bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex differential effects on the joint contribution of air pollution and biological aging on cognitive performance in individuals at risk of Alzheimer’s disease
Authors: Rodríguez‐Fernández Blanca , Sánchez‐Benavides Gonzalo , Minguillon Carolina , Cirach Marta , Nieuwenhuijsen Mark , Sunyer Jordi , Fauria Karine , Molinuevo Jose Luis , De Vivo Immaculata , Navarro Arcadi , Gispert Juan Domingo , Sala‐Vila Aleix , Crous‐Bou Marta , Vilor‐Tejedor Natalia ,   for the ALFA study
Published: December 2023

AbstractBackgroundAir pollution is associated with cognitive performance, risk for AD and may accelerate biological aging. Biological aging due to telomere shortening has been associated with cognitive impairment. However, few studies have looked at the link between air pollution, telomere length, and cognitive performance among sexes. In this study, we investigated the joint effect of sex, air pollution, and leukocyte telomere length (LTL), on cognitive performance in cognitively unimpaired (CU) individuals at risk of AD.MethodThe study included 1,472 middle‐aged CU adults with increased risk of AD from the ALFA study [Table 1]. Residential exposure to air pollutants including nitrogen dioxide (NO2) and particulate matter (PM2.5, PM10) was estimated by land use regression models. LTL was determined by qPCR from DNA extracted from peripheral blood leukocytes. LTL was residualized against chronological age and sex (rLTL). A cognitive battery was administered to assess verbal memory, psychomotor speed, visual processing and executive function. Further, episodic memory (EM), executive function and Preclinical Alzheimer Cognitive Composite (PACC) composites were calculated by averaging normalized raw scores of the subtests. Models were corrected by chronological age, years of education and APOE‐ε4 status. Sex‐specific effects were investigated by adjusting interaction models.ResultThere was no overall effect of neither rLTL nor air pollution on cognitive performance, but crossover interactions with sex were found. Exposure to higher levels of NO2 and PM2.5 were associated with worse EM only in men [Figure 1]. Three‐way interaction models revealed longer rLTL and lower levels of air pollution were associated with better performance on PACC (for PM2.5, PM10 and NO2) and EM (for PM10 and NO2) among men. In women, these associations were only observed at higher exposure levels of air pollution [Figure 2].ConclusionThe results show that lower levels of air pollution allow for the protective effect of rLTL on cognitive performance only in men for whom air pollution had a stronger negative impact. In women, the results show different mechanisms through which air pollution and rLTL affect cognitive performance. Further analyses will be conducted to gain insight into the observed effects.
Cognitively Unimpaired Multiparous Women Have Higher CSF p‐tau181 Levels Which Have More Deleterious Effects on Neurodegeneration and Executive Function
Authors: Brugulat‐Serrat Anna , Escalante Armand González , Sánchez‐Benavides Gonzalo , Milà‐Alomà Marta , Shekari Mahnaz , Ashton Nicholas J. , Karikari Thomas K , Kollmorgen Gwendlyn , Carmona Susana , Falcon Carles , Cacciaglia Raffaele , Anastasi Federica , Grau‐Rivera Oriol , Carboni Margherita , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Gispert Juan Domingo ,   for the ALFA Study
Published: December 2023

AbstractBackgroundEpidemiologic studies show that multiparity (≥3 children) is associated with a higher risk of clincal AD in cognitively unimpaired (CU) women. However, studies exploring the impact of parity on AD biomarkers are scarce. We explored the association between number of children and imaging and fluid AD biomarkers, and the related interaction with neurodegeneration and cognition.MethodWe included 210 CU parous women from the ALFA+ cohort with 34 nulliparous women and 152 men with children as controls. The number of children was dichotomized as <3 children vs ≥3 children. All CSF biomarkers were measured using the Roche NeuroToolKit and Elecsys® immunoassays (both Roche Diagnostics International Ltd), except p‐tau231 and GAP‐43 (ELISA). All plasma biomarkers were measured using the Simoa HD‐X (Quanterix Corp) except sICAM1 (MSD). Jack’s cortical thickness AD signature was used as a marker of neurodegeneration. Cognitive change (3‐year follow‐up) was measured with a PACC‐like composite as well as for individual cognitive domains. Biomarkers differences between parity groups were analyzed with ANCOVA adjusted by age. Independent linear models with biomarkers, AD signature and cognitive change as dependent variable were constructed. The number of children was set as predictor, and age, APOE‐ε4, and age at first birth as covariates in all models. Interaction terms between number of children and biomarkers were modeled. p‐values <0.05 were considered as significant.ResultSeveral biomarkers were significantly higher in grand multiparours women (Table 1). Linear regression results (Table 2, Fig. 1A) showed that multiparity was associated with higher CSF p‐tau181 levels. Moreover, multiparity interacted with CSF p‐tau181 to predict thinner cortical thickness in AD‐sensitive regions and a steeper decline in executive function (Table 2, Fig. 1B & 1C). No significant associations in men and nulliparous women were found.ConclusionHaving ≥3 children increases the risk of higher CSF p‐tau181 levels in CU middle‐aged women, with CSF p‐tau181 having a more deleterious effect on cortical thickness and change on executive function performance. These findings contribute to our understanding of the higher risk for AD observed in CU multiparous women, who show higher susceptibility and more adverse downstream consequences to tau pathology.
The mismatch negativity as an index of cognitive impairment in adults with Down syndrome
Authors: Saini Fedal , Masina Fabio , Wells Jasmine , Rosch Richard , Startin Carla , Hamburg Sarah , Strydom Andre 
Published: December 2023

AbstractBackgroundPeople with Down syndrome (DS) have a high risk of developing Alzheimer’s disease (AD; Zis and Strydom 2018). The mismatch negativity (MMN) is an event‐related potential that can be used to index cognitive decline (Näätänen et al., 2011). Given its relative independence from attentional processes (Naatanen and Näätänen 1992), the MMN may be particularly useful when studying populations with intellectual disability, who may find sustained attention tasks challenging. We therefore investigated the MMN in people with DS and its association with cognitive abilities.MethodsMMN responses to a passive auditory oddball task were recorded from 27 adults with DS (aged 18 to 59) without any hearing impairments. Associations between MMN and age, as well as memory, language, IQ, and attention scores were examined.ResultsThe MMN was present only in young adults up to the age of 40 and the latency was prolonged. Attenuation of MMN amplitude was associated with poorer memory scores. Finally, longer MMN latencies were associated with increased inter‐individual performance variability and worse performance on memory, verbal, and general IQ tasks.ConclusionOverall, our results indicate that MMN amplitude may be associated with AD‐related memory loss, while increased MMN latency seems to reflect verbal abilities in people with DS. Furthermore, the association between MMN latency and inter‐individual performance variability may suggest the presence of AD‐driven white matter degenerations affecting the brian’s frontal lobe. Therefore, the MMN may represent a valuable tool for studying cognitive abilities and AD pathology in DS.
References
:Naatanen R, Näätänen R. 1992. Attention and brain function. Psychology Press.Näätänen R, Kujala T, Kreegipuu K, Carlson S, Escera C, Baldeweg T, Ponton C. 2011. The mismatch negativity: an index of cognitive decline in neuropsychiatric and neurological diseases and in ageing. Brain 134(12):3435‐3453.Zis P, Strydom A. 2018. Clinical aspects and biomarkers of Alzheimer’s disease in Down syndrome. Free Radical Biology and Medicine 114:3‐9.
Single nucleotide polymorphisms linked to Alzheimer’s disease are associated with distinct neuropathological phenotypes
Authors: Laureyssen Celeste , Gawor Klara , Van Dongen Jasper , Kucukali Fahri , Koper Marta J , Ronisz Alicja , Otto Markus , von Arnim Christine , Van Damme Philip , Vandenberghe Rik , Thal Dietmar Rudolf , Sleegers Kristel ,   Complex Genetics of Alzheimer’s Disease group
Published: December 2023

AbstractBackgroundNeurodegenerative brain diseases (NBDs) ultimately result in neuronal loss and subsequent cognitive decline. In Alzheimer’s disease, tau neurofibrillary tangles (NFT) and amyloid plaques are considered as the hallmark lesions, but there are a number of other distinct features that are not exclusive to AD and do occur to a certain extent in other NBDs.MethodWe extracted DNA from a cohort of 382 post‐mortem brains of NBD patients and controls with detailed neuropathological characterization. Genotyping of 85 genetic loci, previously found to be associated with AD, is ongoing using an in‐house developed oxford nanopore technologies (ONT) multiplex assay, allowing simultaneous sequencing of all variants on an ONT Flongle platform. Base‐ calling, alignment to Hg38 and variant calling were performed followed by QC on the data and regression analysis.ResultAssociation testing has currently been performed for 59 of the total 85 SNPs in the assay using either linear or logistic regression. This revealed significant association for an AD risk variant in the SIGLEC11 locus and Braak NFT staging (p = 0.003) and NIA_AA score (p = 0.002). Significance was also found for a risk variant in the EPHA1 locus and Hirano body score (p = 0.008). Furthermore, we found numerous nominally significant associations between risk loci and TDP43 LATE, granulovacuolar degeneration, phases of amyloid plaque distribution and CAA severity.ConclusionThese results possibly highlight biological pathways involved in generating these additional features. Our ongoing work is currently focusing on increasing our sample size to further validate the associations we discovered and optimizing our ONT assay.
Amyloid re‐accumulation after donanemab treatment: summary from 3 interventional trials
Authors: Shcherbinin Sergey , Gueorguieva Ivelina , Cheng Yun‐Ju , Evans Cynthia D. , Case Michael G. , Chidambaram Swathi , Collins Emily C. , Brooks Dawn A. , Sims John R. , Lu Ming 
Published: December 2023

AbstractBackgroundIn TRAILBLAZER‐ALZ, amyloid clearance (defined as reaching <24.1 centiloids, CL) (Navitsky, 2018) was achieved for 40% of participants (mean baseline 107.6 CL) after 6 months of donanemab treatment (Mintun, 2021). The estimated time course of natural amyloid plaque accumulation at the amyloid‐negative stage is approximately 3.3 CL/year (Jagust, 2021). Our objective was to examine the longer‐term effect of donanemab on brain amyloid deposition by evaluating the amyloid re‐accumulation observed in trial participants who reached clearance and were no longer receiving donanemab infusions, and compare it with amyloid accumulation for untreated amyloid‐negative participants.MethodsIn I5T‐MC‐AACD (NCT02624778) and TRAILBLAZER‐ALZ (NCT03367403), we identified N = 46 participants with ≥2 post‐treatment florbetapir scans conducted approximately 6 months after reaching amyloid clearance (Table 1). Part C of ongoing TRAILBLAZER‐EXT trial (NCT04640077) is evaluating participants from TRAILBLAZER‐ALZ at least 52 weeks after the participant’s last dose of donanemab. To examine re‐accumulation rate, a linear regression was used to analyze change in amyloid level during post‐treatment using follow‐up time (in years) as a covariate. Furthermore, an advanced exposure‐response model (ERM) with all available dosing, pharmacokinetic and florbetapir data, over treatment and post‐treatment periods was employed (N = 304).ResultsAmong 46 participants who achieved amyloid clearance after donanemab treatment, a single participant (∼2%) became amyloid‐positive. The average amyloid level (mean±SD) changed from 4.4±8.9 to 3.9±11.4 CL during the observation period (mean 9.7±3.1 months) after stopping dosing. The rate of annualized change in amyloid level is approximately 3.4 CL/year. The rate of change in amyloid level was not significantly associated with amount of amyloid reduced over the treatment period or amyloid level achieved post‐treatment. ERM predicted an average rate of 3.4 CL/year for amyloid re‐accumulation in patients who reached clearance.ConclusionThe post‐treatment florbetapir scans at 9.7±3.1 months for amyloid‐negative I5T‐MC‐AACD and TRAILBLAZER‐ALZ participants suggest that a re‐accumulation rate is comparable with the inherent amyloid accumulation rate. Additional analyses of TRAILBLAZER‐EXT data with the longer post‐treatment period will be presented at the conference. Treatment with donanemab not only reduces amyloid levels in early, symptomatic AD patients below the amyloid‐positive threshold but also places them on a plaque accumulation trajectory similar to untreated, amyloid‐negative patients.
Dietary nitrate intake and the risk of dementia: a population‐based study
Authors: de Crom Tosca O.E. , Vernooij Meike W , Ikram M. Kamran , Voortman Trudy , Ikram M. Arfan , Blekkenhorst Lauren 
Published: December 2023

AbstractBackgroundNitric oxide is a free radical that can be produced from dietary nitrate and positively affect cardiovascular health. With cardiovascular health playing an important role in the etiology of dementia, we hypothesized a link between dietary nitrate intake and the risk of dementia. We therefore aimed to evaluate the association of total, vegetable and non‐vegetable dietary nitrate intake with the risk of dementia and to explore underlying mechanisms involving imaging markers of vascular brain health, i.e. cerebral perfusion, total brain volume, white matter hyperintensity volume, microbleeds, and lacunar infarcts.MethodDietary nitrate intake was assessed using food frequency questionnaires in 9,543 dementia‐free participants (mean age 64 years, 58% women) from the prospective population‐based Rotterdam Study. All participants were followed for the incidence of dementia, and 3,949 of the participants underwent a magnetic resonance imaging scan of the brain during a maximum of three consecutive examination rounds (average interval between scans 4.6 years). We used Cox models to determine the association between dietary nitrate intake and incident dementia. We further used linear mixed models and logistic regression models to assess the association of dietary nitrate intake with changes in imaging markers over time.ResultParticipants consumed on average 102.9 (standard deviation: 66.7) grams of dietary nitrate per day, which came on average for 81% from vegetable sources. During a mean follow‐up of 14.5 years, 1,472 participants developed dementia among whom 1,078 had Alzheimer’s disease. A higher intake of total and vegetable dietary nitrate intake was associated with a lower risk of dementia (hazard ratio (HR) [95% confidence interval (CI)] per 50 mg/day increase: 0.92 [0.87‐0.98] and 0.92 [0.86‐0.97], respectively), but no association between non‐vegetable dietary nitrate intake and the risk of dementia was observed (HR [95% CI]: 1.15 [0.64‐2.07]). Results were similar for Alzheimer’s disease. Dietary nitrate intake was also not associated with brain imaging markers.ConclusionA higher dietary nitrate intake from vegetable sources is associated with a lower risk of dementia. We found no evidence that this association was driven vascular brain health.
Blood‐brain barrier permeability measured with arterial spin labeling as potential cerebrovascular biomarker over the lifespan
Authors: Padrela Beatriz E. , Tee Mervin , Markus Sneve H , Geier Oliver , Mahroo Amnah , Grydeland Håkon , Fladby Tormod , Eickel Klaus , Günther Matthias , Barkhof Frederik , Hilal Saima , Mutsaerts Henk‐Jan , Petr Jan 
Published: December 2023

AbstractBackgroundBlood‐brain barrier (BBB) dysfunction is considered a hallmark of Alzheimer’s disease (AD), making non‐invasive imaging of BBB with arterial spin labeling (ASL) MRI a potential imaging biomarker (BBB‐ASL). However, the normal BBB development over the lifespan is unknown. Here, we created population‐based BBB‐ASL permeability reference maps, and aimed to investigate associations between BBB‐ASL, chronological age, and biological cerebrovascular age – expressed as white matter hyperintensities (WMH) volume.MethodCognitively‐unimpaired (CU) participants were included from Center for Lifespan Changes in Brain and Cognition (LCBC) (n = 28, age 58.9±16.1y) and University of Singapore (n = 30, age 55.8±6.1y). The Singapore cohort is known to be vascularly compromised and thus expected to have early cerebrovascular pathology in the form of WMH. Multi‐echo, multi‐post‐labeling‐delay pseudo‐continuous ASL images were acquired at two identical Siemens 3T scanners and analyzed with ExploreASL. Gray matter (GM) BBB water time‐of‐exchange (Tex) was quantified with and without partial‐volume correction (PVC). For Singapore data, WMH were segmented on 3D FLAIR. Linear regression models were used to investigate associations of Tex with age and WMH volume, with and without covarying for sex and site.ResultBoth site population‐averages (Figure 1) show similar Tex patterns, with slightly higher posterior variability in the Singapore data. GM Tex was negatively associated with age (Figure 2A) irrespective of PVC, and after covarying for sex and site (Table 1). GM Tex was also negatively associated with WMH volume (β = ‐0.005, p = 0.012), although the association became non‐significant if both PVC and sex and site corrections were applied (β = ‐0.005, p = 0.068).ConclusionOur findings support the hypothesis of increased BBB permeability with aging and there are signs of association with increased cerebrovascular age assessed with WMH volume. We aim to further increase our sample size and also investigate associations with other AD biomarkers.
Using real‐world general practitioner data to study the diagnosis and management of dementia: rationale and design
Authors: Baak Brenda N. , Swart Karin M.A. , van Maurik Ingrid S. , Nooralishahi Mahsa , van der Flier Wiesje M. , Herings Ron M.C. 
Published: December 2023

AbstractBackgroundGeneral practitioners (GPs) play a critical role in the early recognition of cognitive deficits and management of dementia. Timely diagnosis is important in light of potential disease‐modifying therapies and the potential to improve patient outcomes. We aimed to establish a real‐world data cohort utilizing data from GPs on individuals with dementia as a starting point, with the goal of gaining valuable insights into trajectories and management of dementia and patient outcomes. Here we describe the rationale and design.MethodWe selected individuals with dementia using Dutch GP data from the PHARMO Data Network, which includes diagnoses, symptoms, examinations, prescriptions, and communication between GPs and specialists. Diagnosis of dementia was defined as a diagnosis code or prescription of anti‐dementia drugs between January 1, 2011 and December 31, 2020. Persons were included if they had one year of history prior to dementia diagnosis. We described the cohort in terms of demographics and screening tests for cognitive impairment.ResultA total of 52,911 individuals with dementia were selected from a source population of 4.7 million persons. The mean age was 81 years (standard deviation [SD] = 8.65) and 31,343 (59%) were female (Table 1). On average, patients have 8.6 years (SD = 4.09) of data available prior to dementia diagnosis and can be followed‐up for 2.8 years (SD = 2.19) after diagnosis. The reason for end of follow‐up was death for 16,978 persons (32%), end of data availability for 21,314 persons (40%), and 14,699 (28%) reached December 31, 2020 and are still registered (i.e., active). We found the Mini‐Mental State Examination (MMSE) in GP records of 31,759 persons (60%), and the Montreal Cognitive Assessment (MoCA) and Rowland Universal Dementia Assessment Scale (RUDAS) for only 1,777 (3%), and 29 persons (<0.5%), respectively.ConclusionWe created a cohort of 52,991 individuals with dementia, providing a starting point for further research on trajectories and management of AD in primary care and patient outcomes. Next steps include matching the cohort with dementia‐free controls, enriching the cohort by established linkages to other data sources (e.g. hospital data), and examining healthcare resource utilization, indicators of cognitive decline, treatment, and young‐onset dementia.
Where is my hand? Proprioceptive disturbances in posterior cortical atrophy and typical Alzheimer’s disease
Authors: Yong Keir X X , Bancroft Matthew J , Bai Yuhan , Hayes Oliver S , Mahendran Sharveena , Ocal Dilek , Brotherhood Emilie V , Hoe Juanita , Kaski Diego , Pisella Laure , Crutch Sebastian J , Day Brian L 
Published: December 2023

AbstractBackgroundPosterior cortical atrophy (PCA) is a neurodegenerative syndrome most commonly caused by Alzheimer’s disease (AD) pathology. PCA is often considered the canonical ‘visual dementia’, characterised by the progressive loss of visual and posterior cortical functions corresponding to parieto‐occipital and occipito‐temporal atrophy. However, patient reports of difficulties finding sleeves of clothes, transferring between postures and determining heading direction imply non‐visual disturbances, consistent with the multisensory role of the posterior parietal cortex. Such reports raise questions regarding AD clinical heterogeneity, representing a substantial challenge to patients' independence and management of PCA and typical AD (tAD).MethodPatient (total n = 39; PCA n = 23; tAD n = 16) and control (n = 19) participants repeatedly reached to a proprioceptive target (their non‐dominant thumb) (Fig.A) with and without vision and tactile feedback (n = 40 trials per participant). The target was positioned passively behind a screen apparatus at five positions using an adjustable foam handrest. The primary outcome measure was absolute (medio‐lateral) error determined using whole‐body motion capture data (Fig.B).ResultAbsolute error was greater without than with vision across groups. However, the effect of removing vision on absolute error was smallest in the control group (estimated mean error with vision [95%CI]: 15mm [6,25]; without vision: 23mm [14,32]), greatest in PCA (with vision: 39mm [30,49]; without vision: 76mm [67,86]) and intermediate in the tAD group (with vision: 26mm [16,37]; without vision: 49mm [39,60]) (vision‐by‐group interaction: p<.001; Fig.C). For ∼5% of trials, absolute error exceeded 200mm in PCA and 120mm in tAD participants (Fig.B; control range: 0.01‐80mm). There was no evidence of an effect of tactile feedback in any group.The effect of target location differed between groups (location‐by‐group interaction: p<.001). Patient reaching errors were particularly apparent under postures where the target arm crossed the body midline (e.g. left arm in right hemispace); this effect was notably evident in the PCA group even with available vision (Fig.C).ConclusionFindings emphasise disturbed spatial awareness in PCA and tAD in the absence of vision, consistent with diminished body position sense‐ proprioception ‐ which may be mediated centrally through posterior parietal vulnerability. Findings suggest implications for assessment and management of disabling dressing, mobility, navigation and balance difficulties.