bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum Nf‐L and GFAP are associated with incident dementia and dementia mortality in older adults: The Cardiovascular Health Study
Authors: Cronjé Héléne Toinét , Liu Xiaojuan , Odden Michelle , Moseholm Kristine F , Seshadri Sudha , Satizabal Claudia L. , Lopez Oscar L. , Bis Joshua C , Djoussé Luc , Fohner Alison E , Psaty Bruce M. , Tracy Russell P. , Longstreth W.T. , Jensen Majken K , Mukamal Kenneth J 
Published: December 2023

AbstractBackgroundAlthough circulating neurofilament light chain (Nf‐L) and glial fibrillary acidic protein (GFAP) have been independently associated with dementia risk, their additive association, and their associations with dementia‐specific mortality have not been investigated. Overall, prospective community‐based studies of these biomarkers, particularly those representing individuals beyond their eighth decade, are lacking.MethodWe investigated 1,712 cognitively healthy participants of the Cardiovascular Health Study (1,042 women [61%], 218 Black [13%], median [IQR] baseline age = 77 [74–80] years). Cox regression models were used to test the associations of serum Nf‐L and GFAP, measured using single molecule array technology, with 19‐year incident dementia and dementia‐specific mortality risk. These primary outcomes were complemented by repeated Modified Mini‐Mental State Exam and the Digit Symbol Substitution Test scores which were used in linear mixed models to test the associations of Nf‐L and GFAP with cognitive decline over three years.ResultMore than half of the participants were diagnosed with incident dementia (N = 975) and 183 dementia‐specific deaths occurred during follow‐up. In covariate, and mutual Nf‐L/GFAP adjusted models, each standard deviation unit higher Nf‐L or GFAP associated with a hazard ratio (HR) of 1.14 (95% confidence interval, 1.03–1.26) and 1.12 (1.04–1.21) for incident dementia, and 1.37 (1.11–1.69) and 1.55 (1.31–1.83) for dementia‐specific mortality (Table 1). These associations were graded and additive, with the strongest associations observed when Nf‐L and GFAP levels were simultaneously elevated (Figure 1). Compared to those in the lowest tertiles of both markers, we observed an additive increase in risk among individuals with both Nf‐L and GFAP levels in the highest tertile [HR, 2.06 (1.60‐2.67) for incident dementia and 9.22 (4.48–18.9) for dementia‐specific mortality, Figure 1]. Nf‐L, but not GFAP, independently associated with faster cognitive decline over three years (Table 1).ConclusionCirculating Nf‐L and GFAP may, independently and jointly, provide useful clinical insight regarding dementia risk and prognosis.
Clock drawing: Does the digital era have an influence on analog clock drawing in our young generation
Authors: Fisher Tali , Ayoub Rawan , Yarovinsky Natalya , Hadad Rafi , Dadi Lee , Stanger Chen , Marinberg Adi , Tanne David , Aharon‐Peretz Judith , Ben‐Hayun Rachel 
Published: December 2023

AbstractBackgroundThe clock drawing test (CDT) is frequently used for the evaluation of people with cognitive impairment. It is particularly sensitive for tasks dependent on executive and visuospatial functions. The original CDT involves drawing a clock with numbers and hands on specific time. As during the last decades, digital clock use became more widespread, our aim in the present study was to evaluate whether the analog clock drawing test can still be useful as an assessment tool for dementia and cognitive decline.MethodThis retrospective study includes three groups: 1) The young group (N = 45, Age: M = 20.2, SD = 2.49) was recruited from IDF (Israel defense force) neurology clinic following headache complaints; 2) The MCI group (N = 28, Age: M = 73.21, SD = 7.24); 3) The Dementia due to Alzheimer’s Disease (AD) group (based on CSF biomarkers) (N = 30, Age: M = 71.27, SD = 9.81). Both groups 2 and 3 were recruited from the Cognition Institute at the Rambam Health Care Campus. All participants underwent the CDT, which was scored according to the Manos scale and compared to relevant norms based on age. One‐way ANOVA was performed to determine if CDT performance varies by group.ResultsAD group CDT scores were lower (M = 3.7, SD = 3.86) compared to the cognitively intact age matching norms (M = 9.57, SD = 0.9), t (244) = 8.522, p<0.0001 as expected. CDT score of the MCI group (M = 8.57, SD = 2.04) did not differ from cognitively unimpaired norms (M = 8.65, SD = 1.69). Surprisingly, The CDT scores of the young group were significantly lower (M = 8.31, SD = 2.22) than expected according to norms (M = 9.22, SD = 1.373), t(246) = 3.543, p = 0.0005. AD group performed significantly worse compared to the other two groups (M = 3.7, SD = 3.86) (F (3) = 20.654, p<0.001).ConclusionWhile the CDT scores in the elderly (MCI and AD) matched previously reported data, young individuals perform significantly worse. These findings may indicate that the CDT test is suitable for use in the elderly population as it is still able to detect cognitive impairment in dementia. However, young people find it difficult to perform, probably due to their limited exposure to analog clocks. These results raise questions regarding the relevance of the CDT during cognitive assessment in the future.
Heparan sulfate 3‐O‐sulfation and Tgfb1 involvement in Alzheimer’s disease related tau aggregation
Authors: Castillo‐Negrete Rafael , Merrick Heloise , Girard Ombeline , Huynh Minh Bao , Diener Martin , Jedlicka Peter , Papy‐Garcia Dulce 
Published: December 2023

AbstractBackgroundAging is the main risk factor for Alzheimer’s disease (AD) characterized by a cognitive decline related to a synaptic disfunction (Chen et al., 2019). In AD brains, tau abnormal phosphorylation coexists with heparan sulfates (HS), suggesting that HS could lead to the formation of neurofibrillary tangles (NFT) (Goedert et al., 1996). In vitro, the aggregation of tau is not possible in the absence of heparin, a highly sulfated HS carrying 3‐O‐sulfation (3S‐HS). 3S‐HS are the product of HS 3‐O Sulfotransferase (HS3ST) enzymes (Sepulveda‐Diaz et al., 2015). In AD, Heparan Sulfate‐Glucosamine 3‐Sulfotransferase 2 (HS3ST2) expression is higher in tauopathy vulnerable brain regions, such as the hippocampus and cortex (Huynh et al., 2019). Previously, we showed in a cellular model that HS3ST2 induces cell autonomous aggregation of tau (Huynh et al., 2022). However, the mechanism leading to an increased expression of HS3ST2, and therefore increase in 3S‐HS synthesis are unknown. Additionally, it is not known the effect of reducing the levels of HS3ST2 in tau oligomerization and aggregation in neurons.MethodPrimary hippocampal neurons (PHN) from the rTg4510 mice model were dissected and maintained in vitro for 20 days (DIV20). All treatments (ALK5inh, Tgfb1) and lentiviral transduction (Lv‐NonTarget, Lv‐shHs3st2) were done at day in vitro 15 (DIV15).ResultIn brain of aged individuals, transforming growth factor TGFB1 is upregulated, modulating gene expression (Doyle et al., 2010). SMAD4 transcription factor is activated upon the dimerization of TGFB receptor targeting specific genes (Martin‐Malpartida et al., 2017). SMAD4 contains genome wide recognition motifs that are present in the Hs3st2 promoter, suggesting a possible regulation. We showed that Hs3st2 is under regulation of Tgfb1 and blocking pSmad2/3 reduces its levels. Contrarily, Hs3st2 levels were increased by increasing pSmad2/3. The importance of Tgfb1 coregulation with Hs3st2 was assessed by blocking the expression of Hs3st2, leading to a decrease in tau oligomerization and aggregation. Finally, we found that the reduction of 3S‐HS enhances synaptic size, and presynaptic/postsynaptic connectivity.ConclusionOverall, we depicted the regulation of Hs3st2, and demonstrate its involvement in synaptic connectivity and tau aggregation, confirming the importance of 3S‐HS in the physiopathology of AD.
Impact of type 2 diabetes mellitus on brain volumes and cognitive performance
Authors: Restrepo Carolina , Khlif Mohamed Salah , Patel Sheila , Alsawaf Shahad , Bird Laura J. , Werden Emilio , Ekinci Elif , MacIsaac Richard , Burrell Louise , Brodtmann Amy 
Published: December 2023

AbstractBackgroundType 2 diabetes (T2DM) is recognised as a major contributor to cognitive decline. People with T2DM demonstrate abnormalities on MRI compared to control individuals. The aim of this analysis was to investigate differences in cognitive performance and brain volume between individuals with T2DM participating in the Diabetes‐and‐Dementia (D2) study and a group of healthy controls (HC) part of the Cognition And Neocortical Volume After Stroke (CANVAS) study.MethodOne hundred and fifty individuals with T2DM and 36 cognitively‐normal participants completed neuropsychological assessments and a 3T‐MRI scan. FreeSurfer was used to estimate total brain volume (TBV), mean cortical thickness and subcortical volumes, including the thalami and caudate nuclei. Averages between left and right volumes were calculated for subcortical structures. WMH volumes were estimated manually using FLAIR MRI. Five cognitive domains, including attention, visuospatial skills, memory, language and executive function were computed using z‐scores. These domains were used to compare cognitive performance between individuals with and without T2DM.Demographic and clinical comparisons were completed in MATLAB using Two‐Sample t‐test (age), Fisher Exact test (education, sex, APOE‐e4), and Wilcoxon Rank Sum test (BMI). A linear regression model was used to compare cognitive performance between the two groups with correction for age, sex and education level (more/less than 12 years), as well as total intracranial volume for comparing brain volumes.ResultParticipants with T2DM were significantly younger, with a higher BMI, had reduced cortical thickness, significantly smaller TBV and smaller subcortical volumes including thalamic, brainstem, amygdala, accumbens area and choroid plexus. Individuals with T2DM exhibited a poorer cognitive performance on tests of language, memory, attention, and visuospatial skills compared to the HC group. There were no significant differences between the two groups in terms of sex, education level, APOE‐e4 carriage, WMH, hippocampal volume (see Table 1).ConclusionT2DM is associated with accelerated structural brain aging, manifesting as cerebral atrophy and poorer cognitive function.
Sequential grey matter atrophy related to Alzheimer’s disease in adults with Down’s syndrome
Authors: Bejanin Alexandre , Morcillo‐Nieto Alejandra O. , Zsadanyi Sara E. , Montal Victor , Pegueroles Jordi , Carmona‐Iragui Maria , Aranha Mateus Rozalem , Vaqué‐Alcázar Lídia , Benejam Bessy , Videla Laura , Barroeta Isabel , Fernandez Susana , Giménez Sandra , González‐Ortiz Sofía , Bargalló Núria , Ribas Laia , Arranz Javier , Rodríguez‐Baz Íñigo , Belbin Olivia , Alcolea Daniel , Blesa Rafael , Lleo Alberto , Fortea Juan 
Published: December 2023

AbstractBackgroundDue to the triplication of the APP gene on chromosome 21, virtually all individuals with Down’s syndrome (DS) present AD neuropathological hallmarks by the age of 40, and have a lifetime risk of developing dementia >90%. However, whether DS follows a stereotypical pattern of AD atrophy has not been investigated. Here, we aimed at defining the sequential grey matter (GM) volume loss across the whole AD continuum in adults with DS.MethodCross‐sectional design. 248 adults with DS (n = 145 asymptomatic [preclinical], n = 93 prodromal/demented AD) and 181 euploid cognitively unimpaired (CU) individuals from the Down Alzheimer Barcelona Neuroimaging Initiative underwent a 3T‐MRI protocol (Table.1). T1‐weighted images were preprocessed using CAT12. GM volumes adjusted for demographics (age, sex) and nuisance variables (TIV, MRI scanner) were computed for each cortical region of the Hammer Atlas and for each DS participant, using the CU group as a reference. Adjusted volumes (W‐scores) were binarized using a threshold of ‐2.33 (corresponding to a regional volume <99th percentiles of the CU group) to examine the brain regions most frequently atrophied in DS compared to CU. Conditional probability analyses were additionally performed in DS to assess if a brain region was more likely to present with atrophy than another.ResultAdults with DS most frequently showed atrophy in the medial temporal lobe, anterior cingulate, and temporo‐parietal regions. This pattern remains essentially similar when using a dynamic range of thresholds (Fig1.A) and across clinical AD stages (Fig1.B), even though the proportion of individuals showing atrophy increased with disease progression (Fig1.C). Interestingly, the anterior cingulate was the most frequently atrophied region in asymptomatic but not prodromal/demented DS. Conditional probability analyses revealed that the hippocampus, amygdala, and anterior cingulate have a significantly higher probability of showing GM loss before any other regions. A second cluster of tempo‐parietal regions appears more likely to show atrophy than most other regions.ConclusionIn DS, GM atrophy appears to follow a stereotypical pattern that strongly resembles the one of sporadic AD. Brain developmental specificities (e.g., anterior cingulate) are coupled with AD‐like atrophy early in the disease and become less predominant with AD progression.
TRIAL21: A COHORT OF ADULTS WITH DOWN SYNDROME AT RISK OF DEVELOPING ALZHEIMER'S DISEASE
Authors: Rebillat Anne‐Sophie , Laffon De Mazieres Clarisse , Hiance‐Delahaye Anne , Baraton Caroline , Bourgerie Anne‐Sophie , Bourgeois Pauline , Clert Manon , Falquero Segolene , Martet Diane , Sacco Silvia , Vilaire Marie , Durand Sophie , Mircher Clotilde 
Published: December 2023

AbstractBackgroundTrisomy 21, in addition to being the first cause of intellectual disability, confers a high risk of developing Alzheimer’s disease (AD). The APP (Amyloid Precursor Protein) gene is located on chromosome 21, leading to high levels of ß‐amyloid peptide. However, there is great variability in the age of onset of symptoms.The objective of this study is to identify factors influencing the age of onset of the disease by following a cohort of adults with trisomy 21MethodThis is a prospective, single‐center, open‐label study. A total of 200 patients aged at least 35 years without a diagnosis of AD at baseline will be included.Baseline visit includes a medical examination, a neuropsychological evaluation, a blood sample and a lumbar puncture (if possible). A brain MRI is performed within 3 months. A medical visit takes place at 12 months. The end‐of‐study visit at 24 months includes a medical examination, a neuropsychological evaluation and a blood sample. An annual follow‐up for 10 years in the care setting is provided.ResultBetween April 2019 and January 2023, 119 patients were included, including 55 women and 64 men. The average age was 48 years.25 lumbar punctures and 90 brain MRI could be performed, as 86 visits at 12 months and 44 visits at 24 months.ConclusionEarly changes related to AD are particularly difficult to detect in adults with Trisomy 21 because of their intellectual disability. The identification of progression factors of the disease is essential to allow an early diagnosis for an appropriate management
Porphyromonas gingivalis Outer Membrane Vesicles as the Major Driver of and Explanation for the Neuropathogenesis, the Cholinergic Hypothesis, Iron Dyshomeostasis,∖ and Salivary Lactoferrin in Alzheimer’s Disease
Authors: Nara Peter N 
Published: December 2023

AbstractBackgroundPorphyromonas gingivalis (Pg) is a primary oral pathogen in the widespread biofilm‐induced “chronic” multi‐systems inflammatory disease(s) including Alzheimer’s disease (AD). It is possibly the only second identified unique example of a biological extremophile in the human body. Having a better understanding of the key microbiological and genetic mechanisms of its pathogenesis and disease induction are central to its future diagnosis, treatment, and possible prevention.MethodThe published literature around the role of Pg in AD highlights the bacteria’s direct role within the brain to cause disease. The available evidence, although somewhat adopted, does not fully support this as the major process. There are alternative pathogenic/virulence features associated with Pg that have been overlooked and may better explain the pathogenic processes found in the “infection hypothesis” of AD. The current paper suggests the highly evolved and developed Type IX secretory cargo system of Pg producing outer membrane vesicles may better explain the observed diseases.ResultA better explanation is offered for the discrepancy in the relatively low amounts of “Pg bacteria” residing in the brain compared to the rather florid amounts and broad distribution of one or more of its major bacterial virulence factors/protein/toxins. Related to this, the “Gingipains Hypothesis”, AD‐related iron dyshomeostasis, and the early reduced salivary lactoferrin, along with the resurrection of the Cholinergic Hypothesis may now be integrated into one working model.ConclusionThus it is hoped this presentation can provide a unifying model for the sporadic form of AD and guide the direction of research, treatment, and possible prevention.
Sex‐specific associations of cerebrospinal fluid YKL‐40 with white matter hyperintensities over a 7‐year follow‐up period
Authors: Peterson Amalia Jo , Zhang Panpan , Moore Elizabeth E. , Eaton James , Pechman Kimberly R. , Liu Dandan , Houston Michelle L , Davis L. Taylor , Gifford Katherine A. , Landman Bennett A. , Blennow Kaj , Zetterberg Henrik , Hohman Timothy J. , Jefferson Angela L. 
Published: December 2023

AbstractBackgroundWomen have a higher prevalence of Alzheimer’s disease (AD), but the underlying reason remains unknown. White matter damage is common in AD and partially attributed to inflammation. Animal models suggest that neuroinflammation with advanced age may differ between sexes, so we assessed whether sex modified associations between neuroinflammation assessed with cerebrospinal fluid (CSF) chitinase 3‐like 1 protein (YKL‐40) and white matter damage in older adults.MethodVanderbilt Memory and Aging Project participants (n = 152, baseline age 73±7 years, 33% female) underwent lumbar puncture at study entry and brain magnetic resonance imaging (MRI) serially over a 7‐year period (mean follow‐up = 5.5 years). CSF YKL‐40 was quantified using an enzyme‐linked immunosorbent assay. MRI T2‐FLAIR was used to quantify total and lobar white matter hyperintensities (WMHs) at each timepoint. Ordinary least squares regression and linear mixed‐effects models related baseline CSF YKL‐40 to baseline and longitudinal WMHs, adjusting for baseline age, sex, race/ethnicity, education, modified Framingham Stroke Risk Profile, cognitive status, apolipoprotein‐e4 status, and intracranial volume. Longitudinal models adjusted for follow‐up time. Models were repeated with a sex interaction.ResultIn main models, CSF‐YKL‐40 was cross‐sectionally unrelated to total and all lobar WMHs (p‐values>0.20) or longitudinal WMH progression (p‐values>0.06). However, CSF YKL‐40 cross‐sectionally interacted with sex on total, frontal, and parietal lobe WMHs (p‐values<0.05). In stratified models, higher CSF YKL‐40 levels related to greater WMH burden in the frontal (b = 0.005, p = 0.04), parietal (b = 0.005, p = 0.02), temporal (b = 0.003, p = 0.01), and occipital lobes (b = 0.003, p = 0.02) in females only. In longitudinal models, CSF YKL‐40 interacted with sex on temporal lobe WMH progression (p = 0.01), such that higher CSF YKL‐40 at study entry was associated with progression of temporal lobe WMHs over time in females only (b = 0.002, p = 0.003).ConclusionHigher levels of neuroinflammation, reflected by higher levels of CSF YKL‐40, are associated with greater WMHs cross‐sectionally and progression over time in females only. Longitudinally, this effect is specific to the temporal lobe, where AD neuropathology originates. Neuroinflammation may be a key, sex‐specific etiology of temporal lobe white matter damage in females. Additional research is needed to characterize the role of this damage in cognitive decline.FundingIIRG‐08‐88733, R01‐AG034962, R01‐AG056534, K24‐AG046373, P20‐AG068082
Hub vulnerability and short path length to entorhinal cortex are associated with tau binding in Alzheimer’s disease: a combined MEG/PET study
Authors: Schoonhoven Deborah N , Millan Ana P , Coomans Emma M. , Yaqub Maqsood , van Nifterick Anne M , Visser Denise , Ossenkoppele Rik , Tuncel Hayel , van der Flier Wiesje M. , de Haan Willem , Scheltens Philip , Stam Cornelis J , van de Giessen Elsmarieke , Hillebrand Arjan , Gouw Alida A 
Published: December 2023

AbstractBackgroundBrain network studies have revealed that highly connected ‘hub’ regions are particularly vulnerable to Alzheimer’s disease (AD) pathology. Additionally, the ‘‘transneuronal spread” hypothesis proposes that a toxic agent (tau) propagates along shortest paths through functionally connected neurons, driven by aberrant neuronal activity. We investigate whether network characteristics as determined using magnetoencephalography (MEG) are correlated to tau pathology in the different stages of AD.MethodWe analysed source‐reconstructed MEG data and dynamic 100‐minutes [18F]flortaucipir PET from 57 subjects positive for amyloid‐beta (Aβ)‐pathology (preclinical AD (n = 16)), mild cognitive impairment (MCI (n = 16)) and AD dementia (n = 25)). Cognitively healthy subjects without Aβ‐pathology were included as controls (n = 25). For each subject, we obtained a network based on the alpha band amplitude envelope correlation (AEC‐c, 8‐13Hz), and theta band phase lag index (PLI, 4‐8Hz), based on the Brainnettome atlas. For each node in the network, we obtained the following measures: weighted degree, degree, betweenness centrality, eccentricity (as measures of hubness); distance to left entorhinal cortex (measure of shortest path/transneuronal spread); hub disruption index for all previous hubness measures (selective hub damage) and [18F]flortaucipir BPND. Pearson’s correlations were calculated between group averages of network measures and tau‐PET binding (FDR‐corrected). Furthermore, we analysed whether network measures of the previous disease stage correlated with [18F]flortaucipir retention in the subsequent disease stage.ResultHub regions were predominantly found in the temporal areas (Fig‐1). Higher ‘hubness’ and shorter neuronal distance to epicentre were associated to higher tau binding in all stages of the AD continuum (Fig‐2a). Disproportional disruption to hub regions in the AEC‐c alpha band was associated with increased tau binding, but the opposite effect was found for the PLI theta band (Fig‐2b). Finally, high weighted degree, degree, and betweenness centrality in the preceding disease stage were correlated with increased tau binding in subsequent disease stages (Fig‐2c).ConclusionHub regions and transneuronal spreading are key mechanisms in the propagation of tau pathology across the AD brain. Furthermore, hubs are particularly vulnerable to tau. The insight that high neuronal activity might play a causal role in Alzheimer’s disease can have implications for early detection and interventional strategies.