bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome‐wide association study of ADNI QT‐PAD biomarkers identifies a novel locus on Chr 12
Authors: Lee Brian N , Yao Xiaohui , Shen Li 
Published: December 2020

AbstractBackgroundIdentifying genetic basis of quantitative biomarkers in Alzheimer’s disease (AD) is a promising method to help deconvolute mechanistic complexity of AD and may lead to a better understanding of disease subtypes. Quantitative Templates for the Progression of Alzheimer’s disease (QT‐PAD, see http://www.pi4cs.org/qt‐pad‐challenge) provides a single, common and shared data freeze from Alzheimer’s Disease Neuroimaging Initiative (ADNI), including 16 imaging, cognitive and fluid AD biomarkers. To reveal novel AD genetic factors, we perform a genome‐wide association study (GWAS) of QT‐PAD biomarkers.MethodParticipants included 1,324 subjects from the ADNI QT‐PAD cohort with both biomarker concentration and genotyping data available. GWAS was performed to examine genetic associations between 565,373 SNPs (after going through a standard QC procedure) and concentrations of 16 key QT‐PAD biomarkers (see Figure 1), with age, gender, and education as covariates. GWAS was performed for both the baseline and m12 QT‐PAD data.ResultsWe identified a novel locus rs5011804 on Chr 12 (baseline p =1.28E‐10, m12 p = 1.88E‐14) significantly associated with higher concentrations of biomarkers CDRSB, FAQ, and ADAS13 at both baseline and m12 visits (Figure 2), suggesting the variation (minor allele C) plays a role in affecting these three AD biomarkers. Figure 1 shows the complete GWAS findings at baseline using the genome‐wide significance threshold of p<5e‐8. This result not only affirms the key AD genes (APOE, TOMM40, PVRL2) but also suggests the promising role of rs5011804 due to its associations with seven QT‐PAD biomarkers. The SNP rs5011804 has a reported association with adult asthma (Vonk et al. 2017, PloS one, 12(3), e0172716) and slightly affects intracranial volume (corrected p = 0.05934) (Hibar et al. 2015, Nature, 520(7546), 224–229) but has not been associated with AD before.ConclusionQT‐PAD provides a standardized method for measuring the AD progression and allows for new quantitative genetics research. Genetic analysis of QT‐PAD biomarkers identified a novel locus in Chr 12 associated with multiple QT‐PAD biomarkers. The identified locus warrants further investigation in independent cohorts as a potential AD risk factor.
Depression and the apathy symptom are associated with poorer cognitive functioning in very old men
Authors: Guerrero‐Berroa Elizabeth , Schmeidler James , Phillips Ruby , Muallem Julia , Suleiman Halima , West Rebecca , Sano Mary , Reisberg Barry , Silverman Jeremy M 
Published: December 2020

AbstractBackgroundOlder adults (65+) are among the fastest growing segments of the population, projected to double by 2050. Oldest‐old (85+) manifest the greatest relative increase in population and have the greatest risk of developing Alzheimer’s Disease (AD). Depression is a chronic, debilitating condition in older adults. Depressive symptoms, particularly apathy—and poor concentration—have been associated with poor cognitive functioning and dementia. However, some associations depend upon gender, age of depression onset, and preexisting cognitive impairment; other studies find no association. Associations have been primarily in relatively young samples, and apathy has infrequently been studied in the very old. We investigated the cross‐sectional associations of depressive symptoms and apathy with cognitive functioning in cognitively normal very old men.MethodsParticipants consisted of 74 cognitively intact male veterans (age = 86 ±5.1 [mean ± SD], range = 76‐98; 81.1 % White, 18.9% Black; 15‐item Geriatric Depression Scale [GDS] = 2.6 ±2.7, range = 0‐12; 13.5% depressed [GDS ≥ 6]) enrolled in the Cardiovascular Risk Factors and Successful Cognitive Aging in Very Old Male Veterans study. The predictors were the GDS‐15 and the apathy item “Have you dropped many of your activities and interests?” Cognitive outcomes, from factor analysis of 11 neuropsychological test scores, were three Varimax factor cognitive domains (Episodic Memory, Attention, Executive Function), and the first principal component (global cognition). Linear regression analyses adjusted for age and education.ResultsDepressive symptoms were significantly associated with poorer global cognition (r = ‐.274, p = .020). Apathy was significantly associated with poorer Attention (r = ‐.403, p < .001) and global cognition (r = ‐.377, p = .001). Apathy remained significant after controlling for the sum of other depressive symptoms.ConclusionThese results extend others’ findings by showing that depressive symptoms, and specifically apathy, are associated with poorer cognitive functioning in very old men. This study highlights the relevance of examining depressive symptoms as predictors of cognitive functioning. The small effect sizes (r ≤ .097) for memory, the hallmark cognitive symptom of AD, suggest possible non‐AD biological involvement. Future studies with larger and more demographically and ethnically diverse samples are warranted.
Metformin reduces behavioral, but not metabolic, disturbances associated with high‐fat diet
Authors: Jones Nahdia S , Rebeck G William 
Published: December 2020

AbstractBackgroundAPOE4 is the strongest genetic risk factor for Alzheimer’s Disease (AD), and obesity is a strong risk factor for developing dementia and cognitive disturbances. Metformin, the first line medication for Type II Diabetes, has been implicated in reducing metabolic and cognitive disturbances. Here we tested whether metformin ameliorated the disturbances associated with high fat diet (HFD) and whether metformin works equally on the APOE3 and APOE4 mice.MethodMale and female human APOE3 and APOE4 knock‐in mice were fed either a HFD (45% kcal fat) or a low fat diet (LFD) (10% kcal fat) for 3 months (3 months‐6 months of age). During the last month of feeding, mice were given 300 mg/kg/day of metformin in drinking water. At the end of feeding, the following metabolic measurements were taken: weight, baseline glucose, and glucose tolerance. The mice were tested on the Open Field Test and Fear Conditioning apparatus.ResultHFD induced a 30% increase in weight in male APOE3 mice and a 20% increase in male APOE4 mice. HFD also induced glucose intolerance in male APOE3 and APOE4 mice. Metformin did not reduce these metabolic disturbances. These metabolic disturbances were not seen in female mice on HFD. HFD decreased average speed and increased anxiety‐like behavior in APOE4 females on the open field test; metformin reduced these effects. With fear conditioning, there was a decrease in context based freezing behavior in female APOE3 mice on HFD, again with a metformin‐associated recovery. There were no behavioral effects of HFD on male mice.ConclusionHFD induced metabolic disturbances in male mice, but there were no differences between APOE genotypes and metformin did not reduce these metabolic disturbances. Furthermore, behavioral effects were only seen in female mice with metformin assisting in the rescue of these effects. The next step is to examine the alterations in the CNS due to HFD and metformin.
Effects of menopausal estrogen loss on the functional brain activity underlying associative memory
Authors: Brown Alana , Gervais Nicole J , Almey Anne , Duchesne Annie , Gravelsins Laura , Reuben Rebekah B , Baker‐Sullivan Elizabeth , Rieck Jenny , Baracchini Giulia , Foulkes William , Meschino Wendy , Grady Cheryl , Einstein Gillian 
Published: December 2020

AbstractBackgroundOvarian removal via bilateral salpingo‐oophorectomy (BSO) prior to spontaneous menopause (SM) is related to increased Alzheimer’s disease (AD) risk (Rocca et al., 2007). Associative learning deficits are considered the earliest AD symptoms, heralding preclinical AD (Fowler et al., 2002). Performance and brain activation during a face‐name associative memory task differ based on reproductive stage and are linked to fluctuating levels of 17β‐estradiol (E2; Rentz et al., 2017). We hypothesized that BSO would affect memory and functional brain activity during associative encoding.MethodMiddle‐age women underwent functional magnetic resonance imaging (fMRI) while completing a face‐name associative memory task (Sperling et al., 2003). Recognition performance and brain activation during face‐name pair encoding were assessed in women with BSO taking E2‐based hormone therapy (BSO+E2; n=10; mean age=46), women with BSO taking no hormone therapy (BSO; n=12; mean age=49), age‐matched women with intact ovaries (AMC; n=14; mean age=44), and older women in spontaneous menopause (SM; n=15; mean age=56).ResultNo group differences in face‐name pair recognition accuracy were found. Multivariate partial least squares analyses (McIntosh & Lobaugh, 2004) revealed significant differences in brain‐behaviour correlations between BSO and SM groups. Accuracy in the SM group correlated positively with activation of the hippocampus, medial temporal, parietal, and frontal lobes, while accuracy in the BSO group correlated negatively with activation of these regions (see Figure). Region‐of‐interest (ROI) analyses revealed that functional activity in the right superior frontal lobe correlated positively with E2 levels in the BSO+E2 group (r=0.83, p=0.01), and negatively with E2 levels in the BSO group (r=‐0.66, p=0.03).ConclusionActivation of distinct brain regions underlying associative memory depends on E2 and age. The BSO group, who experienced menopause approximately 10 years earlier than the SM group, showed significantly different patterns of brain activation compared to the SM group, ultimately to achieve similar recognition accuracy. Importantly, there were no significant differences in performance, indicating that brain changes may precede associative memory changes, and that E2 depletion could play an important role in brain activity underlying women’s associative memory.
The role of psychosocial factors in the formation of non‐cognitive symptoms of dementia
Authors: Sidenkova Alena Petrovna 
Published: December 2020

AbstractBackgroundThe non‐cognitive symptoms actualize a comprehensive medical and social study of dementia. The aim of the study is to study the psychosocial mechanisms of the formation of clinical, functional disorders in dementia, to develop comprehensive medical and psychosocial programs to help patients with dementia and those involved in caring for them, based on the proposals of the psychosocial model of dementia.MethodA selective observational comparative dynamic study of 315 people with dementia of the Alzheimer's and 214 of the patients was carried out. The study used clinical, clinical, neuropsychological, sociometric, and statistical research methods.ResultAn increase in the severity of dementia contributes to a significant (p <0.05) increase in the number of patients in a dependent position in the family. The appearance of psychotic (painful ideas [r = 0.589]), behavioral (agitation / aggression [r = 0.654]), affective (anxiety [r = 0.536], unstable mood / irritability [r = 0.581]) symptoms of dementia contribute to family role changes structure and increase interpersonal distance in the dyad "caretaker ‐ patient." Those who provide unprofessional care for dementia patients in a statistically significant (p <0.05) majority of cases have a high level of emotional involvement in the care process. Changes in family‐role and social parameters, a high level of “expressed” emotions of caregivers have an adverse effect on the development of psychotic (r = 0.618), affective (r = 0.701), behavioral (r = 0.837) dementia disorders. The degree of adherence to anti‐dementia therapy by the caregiver is one of the important factors determining the amount of care received by the patient (r = 0.698). Agitation / aggression (r = 0.761), anxiety (r = 0.562), sleep disturbances (r = 0.521) contribute to increased compliance. The low satisfaction of the caregiver with premorbid (r = 0.698) and current (r = 0.653) relationships with the patient leads to a decrease in the compliance of the caregiver.ConclusionThe formation of cognitive impairment is due to biological causes, their severity depends on the severity of dementia. The mechanism of psychopathological symptoms, functional disorders is heterogeneous depending on the biological causes and psychosocial conditions of functioning of patients.
Brain‐wide spatial analysis to identify region‐specific changes in cell composition associated with resilience to Alzheimer’s disease in the AD‐BXD mouse population
Authors: Gurdon Brianna , Hadad Niran , Telpoukhovskaia Maria , Yates Sharon , Puchades Maja Amedjkouh , Bjaalie Jan , Kaczorowski Catherine C 
Published: December 2020

AbstractBackgroundIndividual differences in brain structure have been associated with variation in brain atrophy and cognitive symptoms in Alzheimer’s disease (AD), but the underlying genetic mechanisms that dictate structural differences are not fully understood. Recent advances in large‐scale immunohistochemistry (IHC) now make it feasible to quantify region‐specific changes in cell composition and relate such changes to both clinically relevant traits (cognitive resilience) and gene expression for novel mechanistic insight.MethodForty hemibrains of adult and middle‐aged AD‐BXD strains, a translational mouse model of human AD, were stained to evaluate neurodegeneration (NeuN), gliosis (Iba1&GFAP), and AD‐specific pathology (AB1‐42) using IHC. Individual differences in cellular composition were quantified using % coverage of each stain across multiple brain regions obtained from the QUINT workflow, in which experimental slices were systematically segmented and registered to the Allen Brain Atlas Common Coordinate Framework. Cellular composition changes in hippocampus were then compared to bulk hippocampal gene expression levels to identify cellular and molecular correlates of resilience to AD.ResultThe % coverage of hippocampal GFAP+ astrocytes, Iba1+ microglia, and AB1‐42+ pathology increased with age and correlated with genes enriched for immune‐related pathways, chromatin remodeling, and mRNA processing. Neuronal cell load (% NeuN coverage) in the hippocampus of AD‐BXD mice was associated with genes enriched for GABA receptor activity, NMDA activation, extracellular matrix integrity, and autophagy. Moreover, in aged mice, genes positively correlated with NeuN coverage were enriched for cognition. This was further supported by the association between % NeuN coverage and improved cognition as measured by better performance on contextual fear memory tasks.ConclusionUsing bulk RNAseq we were able to associate greater glial cell load with increased gene expression and explore pathways correlated with cellular composition in AD‐BXDs; however, it is unclear whether the variation in gene expression is a result of changes in the transcriptional activity of genes in these pathways, cell composition changes, or both. Integration of snRNAseq and brain‐wide quantitative maps will enable us to disentangle gene expression changes from cell composition, and perform genome‐wide studies to map the loci responsible for modulating these changes that underlie resilience in AD.
Drug prescription in elderly hospitalized patients with cognitive impairment in the Italian dementia‐friendly hospital project
Authors: Govoni Stefano , Rosi Alessia , Preda Stefania , Allegri Nicola 
Published: December 2020

AbstractBackgroundOlder patients with cognitive impairment represent a significant proportion of the patients hospitalized for various acute illnesses. The health staff is not prepared to deal with such patients which do not fit the standard of care of the hospital stay. Accordingly, we recorded a series of clinical parameters reflecting the health status and the drug prescriptions at the entry and during hospital stay before and after a brief (5 hrs. frontal teaching) intervention of staff training, focusing on improving the management of patients with cognitive impairment.MethodsParticipants were evaluated within 48 h of admission and at discharge with Mini Mental State Examination (MMSE), Barthel Index, Instrumental Activity of Daily Life (IADL), and Hospital Anxiety and Depression Scale (HADS). A preliminary analysis of 68 hospitalized participants aged 65 and older with cognitive impairment (MMSE ≥ 16, ≤24) allocated in the control group (n = 34, 20 females, 82.38 years) and intervention group (n = 34, 20 females, 81.97 years) was performed. For each patient, the number of prescriptions, sedative and anticholinergic load, and drug–drug interactions were evaluated.ResultsParticipants presented a widespread polypharmacy receiving as average 6.9 (+/‐ 1.7 drugs/daily in the control group) and 5.9 (+/‐ 1.6 drugs/daily in the intervention group), the difference being not statistically significant (P = 0,068). Also, the sedative load presented a trend toward lower values in the intervention group. The results concerning the other clinical indices (submitted elsewhere) show that personnel training significantly improved the functional and anxiety parameters at discharge.ConclusionsThe results suggest that an intervention, focused on improving dementia care practices in health staff, having the potential to improve outcomes for hospitalized older adults with cognitive impairment, but not directly designed to manage drug polypharmacy, is not sufficient to modify drug prescription patterns.
Inhibition of human islet amyloid polypeptide aggregation and cellular toxicity by oleuropein and derivatives from olive oil
Authors: Chaari Ali 
Published: December 2020

AbstractBackgroundBeta‐cell death is the key feature of type 2 diabetes mellitus (T2DM). One hypothesis for the mechanism of this feature is amyloid formation by the human Islet Amyloid Polypeptide (hIAPP). Clinical trials and population studies indicate the healthy virtues of the Mediterranean diet, especially the extra virgin olive oil (EVOO) found in this diet. This oil is enriched in phenolic compounds shown to be effective against several aging and lifestyle diseases. Oleuropein (Ole), one of the most abundant polyphenols in EVOO, has been reported to be anti‐diabetic.MethodI report here a broad biophysical approach and cell biology techniques that enabled me to characterize the different molecular mechanisms by which tyrosol (TYR), hydroxytyrosol (HT), oleuropein (Ole) and oleuropein aglycone (OleA) modulate the hIAPP fibrillation in vitro and their effects on cell cytotoxicity.ResultOleA was found to be more active than Ole, HT and TYR at low micromolar concentrations. I further demonstrated that comparing to other used polyphenols, OleA inhibits the cytotoxicity induced by hIAPP aggregates by protecting more the cell membrane from permeabilization and then from death.ConclusionThese findings highlight the benefits of consuming EVOO and the great potential of its polyphenols. Moreover, they support the possible pharmacological use of EVOO polyphenols for T2DM prevention and therapy as well as for many other amyloid‐related diseases.
Single‐cell RNA sequencing analysis for common molecular signatures of microvascular injury
Authors: Guo Xinying , Zhao Zhen 
Published: December 2020

AbstractBackgroundMild Traumatic brain injury (mTBI) is a significant risk factor for Alzheimer’s disease (AD). Given that microvascular injury is common and persistent following mild TBI and that neurodegeneration is a late consequence following some TBIs, vascular dysfunction may be an important link between mTBI and AD. However, little attention has been focused on how the cerebral vasculature responds following mTBI induced AD. The goal of our work is to evaluate the potential common molecular signatures in cerebral microvessels in conditions such as mTBI, AD affected, and aging using single‐cell RNA sequence (sc‐RNA seq) approach.MethodThe processed single‐cell gene UMI count information from the study of single‐cell sequencing was collected for the secondary analysis using the newest R Seurat Package. Cell count matrix from different groups were integrated using a new method, which is to identify ‘anchors’ across diverse single cell data types in order to transfer information accurately across experiments. After integration, the vasculature cells are taken for another round of clustering to reveal heterogeneity within the vasculature cell. This subsetting of the data enabled us to highlight more subtle changes within the vasculature cell and uncover the unique change which is masked because of few vessel cells.ResultThrough analyzing vascular cells from the sc‐RNA seq data of mTBI dataset and aging dataset, we found differential expression genes of endothelial cells from two datasets, and discovered that microvascular injury is related to the damage of extracellular matrix, metabolic crisis, transport barrier dysfunction, protein refolding, blood flow, signaling, and changes of binding between molecules.ConclusionSingle cell genomics provides unique information about how mTBI and aging impacts diverse cell types, adding new insights into the pathogenic pathways amenable to therapeutics in mTBI induced late‐onset Alzheimer’s disease. Therapeutic approaches against microvessel injury will have important implications for future treatment of AD and other neurodegenerative diseases.
Blood flow improvement trial: Design and enrollment
Authors: MacAlpine Maiya F , Heston Margo B , Gaitán Julian M , Okonkwo Ozioma C , Bendlin Barbara B , Gretebeck Kimberlee A , Gretebeck Randall J 
Published: December 2020

AbstractBackgroundMidlife insulin resistance (IR) has previously been shown to be associated with lower cerebral blood flow (CBF), and is a potentially modifiable risk factor for dementia. The Blood Flow Improvement Trial (BFiT), NCT03117829 , tested a 12 week carbohydrate restricted diet (CRD) and exercise behavioral intervention to reverse IR, and aimed to 1) determine the extent to which improving or normalizing glucose homeostasis improves CBF and cognitive function in individuals with IR, 2) determine whether participants continue to maintain improved or normalized glycemic control for 6 months, and 3) determine changes in the human metabolome as individuals improve or normalize IR and glucose homeostasis through diet and exercise.MethodParticipants were recruited from the Wisconsin Alzheimer’s Disease Research Center and screened for metabolic risk factor eligibility based on the criteria shown in Table 1. The design involved a 12 week diet and exercise intervention focused on self‐monitoring to promote adherence. Exercise was conducted in a supervised group setting 3 days/week for 50 minutes and participants were instructed to exercise on their own an additional 2 days/week. Participants followed a CRD and monitored their own blood glucose with the goal of achieving and maintaining fasting blood glucose <100 mg/dL. Participants underwent baseline, 12 week, and 6 month procedures including urine and blood labs/metabolomics, cognitive testing, fitness testing, and blood flow imaging via MRI (Table 2).ResultThe enrollment goal was 40 participants. 118 individuals were screened for eligibility, and 72.5% of the target enrollment was met; of those participants, nearly 80% completed the 12 week intervention. Of the 23 participants that completed the intervention, mean attendance was 70% for supervised exercise sessions and 81% for weekly behavioral coaching sessions. Figure 1 summarizes screening, enrollment, and procedure completion.ConclusionIR may be a modifiable risk factor for dementia. The BFiT pilot trial was designed to test the feasibility of exercise and CRD to reduce IR and improve brain blood flow in middle‐aged adults. Reasonable enrollment and completion N were achieved. Future analysis will center on barriers to enrollment and adherence, as well as analysis of the primary and secondary outcome measures.