bluuebunny/crossref_metadata_2025_split huggingface dataset:
The associations between glial biomarkers and cognitive changes in individuals at risk of Alzheimer’s disease
Authors: Warmenhoven Noelle , Sánchez‐Benavides Gonzalo , Escalante Armand González , Milà‐Alomà Marta , Shekari Mahnaz , López‐Martos David , Ortiz‐Romero Paula , Kollmorgen Gwendlyn , Carboni Margherita , Minguillon Carolina , Gispert Juan Domingo , Arenaza‐Urquijo Eider M , Palpatzis Eleni , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Grau‐Rivera Oriol 
Published: December 2023

AbstractBackgroundIn preclinical Alzheimer’s disease (AD), previous evidence suggests that glial reactivity may affect cognitive performance. This study aimed to test whether glial markers cerebrospinal fluid (CSF) GFAP, YKL‐40, sTREM2, and plasma GFAP are associated with cognitive change in cognitively unimpaired individuals at risk of AD. We hypothesized that higher levels of glial markers may be associated with better cognitive outcomes.MethodWe included 353 individuals from the ALFA+ cohort with available baseline (BL) glial biomarkers and cognition at follow‐up (FU) 3 years later (Table 1). CSF Aβ42/40, pTau181, YKL‐40, GFAP, and sTREM2, were analyzed using the exploratory Roche NeuroToolKit, a panel of automated robust prototype immunoassays. Plasma GFAP was determined with the Simoa HD‐X (Quanterix) platform using the commercial Neurology 4‐Plex E assay (N4PE). Amyloid pathology was studied with Centiloids derived from [18F]flutemetamol PET. Rate of change ([FU‐BL]/time) in the Preclinical Alzheimer’s Cognitive Composite (PACC) and domain‐specific cognitive composites was used as the dependent variable, glial biomarkers at BL as predictors, and age, sex and education as covariates in linear models. Interaction terms between each glial biomarker and different AD pathology were also explored. Aβ+ was defined as CSF Aβ42/40 <0.071.ResultHigher baseline CSF sTREM2 was associated with a positive PACC rate of change (p = 0.002) (Table 2). These results remained significant after controlling for CSF Aβ42/40, pTau181 and Centiloid levels (all p < 0.01). Moreover, CSF sTREM2 at baseline was associated with a better memory outcome (p = 0.012), independently of amyloid and tau (all p < 0.02), and better executive functioning (p = 0.046), independently of tau pathology (p = 0.011). These positive associations remained in the Aβ‐ group regardless of AD pathology, but not in the Aβ+ group, in which some negative associations were observed when adjusting for Centiloids (YKL‐40, p = 0.024) (Figure 1).ConclusionHigher TREM2‐mediated microglial response in individuals at risk of AD is associated with better cognitive performance. These associations were driven by the Aβ‐ group. These results may have important implications for the design of clinical interventions targeting TREM2 in this early stage of AD.
Hemoglobin levels and vitamin B12 deficiency anemia but not iron status are associated with lower verbal fluency in older adults from the Southern region in Mexico
Authors: la Cruz‐Góngora Vanessa De , Rodriguez Aaron Salinas 
Published: December 2023

AbstractBackgroundSemantic verbal fluency (SMF) has been identified as an early marker of mild cognitive impairment (MCI). Anemia and some micronutrient deficiencies (MD) have been considered as risk factor for MCI. In Mexico, it has been poorly studied the nutritional drivers associated to MCI. Anemia and MD are frequent in vulnerable Mexican population but controversial exist around the criteria to define such entities in older adults (OA).The aim is to analyse the association between hemoglobin concentration, iron and B12 status, as well as the causes of anemia with SVF in older Mexican adults.Methods802 OA from 4 urban localities in Campeche and Yucatan ‐most of them considered themselves as Mayan indigenous‐ donated a capillary and venous blood sample. Hb (g/dL) was measured in capillary blood using Hemocue. Ferritin, vitamin B12, transferrin receptors (stfr), and other biomarkers were analysed in serum. The causes of anemia were classified as: Iron deficiency (ID), B12 deficiency (B12D), inflammatory, renal, multiple and unexplained. We explored the quartiles (Q) of Hb ‐sex adjusted‐, s‐ferritin, and stfr with SVF. Anemia, causes of anemia and MD were modelled separately using multiple linear regression models adjusted by confounders.ResultsAnemia, ID and B12D affected to 35.3%, 5% and 10% of OA, respectively. The mean of SVF was 13‐5±6.5 words. The Q1 [coef = ‐1.4, p = 0.025], Q2 [coef = ‐1.46, p = 0.016] and Q3 [coef = ‐1.13, p = 0.05] of Hb were negatively associated with SVF in comparison with Q4. No association was observed between the quartiles of s‐ferritin, stfr, ID or B12D with SVF. Total anemia (‐0.9, p = 0.047), and particularly B12D anemia (‐3.5, p = 0.018), were associated to lower SVF vs non‐anemics.ConclusionsHigher Hb values (≥13.3 g/dL for women and ≥14.7 g/dL for men) above the cut‐off of anemia were positively associated with SVF independent of MD. This finding suggests that normal Hb values in those ranges of Hb might hide a declining in brain function secondary to an inadequate delivery of cerebral oxygen. Those with B12D anemia had the worse SVF performance. It is necessary to identify the main drivers for the optimal Hb range where the OA is functional independent to target early interventions.
Hippocampal subfield volumes in COVID‐19: a preliminary multicenter study using 7T MRI
Authors: Santini Tales , Alkateeb Salem , Liou Jr‐Jiun , Li Jinghang , Adeyemi Oluwatobi F , de Erausquin Gabriel A. , Garbarino Valentina R. , Goss Monica , Habes Mohamad , Himali Jayandra Jung , Karmonik Christof , Li Karl , Masdeu Joseph C. , Nair Rejani R , Patel Vibhuti N , Snitz Beth E. , Bowtell Richard , Penny Gowland , Roman Gustavo C , Ganguli Mary , Vahidy Farhaan S , Girard Timothy D. , Jacobs Heidi I.L. , Hosseini Akram A. , Seshadri Sudha , Ibrahim Tamer 
Published: December 2023

AbstractBackgroundHippocampal formation atrophy is a well‐established imaging biomarker of several neurological diseases, including Alzheimer’s disease, temporal lobe epilepsy, and schizophrenia. The hippocampus is divided into subfields that have different functions and vary in sensitivity to different diseases. This study investigates the potential interaction between COVID‐19 and the various hippocampus subfields, which may shed light on the long‐term neurological consequences of the virus.MethodWe obtained high‐resolution T1‐weighted (T1w) and T2‐weighted (T2w) MRI images using 7T scanners located at three sites in two countries: Pittsburgh (n = 14) and Texas (San Antonio and Houston) (n = 40) in the USA, and Nottingham, UK (n = 33). We evaluated the hippocampus subfields using the ASHS package [1‐3]. Imaging sets of 51 subjects with minimal or no manual segmentation corrections (Figures 1 and 2) were included in the analysis. We conducted T‐tests with Bonferroni correction, adjusting for age and intracranial volume to identify the differences in hippocampus subfield volumes across groups.ResultParticipants who needed admission into the ICU due to Covid‐19 showed a significantly lower (p‐value = 0.0034) left CA1 volume compared to participants who did not require ICU (Figure 3). In addition, several other non‐significant trends were observed.ConclusionOur preliminary findings suggest that Covid‐19 may impact the hippocampus, particularly in patients who required intensive care. However, the study ‐ as of to date ‐ has a small sample size and lacks a comparison group with patients who were admitted into ICU for acute illnesses other than Covid‐19. Additionally, longitudinal data is needed to track the long‐term effects of the disease on the hippocampal subfields.
Funding: NIH R56AG074467, R01MH111265 and R01AG063525
References: 1. Berron et al. Neuroimage 20172. Yushkevich et al. Human Brain Mapping 20153. Santini et al. Neuroimage: clinical 2021
Post COVID‐19 cognitive rehabilitation effects on depressive symptoms
Authors: Dutra Letícia Silva , Alves Larissa Scoralich , Shigaeff Nadia 
Published: December 2023

AbstractBackgroundMore than 600 million people have been infected by Covid‐19 since the beginning of the pandemic. Common cognitive and psychological symptoms in these patients are memory impairment, attention difficulties, anxiety and depression, and neuropsychological rehabilitation is a possible strategy to improve them. In addition, some studies have shown a decrease in depressive symptoms after starting a cognitive rehabilitation program, although this was not the main objective of rehabilitation.MethodFive patients underwent mood assessment, more specifically, depressive symptoms. For this, the Patient Health Questionnaire‐9 (PHQ‐9) was used. The application was made immediately before and after the cognitive rehabilitation intervention, lasting 20 weekly sessions of about one hour of activity.ResultThe evaluation was performed on five patients with a mean age of 52.5 years (Table 1). These presented measures that indicated the presence of depressive symptoms at the beginning of the study. After 20 sessions of cognitive rehabilitation it was not possible to observe an objective change in depressive symptoms. This can be explained by the reduced number of individuals in the sample, which may have impaired the statistical calculation. But it was observed a clinical improvement of depressive symptoms was observed in 60% of patients and 40% remained stable (Table 2). Clinical improvement was also noted in patients, who reported that they were feeling better and that they resumed activities that they have previously avoided or that they were finding it easier, in addition to perceiving their own evolution throughout the treatment, increasing their sense of self‐efficacy and feeling more hopeful.ConclusionFinally, it is noted that cognitive rehabilitation is a possible strategy to improve not only cognitive impairment, but also the clinical manifestations of depressive symptoms in post‐Covid‐19 patients.
Home‐based cognitive interventions for patients with mild cognitive impairment and dementia. A systematic review
Authors: Rodas Andrea C Alvarado , Ulate Mauricio Molinari , Palacios Mateo Orellana , Martin Manuel Angel Franco 
Published: December 2023

AbstractBackgroundCurrently, there is a search for timely care and intervention on patients with dementia, which have reasonable costs and allow the sustainability and efficiency of national health and social care systems (Livingston et al., 2017). Cognitive interventions delivered in the patient’s home can be an excellent alternative, due to their feasibility(Jang et al., 2021) and accessibility (Rai et al., 2021) to the intervention. The aim of this paper is to describe the evidence on cognitive intervention performed at home for patients with MCI and mild dementia. To describe its characteristics and outcomes, and to address its feasibility and usability.MethodA systematic review was performed using the PRISMA recommendations. We reviewed 190 records from four databases: PubMed, CINAHL, Web of Science, and PsycInfo.The quality of the studies was assessed using the tool “Assessment (mERA) checklist7” (World Health Organization, 2016)ResultTen papers were included. With a mean quality score of 0.76/1 (91.7% agreement).The sample contains (N = 777) patients (MA 75.9). 80% have an education >7 years. 87.1% have a diagnosis of mild dementia. There are (N = 628) caregivers (MA 64.8). Seventy percent (n = 440) are women.Positive results were found in: 71% of studies that looked for results on cognition. 66% of the studies that looked for results on mood and behavioral symptoms. 83% of studies that looked for results on functionality/quality of life. 100% of the studies that looked feasibility, and 75% of the studies that looked for results on the caregiver.ConclusionCognitive intervention in the home of patients with MCI and early dementia showed positive results at a cognitive, emotional and behavioral levels. Likewise, in the caregiving relationship, emotional health and quality of life of caregivers.The use of assistive technologies in the home has some benefits over face‐to‐face care.Outcome‐cost ratio can be a cost‐effective solution for the sustainability and efficiency of national health and social care systems.
AD/ADRD Data Sources: Access and Utilization to Advance Research for Improving Human Health
Authors: Onyeneho Karyn N 
Published: December 2023

AbstractBackgroundAlzheimer’s Disease and Related Dementia (AD/ADRD) cases affect more than 6 million Americans and more than 55 million people globally, leading to the deaths of 1 in every 3 older adults (Alzheimer’s Association, 2023). By 2050, these numbers are projected to climb. The National Institute on Aging is leading efforts to effectively prevent and treat AD/ADRD to improve human health and advance research enabled by accessible, utilizable, and shareable AD/ADRD data sources and investigated the utilization of AD/ADRD genomic datasets for secondary research from generalist and disease‐specific repositories. Multifactorial approaches about the use of the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) and Database of Genotypes and Phenotypes (dbGaP) were investigated to understand efficacies in secondary data useMethodA correlational study was conducted of AD/ADRD data access requests approved in NIAGADS and dbGaP (2020‐2022). NIAGADS (n = 12) and dbGaP (n = 12) datasets (Figures 1 and 2) were obtained for inclusion in the final analysis. A literature review was also conducted of studies published in PubMed, ScienceDirect, PLOS One, and gray literature (2013‐2023) to understand AD/ADRD data access and utilization key drivers (Figure 3). Hypotheses: H1: There is no difference in the approval rates of data access requests from NIAGADS and dbGaP between 2020‐2022; H2: Utilization of AD/ADRD secondary data sources, NIAGADS and dbGaP, have contributed to growth rates of AD/ADRD publications. Independent two‐sample t‐tests were performed to test the hypotheses.ResultH1: dbGaP data access requests approved (M = 0.793, SD = 0.036) compared to NIAGADS data access requests approved (M = 0.887, SD = 0.032) demonstrated no significance in approval rates between 2020‐2022, t(9) = 2.26, p = 0.160. H2: Publication rates from dbGaP (M = 18.8, SD = 20.8) compared to NIAGADS (M = 2.33, SD = 6.24) demonstrated a significance in publication growth rates, t(13) = 2.16, p = 0.002.ConclusionResearchers trust the use of dbGaP and NIAGADS, and other generalist and disease‐specific data sources (such as ADNI, AlzPathway, ALSOD, dbGaP, NCRAD, OMIM, and UPDB), for secondary data analyses. Researchers utilizing these data sources discovered hidden disease‐gene associations, AD/ADRD pathophenotypes, genetic variants affecting gene transcripts, fMRI functional connectivity changes, relationship modeling of inflammatory factors, candidate gene prioritization, and drug therapies. Researchers recognize the value of using data sources for secondary research.
E2814: an anti‐tau therapy engages its CNS target and affects the downstream tangle‐specific biomarker MTBR‐tau243 in Dominantly Inherited Alzheimer’s Disease
Authors: Zhou Jin , Rawal Sumit , Yagi Takuya , Wildsmith Kristin R , Takahashi Eri , Horie Kanta , Barthélemy Nicolas R. , Aluri Jagadeesh , Lalovic Bojan , Boyd Peter , Bateman Randall J. , Reyderman Larisa 
Published: December 2023

AbstractBackgroundE2814 is a human IgG1 antibody that binds to microtubule binding region of tau (MTBR‐tau), a critical domain for the seeding and spreading of tau pathology in Alzheimer’s Disease (AD). It is being developed for the treatment of AD by stopping tau propagation and slowing the associated cognitive decline. E2814 has been evaluated in healthy and Dominantly Inherited Alzheimer’s Disease (DIAD) participants for safety, pharmacokinetics (PK), and cerebrospinal fluid (CSF) target engagement.MethodSeventy‐two healthy participants were enrolled in single and multiple ascending dose cohorts of Study 001 (NCT04231513) and received randomized, double‐blind, placebo‐controlled treatment of E2814. Intravenous infusion of single and multiple doses (once every 4 weeks for three times) were administered. In Study 103 (NCT04971733), 7 DIAD participants with confirmed mutations and mild to moderate cognitive impairment were enrolled and received open‐label treatment of E2814. Four sequential doses were evaluated as intravenous infusion every 4 weeks. Serum and CSF PK, and CSF target engagement (by analyzing both bound and unbound MTBR‐tau299 and MTBR‐tau354 [containing the epitopes of E2814]) were measured in both healthy and DIAD participants, as well as safety assessments. CSF MTBR‐tau243 recapitulating AD tau pathology was also measured in DIAD participants using methods previously described (Horie et al., J Prev Alz Dis 2022).ResultE2814 was safe and well‐tolerated over a wide dose range. No infusion‐related reactions or other clinically significant safety signals were observed with single or repeated dose administration for up to 15 months. E2814 showed a dose‐related increase in serum and CSF exposure with CSF‐to‐serum ratio of ∼0.2%, comparable between healthy and DIAD participants. CSF target engagement was demonstrated by concentration‐related and sustained MTBR‐tau299 and MTBR‐tau354 binding in healthy and DIAD participants. More importantly, E2814 elicited a rapid and robust reduction on MTBR‐tau243, a neurofibrillary tangle‐specific biomarker, in DIAD participants.ConclusionE2814 demonstrated promising safety, PK and CSF target engagement profile in DIAD participants, and showed evidence of downstream effects on tangle‐specific biomarker MTBR‐tau243. Data supports further evaluation in the ongoing Ph2/3 DIAN‐TU Tau NexGen Platform Study in DIAD (NCT05269394) and future exploration in sporadic AD.
APOE and Alzheimer disease risk across age, sex, race, ethnicity, and ancestry: An overview from 68,756 individuals
Authors: Belloy Michael E , Andrews Shea J , Guen Yann Le , Napolioni Valerio , Greicius Michael D 
Published: December 2023

AbstractBackground
APOE*2 and APOE*4 are respectively the strongest protective and risk‐increasing genetic variants for late‐onset Alzheimer’s disease (AD), making APOE status highly relevant towards clinical trial design and AD research broadly. The associations of APOE genotypes with AD are importantly modulated by age, sex, race, ethnicity, and ancestry, but these associations remain unclear, particularly in historically understudied non‐white samples.MethodThe study overview is shown in Figure.1. Various case‐control, family‐based, and longitudinal AD genetic cohorts were available through public repositories and underwent extensive genotype and phenotype quality control. These cohorts contributed data for Non‐Hispanic Whites (NHW), Non‐Hispanic Blacks (NHB), and Hispanics (HISP). Global ancestry was determined using SNPweights v2.1. Case‐control logistic regression models evaluated the AD risk associations of APOE*2 dosage, APOE*4 dosage, and APOE genotype, with regard to APOE*33 as the reference, while adjusting for sex, array/batch/center, and global European, African, and Amerindian ancestry. Different stratified analyses, interaction models, and race/ethnicity heterogeneity tests were evaluated. APOE associations in East‐Asians (EAS) were obtained through meta‐analyses of published AD genetic studies, given the relative paucity of EAS in publicly available genetic cohorts.ResultCompared to prior literature, we made several novel observations (Figure.2). Notably, the associations of APOE genotypes with AD risk were least pronounced in HISP, which was not explained by global ancestry. Further, not just APOE*4, but also APOE*2 followed a reduced association strength with AD risk according to the pattern of EAS > NHW > NHB > HISP (with the exception of APOE*2 in EAS, which showed no significant association). The sex‐by‐age‐specific association of APOE*34 in NHW, which was shown to be stronger in women, was reproduced here at ages 60‐70 years, and additionally replicated in NHB and HISP. There were no other significant sex‐by‐APOE interactions.ConclusionMerited by recent advances in AD genetic cohorts, we provide the largest‐to‐date overview of APOE’s associations with AD risk across important biological and demographic strata. We expect these insights to be critical to guide AD research and clinical trial design. With increased diversity and phenotype harmonization efforts in AD genetics, future extensions on this work are expected to provide additional insights.
Impact of diagnosis timing on AD cost and healthcare utilization
Authors: Yao Wei , Gupta Anya , Shrinath Arjun , Ramesh Viviktha , Yan Jessie , Shah Soham , Prasad Akhilesh , Little Elizabeth , Sharma Vishakha , Alcorn Charles 
Published: December 2023

AbstractBackgroundThis study aims to detect direct cost savings with early detection of Alzheimer’s disease (AD) and related dementias. We hypothesize that earlier diagnosis of AD can reduce direct healthcare costs and unnecessary utilization. A retrospective case‐control study is conducted using Optum Market Clarity Claims/EHR linked dataset on Medicare Advantage population from Jan 1 2011 to Dec 31 2020.MethodBased on whether the patient was diagnosed with prior Mild Cognitive Impairment (MCI) before progressing to an AD diagnosis per ICD‐9/10 cm diagnosis codes, AD patients are categorized into early vs. late diagnosis (for those who were identified in the MCI stage vs not). Both groups are compared on annual all‐cause healthcare costs and frequency of encounters longitudinally spanning across 6 years pre‐index period and 3 years post‐index with AD diagnosis date as the index date. To understand the impact of early diagnosis, we estimated total cost, medical service cost and drug cost post‐index within the first 3 years by risk adjustment on baseline demographics, comorbidities, procedures, lab tests, and visits prior to AD diagnosis using propensity score weighting.ResultEarly‐diagnosed patients (N = 421) have a lower utilization rate of inpatient skilled nursing facility, nursing home and hospitalization than late‐diagnosed patients (N = 2817) after being diagnosed with AD. We also observed average medical service cost savings in all 3 years post‐index, ranging from $320 to $2556 per patient per year. Per cost allocation analysis, medical service cost savings are observed in inpatient, emergency room, inpatient SNF, urgent care, nursing home/assisted living, and observation unit. Risk adjusted cost savings with statistical significance are observed in year 3 post‐index. The mean cost difference between late and early diagnoses: total cost ($15472.11), medical service ($15013.7) and medication cost ($1601.61).ConclusionThe study highlights opportunities for earlier diagnosis and suggests long‐term healthcare savings for AD patients who have been diagnosed at MCI stage compared to patients who were directly diagnosed with AD. Further research is needed to drill down into the driver of cost savings and whether it is attributable to disease management of MCI or other complications.