐mortem human brain tissue from the gray matter of Brodmann area 9 was determined using mass spectroscopy. Brain tissue from 44 subjects with TDP‐43 proteinopathy and 29 controls were analyzed and metabolites were compared. Metabolites were quantified using global untargeted metabolomics (HD4) and compared between cohorts using Welch’s two‐sample t‐test and random forest to rank metabolites in order of importance for predicting TDP‐43 presence in tissue.

Result

There were many metabolites that differed between TDP‐43 and control brains. Many of the metabolites in the top 20 most important predictors overlapped with metabolites deemed important in predicting Alzheimer’s disease, including memantine, sphingadienine, 3‐ureidopropionate, pyridoxal phosphate, 2’‐AMP, 3’‐AMP, pipecolate, 1‐carboxyethylvaline, sphingosine, and malate. However, there were quite a few predictors which were unique to predicting TDP‐43 proteinopathy, including tryptophan – a precursor of serotonin and melatonin, tetradecadienoate – a fatty acid, dihydroxyacetone phosphate (DHAP) – a glycolysis intermediate, homocarnosine – an intermediate in histidine metabolism that can co‐exist with progressive mental deficiency, and phosphatidylcholine and sphingomyelin – important components of the cell membrane.

Conclusion

Many metabolites differed between the TDP‐43 and control brains. Some metabolite differences were the same as those seen in Alzheimer’s disease, and could be because many of the people in our cohort with TDP‐43 pathology also had Alzheimer’s pathology. Many of the metabolite differences were specific to TDP‐43 proteinopathy, which are critical to maintaining brain function, including changes in neurotransmitters, essential amino acids, fatty acids, glycolysis intermediates, and cell membrane products. Further studies are needed to examine whether these metabolites are consistently altered in TDP‐43 proteinopathy.
Design and support of an online ‘control’ condition for the Tele‐Savvy randomized control trial
Authors: Nocera Joe R , Hepburn Kenneth , Griffiths Patricia , Higgins Melinda , Epps Fayron , Brewster Glenna S , Bonds Kalisha , Nash Rachel
Published: December 2020

Background

Tele‐Savvy is a NIA‐supported randomized trial aimed to evaluate an online version of the Savvy Caregiver, an evidence‐based in‐person psychoeducation program aimed at enhancing caregivers’ capacity to manage the day‐to‐day challenges of caregiving by promoting caregiving mastery and reducing caregiving distress. A critical component of the effective evaluation of this online psychoeducation program was the development of an engaging control condition (“Tele‐Savvy Healthy Living Condition”).

Methods

Caregivers were randomly assigned (in a 2:2:1 ratio) to participation in Tele‐Savvy, Healthy Living condition, or waitlist control. For Tele‐Savvy and Healthy Living, groups of 5‐8 caregivers engaged in 7 weekly synchronous online groups led by a trained facilitator. Each condition incorporated daily video lessons which caregivers viewed whenever and as often as they wished. The Healthy Living control condition incorporated evidence‐based, vetted information on healthy lifestyle behaviors (e.g., NIA Go4Life; USDA ChooseMyPlate).

Results

Results demonstrate that engagement of those randomized to the Healthy Living control condition was statistically equal to those in the Tele‐Savvy program (p>0.05). Engagement was assessed by comparison of percent attendance of video conference in the Healthy Living condition (74.08%) versus Tele‐Savvy (68.02%). An intermediate report on the primary outcomes of the trial indicate that, while engaging, the Healthy Living condition did not significantly impact the primary outcomes of the randomized trial. For example, CES‐D‐assessed caregiver depression significantly decreased over time for Tele‐Savvy (p=.002) with no significant changes seen in the Healthy Living condition (p=.689) nor waitlist control (p=.141). Similarly, dyadic strain significantly decreased over time for the Tele‐Savvy group (p=.012) with no significant changes for the Healthy Living condition (p=.968) nor waitlist control (p=.135). Lastly, caregiver competence significantly increased over time for the Tele‐Savvy group (p<.001) with no significant changes for the Healthy Living control group (p=.558) nor waitlist control (p=.327).

Conclusion

This initial work supports the improvements seen in the Tele‐Savvy condition are attributed to the online psychoeducation intervention and not simply the attention received via video conferencing. As such, this work supports an engaging “Control” condition which may serve future trials aimed to evaluate the effectiveness of online psychoeducation programs.
Determinants of subjective cognitive decline among older sexual minority Canadians
Authors: Stinchcombe Arne , Hammond Nicole G
Published: December 2020

Background

Some lines of evidence suggest that older lesbian, gay, and bisexual (LGB) people may be at increased risk of cognitive impairment, stemming from minority stress experiences accumulated throughout the lifespan. Subjective cognitive decline (SCD) is a perceived worsening in cognition and has been associated with dementia in the preclinical stage.

Method

We sought to examine variables associated with SCD among LGB participants in the Canadian Longitudinal Study on Aging (CLSA), a study of over 50,000 individuals. First follow‐up data were used and the mean age was 62.75 (SD=9.34). SCD was measured through the question “Do you feel like your memory is becoming worse?”. The analytic sample included only LGB participants in the study (n=925). Multiple logistic regression was used to estimate the odds of SCD.

Result

Results indicated that lesbian/bisexual women had 1.49 higher odds of reporting SCD (p=.006). Participants who were widowed (p=.041) and older (p=.011) were also at higher odds of reporting SCD.

Conclusion

The findings highlight factors that may increase risk of cognitive decline among individuals within aging sexual minority communities.
Social cognitive abilities in older adults with mild cognitive impairment and dementia
Authors: Chander Russell J. , Numbers Katya T. , Grainger Sarah A. , Cleary Rhiagh , Das Debjani , Mather Karen A. , Kochan Nicole A. , Brodaty Henry , Henry Julie D. , Sachdev Perminder S.
Published: December 2020

Background

Aging is associated with changes in general cognition and social cognition. Many studies have detailed these functions in isolation, comparing young and older adults. More information is needed on how social cognition, including theory of mind (ToM), affective empathy (AE), social perception (SP), and social behavior (SB), is affected at different cognitive stages in older adults.

Method

Cross‐sectional study of 305 older adults from the Sydney Memory and Ageing Study. Dementia was classified based on clinical consensus using DSM‐IV criteria, while mild cognitive impairment (MCI) was classified using the International Working Group criteria. Cognitively normal (CN), MCI, and dementia participants were compared on social cognitive domains including: ToM, via the Reading the Mind in the Eyes Test (RMET) and the Interpersonal Reactivity Index – Perspective Taking subscale (IRI‐PT); AE, via the IRI – Empathic Concern subscale (IRI‐EC); and SP, via the Emotion Recognition Task (ERT). Apathy, which is related to SB, was measured via the Apathy Evaluation Scale (AES).

Result

Mean age 87.00 ± 4.05 years, mean education 11.89 ± 3.36 years, 60.3% female. 141 were CN, 103 had MCI, and 61 had dementia. Across cognitive groups, significant differences were observed for the RMET, ERT (specifically for the recognition of anger, disgust, and happiness), AES, IRI‐PT, and IRI‐EC. In posthoc comparisons, RMET and ERT were significantly poorer in MCI and dementia compared to CN, but not between MCI and dementia. IRI ratings and AES were poorer for dementia compared to MCI and CN, but not between MCI and CN (Table 1). In multivariable logistic regression adjusting for significant risk factors for cognitive impairment, RMET and ERT disgust performance were associated with lower risk of MCI over CN. Only AES significantly differentiated dementia from MCI (Table 2).

Conclusion

Neurocognitive disorders are associated with social cognition changes. ToM and SP appear to be affected in MCI relative to CN. Apathy, known to be linked to SB, appears to be affected in dementia. MCI seems to be associated with impaired ability to recognize specific social cognitive cues, while dementia may be more associated with overall worse social cognitive functioning and observed behavioral changes.
A Mendelian randomization approach to characterize overlap in the pathophysiology of neurological disorders
Authors: Bahena Jorge Alberto , Eiffert Brett , Farias Fabiana H.G. , Ibanez Laura , Mihindukulasuriya Kathie A. , Budde John P. , Cruchaga Carlos , Harari Oscar
Published: December 2020

Background

Neurodegenerative diseases are characterized by progressive neuronal death, leading to loss of cognitive function. This process is thought to commence decades before symptom onset. Consequently, there is a dire need to characterize the pre‐clinical phase of neurodegenerative diseases to provide early intervention. We employed a Mendelian randomization approach to identify genetic overlap across neurological disorders and describe common disease mechanisms.

Method

We utilized our web‐based multi‐omics analytic tool ONTIME (Online Neurodegenerative Trait Integrative Multi‐Omics Explorer, http://ngi.pub/ONTIME/) to apply two‐sample Mendelian randomization to neurological disorders. We estimated the causal effect of 59 cerebrospinal fluid (CSF) analytes and 134 plasma analytes on the risk of Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS), and stroke. Instrumental variables for CSF (N = 672) and plasma (N = 818) analytes were obtained from quantitative genome‐wide association studies we performed using the RBM Human DiscoveryMAP panel.

Result

In CSF, we identified seven analytes that have a causal effect on AD, two analytes that have a causal effect on ALS, and three analytes that have a causal effect on stroke after false discovery rate (FDR) adjustment (Table 1). In plasma, we identified eleven analytes that have a causal effect on AD, eight analytes that have a causal effect on ALS, and five analytes that have a causal effect on stroke after FDR adjustment (Table 2). Furthermore, we detected overlap in the pathogenesis of AD and ALS as well as AD and stroke.

Conclusion

Our results support a growing body of evidence that there is significant genetic and pathophysiological overlap across neurodegenerative diseases. Furthermore, our findings provide evidence that vascular factors contribute to neurodegenerative disease onset. Finally, these results highlight the utility of ONTIME and its Mendelian randomization tool. Users can upload disease summary statistics and test if any CSF or plasma analyte in our catalogue has a causal effect on their uploaded health outcomes.
Functional neural correlates of the WAIS‐IV Block Design Test in older adult with mild cognitive impairment and Alzheimer’s disease dementia
Authors: Joung Haejung , Yi Dahyun , Byun Min Soo , Lee Jun Ho , Lee Younghwa , Ahn Hyejin , Kim Hakyeong , Lee Dong Young
Published: December 2020

Background

While the Wechsler Adult Intelligence Scale IV (WAIS‐IV) Block Design Test (BDT) has is widely used in both research and clinical setting as a measure of cognitive decline in the aging population, its functional neural substrates has not been clearly identified. Hence, the aim of the current study is to identify the functional neural correlates of the BDT in older adults with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia patients.

Method

The current study includes 213 cognitively impaired (135 MCI and 78 AD dementia) middle and old‐aged adults. All participants underwent comprehensive clinical and neuropsychological assessments and 18F‐fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) scans. The BDT performance was assessed using the Wechsler Adult intelligence scale‐IV Korean version. Voxel‐wise analyses were used to investigate the correlation between regional cerebral glucose metabolism and BDT performance. The same analyses were conducted on the subgroups categorized by clinical severity based on the Clinical Dementia Rating.

Result

The participants had a mean age of 73.1 (SD = 7.4) years, mean years of education of 9.8 (SD = 4.9), mean BDT score of 20.9 (SD = 9.1), and 67.1% were female. Significant positive correlations between the BDT performance and regional cerebral glucose metabolism were found bilaterally in the inferior parietal lobule and thalamus, the right superior temporal gyrus and left occipital precuneus.

Conclusion

The findings indicated that BDT performance in MCI and AD dementia patients functionally relies on the brain regions known to be associated with motor and executive functions as well as visuospatial functions.
Perivascular space alteration in idiopathic and familial Parkinson’s disease
Authors: Murdos Amjad , Sheikh‐Bahaei Nasim , Toga Arthur W. , Sepehrband Farshid ,   Parkinson's Progression Markers Initiative
Published: December 2020

Background

Parkinson’s Disease is the second most prevalent neurodegenerative diseases today. There is a growing body of evidence suggesting overlap between Alzheimer’s disease and many Parkinson related neurodegenerative processes. Understanding the vascular impact in patients with Parkinson’s disease can provide new insight on pathological progression and treatment options. Dilation of perivascular spaces has been an important measure of vascular insult in the context of glia‐lymphatic clearance and neurodegenerative diseases. The role of microvascular changes and particularly dilated perivascular spaces in Parkinson’s disease, has not been investigated. Differences in perivascular spaces among patient with idiopathic and familial Parkinson’s disease can provide novel insight on the implications of the genetic components pertaining to Parkinson’s disease.

Method

Total of 470 individuals were analyzed from the PPMI database. Subjects were grouped based on their genetic status of their disease: idiopathic Parkinson’s Disease (n=201), familial Parkinson’s Disease (n=71), healthy controls without genetic risk factor (n=94) and healthy controls with genetic risk factor (n=104). To study the impact of brain glia‐lymphatic pathway pathology on the clinical status of idiopathic and familial Parkinson's disease, total perivascular space volume was compared between these patient populations using a newly developed technique (Figure 1).

Result

The perivascular spaces were significantly larger in the idiopathic and familial Parkinson’s disease subjects compared with the idiopathic and familial control subjects. Interestingly, across different groups the lowest perivascular space volume fraction was observed in the healthy control with genetic risk factor, suggesting a potential protective or compensatory mechanism relating to vascular or glia‐lymphatic system (Figure 2).

Conclusion

Our findings showed that individuals with symptomatic Parkinson’s disease have more enlarged perivascular spaces compared to clinically intact controls independent of their genetic predisposition. It suggests that microvascular changes and particularly perivascular spaces might contribute to the neurodegenerative symptoms through parallel pathways additional to the primary pathological process. These results are very similar to the effect of perivascular spaces in Alzheimer’s disease. More interestingly, our data showed that presence of Parkinson’s genetic factors, does not increase the risk of glia‐lymphatic impairment while in the later stages this impairment can contribute into the clinical picture.
H. pylori infection is associated with cortical thinning in cognitively normal individuals
Authors: Park Jaehong , Song Joohye , Shin Hee Young , Jang Hyemin , Na Duk L , Seo Sang Won , Kim Tae Joon , Kim Hee Jin
Published: December 2020

Background

Helicobacter pylori (H.pylori) is a well known bacteria for development of stomach cancer and chronic inflammation. However, H.pylori’s contribution to the neurodegeneration remains largely unknown. We aimed to evaluate the association between H.pylori infection and brain cortical thickness in cognitively normal individuals.

Method

We recruited 1,926 cognitively normal individuals (age≥ 45 years) who underwent brain 3‐dimensional volume MR images and esophagogastroduodenoscopy biopsy to determine H. pylori infection. The participants were recruited from Health Promotion Center in Samsung Medical Center from September 2008 to December 2014. After excluding participants with missing variables, 1,594 were selected in final analysis. We measured cortical thickness using the standard Montreal Neurological Institute image processing tool CIVET. Multiple linear regression analysis was done to evaluate the relationship between H.pylori infection and brain cortical thickness after controlling for age, intracranial volume, education, CRP, and the presence of metabolic syndrome.

Result

In male, H. pylori infection was associated with cortical thinning in the bilateral lateral temporal, lateral frontal, and right occipital areas. However, in female, H. pylori infection was not associated with cortical thickness.

Conclusion

Our findings suggest that H.pylori infection is associated with neurodegenerative changes in cognitive normal male, regardless of chronic inflammation or metabolic syndrome.
Difference of quantitative EEG between Alzheimer’s disease (AD) dementia and non‐dementia AD
Authors: Kang Seung Wan , Choi Seong Hye , Jeong Jee Hyang , Jang Jae‐Won , Park Kyung‐Won , Kim Eun‐Joo , Kim Hee Jin , Hong Jin Yong , Yoon Soo Jin , Yoon Bora , Kang Dong Won
Published: December 2020

Background

Alzheimer’s disease (AD) is the most common cause of dementia. However, accumulation of beta amyloid plague in the brain which is main pathology of AD could show the various spectrum of cognitive functional stage from preclinical level to overt dementia. It is important to understand functional differences between dementia and non‐dementia of AD to predict progression forward to dementia at prodromal or preclinical stage of AD.

Method

Nineteen channels of resting state EEGs were measured from 45 Alzheimer’s disease subjects who were all confirmed by brain amyloid‐beta PET. Neurocognitive test, activity of daily living (ADL) and MRI were conducted for clinical diagnosis. EEG power spectrum analysis and band‐power ratio, cortical source current density estimated by standardized low resolution brain electromagnetic tomography(sLORETA), functional connectivity between 68 region of interest (ROI) based on imaginary coherence(iCoh) and complex brain networks were analyzed.

Result

20 AD subjects (age: 76.8±7.54) were assessed as dementia, and the other 25 (age: 72.1±6.89) as mild cognitive impairment (MCI) or subjective cognitive decline (SCD) depending on delayed recall memory score. Average CDR was 0.23 in non‐dementia and 1.15 in dementia group. There was no significant difference at delta, but theta power of AD dementia group was significantly increased at all 19 scalp channels. Mid frontal channel (Fz) showed the most distinctive enhancement of theta power. In other hands, beta1 (12∼15Hz) was significantly increased at both temporoparietal area in non‐dementia AD group. These patterns about theta increase and beta 1 decrease in AD dementia group were observed very similarly in cortical source current density. iCoh among ROIs of default mode network (DMN) was significantly decreased at alpha2 band (10∼12Hz). At bilateral frontal pole, rostral middle frontal, anterior cingulate, parahippocampus and precuneus, the degree centrality and characteristic path length significant increased at theta band. In contrast, theta of cluster coefficient and closeness centrality significantly decreased.

Conclusion

AD dementia showed increase of theta and decrease of bet1 both at scalp and cortical level comparing to non‐dementia AD subjects. Both global and local network efficiencies via theta wave were significantly deteriorated in AD dementia. QEEG could well discriminate the differences between dementia and non‐dementia in ADs.