Classification Approach for Attention Assessment via Singular Spectrum Analysis Based on Single-Channel Electroencephalograms.

Attention refers to the human psychological ability to focus on doing an activity. The attention assessment plays an important role in diagnosing attention deficit hyperactivity disorder (ADHD). In this paper, the attention assessment is performed via a classification approach. First, the single-channel electroencephalograms (EEGs) are acquired from various participants when they perform various activities. Then, fast Fourier transform (FFT) is applied to the acquired EEGs, and the high-frequency components are discarded for performing denoising. Next, empirical mode decomposition (EMD) is applied to remove the underlying trend of the signals. In order to extract more features, singular spectrum analysis (SSA) is employed to increase the total number of the components. Finally, some typical models such as the random forest-based classifier, the support vector machine (SVM)-based classifier, and the back-propagation (BP) neural network-based classifier are used for performing the classifications. Here, the percentages of the classification accuracies are employed as the attention scores. The computer numerical simulation results show that our proposed method yields a higher classification performance compared to the traditional methods without performing the EMD and SSA.

Conserved brain myelination networks are altered in Alzheimer's and other neurodegenerative diseases.

INTRODUCTION: Comparative transcriptome analyses in Alzheimer's disease (AD) and other neurodegenerative proteinopathies can uncover both shared and distinct disease pathways. METHODS: We analyzed 940 brain transcriptomes including patients with AD, progressive supranuclear palsy (PSP; a primary tauopathy), and control subjects. RESULTS: We identified transcriptional coexpression networks implicated in myelination, which were lower in PSP temporal cortex (TCX) compared with AD. Some of these associations were retained even after adjustments for brain cell population changes. These TCX myelination network structures were preserved in cerebellum but they were not differentially expressed in cerebellum between AD and PSP. Myelination networks were downregulated in both AD and PSP, when compared with control TCX samples. DISCUSSION: Downregulation of myelination networks may underlie both PSP and AD pathophysiology, but may be more pronounced in PSP. These data also highlight conservation of transcriptional networks across brain regions and the influence of cell type changes on these networks.

Bridging the Gap: Multi-Omics Profiling of Brain Tissue in Alzheimer's Disease and Older Controls in Multi-Ethnic Populations.

INTRODUCTION: Multi-omics studies in Alzheimer's disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked African Americans (AA) and Latin Americans (LA), who are disproportionately affected by AD. METHODS: To bridge this gap, Accelerating Medicines Partnership in AD (AMP-AD) expanded brain multi-omics profiling to multi-ethnic donors. RESULTS: We generated multi-omics data and curated and harmonized phenotypic data from AA (n=306), LA (n=326), or AA and LA (n=4) brain donors plus Non-Hispanic White (n=252) and other (n=20) ethnic groups, to establish a foundational dataset enriched for AA and LA participants. This study describes the data available to the research community, including transcriptome from three brain regions, whole genome sequence, and proteome measures. DISCUSSION: Inclusion of traditionally underrepresented groups in multi-omics studies is essential to discover the full spectrum of precision medicine targets that will be pertinent to all populations affected with AD.

Large-scale Deep Proteomic Analysis in Alzheimer's Disease Brain Regions Across Race and Ethnicity.

Introduction: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, yet our comprehension predominantly relies on studies within the non-Hispanic White (NHW) population. Here we aimed to provide comprehensive insights into the proteomic landscape of AD across diverse racial and ethnic groups. Methods: Dorsolateral prefrontal cortex (DLPFC) and superior temporal gyrus (STG) brain tissues were donated from multiple centers (Mayo Clinic, Emory University, Rush University, Mt. Sinai School of Medicine) and were harmonized through neuropathological evaluation, specifically adhering to the Braak staging and CERAD criteria. Among 1105 DLPFC tissue samples (998 unique individuals), 333 were from African American donors, 223 from Latino Americans, 529 from NHW donors, and the rest were from a mixed or unknown racial background. Among 280 STG tissue samples (244 unique individuals), 86 were African American, 76 Latino American, 116 NHW and the rest were mixed or unknown ethnicity. All tissues were uniformly homogenized and analyzed by tandem mass tag mass spectrometry (TMT-MS). Results: As a Quality control (QC) measure, proteins with more than 50% missing values were removed and iterative principal component analysis was conducted to remove outliers within brain regions. After QC, 9,180 and 9,734 proteins remained in the DLPC and STG proteome, respectively, of which approximately 9,000 proteins were shared between regions. Protein levels of microtubule-associated protein tau (MAPT) and amyloid-precursor protein (APP) demonstrated AD-related elevations in DLPFC tissues with a strong association with CERAD and Braak across racial groups. APOE4 protein levels in brain were highly concordant with APOE genotype of the individuals. Discussion: This comprehensive region resolved large-scale proteomic dataset provides a resource for the understanding of ethnoracial-specific protein differences in AD brain.

Reducing omission of eye drops during hospital admission.

BACKGROUND/AIMS: Chronic ophthalmic conditions, such as glaucoma and dry eye disease, are frequently encountered debilitating eye conditions that can lead to substantial reduction in vision and quality of life. However, there is ongoing evidence to suggest that topical ophthalmic therapy is inappropriately omitted on admission to hospital. The primary aim of this audit was to investigate the trust adherence to the National Institute for Health and Care Excellence guideline on the prescribing standard of eye drops during hospital admission. The secondary aim was to raise awareness and ensure successful compliance with national standards to reduce unintentional omission of eye drops on admission and subsequent complications. METHOD: Electronic medical records of all medical and surgical adult inpatients were studied prospectively on two different occasions. The quality of documentation of eye drops in clerking notes, the length of time taken between the admission and prescription of eye drops, and the accuracy of the prescription were examined. Following the initial audit, interventions focusing on clinician education were implemented. This includes highlighting the importance of eye drops in all departmental mandatory introductory sessions and putting up posters on all the wards as prompts. The same data collection method was used in the reaudit. RESULTS: In the initial audit, 64 (mean age 81.8±8.9 years) patients with regular prescriptions for eye drops were identified; 38 (59.4%) patients had eye drops for dry eye disease only, 20 (31.3%) patients had eye drops for glaucoma only, and six (9.4%) patients had eye drops for both. In the reaudit, 57 (mean age 76.7±15.3 years) patients were identified; 42 (73.7%) patients had eye drops for dry eye disease only, 10 (17.5%) patients had eye drops for glaucoma only, and five (8.8%) patients had eye drops for both. Following the intervention, there was a significant improvement in documentation of ocular diagnosis and eye drops on clerking notes from 41% to 65% (P=0.008), and eye drop reconciliation within 24 hours of admission improved from 45% to 75% (P=0.0008). All patients (100%) received the correct eye drop prescription before and after the intervention. CONCLUSIONS: Education is effective in promoting adherence to national guidelines and reducing the incidence of inappropriate omission of eye drops on admission to hospital.

Clinical Deep Phenotyping of ABCA7 Mutation Carriers.

BACKGROUND AND OBJECTIVES: Putative loss-of-function (pLOF) ABCA7 variants that increase Alzheimer disease (AD) risk were identified; however, deep phenotypic characterization of these variants in mutation carriers is limited. We aimed to obtain deep clinical phenotypes of ABCA7 pLOF mutation carriers from a large retrospectively reviewed series. METHODS: Genotypes were determined for 5,353 individuals evaluated at Mayo Clinic for 6 reported ABCA7 pLOF variants (p.E709fs, p.Trp1214X, p.L1403fs, c.4416+2T>G, p.E1679X, and c.5570+5G>C). Medical records of 100 mutation carriers were reviewed for demographics, clinical phenotypes, and diagnoses. Eleven mutation carriers had autopsy-based neuropathologic diagnoses. RESULTS: We confirmed that ABCA7 pLOF mutations confer AD risk in our series of 2,495 participants with AD and 2,858 cognitively unaffected participants. Clinical review of 100 mutation carriers demonstrated phenotypic variability of clinical presentations with both memory and nonmemory cognitive impairment and a subset presenting with motor symptoms. There was a wide range of age at onset of cognitive symptoms (ages 56-92 years, mean = 75.6). Ten of the 11 autopsied mutation carriers had AD neuropathology. ABCA7 pLOF mutation carriers had higher rates of depression (41.6%) and first-degree relatives with cognitive impairment (38.1%) compared with the general population. DISCUSSION: Our study provides a deep clinical review of phenotypic characteristics of mutation carriers for 6 ABCA7 pLOF mutations. Although memory impairment was the most common initial symptom, nonmemory cognitive and/or motor symptoms were present in a substantial number of mutation carriers, highlighting the heterogeneity of clinical features associated with these mutations. Likewise, although AD neuropathology is the most common, it is not the only autopsy-based diagnosis. Presence of earlier ages at onset, higher rates of depression, and first-degree relatives with cognitive impairment among mutation carriers suggest that these genetic variants may have more aggressive clinical features than AD in the general population. This deep phenotyping study of ABCA7 pLOF mutation carriers provides essential genotype-phenotype correlations for future precision medicine approaches in the clinical setting.

Transcript levels in plasma contribute substantial predictive value as potential Alzheimer's disease biomarkers in African Americans.

BACKGROUND: African Americans (AA) remain underrepresented in Alzheimer's disease (AD) research, despite the prevalence of AD being double in AA compared to non-Hispanic whites. To address this disparity, our group has established the Florida Consortium for African American Alzheimer's Disease Studies (FCA3DS), focusing on the identification of genetic risk factors and novel plasma biomarkers. METHOD: Utilizing FCA3DS whole exome sequence (WES) and plasma RNA samples from AD cases (n=151) and cognitively unimpaired (CU) elderly controls (n=269), we have performed differential gene expression (DGE) and expression quantitative trait locus (eQTL) analyses on 50 transcripts measured with a custom nanoString® panel. We designed this panel to measure, in plasma, cell-free mRNA (cf-mRNA) levels of AD-relevant genes. FINDINGS: Association with higher plasma CLU in CU vs. AD remained significant after Bonferroni correction. Study-wide significant eQTL associations were observed with 105 WES variants in cis with 22 genes, including variants in genes previously associated with AD risk in AA such as ABCA7 and AKAP9. Results from this plasma eQTL analysis identified AD-risk variants in ABCA7 and AKAP9 that are significantly associated with lower and higher plasma mRNA levels of these genes, respectively. Receiver operating characteristic analysis of age, sex APOE-ε4 dosage, CLU, APP, CD14, ABCA7, AKAP9 and APOE mRNA levels, and ABCA7 and AKAP9 eQTLs, achieved 77% area under the curve to discriminate AD vs. CU, an 8% improvement over a model that only included age, sex and APOE-ε4 dosage. INTERPRETATION: Incorporating plasma mRNA levels could contribute to improved predictive value of AD biomarker panels. FUNDING: This work was supported by the National Institute on Aging [RF AG051504, U01 AG046139, R01 AG061796 to NET; P30 AG062677 to JAL and NGR]; Florida Health Ed and Ethel Moore Alzheimer's Disease grants [5AZ03 and 7AZ17 to NET; 7AZ07 to MMC; 8AZ08 to JAL].

Transcriptional landscape of human microglia implicates age, sex, and APOE-related immunometabolic pathway perturbations.

Microglia have fundamental roles in health and disease; however, effects of age, sex, and genetic factors on human microglia have not been fully explored. We applied bulk and single-cell approaches to comprehensively characterize human microglia transcriptomes and their associations with age, sex, and APOE. We identified a novel microglial signature, characterized its expression in bulk tissue and single-cell microglia transcriptomes. We discovered microglial co-expression network modules associated with age, sex, and APOE-ε4 that are enriched for lipid and carbohydrate metabolism genes. Integrated analyses of modules with single-cell transcriptomes revealed significant overlap between age-associated module genes and both pro-inflammatory and disease-associated microglial clusters. These modules and clusters harbor known neurodegenerative disease genes including APOE, PLCG2, and BIN1. Meta-analyses with published bulk and single-cell microglial datasets further supported our findings. Thus, these data represent a well-characterized human microglial transcriptome resource and highlight age, sex, and APOE-related microglial immunometabolism perturbations with potential relevance in neurodegeneration.

Alzheimer's disease and progressive supranuclear palsy share similar transcriptomic changes in distinct brain regions.

Vast numbers of differentially expressed genes and perturbed networks have been identified in Alzheimer's disease (AD), however, neither disease nor brain region specificity of these transcriptome alterations has been explored. Using RNA-Seq data from 231 temporal cortex and 224 cerebellum samples from patients with AD and progressive supranuclear palsy (PSP), a tauopathy, we identified a striking correlation in the directionality and magnitude of gene expression changes between these 2 neurodegenerative proteinopathies. Further, the transcriptomic changes in AD and PSP brains ware highly conserved between the temporal and cerebellar cortices, indicating that highly similar transcriptional changes occur in pathologically affected and grossly less affected, albeit functionally connected, areas of the brain. Shared up- or downregulated genes in AD and PSP are enriched in biological pathways. Many of these genes also have concordant protein changes and evidence of epigenetic control. These conserved transcriptomic alterations of 2 distinct proteinopathies in brain regions with and without significant gross neuropathology have broad implications. AD and other neurodegenerative diseases are likely characterized by common disease or compensatory pathways with widespread perturbations in the whole brain. These findings can be leveraged to develop multifaceted therapies and biomarkers that address these common, complex, and ubiquitous molecular alterations in neurodegenerative diseases.

Infectious keratitis: an update on epidemiology, causative microorganisms, risk factors, and antimicrobial resistance.

Corneal opacity is the 5th leading cause of blindness and visual impairment globally, affecting ~6 million of the world population. In addition, it is responsible for 1.5-2.0 million new cases of monocular blindness per year, highlighting an ongoing uncurbed burden on human health. Among all aetiologies such as infection, trauma, inflammation, degeneration and nutritional deficiency, infectious keratitis (IK) represents the leading cause of corneal blindness in both developed and developing countries, with an estimated incidence ranging from 2.5 to 799 per 100,000 population-year. IK can be caused by a wide range of microorganisms, including bacteria, fungi, virus, parasites and polymicrobial infection. Subject to the geographical and temporal variations, bacteria and fungi have been shown to be the most common causative microorganisms for corneal infection. Although viral and Acanthamoeba keratitis are less common, they represent important causes for corneal blindness in the developed countries. Contact lens wear, trauma, ocular surface diseases, lid diseases, and post-ocular surgery have been shown to be the major risk factors for IK. Broad-spectrum topical antimicrobial treatment is the current mainstay of treatment for IK, though its effectiveness is being challenged by the emergence of antimicrobial resistance, including multidrug resistance, in some parts of the world. In this review, we aim to provide an updated review on IK, encompassing the epidemiology, causative microorganisms, major risk factors and the impact of antimicrobial resistance.

12-year analysis of incidence, microbiological profiles and in vitro antimicrobial susceptibility of infectious keratitis: the Nottingham Infectious Keratitis Study.

BACKGROUND/AIMS: To examine the incidence, causative microorganisms and in vitro antimicrobial susceptibility and resistance profiles of infectious keratitis (IK) in Nottingham, UK. METHODS: A retrospective study of all patients who were diagnosed with IK and underwent corneal scraping between July 2007 and October 2019 (a 12-year period) at a UK tertiary referral centre. Relevant data, including demographic factors, microbiological profiles and in vitro antibiotic susceptibility of IK, were analysed. RESULTS: The estimated incidence of IK was 34.7 per 100 000 people/year. Of the 1333 corneal scrapes, 502 (37.7%) were culture-positive and 572 causative microorganisms were identified. Sixty (4.5%) cases were of polymicrobial origin (caused by ≥2 different microorganisms). Gram-positive bacteria (308, 53.8%) were most commonly isolated, followed by Gram-negative bacteria (223, 39.0%), acanthamoeba (24, 4.2%) and fungi (17, 3.0%). Pseudomonas aeruginosa (135, 23.6%) was the single most common organism isolated. There was a significant increase in Moraxella spp (p<0.001) and significant decrease in Klebsiella spp (p=0.004) over time. The in vitro susceptibilities of Gram-positive and Gram-negative bacteria to cephalosporin, fluoroquinolone and aminoglycoside were 100.0% and 81.3%, 91.9% and 98.1%, and 95.2% and 98.3%, respectively. An increase in resistance against penicillin was observed in Gram-positive (from 3.5% to 12.7%; p=0.005) and Gram-negative bacteria (from 52.6% to 65.4%; p=0.22). CONCLUSION: IK represents a relatively common and persistent burden in the UK and the reported incidence is likely underestimated. Current broad-spectrum antimicrobial treatment provides a good coverage for IK, although challenged by some level of antimicrobial resistance and polymicrobial infection.

Risk Factors, Clinical Outcomes, and Prognostic Factors of Bacterial Keratitis: The Nottingham Infectious Keratitis Study.

Background/Aim: To examine the risk factors, clinical characteristics, outcomes, and prognostic factors of bacterial keratitis (BK) in Nottingham, UK. Methods: This was a retrospective study of patients who presented to the Queen's Medical Centre, Nottingham, with suspected BK during 2015-2019. Relevant data, including the demographic factors, risk factors, clinical outcomes, and potential prognostic factors, were analysed. Results: A total of 283 patients (n = 283 eyes) were included; mean age was 54.4 ± 21.0 years and 50.9% were male. Of 283 cases, 128 (45.2%) cases were culture-positive. Relevant risk factors were identified in 96.5% patients, with ocular surface diseases (47.3%), contact lens wear (35.3%) and systemic immunosuppression (18.4%) being the most common factors. Contact lens wear was most commonly associated with P. aeruginosa whereas Staphylococci spp. were most commonly implicated in non-contact lens-related BK cases (p = 0.017). At presentation, culture-positive cases were associated with older age, worse presenting corrected-distance-visual-acuity (CDVA), use of topical corticosteroids, larger epithelial defect and infiltrate, central location and hypopyon (all p < 0.01), when compared to culture-negative cases. Hospitalisation was required in 57.2% patients, with a mean length of stay of 8.0 ± 8.3 days. Surgical intervention was required in 16.3% patients. Significant complications such as threatened/actual corneal perforation (8.8%), loss of perception of light vision (3.9%), and evisceration/enucleation (1.4%) were noted. Poor visual outcome (final corrected-distance-visual-acuity of <0.6 logMAR) and delayed corneal healing (>30 days from initial presentation) were significantly affected by age >50 years, infiltrate size >3 mm, and reduced presenting vision (all p < 0.05). Conclusion: BK represents a significant ocular morbidity in the UK, with ocular surface diseases, contact lens wear, and systemic immunosuppression being the main risk factors. Older age, large infiltrate, and poor presenting vision were predictive of poor visual outcome and delayed corneal healing, highlighting the importance of prevention and early intervention for BK.

Plasma Biomarkers of Alzheimer's Disease in African Americans.

BACKGROUND/OBJECTIVE: The aim of this study was to determine if plasma concentrations of 5 surrogate markers of Alzheimer's disease (AD) pathology and neuroinflammation are associated with disease status in African Americans. METHODS: We evaluated 321 African Americans (159 AD, 162 controls) from the Florida Consortium for African-American Alzheimer's Disease Studies (FCA3DS). Five plasma proteins reflecting AD neuropathology or inflammation (Aß42, tau, IL6, IL10, TNFα) were tested for associations with AD, age, sex, APOE and MAPT genotypes, and for pairwise correlations. RESULTS: Plasma tau levels were higher in AD when adjusted for biological and technical covariates. APOEɛ4 was associated with lower plasma Aß42 and tau levels. Older age was associated with higher plasma Aß42, tau, and TNFα. Females had lower IL10 levels. Inflammatory proteins had strong pairwise correlations amongst themselves and with Aß42. CONCLUSION: We identified effects of demographic and genetic variants on five potential plasma biomarkers in African Americans. Plasma inflammatory biomarkers and Aß42 may reflect correlated pathologies and elevated plasma tau may be a biomarker of AD in this population.

Seasonal patterns of incidence, demographic factors and microbiological profiles of infectious keratitis: the Nottingham Infectious Keratitis Study.

PURPOSE: The purpose of this study is to examine the seasonal patterns of incidence, demographic factors and microbiological profiles of infectious keratitis (IK) in Nottingham, UK. METHODS: A retrospective study of all patients who were diagnosed with IK and underwent corneal scraping during 2008-2019 at a UK tertiary referral centre. Seasonal patterns of incidence (in per 100,000 population-year), demographic factors, culture positivity rate and microbiological profiles of IK were analysed. RESULTS: A total of 1272 IK cases were included. The overall incidence of IK was highest during summer (37.7, 95% confidence interval (CI): 31.3-44.1), followed by autumn (36.7, 95% CI: 31.0-42.4), winter (36.4, 95% CI: 32.1-40.8) and spring (30.6, 95% CI: 26.8-34.3), though not statistically significant (p = 0.14). The incidence of IK during summer increased significantly over the 12 years of study (r = 0.58, p = 0.049), but the incidence of IK in other seasons remained relatively stable throughout the study period. Significant seasonal variations were observed in patients' age (younger age in summer) and causative organisms, including Pseudomonas aeruginosa (32.9% in summer vs. 14.8% in winter; p < 0.001) and gram-positive bacilli (16.1% in summer vs. 4.7% in winter; p = 0.014). CONCLUSION: The incidence of IK in Nottingham was similar among four seasons. No temporal trend in the annual incidence of IK was observed, as reported previously, but there was a significant yearly increase in the incidence of IK during summer in Nottingham over the past decade. The association of younger age, P. aeruginosa and gram-positive bacilli infection with summer was likely attributed to contact lens wear, increased outdoor/water activity and warmer temperature conducive for microbial growth.

Genome-wide analysis identifies a novel LINC-PINT splice variant associated with vascular amyloid pathology in Alzheimer's disease.

Cerebral amyloid angiopathy (CAA) contributes to accelerated cognitive decline in Alzheimer's disease (AD) dementia and is a common finding at autopsy. The APOEε4 allele and male sex have previously been reported to associate with increased CAA in AD. To inform biomarker and therapeutic target discovery, we aimed to identify additional genetic risk factors and biological pathways involved in this vascular component of AD etiology. We present a genome-wide association study of CAA pathology in AD cases and report sex- and APOE-stratified assessment of this phenotype. Genome-wide genotypes were collected from 853 neuropathology-confirmed AD cases scored for CAA across five brain regions, and imputed to the Haplotype Reference Consortium panel. Key variables and genome-wide genotypes were tested for association with CAA in all individuals and in sex and APOEε4 stratified subsets. Pathway enrichment was run for each of the genetic analyses. Implicated loci were further investigated for functional consequences using brain transcriptome data from 1,186 samples representing seven brain regions profiled as part of the AMP-AD consortium. We confirmed association of male sex, AD neuropathology and APOEε4 with increased CAA, and identified a novel locus, LINC-PINT, associated with lower CAA amongst APOEε4-negative individuals (rs10234094-C, beta = -3.70 [95% CI -0.49--0.24]; p = 1.63E-08). Transcriptome profiling revealed higher LINC-PINT expression levels in AD cases, and association of rs10234094-C with altered LINC-PINT splicing. Pathway analysis indicates variation in genes involved in neuronal health and function are linked to CAA in AD patients. Further studies in additional and diverse cohorts are needed to assess broader translation of our findings.

Potential exerkines for physical exercise-elicited pro-cognitive effects: Insight from clinical and animal research.

A sedentary lifestyle is now known as a critical risk factor for accelerated aging-related neurodegenerative disorders. In contract, having regular physical exercise has opposite effects. Clinical findings have suggested that physical exercise can promote brain plasticity, particularly the hippocampus and the prefrontal cortex, that are important for learning and memory and mood regulations. However, the underlying mechanisms are still unclear. Animal studies reveal that the effects of physical exercise on promoting neuroplasticity could be mediated by different exerkines derived from the peripheral system and the brain itself. This book chapter summarizes the recent evidence from clinical and pre-clinical studies showing the emerging mediators for exercise-promoted brain health, including myokines secreted from skeletal muscles, adipokines from adipose tissues, and other factors secreted from the bone and liver.

Global convergence and limit cycle behavior of weights of perceptron.

In this paper, it is found that the weights of a perceptron are bounded for all initial weights if there exists a nonempty set of initial weights that the weights of the perceptron are bounded. Hence, the boundedness condition of the weights of the perceptron is independent of the initial weights. Also, a necessary and sufficient condition for the weights of the perceptron exhibiting a limit cycle behavior is derived. The range of the number of updates for the weights of the perceptron required to reach the limit cycle is estimated. Finally, it is suggested that the perceptron exhibiting the limit cycle behavior can be employed for solving a recognition problem when downsampled sets of bounded training feature vectors are linearly separable. Numerical computer simulation results show that the perceptron exhibiting the limit cycle behavior can achieve a better recognition performance compared to a multilayer perceptron.