bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel approach to isolate brain‐cell–derived exosomes from plasma to better understand pathogenesis of Alzheimer’s disease
Authors: Kumar Ashish , Hughes Timothy M. , Craft Suzanne , Deep Gagan 
Published: December 2020

AbstractBackgroundExosomes are nano‐vesicles ∼30‐150 nm in diameter that are released by all cell types and present in all biofluids. Exosomes are loaded with unique cargo, including RNAs, proteins, lipids, and metabolites that relate to the cell of origin and the patho‐physiological state of the organism. Discovery of brain cells‐derived exosomes in the circulation led to studies examining their role as potential mediators as well as ‘liquid biopsies’ for Alzheimer’s disease and related dementias (ADRD). However, currently, most work with exosomes focus on one class of exosome subtype at a time. Here, we have developed a novel and sensitive method to simultaneously extract pure and biologically active exosomes secreted from various cells of the neurovascular unit, including: neuron‐derived exosomes (NDE), astrocytes‐derived exosomes (ADE), endothelial‐derived exosomes (EDE), pericyte‐derived exosomes (PDE), and oligodendrocyte‐derived exosomes (ODE).MethodWe employed ExoQuick precipitation method to isolate total exosomes from the plasma of age‐matched individuals with normal cognition or AD. We optimized methods to label specific antibody with photo‐cleavable (PC)‐biotin. Next, we extracted exosomes of the neurovascular unit from the total exosomes using streptavidin coated magnetic beads and biotin or PC‐biotin‐tagged antibodies (L1CAM for NDE; GLAST for ADE; PDGFRα for ODE; CD31 for EDE and PDGFRβ for PDE). To release the exosomes, magnetic beads were exposed to UV light (280 nm). We performed immunogold labelling, transmission electron microscopy (TEM), flow cytometry and ELISA to validate the isolated exosome populations.ResultFollowing our novel methods, we extracted NDE, ADE, EDE, PDE, and ODE from total plasma exosomes. We validated the purity of each exosome population by flow cytometry, and confirmed the surface expression of exosomal biomarkers (CD63 and CD9) by immunogold labelling and TEM. Lastly, ELISA analyses showed that Aβ1‐42 was absent in all exosome populations from healthy individuals but significant level of Aβ1‐42 was detected in all the exosome populations (NDE, ADE, EDE, PDE, and ODE) from AD patients.ConclusionWe have developed a novel, sensitive and reproducible method to isolate and characterize various brain cells‐derived exosomes from plasma which could lead to development of novel blood based exosomal biomarkers to better understand AD pathogenesis.
Exploring retinal imaging as a novel biomarker of Alzheimer’s disease
Authors: Young Kelly Z , Moinuddin Omar , Khandwala Nikhila , Albin Roger L , Barmada Sami , Besirli Cagri 
Published: December 2020

AbstractBackgroundAlzheimer disease (AD) and frontotemporal dementias (FTD) exhibit distinct pathologies but are difficult to reliably differentiate on clinical grounds. Detailed neuropsychiatric evaluations, cerebrospinal fluid analysis, and anatomic or molecular imaging may improve diagnostic accuracy. Even so, these modalities are expensive, time‐consuming, and often inaccessible. The retina is a developmental outgrowth of the brain, and visual dysfunction is well documented in dementia subjects. As such, the retina may be a useful surrogate for diagnosing and monitoring the progression of dementias. We explored the potential role of multimodal retinal imaging for identifying ocular biomarkers of dementia and correlated our findings with cerebral amyloid burden.MethodWe recruited 5 participants with mid‐to‐late stage AD, 2 participants with mid‐to‐late stage FTD, as well as 9 age‐matched healthy controls. Each participant underwent comprehensive ophthalmologic examination and ocular imaging (Optical Coherence Tomography (OCT), OCT‐angiography (OCTA), wide‐field fundus photography, near‐infrared imaging, and fundus autofluorescence). Ocular findings were then correlated with cerebral amyloid burden, as detected by [11C]PiB PET.ResultWe did not observe significant differences in retinal layer thicknesses, retinal perfusion, or sizes of the superficial avascular zones between PET‐confirmed AD, clinically diagnosed FTD, and control subjects. AD subjects consistently demonstrated higher autofluorescence signal intensity (18.5 au), as detected by fundus autofluorescence imaging compared to FTD (16.0 au) and age‐matched control subjects (16.3 au). Near‐infrared ocular imaging also revealed a 1.95 fold increase in retinal reflectance in AD subjects compared to FTD and control subjects.ConclusionIdentification of novel dementia biomarkers is essential for accurate diagnosis and monitoring of dementia progression. Recent studies highlighted the potential use of OCT and OCT‐A to identify retinal layer thickness changes in AD and FTD. Our pilot study suggests that autofluorescence and near‐infrared reflectance, but not OCT or OCT‐A, detect retinal imaging changes that correlate with cerebral amyloid burden. These modalities may thus serve as accurate dementia biomarkers to aid in diagnosis, assessing pathologic severity, and gauging response to therapy in AD and FTD.
How understudied populations leverage our understanding of Alzheimer’s disease genetics
Authors: Dehghani Nadia , Bras Jose , Guerreiro Rita 
Published: December 2020

AbstractBackgroundThe majority of genome‐wide association studies have been conducted using samples with a European genetic background. As a field, we acknowledge this limitation and the need to increase the diversity of populations studied. A major challenge when designing and conducting such studies is to assimilate large samples sizes to have enough statistical power to detect variants associated with disease, particularly when trying to identify variants with low and rare minor allele frequencies. In this study, we aimed to illustrate the benefits, to genetic characterization of Alzheimer’s disease (AD), in researching currently understudied populations. This is important for both fair representation of world populations and the translatability of findings.MethodWe have conducted a thorough literature search to understand the contributions of studies, on different populations, to AD genetics.ResultTo accomplish this, we have systematically quantified the number of studies identifying mutations in known disease‐causing genes, in all countries across the world, and discussed the contributions of research in understudied populations to the identification of novel genetic factors in this disease. Related to this, we compared the varied effects of genome‐wide significant SNPs across populations by focusing on loci that show different association profiles between populations (a key example being APOE).ConclusionThis work functions to both highlight how understudied populations have furthered our understanding of AD genetics, and to help us gage our progress on understanding the genetic architecture of this disease in all populations.
Interactive associations of nocturnal sleep disturbance and vascular risk with prospective cognitive decline in clinically normal elderly individuals: Findings from the National Alzheimer's Coordinating Center Uniform Data Set
Authors: Bubu Omonigho M , Mbah Alfred , Umasabor‐Bubu Ogie Queen , Mukhtar Fahad , Turner Arlener D , Williams Natasha , Ogedegbe Gbenga , Jean‐Louis Girardin A , Osorio Ricardo S 
Published: December 2020

AbstractBackgroundWe determined whether Nocturnal Sleep Disturbance (NSD) and vascular risk act together to promote prospective cognitive‐decline in clinically normal older adults; and, evaluated the unique influence of their combined risk on prospective cognitive decline beyond that of commonly used Alzheimer’s disease (AD) biomarkers.MethodLongitudinal study utilizing data from the National Alzheimer's Coordinating Center (NACC) Uniform Data set (UDS). Participants (N=361) were cognitively normal at baseline and had baseline medical data to quantify vascular risk, using an adaptation of the Framingham Heart Study general cardiovascular disease (aFHS‐CVD) risk‐score and CSF‐Aβ, CSF P‐tau, CSF T‐tau and MRI‐imaging data with at least one UDS follow‐up visit. The Neuropsychiatric Inventory Questionnaire characterized NSD and incident mild cognitive impairment (MCI) diagnosis during UDS follow‐up characterized prospective cognitive decline. Logistic mixed‐effects models with random intercept and slope, controlling for age, sex, education, APOE‐ε4 and their interactions with time examined associations between the NSD/ FHS‐CVD risk score and longitudinal cognitive‐decline.ResultOf the 361 participants, 223 (62%) were women and 35 (9.7%) had NSD. The proportion of males versus females with sleep problems was 10.9% vs. 9.3% respectively. For participants with NSD and no NSD, the mean (SD) age was 71 (7.3) and 70 (5.7) years and average follow‐up time was 5.2 (2.6) and 4.9 (2.7) years, respectively. Both NSD (OR: 1.42, P < .003) and higher aFHS‐CVD risk score (OR; 1.63, P < .001) were significantly associated with increased/faster likelihood to develop incident MCI. The interaction of NSD and the aFHS‐CVD risk‐score with time was significant (P < .001) suggesting an increase in the likelihood of conversion to MCI increased over time. Stratifying aFHS‐CVD risk score into tertiles, NSD participants in the highest (OR: 2.82, P < .003) and middle tertile (OR: 2.38, P < .001) were significantly more likely to develop incident MCI, compared with participants without NSD in the lowest aFHS‐CVD risk score tertile, suggesting a synergistic effect. This effect remained robustly associated with incident MCI even after adjustment for AD biomarkers.ConclusionIn elderly cognitive‐normal individuals, NSD and vascular risk may be alternate and non‐invasive measures of assessing risk of prospective cognitive‐decline in preclinical AD.
Late‐life literacy training for improving memory and brain connectivity: Baseline results
Authors: Resende Elisa de Paula França , Lara Vivian Proença , Santiago Ana Luisa Carvalho , Friedlaender Clarisse Vasconcelos , Rosen Howard J , Grinberg Lea Tenenholz , Silva Lênio Lúcio Gávio , de Souza Leonardo Cruz , Caramelli Paulo 
Published: December 2020

AbstractBackgroundHigher education acquired through the lifespan is believed to buffer the cognitive decline associated with neurodegenerative diseases. However, whether acquiring education later in life can improve memory is unknown.MethodsWe recruited illiterate adults that enroll in a late‐life literacy program to determine the impact of literacy training in adulthood on memory. Participants underwent baseline literacy tests and episodic memory was assessed with the Free and Cued Selective Reminding test (with pictures).ResultsAt baseline, 43 illiterate adults that did not know how to read and write participated in the study. They had a mean age of 50.3 (SD 14.3) year‐old, 19 (44%) were males, 37 (90%) were non‐Caucasians and 24 (57%) were from low‐socioeconomic background. The main reason they did not attended school when they were young was that they had to work (n=21, 49%). Baseline clinical characteristics of participants were smoking in 26%, depression in 25% and anxiety in 16%. The mean free delayed‐recall was 10.6 (SD 3.1), out of 16 figures.ConclusionHere we present the baseline characteristics of this group of illiterate adults that engage in a late‐life literacy program. The results show that the participants recruitment is feasible and representative of such illiterate adult populations. Although episodic memory is normal, there is room for memory improvement to be studied in the follow up visit.
Knockout of microglial P38A mapk in a mouse model of Alzheimer’s disease
Authors: Braun David J. , Davis Verda A. , Van Eldik Linda J. 
Published: December 2020

AbstractBackgroundThe p38a MAPK signaling pathway is a well‐established regulator of neuroinflammation, and pharmacological inhibitors of this pathway can protect against cognitive impairment in animal models of Alzheimer’s disease (AD). This protection by p38a inhibitors might be mediated via protective effects on neurons, anti‐inflammatory effects on glia, or some combination thereof. To assess whether reduction of p38‐dependent microglial proinflammatory responses is beneficial in this context, we generated AD model mice with microglial knockout (KO) of p38a.MethodThe APPswe/PS1dE9 (MMRRC #34832) mouse AD model was crossed with p38afl/fl mice (Jax #031129) to generate AD model mice homozygous for the floxed p38a allele. These were subsequently crossed with CX3CR1CreERT2 mice (Jax #020940) that express a tamoxifen‐inducible promoter allowing for removal of p38a from microglia. This breeding scheme generated four groups of mice, used in a 2 x 2 study design: WT and AD mice with floxed p38a, with or without a copy of the myeloid‐specific Cre allele. All mice were placed on tamoxifen diet (400 ppm) for 4 weeks beginning at 5 months of age, near the beginning of amyloid plaque deposition in this AD model. After administration of tamoxifen, mice were returned to normal chow for several months, allowing turnover of peripheral myeloid cells. Mice underwent behavioral testing in open field and novel spatial recognition y‐maze (8 months of age), and radial arm water maze (11 months of age). Microglial isolation via fluorescence‐activated cellular sorting and subsequent RNAseq analysis was performed on a subset of 4 mice per group.ResultsMicroglial p38a KO had no effect on the hyperlocomotive phenotype associated with amyloid overexpression in this model; however, p38a KO increased errors in the RAWM test of spatial learning and memory in the AD model but not WT mice.ConclusionsThe p38a signaling pathway in microglia is important in restricting amyloid‐associated cognitive decline. We are currently characterizing the effects of microglial p38 KO on amyloid pathology, neuroinflammation, and microglial gene expression.
Cataract surgery is associated with reduced risk for Alzheimer’s disease
Authors: Lee Cecilia S , Gibbons Laura E , Lee Michael L , Lee Aaron Y , Yanagihara Ryan T , Crane Paul K , Larson Eric B 
Published: December 2020

AbstractBackgroundVisual improvement after cataract surgery is well‐established, but the literature on the potential impact of cataract surgery on Alzheimer’s disease (AD) is conflicting. Using data from a large, well‐characterized cohort, we sought to determine whether cataract surgery was associated with lower risk of developing AD.MethodThe Adult Changes in Thought (ACT) study is a 25‐year‐old ongoing population‐based study of participants recruited from Kaiser Permanente Washington (KPW) membership rolls, aged ≥ 65 without dementia at enrollment and followed until dementia or death. AD was diagnosed using established research criteria. Extensive clinical data were obtained during study visits and via KPW electronic medical records (EMR). Eye‐related diagnoses and procedures were based on ICD‐9/10 and CPT codes. We used Cox proportional hazard regression modeling for probable or possible AD. Because healthier participants might have been more likely to receive surgery, we built marginal structural models accounting for several health and cognitive factors as one of several secondary analyses. We also examined the associations between AD and glaucoma surgery as a comparator procedure.ResultA total of 3,719 participants with cataract diagnosis were included, with 840 incident AD cases. 1,815 (49%) underwent cataract surgery and 1,914 did not (Table 1). The adjusted HR of developing AD in people who underwent cataract surgery was 22% lower than those who did not undergo cataract surgery (HR=0.78, [95%CI 0.68, 0.91], p=0.001), and the effect was stronger for recent surgery (Table 2; Figure). Secondary analyses to account for healthy patient bias yielded similar results, as did omitting the original cohort with a shorter EMR history, or just considering cataract diagnosis after baseline. Ignoring cataract surgery 2 years prior to AD yielded stronger effect. Glaucoma surgery was not associated with AD.ConclusionCataract surgery is associated with lower risk of AD in this prospective, population‐based study. This finding does not appear to be due to healthier participants receiving surgery. Further research on the implications of eye conditions and treatments on Alzheimer’s disease is warranted.
Characterization of older, cognitively normal obstructive sleep apnea patients at risk of prospective cognitive decline using the NIA‐AA Research Framework
Authors: Bubu Omonigho M. , Turner Arlener D. , Jean‐Louis Girardin A , Osorio Ricardo S. 
Published: December 2020

AbstractBackgroundThe association between Obstructive Sleep Apnea (OSA) and cognition in older‐adults is conflicting. We determined to characterize older OSA‐patients using the NIA‐AA Research Framework and test whether OSA accelerates cognitive decline in preclinical Alzheimer’s disease (AD)MethodCommunity‐dwelling cognitively normal elderly participating on a study on memory, sleep and aging, with baseline AD biomarker data and both baseline and follow‐up neuropsychological data were included. OSA was defined using AHI4%. Data‐driven, clinically relevant thresholds for CSF‐Aβ42 (≤375pg/ml), and CSF P‐tau (≥53.7pg/ml) indicated OSA participants AT(N) status using the NIA‐AA Research Framework. Twenty‐four participants with non‐AD pathologic change defined as A‐T+ were excluded leaving 127 for the analysis. Main outcome was the annual rate‐of‐change in global cognition (calculated as an average composite Z‐score of episodic memory, language and executive function cognitive tests domains). Linear mixed‐effects models with random intercept and slope were used to assess associations between AT(N) characterized OSA subjects, and longitudinal changes in global cognition, controlling for age‐at‐baseline, sex, APOE4‐status, years‐of‐education, and their interactions with time.ResultOf the 127 participants, 81 (63.8%) were women. The mean (SD) age was 69.6 (7.3) years and follow‐up time was 2.46 (0.64) years. Eight (6.3%) met biomarker criteria for AD (OSA+/A+/T+ [n=4] and OSA‐/A+/T+ [n=4]). Forty‐four participants (34.6%) were amyloid positive (OSA+/A+ [n=20] and OSA‐/A+ [n=24]). Sixteen (12.6%) were OSA+/A+/T‐, and 20 (15.7%) were OSA‐/A+/T‐. Eighty‐three (63.4%) had normal AD biomarkers (OSA+/A‐/T‐ [n=40] and OSA‐/A‐/T‐ [N=43]). Regardless of OSA status, relative to normal AD biomarkers, amyloid positive participants i.e. AD pathologic change, showed significant faster rate‐of‐decline in global cognition (β = −0.066, 95%CI, −0.088, −0.046; P < .001). However, OSA+/A+/T‐ participants showed even more significantly faster rate‐of‐decline in global cognition compared to OSA‐/A+/T‐ participants (β = −0.042, 95%CI, −0.063, −0.019; P < .001), suggesting an OSA/Aβ42 synergism independent of PTau. OSA+/A‐/T‐ or OSA‐/A‐/T‐ participants (normal AD biomarkers) did not show any significant cognitive change over time.ConclusionAmong amyloid positive healthy‐elderly, OSA and Aβ demonstrate synergism related to cognitive decline that might be independent of tau deposition. Clinical trials in a population of elderly OSA cognitive‐normal individuals should target at minimum persons with Alzheimer’s pathologic change.
Functional assessment of cognitively impaired older adults: Are we asking the right questions?
Authors: Calia Clara , Pickett Eleanor , O'Donal Freddie , Parra Mario A. 
Published: December 2020

AbstractBackgroundRecent attention has turned to the development of preventative treatments for Alzheimer’s disease (AD) by targeting the early stages of impairment. However, current neuropsychological and functional assessments are not ideally suited to identify early deviations from healthy ageing (HA). The Details of Functions of Everyday Life (DoFEL; Parra & Kaplan, 2019) is a theory‐driven scale that incorporates cognitive constructs sensitive to the preclinical stages of dementia (memory binding). DoFEL can help assess the extent to which instrumental functions of daily living are supported by such cognitive abilities and if so, whether by asking the right questions through such a scale we could unveil subtle and still undetected impairments. We predict this would increase the sensitivity of scales to detect older adults with cognitive impairment who are at a high risk of dementia.MethodsTwenty‐five MCI and 21 HA controls (ACE‐R score ≥ 88) (Mioshi et al., 2006) underwent an extensive baseline neuropsychological assessment followed by yearly follow‐up assessments. The DoFEL is an informant‐based neuropsychological assessment that measures a range of functional abilities which rely on different forms of binding functions. This measure includes 82 statements subdivided into 7 functional domains that comprehensively assess different aspects of daily living. Higher DoFEL score indicate greater impairment.ResultsFive key findings from this study were: (1) The total DoFEL score differentiates MCI from HA U=406.00, p=0.002. Higher scores were detected in individuals with MCI (Mdn= 0.41, Mean rank= 29.24) than in the HA (Mdn= 0.35, Mean rank= 16.67). (2) Individuals with MCI showed domain‐specific impairments on DoFEL such as Objects and People, Technology and Communication, Work and Social Life. (3) Relative to HA, MCI patients presented with impaired functional abilities that rely on relational (i.e., forming associations, p=0.001) and conjunctive (i.e., forming object identity, p=0.004). (4) DoFEL scores correlate with (r= ‐0.62, p=0.000), and predicts cognitive performance on the ACE‐R (β= ‐128.68, t(44)= ‐6.97, p=0.000).ConclusionDoFEL can detect differences between individuals with MCI and HA in overall and specific functional abilities seemingly supported by binding functions and therefore may be a useful tool to identify individuals at risk of developing AD.