bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of omega‐3 fatty acids on cerebral white matter hyperintensities and medial temporal lobe atrophy in older non‐demented adults: A 3‐year randomized‐controlled phase 2 trial
Authors: Bowman Gene L , Silbert Lisa C , Dodge Hiroko H , Hagen Kirsten , David Jason C , Murchison Charles F , Lahna David , Kaye Jeffrey , Quinn Joseph F , Shinto Lynne 
Published: December 2020

AbstractBackgroundThe n‐3 PUFA may modulate risk for age‐related cognitive impairment through vascular mechanisms. MRI derived cerebral white matter hyperintensities (WMH) presumptively reflect small vessel disease and their accumulation increases risk for age‐related cognitive decline and dementia. Blood n‐3 PUFA are consistently associated with reduced WMH and stroke. The primary aim here was to evaluate n‐3 PUFA supplementation on WMH accumulation over 3 years in an older population with evidence of WMH and absence of n‐3 PUFA supplementation.MethodsThe study was a double‐blind, placebo‐controlled trial, with participants randomized to a daily dose of fish oil (1650 mg combined eicosapentaenoic acid‐EPA and docosahexaenoic acid‐DHA) or placebo oil (soybean) for a 3‐year intervention. Main inclusion criteria were: non‐demented (MMSE > 24), age > 74 years, WMH volume > 5.0 cc, and plasma n‐3 PUFA (EPA+DHA) < 110 umol/L (or < 5.5 percent of total fatty acids). The primary endpoint was 3‐year change in total WMH volume. Secondary endpoints include changes in regional brain volumes and white matter integrity. Exploratory endpoints include measures of cerebral blood flow, domain‐specific and global cognitive measures with subgroup analyses by APOE4 genotype. A linear mixed‐effects model was used to assess the outcomes.Results102 subjects were enrolled (mean age 81±4.4, MMSE 27.8±1.7; 60% female, 27.5% APOE4 positive) and a total of 78 participants completed the trial. Supplementation had no beneficial effect on rate of WMH progression, which increased by a mean of 1.07 cc per year in the n‐3 PUFA group vs 1.12 cc per year in the placebo group (p = 0.30 for time*trial arm interaction). Three‐year changes in executive cognitive function z‐scores were not different between treatment groups (p = 0.24). No differences in adverse events between groups were observed .ConclusionN‐3 PUFA compared with placebo, failed to slow 3‐year WMH accumulation and executive function decline in older non‐demented adults presenting with evidence of WMH. N‐3 PUFA at the 1.65‐gram dose appears safe in older adults over 3‐years. Additional MRI and cognitive outcomes with detailed safety profiles are planned for presentation.
Reduced [18F]flortaucipir retention in white matter hyperintensities compared to normal‐appearing white matter
Authors: Moscoso Alexis , Whitman A.J. , Baker Suzanne L. , La Joie Renaud , Pascoal Tharick A. , Rosa‐Neto Pedro , Rabinovici Gil D. , Jagust William J. , Grothe Michel , Schöll Michael 
Published: December 2020

AbstractBackgroundRecent research has suggested that the use of white matter (WM) reference regions for longitudinal tau PET imaging might result in more stable estimates of tau accumulation. However, tau tracers display affinity for the β‐sheet structure formed by proteins such as the myelin basic protein, a major component of axons, and thus WM lesions might influence tau tracer retention in the WM. Here, we explored whether [18F]flortaucipir shows reduced retention in WM lesions, assessed as WM hyperintensities (WMH), and further studied how [18F]flortaucipir retention in WM changes over time.MethodWe included data from 678 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who had undergone a baseline [18F]flortaucipir‐PET as well as T1 and FLAIR MRI scanning. WMH were automatically delineated in the FLAIR images using the Lesion Segmentation Toolbox in SPM12. To avoid partial volume effects, we eroded the WM and WMH masks so that all voxels within a distance of 3 mm from any non‐WM voxel were removed. The inferior portion of the cerebellar gray matter was used as the reference region to derive Standardized Uptake Value Ratios (SUVR). SUVR in WMH and normal‐appearing WM (NAWM) were compared using paired t‐tests. Among participants with at least one‐follow up [18F]flortaucipir scan (N=217, mean follow‐up time 1.5 years), longitudinal SUVR changes in the WM were estimated using Linear Mixed Models.ResultOlder age was associated with lower SUVR in both NAWM (r=‐0.10, p=0.007) and WMH (r=‐0.21, p<0.001) but not with [18F]flortaucipir retention in the medial temporal cortex after adjusting for amyloid‐β (Aβ) status and diagnosis (r=‐0.04, p=0.36, Meltzer‐corrected for partial volume effects). Compared to NAWM, WMH areas displayed significantly reduced SUVR independently of cognitive impairment and Aβ status (p<0.001, Figure 1). Longitudinal analyses revealed that SUVR in the WM decreased over time (‐0.009 SUVR/year, p=0.003), while medial temporal SUVR increased (0.009 SUVR/year, p=0.03).ConclusionLow [18F]flortaucipir retention in the WM is associated with advancing age and presence of WM lesions, supporting the hypothesis that [18F]flortaucipir retention in the WM might reflect its myelin content. These findings do not support the use of WM reference regions for [18F]flortaucipir PET imaging.
LatAm‐FINGERS (Latin America)
Authors: Crivelli Lucia 
Published: December 2020

AbstractBackgroundLatAm‐FINGERS is a Latin American initiative to develop a multicenter, randomized controlled trial for the prevention of cognitive deterioration and dementia and to share, compare and harmonize the data. LatAm‐FINGERS gathers Argentina, Bolivia, Brazil, Chile, Colombia, Costa Rica, Cuba, Dominican Republic, Ecuador, Mexico, Paraguay, Peru, Puerto Rico, and Uruguay.Method1,400 subjects (100 older adults from each country) at a high risk of cognitive deterioration due to sedentary lifestyle, poor diet, and a suboptimal metabolic‐cardiovascular profile will be randomly assigned to a Systematic Lifestyle Intervention (SLI) or a Flexible Lifestyle intervention (FLI). The SLI group will receive dietary counseling, intensive physical exercise, cognitive training and control of cardiovascular risk factors. The FLI group will receive regular health advice. Participants will be evaluated every six months. Baseline assessment will include clinical and neuropsychological assessment, APOE genotyping, and MRI. Aims: 1. A) To evaluate the feasibility of the FINGER multi‐domain lifestyle intervention in Latin America B) To evaluate the efficacy of the intervention, primarily on a global cognitive composite score ‐Preclinical Alzheimer Cognitive Composite (PACC)‐ and on specific cognitive domains: episodic memory, executive function, and processing speed. Efficacy variables were selected in order to be harmonized with the original FINGER project and with the ongoing U.S. POINTER protocol. See table 1. Data Sharing: Data collected in each center will be housed in REDCap (Research Electronic Data Capture) at the University of São Paulo Medical School and backup will be stored on a cloud. The data sharing will be managed jointly by the LatAm FINGERS steering committee (SC). Reputable investigators will be welcomed to apply two years after the study is completed. Requests for data will be reviewed by two members from the LatAm FINGERS SC and the decision to grant access to data will be based on scientific merit. The LatAm FINGERS will request the Data Transfer Agreement. Status and Timeline: Protocol design has been completed, application for Alzheimer's Association funding has been submitted and review and response are pending. Recruitment of subjects is expected to begin in June 2020. Preliminary data release is expected by Dec. 2020.
The pattern of performance on sensitive tests of four cognitive domains differentiates groups with progressive cognitive decline in Alzheimer's disease
Authors: Maljkovic Vera , Battioui Chakib 
Published: December 2020

AbstractBackgroundA screening challenge for Alzheimer’s disease (AD) is a paucity of tests sensitive to the different stages of the disease continuum. Progression of clinical disease suggests that multiple tests, sensitive to individual stages of disease development, may better define the range of cognitive abilities and predict the next cognitive domain to decline.Method78 healthy controls and 29 clinically diagnosed cognitively impaired participants (23 Mild Cognitive Impairment, MCI, 6 mild Alzheimer’s dementia, mildAD) ages 60‐76, self‐administered at home 9 CANTAB tasks on a provided iPad (Maljkovic et al, AAIC 2019). Four tasks were selected for further analysis: spatial working memory (SWM), paired‐associates learning (PAL), pattern recognition matching‐delayed (PRM‐del) and executive function task ‘One‐touch‐stockings‐of‐Cambridge’ (OTS). We performed two independent cross‐sectional analyses:
(1) Top‐down.
We manually created good/poor performance regimes for each test, resulting in 16 test‐by‐performance combinations, and sorted subjects according to their performance.
(2) Bottom‐up.
We performed a K‐means cluster analysis.Result(1) Top‐down. The 5 combinations with the highest number of participants (total of 85%) show progression of cognitive decline from the loss of SWM, through the losses of PAL, PRM‐del, and finally OTS (Table 1, left columns of numbers). (2) Bottom‐up. K‐means cluster analysis produced 5 categories with same cognitive profiles (Table 1, right columns). Both results show the number of healthy controls decreasing and the number of symptomatic participants increasing across groups. The two methods are also highly concordant in determining individual participants’ cognitive profiles: 80% of the participants from the 5 most numerous manually‐generated categories were assigned to the analogous group by the cluster analysis; 19% were assigned to an adjacent category (Table 2).ConclusionThe performance pattern on tests of different cognitive domains, relevant to clinical stages of AD, shows separation between groups with progressive levels of cognitive decline. This type of at‐home, self‐administered, testing on a personal device can evaluate current cognitive ability and may predict the next domain of cognitive loss. Results imply that an individual with AD would pass through these stages of cognitive decline over time, a hypothesis that needs to be tested in a longitudinal study.
Community‐based housing and NPI‐care practices for adults with intellectual disability and dementia
Authors: Janicki Matthew 
Published: December 2020

AbstractBackgroundAging persons with intellectual disability (ID) represent a vulnerable population with respect to cumulative neuropathological conditions, including dementia. Adults with Down syndrome (DS), a subset, have a recognized high risk for Alzheimer’s disease. With dementia present, how to provide post‐diagnostic supports is challenging. Dementia care group homes (GHs) along with NPIs are emerging as a mode for providing out‐of‐home community supports. Data from a longitudinal study provide insights on what care organizations need to consider when organizing specialty group home care. The study, begun in 2011, followed three co‐located homes providing NPIs to 15 adults with dementia. Findings revealed trajectories of changes over time, housing need/function level patterning, and health status outcomes. Key findings noted 3 age‐of‐admission clusters (□; = 50.5; □; = 57.1; χ = 66.8); overall mortality (□;age‐death = 65.4; ID = 69.3; DS = 56.3) – half of original entrants died within 7 years; age at entry (□; = 59.1); years from entry to death (□; = 5.4 yrs); LOS (□; = 49.4 months/4.12 yrs); morbidities (number of co‐morbidities decreased among survivors). In same period, 8/15 deaths in GHs vs 3/15 deaths in Controls. NPI‐related practices included day program activities (adults in mid‐ to later stages were engaged in regular off‐site day activities that agency provided; adults with advanced dementia remained in homes), staffing patterns differed based on level of care – more staff assigned to homes with residents with advanced dementia, and staff training included dementia capable communications, engagement, and managing daily routines. Trends showed adults with Down syndrome were admitted to homes earlier but had more life‐years in the GHs than older adults admitted at later age but who succumbed earlier to disease complications. Dementia care GHs should expect varied trajectories of decline; mortality linked to complexity of pre‐existing conditions and progression of dementia; changes in the focus of care needs over time (including advanced dementia and end‐of‐life care). Dementia care GHs can enable provision of in‐community group housing and quality care in accord with stage‐defined functional changes and needs if structured in a planful way (factoring in dementia‐stage, dementia type, mortality expectations, health status, patterns of care needs, dementia‐related behaviors, aging‐related issues, and probable trajectories of decline of the residents).
Receptor for advanced glycation end products mediates meningitis‐triggered amyloid‐β accumulation and cognitive impairment
Authors: Barichello Tatiana , Generoso Jaqueline S , Giridharan Vijayasree V , Collodel Allan , Dominguini Diogo , Petronilho Fabricia , Dal‐Pizzol Felipe 
Published: December 2020

AbstractBackgroundPneumococcal meningitis is a life‐threatening infection of the central nervous system (CNS), and half of the survivors of meningitis suffer from neurological sequelae. We hypothesized that pneumococcal meningitis causes CNS inflammation via the disruption of the blood‐brain barrier (BBB) and by increasing the expression of the receptor for advanced glycation end products (RAGE) in the brain, which then causes glial cell activation and cognitive impairment, triggering similar Alzheimer's disease pathology.MethodTo test our hypothesis, sixty‐day‐old male Wistar rats were subjected to meningitis by receiving an intracisternal injection of Streptococcus pneumoniae or artificial cerebrospinal fluid (aCSF) as a control group and were treated with a high‐affinity RAGE‐specific inhibitor (FPS‐ZM1) in saline or placebo. Rats also received ceftriaxone 100 mg/kg, i.p., bid, and fluid replacements. We evaluate the blood‐brain barrier at 12, 18, and 24 hours after meningitis induction or aCSF. At ten days after the meningitis induction, we evaluate behavioral tasks, including open field, novel object recognition task, and Morris water maze. After the behavioral tasks, the brain of the animals was removed to evaluate RAGE, amyloid‐beta (Aβ1‐42), and glial cells activation.ResultWe demonstrated that experimental pneumococcal meningitis triggered BBB disruption at 12, 18, and 24 hours after meningitis induction, and FPS‐ZM1 treatment significantly suppressed BBB disruption. Ten days after meningitis induction, surviving animals were free from infection, but they presented increased levels of TNF‐α and IL‐1β in the prefrontal cortex (PFC); high expression levels of RAGE and Aβ1‐42, high levels of microglial cell activation in the prefrontal cortex (PFC) and hippocampus, and memory impairment, as evaluated by the open field, novel object recognition task, and Morris water maze behavioral tasks.ConclusionPneumococcal meningitis can increase the RAGE and Aβ1‐42 in the brain of the animals. Targeting RAGE inhibition was able to reduce cytokine levels, decrease the expression of RAGE and Aβ1‐42, inhibit microglial cell activation, and improve cognitive deficits in meningitis survivor rats.
Performance of validated microRNA biomarkers for Alzheimer’s disease in mild cognitive impairment
Authors: Saugstad Julie A 
Published: December 2020

AbstractBackgroundCerebrospinal fluid (CSF) microRNA (miRNA) biomarkers of Alzheimer’s Disease (AD) have been identified, but have not been evaluated in prodromal AD, including Mild Cognitive Impairment (MCI). Here we evaluated the expression of our previously validated CSF miRNA biomarkers for AD in MCI.MethodWe measured the expression of 17 validated miRNA biomarkers for AD in CSF samples from AD, MCI, and cognitively unimpaired controls. We then examined classification performance of the miRNAs individually and in combination. For each miRNA, we assessed median expression in each diagnostic group and classified markers as trending linearly, nonlinearly, or lacking any trend across the three groups. For trending miRNAs, we assessed multimarker classification performance alone and in combination with apolipoprotein E ɛ4 allele (APOEɛ4) genotype and amyloid‐β42 to total tau ratio (Aβ42:T‐Tau). We identified predicted targets of trending miRNAs using pathway analysis.ResultFive miRNAs showed a linear trend of decreasing median expression across the ordered diagnoses (control to MCI to AD). The trending miRNAs jointly predicted AD with area under the curve (AUC) of 0.770, and MCI with AUC of 0.705. Aβ42:T‐Tau alone predicted MCI with AUC of 0.758 and the AUC improved to 0.813 (p = 0.051) after adding the trending miRNAs. Multivariate correlation of the five trending miRNAs with Aβ42:T‐Tau was weak.ConclusionSelected miRNAs combined with Aβ42:T‐Tau improved classification performance (relative to protein biomarkers alone) for MCI, despite weak correlation with Aβ42:T‐Tau. Together these data suggest that that these miRNAs carry novel information relevant to AD, even at the MCI stage. Preliminary target prediction analysis suggests novel roles for these biomarkers.
Heightened sensitivity of people with Alzheimer’s disease to the side effects of antipsychotic drug amisulpride may be mediated through an interaction with glucose transporter 1 at the blood‐brain barrier
Authors: Boyanova Sevda , Wang Hao , Fleckney Alice L , Gatt Ariana , Farag Doaa B , Rahman K Miraz , Vizcay‐Barrena Gema , Fleck Roland , Reeves Suzanne J , Thomas Sarah A 
Published: December 2020

AbstractBackgroundAmisulpride is an atypical antipsychotic which antagonises dopamine (D2, D3) receptors in vitro and in vivo (Schoemaker et al., 1997). Older people, particularly those with dementia are more susceptible to antipsychotic side effects, including amisulpride (Reeves et al., 2017). Clinical and basic science research suggested that blood‐brain barrier (BBB) disruption underpins this heightened sensitivity by increasing central drug access (Sekhar et al., 2019; Harwood et al., 1994). The current study examines healthy and Alzheimer’s disease (AD) physiology to further understand this increased sensitivity.MethodWe investigated the BBB transport of amisulpride in 5xFamilial Alzheimer’s mouse model (5xFAD), and in age‐matched wild type mice (WT, C57/BL6) (12‐15 months old). 5xFAD mice express human amyloid precursor protein and presenilin 1 transgenes with five AD‐linked mutations, they develop Aβ plaques and cognitive impairments (Oakley et al., 2006). All experiments were performed according the Animal Scientific Procedures Act (1986) and Amendment Regulations 2012. Anaesthesia was applied via intraperitoneal injection of medetomidine hydrochloride and ketamine mixture. The mice were perfused with artificial plasma, containing [3H]amisulpride (6.5 nM) and [14C]sucrose (9.4 μM). Brain amyloid plaques were confirmed in 5xFAD mice by transmission electron microscopy. In silico molecular docking using AuDock Vina and GOLD software identified transporters of interest for our model substrate. Amisulpride was considered a substrate for a given transporter, if it had free energy binding lower than ‐5 kcal/mole and high chem score.ResultCompared to WT (n=6), the 5xFAD (n=7) mice had increased striatal [3H]amisulpride uptake of 79% (t=1.975, df=11, p=0.0370). The [14C]sucrose (passive permeability measure) permeability was not significantly changed. Preliminary in silico analysis suggested that amisulpride is a substrate for glucose transporter 1 (GLUT1) and a very weak substrate for multidrug and toxin extrusion transporter (MATE2) (Table 1).ConclusionIn silico studies suggested amisulpride interacts with BBB solute carrier (SLC) transporters: organic cation transporter (OCT1), plasma membrane monoamine transporter (PMAT), MATE1 (Sekhar et al., 2019), GLUT1 and MATE2, but not with the adenosine triphosphate binding cassette (ABC) transporter P‐glycoprotein. The increased brain permeability to amisulpride in 5xFAD mice suggests altered BBB transporter function, possibly due to SLC transporter expression changes associated with AD.
Ablation of astrocytes affects Aβ degradation, microglia activation and synaptic connectivity in an ex vivo model of Alzheimer’s disease
Authors: Davis Nicola , Mota Bibiana Castagna , Stead Larissa , Palmer Emily OC , Lombardero Laura , Rodriguez‐Puertas Rafael , de Paola Vincenzo , Barnes Samuel J , Sastre Magdalena 
Published: December 2020

AbstractBackgroundAstrocytes provide vital support to neurons in normal and pathological conditions. In Alzheimer's disease (AD) brains, reactive astrocytes have been found surrounding amyloid plaques, forming an astrocytic scar. However, their role and potential mechanisms through which they affect neuroinflammation, amyloid pathology and synaptic density in AD remain unclear.MethodTo explore the role of astrocytes on amyloid pathology and neuroinflammatory markers, we pharmacologically ablated astrocytes in organotypic brain culture slices (OBCSs) generated from the 5XFAD mouse model of amyloidosis with selective astrocytic toxin L‐alphaaminoadipate (L‐AAA). To examine the effects on synaptic circuitry, we measured dendritic spine number and size in OBCSs from Thy‐1‐GFP transgenic mice incubated with synthetic amyloid‐beta (Aβ)42, or double transgenics Thy‐1‐GFP/5XFAD mice treated with L‐AAA or vehicle for 24h.ResultTreatment of OBCSs with L‐AAA resulted in an increased expression of proinflammatory cytokines, such as TNF‐α in conditioned media, without changes in microglial density. In addition, pharmacological ablation of astrocytes led to an increase in Aβ levels in homogenates of OBCS from 5XFAD mice compared with vehicle controls, associated with reduced expression of Neprilysin and Apolipoprotein E, which are involved in Aβ clearance. In addition, OBSCs from wild‐type mice treated with L‐AAA and synthetic amyloid presented 56% higher levels of Aβ in culture media compared to sections treated with Aβ alone, concomitant with reduced expression of the Aβ degrading enzyme IDE in culture medium, suggesting that astrocytes contribute to Aβ clearance and degradation. Quantification of hippocampal dendritic spines revealed a reduction in their density following L‐AAA treatment in all groups analysed. In addition, pharmacological ablation of astrocytes resulted in a decrease in spine size in 5XFAD OBCSs but not in OBCSs from WT treated with synthetic Aβ compared to vehicle control.ConclusionAstrocytes play a protective role in AD by aiding Aβ clearance and supporting synaptic plasticity.