bluuebunny/crossref_metadata_2025_split huggingface dataset:
The association of Alzheimer’s disease and cerebrovascular disease biomarkers towards the neurodegeneration of the cholinergic pathways
Authors: Cedres Nira , Ferreira Daniel , Nemy Milan , Machado Alejandra , Pereira Joana B. , Wahlund Lars‐Olof , Zettergren Anna , Teipel Stefan J. , Grothe Michel J. , Eriksdotter Maria , Stepankova Olga , Vyslouzilova Lenka , Blennow Kaj , Zetterberg Henrik , Kern Silke , Skoog Ingmar , Westman Eric 
Published: December 2021

AbstractBackgroundTo determine the contribution of amyloid pathology and tau pathology in combination with cerebrovascular pathology, towards the neurodegeneration of the cholinergic white matter projections.MethodWe included a sample of 203 cognitively unimpaired individuals derived from the H70 Gothenburg Birth Cohort Studies (all of them 70‐years‐old, 51% female). Amyloid (A) and tau (T) pathology were determined by cerebrospinal fluid levels of Amyloid‐β42/40 ratio, Amyloid‐β38 and phosphorylated tau. Cerebrovascular pathology (V) was determined by automatically segmented white matter lesions detected in magnetic resonance imaging (MRI). Cholinergic white matter projections (i.e. cingulum pathway and external capsule pathway) were modelled using tractography based on diffusion tensor imaging data. Sex and APOE ε4 carriership were also included in the analysis. To assess association of the markers with the integrity of cholinergic projections we used random forest regressionResultwhite matter lesion burden was the most important contributor towards the neurodegeneration of both cholinergic pathways (figure 1). Levels of Amyloid‐β38 and phosphorylated tau also contributed to the cholinergic pathways, especially to the external capsule pathway. Amyloid‐β42/40 ratio levels and APOE ε4 carriership did not show substantial contribution. Females showed poorer integrity in the external capsule pathway.ConclusionUnderlying cerebrovascular disease (V) in cognitively unimpaired elderly plays a central role in the neurodegeneration (N) of the cholinergic pathways to the cerebral cortex. Future research should elucidate the impact of cerebrovascular pathology to the cholinergic disruption and cognitive impairment in pathological populations.
Changes in clinical indices of multimorbidity and frailty predict subsequent cognitive decline: Findings from the Look AHEAD and Look AHEAD MIND studies
Authors: Espeland Mark A. , Bahnson Judy , Evans Joni K. , Hayden Kathleen M. , Justice Jamie , Johnson Karen C. , Johnston Craig , Munshi Medha , Simpson Felicia R. , Kritchevsky Stephen B. 
Published: December 2021

AbstractBackgroundTwo common features of aging are increases in the number of chronic diseases and in the number of deficits in functional, behavioral, and clinical characteristics. Accordingly, indices of multimorbidity and deficit accumulation (i.e. frailty indices) have been promoted as clinical markers of biological aging. As such, it is to be expected that changes over time in these indices should be predictive of downstream changes in important functions, such as cognition.MethodWe examined associations that 8‐year changes in 1) a multimorbidity index comprised of 9 chronic diseases (e.g. CHD, cancer, depression) and 2) a frailty index (FI) based on deficit accumulation in 38 functional, behavioral, and clinical characteristics had with subsequent standardized measures of cognitive function over 10 years. We drew data from the Look AHEAD clinical trial of a multidomain intensive lifestyle intervention (ILI) in 3841 adults, aged 45‐76 years at baseline, who were at risk for accelerated biological aging due to overweight/obesity and type 2 diabetes mellitus, and who underwent cognitive assessment. The domains of memory, attention, and executive function were assessed with validated instruments and combined to form a composite cognitive measure.Result1501 (39%) of the cohort had increases of one and 867 (23%) had increases of >2 chronic diseases. Older individuals, males, and non‐Hispanic Whites tended to be over‐represented among those with the greatest increase in multimorbidities. The 33%ile of the distribution of FI changes was ‐0.005 and the 67%ile was 0.048. Greater FI increases tended to occur among individuals who were older, non‐Hispanic White, heavier, and who had greater baseline multimorbidity. Changes in multimorbidity and FI were moderately correlated (r=0.25; p<0.001). As seen in the attached table, greater increases in both multimorbidity and FI were associated with subsequently worse levels of executive function, attention, and composite cognitive function (p<0.001). While assignment to ILI was associated with smaller increases in both indices of aging, this did not translate overall to better cognitive functioning.ConclusionAccelerated aging, as captured by these geroscience‐informed indices, predicts subsequent poorer cognitive function. However, whether interventions generally targeting multimorbidity and FI reduce risks for cognitive impairment remains to be seen.
Assessing sex differences between mid‐life cardiovascular conditions or risk factors and mid‐life cognition decline
Authors: Huo Nan 
Published: December 2021

AbstractBackgroundThe association between mid‐life cardiovascular diseases or risk factors and cognition decline has been reported. However, sex differences in these associations have rarely been examined.MethodWe included 2,351 participants enrolled in the population‐based Mayo Clinic Study of Aging who were aged 30‐69 years at baseline. Participants were evaluated every 15 months by a coordinator, neurologic evaluation, and neuropsychological testing. The neuropsychological testing used nine tests to calculate global cognitive and domain‐specific (memory, language, executive function, and visuospatial skills) z‐scores. Nurse abstractors reviewed participant medical records to determine the presence and age at onset of cardiovascular diseases and risk factors. Linear mixed‐effect models evaluated the association between baseline cardiovascular conditions (coronary heart disease, myocardial infarction, atrial fibrillation, angina) or risk factors (hypertension, diabetes, dyslipidemia) and global and domain‐specific cognitive decline. Multivariable models adjusted for demographics, APOE, depression, and other medical conditions. Interactions between sex and each cardiovascular conditions or risk factors were examined; results were stratified by sex if the interaction was p<0.05.ResultOverall, 1651 (70.3%) participants had at least one cardiovascular condition or risk factor; the proportion of men was higher than women (875 (74.9%) vs.777 (65.7%), p<0.0001). Cross‐sectionally, baseline cardiovascular conditions and risk factors were not associated with cognitive performance in multivariable analyses and there were no sex differences. Longitudinally, several cardiovascular conditions and risk factors were associated with declines in global and/or domain‐specific z scores, with the exception of visual spatial z‐scores. Most cardiovascular conditions were more strongly associated with cognition among women: coronary heart disease, myocardial infraction, and angina were associated with global cognition decline only in women. Additionally, diabetes, dyslipidemia, and coronary heart disease were associated with language z‐score decline only in women.ConclusionMiddle aged cardiovascular conditions and risk factors are associated with mid‐life cognitive decline. Moreover, some specific cardiovascular conditions and risk factors, such as coronary artery disease, myocardial infraction, and angina have stronger associations with cognition decline among women.
Air pollution and neighborhood racial composition and their association with memory and memory decline in NHATS
Authors: Dang Kristina , Weuve Jennifer , Haan Mary , Allen Isabel Elaine , Brauer Michael , Lane Kevin , Glymour M Maria 
Published: December 2021

AbstractBackgroundMemory decline is a harbinger of Alzheimer’s disease (AD). Air pollution was recently added as a dementia risk factor by the Lancet Commission, and area‐level factors, such as neighborhood racial composition (a measure of structural racism) may modify the effects of air pollution. We examined the relationship between air pollution and neighborhood racial composition on memory and decline in a sample of older adults in the United States.MethodNHATS is a nationally‐representative sample of 8,245 participants 65+ years at baseline (2011). Annual averages of fine particulate matter (PM2.5, IQR = 2.2 μg/m3), nitrogen dioxide (NO2, IQR = 5.5 ppb), and ozone (O3, IQR = 8.4 ppb) at baseline and Census ACS data were assigned to the Census tract of participants. The Index of Concentration at the Extremes, defined as: [(number in most disadvantaged extreme, i.e., Blacks) ‐ (number in most privileged extreme, i.e., Whites)]/(total people) was calculated for each census tract as a measure of neighborhood racial composition. A composite measure of episodic memory was constructed as the average of z‐scored delayed and immediate word list recall. We used linear mixed effects models to examine the association between each air pollutant and neighborhood racial composition with memory and memory decline over 6 years, adjusting for a number of individual‐ (age, race/ethnicity, gender, education, smoker, practice effects) and area‐ (census division, urban tract) level covariates, with random effects for census tract and participant.ResultIncreases in air pollution (per IQR) were weakly associated with worse memory at baseline [PM2.5 ‐0.02 (95% CI: ‐0.05, 0.006); NO2 ‐0.03 (‐0.06, 0.002); O3 ‐0.03 (‐0.06, ‐0.0004) SD‐units in memory]. PM2.5 increased the rate of memory decline by ‐0.01 (‐0.02, ‐0.0008); while NO2 increased the rate of memory decline by ‐0.008 (‐0.01, ‐0.0007). Neighborhood racial composition was significantly associated with worse memory (for more disadvantaged neighborhoods) in all air pollution models, but it did not modify the effect of air pollution on memory nor memory decline.ConclusionIn this cohort of older adults, we found that PM2.5 and NO2 increase the rate of memory decline, while neighborhood racial composition does not modify this effect of air pollution.
Phase‐specific health system costs of dementia in Ontario, Canada: A propensity score‐matched cohort study
Authors: Bronskill Susan E , Maclagan Laura C , Mondor Luke , Fu Longdi , Guan Jun , Sewell Isabella J , Iaboni Andrea , Wodchis Walter P , Swartz Richard H , Maxwell Colleen J , de Oliveira Claire 
Published: December 2021

AbstractBackgroundDue to increases in the prevalence of dementia across Canada, the economic burden of dementia on provincial health systems is expected to rise. A better understanding of the phase‐specific costs of dementia care, such as periods immediately prior to and following diagnosis as well as other critical points in the life course are needed to support capacity planning. We estimated the phase‐specific costs of dementia over time among older adults and by sex.MethodWe identified a cohort of 164,640 Ontario residents aged 66+ years, ascertained with incident dementia and residing in the community between April 1st, 2010 and March 31st, 2017. Controls, who had no previous dementia diagnosis, were 1:1 propensity‐score matched to persons with dementia and individuals were followed to death or study end (March 31st, 2018). Costs included inpatient care, emergency department care, ambulatory care, home care, long‐term care, physician and healthcare professional services, and prescription drugs. Phase‐based costing methodology examined mean net costs of dementia care throughout four phases of disease progression (pre‐diagnosis, initial, continuing, terminal) and 5‐year net costs.ResultPersons with dementia and matched controls (mean age 81.3 years; 58.7% female) were followed for an average of 3.2 years. Mean net costs of dementia were highest in the terminal phase ($32,679), followed by the initial ($17,656) and continuing phases ($13,423). Higher costs in the dementia group in the terminal phase were driven by acute care (net cost: $16,324, 95% CI [15,478, 17,170]) and long‐term care ($14,006, 95% CI [13,848, 14,164]). Net home care costs were highest in the initial phase ($1,839, 95% CI [1,796, 1,882]). The net 5‐year cost of dementia was $48,077 (95% CI [$47,183, $48,970]; women had higher 5‐year net costs than men ($50,158, 95% CI [$49,053, $51,263] vs. $44,800, 95% CI [$43,323, $46,277]).ConclusionObserved higher net costs of dementia in specific phases (terminal) and sectors (acute care, long‐term care, home care) highlight where to target interventions to optimize healthcare use and costs that respects quality of life for older adults with dementia and their family care providers.
Quantifying the longitudinal cognitive resilience to Alzheimer’s disease and other neuropathologies
Authors: Wagner Maude , Wilson Robert S , Leurgans Sue E , Bennett David A , Grodstein Fran , Capuano Ana W 
Published: December 2021

AbstractBackgroundCognitive resilience (CR) refers to the ability to maintain a better‐than‐expected cognitive level or slope of cognitive change based on the degree of brain pathology. Different approaches have been used to quantify CR as a continuous variable. These approaches examine cognitive level at a single point or examine cognitive change over time irrespective of cognitive level and assuming a linear change. We propose a continuous measure of CR that reflects cognitive level while taking into account the entire observed non‐linear cognitive trajectory.MethodWe used data from 1220 individuals with ≥2 measures of global cognition and brain autopsy in the Religious Order Study and Rush Memory and Aging Project to compute three versions of CR. The CR1 focuses on cognitive level at a single point. It was calculated as the standardized residuals obtained proximate to death in a linear regression model, with demographics and 8 neuropathologies as covariates. The CR2 represents the residual (random) slope of cognition obtained in a latent process mixed (LPM) model assuming a linear cognitive change. Finally, the proposed CR3 examines cognitive levels over time. It was computed as the mean of differences between person‐specific and marginal error‐free predictions of cognition from a LPM model with time approximated by natural cubic splines. The LPMs of CR2 and CR3 included interactions of demographics and pathology with time. To assess the validity of our approach, we compared the continuous associations of CRs with established reserve risk factors (e.g., cognitive activity) and dementia risk factors (e.g., depressive symptoms, neuroticism) at cohort baseline.ResultThe proposed CR3 was highly correlated with CR1 (r=0.81) and moderately correlated with CR2 (r=0.51). The established reserve risk factors were all associated with CR1 and CR3 but not with CR2, and effect estimates were largest for CR3. All CRs were negatively associated with depressive symptoms and neuroticism (all‐P<.0004), but none was associated with ApoE‐ε4 (all‐P>.508). In a sensitivity analysis, we showed that findings remained consistent when randomly reducing repeated measures of cognition or allowing only a 10‐year follow‐up.ConclusionIncorporating longitudinal cognitive levels is an alternate way to quantify CR in cohort studies.
Plasma Ab42/40 levels differ by postmenopausal stage
Authors: Maki Pauline M. , Ances Beau M. , Terpstra Melissa , Salat David H. , Woods Roger , Essen David , Barch Deanna M. , Bookheimer Susan Y. 
Published: December 2021

AbstractBackgroundAlthough all women who live into late life experience reproductive aging (menopause), there is little understanding about how reproductive aging, as distinct from chronologic aging, influences the development of AD. Studies indicate that some AD biomarkers differ between peri‐ and postmenopausal women, but no studies to date have examined AD biomarkers across (sub)stages of the postmenopause. Here we compared plasma Ab42/40 levels in Early versus Late Postmenopausal women. We hypothesized that plasma levels of Ab42/40 would be lower in the Late versus Early Postmenopause group.MethodParticipants included women from the Human Connectome Aging Project who had plasma Ab42/40 and were either in the Early Postmenopause (i.e., Stages +1a, +1b or +1c; >0 and <6 years after the final menstrual period; FMP) or Late Postmenopause (Stage +2; > 6 years after the FMP) according to the Stages of Reproductive Aging Workshop +10 criteria. Plasma Aβ42/40 was measured using an immunoprecipitation and liquid chromatography‐mass spectrometry assay. A univariate analysis of variance was conducted to compare plasma Ab42/40 in Early versus Late Postmenopause groups controlling for age, education, MOCA score, and ApoE carrier status.ResultThe sample included 42 women (mean age=66.2 years; mean MoCA=25.88; 73.8% white). Plasma Ab42/40 were significantly higher in the Early (n=10; mean age=55.77) versus Late Postmenopause (n=32; mean age=69.44) groups with mean values of 0.11 (SE=.002) and 0.103 (SE=.001), respectively, F(1,28)=7.23, p=.01. We restricted a second analysis to women age 60 years and under to optimally control for age differences between the groups (n=18, mean age=56.56 years; mean MOCA=26.04; mean education=17.17 years; 56% white, Early n=10). Again, plasma Ab42/40 were significantly higher in the Early (n=10; mean age=55.77) versus Late Postmenopause (n=32; mean age=57.56) groups with mean values of 0.11 (SE=.002) and 0.105 (SE=.003), respectively, F(1,13)=6.52, p =.025.ConclusionAdvanced reproductive stage, independent of chronologic age, may be associated with a lower plasma Ab42/40, a pattern shown to be predictive of the development of AD. These findings add to a body of AD biomarker studies showing differences between perimenopausal and postmenopausal women, and suggest that AD biomarkers also differ within distinct stages of the postmenopause.
Exercise: Just what the doctor ordered, but why? Elucidating mechanisms for women’s increased HDL benefit from exercise
Authors: Bernier Rachel A. , Banks Sarah J. , Clark Alexandra L. , Shepherd Alyx L. , Sundermann Erin E. 
Published: December 2021

AbstractBackgroundHigh‐density lipoprotein (HDL) is protective against cardiovascular disease (Di Angelantonio et al., 2009), a risk factor for AD pathogenesis (Brickman et al., 2015). Aerobic exercise can increase HDL concentration (Hsu et al., 2019), and evidence suggests this HDL benefit occurs more so in women than in men (Werner et al., 1995). Both HDL and exercise are associated with tumor necrosis factor alpha (TNFα), a proinflammatory cytokine (Park et al., 2003). Given known sex differences in the immune response (Hanamsagar & Bilbo, 2016), TNFα levels may represent a potential mechanism by which women’s HDL levels benefit more so from exercise. We sought to replicate the stronger exercise‐HDL link in women versus men and examine TNFα as a potential mediator in a group of cognitively normal (CN) older adults.MethodThis study included 2957 CN participants (51% women; 41% Black, 59% White; mean age=73.6 (SD=2.9) years) from the Health, Aging, and Body Composition (Health ABC) study who underwent a blood draw for biomarker analysis of HDL and TNFα levels. Exercise level was measured via a standardized physical activity questionnaire categorized (0‐6) based on Kcal/week for all types of walking, exercise, and recreation, and examined continuously. Regression analyses were employed to examine exercise‐by‐sex interactions on HDL‐level (mg/dL) and the mediating effect of TNFα (pg/mL). Covariates included age, race, and body mass index.ResultRegressions adjusting for covariates revealed significant exercise‐by‐sex interactions on HDL (ß=0.12, p=.022), whereby higher levels of exercise related to higher HDL in women (ß=0.06, p=.023) but not in men (ß=‐0.01, p=.653). TNFα level negatively related to HDL in women (ß=‐0.24, p<.001), and adjusting for TNFα eliminated the female‐specific exercise‐HDL association (ß=0.04, p=.150).ConclusionThis female‐specific association was eliminated when adjusting for TNFα, suggesting that exercise may benefit HDL in women through ameliorating effects on the neuroinflammatory pathway. Findings underscore the importance of exercise as a mitigator of vascular risk and, in turn, AD risk, particularly in women. Future studies should examine these interrelationships longitudinally and across the AD spectrum.
Evaluation of class C CpG ODN efficacy and safety profile in a squirrel monkey model of AD pathology
Authors: Patel Akash G , Nehete Pramod N , Nehete Bharti P , Karimi Sohail G , Genovese Thomas S , Debure Ludovic , Drittel Brian D , Guttman Daniel Ezra , Williams Lawrence E , Wisniewski Thomas , Scholtzova Henrieta 
Published: December 2021

AbstractBackgroundA drawback of current immunotherapeutic approaches is limited effectiveness against cerebral amyloid angiopathy (CAA) and CAA‐linked complications. The failures of many Alzheimer’s disease (AD) clinical trials have been related to poor translatability of promising rodent data to humans. Our initial study using a non‐human primate (NHP) model of AD amyloid pathology with a propensity for developing abundant CAA, squirrel monkey (SQM), indicates that chronic administration of TLR9 agonist, Class B CpG ODN, safely ameliorates CAA. Here, we advanced our work to evaluate the long‐term efficacy and safety of Class C CpG ODN, which has shown favorable safety profiles in a variety of human diseases. The present study was designed to assess CpG ODN immunostimulatory patterns and to monitor disease progression by a combination of behavioral measures and biomarker signatures of pathology development.MethodGeriatric SQMs received either CpG ODN or saline every 4 weeks as part of an ongoing long‐term treatment study (currently in month 22). Changes in mRNA expression levels were periodically evaluated in isolated PBMCs prior to and 24hrs after representative injections using the Nanostring nCounter System. SIMOA and Luminex assays were used to measure AD related fluid biomarkers. Both treatment groups were subjected to locomotor activity testing prior to cognitive assessment.
ResultLongitudinal Nanostring analyses demonstrated significant up‐regulation of IFN‐inducible genes (e.g., IFIT2, Mx2/MxB, GBP1, MIG, IP10), specific cytokine‐chemokine genes, and TLR9 signaling genes (e.g., UNC93B1) following CpG ODN injections. Ongoing SIMOA examination of neurofilament light, a biomarker of neurodegeneration, showed higher plasma levels in the control group compared to CpG ODN group. Our preliminary measurements of a biomarker of glial injury, YKL‐40, indicated increased plasma levels in control animals compared to CpG ODN‐treated animals. Monitoring of additional AD pathology and cerebrovascular dysfunction biomarkers throughout the treatment period will further assess CpG ODN efficacy and safety. Importantly, no significant differences were observed between treatment groups in locomotor performance. Cognitive assessments are underway.ConclusionOverall, the present findings provide essential information prior to any clinical use of CpG ODN in AD. The use of this advantageous model is important to reach efficient translation for human benefit.