bluuebunny/crossref_metadata_2025_split huggingface dataset:
The PRagmatic EValuation of evENTs And Benefits of Lipid‐lowering in oldEr adults (PREVENTABLE) trial: Study design and procedures for cognitive assessment and adjudication
Authors: Sachs Bonnie C. , Rapp Stephen R. , Kistler Christine E , Musi Nicolas , Supiano Mark A. , Pajewski Nicholas M. , Callahan Kathryn E. , Alexander Karen P. , Shah Raj C , Snyder Heather M. , Carrillo Maria C. , Espinoza Sara , Williamson Jeff D. 
Published: December 2021

AbstractBackgroundNo existing therapies for Alzheimer’s disease and related dementias fundamentally alter the trajectory of the disease. While observational data suggests statins may reduce cognitive and functional decline in older adults, randomized evidence is lacking.MethodThe PRagmatic EValuation of evENTs And Benefits of Lipid‐lowering in oldEr adults (PREVENTABLE) trial is funded by the National Institute on Aging, National Heart, Lung, and Blood Institute, and supported by the Alzheimer’s Association. The trial will test the primary hypothesis that randomization to atorvastatin 40 mg versus placebo results in superior survival free of incident dementia or persistent physical disability over 5 years. The development of mild cognitive impairment (MCI) is a secondary endpoint. The target sample size is 20,000 participants ≥75 years without dementia recruited from 90 sites across the US from the National Patient‐Centered Clinical Research Network and the Veterans Affairs system. The trial will use a pragmatic, standardized telephone‐based cognitive battery, centrally administered annually, which includes a cognitive screener, the Telephone Interview for Cognitive Status‐modified (TICSm). Based on TICSm scoring, an extended phone cognitive battery will be performed that includes measures of attention/executive function, verbal memory, language, and mood. In addition, the Functional Activities Questionnaire will be administered to a trusted contact. A telephone assessment of physical and functional status will also be administered annually. Cognitive and functional data will be adjudicated by a panel of experts, blinded to treatment assignment, to determine the occurrence of MCI (and subtype) or probable dementia.ResultPREVENTABLE will utilize pragmatic data sources (electronic health records and administrative claims) to obtain relevant medical data; however, these mechanisms are unreliable at identifying incident dementia and MCI. The pandemic required modification of cognitive testing, embracing a purely telephonic approach at baseline, which will nonetheless permit cognitive adjudication of participants. Recruitment will be ongoing through April 2023 with results available in 2026.ConclusionPREVENTABLE represents the largest randomized pragmatic trial examining cognitive outcomes associated with statin use in older adults. Launching during the pandemic required adaptation to remote assessment, which will facilitate progress towards efficient and novel methods for pragmatic clinical trials aimed at preventing dementia.
Quantitative R1 in the locus coeruleus in Alzheimer’s disease dementia
Authors: Bhalla Deepali M. , Kohli Akshay , Betts Matthew , Pasquesi Mary‐Elizabeth , Nair Veena A. , Düzel Emrah , Kecskemeti Steven R. , Alexander Andrew L. , Johnson Sterling C. , Prabhakaran Vivek , Bendlin Barbara B. 
Published: December 2021

AbstractBackgroundPrior studies employing neuromelanin‐sensitive MRI have linked neurodegeneration in the locus coeruleus (LC) to Alzheimer’s disease (AD) pathology. MPnRAGE (Keckskemeti et al., 2016), a novel MRI technique developed at UW‐Madison, generates multiple inversion recovery contrasts and quantitative T1 relaxometry. Quantitative R1 (= 1/T1), the longitudinal relaxation rate, is sensitive to brain myelin, lipid, and iron content according to post‐mortem studies. As prior studies suggest altered quantitative R1 (QR1) among individuals with AD pathology, this imaging marker may be sensitive to AD‐associated pathology in the LC, one of the first regions in the brain to show signs of AD pathology (Braak et al., 2011). Here we performed preliminary assessments to test for differences in QR1 among individuals with and without clinical mild cognitive impairment (MCI‐AD), or AD dementia. We hypothesized that R1 would be lower among individuals with AD and MCI compared to unimpaired controls.MethodParticipants were enrolled in the Alzheimer’s Disease Connectome Project (ADCP) at UW‐Madison. 103 older adults diagnosed as cognitively unimpaired (N=53), MCI‐AD, and AD‐Dementia (Table 1) underwent MPnRAGE at a 1mm3 resolution. MPnRAGE‐derived QR1 maps were registered to MNI space using SPM12. LC masks (from Betts et al., 2017) were transformed to subject space to extract mean R1 in the bilateral LC using the Marsbar toolbox. Multiple linear regression was run within Rstudio to investigate the relationships between age, R1, and diagnosis. The main effects of interest included age and diagnosis, as well as their interaction. Sex was included as a covariate.ResultNo significant associations were found between QR1 and age, diagnostic status, and their interaction. The main effect of age on R1 trended toward significance (p=0.059). Age trends are shown in Figure 1. Sex was not a significant covariate.ConclusionWhile QR1 was not significantly associated with age or clinical diagnosis within the LC, further research will evaluate the extent to which QR1 is altered among other regions affected by AD pathology. Further, R1 could be tested between groups stratified by AD biomarker status. Finally, the LC is a small structure, thus future work could also test R1 estimated at higher resolution.
Cardiovascular risk moderates aerobic exercise efficacy on executive function in subcortical ischemic vascular cognitive impairment
Authors: Liu‐Ambrose Teresa , Barha Cindy K , Dao Elizabeth , Hsiung Ging‐Yuek Robin , Marcotte Lauren , Tam Roger 
Published: December 2021

AbstractBackgroundAerobic exercise can promote cognitive function in adults with Subcortical Ischemic Vascular Cognitive Impairment (SIVCI) by modifying cardiovascular risk factors. However, one’s cardiovascular health may attenuate the benefits of aerobic exercise on cognitive outcomes in SIVCI. We examined whether baseline Framingham Cardiovascular Risk Profile Score (FCRP) moderates the effect of a 6‐month progressive aerobic exercise program on executive function in adults with SIVCI.MethodA secondary analysis of a proof‐of‐concept randomized controlled trial in 71 adults, who were randomized to either: 1) 3x/week progressive aerobic exercise program (AT); or 2) education program (CON). Three executive processes were measured: 1) response inhibition by Stroop Colour Word Test; 2) working memory by digits backward test, and 3) set shifting by the Trail Making Test (B‐A). Baseline cardiovascular risk was calculated using the FCRP, and participants were classified as either low risk (<20% FCRP score; LCVR) or high risk (>20% FCRP score; HCVR). A complete case analysis (n=57) was conducted using an analysis of covariance (ANCOVA) to evaluate between‐group differences in the three executive processes. Age, baseline Montreal Cognitive Assessment score, education, and baseline score for the outcome variable were entered as covariates in all models.ResultA significant interaction was found between FCRP and group (AT or CON) for the digit span backward (F(1,49)=4.67, p=0.03) and the Trail Making Test (F(1,50)=4.09, p=0.04). On the digit span backward test, AT improved performance compared to CON (3.74±.33 vs. 2.75±.46) in those with LCVR, while in those with HCVR, AT did not improve performance compared to CON (2.97±.45 vs. 3.76±.41). Similarly, for the Trail Making Test (B‐A), AT improved performance compared to CON (52.66±13.27 vs. 80.12±17.82) in those with LCVR, while AT was not beneficial compared to CON in those with HCVR (98.80±18.06 vs. 59.92±17.09).ConclusionBaseline cardiovascular risk significantly moderates the efficacy of aerobic exercise on working memory and set shifting in adults with SIVCI. Our findings highlight the importance of intervening early in the disease course of SIVCI, when cardiovascular risk may be lower, to reap maximum benefits of aerobic exercise.
CSF and blood biomarkers: How strongly do they reflect Alzheimer's pathophysiology and are they dynamic?
Authors: Zetterberg Henrik , Karikari Thomas K. 
Published: December 2021

AbstractBackgroundThe past few years have seen a rapid development of biofluid‐based biomarkers for Alzheimer’s disease (AD) pathophysiological processes. The goal of this presentation is to critically review how well the currently available biofluid‐based biomarkers for AD reflect brain pathological changes. This has important implications for the interpretability of biomarkers in clinical trials and practice, and for how fluid‐based biomarkers could be most effectively used together with imaging in different contexts.MethodAn overview of the biofluid‐based biomarker landscape with emphasis on amyloid accumulation, tau aggregation, neurodegeneration, synaptic dysfunction, glial activation, and inflammation will be given. Available data on biomarker concentrations and dynamics in relation to tissue changes will be scrutinized, and the lack of anatomic information discussed.ResultOriginally, CSF and plasma total tau (T‐tau) and phosphorylated tau (P‐tau) concentrations were thought to reflect neurodegeneration and tangle pathology, respectively. However, animal and human experimental studies now suggest that CSF and plasma T‐tau and P‐tau reflect amyloid β (Aβ)‐induced neuronal tau phosphorylation and secretion, which in turn may be predictive of future neurodegeneration and tangle pathology. CSF Aβ42/Aβ40 ratio is the fluid biomarker with the firmest correlation with brain pathology; the ratio reliably reflects Aβ accumulation in the brain. Similar results have recently been obtained using plasma. But why does this biomarker show such an intriguing bimodal distribution? How rapid is the change from a normal to abnormal ratio? Regarding neurodegeneration, the best‐established biomarker is neurofilament light (NfL). It can be measured in CSF and blood, but can the two sample types be used interchangeably? And how can we be certain that a change in NfL reflects a change in AD‐related neurodegeneration and not something else, e.g., cerebrovascular disease? Biomarkers for synaptic dysfunction, glial activation, and inflammation will be discussed in similar ways.ConclusionCSF and plasma Aβ42/Aβ40 ratio is a relatively direct marker of brain Aβ pathology, whilst the other biomarkers seem to reflect tissue reactions to Aβ, which likely eventually translates into manifest neuropathological changes. More research using imaging and neuropathological measures is needed to validate and examine this further.
Cognability: An ecological model of cognitive function and neighborhood design
Authors: Finlay Jessica M , Esposito Michael , Clarke Philippa 
Published: December 2021

AbstractBackgroundNeighborhood environments are linked to multiple established risk factors for cognitive decline and dementia including physical inactivity, depression, obesity, hypertension, and diabetes. As an upstream influence on modifiable risk factors, neighborhood environments may help delay or prevent the onset of cognitive impairment. They may promote physical activity, social engagement, intellectual stimulation, and healthy eating; reduce exposure to air pollution; and limit stress levels related to environmental factors such as traffic and noise. Ecological theoretical models of cognitive health are needed to systematically investigate the environments in which people develop and navigate cognitive decline. This paper builds evidence for a new concept of ‘cognability’: an innovative theoretical approach to indicate how supportive a neighborhood is to cognitive health through community resources and neighborhood amenities that support socially, physically, and intellectually active aging in place.MethodWe conducted analyses in the Reasons for Geographic and Racial Differences in Stroke study, a national sample of aging Black and white Americans (n=21,151, mean age at assessment 67 years). We used a confirmatory factor analysis of five cognitive tests measuring verbal learning, memory, and executive function (Root Mean Square Error of Approximation=0.013; Comparative Fit Index=0.999), and output standardized scores for each participant. Contextual measures were created for urban‐dwelling participants using a kernel density method to capture proximity and availability of neighborhood amenities. Multilevel generalized additive models estimated associations between global cognitive function and access to neighborhood places for physical activity, socialization, and intellectual stimulation.ResultAnalyses identified statistically significant positive associations between cognitive function and access to civic and social organizations (p‐value=<0.001), senior centers (p‐value=0.004), coffee shops and fast‐food restaurants (p‐value=<0.001), parks (p‐value=<0.001), recreation amenities (p‐value=0.023), walkable destinations (p‐value=<0.001), and arts/cultural sites (p‐value=<0.001).ConclusionLiving in neighborhoods with more opportunities for social interaction, physical activity, and intellectual stimulation may support cognitive function among older adults aging in place. Promoting ‘cognability’ via neighborhood intervention and urban planning may complement and enhance biomedical and individual lifestyle approaches.
Protective effects of eicosapentaenoic acid on metabolic features and cognitive function in the APPswePS1dE9 Alzheimer’s mouse model
Authors: Yavari Mahsa , Ramalingam Latha , Harris Breanna N , Kahathuduwa Chanaka , Chavira Angela , Biltz Caroline , Mounce Philip , Alers Kaylee Alers , Davis Mckenna , Zu Yujiao , Moustaid‐Moussa Naima 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) is characterized by amyloid‐beta (Aβ) plaque deposition and may be exacerbated by aging‐induced neuroinflammation and obesity. We hypothesized that compared to high fat (HF) diets, FO with anti‐inflammatory and anti‐obesity properties, would reduce metabolic and cognitive dysfunctions in an AD amyloidogenic mouse model of obesity.MethodTwo‐month‐old, both sexes, APPswePS1E9 transgenic (TG) and non‐TG littermates were randomly assigned and fed low fat (LF), HF, or HF supplemented with FO for eight months (n=8‐10/group). Body weight and food intake were recorded weekly, and body composition was measured bi‐monthly. Glucose Tolerance Test (GTT) and Morris water maze (MWM) were measures at 5‐ and 9‐ months, respectively. At termination, blood and tissues were collected. Serum Aβ‐40 levels were measured by immune‐multiplexing. Missing data were imputed via multiple imputations. Outcomes were analyzed in three‐way ANOVA, modeling genotype interactions, sex and diet, and subsequent Tukey‐corrected pair‐wise comparisons using R (version 4.0.2).ResultOn average, fat mass (FM) of non‐TG mice did not differ from TG mice. However, TG mice ate more (p < 0.001), trended towards lower glucose clearance (p = 0.066) and had higher Aβ‐40 (p < 0.05) vs. non‐TG mice. On average, male were fatter (p < 0.001) and more glucose intolerant compared to female mice (p < 0.001), yet there were no sex differences for Aβ‐40 (p = 0.8718). On average, LF diet decreased final FM and improved GTT vs. HF and FO diets (p < 0.001); however, adiposity and GTT were not different between FO and HF fed mice. Interestingly, compared to HF, FO decreased serum Aβ‐40 in TG male mice (p = 0.0182), but not among TG female or non‐TG mice. This unique between‐group difference was not apparent for FM or GTT. In MWM test, HF non‐TG mice found the platform faster than TG mice (p = 0.037).ConclusionOverall, LF diets conferred metabolic improvements over HF diets, while long term supplementation of FO to HF diets had limited metabolic and cognitive benefits. Interestingly, FO reduction of serum Aβ‐40 in AD mice merits further investigation.
Correlations between neuropsychological performance and functional measures: Preliminary findings from the novel cognitive and functional measure for Alzheimer’s Disease prevention trials (NoMAD)
Authors: Bell Sophie A. , Kim Hyun , Cohen Hannah R. , Lee Seonjoo , Rivera Andres M. , Brickman Adam M. , Harvey Philip D. , Schneider Lon S. , Gordon Marc L. , Goldberg Terry E. 
Published: December 2021

AbstractBackgroundTwo novel measures of cognition and function, the No Practice Effects (NPE) cognitive battery and the Miami Computerized Functional Assessment Scale (CFAS), were designed to have robust psychometric properties and reduced practice and ceiling effects for use in preclinical and early‐stage Alzheimer’s disease clinical trials. In this preliminary analysis, we sought to identify different cognitive domains in the NPE and evaluate their relationships with the CFAS functional measures.MethodFifty‐one cognitively healthy older adults (mean age 69.44 ± 6.29, 65.30% female) with baseline cognitive and functional assessments were included. We conducted an exploratory factor analysis to identify different cognitive domains within the NPE. We then computed a composite score for each domain and conducted partial Spearman correlations with CFAS functional measures, controlling for age, education and gender, and intracranial volume.ResultThe factor analysis yielded three factors corresponding to 1) episodic memory, 2) non‐verbal executive processes and speed, and 3) verbal working memory (loadings > 0.5). Composite scores from these factors exhibited strong correlations with CFAS functional measures. In particular, a greater executive functioning and speed composite score was significantly associated with a faster completion time (rs’s ≥‐.44) and more efficient performance (rs’s ≥.37) on most CFAS functional measures (p’s<.05).ConclusionMulti‐domain factors were identified in our novel cognitive measures. These cognitive domains strongly correlated with everyday functioning measures. Our results suggest that cognitive measures, particularly processing speed and executive function measures, obtained in clinic may be related to everyday function in older adults.
A study of MCI drivers' perception and acceptability of safety support
Authors: Suzuki Mio 
Published: December 2021

AbstractBackgroundIn Japan, around 30% of the older adults have dementia or MCI, and many of them drive daily. They have encouraged to surrender their driving licenses, but that have not been effective. It's said that older adult drivers are not aware of the dangers of driving, and they're not willing to switch to safety support vehicles. Hence in this study, I examined the relationship between MCI drivers’ driving behavior and their awareness or acceptability of safety support.MethodIn this study, the 196 subjects including MCI or dementia drove in a driving school to induce dangerous driving. When their behavior was dangerous, the following safety support was provided, and the changes in driving behavior and awareness were recorded: 1) The instructor sitting in the passenger seat gave advice at that moment, 2) The instructor gave advice after the experiment, 3) A alert was sounded, 4) Their driving were evaluated by scoring. After a few months, it was checked whether the subjects remembered the behavior and advice. The driving behavior on public roads was also recorded, and the awareness was investigated when the advice given later.ResultIt was found that MCI drivers behaved dangerously when the driving load was increased by multitasking, whether in a driving school or on public roads. However, since they underestimated their own dangerous driving and did not recognize it as dangerous, the post‐experimental advice was found to be ineffective. On the other hand, it was also revealed that giving advice or sounding a warning sound at the moment of dangerous driving increased the mental load of MCI subjects and might have negative effects on their subsequent driving. In the case of MCI drivers, the advice induced risky driving because they became too attached to the advice and neglected other driving skills.ConclusionAlthough immediate and specific driving advice or warnings are generally considered effective, they have been found to have a negative effect on MCI drivers. On the other hand, it is necessary to develop safe driving support measures that are immediate but do not give too much information, because drivers forget about dangerous driving over time.
Blood markers of neuronal/axonal and glial injury for clinical progression in a predominately Hispanic cohort: The Texas Alzheimer’s Research and Care Consortium
Authors: Gonzales Mitzi M. , Wang Chen‐Pin , Short Meghan I. , MacCarthy Daniel , Kautz Tiffany , Satizabal Claudia L. , Zare Habil , O'Bryant Sid , Seshadri Sudha 
Published: December 2021

AbstractBackgroundThe clinical translation of biofluid markers for Alzheimer’s disease and related dementias (ADRDs) requires validation in diverse cohorts. The goal of the study was to evaluate if blood biomarkers of neuronal/axonal and glial injury predict cognitive decline and clinical disease progression in a predominately Hispanic cohort from the Texas Alzheimer’s Research and Care Consortium.MethodParticipants included 745 Hispanic and 274 non‐Hispanic white participants, aged 55‐89 years, who annually completed cognitive assessments, the Clinical Dementia Rating scale (CDR), and dementia consensus reviews. Serum from the baseline examination was assayed to quantify levels of total tau (t‐tau), neurofilament light (NFL), ubiquitin carboxyl‐terminal hydrolase LI (UCHLI), and glial fibrillary acidic protein (GFAP) using the Simoa Neurology 4‐Plex Kit (Quanterix), as well as soluble CD14 (sCD14) and chitinase‐3‐like protein 1 (YKL‐40) using commercial ELISAs (R&D Systems). Generalized estimating equations were used to evaluate the associations between serum biomarkers and longitudinal cognitive outcomes, as well as disease progression (CDR Sum of Boxes), adjusting for covariates of age, sex, ethnicity, education, body mass index, systolic blood pressure, diabetes, APOE ε4 status, and clinical diagnosis. Cox proportional hazard models were used to evaluate the associations between serum biomarkers and incident mild cognitive impairment (MCI) and dementia with adjustment for the covariates listed above.ResultAcross the average four‐year follow‐up period, 162 individuals developed MCI and 96 developed dementia (Table 1). As displayed in Table 2, serum GFAP levels predicted cognitive decline across most cognitive domains. Serum t‐tau levels were associated with declines in global cognition, learning, and memory. Serum GFAP (b=0.154, SE=0.028, p<0.001), NFL (b=0.069, SE=0.026, p=0.007), and t‐tau (b=0.065, SE=0.023, p=0.004) predicted clinical progression. Higher GFAP levels at baseline were associated with increased risk of incident dementia (HR=1.485, p=0.009). None of the biomarkers predicted incident MCI.ConclusionSerum GFAP levels were associated with multi‐domain cognitive decline, clinical progression, and incident dementia risk. The results suggest that reactive astrogliosis may be an important mechanism underlying a progressive neurodegenerative disease course in our predominately Hispanic sample. With further validation, serum GFAP may hold utility for predicting disease progression and monitoring the efficacy of newly emerging treatments.