bluuebunny/crossref_metadata_2025_split huggingface dataset:
Post‐covid cognitive performance in subjects at risk of developing dementia in Uruguay
Authors: Mariani Francesca , Damian Andres , Bocos Laura , Cortabarría Lucia , Leites Alice , Santero Sofia , Contreras Valeria , Ferrando Rodolfo , García‐Fontes Margarita , Reyes Laura , Arredondo Florencia , Abin‐Carriquiry Juan Andrés , Menendez Mercedes , Amestoy Alejandra , Torheim Maren , Superchi Roberto , Suarez Ramon , Preciozzi Fabian , Fernandez Lucia , Uriarte Laura , Dansilio Leandro , Dansilio Sergio , Charamelo Ana , Allegri Ricardo Francisco , Caramelli Paulo , Lopera Francisco , Nitrini Ricardo , Sevlever Gustavo , Sosa Ana Luisa , Calandri Ismael Luis , Crivelli Lucía , Salinas‐Contreras Rosa Maria , Suemoto Claudia Kimie , Velilla Lina M , Yassuda Monica Sanches 
Published: December 2023

AbstractBackgroundthe study of the medium and long‐term consequences of coronavirus infection (SARS‐CoV‐2) is of great relevance from the clinical and public health perspective. Recent evidence has shown that patients may present cognitive complaints after overcoming the acute stage of infection, particularly memory disturbances. Although significant progress has been made in the knowledge of this sequel, the studies are generally limited by small sample sizes, cognitive screening techniques with ceiling effects, and samples with healthy subjects without comorbidities, among others. The objective of this study is to compare the cognitive performance of subjects at risk of developing dementia with and without a history of SARS‐CoV‐2 in Uruguay.Methodparticipants from the LatAm FINGERS Uruguay Project were included. Performance in the different cognitive tests (symbol‐digit, trail making A, trail making B, free and cued selective remingind test) included in the project protocol was compared between the participants with and without a history of covid infection.Results27 subjects with a history of covid infection prior to baseline cognitive assessment and 62 subjects without a history of covid infection were analyzed. None of the participants had serious complications or requiring hospitalization due to SARS‐CoV‐2 infection. The performance of both groups in attentional, executive and memory tests was compared. There were no significant differences between groups.Conclusionsthe impact of covid on cognition is still a controversial topic. In our sample of subjects at risk of dementia, there was no evidence of impaired cognitive performance due to SARS‐CoV‐2 infection. More studies in underrepresented populations with larger samples are needed to address this issue.
The impact of sex on the progression of AD atrophy‐based subtypes
Authors: Inguanzo Anna , Poulakis Konstantinos , Oltra Javier , Ferreira Daniel , Mohanty Rosaleena , Westman Eric 
Published: December 2023

AbstractBackgroundRecently, longitudinal subtypes in AD have been identified based on their different brain atrophy trajectories (Poulakis et al. 2022 Nat Commun), which follow either mediotemporal or cortical pathways. The mediotemporal pathway, which is the most prevalent, includes three longitudinal subtypes: the limbic predominant plus (LPA+), the limbic predominant (LPA), and the minimal atrophy (MA) subtypes. While the LPA+ is characterised by the fastest rate of atrophy starting in the entorhinal cortex and later spreading to the temporal lobe and the rest of the cortex, the LPA is restrained to atrophy in temporal regions. The MA subtype, on the other side, is characterised by minimal atrophy in mediotemporal areas. Although the discovery of brain atrophy trajectories in AD represents a significant contribution towards precision medicine, the impact of sex – a major risk factor for AD – on these trajectories has yet to be explored.MethodWe used longitudinal magnetic resonance imaging data as well as clinical data (up to 5 timepoints) from 3 international AD cohorts (ADNI, J‐ADNI and AIBL). AD individuals had previously been identified, as one of the following longitudinal subtypes: LPA+ (N = 23, 61% females), LPA (N = 93, 48% females), and MA subtype (N = 189, 48% females). We applied linear mixed effect models (LMMs) on 34 cortical and 7 subcortical regions to assess differences in sex within each AD longitudinal subtype. Results were adjusted for ageing effects, cohort, disease duration and intracranial volume.ResultLPA+ females showed greater atrophy over time compared to LPA+ males in frontal regions as well as in the lingual and the parahippocampal gyri. LPA females tended to show greater atrophy in the medial orbitofrontal cortex compared to LPA males. Finally, within the MA subtype, females showed greater atrophy than males in the hippocampus over time.ConclusionThis study demonstrates that sex‐specific regional vulnerabilities are crucial to consider in the study of AD heterogeneity, particularly within the mediotemporal pathway. Our results reveal that females exhibit distinct atrophy patterns over time compared to males in different AD subtypes, emphasizing the importance of investigating sex‐related differences to develop more targeted and effective interventions for AD.
Enhanced memory for negative words is associated with amnestic mild cognitive impairment and in vivo cerebral amyloid‐β burden independently of depression
Authors: Mah Linda , Verhoeff Nicolaas Paul L.G. , Butters Meryl A. , Fischer Corinne E. , Flint Alastair , Graff‐Guerrero Ariel , Herrmann Nathan , Lanctôt Krista L. , Mulsant Benoit H. , Pollock Bruce G. , Rajji Tarek K. ,   PACt‐MD Study Group
Published: December 2023

AbstractBackgroundEmotion dysregulation was studied as a potential risk marker for Alzheimer’s disease (AD) by assessing emotional memory in high AD‐risk groups characterized by the presence of mild cognitive impairment (MCI) or remitted major depressive disorder (rMDD) and by evaluating the relationship between emotional memory and in vivo cerebral amyloid‐β deposition.Method435 participants enrolled in the PACt‐MD clinical trial of cognitive remediation plus transcranial direct current stimulation were evaluated at baseline. The sample included 127 older adults with amnestic mild cognitive impairment (aMCI), 51 non‐amnestic MCI (naMCI), 60 rMDD without MCI, 81 rMDD+aMCI, 42 rMDD+naMCI, and 74 cognitively unimpaired older adults (CU). Diagnoses were established during a consensus conference based on psychiatric, medical, and neuropsychological assessment. Emotional memory was assessed by evaluating immediate and short‐term delayed recall of 15 personality adjectives (5 each of positive, negative and neutral words) from the Emotional Verbal Learning Test (Mah et al., 2017, American Journal of Geriatric Psychiatry, 25:1160). A subset (N = 167) completed a Positron Emission Tomography (PET) scan with carbon‐11 Pittsburgh Compound B ([11C] PIB). Valence and diagnostic group effects on recall were assessed using mixed ANOVA. Regression modelling assessed the association between emotional memory bias and amyloid‐β burden.ResultRelative to CU, both aMCI and rMDD+aMCI groups showed enhanced memory for negative words at immediate recall, which persisted after short delay in the aMCI group only (F(1, 339) = 2.66, p = .048; Figure 1). Enhanced memory for negative words at short delay was predictive of in vivo cerebral amyloid‐β deposition (standardized beta = .117, t = 1.84, p = .067), over and above the contributions of age, sex, Apolipoprotein E genotype, depression diagnosis and symptoms, and long delayed verbal recall (F(4,154) = 25.8, p<.001, R2 = .41; Figure 2).ConclusionThe association between enhanced memory for negative personality adjectives and aMCI replicates earlier work in single‐domain aMCI (Mah et al., 2017) and suggests that aMCI is characterized by a negativity bias in memory. These findings, taken together with the relationship between a negativity bias in memory and amyloid‐β burden, suggest that emotion dysregulation, in the form of enhanced memory for negative information, is a potential marker of AD risk.
Sex differences in plasma biomarkers for identifying Aβ pathology in CN and MCI individuals: Implications for Clinical Trials
Authors: Milà‐Alomà Marta , Aloma Zachary Hausle Mila , Zobel‐Thropp Pamela , Tosun Duygu 
Published: December 2023

AbstractBackgroundOur objective was to investigate whether sex influences plasma biomarker levels and performance in identifying Aβ‐PET‐positivity in CU and MCI ADNI participants.MethodThe study included 417 participants (Table1) with known Aβ‐PET status and plasma Aβ42/Aβ40 (IP‐LC‐MS/MS), and pTau181, tTau and NfL (Simoa HD‐X). We used ANCOVA to examine the effect of age, sex and APOEε4 on plasma biomarkers, and the interactions between sex, APOEε4 and age. ROC analyses were performed to determine the added value of each plasma biomarker, alone or in combination, to a base model of risk factors age and APOEε4 in the entire sample. The models were then applied to subsets of women and men separately, and the AUCs were compared with DeLong test. The same models were run separately for CU and MCI individuals, and Random Forest (RF) analyses were performed to assess each variable’s importance.ResultIn CUs, women had higher Aβ deposition but lower plasma pTau181 than men. In contrast, MCI men had lower plasma Aβ42/40 than MCI women. In CU men, there was a steeper increase of pTau with age (Figure1), whereas APOEε4 had a stronger effect on pTau in MCI women. ROC analyses indicated that in CUs, addition of Aβ42/40 to risk factors performed better than using risk factors alone for both sexes. In MCIs, the addition of any plasma biomarker improved the base model in men, but not in women (Figure2). In RF analyses, plasma Aβ42/40 had the strongest importance for model accuracy in CU men and women. In women with MCI, Aβ42/40 and tau have similar importance and were only slightly superior to risk factors, while in men, Aβ42/40 had the strongest importance.ConclusionSex differences were observed in plasma Aβ42/40 and pTau, and in the impact of risk factors, which varied by clinical stage. In MCIs, the classification performance varied by sex, with a greater added value of plasma biomarkers, particularly Aβ42/40, in men. These findings emphasize the need to consider sex differences when using plasma biomarkers for clinical trials, especially in MCIs. Further studies are necessary to elucidate the underlying mechanisms and implications of these observations.
The case for low‐dose BACE inhibition
Authors: Watkins Elyse , Vassar Robert J. 
Published: December 2023

AbstractBackgroundAlzheimer disease (AD) is the most common cause of dementia in older individuals (>65 years) and has a long presymptomatic phase. Positive trials of anti‐amyloid‐β immunotherapy have confirmed that amyloid contributes to cognitive deficits in patients. However, these therapies are costly and require monthly or bi‐weekly infusions. Furthermore, in their current state, anti‐amyloid immunotherapy is approved for treatment of AD once symptoms have already appeared, which may be late in the cascade of neuronal damage. There is substantial need for an inexpensive and minimally invasive preventative therapy that could be taken during the pre‐symptomatic stage of AD, or in combination with amyloid immunotherapy to be taken after amyloid clearance to prevent the reemergence of plaques. Small‐molecule inhibitors of β‐site amyloid precursor protein (APP)‐cleaving enzyme 1 (BACE1) reduce the production of amyloid‐β peptide, are taken orally, and are among the most advanced drug candidates for AD. However, to date all phase II and phase III clinical trials of BACE inhibitors were either concluded without benefit or discontinued owing to futility or the occurrence of adverse effects. Adverse effects included early, mild cognitive impairment primarily in memory domains, and trials that have conducted follow‐up testing after study completion suggest that the cognitive impairment is reversible. In this talk, I discuss the status of BACE inhibitors and suggest ways in which the results of the discontinued trials can inform the development of future clinical trials of BACE inhibitors.MethodN/AResultN/AConclusionN/A
Preliminary validation of the Stress and Adversity Inventory for Adults (Adult STRAIN) in Dutch and its associations with in‐vivo locus coeruleus integrity
Authors: Engels Nina , Riphagen Joost M. , Van Egroo Maxime , Spahr Chandler M. , Slavich George M , Jacobs Heidi I.L. 
Published: December 2023

AbstractBackgroundThe Stress and Adversity Inventory (STRAIN) systematically assesses lifetime stressor exposure, but its validity has yet to be established in The Netherlands. This work aims to validate the Dutch translation of STRAIN and its association with key biological correlates: cortisol measures and the locus coeruleus (LC), a brainstem nucleus involved in stress responses and accumulating phosphorylated tau early in adulthood.MethodsEighty‐seven cognitively unimpaired Dutch participants (31‐81 years; ∼45% female; Table 1) completed stress‐ and affective‐related questionnaires, cognitive testing, salivary and plasma cortisol measurements, and 7T‐MRI. The STRAIN was administered after translation into Dutch. LC MRI signal intensity was extracted from an MT‐TFL sequence by normalizing LC signal against the pontine tegmentum (reference region) and creating a sample‐specific LC template. Pearson correlation models assessed associations between STRAIN summary scores (total stressor count and severity), and stress‐related (MIA‐Anxiety, PSS, DASS‐Stress, NEO PI‐R‐Neuroticism), affective (DASS‐Anxiety‐Depression, HDRS), cognitive (WLTDR, LDST, STR3), stress‐related biological (salivary‐, plasma cortisol), and LC measures (Table 1). HDRS models employed Spearman correlations. Age and sex were included as covariates, additionally including education for cognitive measures. Analyses were FDR‐corrected and conducted based on complete cases.ResultsOverall, the sample had relatively low lifetime stressor counts (M = 14.08; Figure 1A). When assessing concurrent validity, the STRAIN was positively associated with other stress measures (r = .21,.36; pFDR
<.05; Figure 1B,C). Models including cortisol revealed that less stressor exposure and severity were associated with higher cortisol levels (r = ‐.22,‐.23; pFDR
<.05). Affective and cognitive measures were investigated for discriminant validity. STRAIN was not associated with DASS, but was positively associated with HDRS (r = .17,.28; pFDR
<.05). Generally, greater stressor exposure was related to poorer cognitive performance (r = .13,‐.19; pFDR
<.05), except for a positive association between WLTDR and stressor severity (r = .18; pFDR
<.05). No significant associations were found with LC MRI signal intensity (Figure 1B).ConclusionThis study demonstrates preliminary good concurrent and discriminative validity for the Dutch STRAIN translation, even among individuals with low‐to‐moderate self‐reported stress levels. We found no direct associations between LC integrity and lifetime stressors. Future research will investigate associations with other STRAIN domains and potential moderating effects of Alzheimer’s Disease‐related biomarkers on the relationship between cumulative stressor exposure and LC integrity.
A novel automated multiplex immunoassay for the ultrasensitive detection of blood‐based biomarkers for neurodegenerative diseases
Authors: Ma Xiao‐Jun , Ariyapala Ishara , Alganem Khaled , Hao Qinyu , Feng Wei , Zhang Bingqing , Blennow Kaj , Luo Yuling , Zetterberg Henrik 
Published: December 2023

AbstractBackgroundEfforts to identify accurate blood biomarkers for neurodegenerative disease hallmarks have been hampered by the lack of a proteomic tool that has the required sensitivity to detect very low concentrations of brain‐derived proteins in plasma or serum and the ability to multiplex many analytes in a single assay. Here we evaluated NULISA™, a recently developed novel immunoassay with attomolar level sensitivity and high multiplex capability1, for its ability to detect serum biomarkers associated with Alzheimer’s disease.MethodSerum samples from 31 Alzheimer’s disease (AD) patients and 31 non‐AD controls were analyzed using NULISA with a 200plex inflammation panel targeting a broad spectrum of inflammation‐related cytokines, chemokines and other proteins. Five samples failed quality control and were excluded from further analysis, resulting in 28 AD and 29 control samples in the final dataset. Linear model analysis, including age and sex as covariates, was performed for each target for differential expression between AD patients and controls.ResultTwo significant proteins were identified. The level of glial fibrillary acidic protein (GFAP) was 1.84‐fold higher in AD patients (adjusted p‐value = 0.00014), whereas the level of S100 calcium‐binding protein A12 (S100A12) was 2‐fold higher in non‐AD controls (adjusted p‐value = 0.031). GFAP serum levels correlated strongly with total tau (Spearman rho = 0.69, p = 1.7e‐09), p‐tau181 (rho = 0.69, p = 1.7e‐09) and amyloid beta 42 (rho = ‐0.71, p = 4.7e‐10) levels in cerebrospinal fluid (CSF). S100A12 levels also correlated significantly with total tau (rho = ‐0.39, p = 0.0031), p‐tau181 (rho = ‐0.36, p = 0.0053) and amyloid beta 42 (rho = 0.38, p = 0.0067) CSF levels. Receiver operating characteristic analysis demonstrated that GFAP strongly discriminated AD from controls with an area under the curve (AUC) of 0.93 (95% CI 0.87‐1.0), and S100A12 also exhibited good discrimination with an AUC of 0.72 (95% CI 0.59‐0.86).ConclusionThis exploratory study identified serum GFAP levels as a strong discriminatory biomarker for AD, consistent with previous studies. S100A12 also demonstrated significant associations with AD and CSF biomarkers and thus warrants further study. NULISA holds great promise for the discovery and validation of blood‐based biomarkers for the early detection and monitoring of neurodegenerative diseases.1. Feng, W. et al. bioRxiv 2023.04.09.536130 (2023) https://doi.org/10.1101/2023.04.09.536130.
In vivo [18F]SMBT‐1 imaging of reactive astrocytes in mouse models of Alzheimer’s disease ‐ temporospatial relationship with amyloid, tau and microgliosis
Authors: Kong Yanyan , Maschio Cinzia , Yao Bolin , Shi Kuangyu , Rominger Axel , Xiao Jianfei , Huang Qi , Guan Yihui , Ni Ruiqing 
Published: December 2023

AbstractBackgroundReactive astrocytes play an important role in the pathogenesis of Alzheimer’s disease (AD). Here, we aim to investigate the temporospatial relationship between reactive astrocytes, microgliosis, tau and amyloid‐β by using in vivo multitracer imaging in AD transgenic mouse models.MethodPositron emission tomography (PET) imaging with [18F]SMBT‐1 (monoamine oxidase‐B for reactive astrocytes), [18F]DPA‐14 (translocator protein for microgliosis), [18F]PBB3 (tau), and [18F]florbetapir (Aβ) was carried out in 5‐ and 12‐month‐old APP/PS1, 12‐month‐old 3×Tg mice, and aged‐matched wild‐type mice. The brain regional referenced standard uptake value (SUVR) was computed with the cerebellum as reference region. Immunofluorescence staining was performed with antibodies against monoamine oxidase‐B, astrocytes, translocator protein, microglia, tau, and amyloid in mouse brain slices.Result[18F]SMBT‐1 SUVRs were higher in the cortex and hippocampus of 12‐month‐old APP/PS1 mice than age‐matched wild‐type mice. [18F]DPA‐14 SUVRs were higher in the brain stem and amygdala of 5 and 12‐month‐old APP/PS1 mice than in age‐matched wild‐type mice. [18F]PBB3 were higher in the cortex, striatum and hippocampus of APP/PS1 mice than in 5‐month‐old APP/PS1 mice and wild‐type mice. [18F]florbetapir SUVRs were higher in the brain stem, thalamus and midbrain of APP/PS1 mice at 5 months than in age‐matched wild‐type mice. No significant difference in the regional [18F]SMBT‐1, [18F]DPA‐14, [18F]PBB3, [18F]florbetapir or [11C]PIB SUVR was observed in 12‐month‐old 3×Tg mice compared to age‐matched wild‐type mice, which is validated by the limited 6E10‐positive amyloid plaques and AT8‐positive tau deposits.ConclusionThe findings provide in vivo evidence for different regional distribution of reactive astrocytes and microgliosis in animal models of AD.
Value of blood‐based biomarkers for differential diagnosis of Alzheimer’s disease: the ActiGliA cohort
Authors: Kurz Carolin Isabella , Carli Laura , Guersel Selim Üstün , Schrurs Isabelle , Jethwa Alexander , Carboni Margherita , Bittner Tobias , Rauchmann Boris‐Stephan , Brendel Matthias , Burow Lena , Haeckert Jan , Tato Maia , Utecht Julia , Papazov Boris , Pogarell Oliver Michael , Palleis Carla , Weidinger Endy , Stöcklein Sophia , Haass Christian , Levin Johannes , Höglinger Günter , Perneczky Robert 
Published: December 2023

AbstractBackgroundCerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers of Alzheimer’s disease (AD), ß‐amyloid (Aß) and tau, can identify early disease stages with high accuracy. However, this approach is not suitable for routine clinical care because of the high costs and invasiveness. Implementation of blood‐based biomarkers (BBBM) in the diagnostic process may facilitate the identification of persons with AD in the earliest stage possible and may reliably differentiate AD from healthy aging and other non‐AD dementias like corticobasal syndrome (CBS).MethodFrom the prospective ActiGliA study we included 27 participants with probable AD (including participants with mild cognitive impairment [n = 16] and AD‐related dementia [n = 11]), 17 age‐matched controls with subjective cognitive impairment, 9 participants with corticobasal syndrome and underlying Aß‐pathology (Aß[+]CBS), and 26 participants with Aß[‐]negative CBS. The diagnostic value of different BBBMs in differentiating amyloid‐positive from ‐negative cases was examined. All participants underwent a thorough diagnostic work‐up, including CSF and blood sampling, neuropsychological tests, amyloid‐PET, and magnetic resonance imaging. Blood biomarkers (Aß1‐40, Aβ1‐42, apolipoprotein E4 [ApoE4], glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL], and phosphorylated‐tau181 [pTau181]) were measured using Elecsys® plasma prototype immunoassays.ResultIn amyloid‐positive cases, plasma concentrations of Aβ1‐42/1‐40 ratio were decreased while ApoE, GFAP, and pTau181 levels were elevated. In the entire cohort, blood and CSF levels of both Aß1‐42/Aß1‐40 ratio and pTau181 were significantly positively correlated. ApoE4, GFAP, and particularly pTau181 levels showed a strong negative association with neuropsychological performance. A positive association between NfL levels and hippocampal atrophy was demonstrated. pTau181 levels revealed an are under the curve (AUC) of 0.885 in the discrimination between amyloid‐positive and ‐negative cases, plasma ApoE4 levels and Aß1‐42/Aß1‐40 ratio showed an AUC of 0.774 resp. 0.815. Regarding differentiation of AD from healthy aging and other dementias, elevated NfL levels were associated with a diagnosis of CBS and Aß[+]CBS, while elevated pTau181 and ApoE4 levels indicated a diagnosis of AD.ConclusionBBBMs may be useful in differentiating amyloid PET‐positive from amyloid PET‐negative cases and in differentiating AD from healthy aging and non‐Alzheimer dementias. These results must be validated in a larger cohort.