bluuebunny/crossref_metadata_2025_split huggingface dataset:
Age determines the profile of cognitive impairment after COVID‐19. Results of an international, multi‐cohort, pooled analysis and meta‐analysis
Authors: Gonzalez‐Aleman Gabriela , Vavougios George D. , Tartaglia Carmela , Guekt Alla , Uvais Nalakath A. , Hosseini Akram A. , D'Avossa Giovanni , Ferreccio Catterina , Perez‐Lloret Santiago , Botero‐Rojas Camila , Insua Francisco Gonzalez , Figueredo‐Aguiar Mariana 
Published: December 2023

AbstractBackgroundEvidence‐based data are still lacking to define de characteristics of cognitive impairment after COVI‐19. Previous findings suggest that Covid‐19 sequelae may resemble early Alzheimer’s disease (AD). In this abstract, our team present data from Argentina, Canada, Russia, Greece, and the UK including 1919 patients and 1031 controls.MethodParticipants were 18 to 97 years old. Neuropsychological evaluation included Montreal Cognitive Assessment – MoCA, Toronto Cognitive Assessment‐ TORCA, and/or batteries specially built for the evaluation of cognitive dimensions. Some cohorts included the anosmia. Participants were evaluated at a maximum of 6 months after discharge. A factorial analysis was performed on each country identifying 3 factors that could be compared between countries: one accounting for memory and language, the second is an attentional factor, and the last is a working memory factor. Between countries that have young population, there was a fourth factor accounting for executive functioning (planning and inhibition). We carried out meta‐analysis of common factors and co‐variates.ResultAverage duration of formal learning is 11.06 ± 5.11 years, and the mean age is 52.61 ± 15.87 years. Meta‐analysis revealed an impairment in language (verbal fluency) for all patients vs controls. Factorial scores revealed that all the participants were impaired in attentional tasks but those over 60 years old were impaired also in working memory and the youngest participants in executive functioning. Significant differences between cases and controls in attentional, memory, and language tasks identified 4 different groups: normal cognition (71%); one dimension impaired (20.5%); two dimensions impaired (6.5%); and three dimensions impaired (2%). In older adults, these proportions rise to 28% for the impairment in one dimension; 11.5% for two dimensions, and 3.5% for three dimensions and is significantly associated with the infection diagnoses (p = 0.013) and with presence and severity of anosmia (p = 0,000).ConclusionOlder adults are at greater risk of suffering persistent cognitive impairment after recovery from SARS‐CoV‐2 infection and cognitive impairment is correlated with the presence and severity of anosmia.
Amygdala volume as neuroimaging marker of limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) in neurodegenerative disease: a post‐mortem MRI and pathology study
Authors: Wesseling Alex , Calandri Ismael Luis , Ossenkoppele Rik , van de Berg Wilma D.J. , Rozemuller Annemieke J.M. , Pijnenburg Yolande A.L. , Hoozemans Jeroen , Jonkman Laura E. 
Published: December 2023

AbstractBackgroundLimbic‐predominant age‐related TDP‐43 encephalopathy (LATE) is characterised by hyper‐phosphorylated TAR DNA‐binding protein 43 (TDP‐43) aggregates within the amygdala and (para)hippocampal regions. LATE neuropathological change can occur in patients with neurodegenerative disorders including Alzheimer’s (AD) and Parkinson’s disease (PD), as well as in healthy controls. LATE is associated with lower cognitive performance in AD patients. No neuroimaging marker for LATE is currently available, but identification would be of importance for accurate disease prognosis and as potential exclusion criteria for e.g. AD clinical trials. The current study aims to assess whether MRI‐measured amygdala and hippocampal volume can differentiate LATE status in neuropathological‐confirmed AD and PD brain donors.MethodPost‐mortem in‐situ 3DT1 3T‐MRI data were collected for 15 cases (9 AD and 6 PD) with post‐mortem confirmed LATE neuropathological change, as well as 30 non‐LATE (18 AD and 12 PD) donors. Each donor with LATE was matched with two non‐LATE donors on age, sex and neuropathological (i.e. Thal and Braak) staging. Neuropathological assessment was done on tissue of the right hemisphere. Amygdala volume, including amygdala subfield volumes, as well as hippocampal volume, were calculated using Freesurfer (version 7.1.1) and corrected for total intracranial volume. Group differences were assessed with univariate analyses using post‐mortem delay as covariate, subfield analysis were Bonferroni corrected.ResultBrain donors with LATE neuropathological change showed significantly lower right amygdala (p = .002) and right hippocampal (p = .007) volumes (figure 1). Amygdala subfield volumes were available for 13 LATE and 27 non‐LATE cases. When investigating the amygdala subfields, we found significant LATE compared to non‐LATE differences within the anterior amygdaloid area (p = 0.005) and the lateral nucleus (p = 0.002) (figure 2). In AD (n = 27), LATE cases showed significantly lower right amygdala (p = .023) and right hippocampal (p = .003) volumes compared to non‐LATE cases. In PD (n = 18), only the volume of the right amygdala was significantly lower in LATE cases compared to non‐LATE cases (p = .043) (figure 3).ConclusionMRI‐measured amygdala volume, especially of the anterior and lateral nucleus, can differentiate LATE neuropathological change, and may therefore serve as a promising neuroimaging biomarker in neurodegenerative disease.
Social relations, cognitive health disparities and COVID‐19 stress
Authors: Antonucci Toni C , Brauer Simon , Zahodne Laura B. , Ajrouch Kristine J 
Published: December 2023

AbstractBackgroundThe prevalence and incidence of COVID‐19 was higher among racial/ethnic minority groups in the U.S. (APM Research Lab, 2020), but stressor types, resilience, and impacts on cognitive health are unknown. Economic and socioemotional stress each affect health and contribute to racial/ethnic health disparities (Sternthal, et al., 2011). Further, changes in stress and social relations influence cognitive decline (Dickinson et al., 2011; VonDras et al., 2005). However, it is unclear if associations are similar across racial/ethnic groups.MethodParticipants in the recently completed U.S. based Detroit Area Wellness Network COVID‐19 Supplement (DAWN‐CS) project (N = 606) were recruited from a longitudinal cohort study (i.e., Social Relations Study; Antonucci & Akiyama, 1994), supplemented by address‐based and respondent‐driven sampling to obtain a racially/ethnically balanced sample of Middle Eastern/Arab (MENA), Black, and White older adults (aged 65+). Eligible persons (aged 65+) within screened households were selected with probability to allow appropriate inference to the target population. Inclusion criteria for DAWN‐CS were: age 65+, fluency in English or Arabic, and identifying as MENA, Black, or White. Participants were administered psychosocial questionnaires and cognitive measures via telephone. Global cognition was a latent variable indicated by episodic memory, language, attention, and working memory tests.ResultOlder adults who saw their network members more frequently during the COVID‐19 pandemic reported more economic stress and demonstrated worse cognitive health. Within‐group analyses showed unique patterns: only among Black older adults was there an association between more contact frequency and higher economic stress. Further, the association between economic stress and worse cognitive health was evident among MENA and White older adults, but not Black older adults. Pandemic‐related socioemotional stress (e.g., conflict with family and friends) did not vary by race/ethnicity and was not associated with contact frequency during the COVID‐19 pandemic. Further analyses examine whether social relations buffered the effects of pandemic‐related economic stress on cognitive health.ConclusionIncluding underrepresented populations in the study of social relations, stress and cognitive health advances science and addresses societal health in its entirety. Strengths of this study include its racially/ethnically balanced sample, which improved the power and validity of racial/ethnic group comparisons.
Are there baseline structural MRI differences between individuals who progress along the Alzheimer’s disease continuum and those who remain cognitively stable? A systematic review
Authors: Saadat Nazanin , Parker Ashleigh F. , Kwan Heather , Grewcock Riley , Gawryluk Jodie 
Published: December 2023

AbstractBackgroundEarly identification of individuals that will progress along the continuum from normal cognition to mild cognitive impairment (MCI) and to Alzheimer’s disease (AD) is imperative for timely prevention and intervention measures. Structural magnetic resonance imaging (MRI) is a non‐invasive technique commonly used to examine neurodegeneration. The current review summarizes the literature on structural brain differences between individuals who experience conversion to MCI from normal cognition or AD from MCI and those who remain stable.MethodMedline and PsycINFO databases were searched for studies that compared baseline structural MRI of individuals who converted from normal cognition to MCI, or from MCI to AD, to those with normal cognition or MCI who remained cognitively stable. Inclusion criteria included studies with baseline structural MRI, cognitive follow‐up to assess conversion/stability, and comparison between converters and non‐converters. Two authors reviewed each abstract and a third review resolved any conflicts. The same process was used for full‐text articles. Information regarding sample size, acquisition and analysis and results were extracted and all studies were reviewed for quality using the AXIS tool.ResultA total of 1670 studies were imported for screening in Covidence and 440 duplicates were removed. Following abstract screening, 293 studies were eligible for full‐text review. Many of the identified studies took a region of interest approach focused on hippocampal volume and found significant differences between converters and non‐converters. Many studies used multi‐site, multimodal databases (e.g., Alzheimer’s Disease Neuroimaging Initiative) to retrospectively examine converters and non‐converters. Many more studies looked at individuals who converted from MCI to AD than normal cognition to MCI. Further analyses of the full text review and findings will be presented.ConclusionCharacterization of baseline differences in brain structure between those who progress on the AD continuum and those who remain stable is crucial for early diagnosis and treatment. The current review indicates that such differences are evident on structural MRI. The medial temporal lobes have been identified as a region of interest. However, it will be important for future research to use a whole brain approach and for further examination of individuals who convert from normal cognition to MCI.
Tau and lipid coalescence drives early lipid dysregulation in Alzheimer’s disease
Authors: Oliveras Anna 
Published: December 2023

AbstractBackgroundIn Alzheimer’s disease (AD), intraneuronal tau protein accumulation into neurofibrillary tangles correlates with clinical signs and neurodegeneration1. Besides neurotoxic protein aggregation, dysregulation of lipid metabolism is emerging as a common disease mechanism2. The main regulators of lipid metabolism in the brain are astrocytes and astrocyte‐neuron communication is key to provide metabolic support to neuron3. While tau has been suggested to bind to lipids4, little is known about the potential tau‐lipid interactions in the brain, it’s role in neuron‐astrocyte crosstalk and how this relates to AD pathology.MethodsWe employ a multiscale approach harnessing human 2D and 3D multicellular models combined with advanced imaging techniques, spanning from single molecule insights to ultrastructural features and functional imaging. We aim to unravel the structural and functional complexity of emerging protein‐lipid landscapes in AD and to elucidate how their misregulation triggers early lipid dyshomeostasis.ResultsTau propagates in brain organoids in highly dynamic intracellular droplet‐like structures rich in lipids. Strikingly, the molecular identity of tau droplets is cell‐type specific; tau interact with lipids in neurons but not in astrocytes (fig.1‐2). The dynamics of neuronal tau‐lipid accumulations are driven by microtubule interactions and show liquid‐like behavior. Furthermore, highly dynamic tau‐lipid droplets transition to stillness overtime giving rise to a heterogenous spectrum of conformational ensembles of tau (fig.3).ConclusionTau‐lipid interactions in vivo are neuron‐specific. Lipid colocalization correlates with dramatic changes in the structural properties of tau. In neurons, tau and lipids coalesce in highly dynamic intracellular liquid‐like droplets that undergo time‐dependent transition to potential pathological states. Our results highlight intriguing functional implications of cell‐type specific tau‐lipid interactions impacting on neuron‐astrocyte communication and overall brain lipid metabolism. Targeting tau‐lipid interactions in neurons promise exciting new avenues in AD therapeutic strategies.1. Busche, et al. Synergy between amyloid‐β and tau in Alzheimer’s disease. Nat. Neurosci. (2020).2. Yin. Lipid metabolism and Alzheimer’s disease: clinical evidence, mechanistic link and therapeutic promise. FEBS J. (2022).3. Yang, et al. Lipid metabolism and storage in neuroglia: role in brain development and neurodegenerative diseases. Cell Biosci. (2022).4. Sallaberry, et al. Tau and Membranes: Interactions That Promote Folding and Condensation. Front. Cell Dev. Biol. (2021).
Precision Medicine in Alzheimer’s Disease: Phenotype Investigation, Medication Effects and Variant Analysis in Cell Type Specific Subgroups
Authors: Tost Eric Palanques , Grenn Francis , Hu Junming 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is characterized by cognitive decline and dementia and has few clinically approved treatments. The clinical and neuropathological heterogeneity of AD suggests the existence of AD subgroups with unique mechanisms and implies the need for cell‐type specific subtyping and treatments. The goal of this project was to investigate the differential effects of medications on cognitive tests in eight previously defined brain cell type‐based polygenic risk scores (PRS).MethodMedication usage information, imputed genotypes, phenotypic data and cognitive test scores were collected for 487,409 participants from the UK Biobank to use in the analysis of the different PRS groups. We determined the characteristics of the PRS used by comparing 16 phenotypes in high and low risk subjects. Association between four cognitive test scores (fluid intelligence, reaction time, prospective memory, and pairs matching) and medication status (treated vs. untreated) was determined using logistic regression. Cognitive scores were rank‐transformed for the analysis, and the logistic regression was performed separately for high‐risk and low‐risk genetic groups. Genome‐wide association studies (GWAS) were used to detect genetic variants linked to medication usage. This analysis was repeated for all, high risk and low risk samples, using only medications that demonstrated a significant association with improved cognitive function during follow up examination.ResultPhenotypic variation was wide among different PRS groups. Genetically different PRS groups shared phenotypic characteristics, suggesting that different underlying mechanisms lead to similar outcomes. Six medications were significantly associated (P<0.05) with improved cognitive function during follow‐up examination. Atenolol, a high blood pressure medication, was associated with the largest gain, with an improvement on the effect of cognitive function by 67% in the high‐risk compared to the low‐risk subjects from an astrocyte genetic subtype (Ast‐M9). The atenolol GWAS focused on the Ast‐M9 high risk group identified two genome wide significant variants at the same locus. These were previously shown to be associated with phenotypes related to blood pressure and were known eQTLs.ConclusionOur findings suggest potential novel implications for genetic subtype‐driven treatment options for AD. Further research is needed to validate these associations that may explain differential effects of medications in AD‐subtypes.
Investigating the endocytic mechanism of pathological tau at the synapse
Authors: Stuart Skye , Moretto Edoardo , Schiavo Giampietro 
Published: December 2023

AbstractBackgroundThe spatiotemporal spread of pathological tau observed across anatomically connected brain areas in Alzheimer’s disease suggests that tau pathology propagates trans‐synaptically. The underlying endocytic mechanisms of tau occurring at the post‐synapse remains poorly characterised. This study aims to investigate the mechanism/s controlling neuronal endocytosis of tau at the synapse, and understand how this mechanism is altered in tauopathies, with the goal of identifying targets to prevent pathological tau spread.MethodTo achieve this ambitious target, human tau undergoing synaptic endocytosis will be monitored in living neurons with confocal microscopy in specifically designed unidirectional microfluidic devices. Incorporating this novel model, targeted screening using pharmacological and genetic approaches will identify which endocytic mechanisms are exploited by pathological tau to enter neurons. Finally, targets of interest will be further investigated through co‐localisation studies to human tau and post‐synaptic markers using super‐resolution microscopy.ResultPreliminary experiments showed that by infecting an isolated population of neurons with the P301S‐tau mutant, tau‐positive puncta and aggregates are detected in synaptically connected neurons, suggestive of trans‐synaptic tau propagation. In addition, we demonstrated that tau transfer is dependent on neuronal stimulation, supporting the notion that tau spreads across synapses in an activity‐dependent manner.ConclusionFurther work is required to optimise this experimental set up for investigating the exact mechanisms underlying tau endocytosis at the post‐synaptic level. Elucidating the specific pathways involved in tau uptake at the synapse will aid the identification of novel targets to prevent pathogenic tau spread and tauopathy progression.
Description of the Gut Microbiome Composition in Puerto Ricans with Alzheimer’s Disease Compared to Healthy Controls
Authors: Sepulveda Vanessa , Soler‐Llompart Cecilia Michelle , Sala‐Morales Ana Cecilia , Godoy‐Vitorino Filipa , Santiago‐Berríos Michel , Ruiz‐Adames Javier A. , Olivieri‐Henry Gerianne , Pérez‐Luzunaris Fabián J. , Herrero‐Rivera Carlos 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is the most common type of dementia, a debilitating disorder that could result in complete loss of mental functions and death. In Puerto Rico, AD is the fourth leading cause of death, while in the United States is the sixth. Evidence suggests that the gut microbiome plays a role in the pathophysiology of AD through neuroinflammation and amyloid deposition at brain. Our Objective: Study the gut microbiome composition and diversity of Puerto Ricans with AD compared to cognitive‐intact controls and associate the microbiome with cognitive impairment.MethodWe recruited 53 participants, 28 with AD and 25 controls, who underwent clinical and cognitive assessments(MoCA/CDR). Genomic DNA extractions performed on collected fecal samples. NextGen Illumina MiSeq was used to sequence 16S rRNA genes (V4 region) and analyzed with standard pipelines for microbiome species.ResultPreliminary analyses showed no statistically significant differences between AD and controls in bacterial diversity and richness. However, AD participants showed an abundance of Euryachaeota, while controls had higher levels of Bacteroidetes. We found significant differences in alpha diversity with cognitive decline and a reduction of Roseburia ‐a known butyrate producer with protective and anti‐inflammatory properties‐ in participants with severe cognitive impairment.ConclusionFirst study in Puerto Rico comparing a neurodegenerative disease common in the aging population with the gut microbiome. The study of the Gut‐Brain‐Axis may open the possibility for preventive microbiota‐based therapies and strategies for a healthy microbiome resulting in better outcomes for our patients with and without AD.
Prediction of functional dependence with digital clock drawing, word recall, and assessment of lifestyle and health factors
Authors: Gomes‐Osman Joyce Rios , Jannati Ali , Banks Russel R , Ciesla Marissa R , Toro‐Serey Claudio R , Libon David R , Swenson Rodney , Tobyne Sean , Showalter John , Pascual‐Leone Alvaro 
Published: December 2023

AbstractBackgroundDistinguishing mild cognitive impairment (MCI) and Alzheimer’s disease‐related dementia (ADRD) requires assessing the clinical impact of cognitive deficits on a patient’s activities of daily living. To accurately monitor cognitive decline, it is thus critical to combine early screening of cognitive deficits with the assessment of functional impairment. The Digital Clock and Recall (DCR™), consisting of DCTclock™ and a 3‐word delayed recall, employs AI‐enabled performance analyses to evaluate memory, executive function, visuospatial abilities, and motor functions. The Life and Health Questionnaire (LHQ) is a brief digital survey that captures key lifestyle and health factors for cognitive decline/dementia. We evaluated whether the combination of the DCR and LHQ can predict functional status, measured by the Functional Abilities Questionnaire (FAQ) reported by an informant, in older individuals with statuses ranging from cognitively unimpaired to MCI and ADRD.Method849 participants from a multisite study (age mean±SD = 72.1±6.7; 56.8% female; years of education mean±SD = 15.4±2.7), classified as cognitively unimpaired (n = 369), MCI (n = 262), or ADRD (n = 215). Mild (mFD) and moderate (modFD) levels of functional dependence were defined as FAQ score ≥ 6 and ≥ 9, respectively. We conducted 10‐fold cross‐validated regularized logistic regressions using LHQ responses and DCR metrics to predict mFD or modFD, controlling for age, sex, and education.ResultLHQ significantly predicted mFD and modFD (p’s<0.001, R2 = 0.13, and R2 = 0.12). Adding DCR metrics to the model improved both models (p’s<0.001, R2’s = 0.18 and 0.13, respectively). Surviving LHQ questions for predicting mFD related to unintended weight loss, social engagement/volunteering, cognitively stimulating tasks, sleep, and life satisfaction/purpose. Surviving LHQ questions for predicting modFD related to unintended weight loss, social engagement/volunteering, cognitively stimulating tasks, and sleep.ConclusionA brief assessment that can be completed in primary care settings in <10 min consisting of an objective digital cognitive assessment and a survey of self‐reported lifestyle and health factors can not only identify early cognitive impairment but also reliably predict level of functional dependence in instrumental activities of daily living ‐ without need for an informant.