bluuebunny/crossref_metadata_2025_split huggingface dataset:
Self‐reported sleep duration is not associated with pet amyloid deposition in the oldest‐old: The 90+ Study
Authors: Melikyan Zarui A. , Mander Bryce A , Greenia Dana E. , Fletcher Evan M. , DeCarli Charles , Phelan Michael , Kawas Claudia H. , Corrada Maria M.M. 
Published: December 2020

AbstractBackgroundSome, but not all cross‐sectional studies have suggested a relationship between sleep and PET‐measured amyloid burden in older adults without cognitive impairment. It is hypothesized that amyloid clearance from the brain is related to sleep duration. Our aim is to examine the cross‐sectional association between self‐reported sleep duration and amyloid accumulation in the oldest‐old (90+ years), a group with high prevalence of amyloid burden and sleep changes.MethodWe analyzed data on 115 participants of The 90+ Study, a longitudinal study of aging and dementia, who reported their monthly average nocturnal sleep duration using the Medical Outcomes Study Sleep Scale (MOS) and had 18F‐florbetapir (amyloid) PET. Sleep duration was categorized as <8, 8 (reference, mean sleep duration) and >8 hours. Standardized uptake value ratio (SUVr) was computedfor the posterior cingulate/precuneus (region affected early by Alzheimer’s neuropathological changes) and analyzed both as continuous and binary (SUVr <0.8 vs. ≥0.8) variables. Cognitive diagnosis from the clinical evaluation closest to PET was used to categorize participants as normal vs. cognitively impaired (dementia or cognitive impairment without dementia). We analyzed sleep duration in relation to SUVr using multiple linear regression and logistic regression, controlling for age, Geriatric Depression Scale score, sleep medications, and cognitive diagnosis at the time of MOS; and additionally sex, education, APOEe4 status, and time between MOS and PET.ResultAt the time of MOS, average age was 95 years, 60% were women, 65% had normal cognition. The average sleep duration was 8 hours. Average PET SUVr was 0.77 and 33% of participants were amyloid positive. Amyloid burden was higher (0.80 vs. 0.75) and sleep was longer (8.14 vs. 7.51 hours) in cognitively impaired compared to cognitively normal participants (Table 1). Sleep duration was not associated with amyloid accumulation in the entire group analysis or when stratified by cognitive diagnosis (Tables 2 and 3, Figure 1).ConclusionIn this group of oldest‐old individuals, self‐reported sleep duration was not associated with amyloid accumulation in the posterior cingulate/precuneus. It is possible that amyloid accumulation is not associated with sleep in this age group or it is associated with other sleep‐related measures.
Role of extracellular vesicles in early synaptic dysfunction in AD
Authors: Prada Ilaria , Gabrielli Martina , D'Arrigo Giulia , Arancio Ottavio , Verderio Claudia 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with amyloid‐β (Aβ) and tau protein accumulation. Synaptic dysfunction is an early mechanism in AD which involves progressively larger areas of the brain over time. However how synaptic dysfunction starts and propagates is unknown. The hypothesis we are testing is that extracellular vesicles (EVs) released by microglia exposed to and carrying Aβ42 (Aβ‐EVs) may be responsible for these early events in AD.MethodCombining optical manipulation and time lapse imaging to place single EVs on RFP‐positive cultured neuron dendrites and test their effects on the synapse, we show that Aβ‐EVs rapidly alter dendritic spine morphology (a structural correlate of synaptic strength) locally at the site of interaction.ResultAβ‐EVs induce a significant increase in the density of immature protrusions around the contact site (<7 µm from the contact point) starting 2 min after EV adhesion, compared to EVs released by microglia not exposed to Aβ42 (ctrl‐EVs). Almost no alteration was detected far from the contact site (>60 µm).ConclusionEmploying the same methodologies, we are currently monitoring Aβ‐EV‐neuron dynamics at the neuronal surface, to test whether Aβ‐EVs may propagate dendritic spine alterations to adjacent regions over time, contributing to the spreading of synaptic deficits. Our data provide evidence of the involvement of microglial EVs in early synaptic dysfunction in AD, paving the way for novel therapeutic strategies.
Prescription medications and co‐morbidities in late middle‐age are associated with lower executive function: Results from WRAP
Authors: Du Lianlian , Koscik Rebecca L , Chin Nathaniel A , Bratzke Lisa C , Cody Karly Alex , Erickson Claire M , Jonaitis Erin M , Mueller Kimberly D , Johnson Sterling C 
Published: December 2020

AbstractBackgroundAging is often accompanied by the accumulation of chronic illnesses such as diabetes, cardiovascular disease or hypertension and a corresponding increase in use of medications to manage these conditions. Polypharmacy (use of multiple prescription medications) is a growing health concern and has been associated with poorer clinical outcomes in older adults. This study investigates associations between comorbidities, polypharmacy and longitudinal cognitive performance in an Alzheimer’s disease (AD) risk‐enriched cohort, the Wisconsin Registry for Alzheimer’s Prevention (WRAP).MethodEligible WRAP participants included 1039 (free of dementia or clinical impairment not due to mild cognitive impairment (MCI) and with >=2 visits with cognitive composites, self‐reported health history, and concurrent medication records. Sums of prescribed medications and self‐reported co‐morbidities (include self‐ report over the lifetime) (Table 1) were calculated for each visit and converted to z‐scores for use in mixed effects models of cognition (covariates: age, gender, education, WRAT III reading recognition, practice and study site). Linear mixed effects analyses first examined whether associations between medications, comorbidities and cognitive z‐scores varied across cognitive domains of working memory, immediate recall, delayed recall, executive function, and a preclinical Alzheimer’s cognitive composite (PACC3) before examining associations with each cognitive composite. In secondary analyses, we examined whether number of medications and comorbidities interacted with each other or modified age trajectories.ResultSample characteristics are shown in Table 2 overall and by gender (mean(sd) baseline age=58.99(6.60)). More comorbidities were associated with more prescription medications (Figure 1). More comorbidities and medications were associated with lower executive function (β = ‐0.11, p=.002; β = ‐0.07, p = 0.047; Table 3); using z‐scores of 10th and 90th centile with model parameters, those with low co‐morbidities and medications performed an average of 0.39 SD higher than those elevated on both (Figure 2).ConclusionAssociations between medications, comorbidities, and executive function suggest that persons with more comorbidities and medications may be either at increased risk of reaching clinical levels of impairment earlier than healthier, less medicated peers, or may have potentially reversible clinical impairment. Researchers should be aware of the possibility that medication use and comorbidity may impact cognitive performance (and by extension, adjudicated cognitive status).
Perivascular space dilation in white matter mediates a significant relationship between white matter hyperintensity burden and venous collagenosis
Authors: Lahna David , Schwartz Daniel L. , Woltjer Randy , Black Sandra E. , Roese Natalie E. , Dodge Hiroko H. , Boespflug Erin L. , Keith Julia , Gao Fuqiang , Ramirez Joel , Silbert Lisa C. 
Published: December 2020

AbstractBackgroundPeriventricular T2 MRI white matter hyperintensities (WMH) are commonly observed in older individuals and are associated with cognitive and motor decline. While likely vascular in origin, the specific etiology of WMH remains unknown. Vascular insufficiency due to venous collagenosis has been implicated. Collagenosis may also interfere with perivascular fluid flow leading to dilation of perivascular spaces (PVS). PVS are thus an unexplored potential mediating factor between collagenosis and periventricular WMH.MethodBrain tissue from 25 Oregon Alzheimer’s Disease Center subjects was selected based on availability of in vivo 1.5 Tesla MRI (Table 1), which was used to quantify whole brain WMH burden. Three paraffin embedded 6μm thick coronal blocks of tissue per subject from anterior, middle and posterior white matter abutting the ventricle were stained with Masson’s Trichrome and Smooth Muscle Actin (SMA). Slides were scanned and an automated hue based algorithm identified 547 vessels and segmented them into blue collagen vessel walls, lumen holes within them and perivascular spaces outside them (Figure 1). Pearson correlation coefficients were calculated to assess relationships between PVS, periventricular WMH and collagenosis. Coregistered SMA images were used to classify vessels into veins (n=163) and arteries (n=251). Multiple linear regressions accounting for sex, age at death, and MRI to death interval followed by a Sobel test of mediation were calculated to determine the mediating effect of PVS on the relationship between collagenosis and periventricular WMH.ResultPeriventricular WMH volume, collagenosis and PVS were correlated with each other (p<.001) (Figure 1). In separate regression models, PVS and collagenosis in veins were significant predictors of WMH volume (p=.005, p=.007) but not in arteries (p=.256, p=.244). A Sobel test of the mediating effect of PVS on the relationship between collagenosis in veins and WMH burden was significant (p=.027) and the remaining direct effect of collagenosis on WMH was not significant (p=.21) (Figure 2).ConclusionPerivascular space dilation is an under recognized mechanism which may mediate the relationship between the development of venous collagenosis and periventricular WMH in an aged population.
The association of pain with dementia: Findings from the Mexican Health and Aging Study, 2012‐2015
Authors: Milani Sadaf Arefi , Rodriguez Martin A. , Samper‐Ternent Rafael , Wong Rebeca 
Published: December 2020

AbstractBackgroundMounting evidence suggests that pain is associated with cognitive decline; however, most of these studies are limited to high‐income countries. As the number of older adults living in low and middle‐income countries (LMICs) increases, by 2030 the majority of individuals living with dementia will reside in these countries. This makes Mexico, a LMIC facing a rapidly aging population, an important setting to investigate the relationship between pain and dementia.MethodsUsing data from the 2012 and 2015 waves of the Mexican Health and Aging Study (MHAS), a longitudinal, nationally representative study of Mexicans aged 50 and older, we assessed the association between pain and dementia. Participants who completed a direct interview, had complete information on pain, dementia, and relevant covariates, and who did not have dementia in 2012 were included (n=10,617). Pain was categorized as no pain, non‐persistent pain, and persistent pain. Persistent pain was defined as moderate or severe pain reported in both 2012 and 2015. Any other pain reported was categorized as non‐persistent pain. Dementia was classified using a modified version of the Cross‐Cultural Cognitive Examination. Multivariate logistic regression models were used to assess this association, adjusting for demographic, socioeconomic, and health factors.ResultsOverall, 4.9% of participants had dementia in 2015. Among participants with dementia, 51.7% reported non‐persistent pain and 22.5% reported persistent pain compared to 39.6% and 11.9% of those without dementia, respectively. After adjustment, both non‐persistent pain (OR: 1.87; 95% CI: 1.49, 2.34) and persistent pain (OR: 2.23; 95% CI: 1.67, 2.98) were associated with an increased odds of dementia, compared to no pain. Increasing age, ADL limitations, depression, diabetes, and stroke were associated with increased odds of dementia while higher educational attainment, consumer durables, and physical activity were associated with decreased odds of dementia.ConclusionsThere was a substantial amount of pain reported among Mexicans aged 50 and older with dementia. Reporting any type of pain was associated with an increased odds of dementia, compared to reporting no pain. Given that both pain and dementia decrease quality of life, future work should further evaluate this relationship to inform interventions.
Cholesterol‐dependent regulation of amyloid processing in neurons
Authors: Wang Hao , Kulas Joshua A. , Ferris Heather A. , Hansen Scott B. 
Published: December 2020

AbstractBackgroundApolipoprotein E (apoE), a cholesterol transport protein, is the most prevalent genetic risk factor in sporadic Alzheimer’s disease (AD). Cholesterol regulates the localization of Aβ‐producing enzymes with their substrate amyloid precursor protein (APP) in nanoscale lipid domains (rafts). Anecdotal evidence suggests apoE links to Aβ production through cholesterol’s effect on lipid rafts, but so far there has been little scientific validation of this link or the role of astrocyte‐derived cholesterol on neuronal Aβ production.MethodThe effects of astrocyte‐derived cholesterol on primary cortical neurons from wildtype and astrocyte‐specific knockout mice were determined using dSTORM super resolution imaging. The pair correlation (i.e. co‐localization) of APP with its hydrolytic enzymes (α‐, β‐, and γ‐secretases) was used to establish the mechanism of enzyme activation (substrate presentation) and indirectly show the likely resultant cleavage products Aβ and soluble APPα (sAPPα). The cleavage products Aβ and sAPPα were directly confirmed with ELISA. Inflammatory specific increases in cholesterol from primary astrocytes were measured using an fluorescent cholesterol assay.ResultSuper resolution imaging of primary neurons shows apoE utilizes astrocyte‐derived cholesterol to specifically traffic APP into lipid rafts where it interacts with β‐ and γ‐secretases to generate Aβ‐peptide. Inflammatory cytokines including IL‐1β and IL‐6 induce cholesterol synthesis in astrocytes. Treatment with cholesterol‐free apoE, or knockdown of cholesterol in astrocytes decreases cholesterol in cultured neurons and causes APP to traffic out of lipid rafts where it interacts with α‐secretase and gives rise to sAPPα, a neuronal protective product of APP. Sub‐cellular localizations of α‐, β‐, and γ‐secretases does not respond to changes in cellular cholesterol, suggesting the Aβ/sAPPα ratio is regulated by the trafficking of the substrate and not the enzymes.ConclusionAstrocytes regulate Aβ production through the delivery of cholesterol to neurons. This suggests that the cholesterol is used as a signaling molecule and the concentration is kept low in neurons to allow for astrocyte signaling. Under disease condition, pro‐inflammatory cytokines released by activated microglia induce cholesterol synthesis in astrocytes, contributing to increased Aβ production. This study establishes a mechanism that directly links apoE and inflammation with Aβ regulation and the risk of developing AD.
Plasma biomarkers predict amyloid pathology in cognitively unimpaired individuals
Authors: den Braber Anouk , Verberk Inge M.W. , Tomassen Jori , Stoops Erik , Mauroo Kimberley , Willemsen Gonneke , Nivard Michel G. , Van Berckel Bart N.M. , Scheltens Philip , Visser Pieter Jelle , de Geus Eco J.C. , Teunissen Charlotte E. 
Published: December 2020

AbstractBackgroundPlasma biomarkers have shown promising for identification of patients with Alzheimer’s Disease (AD), but whether this holds for the earliest preclinical stages needs further study. We aimed to investigate the predictive value of plasma amyloid‐β1‐42/1‐40 and glial fibrillary acidic protein (GFAP) for identifying amyloid pathology in cognitively unimpaired individuals. We tested this using plasma samples collected at time of CSF/PET amyloid assessment and, using plasma samples collected 10 years before CSF/PET amyloid assessment.MethodsWe selected 151 subjects with normal cognition from the EMIF‐AD PreclinAD study. Amyloid status was defined using visual read of dynamic [18F]flutemetamol PET images or CSF amyloid‐β1‐42/1‐40 (Euroimmun) <0.065. For a subsample of participants (n=42), plasma samples were available that had been collected 10 years before CSF/PET amyloid assessment as part of the Netherlands Twin Register‐Biobank Study. Simoa assays were applied to measure amyloid‐β1‐42/1‐40 (ADx NeuroSciences‐AmsterdamUMC Amyblood) and GFAP (Quanterix) plasma levels. Pearson correlations were assessed between plasma, CSF and PET biomarkers. ROC curve analysis was used to determine the value of each plasma biomarker in predicting CSF/PET amyloid status.ResultsAmyloid‐positive individuals had lower plasma amyloid‐β1‐42/1‐40 and higher GFAP levels (Table 1). In samples collected at time of CSF/PET amyloid assessment, significant correlations were found between plasma amyloid‐β1‐42/1‐40 and CSF (r=.22,p=.048) and PET (r=‐.23,p=.035) amyloid, and between plasma and CSF GFAP (r=.33,p=.002). Both plasma markers were able to discriminate amyloid status with similar negative predictive value (.90), with amyloid‐β1‐42/1‐40 showing higher sensitivity (.72) and GFAP higher specificity (.81). Combining the two did not improve results (Table 2). Plasma amyloid‐β1‐42/1‐40 and GFAP in samples collected 10 years prior to CSF/PET amyloid assessment were also able to discriminate amyloid status (Table 3). In addition, correlations between these and biomarker levels from plasma collected at time of PET/CSF amyloid assessment were modest for amyloid‐β1‐42/1‐40 (r=.36, p=.018), and high for GFAP (r=.82, p<0.001).ConclusionOur data suggest that amyloid‐β1‐42/1‐40 and GFAP plasma markers can be used to identify AD pathology in cognitively unimpaired individuals at present and prospectively. In addition, the high negative predictive value indicates these markers’ potential as pre‐screening tools for secondary prevention trials.
A randomized controlled trial measuring changes in cerebral blood flow after levetiracetam in patients with Alzheimer’s disease
Authors: Musaeus Christian Sandøe , Zhao Li , Dai Weiying , Breton Jocelyn , Shafi Mouhsin , Alsop David C. , Press Daniel Z. 
Published: December 2020

AbstractBackgroundRecent studies have shown that almost half of patients with Alzheimer’s disease demonstrate signs of epileptic activity as measured with EEG. Subclinical epileptic discharges can disrupt network activity, which is critical for long term memory. Therefore, suppressing epileptiform discharges may represent a novel therapeutic target for patients with Alzheimer’s disease. In the current randomized controlled trial, we recruited patients with mild Alzheimer’s disease and investigated the effect of a single administration of 2.5 mg/kg or 7.5 mg/kg of levetiracetam as compared with placebo on cerebral blood flow as measured with arterial spin‐labeling MRI (ASL‐MRI).MethodWe conducted a double‐blind, within‐subject crossover study in which nine participants with mild Alzheimer’s disease received placebo, 2.5 mg/kg, and 7.5 mg/kg of LEV intravenously in a randomized order across three sessions. Afterwards, participants underwent ASL‐MRI and performed a variety of neuropsychological cognitive tests. The regions with significant perfusion changes were analyzed with Statistical nonParametric Mapping (SnPM) toolbox.ResultWhen comparing 2.5 mg/kg levetiracetam with placebo, we found significant (p<0.03 with family wise error corrected at a level of 0.05) increases in relative cerebral blood flow in a cluster involving both temporal lobes, including the hippocampus, with greater involvement on the left side. We found decreases in a cluster including the posterior cingulate cortex and precuneus. No clear changes were found following the higher dose. No significant differences in cognitive performance were found between the three groups, suggesting that the intervention neither worsened nor improved cognition.ConclusionIn the current study, we found that in mild Alzheimer’s disease patients without any history of epilepsy a low dose of levetiracetam leads to changes in the cerebral blood flow in areas known to be affected early in the disease. One possible explanation could be that in mild AD, epileptic activity in the hippocampus leads to an excessive inhibition, and so relieving the inhibition with levetiracetam leads to an increased blood flow. These findings provide evidence of a potential beneficial effect of levetiracetam in patients with Alzheimer’s disease, but larger studies are needed, particularly with longer dosage schedules to determine whether there are any clinical improvements.
Exploring uptake of a university‐level educational intervention to prevent cognitive decline and reduce dementia risk: The Tasmanian Healthy Brain Project
Authors: Hill Edward , Bindoff Aidan , Bartlett Larissa , Summers Mathew J , Vickers James C 
Published: December 2020

AbstractBackgroundResearch suggests a substantial proportion of Alzheimer’s disease (AD) cases could be delayed, or even prevented, through modifying lifestyle factors. Low educational attainment has been associated with increased vulnerability to age‐related cognitive decline through reduced cognitive reserve. Strategies to enhance cognitive reserve in older adults may therefore provide cognitive resilience and reduce an individual’s AD risk. The Tasmanian Healthy Brain Project (THBP) is a longitudinal, prospective cohort study established to examine this possibility by following the cognitive health trajectory of older Australians engaging in university‐level education. To characterise predictors of uptake and inform recruitment for future educational interventions, we present an exploratory examination of university‐level education uptake in older Australian adults.MethodUpon entry to the ongoing THBP, participants opted (non‐random assignment) to enrol in fee reduced university‐level education at the University of Tasmania. All participants undergo biennial assessments involving a comprehensive battery assessing neuropsychological, cognitive, psychological, social and clinical domains. For the current study, membership of experimental (intervention) group vs controls (non‐intervention) was treated as a binary outcome utilising logistic binomial regression. Baseline age, education, gender, prior cognitive reserve (PCR), APOE, Dementia Rating Scale and Hospital Anxiety and Depression Scale were included in linear and generalized additive models. Bayes Factors (computed using bridge sampling) were estimated to provide support for main effects models. All statistical analyses were performed in R (v3.6.1).ResultOf 562 THBP participants, 437 (22.2%) elected to undertake university‐level education and 125 (77.8%) controls did not. On average, the interventional group was younger, more educated, displayed higher prior cognitive reserve and lower penetrance for APOE‐ε4 allele (Table 1). Logistic binomial regression suggested that of the variables assessed, age was the primary predictor of educational uptake (Figure 1).ConclusionIn our models, a participant’s baseline age was the only variable to display an association with interventional group adherence to a university‐level education. In the current research climate where encouraging lifestyle risk factor modifications to reduce dementia risk, educational interventions may enhance cognitive resilience to age‐related cognitive decline, therefore recruitment efforts should be designed to target a wider age range in more demographically diverse populations.