bluuebunny/crossref_metadata_2025_split huggingface dataset:
Omega 3/6 ratios: Usage and epigenetic changes in health and Alzheimer's disease
Authors: Andrade Victor 
Published: December 2021

AbstractBackgroundFrom our previous research, we identified circulating metabolites that are associated with cognitive performance and dementia including polyunsaturated fatty acids (PUFA), in particular plasma levels of Omega‐3. To follow up on this finding, we sought to explore potential mechanism mediating the effect of Omega‐3 and Omega‐6 on these neurodegenerative phenotypes. Herein, we hypothesized that modulation of immune response and inflammation may mediate the effect of PUFA on neurodegenerative diseases.Methods1.Validate our PUFA ratios hypothesis on the MAPT intervention study. 2.Evaluate the epigenetic mechanisms modulation derived from genetics using genome‐wide association studies. 3.Corroborate previous results on real methylation data from the DELCODE study using the EPIC array. 4.Evaluate the biological age derived by epigenetics and its implications in healthy and cognitively affected subjects.ResultsThe effect of the PUFA ratios follows the same trend on the MAPT study as previously described during our first period. We observed that the methylation of the genes coding for key enzymes of PUFA metabolism is modulated by levels of Omega‐3. Likewise, these methylation changes have been described in susceptibility genes for Alzheimer’s disease (AD) that modulate immune response. Finally, methylated signals also enabled the prediction of biological age. We observed that biological age in DELCODE participants differs from chronological age depending on the status of the participants.ConclusionsThe present analysis suggests that PUFA ratios are associated with cognitive decline as we previously described. Moreover, we suggest that genetic signals located in the immune‐related gene cluster MS4A are modulated by changes in DNA methylation. The same epigenetic modulation seems to mediate the genetic effect discovered in the sTREM2 GWAS. Interestingly, methylation modulation in MS4A gene has been previously reported using an independent approach. Likewise, TREM2 locus seems to be affected by methylation changes. Finally, our methylation data allowed us to analyze the biological age of cognitively affected individuals and find some clear differences with their chronological ages. Using our results, we will explore whether PUFA levels, and the ratio built on Omega‐6 and Omega‐3, modulate levels of CSF sTREM2 offering thereby a potential connection between PUFA levels and neuroinflammation in the context of AD.
How knowledge of elevated amyloid impacts neuropsychological performance in cognitively normal older adults: Findings from the REVEAL SCAN Study
Authors: Karlawish Jason , Harkins Kristin , Chen Clara A , Cupples L. Adrienne , Roberts J. Scott , Welsh‐Bohmer Kathleen A. , Green Robert C. 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) prevention trials enroll cognitively unimpaired persons with AD biomarkers. The REVEAL‐SCAN trial tested whether knowledge of elevated amyloid affects these persons' cognitive test performance.MethodCognitively unimpaired adults age 65‐80 with a first degree relative with AD, intact cognitive and functional status, and no unstable psychiatric or medical conditions received an AD dementia risk estimate and random assigned to either learn their amyloid (18F‐amyvid) PET scan result (D+) or to learn it 6 months later (D‐). At 6 weeks and 6‐months post‐disclosure, participants completed the ADCS‐PACC battery, a composite of 4 measures: Free and Cued Selective Reminding Test (free portion only), Logical Memory IIa test, Digit‐Symbol Substitution test, and Mini Mental State Exam. Scores from each test are standardized to a common Z‐score metric and a composite score is calculated by summing these standardized Z‐scores. We hypothesized that follow‐up ADCS‐PACC scores would be lower among elevated (A+) disclosed participants (D+) than elevated (A+) nondisclosed (D‐) participants.Result315 participants were randomized (84 elevated (41 A+D+/43 A+D‐), 231 not elevated (118 A‐D+, 113 A‐D‐)). We report analyses comparing PACC scores between A+D+ and A+D‐. Table 1 shows no statistically significant between group differences in participant characteristics. Both before and after multiple imputation and dropping outliers that were >2 SD from the mean, PACC scores did not differ between groups at baseline. Linear regression mixed‐effects with repeated measures model (MMRM) adjusted for baseline PACC scores and time point showed that estimated mean scores at 6‐week and 6‐month did not differ between A+/D+ and A+D‐ participants (Model 1: D+ estimated mean 0.35, 95% CI: ‐0.13 to 0.84, compared to D‐ estimated mean 0.84, 95% CI: 0.38 to 1.31). The effect of disclosure on follow‐up PACC scores remained non‐significant after additionally adjusting for gender, race, education, and completion of follow‐up testing during COVID (Model 2: D+ estimated mean ‐0.38, 95% CI: ‐1.10 to 0.33, compared to D‐ estimated mean 0.06, 95% CI ‐0.65 to 0.78).ConclusionKnowledge of elevated amyloid among cognitively unimpaired individuals does not change performance on measures of cognition. Inspection of the variance suggests a dampening of practice effect.
Effects of intermittent theta burst stimulation (iTBS) on executive function and neuropsychiatric symptoms in older adults with mild to moderate dementia due to Alzheimer's disease: Preliminary findings of a randomized double‐blind clinical trial
Authors: Costa Mônica Vieira , de Paula Jonas Jardim , Viana Bernardo de Mattos , Burgos Ivonne Carolina Bolaños , Ávila Rafaela , Hansen Erika de Oliveira , Braga Nayara Rodrigues , Faria Karen Costa , Bicalho Maria Aparecida Camargos 
Published: December 2021

AbstractBackgroundStudies on brain networks indicate that the functional integration between brain networks decreases progressively with Alzheimer`s disease (AD). The intermittent Theta Burst Stimulation (ITBS) has been shown to modulate the connectivity of DMN administered to parietal (PPC) and dorsolateral prefrontal (DLPFC) cortex.MethodWe selected 9 patients with AD, and a randomized double‐blind clinical trial was performed comparing the active iTBS (n=5) with sham group (n=4)of older adults with mild to moderate AD. Active iTBS condition were submitted to 21 iTBS sessions on the right and left DLPFC and the right and left PPC. All participants were assessed at baseline, week 3,week 6, 3 and 6 months. Executive functions were assessed by validated and standardized tests for this population. Behavioral symptoms were evaluated by Neuropsychiatric Inventory (NPI). The changes in performance between assessments were compared using the reliable change index (RCI).ResultOn phonemic verbal fluency two participants from intervention group show decline of this ability. One of them in the 3rd week (RCI = ‐2.16) and in the 6th week (RCI = ‐3.24). And another only in the 6th week (RCI = ‐3.24). After this period, the performance was similar to that of the baseline for both. Despite this, there were three patients who showed change in phonemic verbal fluency in the third week. One participant from sham group also showed improvement in the sixth week (RCI = 2.16).Regarding working memory, a sham participant showed decline in this ability after the sixth week assessment (RCI = ‐7.38) and this performance remained below that presented in the baseline until the sixth month. And another from intervention group showed improvement in the third week (RCI = 2.46), but from the sixth week on, the performance returned to the same level as the baseline.ConclusionThe improvement and impairment of cognitive variables in comparison to baseline was associated with temporal proximity of neurostimulation procedures for both groups. It is still necessary to expand the sample size to clarify which factors impact on this outcomes.
Frailty may not be a predictor of progression from MCI to dementia
Authors: Rogers Emily , Pascual‐Leone Alvaro 
Published: December 2021

AbstractBackgroundSome studies have reported that an individual’s degree of frailty influences the risk of progression from MCI to dementia and correlates with the extent to which those with AD manifest the clinical symptoms of dementia. However, the construct of frailty generally includes factors that can directly compromise cerebro‐vascular function (e.g., cardiac disease or hypertension) or be manifestations of mental and cognitive impairment due to brain pathology. This broad definition of frailty may be problematic in that it measures what it seeks to predict.MethodTo explore the utility of frailty to predict progression from MCI to dementia, we tracked clinical, health, demographic, executive function and behavioral features from the National Alzheimer’s Coordinating Center (NACC) dataset. In 5923 samples over 65 years, with a diagnosis of MCI and at least one visit after MCI diagnosis, 3359 remained MCI at the end of the study while 2564 progressed to dementia. We analyzed common frailty contributors, as well as all other possible variables with sufficient data coverage.ResultAmong these, only 7 of the 40 most commonly considered contributors to frailty were statistically significant differences between MCI patients progressing to dementia and those remaining MCI. The 7 significant features were difficulty in remembering dates, in paying bills, in shopping, in traveling around the neighborhood, in preparing meals, feelings of apathy and change in appetite. Using statistical tests to determine significant categorical features differentiating MCI patients progressing to dementia from those remaining MCI, we found a total of 34 features, of which 21 might be considered executive functioning measures and 5 behavioral symptoms.ConclusionOur findings show that the metrics of frailty that are predictive of progression from MCI to dementia are essentially cognitive measures and thus the construct of frailty may simply be identifying patients with more advanced brain disease, who predictably would be at a greater risk of becoming diagnosed with dementia. The frailty construct may thus mainly offer a metric of dementia severity, and not really a predictor of developing it.
Identification of key genes and pathways involved in Alzheimer’s disease through bioinformatic analysis
Authors: Tunali Nagehan Ersoy , Düzenli Ömer Faruk 
Published: December 2021

AbstractBackgroundAlthough there has been an intensive research on the molecular mechanisms of AD, there’re still unexplored pathways due to the heterogeneity of the disease mechanisms and variations in experimental approaches. Therefore, bioinformatics to would be helpful in deciphering the key gene expression patterns in existing datasets, which will eventually serve as biomarkers for AD.MethodIn this study, we aimed to identify the key genes and miRNAs involved in AD via bioinformatic analyses. We selected the GEO dataset GSE48350, which contains the microarray data collected from entorhinal cortex (EC), hippocampus (H), postcentral gyrus (PCG) and superior frontal gyrus (SFG) of the 80 AD and 173 healthy brains. We first identified the differentially expressed genes (DEGs) using the GEO2R web tool. Then, functional enrichment analysis (FEA) was performed by using DAVID. Protein‐protein interaction (PPI) networks were drawn by using STRINGdb and the hub proteins were detected by using the Cytohubba module in the Cytoscape program. miRNA detection was performed by using the miRDB web tool.ResultWe identified 12, 49, 69, 7, and 26 downregulated and 16, 51, 245, 10, and 44 upregulated genes as in all parts of the brain, EC, H, PCG and SFG regions, respectively. PPI analysis revealed the top three hub proteins as: GFAP, CXCR4, FOS in the EC; SNAP25, GRIN1, SLC32A1 in H; GFAP, SST, CXCR4 in FG regions and GFAP, SLC32A1, SST in the whole brain. According to FEA, the identified genes are involved in chemical synaptic transmission, neurotransmitter release, extracellular matrix organization, and inflammatory response. Upon analysis of the miRNA target database, we identified seven miRNAs targeting these genes. The most exciting miRNA turns out to be hsa‐miR548 family, since it targets CXCR4, FOS and GFAP.ConclusionThe identified DEGs may serve as biomarkers and drug targets for AD. Therefore, additional experiments on expressions of these genes in the plasma or cerebrospinal fluid samples of the patients should be performed. Also, miR‐548 family should be explored as a candidate drug target.
The prevalence of unrecognized cognitive impairment in geriatric surgical patients: A systematic review and meta‐analysis
Authors: Kapoor Paras , Saripella Aparna , Chen Lina , Riazi Sheila , Wong Jean , Englesakis Marina , Nagappa Mahesh , Chung Frances 
Published: December 2021

AbstractBackgroundPre‐existing cognitive impairment is emerging as a predictor of poor postoperative outcomes in older surgical patients (Guenther, 2020). Due to a substantial under‐diagnosis of cognitive impairment in the elderly, the prevalence of undiagnosed cognitive impairment has not been well defined in those undergoing surgery (Elman, 2018). The objective of this systematic review and meta‐analysis is to determine the pooled prevalence of unrecognized cognitive impairment in the elderly undergoing elective noncardiac surgery.MethodAn expert librarian conducted the literature search, which included MEDLINE (Ovid), PubMed (non‐MEDLINE records only), Embase, Cochrane Central, Cochrane Database of Systematic Reviews, PsycINFO, and Emcare Nursing for relevant articles from 1946 to April 2021. Inclusion criteria were (1) patients ≥ 60 years old undergoing elective non‐cardiac surgeries; (2) preoperative cognitive impairment assessed by validated cognitive screening tests; (3) published in English language. Descriptive analysis was conducted for the cognitive impairment group. Data were extracted from each study and prevalence of cognitive impairment with 95% confidence interval (CI) was calculated for each study. We used the random effect model to calculate the pooled prevalence value with 95% CI. Comprehensive meta‐analysis software was used for statistical analysis (Borenstein, 2013).ResultOf 8,895 citations, 20 studies were included consisting of 4,159 patients undergoing a variety of elective non‐cardiac surgeries. All but one study were prospective cohort studies, with the exception being a cross‐sectional study. The mean age among patients with unrecognized cognitive impairment was 73.1 ± 7.2 years, and 43.6% were male. The pooled prevalence of cognitive impairment was 40.2% (95% CI: 31.0%, 50.1%; P=0.005; predictive interval: ‐1.47 to 2.27 (Table 1). The forest plot displays non‐overlapping CI's, indicating high heterogeneity within the data (I2: 97%). Influential analysis of any study showed that removal of each study did not significantly alter the pooled prevalence result. Meta‐regression analysis based on age, gender, and body mass index (BMI) did not change the final inference of our results.ConclusionThe prevalence of unrecognized cognitive impairment is very high at 40.2% in geriatric patients undergoing elective non‐cardiac surgery.
Multivariate computational linguistic analysis for early detection of cognitive impairment
Authors: Lee Evan T. , Ebinu Julius O. 
Published: December 2021

AbstractBackgroundThe overarching goal of this study was to develop a novel computational linguistic algorithm that can be used to build a machine learning platform for recognizing changes in cognitive abilities during the progression of psychopathological disorders or predicting clinical prognosis following a brain injury or therapeutic interventions.MethodThe computational linguistic algorithm developed in this study evaluates lexical diversity, lexical complexity, and emotional tones in a quantitative manner. An existing algorithm that quantifies idea density was also included in this study. The initial proof‐of‐concept study was performed on various published books by well‐known authors, including Iris Murdoch who developed Alzheimer’s disease (AD) later in life. Ten interviews of patients with mild AD and ten interviews of healthy age‐matched individuals were evaluated. The transcript of each video was produced manually. Each transcript was analyzed using the computational linguistic algorithm for lexical diversity/complexity, emotional tones, and idea density. Quantitative linguistic values were compared between patients with mild AD and healthy age‐matched individuals.ResultA computational linguistic analysis of various books resulted in findings that were consistent with the nature and subject of each book. Among all the computational linguistic variables evaluated in this study, the book written by Irish Murdoch after the onset of AD showed a decrease in the level of lexical complexity by 17.5%. Interestingly, a 20% decrease in the level of lexical complexity was also noted when video interviews of patients with mild AD were compared to normal age‐matched individuals. The video transcripts of AD patients showed a statistically significant increase in the levels of anger, fear, and sadness. We are currently conducting a study to compare computational linguistic variables in response to writing prompts between patients with mild AD and healthy age‐matched individuals. Preliminary results indicate that patients with AD show a similar decrease in the level of lexical complexity as well as quantifiable changes in emotional tones.ConclusionThe computational linguistic algorithm developed in this study may lead to a machine learning approach or artificial intelligence platform to detect linguistic changes that may occur in the human cognitive state for both diagnosis and/or prognosis of mental health conditions.
Assessing the effect of modified Mediterranean‐ketogenic diet on mild cognitive impairment patients through plasma neuron‐derived exosomes
Authors: Kumar Ashish , Sharma Mitu , Singh Sangeeta , Su Yixin , Hsu Fang‐Chi , Craft Suzanne , Deep Gagan 
Published: December 2021

AbstractBackgroundRecently, we compared the effect of a high‐fat and low‐carb Modified Mediterranean‐Ketogenic Diet (MMKD) and a low‐fat American Heart Association Diet (AHAD) on 11 cognitively normal (CN) and 9 with mild cognitive impairment (MCI) older adults as a suggestive preventative intervention for Alzheimer’s disease (AD). We reported the promising effect of the MMKD on MCI patients as it was well‐tolerated and associated with increased cerebrospinal fluid (CSF) Aβ1‐42, decreased tau, and increased cerebral perfusion. Here, we characterized the plasma neuron‐derived exosomes (NDE) to further understand the molecular mechanisms underlying the efficacy of the MMKD against MCI.MethodThe completed study consisted of a randomized crossover design in which participants (both CN and MCI) consumed either the MMKD or the control AHAD for six weeks. Total exosomes (TE) were isolated from plasma by precipitation method, and NDE were enriched using Biotin‐tagged CD171 antibody attached with streptavidin‐magnetic beads. The purity, concentration, and size of TE and NDE were assessed by flow cytometry, nanoparticle tracking, immunogold‐labeling, electron microscopy, and exosome antibody array. NDE was characterized for several AD and neurodegeneration‐related biomarkers, advanced glycation endproducts (AGEs), glutamate, glutamate receptors, and β‐hydroxybutyrate (BHB) by ELISA and colorimetric assays. NDE effect on NF‐kB activity in human monocytes was studied as a molecular surrogate for inflammation.ResultWe confirmed the size, shape, and purity of both TE and NDE by multiple methods. Importantly, the MMKD treatment strongly reduced the level of Aβ1‐42 (by 50%, p=0.001), p(181)Tau (by 17%), and neurofilament L (by 55%, p=0.03) in the MCI group, but not with AHAD. MMKD reduced the AGEs in both CN and MCI groups and strongly increased the glutamate level in NDEs from the MCI group (6 fold, p<0.001) but did not affect glutamate in CSF. The MMKD also modulated the expression of various glutamate receptors (GRIN1, GRIA1, GRIN2A, and GRIN2b). Interestingly, we detected BHB in NDEs, though no significant change was observed. MMKD inhibited the NF‐κB activity in monocytes suggesting a strong anti‐inflammatory effect.ConclusionNDE offers a promising peripheral measure to assess the efficacy and molecular mechanism of MMKD action against MCI.
Association between sleep health and cognitive reserve in older adults with cognitive concerns
Authors: Kerner Nancy , Espejo Kimberly , Bell Sophie A. , Pollina Julianna , Goldberg Terry E. , Devanand Davangere P 
Published: December 2021

AbstractBackgroundWe examined the association between sleep health consequences and perceived fatigability within the context of carrying out everyday activities in non‐demented older adults and investigated whether cognitive reserve (CR; individual differences in susceptibility to cognitive decline due to brain aging, pathology, or insult) moderated this relationship.MethodThis was a cross‐sectional study. We prospectively screened adults age 55‐90 years at a Memory Research Clinic. An IRB approved the study protocol, and informed consent was obtained. Patients with cognitive concerns underwent neurocognitive testing to determine cognitive status based on the ADNI criteria. Inclusion criteria: the ADNI criteria for cognitively normal or MCI. Exclusion criteria: 1) depression assessed with the Geriatric Depression Scale (GDS>5) and DSM‐5 criteria, 2) history of primary psychiatric illnesses, 3) medical conditions associated with fatigue, and 4) a history of obstructive sleep apnea diagnosed by a clinical sleep physician. Measures included the PROMIS Sleep‐related Impairment (SRI); the Neuro‐QOL Cognitive function (CogF) and Fatigue measure, which yields “fatigue symptom severity (Fat_Sx)” and “perceived fatigability (Fatiga)” subscales. CR was assessed with the CR Index questionnaire (CRIq). Linear regression models were fit to the fatigue outcomes and included the SRI, CR, and their interaction as predictors. If the interaction was significant, SRI slopes were assessed at CR=mean and mean ±1SD. All analyses were adjusted for age, sex, and education.ResultThere were 37 subjects in this study; mean age of 70.8 years (SD=9.3); 70.3% subjects were female; 86.5% white, 10.8% Hispanic, and 2.7% others. CR significantly moderated the relationship between SRI and perceived fatigability (F (1,32)=18.64, p=0.011). A higher SRI score was associated with a higher perceived fatigability severity with a low CR (CRIq mean‐1SD)=108.6; b(se)=.493(.089), p<0.001) and a mean CR (CRIq mean=128.0; b(se)=.274(.076); p=0.001), but not a high CR (CRIg mean+1SD=147.4; b(se)=0.1278; p=0.636). Moreover, higher perceived fatigability was associated with lower cognitive function (b(se)=‐.24 2(0.077), p=0.004), controlling for age, gender, and education.ConclusionPoorer cognitive function was significantly associated with greater fatigability within the context of managing everyday activities. Greater cognitive reserve may reduce the detrimental influence of poor sleep health on perceived fatigability in managing daily function during the preclinical stages of dementia.