bluuebunny/crossref_metadata_2025_split huggingface dataset:
Joint linkage and association mapping of preserved cognition in the old‐order Amish
Authors: Ramos Jairo , Jaworski James , Adams Larry D. , Laux Renee A. , Caywood Laura J. , Prough Michael , Clouse Jason E. , Herington Sharlene D. , Slifer Susan H. , Fuzzell M. Denise , Fuzzell Sarada L. , Sewell Jane L. , Miller Sherri D. , Song Yeunjoo E. , Miskimen Kristy , Main Leighanne R. , Ogrocki Paula , Lerner Alan J. , Vance Jeffery M. , Cuccaro Michael L. , Haines Jonathan L. , Pericak‐Vance Margaret A , Scott William K. 
Published: December 2020

AbstractBackgroundMost studies on Alzheimer Disease (AD) have focused on the identification of variants associated with increased risk. The Amish is a genetically homogeneous population ideal to investigate susceptibility genes for complex traits such as AD. This study aims to use family‐based linkage and association approaches to identify genetic variants that protect against the development of cognitive impairment (CI), the central feature of AD.MethodA total of 800 adults from Amish communities in Indiana and Ohio were screened for CI using the 3MS test. Individuals were classified as cognitively normal (CN) if the 3MS score was ≥87 at age 75 and cognitively impaired if < 87 at any age. Samples were genotyped on the Illumina Infinium Global Screening or Expanded Multi‐Ethnic Genotyping Array. Over 7 Million common and rare variants were then imputed using the HRC reference panel. For the linkage analysis 75 nuclear families containing at least two CN individuals were analyzed using Merlin to fit multipoint non‐parametric linkage models and parametric affected‐only (AO) dominant and recessive models using a map of more than 40,000 genotyped markers. The genome‐wide association study (GWAS) of imputed variants utilized the program Genesis to fit a logistic regression model 426 CN to 360 CI, associating each variant with cognitive status while adjusting for sex, pc1, pc2 and relatedness.ResultThe top linkage peaks were seen in the parametric multipoint AO dominant model: Chr3 (HLOD = 2.6) ∼3.9 mb region (21.0 mb – 24.9 mb) and Chr11 (HLOD 2.1) ∼6.5 mb (11.0 mb – 17.5 mb). In the GWAS analysis, no variants reached genome wide significance (5 × 10−8). However, using a lower significance threshold for regional association under a linkage peak (p < 10−5), 7 associated variants were identified in two regions under the Chr11 peak.ConclusionWe identified a 6.5 mb area of interest on chromosome 11 associated with preserved cognitive function in Amish adults over age 75, which is near OTOG a previously reported gene associated with AD. This region merits further investigation for functional variants that might slow or prevent the development of cognitive impairment in older adults.
Diversity to discovery: Addressing health disparities in dementia research as a path to scientific breakthroughs, personalized treatment and community health
Authors: Lam Ann , Krebs Catharine , Ohayon Elan 
Published: December 2020

AbstractBackgroundThere has been growing recognition of health disparities and lack of diversity in neuroscience and the dementia field in particular. These issues manifest across multiple scales in research, clinical, and public policy domains. However, the degree to which various diversity issues and scales interconnect has been underestimated and mostly overlooked. Moreover, a focus on animal experimental systems has exasperated the problem by creating frameworks of dementia largely devoid of human diversity elements. Here we present analyses of national research resources (e.g., U.S. biobanks) and siloing of data to quantify and highlight the lack of diversity. We then forward human‐based research, clinical and public policy strategies that can help address diversity issues and help uncover foundational mechanisms across scales.MethodsThe framework includes analyses of [1] publicly available demographic data in national tissue and biospecimen banks [2] recent biological‐focused mechanistic studies that examine risk factors [3] public policy on diversity and disparities in medical and care services research.Results[1] Analyses of demographic data in biobanks revealed significant incongruencies in the availability of specimens for the most impacted minority groups in the United States. [2] Even in studies of genetic‐related risk factors of diverse populations, exclusion criteria made it such that mechanistic theories would be easily biased by the lack of training of researchers to the sensitivity of diversity‐related risk factors. [3] At public health and clinical trials level of investigation, researchers and Alzheimer's communities are rapidly developing more inclusive, diversity‐aware relationships and research approaches but these need to be increasingly connected to research domains to help provide biological insight into dementia pathogenesis and prevention.ConclusionsThese analyses demonstrate the need for further implementation of diversity and disparities through human‐based research programs (e.g., genetic analysis, patient‐derived cell cultures, biospecimen studies, computational modeling, etc.), as well as greater transparency in funding allocations and policies that integrate complex diversity factors into mechanistic, phenomenology and community‐level studies of dementia. Human‐based preclinical approaches can all provide greater insights and new models for personalized prevention and intervention but will need to directly include diversity‐related elements in research design in order to forward discovery.
Barriers to recruitment for research procedures in studies of Alzheimer’s disease and related disorders
Authors: Hofmann Bailey L , Serrano Kristen Jade , Shifflett Benjamin , Gigliotti Christina , Little Emily A , Salmon David P , Peavy Guerry M 
Published: December 2020

AbstractBackgroundFemales and individuals of Latinx ethnicity have increased risk of developing Alzheimer’s Disease (AD) but are underrepresented in neurodegenerative research. It is critical to understand reasons for this underrepresentation so they can be addressed to ensure that findings are generalizable to the entire population. A potential barrier to AD research is willingness to participate in relatively invasive research procedures (e.g., lumbar puncture (LP), amyloid PET imaging). This willingness may vary by demographic/ethnicity factors thereby producing disparities in research participation. The purpose of this study is to investigate whether gender, education, age, and ethnicity are associated with willingness to participate in research procedures commonly used in observational studies and clinical trials of neurodegenerative disease.MethodA questionnaire that assessed demographics and willingness to participate (yes/no/maybe) in various research procedures [i.e., blood draw, magnetic resonance imaging (MRI), LP, amyloid PET imaging, brain autopsy, clinical trials] was administered in English or Spanish to 81 individuals (mean age=73.2+7.8; mean education=13.7+5.2) after they completed cognitive testing as part of community Memory Screening events. There were 32 Latinx and 49 non‐Latinx participants. There were 29 males and 50 females (gender unreported by two). Willingness to participate was reclassified into binary (yes/not yes) measures. Logistic regression models simultaneously controlling for age and education with gender and ethnicity as predictor variables were used.ResultOverall, a majority of participants were amenable to blood draw (84.5%‐yes), MRI (77.8%‐yes), Amyloid PET (56.8%‐yes), brain autopsy (61.7%‐yes), and observational study (68.8%‐yes). A smaller percentage were amenable to LP (34.6%‐yes) and clinical trials (41.8%‐yes). Women were less likely than men to express willingness to agree to amyloid PET imaging (Odds Ratio: 0.18; p‐value < 0.05). Higher education level was associated with higher odds of willingness to participate in a clinical trial (Odds Ratio: 1.28; p‐value < 0.01). Ethnicity and interaction effects between gender and ethnicity had no statistically significant effects on agreement to specific procedures.ConclusionThe findings reveal that gender and education are important in predicting attitudes toward participation in specific types of research procedures. These results could help inform recruitment strategies that maximize participation of underrepresented groups in research.
Investigating whether fractional anisotropy is associated with reduced reaction time cost on an attentional control task
Authors: McKay Nicole Sarah , Gordon Brian A. , Strain Jeremy F , Wang Qing , Morris John C. , Balota David A. , Benzinger Tammie L.S. 
Published: December 2020

AbstractBackgroundPrevious research has shown that with age and disease, the integrity of white matter (WM) structures can decline. One such measure of WM integrity is fractional anisotropy (FA), where lower values are often associated with disrupted WM. Similarly, previous work has highlighted that attentional control also declines with age and disease. It was therefore of interest to investigate whether FA was associated with cognitive ability in an aging population. To assess this, we derived a measure of attentional control performance from the Consonant‐Vowel, Odd‐Even (CVOE) task.Method246 participants aged 42‐87 years (M = 69, SD = 8.5), who were enrolled in studies at the Knight ADRC, were included in this analysis. Participants were classified as cognitively normal (CDR = 0, n = 185), or cognitively impaired (CDR > 0, n = 61). All participants completed an MRI, and the CVOE task. Tract‐Based Spatial Statistics (TBSS) were run on FA maps calculated for the participants. We used reaction time (RT) cost, the burden caused by the most difficult aspects of this task, as our behavioral measure of interest. This measure was calculated as the difference between RTs on congruent vs incongruently ordered trials.ResultUsing TBSS, we found that the relationships between FA and RT‐cost were significantly different for each group (Figure 1). More specifically, we found no relationship between RT‐cost and FA in our cognitively normal individuals (r = 0.14, p = 0.052; Figure 2). In contrast, we do observe a significant negative relationship between RT‐cost and FA in our cognitively impaired individuals (r = ‐0.64, p < 0.01; Figure 3).ConclusionOverall, we found a strong relationship between WM integrity and cognitive performance, as measured by the CVOE task. That is, as integrity becomes more compromised, participants become slower at switching between trial types within the CVOE task. Importantly, this relationship is only observed for individuals who are cognitively impaired. Taken together, our results add to a body of literature that report a relationship between WM integrity and cognitive performance, but hint that further development of more sensitive cognitive tasks may be needed to fully understand this relationship.
Sex differences of innate immune activation in amyloid positive predementia cases
Authors: Kirsebom Bjørn Eivind , Nordengen Kaja , Selnes Per , Torsetnes Silje Bøen , Sharma Kulbhushan , Gisladottir Berglind , Fladby Tormod 
Published: December 2020

AbstractBackgroundInnate immunity is linked to Alzheimer’s disease, as shown by genome‐wide association studies and experimental data. There is, however, a sexual dimorphism in the activation of the innate immune system. Here, we investigate sex‐differences in immune activation by comparing glial activation markers in CSF from males and females with amyloid pathology as compared to healthy controls.MethodA total of 110 CSF Aβ‐ healthy controls (n=52 males and n=58 females), and 121 CSF Aβ+ (n=70 males and n=51 females) non‐demented cases with cognitive symptoms from the Dementia Disease Initiation (DDI) cohort were included in the analyses. CSF levels of sTREM2, YKL‐40 and MCP‐1 were determined using Mesoscale Discovery. Amyloid pathology was determined using CSF Aβ1‐42 threshold of 708 pg/mL. CSF total tau was included in our models to investigate potential sex differences of active neurodegeneration. We compared CSF concentrations using three‐way ANCOVA with age as a covariate, investigating main effects, two‐way interaction effects between sex and CSF Aβ status and three‐way APOE‐ε4 interactions with sex and CSF Aβ.ResultSignificant interaction effects between sex and CSF Aβ status showed lower CSF YKL‐40 (p<.001), sTREM2 (p<.05) and MCP‐1 (p<.0001) levels in Aβ+ women as compared to males. No differences in levels were found between male and female healthy controls. Furthermore, we found that only Aβ+ males had increased YKL‐40 (p<.001), sTREM2 (p<.05) and MCP‐1 (p<.05) levels compared to healthy controls, whilst Aβ+ females showed no significant differences in levels. Men had slightly higher levels of CSF total tau as compared to women, however, this difference did not reach the threshold for statistical significance (p=.07). No main effects or interaction effects with APOE‐ε4 were found.ConclusionWe found consistent differences in innate immune activation in Aβ+ females, but not related to APOE‐ε4 genotype. However, a slight non‐significant increase in a CSF marker of neurodegeneration in men may in part contribute to the observed differences in immune activation in our sample. The low level of innate immune activation has yet to be linked to differences in disease progression.
Relationship of hearing impairment with MRI brain volumes and cognitive decline in the Atherosclerosis Risk in Communities study
Authors: Deal Jennifer A , Power Melinda C , Betz Joshua , Reed Nicholas S , Albert Marilyn S , Gottesman Rebecca F , Resnick Susan M , Sharrett Richey , Jack Clifford R , Lin Frank R 
Published: December 2020

AbstractBackgroundHearing impairment is associated with cognitive decline but whether it is a cause or marker is unknown. We investigated the association of hearing impairment with brain volumes and 8‐year cognitive decline. Because the superior temporal gyrus (STG) is the location of the primary auditory cortex, we stratified results by STG volume to investigate if the association of hearing and cognition differed among participants with and without evidence of possible hearing‐related brain atrophy.MethodWe used data from 1195 community‐dwelling adults (72‐94 years, 61% female, 36% black) from the Atherosclerosis Risk in Communities Study. A composite cognitive score was created from 10 neuropsychological tests administered at 3 study visits spanning 8 years (2011‐13 to 2018‐19). Brain volumes were calculated from structural magnetic resonance imaging scans for 6 regions of interest. Pure tone air conduction hearing thresholds (frequencies 0.5‐4 kHz) were obtained in 2016‐17 and averaged, with better‐ear hearing impairment defined as an average >25 dB. Multivariable‐adjusted linear regression was used to estimate cross‐sectional differences in standardized brain volumes, adjusting for intracranial volume, demographic and clinical covariates. We estimated differences in annual rates of cognitive change by hearing impairment status adjusting for demographic and clinical covariates using linear mixed models; results were stratified by intracranial volume‐adjusted STG volume (below vs. equal to or greater than the median value).ResultThe mean STG volume difference comparing hearing impairment to normal hearing was ‐0.121 standard deviations (SD) (95% CI: ‐0.213, ‐0.028). Overall, the difference in the rate of cognitive decline associated with hearing impairment was ‐0.014 SD (‐0.023, ‐0.005). Hearing was more strongly associated with cognitive decline among participants with smaller STG volumes; rate difference, ‐0.014 SD (‐0.027, ‐0.002) compared to ‐0.008 (‐0.022, 0.006) for participants with larger STG volumes.ConclusionHearing impairment was associated with smaller brain volumes in the primary auditory region, but not with other regions. Our stratified analysis suggests that hearing treatment might be an important possible strategy to delay cognitive decline, even among participants with hearing‐related brain atrophy. Furthermore, the adverse cognitive effects of hearing impairment could potentially be mitigated if early hearing treatment can prevent STG atrophy.
Cerebrospinal fluid insulin concentration increases and correlates with memory improvements after intranasal insulin administration
Authors: Kellar Derek A. , Register Thomas C. , Dahl Deborah , Craft Suzanne 
Published: December 2020

AbstractBackgroundThere are currently no effective treatments for Alzheimer’s disease (AD) which has prompted research into alternative therapeutic options; one such promising option is intranasal insulin (INI). Although INI treatment over 4 months improved memory, no study has verified whether INI administration elevates insulin in the central nervous system and whether elevations are accompanied by enhanced memory performance.MethodThis study examined the effect of acute INI administration on cerebrospinal fluid (CSF) insulin levels and memory measured by the auditory‐verbal learning task (AVLT) in mild cognitive impairment (MCI, n=11, mean age=68+‐4.8) and cognitively unimpaired adults (n=8, age=67.5+‐4.1). Participants were randomized to receive insulin (Humulin‐R 20 IU) or placebo at their first visit using an intranasal delivery device and returned two‐to‐six weeks later to repeat the visit with the other substance. Fasting participants underwent a blood draw, INI or placebo administration, AVLT, lumbar puncture (LP), blood draw, and delayed AVLT. CSF and plasma insulin measured with ultra‐sensitive ELISA and AVLT scores were compared between placebo and insulin visits. Linear modeling was performed in SAS with visit as a repeated factor and covariates BMI, cognitive status, sex, age, race, and Montreal Cognitive Assessment (MOCA) score. Non‐contributory covariates (p>0.15) were removed.ResultCSF insulin concentration increased after INI administration (p<0.05) while peripheral insulin levels remained unchanged. INI also trended to increased AVLT immediate recall (p<0.1). CSF insulin concentration changes and AVLT changes were positively correlated (p< 0.05). Participants with higher baseline MOCA scores showed greater increases in CSF insulin after INI relative to placebo administration (p<0.05).ConclusionINI is effectively transported into the CNS without modulating peripheral levels. In the brain, insulin may act to increase cognition in a concentration‐dependent manner. INI may be a good therapeutic option for adults with MCI or AD for whom CSF insulin levels are enhanced through intranasal delivery.
Association between left hemisphere MK6240 uptake and language dysfunction in aging and Alzheimer’s disease
Authors: Poltronetti Nina Margherita , Rahmouni Nesrine , Lussier Firoza Z , Stevenson Jenna , Stevenson Alyssa , Benedet Andréa Lessa , Tissot Cécile , Pascoal Tharick A. , Chamoun Mira , Kang Min Su , Therriault Joseph , Savard Melissa , Mathotaarachchi Sulantha , Gauthier Serge , Rosa‐Neto Pedro 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is characterized by a progressive deterioration of multiple cognitive domains. The relative effect of amyloid plaques, neurofibrillary tangles and neurodegeneration on cognitive decline, more specifically in the language‐related areas, is still unclear. The objective of this study was to investigate the independent effects of Amyloid‐β, Tau and neurodegeneration on language using The Boston Naming Test.MethodThe present study was conducted in a population of 163 individuals (116 cognitively unimpaired, 33 mild cognitively impaired and 14 AD). Boston naming Test (BNT) was used to measure the confrontational word retrieval in individuals. Tau was assessed with [18F]MK6240. [18F]MK6240 standardized uptake value ratios (SUVRs) used the cerebellum grey matter as the reference region and were calculated between 90‐110 min post‐injection. A voxel‐based regression model evaluated the relationship between BNT and [18F]MK6240, adjusting for age, sex, years of education, diagnosis. Analyses were corrected for multiple comparisons using random field theory at p<0.001.ResultIn the present study, negative associations were observed between the levels of BNT scores and accumulation of tau indexed by [18F]MK6240‐PET. The brain regions affected were the medial frontal, parietal and temporal lobes, with a predominance in the left hemisphere.ConclusionThese results support the claim that only tau seems to be related to language dysfunction in aging and AD. Associations were more pronounced in the left hemisphere, recapitulating known functional neuroanatomy of language production in humans. Our results support the emerging concept that tau pathology is a major driver of local neurodegeneration and domain‐specific cognitive impairment.
Changes in body mass index in young adulthood and late‐life dementia risk in a large diverse cohort
Authors: Gilsanz Paola , Mayeda Elizabeth Rose , George Kristen M. , Peterson Rachel , Eng Chloe W. , Glymour M Maria , Quesenberry Charles P , Whitmer Rachel A. 
Published: December 2020

AbstractBackgroundMidlife obesity is associated with dementia risk, yet the relationship between body mass index (BMI) during young adulthood and dementia is unclear.MethodWe evaluated 6,947 members of an integrated healthcare delivery system who underwent clinical exams in their 20s and 30s starting in 1964‐1973 and were members as of 1/1/1996. Individuals were classified as underweight (18.5‐25.0 kg/m2), normal weight (18.5‐25.0 kg/m2), overweight (25.0‐30.0 kg/m2), or obese (30+ kg/m2) based on BMI calculated with height and weight measured during the first MHC visit from each age range. Changes in BMI were classified as: 1) consistently normal‐/over‐weight, 2) obesity onset, 3) obese to normal‐/over‐weight, and 4) consistently obese. Dementia diagnoses were abstracted from electronic medical records from 1/1/1997‐9/30/2017. Cox proportional hazard models adjusted for age (as time scale), race/ethnicity, sex, and education evaluated associations between BMI and BMI change categories with dementia risk overall and by sex.ResultThe sample was 61.7% female, 6.7% were obese in their 20s, 11.1% were obese in their 30s, and 3.5% experienced dementia during follow‐up. Individuals who were obese in their 20s were at elevated dementia risk (HR=2.14, 95% CI:1.43‐3.20) compared to normal weight counterparts; there was no difference in dementia risk among underweight individuals (HR=0.70, 95% CI:0.31‐1.59) or overweight individuals (HR=1.80, 95% CI 0.79‐1.49). Individuals who were overweight (HR=1.35, 95% CI:1.00, 1.82) and those who were obese (HR=1.76, 95% CI: 1.21‐2.57) in their 30s were at elevated dementia risk compared to normal weight counterparts; there was no association between being underweight and dementia risk (HR=0.59, 95% CI: 0.19‐1.86). Individuals who were consistently obese had more than double the risk of dementia (HR=2.42, 95% CI:1.61‐3.65) than consistently normal‐/over‐weight individuals; there was no association between obesity onset or going from obese to normal‐/over‐ weight and dementia risk. The associations between BMI in one’s 20s, BMI in one’s 30s, and BMI change with dementia risk did not significantly differ by sex.ConclusionObesity during young adulthood (i.e. 20s and 30s) and being overweight during one’s 30s were associated with elevated dementia risk. Consistent obesity during young adulthood more than doubled an individual’s risk of dementia.