bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Role of Apolipoprotein E4 Allele in the Gut Microbiome of Puerto Ricans with Alzheimer’s Disease
Authors: Olivieri‐Henry Gerianne , Sepulveda Vanessa , Soler‐Llompart Cecilia Michelle , Sala‐Morales Ana Cecilia , Santiago‐Berríos Michel , Ruiz‐Adames Javier A. , Pérez‐Luzunaris Fabián J. , Herrero‐Rivera Carlos , Godoy‐Vitorino Filipa 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) causes dementia, a debilitating disorder that gradually declines mental function and ends with death. Evidence suggests that the apolipoprotein E (ApoE) gene influences Alzheimer’s risk. Allele E2 is neuroprotective, E3 is neutral, and E4 is associated with a higher genetic risk for AD. Our main goal was to study the gut microbiome of Puerto Ricans with AD compared to unimpaired cognitive controls and its association with ApoE allele variants. We hypothesized that people with AD and does with less protective alleles have reduced microbial diversity.MethodsWe present the preliminary results of forty eight participants (n = 48), 24 with AD and 24 controls, with clinical and cognitive assessments. Fecal samples were collected for genomic DNA extractions followed by 16S rRNA genes (V4 region) amplification and ApoE genotyping was done at the PR‐INBRE CRI genomics core, using real‐time PCR TaqMan‐BHQ probes.ResultsControls, even with a single E4 allele, showed higher abundance of Ruminococcus bicirculans, absent in AD patients. Clostridium leptum was in higher abundance in controls with neuroprotective alleles E2E3 and in considerably reduced abundance in AD patient with E3E4 phenotype. Methanobrevibacter was in higher abundance in participants with any E4 allele than those with either E2 or E3 alleles. Faecalibacterium and Bacteroides were in higher abundance in controls compared to AD patients. Faecalibacterium, Ruminococcus, Clostridium and Bacteroides are anti‐inflammatory taxa and butyrate producers. Methanobrevibacter could favor metabolizing acetate to methane and thus antagonize the health‐directed butyrate benefits.ConclusionParticipants with any ApoE E4 allele have decreasing butyrate‐producing gut bacteria. This developing study area may open the possibility for preventive microbiome‐based therapies that could result in a clinical benefit for patients with and without AD.
Systemic exposures of gantenerumab: An integrated population pharmacokinetics (popPK) analysis across multiple clinical studies
Authors: Schwab Dietmar , Jolivet Sebastien , Gibiansky Leonid , Lott Dominik 
Published: December 2023

AbstractBackgroundCharacterization of gantenerumab systemic exposure is important to inform dose selection and understand the factors that influence pharmacokinetics (PK), such as participant‐ or study‐specific characteristics, and the safety and efficacy of gantenerumab treatment.MethodGantenerumab systemic PK following subcutaneous administration was investigated in multiple clinical studies, including single‐dose studies in healthy participants with dense PK sampling and multiple‐dose studies in participants living with AD (pwAD) with sparse PK sampling. An integrated population PK (popPK) analysis was conducted across six single‐dose studies in healthy participants and seven multiple‐dose studies in pwAD using nonlinear mixed‐effects modelling in NONMEM v7.2. The studies in pwAD included GRADUATE I and II (NCT03444870; NCT03443973), GRADUATION (NCT04592341), and the legacy studies SCarlet RoAD (NCT01224106) and Marguerite RoAD (NCT02051608) including their open‐label extensions. In total, 23,200 observations from 3,053 participants were available for analysis. Covariate assessments included demographic characteristics, laboratory values, disease status, concomitant medication, and study‐specific factors.ResultA robust popPK model was established incorporating data from multiple clinical studies with diverse titration and dosing regimens. Main factors identified as influencing exposure were body weight, serum albumin, drug substance generation, and Asian race. Moderate variability at steady‐state (AUCss) was observed, as determined by a coefficient of variation of 22.4% in clearance. Steady‐state exposure in the GRADUATE and GRADUATION studies was slightly higher than expected and within a comparable range versus the legacy studies (see figure). Dosing frequency had no impact on average plasma exposure and a minor impact on minimum and maximum plasma concentrations at steady‐state. The ratio of the plasma concentration–time profile for dosing every week and every 2 weeks was within a 0.8 to 1.25 margin. Low immunogenicity was observed, with 4.8% of the GRADUATE participants being ADA‐positive. The impact of ADAs on exposure was small.ConclusionSystemic exposure of gantenerumab was well characterized in a popPK analysis. Participants in the GRADUATE, GRADUATION and legacy studies had comparable exposures, with a minor impact of dosing frequency. The lower amyloid removal reported in the GRADUATE studies versus the legacy studies cannot be explained by differences in PK.
Associations of physical activity with cerebrospinal fluid biomarkers of neurodegeneration, neuroinflammation, and Alzheimer’s disease
Authors: Planalp Elizabeth M. , Van Hulle Carol A. , Bendlin Barbara B , Blennow Kaj , Carboni Margherita , Carlsson Cynthia M , Engelman Corinne D. , Kollmorgen Gwendlyn , Ma Yue , Okonkwo Ozioma , Johnson Sterling C , Zetterberg Henrik , Merten Natascha 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) and related dementias are public health concerns often with long preclinical phases. Thus, intervention and prevention methods in midlife could prove efficacious. Cerebrospinal fluid (CSF) biomarkers can change early in the disease process and have been utilized for dementia diagnostics. Multiple health‐related lifestyle factors have been associated with risk for AD, yet existing research on lifestyle factors has focused on clinical outcomes such as cognitive decline, mild cognitive impairment and/or AD dementia; their associations with early changes in CSF are less understood. Our aim was to determine whether physical activity (PA), a modifiable lifestyle factor, is associated with biomarkers for neurodegeneration, glial activation, and inflammation.MethodParticipants were N = 204 cognitively unimpaired adults (aged 45–80 years) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center, two on‐going, longitudinal studies of preclinical AD. PA was defined as the weekly metabolic equivalent (MET), calculated by scoring amount and intensity of mild, moderate, and vigorous exercises per week (range 0–79 METS). We assessed CSF biomarkers using robust exploratory prototype assays from the NeuroToolKit research platform (Roche Diagnostics International, Switzerland). Participants also completed demographic and health questionnaires (Table 1). We used linear regression models to assess associations between PA and CSF biomarkers, adjusting for age at biomarker assessment, sex, education, and chronic health conditions (diabetes, hypertension, cardiovascular disease).ResultPreliminary results showed that participants who engage in more PA had higher CSF S100B concentrations, a pro‐inflammatory calcium‐binding protein (standardized b change per MET = 0.0013, 95% confidence interval: 0.0003–0.0023; p = .01). No other PA‐biomarker associations were significant.ConclusionHigher PA was significantly associated with higher CSF concentration of S100B, a marker of (astro‐)glial activation. Future studies will need to examine whether PA is associated with higher S100B in individuals along the disease continuum of AD, and whether this is reflected in the blood. Longer follow‐ups may be needed to determine associations of PA with other biomarkers, where we had limited variation in this primarily healthy study cohort.
Atrophy of Brodmann Area 36 differentiates age‐related subjective memory decline from cognitively normal older adults and is associated with NPTX2
Authors: Corona‐Long Caitlin A , Chang Elizabeth , Speck Caroline L , Gallagher Michela , Bakker Arnold 
Published: December 2023

AbstractBackgroundAdvancing age is associated with changes in cognitive functions, particularly memory, although there are significant individual differences between subjects. While some older adults experience minimal cognitive decline, others exhibit more pronounced deterioration that can progress to Alzheimer’s disease dementia (AD). Some older individuals report subjective memory complaints (SMC) despite normal scores on objective memory assessments. Longitudinal studies suggest that SMC may be predictive of AD dementia and precedes the onset of mild cognitive impairment (MCI) by around 15 years. However, given large individual differences and biases towards reporting complaints, objective measures are needed to identify those individuals who are on a trajectory of decline relevant to AD.MethodIn the current study cognitively normal older adults, older adults with SMC, and patients with MCI were recruited from the ADRC and the community to complete neuropsychological assessment, an MRI scan and a lumbar puncture to assess what measures are associated with self‐reported SMC. Structural MRI scans were analyzed using the Automated Segmentation of Hippocampal Subfields (ASHS) pipeline. Cerebrospinal fluid (CSF) was analyzed using standard methods to obtain fluid biomarkers associated with AD.ResultConsistent with previous reports, entorhinal cortex volume significantly differed between cognitively normal older adults and patients with MCI. However, entorhinal cortex volume did not differentiate between controls and SMC subjects. Instead, volume of Brodmann area (BA) 36 was significantly different between control participants and SMC subjects as well as between controls and patients with MCI. Furthermore, volume of the right BA35 and BA36 was moderately correlated with neuronal pentraxin‐2 (NPTX2), a marker of synaptic integrity that is reduced in AD. Volume of the right BA36 was additionally correlated with measures of cognition including the Mini‐Mental Status Exam and objective measures of memory function.ConclusionTogether these findings show that particularly atrophy of BA36 may provide an objective measure differentiating between cognitively normal older adults and those with SMC, and in identifying the early stages of AD prior to a diagnosis of aMCI.
Cross‐sectional associations between amyloid and tau PET and cognitive performance in Black adults without dementia: Preliminary results from the African Americans Fighting Alzheimer’s in Mid‐life study
Authors: Ennis Gilda E. , Langhough Rebecca E , Cody Karly Alex , Zuelsdorff Megan , Bouges Shenikqua , Carter Fabu P. , James Taryn T. , Salazar Hector , Betthauser Tobey J , Asthana Sanjay , Johnson Sterling C , Bendlin Barbara B , Gleason Carey E. 
Published: December 2023

AbstractBackgroundFew studies have examined amyloid and tau and cognitive performance in samples solely comprised of African American (AA) adults. The African Americans Fighting Alzheimer’s in Mid‐life (AA‐FAIM) study (n = 293 active AA participants) is currently collecting amyloid and tau positron emission tomography (PET) scans. Preliminary cross‐sectional associations between amyloid and tau PET and cognitive performance are presented here.MethodN = 55 adults without dementia had amyloid and/or tau PET (n = 48 had amyloid PET; n = 47 had tau PET; n = 40 had both scans). 11C‐Pittsburgh Compound B (PiB) PET quantified cortical β‐amyloid. 18F‐MK‐6240 PET measured tau in entorhinal cortex (EC), medial temporal lobe (MTL), and temporal lobe meta‐ROI. Amyloid and tau PET positivity cut‐points were derived from prior research. Cognitive assessment included immediate and delayed recall (RAVLT) and Trails B. Linear regression tested associations between amyloid and tau PET and cognition.ResultsIn those with both amyloid and tau PET, seven (17.5%) were amyloid and EC tau PET positive (Table 1). Increased amyloid PET DVR and amyloid PET positivity were significantly related to increased tau PET SUVR in models unadjusted and adjusted for age and sex (Figure 1). In the combined sample (n = 40), neither amyloid nor tau PET was significantly related to cognition in models adjusted for age, education, and prior‐test‐exposure (or remote testing when recall was analyzed) (p‐values>.06). In the tau PET sample (n = 47), increased tau in EC and MTL was significantly related to worse immediate recall in adjusted models; in contrast, amyloid was not significantly related to cognition (Table 2) in the amyloid PET sample (n = 48). Associations between PET and cognition were similar following removal of n = 4 MCI participants.ConclusionsPreliminary results in this small sample suggest that elevated brain tau is related to verbal‐learning and recall in a sample of AAs without dementia; results related to amyloid did not reach statistical significance. A larger sample size is needed to increase the statistical power to detect associations and improve the precision and comparability of tau and amyloid parameter estimates. Recruitment of more participants for longitudinal PET and cognitive testing is planned to refine characterization of AD‐related change in the AA‐FAIM cohort.
The effects of type 2 diabetes on prefrontal cortex‐dependent cognitive function in older African American APOE‐ε4 carriers
Authors: Napoleon Darian A. , Gills Joshua L. , Osiecka Zuzanna , Malin Steven K. , Fausto Bernadette A. , Gluck Mark A. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a leading cause of death in the United States and disproportionately impacts African Americans. AD has recently been characterized as “type 3 diabetes” due to evidence that hyperglycemia impairs cognitive function. Individuals with the Apolipoprotein ε4 (APOE ε4) allele may also have triple the risk of Alzheimer’s disease. However, few data exist examining the effects of hyperglycemia on working memory and the moderating effects of AD genetic risk. Therefore, this study examined the effect of untreated diabetes (non‐medicated) on prefrontal cortex‐dependent cognitive performance in older African Americans.MethodNinety older cognitively healthy African Americans (60‐91y, 78% female) were recruited for this cross‐sectional study. HbA1c was used to define untreated type 2 diabetes (>6.5%; no glucose‐lowering medications), prediabetes (5.7%‐6.4%), and normoglycemia (<5.7%). Saliva samples were also collected for APOE genotyping, and all participants underwent a cognitive assessment consisting of the Digit Span test (a measure of working memory). Body mass index (BMI) and estimated aerobic fitness (VO2 max) were also determined. Participants were classified as non‐diabetic (ND) or diabetic (D). ANCOVA was used to examine group differences (with and without stratification by APOE status) in Digit Span performance with age, sex, education, depressive symptomology, BMI, and estimated VO2 max as covariates.ResultThere was no difference across groups in age (ND: 71.4±6.8 vs. D: 70.1±4.7), BMI (ND: 31.0±8.7 vs. D: 32.4±7.4), VO2 max (ND: 12.9±2.0 vs. D: 12.6±1.8), or education status (ND: 13.9±2.2 vs. D: 13.0±2.5) across groups (p > 0.05). People with diabetes demonstrated worse pre‐frontal cortex‐dependent performance (D: 18.7±1.6 vs. ND: 22.4±0.61, p = 0.039) than those without diabetes. Moreover, individuals with diabetes and the APOE ε4 genotype performed significantly worse on the Digit Span assessment than those with diabetes and without the risk allele (16.50±0.71 vs. 21.4±6.7, p = 0.044).ConclusionThese results suggest that untreated people with type 2 diabetes are characterized by reduced working memory which is exacerbated by AD genetic risk. This result is independent of aerobic fitness and BMI, suggesting that interventions focused on pathologies related to hyperglycemia may be needed to improve cognition in older African American adults.
Examining the Effects of Hospitalization in ADNI Subjects: Characterizing Changes in Cognition and Glucose Metabolism Associated with Inpatient Hospital Stays
Authors: Struble Helen , Liu Stephen S. , Silverman Daniel H. 
Published: December 2023

AbstractBackgroundRisk of inpatient hospitalization and dementia both increase with age, though no study has attempted to characterize lasting changes in regional brain metabolism occurring after inpatient hospitalization.MethodWe screened adverse events reported to the Alzheimer’s Disease Neuroimaging Initiative (ADNI), identifying subjects with minimum one‐night hospitalizations and two pre‐ and two post‐hospitalization ADNI visits. 523 visits from 133 subjects were included in neuropsychological analysis, with 55 subjects hospitalized for major surgery. An analogous “event date” was set in demographically matched control subjects using the median elapsed time from first visit to hospitalization; 352 visits from 88 controls were included. Memory and executive function composite scores were used to calculate pre‐ and post‐event cognitive trajectories. Pre‐ and post‐event FDG‐PET images were acquired and quantitatively examined using standardized volume of interest (sVOI) analysis. Students t‐tests were used to determine the difference in pre‐ and post‐event trajectories within groups and between groups.ResultWithin‐group analysis of inpatient subjects revealed significantly declined trajectory of memory and executive function after hospitalization (p<0.001, p = 0.02), though the difference in pre‐ and post‐event trajectory did not differ significantly from the control group. There was no significant difference in change in trajectory between subjects with surgical and non‐surgical hospitalizations. To prevent the dilution of metabolic alterations that may begin on one‐side, the sVOI with the greatest decline between post‐ and pre‐event trajectory was chosen for all bilateral volumes. Within the inpatient group, significant decline in metabolic trajectory after hospitalization was observed in the inferior lateral anterior and medial anterior temporal volumes (p<0.005, p<0.0005). This change in metabolic trajectory in the anterior temporal volumes after hospitalization was not significantly different between surgical and non‐surgical subjects. Finally, the decline in trajectory observed in the inferior lateral and medial anterior temporal volumes in the inpatient group was significantly greater than the control group (p = 0.05, p = 0.005), in which no significant decline in trajectory was observed.ConclusionInpatient hospitalization is associated with accelerated decline in metabolic trajectory after discharge in two anterior temporal volumes, regardless of whether the hospitalization was associated with a major surgery.
Overcoming Recruitment Challenges and Increasing Representation and Diversity of Participation in Early MCI Clinical Trials: The MIND Study Experience
Authors: Lewandowski Agnes , Newhouse Paul A , Aisen Paul S. S , Ismail Andalib , Andrews Patricia , Brody Mark , Goldstein Mark , Li Clara , Mintzer Jacobo E , Scharre Douglas W. , Szigeti Kinga , Turner R. Scott , Raman Rema 
Published: December 2023

AbstractBackgroundThe MIND (Memory Improvement with Nicotine Dosing) study is an ongoing trial to determine whether long‐term transdermal nicotine treatment results in sustained cognitive improvement and attenuation of cognitive decline in patients with MCI. To improve the demographic representation of screened and randomized study participants, the MIND Study Underrepresented Group (URG) Recruitment and Retention (R&R) Initiative was established.MethodThe goal was to increase the screenings and randomizations of participants who self‐report as belonging to an underrepresented race or ethnic group or report a low educational attainment level (high school completion or less). Key elements of the initiative comprised of: (a) financial support of site infrastructure, (b) centralized support with culturally relevant recruitment materials, (c) monthly meetings to secure best practices, and (d) dissemination of successful strategies. Measurement of success included overall screening and randomization rates, as well as qualitative and quantitative metrics reported by initiative sites.ResultNine sites (25% of active study sites) participated in this initiative from March 2022‐February 2023. The first three months required development of site‐specific recruitment plans, goal setting, and needs assessments. During this year, we observed an increase in URG screenings (21.3%) and randomizations (33.3%) (Table 1). Similar increases were observed in race and ethnicity (25.4% and 44% respectively) as well as low educational attainment (21.2% and 31.6% respectively) groups. This initiative improved the overall URG monthly screening from 2.23/month prior to the initiative to 2.42/month during the initiative and the monthly randomization rate from 0.93/month to 1.58/month. Site‐reported data on the pre‐screening activity indicated that the main reasons for pre‐screen fails were participants either not belonging to an URG (56%) or not meeting MCI criteria (20%). Concerns around study burden, study partner availability and nicotine were reported in less than 10% of the pre‐screened individuals.ConclusionThis initiative successfully increased the representation of screened and randomized MIND Study participants with respect to self‐reported race, ethnicity, and educational level. Initial success suggests that a multifaceted approach coordinated through close collaborations between sites and the central coordinating center are necessary to screen and randomize representative populations in early MCI trials.
Reliability of VPA Learning Over Repeat Exposures Across an Extended Interval Using Automated Remote Method
Authors: Kaula Alexander J , Taptiklis Nick , Cormack Francesca K 
Published: December 2023

AbstractBackgroundThe current study examined the test‐retest reliability of a newly developed Learning Over Repeat Exposures (LORE) paradigm using Verbal Paired‐Associates. This LORE paradigm involves the acquisition of a set of 8 verbal paired associates over a 5‐day “burst”. In this investigation, two bursts, separated by a nine‐month interval, were compared to assess the stability of novel learning outcome measures, such as the learning slope (between day 1 and the day of max performance) and first overnight forgetting.MethodAn opportunistically recruited sample of 14 participants (out of an initial pilot study of N = 20) completed the VPA‐LORE task using the Cambridge Cognition ‘NeuroVocalix’ platform, which employs text‐to‐speech and automated speech recognition technology to remotely administer and score the task, enabling its potential use at scale. The task structure consists of an immediate recall following presentation on the first day of a burst, and a single recall attempt followed by a presentation on subsequent days. As with the pilot study, neither floor nor ceiling effects were observed, and performance was in the expected range.ResultThe observed moderate to strong correlations between the two bursts revealed good reliability for the measures examined: learning slope from day 1 to day of max score, r
s = .815, first day immediate recall, r
s = .736, max pairs learned, r
s = .707, and day 1 forgetting r
s = .702. In total, participants missed only a few visits, with six missing sessions out of a total of 140 sessions, representing 4.3% of all sessions. The retention of 14 participants from the original pilot study also highlights the feasibility and acceptability of this method.ConclusionThese results suggest that the VPA‐LORE paradigm, delivered via the NeuroVocalix platform, is a stable and reliable assessment tool even when considering extended intervals between bursts and accounting for missing data. The novel learning measures derived from the VPA‐LORE paradigm provide valuable insights into learning processes and could further enhance cognitive assessment. Future research could explore the applicability of the paradigm for clinical populations and longitudinal studies in cognitive assessment.