bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brain Glucose Metabolism Changes in Long‐COVID: A Brazilian Cohort Study
Authors: Silveira Maiele Dornelles , Machado Luiza Santos , Ferrari‐Souza João Pedro , de Bastiani Marco Antônio , Povala Guilherme , Borelli Wyllians Vendramini , Senger Joana Emilia , da Silva Ana Paula Bornes , de Mello Guilherme Bastos , da Ros João Pedro Uglione , Jotz Arthur Viana , Kadan Matheus Fakhri , Pascoal Tharick A. , Rosa‐Neto Pedro , Schumacher‐Schuh Artur Francisco , Matushita Cristina Sebastião , Radaelli Graciane , Lourenco Mychael V , Soder Ricardo Benardi , Coutinho Artur Martins , de Paula Faria Daniele de Paula , da Costa Jaderson Costa , Souza Diogo O. , de Souza Débora Guerini , Zimmer Eduardo Rigon 
Published: January 2025

AbstractBackgroundThe COVID‐19 pandemic is a public health crisis, and its lasting consequences are not yet fully understood. Epidemiological data suggest that low‐ and middle‐income countries, such as Brazil, will bear a considerable burden of COVID‐19‐related comorbidities. Individuals who have survived COVID‐19 often report persistent symptoms, including neurological manifestations such as brain fog. However, the underlying brain biological changes behind the neurological symptoms remain undefined. Here, our goal was to assess the influence of long‐COVID on brain metabolism in adults from a Brazilian cohort.MethodBrazilian individuals (n=49) were recruited, examined through clinical and neuropsychological assessments, and divided into Control and Long‐COVID groups. Then, they underwent a brain [18F]FDG‐PET scan. Images were normalized by the global mean. Differences between groups were assessed through a [18F]FDG‐PET voxel‐wise linear regression accounting for age, sex and years of education (Table 1). The analysis was corrected for multiple comparisons using the cluster‐wise random field theory method (significant t < ‐3.28 and t > 3.28).ResultLong‐COVID group exhibited recurring symptoms such as fatigue, memory complaints and lack of concentration (Table 1). They also exhibited hypometabolic clusters in the left superior parietal lobe (tmax=‐4.03; p < 0.001) and right insular cortex (tmax=‐3.31; p < 0.001) (Figure 1). Hypermetabolic clusters were found in the left whole cerebellum (tmax=4.92; p < 0.0001), right dorsolateral prefrontal cortex (tmax=3.83; p < 0.001), and right postcentral gyrus (tmax=4.24; p < 0.001) (Figure 2).ConclusionOur preliminary results demonstrate region‐dependent dual response on brain metabolism due to Long‐Covid. More specifically, glucose hypometabolism was found in regions associated with cognitive domains and affective modulation. By contrast, glucose hypermetabolism was observed in brain areas associated with motor coordination and sensory processing. Metabolic changes in these regions should be further evaluated to advance in the understanding of the pathophysiological mechanisms associated with persistent neurological manifestations seen in individuals presenting with Long COVID.
Residential Neighborhood Disadvantage and Amyloid Positivity: Findings from IDEAS
Authors: Windon Charles , Tsoy Elena , Livaudais‐Toman Jennifer , Hanna Lucy , Gatsonis Constantine , Carrillo Maria C. , Apgar Charles , Dilworth‐Anderson Peggye , Karliner Leah , Hillner Bruce E , Neilands Torsten B , Palmer Nynikka , Possin Katherine L , Stewart Anita L. , Whitmer Rachel A. , Wilkins Consuelo H. , Rabinovici Gil D. 
Published: January 2025

AbstractBackgroundResidence in a disadvantaged neighborhood (e.g., high poverty rate, poor housing, etc.) is associated with greater dementia risk and possibly greater postmortem Alzheimer’s pathology. It remains unknown if neighborhood disadvantage is associated with in vivo beta‐amyloid positron emission tomography (PET) for Alzheimer’s. We examined this using data from the Imaging Dementia Evidence for Amyloid Scanning (IDEAS) study.MethodsIDEAS captured >18,000 PET scans among cognitively impaired Medicare beneficiaries from 595 US dementia clinics between 2016‐2018. We defined neighborhood disadvantage using Area Deprivation Index (ADI), a validated composite of 17 social determinants measures captured in American Community Survey and US Census data. IDEAS participant zip code data was linked to census block group for ADI value calculation through geocoding.Association between visual interpretation of PET in IDEAS (positive/negative) and state‐level ADI (1‐10; 10 being greatest disadvantage) was examined via logistic regression controlling for covariates (age, sex, education, level of impairment (MCI vs dementia), race/ethnicity, comorbid conditions) with cluster adjusted standard errors by practice location.ResultsAmong 13,961 cognitively impaired participants, 61.6% were amyloid positive, 56.5% had MCI, and 50.4% were female (Table 1). The majority (90.2%) were non‐Latino White with 4.7% Latino, 3.2% Black, and 1.9% Asian representation (Table 1). Participants were highly educated (68.1% beyond high school) and 31.0% (4,333/13,961) resided in neighborhoods of greater disadvantage (ADI ≥ 6) (Figure 1).Greater ADI was associated with lower odds of amyloid positivity (aOR 0.61, 95% CI 0.51‐0.73, p<.001 for ADI 10 vs ADI 2 and aOR 0.87, 0.76‐1.00, p .051 for ADI 2 vs. ADI 1(ref)). Latino (aOR 0.62, 0.48‐0.80, p<.001), Black (aOR 0.58, 0.48‐0.72, p<.001), and Asian (aOR 0.42, 0.31‐0.58, p<.001) identity was associated with lower odds of amyloid positivity along with multiple comorbidities (Table 2).ConclusionWe observed a relationship between residence in a more disadvantaged neighborhood (higher ADI) and lower rates of amyloid positivity. Given this finding and known association between neighborhood disadvantage and postmortem AD pathology, it is possible non‐amyloid pathology also contributes towards cognitive impairment among individuals from disadvantaged neighborhoods and among diverse groups. This has implications for clinical use of novel amyloid lowering therapies.
Longitudinal plasma and CSF analyses in Down syndrome. Results from the DABNI cohort
Authors: Alcolea Daniel , Montoliu‐Gaya Laia , Carmona‐Iragui Maria , Barroeta Isabel , Videla Laura , Benejam Bessy , Arranz Javier , Lleo Alberto , Blennow Kaj , Ashton Nicholas J. , Zetterberg Henrik , Fortea Juan 
Published: January 2025

AbstractBackgroundAlzheimer´s disease (AD) is the main cause of death in adults with Down syndrome (DS). We describe the unique contributions of the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI) cohort by studying longitudinal changes in plasma and cerebrospinal fluid (CSF) markers.MethodWe included DABNI participants with DS that contributed at least two plasma and/or CSF samples and were asymptomatic (aDS, n=155), had prodromal AD (pDS, n=46) or had AD dementia (dDS; n=53) at baseline, together with 172 euploid cognitively normal controls (CN). All participants underwent longitudinal assessments, including repeated cognitive and neuropsychological assessments, plasma and CSF analyses. We applied linear‐mixed models to study changes over time in measures of GFAP, NfL and pTau217 in plasma and in AB42/AB40, NfL and pTau217 in CSF and their association with the symptomatic stages of AD.ResultPlasma GFAP and NfL showed higher increases in dDS compared to pDS, and in pDS and dDS compared to aDS and CN (Figure 1A and 1B). Plasma pTau217 showed higher increases in pDS and dDS compared to aDS and CN, but there were no differences between pDS and dDS (Figure 1C). In CSF, no significant longitudinal changes were detected in AB42/AB40 (Figure 1D), whereas both NfL and pTau217 showed higher slopes in advanced symptomatic stages (Figure 1E and 1F).ConclusionOur results indicate that longitudinal changes in plasma markers are associated to different stages in the continuum of AD in DS. These changes could be useful to track the progression of the disease.
Selection of Biomarkers and Clinical Endpoints for Clinical Trials Targeting Down syndrome‐related Alzheimer’s disease (DSAD)
Authors: Rafii Michael 
Published: January 2025

AbstractBackgroundMajor advances have been made over the past decade in understanding Down syndrome‐related AD by utilizing the latest AD biomarkers such as brain imaging and biofluid assays. Cognitive measures that can discern decline related to AD have been developed and validated in people with DS. We are now able to incorporate these data to help design clinical trials against AD in people with DS.MethodThe NIH‐funded Alzheimer’s Clinical Trial Consortium ‐ Down Syndrome (ACTC‐DS) was launched in 2018 to serve as a platform for conducting clinical trials to treat and prevent AD dementia in people with DS. We have enrolled over 200 adults with DS who will be offered the opportunity to enroll in interventional clinical trials for AD specifically designed for people with DS.ResultWe have launched a phase 1b/2, multicenter, double‐blind, randomized, placebo‐controlled study to assess the safety, tolerability, immunogenicity, and pharmacodynamic effects of ACI‐24.060 in in adults with Down syndrome and plan to launch two additional trials this year.ConclusionData from longitudinal biomarker studies are informing the design and conduct of clinical trials targeting AD in people with DS.
Does socioeconomic status modify the association between glycemic level and MRI markers of ADRD risk in middle‐aged adults?
Authors: Kraal A. Zarina , McFarlane Hugh V. , Pyne Jeffrey D. , Turney Indira C. , Lao Patrick J. , Mazen Jessica , Brickman Adam M. , Manly Jennifer J. 
Published: January 2025

AbstractBackgroundHigh glycemic levels, indexed by hemoglobin A1c (HbA1c), heighten risk for Alzheimer’s Disease and Related Dementias (ADRD). Previous studies suggest that high HbA1c and low socioeconomic status (SES) may be associated with MRI markers of ADRD risk, including lower cortical thickness and greater white matter hyperintensities (WMH). The weathering hypothesis suggests that the stress of low SES accelerates and exacerbates physiological deterioration, leading to worsening health outcomes. However, the role of SES as a potential moderator of the associations between HbA1c and MRI markers of ADRD is underdeveloped. We hypothesized that higher HbA1c and lower SES are associated with MRI markers of ADRD risk, and the association between HbA1c and MRI markers is stronger among individuals with low SES.MethodParticipants were middle‐aged adults in the Offspring Study of Racial and Ethnic Disparities in Alzheimer’s Disease (N=616; age=54.5±10.6; 68.6% Latinx, 21.2% Non‐Latinx Black, 7.2% Non‐Latinx White; 65.6% women). HbA1c level was determined from blood assays. MRI markers included cortical thickness of AD signature regions and log‐transformed WMH. Confirmatory factor analysis estimated SES from self‐reported income and education. Structural equation models quantified main and interaction effects of HbA1c and SES on MRI markers, adjusting for age, sex, and prediabetes/type 2 diabetes.ResultThere were no main or interaction effects of HbA1c and SES on either MRI marker, independent of covariates. However, examination of moderation by each SES indicator showed that higher HbA1c was associated with lower cortical thickness among participants with high income (unstandardized estimate= ‐0.0214, SE=0.0107, 95%CI[‐0.0424, ‐0.0003]). Effect estimates were similar in analyses restricted to individuals with prediabetes and type 2 diabetes (n=250; age=58.1±9.0; 72.8% Latinx, 23.6% Non‐Latinx Black, 3.7% Non‐Latinx White; 68.8% women).ConclusionHbA1c‐related effects on markers of ADRD risk in middle‐age may occur via neurodegenerative processes. Associations involving cerebrovascular pathways warrant further investigation. Examination of other indicators of SES (e.g., occupation, wealth, debts) and region‐specific WMH may help clarify the role of SES in modifying the link between glycemic level and brain health.
In‐Vivo Characterization of Blood‐Brain Barrier Permeability in Cognitively Normal APOE e4 Carriers and Non‐Carriers
Authors: Solders Seraphina K. , Shen Qian , Rivera Charlotte S. , Banks Sarah , Reas Emilie T. 
Published: January 2025

AbstractBackgroundAn intact blood‐brain barrier (BBB) is critical for optimal brain health, and even transient or highly localized disruption of the BBB can have devastating consequences for neural functioning. BBB breakdown has been implicated in Alzheimer’s Disease (AD) pathogenesis, and elevated BBB permeability has been observed in APOE e4 carriers compared to non‐carriers. As prior studies have focused on a priori, AD‐vulnerable regions rather than whole‐brain analyses, little is understood about broader patterns of BBB breakdown that may relate to AD risk. This study aims to identify preclinical cerebrovascular differences in cognitively normal individuals who are genetically at high‐risk for AD.MethodDynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) was performed on 34 cognitively normal older adults (average age = 76.6 years; 18 women) from the UC San Diego Alzheimer’s Disease Research Center, evenly split by APOE e4 status. Data were processed using ROCKETSHIP and average BBB permeability values were extracted from the Desikan‐Killiany atlas cortical gray matter regions. Permeability values were averaged across hemispheres, resulting in 34 measurements. ANCOVAs predicted BBB permeability within each region from e4 status, age, sex, and the interaction between sex and e4 status.ResultAPOE e4 carriers showed elevated BBB permeability throughout the superolateral frontal and parietal cortices and some occipital cortex compared to non‐carriers. The strongest effects were found in the caudal‐middle and superior frontal, pre‐ and paracentral, and superior parietal gyri. Further, there was a pattern of sex by e4 carrier status interaction whereby the e4 effect was stronger in men than women.ConclusionOlder adults who carry at least one APOE e4 allele show increased BBB permeability compared to e4 non‐carriers primarily in superior frontal and parietal regions, a spatial pattern that is notably distinct from the typical topography of AD pathology. This effect may be moderated by sex, such that men may be more vulnerable to the detrimental effects of APOE e4 on certain regions of the BBB compared to women. These findings raise implications for important questions regarding APOE4 dose effects, the mechanisms by which APOE regulates BBB functioning, and the evolution of BBB permeability through the disease course.
Effects of APOE genotype on cortical atrophy in early onset Alzheimer’s disease
Authors: Chan Diane , Brickhouse Michael , Zaitsev Alexander , Wong Bonnie , Hammers Dustin B. , Dage Jeffrey L. , Foroud Tatiana M. , Eloyan Ani , Nudelman Kelly N. , Nemes Sára , Carrillo Maria C. , Rabinovici Gil D. , Apostolova Liana G. , Dickerson Bradford C. , Touroutoglou Alexandra ,   the LEADS Consortium
Published: January 2025

AbstractBackgroundAPOE‐ɛ4 is a major risk factor for Alzheimer’s disease (AD); its effects have been examined in late‐onset AD (LOAD) but less so in early‐onset AD (EOAD). In LOAD, APOE genotype has strong effects on episodic memory and medial temporal lobe (MTL) atrophy (Wolk & Dickerson, 2010). However, EOAD often presents with more cognitive impairments in executive function, language, and visuospatial abilities than memory. These differences reflect more prominent atrophy in posterior lateral temporal and inferior parietal cortex that mainly constitute the EOAD‐signature of atrophy. Based on the cognitive and neuroanatomical profile of EOAD, we hypothesized that EOAD ɛ4 carriers will have relatively more atrophy in MTL regions subserving episodic memory, whereas non carriers would express more atrophy in cortical regions of the EOAD‐signature involved in executive function, language, and visuospatial abilities including inferior parietal and posterior temporal regions. We also expected worse performance on episodic memory tests in ɛ4 carriers with EOAD.MethodsWe examined the effects of APOE genotype on cortical atrophy and episodic memory of 144 ɛ4 carriers and 117 ɛ4 non‐carriers with EOAD from the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS). Between‐group comparisons using independent T‐tests were made for morphometric measures of cortical atrophy in MTL and hippocampus localized in LOAD as well as in cortical regions within our newly developed EOAD‐Signature tool (Touroutoglou et al., 2023). ANCOVA with Bonferonni’s correction was used to evaluate for effects of age on significant differences between groups.ResultsAs predicted, ɛ4 carriers with EOAD had more atrophy in the MTL and bilateral hippocampi, whereas non‐carriers had more atrophy in regions of the EOAD‐signature including bilateral caudal temporal, parietal lobule, middle frontal gyrus, mid temporal, posterior cingulate cortex, precuneus, superior frontal gyrus, superior parietal lobule. Post hoc vertex wise cortical maps further confirmed the specificity of the results. In addition, ɛ4 carriers had worse performance on episodic memory testing (AVLT delayed recall). These results were not explained by a difference in age between the groups.ConclusionsThese results are consistent with prior work (Nemes et al. 2023) and support the hypothesis that the ɛ4 genotype modulates distinct neuroanatomic phenotypes of AD in EOAD patients.
Vulnerability of locus coeruleus projections during aging
Authors: Zufiria‐Gerboles Blanca , Veréb Daniel , Pereira Joana B 
Published: January 2025

AbstractBackgroundThe locus coeruleus (LC) is an important noradrenergic nucleus that supplies noradrenaline to the brain through extensive cortical and subcortical projections. Recent studies established that the LC is vulnerable to aging and common neurodegenerative disorders, including Alzheimer’s disease. However it is currently unclear how these projections differ between age groups and how they are affected by common age‐related comorbidities.MethodHere, we employ probabilistic tractography to characterize structural connectivity of the LC over aging using 3T diffusion‐weighted MRI in a population‐based cohort aged from 18 to 88 years of age (n=618). We assessed the relationship between age and connectivity, as well as common age‐related comorbidities, such as subjective memory problems, hypertension, diabetes, depression and sleep disturbances. Age‐related differences were assessed using Spearman’s rank correlation, whereas comorbidity‐related changes were investigated using partial least square analyses, corrected for age, sex and education.ResultThe tractogram of the LC contained connections consistent with previous tractography and tracer studies. LC connectivity exhibited a marked decrease to a variety of brain areas including frontal and temporal regions, as well as the bilateral thalami and the left caudate (Spearman’s R < ‐0.2, pFDR<0.001). Participants with subjective memory problems exhibited increased LC connectivity to the ventral anterior cingulate cortex (p=0.0032). Participants with hypertension and diabetes exhibited decreased LC connectivity to the left middle frontal gyrus, the right amygdala and bilateral thalami (0.0001<p<0.014). Higher depression was associated with lower LC connectivity to the middle frontal, superior and inferior temporal gyri, whereas sleep problems were related to reduced temporal LC connectivity (p<0.05).ConclusionThese results provide an in vivo account of how the structural connectivity of the LC changes through aging and imply that LC connections are further affected by common age‐related disorders.
Is there Evidence for a Continued Benefit for Long‐Term Lecanemab Treatment? A Benefit/Risk Update from Long‐Term Efficacy, Safety and Biomarker Data
Authors: van Dyck Christopher H. , Sperling Reisa A , Dhadda Shobha , Li David , Hersch Steven , Irizarry Michael C. , Kramer Lynn D 
Published: January 2025

AbstractLecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to amyloid‐beta (Aβ) protofibrils, was formally evaluated as a treatment for early Alzheimer’s disease in a phase 2 study (Study 201) and the phase 3 Clarity AD study. These trials both included an 18‐month, randomized study (core) and an open‐label extension (OLE) phase where eligible participants received open‐label lecanemab for up to 30 months to date. Clinical (CDR‐SB, ADAS‐Cog14, and ADCS‐MCI‐ADL), biomarker (PET, Aβ42/40 ratio, and ptau181) and safety outcomes were evaluated. Results demonstrated that lecanemab substantially reduced markers of amyloid and significantly slowed clinical decline on multiple measures of cognition, function, and quality of life in early AD at 18 months and continued for 30 months to date. Lecanemab was associated with amyloid‐related imaging abnormalities (ARIA) and infusion reactions, tending to occur early in treatment. Although lecanemab has established a clear benefit/risk benefit for 18 months of treatment, the evidence for continued treatment beyond 18 months has yet to be firmly established. In an effort to evaluate the current evidence base for longer‐term dosing, this presentation will summarize the latest clinical and biomarker results from the lecanemab Clarity AD study, including the latest efficacy and safety data out to at least 30 months. We will share details on how lecanemab has demonstrated the ability to slow tau spread in different brain regions of individuals with early Alzheimer’s disease and discuss the relevance of these data on continued treatment. Evaluations of clinical and biomarker outcomes by participants considered as having a ‘delayed start’ (core:placebo followed by OLE:lecanemab) versus those with an ‘early start’ (core:lecanemab followed by OLE:lecanemab) cohorts will be presented and discussed. Finally, the overall case for the need and benefit of early initiation and continued dosing, considering mechanistic, pharmacology, biomarker and clinical results, will be discussed.