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

AbstractBackgroundLong COVID is an under‐characterized disorder that affects a wide range of individuals after COVID‐19 resolution. Long COVID individuals report persistent neurological manifestations, such as anxiety. Understanding its effects in the brain might help uncover the actual burden imposed by the pandemic sequelae and either define or discard long COVID as a risk factor for neurodegenerative diseases. Here, we aim to identify whether there is an association between brain metabolism and anxiety in an underrepresented population.MethodCommunity‐dwelling individuals, above 50 years old, from Porto Alegre, Brazil, were divided into long COVID (n=39) and control groups (n=10) were evaluated with a battery of neuropsychological testing, including the GAD‐7 scale of anxiety. Then, they underwent a brain [18F]FDG‐PET scan (images normalized by the pons). We conducted a voxel‐wise linear regression testing the association between [18F]FDG metabolism and GAD‐7, and corrected for education, sex, and age. The analysis was corrected for multiple comparisons using the cluster‐wise random field theory method (significant t<‐3.34 and t>3.34, p<0.001, df=35).ResultWe found that GAD‐7 score presented a widespread negative association with [18F]FDG metabolism in multiple gray and white matter regions (Figure 1). Specifically, hippocampus (tmax =‐3.34, p=0.002), amygdala (tmax=‐3.82, p=0.0005), cerebellum (tmax=‐4.28, p=0.0001), and lateral occipitotemporal gyrus (tmax=‐5.26, p=0.0001) had the most relevant associated clusters in gray matter, while temporal lobe (tmax=‐3.9, p=0.0004) and frontal lobe (tmax=‐4.33, p=0.0001) presented the most relevant associated clusters in white matter.ConclusionAnxiety symptoms are a highly self‐reported symptom in long COVID. Here we show that anxiety is widely associated with reduced brain glucose metabolism in crucial areas for the limbic system and cognition, such as the hippocampus and amygdala. The peculiar associations between anxiety and FDG metabolism in white matter may suggest inflammatory responses triggered by long COVID. These data provide new insights into the mechanisms underlying long COVID symptoms in the brain.
Exploring the utility of Plasma GFAP as a secondary endpoint in Alzheimer's disease Clinical trials to monitor disease progression
Authors: Abbas Sarah , Ferreira Pamela C.L. , Bellaver Bruna , Povala Guilherme , Rohden Francieli , Aguzzoli Cristiano Schaffer , Zalzale Hussein , Bauer‐Negrini Guilherme , Soares Carolina , Ferrari‐Souza João Pedro , Leffa Douglas Teixeira , Lussier Firoza Z , Madeiros Marina Scop , Rodrigues Matheus Scarpatto , Oliveira Markley , Felix Cynthia , Tissot Cécile , Therriault Joseph , Benedet Andrea L. , Ashton Nicholas J. , Cohen Ann D , Lopez Oscar L. , Tudorascu Dana , Villemagne Victor L , Saeed Anum , Karim Helmet T. , Hong Chang Hyung , Roh Hyun Woong , Karikari Thomas K , Zetterberg Henrik , Blennow Kaj , Zimmer Eduardo R. , Rosa‐Neto Pedro , Son Sang Joon , Pascoal Tharick Ali 
Published: January 2025

AbstractBackgroundRecent anti‐amyloid clinical trials have incorporated plasma glial fibrillary acidic protein (GFAP) as an exploratory endpoint, reporting a notable decrease in plasma GFAP levels over time. Additionally, plasma GFAP has been associated with Aβ pathology and cognitive decline in individuals with cognitive impairment, making it a robust biomarker of neuroinflammation for Alzheimer’s disease (AD). Here, we tested the utility of changes in plasma GFAP as a secondary endpoint in AD clinical trials focusing on cognitively impaired (CI) individuals.MethodWe evaluated CI Aβ+ individuals from two distinct cohorts: TRIAD (n=29, mean age (SD) = 71.5 (6.48), %MCI=44.8 and BICWALZS (n=65, mean age (SD) = 71.5 (6.48), %MCI=66.1]. All individuals had Aβ PET measurements at baseline. Paired t‐tests compared plasma GFAP levels between baseline and follow‐up. Cox proportional‐hazards analysis was performed to assess whether changes in plasma GFAP levels were predictive of increased odds for increasing CDR sum of boxes score over time. Sample size estimation was based on a hypothesized 25% drug effect on plasma GFAP reduction.ResultWe found a significant increase in plasma GFAP levels compared to baseline in both cohorts (Figures 1A and 1B). The percentage change in the research‐based cohort was slightly higher, likely attributed to a higher proportion of AD individuals compared to the memory clinic cohort (Figure 1C). Longitudinal plasma GFAP was associated with an increased risk of worsening cognition over time (Figures 2A and 2B). The effect size was slightly higher in the memory clinic cohort likely due to a relatively smaller standard deviation (Figure 3A). Inclusion of CI Aβ + individuals in a clinical trial testing a hypothesized 25% drug effect would necessitate 1354 participants in the research‐based cohort and 977 participants in the memory clinic cohort per study arm (Figure 3B).ConclusionChanges in GFAP are associated with worsening cognition over time in CI Aβ + individuals. Our findings suggest Plasma GFAP as a robust biomarker to be used as a secondary endpoint to monitor disease progression in CI Aβ + in AD clinical trials. Our findings, replicated in both research and clinical settings, may have implications in AD clinical trials composed of a real‐world population.
Cognitive training related changes in fMRI activations: a neural mechanism of transfer to executive functions in normal aging
Authors: Skolasinska Paulina , Qin Shuo , Lee Hyun Kyu , Voss Michelle W , Basak Chandramallika 
Published: January 2025

AbstractBackgroundImprovement of cognitive functions is often accompanied by changes in brain function after cognitive training in older adults. In this large‐scale dual‐site fMRI study we investigated the effects of BrainHQ cognitive training (CT; ®Posit Science Inc.) and an active control (AC) group on brain activations during a demanding executive control (EC) task among cognitively normal older adults. CT was an adaptive, speed‐based program, with conflict resolution and switching, Participants in the AC arm played non‐timed casual games with low demands on EC. We expected changes in the activations of brain regions related to motor processing and control mechanisms on a hybrid block/event‐related Task‐switching fMRI paradigm alongside improvements in performance.MethodsWe identified brain regions differentially sensitive to the effects of CT and AC interventions using group‐by‐time generalized linear models to determine block‐related (single and dual blocks), and event‐related activations. The latter determined regions sensitive to varieties of cognitive and motor control processes, including local switch cost (switch‐nonswitch trials) and compatibility switch cost (CSC; incompatible‐compatible trials). The resulting activations were subjected to linear mixed models (LMM) to determine post‐training group differences, after controlling for differences in baseline activation.ResultsCompared to AC, CT showed consistently increased activations in the premotor and right prefrontal cortices–regions related to higher‐order motor planning and EC, following the intervention. Increased activation of this region was correlated to gains in Task‐switching accuracy and the EC construct. A CSC‐sensitive region was a large right‐lateralized frontoparietal area including both EC areas and regions involved in sensorimotor function. Post‐training, CT showed lower activation than AC, who showed an increase, but only during the compatible condition. Increased activation observed in AC was maladaptive to cognition as it correlated with reduced gains in the EC construct. Group‐by‐time interactions favoring CT were also observed in cognitive and motor processing cerebellar regions.ConclusionsCompared to AC, CT showed compensatory adaptive changes in fMRI activations that were beneficial to cognition beyond the fMRI task. Training‐related changes on the Task‐switching paradigm can provide meaningful information on neural underpinnings of transfer to tasks of similar cognitive functions in normal aging.
Exploring Peripheral Blood Biomarkers for Dementia Diagnosis in Latin American Populations
Authors: Caviedes Ariel , Orellana Paulina , Hernandez Hernan , Slachevsky Andrea , Behrens María Isabel , Matallana Diana , Lopera Francisco , Custodio Nilton , Bruno Martin Alejandro , Funes José Alberto Avila , Takada Leonel Tadao , Pina‐Escudero Stefanie D , Valcour Victor , Kosik Kenneth S. , Miller Bruce L. , Yokoyama Jennifer S. , Ibañez Agustin , Duran‐Aniotz Claudia 
Published: January 2025

AbstractBackgroundDementia, encompassing Alzheimer's disease (AD) and frontotemporal dementia (FTD), poses a substantial public health challenge in Latin America. Barriers such as a shortage of healthcare professionals, limited medical accessibility, and underdiagnosis contribute to the complexity. While biomarkers aligned with the ATN framework (Amyloid, Tau, Neurodegeneration) have revolutionized diagnosis, their cost limits adoption in Latin America. Existing research focuses predominantly on North American or European cohorts, leaving a significant gap for the region. Our groundbreaking study aims to investigate, for the first time, ATN‐related proteins in AD, FTD, and control subjects using blood samples from the ReDLat cohort. This research addresses critical gaps in dementia diagnosis specific to Latin America, guided by insights from the ATN framework.MethodWe enrolled 500 participants (AD, FTD, and healthy controls‐HC) from Argentina, Chile, Colombia, Mexico, and Peru through the Multi‐Partner Consortium to Expand Dementia Research in Latin America (ReDLat). Plasma samples were collected in EDTA tubes, aliquoted, shipped on dry ice, and stored at ‐80°C following standard methods. We assess the plasma levels of Aβ40, Aβ42, p‐tau181, and NfL across groups (AD, FTD, HC) using Lumipulse G600II from Fujirebio, an advanced automated system which detects proteins via chemiluminescence.ResultOur analysis revealed a significant decrease in the Aβ1‐42/40 ratio between AD and FTD patients compared to HC. Additionally, we observed a significant increase in p‐tau181 levels in both AD and FTD patients relative to HC, with a significant difference between AD and FTD. NfL levels were significantly higher in AD and FTD patients compared to HC.ConclusionOur findings demonstrate substantial differences in Aβ1‐42/40 ratio, phosphorylated Tau, and NfL levels between AD, FTD, and control subjects. These distinct biomarker profiles hold promise for distinguishing between various forms of dementia and healthy individuals. Importantly, our study addresses the critical gap in dementia research within LA populations, offering valuable insights into the potential impact of regional factors on biomarker dynamics.
Association of Plasma Alzheimer’s Disease Biomarkers with White Matter Hyperintensity Volume in Diverse Populations: A HABS‐HD Study
Authors: Trammell Antoine R , Lah James J. , Goldstein Felicia , Parker Monica W , Hales Chadwick M , Davis Crystal P , Dorbin Cornelya D , Saleh Sabria , Murphy‐Tchivzhel Elizabeth , Rose Alecia Michella , O'Bryant Sid E. 
Published: January 2025

AbstractBackgroundOlder African American (AA) and Hispanic American (HA) adults have a higher risk for Alzheimer’s disease (AD) than older non‐Hispanic white (NHW) adults. Cerebrovascular disease reflected by white matter hyperintensity (WMH) lesions on magnetic resonance imaging (MRI) may influence ADRD risk in these groups. Amyloid and tau PET data from studies of mostly NHW participants show a relationship between AD pathology and WMH lesions. Using a diverse cohort, this study investigates relationships between plasma AD biomarkers and WMH volume.MethodWe analyzed plasma AD biomarkers, WMH volume, and self‐reported participant race (NHW, HA, AA) obtained during baseline visits for the Health and Aging Brain Study: Health Disparities. Plasma AD biomarkers included amyloid‐beta40 (Aβ40), amyloid‐beta42 (Aβ42), total tau (T‐tau), phosphorylated tau181 (P‐tau181), and neurofilament light (NfL) from single‐molecule enzyme‐linked immunosorbent assays. From self‐reported race and baseline global Clinical Dementia Rating scores (normal=0, impaired≥0.5), we created race/cognitive groups (white/normal, white/impaired, AA/normal, AA/impaired, HA/normal, HA/impaired). Using ANOVA and chi‐square, we compared baseline characteristics, plasma AD biomarkers, and WMH volume in the groups. We tested associations between plasma AD biomarkers and WMH volume with linear regression adjusted for age, education, and sex.ResultData from 3,035 participants was analyzed (mean age: 65.2; female: 62.3%; impaired: 20.1%). AA persons were younger (NHW: 68.6, AA: 62.9, HA: 62.3. p<.0001) and had the highest WMH volume (NHW: 4.16, AA: 18.4, HA: 3.18, p<.0001). AA and HA participants had the lowest Aβ42 (NHW:10.9, AA:10.2, HA:10.1, p<.0001), while HA persons had the lowest Aβ40 (NHW: 223, AA: 220, HA: 207, p=0.0003). NHW persons had the highest P‐tau181 (NHW: 2.38, AA: 1.95, HA: 1.92, p<.0001) and NfL (NHW:19.1, AA: 12.3, HA: 17.1, p<.0001). Regression showed higher WMH volume was associated with higher Aβ40 (β=.02, p=.02), P‐tau181 (β=.29, p=.01), and T‐tau (β=1.55, p=.0002) in the HA/impaired group.ConclusionOur results show associations between plasma AD biomarkers and WMH volume in cognitively impaired HA adults who also have low WMH burden compared to other groups. Further studies to discern potential mechanisms and the potential diagnostic prognostic utility of plasma AD biomarkers on AD risk are needed.
The impact of lecanemab and donanemab on future Alzheimer’s disease clinical development
Authors: Dickson Samuel P. , Mallinckrodt Craig , Burstein Aaron H , Nisenbaum Laura , Fillit Howard M , Hendrix Suzanne B. 
Published: January 2025

AbstractBackgroundA new era of Alzheimer’s disease (AD) research is beginning now that multiple monoclonal antibodies (mABs) are on the market. Their use may not be widespread initially but will be more common in clinical sites likely to participate in clinical trials and will continue to grow. Many AD investigational treatments have been studied as add‐on to acetylcholinesterase inhibitors; however, putative disease‐modifying therapies (DMTs) like mABs are expected to alter the underlying rate of progression, potentially reducing our ability to detect effects of other DMTs on top of mABs. In addition, if the mechanism of action (MOA) also targets amyloid, the treatment effect may be further reduced by co‐administration (antagonism). Alternatively, treatments that target complementary mechanisms may actually perform better (synergy). This new context requires careful consideration when powering clinical trials.MethodWe consider two clinical trial design scenarios. The first is a two‐arm trial to test a treatment as an add‐on to a mAB. The second is a four‐arm combination trial to represent the scenario where the mAB is started at the same time as investigational treatment. We calculate the required sample sizes for studies in three different patient populations: secondary prevention (MSDR = 0.34, 2‐year study), early AD (MSDR = 0.55, 18‐month study), and mild‐to‐moderate AD (MSDR = 0.67, 1‐year study). We consider scenarios with additivity, 30% antagonism, and 30% synergy.ResultAs shown in the table, the expected interaction with mAB treatment can have a large effect on study design decisions, with antagonistic treatment effects requiring more than three times the sample size of a synergistic treatment in most scenarios. The four‐arm scenario also usually requires around a threefold increase in sample size compared to a simple add‐on study.ConclusionStudies evaluating investigational therapies as add‐on to mABs are complex, and their cost to run will depend on how interactive the two treatments are. Treatments that are likely to work better with amyloid removed will be easier to study in this new context due to their complementary MOA. Symptomatic treatments may require fewer additional subjects than disease‐modifying treatments given the same expected effect size in the absence of mABs.
In vivo 18F‐MK6240 tau PET imaging in relation to peripheral inflammation and episodic memory in late middle‐aged adults
Authors: Malarte Mona‐Lisa , Chiotis Konstantinos , Ioannou Konstantinos , Rodriguez‐Vieitez Elena 
Published: January 2025

AbstractBackgroundDetecting early stages of Alzheimer's disease (AD) remains a crucial yet complex challenge. While recent interest has surged in detecting biomarkers linked with the disease preclinical phase, a comprehensive understanding of the concomitant peripheral biological pathways before the potential disease onset is necessary. We aim to explore the associations between the 18F‐MK6240 tau PET tracer with plasma inflammatory markers, other AT(X)N biomarkers and episodic memory.MethodThe cross‐sectional sample consisted of n=132 cognitively unimpaired late middle‐aged Hispanic individuals (64.5 ± 3.4 years old, 34.1% APOE4 carriers, 69.7% female, 10.7 ± 4.0 years of education) from Northern Manhattan (AD Knowledge Center database). All individuals underwent multi‐modal imaging with T1‐weighted MRI, T2‐weighted FLAIR MRI, Aβ PET (18F‐florbetaben), tau PET (18F‐MK6240), plasma measures of inflammation (OLINK panel of 92 markers), plasma neuronal injury (NfL), and neuropsychological assessments. Data on demographics: age, sex, education, APOE, body mass index (BMI), and diabetes mellitus, were also included. Using the median split to dichotomize global Aβ and NfL measures, the study sample was stratified into four groups: “Aβ‐low, NfL‐low” (Group 0); “Aβ‐high, NfL‐low” (Group 1); “Aβ‐high, NfL‐high” (Group 2); and “Aβ‐low, NfL‐high” (Group 3).ResultOur results revealed that 18F‐MK6240 tau PET is sensitive in detecting early neocortical tau pathology, even without evident neuronal injury (Figure 1). Plasma inflammation was not directly linked with Aβ or tau pathologies but strongly associated with NfL (Figure 2). Markers of neuronal injury (NfL), cerebrovascular injury (WMH) and specific inflammatory markers were associated with lower episodic memory (Figure 1). High NfL correlated with factors such as high inflammation, BMI, diabetes and older age.ConclusionThe study emphasizes the complex nature of early AD markers suggesting that, aside from Aβ and tau, peripheral markers of NfL and inflammation are also central. Our findings call for a broader perspective in identifying early AD markers, underscoring the interplay between neuronal damage, inflammation, comorbidities and early cognitive changes.
Prior infections and polymorphism in NECTIN2 gene are synergistically associated with reduced hippocampal volume, a biomarker of neurodegeneration, in older women
Authors: Ukraintseva Svetlana , Popov Vladimir , Duan Hongzhe , Yashkin Arseniy , Akushevich Igor , Arbeev Konstantin , Yashin Anatoliy 
Published: January 2025

AbstractBackgroundA growing body of research suggests a connection between Alzheimer’s disease (AD) and prior infections, although the mechanisms are not well understood. We recently reported a significant association between a history of adult infections and smaller brain hippocampal volume (HV), a major biomarker of neurodegeneration, in female participants of the UK Biobank (UKB). Here we further investigate this connection, taking into account the rs6859 polymorphism in the NECTIN2 gene, an established genetic risk factor for AD that is also involved in vulnerability to infections.MethodsWe estimated the associations between adult history of infections and HV assessed later in life, at ages 65‐80 years, in the presence and absence of the AD risk variant (A) of rs6859, using the UKB subsample with respective information (N=11,765; 48% women). Infectious disease diagnoses were based on ICD‐10 codes. The left/right HV was measured by magnetic resonance imaging (MRI) in cubic millimeters (mm3) and normalized. Analysis of variance (ANOVA), Tukey’s test, Welch test, and regression were used to examine statistical significance.ResultsPrior infections and carrying the AD risk variant rs6859 (A) were synergistically associated with a significant reduction in the left HV by ∼2.1% (p‐value=0.03) and in the right HV by ∼2.2% (p‐value=0.01) in women aged 65‐80 years. Results for men did not reach statistical significance.ConclusionResults of our study suggest that prior infections and rs6859 in the NECTIN2 gene synergistically contribute to neurodegeneration in older women. A potential explanation of this effect could be that carrying the rs6859 (A) may aggravate AD‐related brain pathology triggered by infections because this genetic risk factor for AD also increases the brain’s vulnerability to infections. This hypothesis needs confirmation in biomedical research. The observed sex difference may reflect a higher vulnerability of the female brain to infection‐related factors due to hormonal or other differences between males and females, which deserves further investigation.