bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Antidepressant Therapy Selective Norepinephrine Reuptake Inhibitors (SNRIs) Reduces the Risk of Alzheimer’s Disease
Authors: Cortes‐Flores Helena , Torrandell‐Haro Georgina , Brinton Roberta Diaz 
Published: December 2023

AbstractBackgroundDepression has been established as a risk factor for developing Alzheimer’s Disease (AD). Further, depression is a common symptom of the prodromal phase of the disease and acts as an accelerating factor for cognitive decline before and after dementia diagnosis. Based on this association, analyses of real‐world medical data were conducted to determine the impact of anti‐depressive pharmacological therapy, Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), on risk of AD diagnosis. This study aimed to determine the effect of SNRI therapy on AD incidence, as well as determining responder vs non‐responder phenotypes on demographic characteristics, comorbidity burden, and co‐treatment profile.MethodA retrospective analysis was conducted using the Mariner insurance claims dataset and included patients 60 years of age and older with a diagnosis of depression. To minimize bias, a propensity score matching was conducted to adjust for age, gender, cci and comorbidities. The propensity score matched population was surveyed for a diagnosis of AD after at least 1 year of SNRI drug exposure, and different durations of SNRI therapy were analyzed. Responders were detected through sensitivity analyses based on comorbidities and drug combinations.ResultThe propensity score matched group included 307,671 patients exposed to SNRIs and 307,671 patients with no exposure to any antidepressant therapy. SNRI therapy was associated with a significant decrease in risk of AD diagnosis (RR [95%CI]: 0.73 [0.70–0.76]; P<.0001), with women (RR [95%CI]: 0.66 [0.63–0.70]; P<.0001) exhibiting greater risk reduction compared to men (RR [95%CI]: 0.88 [0.82–0.95]; P<.0001). Long‐term SNRI treatment (>6 years) was associated with the greatest AD risk reduction (RR [95%CI]: 0.50 [0.47–0.53]; P<.0001). Responders exhibited higher incidence of obesity and greater use of anti‐inflammatories.ConclusionSNRI therapy was associated with a significant reduction in AD risk. Furthermore, increased duration of SNRI therapy was associated with greater AD risk reduction. Responders displayed fewer comorbidities and co‐treatments although they had a higher incidence of obesity. Clinically, these findings, based on real‐world psychiatric care, provide data regarding long‐term neurological health outcomes of SNRI anti‐depressant therapy. From a mechanistic perspective, data reported herein indicate that sustaining noradrenergic function is a key pathway involved in preventing AD.
Towards the future of ADRD diagnosis: combination of a brief digital cognitive battery and plasma biomarkers for diagnosis and prognosis of disease
Authors: Tsoy Elena , VandeVrede Lawren , La Joie Renaud , Rodriguez Anne‐Marie , Windon Charles , Smith Karen , Dilworth‐Anderson Peggye , Rabinovici Gil D. , Possin Katherine 
Published: December 2023

AbstractBackgroundScalable and accurate diagnostic markers of Alzheimer’s disease and related dementias (ADRD) are urgently needed. A combination of a sensitive brief digital cognitive assessment and plasma biomarkers could represent a promising scalable alternative to standard diagnostic procedures. We evaluated the performance of the TabCAT Brain Health Assessment Cognitive Score (BHA‐CS) and plasma Aβ42/40, pTau‐181, NfL, and GFAP at predicting concurrent Aβ positivity on CSF or PET, concurrent disease severity, and future functional decline.MethodParticipants were 309 subjectively or objectively impaired older adults enrolled in longitudinal observational studies at UCSF (Table 1), who completed a blood draw and TabCAT‐BHA at baseline. Biomarker concentrations were measured using commercially available Quanterix kits. Receiver operating characteristic analyses were used to determine the accuracy of combined BHA‐CS and plasma biomarkers in discriminating between Aβ+/‐ status on CSF/PET at baseline. Multiple regressions were used to examine baseline associations of BHA‐CS and plasma markers with disease severity measured by Clinical Dementia Rating Sum of Boxes (CDR‐SB). Linear mixed effect models were used to examine the associations of baseline BHA‐CS and biomarker values with longitudinal decline on CDR‐SB. All analyses controlled for age, sex, education, and baseline diagnosis.ResultpTau‐181 was the strongest predictor of Aβ positivity (AUC = .745; 95%CI: .656‐.833), with no significant improvements in the AUC with the addition of any combination of markers (Figure 1). In a combined model with all markers included simultaneously, BHA‐CS (B = ‐0.678, P<.001) and plasma NfL (B = 0.625, P = .01) were the only unique significant predictors of concurrent CDR‐SB. In a combined mixed model with all markers included simultaneously, baseline BHA‐CS, pTau‐181, NfL, and GFAP were unique significant predictors of CDR‐SB decline (Figure 2), and together accounted for 27% of longitudinal variance in CDR‐SB.ConclusionOur findings indicate unique and complementary roles of scalable digital cognitive and plasma biomarkers as diagnostic and prognostic markers of ADRD. At baseline, whereas pTau‐181 was most accurate at predicting Aβ positivity, a combination of BHA‐CS and NfL was most accurate at predicting concurrent disease severity. In longitudinal analyses, a model that combined baseline cognitive testing results and plasma pTau‐181, NfL, and GFAP was most accurate at predicting future decline.
Relationships between neuroimaging parameters, APOE genotypes and composite scores for memory, executive functioning and language from the National Alzheimer’s Coordinating Center (NACC)
Authors: Lee Michael L. , Scollard Phoebe , Gibbons Laura E , Mukherjee Shubhabrata , Choi Seo‐Eun , Klinedinst Brandon S , Trittschuh Emily H. , Mez Jesse B. , Saykin Andrew J. , Dumitrescu Logan C , Kukull Walter A. , Hohman Timothy J. , Crane Paul K 
Published: December 2023

AbstractBackgroundWe harmonized composite scores for memory, executive functioning (EF), and language from granular cognitive data from the National Alzheimer’s Coordinating Center (NACC) uniform dataset on 39,965 individuals. We explored if our cognitive scores correlated with APOE genotype and structural magnetic resonance imaging data.MethodIn our previously published harmonization methods we used confirmatory factor analysis models, guided by theoretical considerations from content experts, to estimate domain scores. For this cross‐sectional analysis of last visits in participants over age 60, we obtained APOE genotype data (n = 28,558 individuals) and FreeSurfer regional volume data (n = 2,404 individuals). We looked at relationship between cognitive performance and APOE genotype grouping by disease group (normal cognition, mild cognitive impairment (MCI), or AD dementia). We ran student’s two sample t‐test to assess the effect of APOE ε4 genotype on cognitive domain score. We also ran regression models for cognitive domain scores on each FreeSurfer region selected a priori on the basis of assumed association on that index domain adjusting for age, gender and APOE genotype.ResultRelevant demographic and clinical data are summarized in Table 1. Associations with APOE genotype and each cognitive domain are shown in Figure 1. As expected, participants with at least one APOE ε4 alleles compared with none had lower composite memory scores (p<0.01, t‐test) compared with those with none in participants with dementia and MCI. APOE ε4 carriers also had lower language scores in participants with dementia (p = 0.037, t‐test). Among the FreeSurfer regions, composite memory scores were strongly associated with hippocampal volume, parahippocampus and entorhinal cortex thickness across all dementia categories (Table 2). EF scores were associated with 2 EF brain regions of interest in participants with dementia. Language scores were associated with 2 language regions of interest in participants with dementia.ConclusionOur analyses shows composite scores are associated with APOE genotype in participants with dementia and relevant brain regions in the memory domain across all dementia categories. Our analyses shows that our cognitive scores correlate with memory brain regions and APOE genotype in expected directions.
Sepsis as a risk factor for Alzheimer’s disease pathophysiology
Authors: Giridharan Vijayasree V , Catumbela Celso , Catalão Carlos Henrique V R. , Ganesh Bhanu Priya , Petronilho Fabricia , Dal‐Pizzol Felipe , Morales Rodrigo , Barichello Tatiana 
Published: December 2023

AbstractBackgroundThe sepsis‐induced polymicrobial infection leads to life‐threatening organ dysfunction that accounts for high mortality and morbidity worldwide. More than half of those who survive sepsis have a worse quality of life and long‐term cognitive deficits. Significant alteration of gut microbiota has been documented in sepsis patients, impacting both compositional and functional levels. In this context, we aimed to explore the cross‐link between the gut‐brain axis on sepsis‐induced long‐term cognitive decline using Alzheimer’s disease mouse model.MethodMale, 50‐day‐old APP/PS1 mice were subjected to a gold standard sepsis model by cecal ligation and perforation (CLP) surgery to induce sepsis or sham surgery as a control group. Longitudinally, at 3, 30, and 120 days after sepsis or sham surgery, feces were collected for 16S rRNA sequencing and short‐chain fatty acids (SCFAs) evaluation. The gut was collected for histology, mucin, and amyloid‐beta (Aβ) staining. The brain was collected to measure inflammatory mediators, neuroinflammatory markers (IBA‐1 and GFAP), and soluble and insoluble Aβ. Assessment of cognition was performed using novel object recognition (NOR) at 30 and 120 days after sepsis.ResultSepsis mice demonstrated an altered microbiome measured by alpha diversity, beta diversity, and relative abundance at 30 and 120 days. In the long‐term after sepsis, SCFAs were reduced, villi length and crypt depth decreased, and fucosylated goblet cells were significantly reduced in sepsis mice demonstrating gut dysfunction. However, no positive signal for Aβ was observed in the gut. In the brain, at 30 and 120 days, proinflammatory cytokines were increased in PFC, and decreased anti‐inflammatory cytokines in the hippocampus were observed. The neuroinflammation after infection was verified by measuring the glial cell activation. Compared to the age‐matched control, sepsis mice elevated Aβ burden at 120 days after surgery. Further, after CLP surgery, long‐term mice demonstrated a significant reduction in the recognition index in the NOR task.ConclusionSepsis‐induced enteric dysbiosis, gut modulation, increased brain inflammatory cytokines, and insoluble Aβ levels negatively regulated the cognitive behavior in APP/PS1 mice. Therefore, gut microbiota can be modified to impact the sepsis‐induced long‐term cognitive decline in sepsis survivors positively.
Distinct immune signatures associated with sex and genotype in the 12m novel hAPP hAPOE mouse risk model of Alzheimer’s disease
Authors: Van Rossum Hannah , Delatorre Nicole , Brinton Roberta Diaz 
Published: December 2023

AbstractBackgroundUnderstanding the biology of model systems is critically important in the identification of biomarkers to delay or prevent Alzheimer’s disease. Previous findings in our group demonstrate sex differences in immune transcripts in the AD brain and in the humanized apolipoprotein E (APOE) mouse risk model. With this study, we extend these discoveries to further investigate the effect of APOE genotype using a novel risk mouse model with humanized amyloid precursor protein (APP) and humanized‐APOE transgenes (Jackson Laboratory). We test the hypothesis that during midlife aging, hAPP hAPOE ε4/4 genotype, and female sex will show increased risk profiles for Aβ 42:40 ratio and immunophenotypes associated with Alzheimer’s disease.MethodTo identify midlife (12 months; human correlate 44 years) immunophenotypes that may contribute to AD 3 different risk genotypes were studied: hAPP (6 male /6 female), hAPP hAPOE ε3/3 (16 male/16 female), and hAPP hAPOE ε4/4 (16 male /16 female). The left hemisphere of the brain was collected and prepared for multi‐color flow cytometry. Microglial reactivity (MHCII, CD68), phagocytosis (pHrodo), oxidative stress (CellRox), and the presence of lymphocytes (CD3, CD4, CD8, CD19) were determined. Peripheral blood was collected and assessed for monocytes and lymphocytes while plasma was isolated and ELISA was used to detect the presence of Aβ 40‐42, and levels of pro‐inflammatory cytokines. Female animals were monitored daily by lavage to determine midlife endocrine status.ResulthAPP hAPOE ε4/4 animals demonstrated accelerated endocrine aging compared to hAPP hAPOE ε3/3 animals. Plasma beta‐amyloid 42:40 ratio, and levels of IL‐1B, and IL‐6 showed a significant interaction between sex and hAPP hAPOE genotype (p<0.05, p<0.05, p<0.05). Plasma levels of IL‐5 and CXCL1 trended toward genotype significance with p = 0.0544 and p = 0.0556, respectively. Percentage of MHCII+ activated microglia was significantly impacted by sex (p = 0.0005) and by genotype (p<0.0001).ConclusionThe interaction between hAPP and hAPOE genotype, in coordination with biological sex significantly impacts immunophenotypes of the CNS and periphery during midlife aging. Precision interventions targeting sex and genotype‐dependent prodromal immune biomarkers may serve as an opportunity to support homeostatic immune milieu or to modulate harmful inflammatory signaling and reduce risk of AD or delay AD onset.
Development and comprehensive evaluation of high‐resolution 0.5 mm isotropic T2‐weighted, PD‐weighted, T2 map and FLAIR templates of the MIITRA atlas.
Authors: Ridwan Abdur Raquib , Niaz Mohammad Rakeen , Wu Yingjuan , Zhang Shengwei , Bennett David A. A , Arfanakis Konstantinos 
Published: December 2023

AbstractBackgroundVoxel‐wise, disease‐monitoring and other MRI investigations involving T2‐weighted(T2w), PD‐weighted(PDw), T2 map and FLAIR templates typically utilize young adult templates such as those of the ICBM atlas. Moreover, a comprehensive assessment of how such available standardized templates perform on aging population has not yet been performed. Here, a high‐resolution older‐adult population based T2w, PDw T2 map and FLAIR templates of the MIITRA atlas was developed using theories of super‐resolution and sparse‐representation and compared to other available standardized templates in terms of image quality, spatial normalization accuracy and representativeness of the older adult brain.MethodT1‐weighted MPRAGE of isotropic 1mm resolution, five spin‐echo(0.5×0.5×0.5 mm3,TE = 20,40,60,80,100ms) and FLAIR data (0.5×0.5×4 mm3) were collected on 3T MRI scanners for 400 non‐demented older adults (50% male; 65‐95 years of age, 54% white and 43% black) participating in the construction of the MIITRA atlas. The subject T2 maps and PD‐weighted data were computed by fitting the T2 decay equation. The template construction technique involved upsampling the images to 0.5×0.5×0.5 mm3 using non‐local upsampling, and converting the T2‐weighted(TE = 60ms) to synthetic T1‐weighted, followed by linear registration to upsampled T1‐weighted data using ANTs. Next, the resulting transformations concatenated with the combined iterative T1w and DTI driven MIITRA atlas deformations were used to forward map each participant to exact physical locations in the MIITRA space. Finally, sparse representation data fusion technique was utilized on the transformed signals to construct the templates at isotropic 0.5mm resolution (Figure.1). MIITRA third echo T2‐weighted and FLAIR template was compared to available standardized templates (Figure. 2) in terms of inter‐subject spatial normalization accuracy when used for spatial normalization of 400 ADNI T2‐weighted and FLAIR participants respectively.ResultThe T2‐weighted and FLAIR templates of the MIITRA atlas exhibited higher image sharpness exemplified by higher spatial frequency content of the normalized power spectra(Figure. 2). MIITRA templates demonstrated higher inter‐subject spatial normalization accuracy and required the least deformations for spatial normalization of ADNI data(Figure. 3)ConclusionThe new T2w, PDw, and FLAIR templates of the MIITRA atlas exhibited superior image quality, required lower deformations, facilitating higher spatial normalization accuracy for use in studies on older adults such as the ADNI datasets.
Machine‐learning based classification of Frontotemporal dementia in electronic health records for genetic discovery
Authors: Below Jennifer E. , Shaw Douglas , Evans Grahame , Baker James T , Bohlender Ryan J , Petty Alex , Petty Lauren E , Roshani Rashedeh , Lifferth Jonathan , Bastarache Lisa , Naj Adam C. , Bush William S. , Darby Ryan , McMillan Corey T , Samuels David , Huff Chad D 
Published: December 2023

AbstractBackgroundFrontotemporal dementia (FTD) is a neurodegenerative syndrome characterized by distinct subtypes, each with unique clinical presentations and varying neuropathologic features. Although FTD is highly heritable, it is frequently undiagnosed and genetic causes of FTD are rarely determined, limiting what is known about the medical phenome associated with FTD. Here, we perform a combination of innovative strategies to improve detection of FTD in a large electronic health record (EHR) using machine‐learning (ML) and uncover genetic factors for FTD.Method123 FTD cases and 615 matched controls were identified via diagnostic codes and confirmed by manual expert review of medical notes in Vanderbilt University Medical Center’s (VUMC) EHR. We then applied a feature selection algorithm which calculated the frequency for each phecode within a randomly generated and demographically matched control set. A p‐value denoting the enrichment of each phecode was calculated based on the observed phecode frequency relative to the permutation‐derived null distribution. 28 phecodes were enriched in FTD cases compared to controls. Top predictors included “Neurological disorders”, “Memory loss”, Aphasia”, and “Parkinson’s disorder”. We then developed a classification and regression tree model that leveraged enriched phecodes to label an undiagnosed case set in VUMC’s EHR‐linked DNA databank, BioVU. The model was trained on 96 cases and 481 controls, with 28 cases and 139 controls reserved for testing.ResultOf the testing set, 19 of the FTD cases were classified as cases and 5 were misclassified as controls. 135 controls were classified as such and 4 were misclassified as cases, indicating 82% PPV. Application of this model in BioVU resulted in an expanded case set of inferred FTD, which is currently being leveraged in genomic analyses to identify causal variants. We have identified a genomic segment on chromosome 1 (146.9MB‐147.3MB) spanning ACP6 and GJA5 that is shared in significant excess among FTD cases. These genes have been associated with intellectual disability, aphasia, and autism.ConclusionOur results demonstrate both the potential of machine learning‐based approaches for case acquisition in dementia subtypes that are often underdiagnosed in medical record databases and illustrate how inferred cases can be leveraged for novel gene discovery.
Informant‐ and Patient‐reported Subjective Cognitive Decline: a preliminary analysis of the Brazilian Subjective Cognitive Decline Cohort
Authors: De Souza Haniel Bispo , Souza Victória Tizeli , Giordani Manuella Edler Zandoná , da Mota Simone Sieben , De Marchi Bruno De Oliveira , Formoso Carolina Rodrigues , Rivas Gabriela Raquel Paz , Carvalho Guilherme Da Silva , Beltrami Lucas Bastos , Santos Rhaná Carolina , Suwa Samuel Masao , Slaviero Wesley , de Albuquerque Ana Letícia Amorim , Strelow Matheus Zschornack , Carello‐Collar Giovanna , Chaves Marcia L Fagundes , Zimmer Eduardo R , Castilhos Raphael Machado 
Published: December 2023

AbstractBackgroundSubjective Cognitive Decline (SCD) is characterized by self‐experience of deterioration in cognitive performance in cognitive unimpaired (CU) individuals and may represent a preclinical stage of neurodegenerative diseases, especially Alzheimer’s disease (AD). Informant‐reported cognitive complaints appear to increase the risk for cognitive decline in SCD individuals. We aimed to describe a preliminary analysis of informant‐ and patient‐reported SCD in the ongoing Brazilian SCD (BRASCODE) Cohort.MethodWe are evaluating CU individuals older than 65 years‐old with cognitive complaints (and at least one SCD‐plus criteria). Biofluid‐ and imaging‐based biomarkers are being performed. Here, we evaluated the concordance of complaints between patients/informants and correlated them with patient’s sociodemographic and clinical variables. We described continuous variables as median (interquartile range, IQR) and categorical as frequencies. We performed a linear regression analysis with informant‐related complaints as the dependent variable, measured by the Subjective Cognitive Decline Scale, that ranges from 0 to 14, with scores ≥ 7 indicating complaint.ResultBetween March and November 2022, 52 SCD patients were included, 70 (68‐73) years of age, 73.1% (n = 38) women. The median SCD‐patient and SCD‐informant scale was 8.5 (7 ‐ 9.25) and 5 (3 ‐ 7.25), respectively. The minority (20, 38.5%) of the informants agreed with the patients' cognitive complaints. The patients had a median of 3 (2 ‐ 4) SCD‐plus criteria, mainly age at onset of SCD ≥ 60 years‐old (16, 80%) and concerns associated with SCD (15, 75%) (Table 1). The SCD‐patient scale correlated negatively with patient age (rho = ‐ 0.362; p‐value = 0.008) and the SCD‐informant scale correlated negatively with patient education (rho = ‐ 0.349; p‐value = 0.01). In the linear regression analysis, the SCD‐informant scale was associated with the patient’s black race and education (p = 0.00141) (Table 2).ConclusionIn the ongoing BRASCODE cohort, the preliminary baseline analysis showed that most informants did not agree with the patients complaints, but education and race seem to influence the informant’s complaints. The increase in the sample size, AD biomarkers analysis, and follow‐up may bring valuable information about the relationship between patient’s and informant’s complaints.