bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiple pathologies underlying a very late‐onset schizophrenia‐like psychosis
Authors: Socher Karen L R , Rodriguez Roberta Diehl , Otaduy Maria Concepción Gracía , Martin Maria Da Graça Morais , Espadoto Beatriz , Suemoto Claudia Kimie , da Costa Leite Claudia , Costa Paula Akemi Nagai , Grinberg Lea T. , Brucki Sonia , Nitrini Ricardo 
Published: December 2023

AbstractBackgroundVery late‐onset schizophrenia‐like psychosis term was recently introduced and includes schizophrenia, delusional disorders, and paranoid psychosis after 60 years. More than 60% of cases are due to secondary causes, mostly neurodegenerative diseases. We described clinical, neuropathological, and radiological findings of a woman with psychotic symptoms preceding cognitive impairment.MethodClinical data were obtained by interview with a next of kin. Both hemispheres were fixed in 4% buffered paraformaldehyde within 15 hours of death. The following samples from both fixed hemispheres were embedded in paraffin: middle and inferior frontal, middle and superior temporal, superior frontal and anterior cingulate gyri, angular gyrus, insula, visual cortex, hippocampal formation at the level of the lateral geniculate body, amygdala, basal ganglia at the level of the anterior commissure, thalamus, midbrain, brainstem, and cerebellar cortex and dentate nucleus. All areas were stained with hematoxylin and eosin (H&E), and immunohistochemistry with antibodies against β‐amyloid (4G8), phospho‐tau (AT8), phospho α‐synuclein (81A), phospho TDP‐43, and p62.ResultA 69‐year‐old woman started with visual and auditory hallucinations and delusions, followed by cognitive impairment and hyperorality. Three years later, she became bedridden and died at 73. Postmortem 7T MRI showed diffuse cortical atrophy more prominent in the temporal cortex and anterior hippocampus. Unfixed brain 887g weight. Macroscopy depicted cortical brain atrophy with enlargement of the lateral ventricles, depigmentation moderate of substantia nigra, and severe of locus coeruleus. Microscopy showed bilateral hippocampal sclerosis. At immunohistochemistry: diffuse Lewy‐type pathology corresponding to Braak stage 6 of PD‐related pathology, Braak staging VI for AD, amyloid deposits in diffuse, cored, and perivascular plaques in cortical and subcortical areas (CERAD B and Thal 5), and neuronal, glial TDP‐43 inclusions were found in cortical and limbic areas corresponding to LATE 3 and Staging 6.ConclusionLate‐onset psychosis is associated with frontotemporal involvement and is frequently observed in those with C9orf72 mutation. Co‐pathologies may influence clinical and neuropsychiatric presentation and disease progression in mixed dementias.
Interactions between APOE Genotype, the Gut Microbiome and Polyphenol Metabolism
Authors: Hunt Thomas J , Martinsen Anneloes , Minihane Anne‐Marie , Flanagan Emma , Hornberger Michael , Mena Pedro , Rio Daniele Del , Muller Michael , Kroon Paul , Vauzour David 
Published: December 2023

AbstractBackgroundAPOE genotype is the most significant genetic risk factor for the development of Alzheimer’s disease, with 40‐60% of Alzheimer’s patients carrying at least one APOE4 allele. In addition to its pleiotropic effects on ageing and the brain, recent evidence suggests that APOE genotype may also affect the gut microbiome structure and function. Dietary polyphenols ‐ bioactive molecules found in fruits and vegetables ‐ have been reported to slow cognitive decline and to affect gut microbiota speciation and metabolism. However, differences in the metabolism of these bioactive compounds according to APOE genotypes have not been previously explored.MethodTo address this knowledge gap, we ran an animal study using APOE3 and APOE4 targeted replacement (TR) mice. Animals were fed on a low‐fat diet (10 kcal% from fat), a high‐fat diet (45 kcal% from fat) or a high‐fat diet supplemented with a flavan‐3‐ols rich cocoa extract (100 mg/kg body weight) for 16 weeks. This model has been widely used as a physiologically relevant model for age‐related neuroinflammation and cognitive decline in humans, with consistently higher levels in the APOE4‐TR vs. APOE3‐TR mice, particularly if fed a “western type‟ high fat diet.ResultSignificant shifts in microbiome beta diversity were observed in APOE3‐TR mice only under a high fat diet, with these mice acquiring an APOE4‐TR‐like phenotype. Addition of flavan‐3‐ol rich cocoa reversed this shift by increasing rc4_4, Prevotella, Aldercreutzia and Faecalibacterium genera (log LDA score >2; FDR p‐adjusted 0.1) in APOE3‐TR mice. Surprisingly, flavan‐3‐ol rich cocoa did not affect the structure of the APOE 4 mice’s microbiome. Such results were paralleled by an increased urinary excretion of the colon flora‐derived flavan‐3‐ol metabolites 5‐(3’,4’‐dihydroxyohenyl)‐γ‐valerolactone (p<0.05), 5‐(hydroxyphenyl)valeric acid‐4‐sulfate (p<0.01) and 4‐hydroxy‐5‐(hydroxyphenyl)valeric acid sulfate (p<0.01) in APOE4‐TR mice. These preliminary findings were further validated in a human cohort study (COMBAT Study; NCT03679533) following 12‐week consumption of flavan‐3‐ols rich cranberries.ConclusionThe relationship between polyphenols intake and APOE genotype is intriguing, and further work is required to gain a better understanding of the physiological and molecular mechanisms underlying such disparity between the genotypes.
Identifying and differentiating dementias with EEG fractal dimension distributions
Authors: Yoder Keith J , Brookshire Geoffrey , Gerrol Spencer , Quirk Colin , Lucero Ché 
Published: December 2023

AbstractBackgroundAlzheimer’s disease dementia (AD‐dementia) and non‐AD dementia have both been associated with decreases in fractal dimension and spectral slowing in electroencephalography (EEG). Here, we describe a set of EEG features ‐ Fractal Dimension Distributions (FDD) ‐ which quantifies the stability of fractal dimensions over time within specific frequency bands. We compare the performance of models trained using this FDD feature to models using age, spectral power, or overall fractal dimension.MethodWe analyzed resting‐state data from older adults (age M = 71, range = 55‐86) with subjective cognitive impairment (SCI; N = 97, 59 female) or dementia (N = 51, 32 female), including 38 with AD (N = 33). We calculated the Fractal Dimension Distributions (FDD) by first computing the Higuchi fractal dimension within moving windows, then summarizing the distribution of these fractal values using the mean and standard deviation within standard frequency bands. Finally, we trained regularized logistic regression models to classify participants as having SCI or dementia, and as having SCI or AD‐dementia. We compared the performance of models using FDD or standard measures of fractal dimension. Models were evaluated using balanced accuracy, weighted sensitivity, and weighted specificity calculated using 5‐fold cross‐validation.ResultFor SCI vs Dementia, the model using FDD (accuracy = 74%, sensitivity = 67%, specificity = 81%, p < .001) had higher accuracy, sensitivity, and specificity than models trained on age, standard measures of fractal dimension, or spectral power. Similarly, the model trained to predict SCI vs AD‐Dementia was most accurate when using FDD (accuracy = 73%, sensitivity = 59%, specificity = 97%, p < .005). The features useful for discriminating SCI from Dementia partially overlapped with the features useful for discriminating SCI from AD‐Dementia.ConclusionOur novel feature, FDD, outperforms standard measures of fractal dimensions or spectral band power at discriminating between SCI and dementia. Moreover, FDD may help to distinguish between AD and other varieties of dementia.
Left Frontoparietal Connectivity Counteracts Locus Coeruleus‐Related Attentional Decline in Preclinical Alzheimer’s Disease
Authors: Pahl Jennifer , Prokopiou Prokopis C. , Bueicheku Elisenda , Schultz Aaron P. , Papp Kathryn V. , Rentz Dorene M. , Sperling Reisa A. , Johnson Keith A. , Jacobs Heidi I.L. 
Published: December 2023

AbstractBackgroundAutopsy work reported that neuronal density in the locus coeruleus (LC) provides neural reserve against cognitive decline in dementia. Recent neuroimaging and pharmacological studies have also ascribed a protective role of the LC against cognitive decline, possibly mediated by prefrontal functional connectivity (FC). Interestingly, higher left frontoparietal network (LFPN) FC provides resilience against cognitive decline in preclinical sporadic or autosomal Alzheimer’s disease (AD). Given that the FPN and the LC play an important role in attentional control, and attention deficits are affected early in the disease process, we aimed to examine whether LFPN‐FC can counteract the impact of poor LC structural health on attention in the context of AD pathology.Method143 participants from the Harvard Aging Brain study who underwent 3T resting‐state functional MRI, LC structural imaging, PiB(Aβ)‐PET, and up to 4 years of cognitive follow‐ups were included (90 F, mean age = 75±9.88, Table 1). The Digit Symbol Substitution Test (DSST) assessed attentional control. Robust linear regression associated LC integrity or LFPN connectivity to DSST performance at baseline. Robust mixed effect analyses examined the associations between DSST decline and (i) the two‐way interaction between LC integrity (or LFPN‐FC) and PiB (DVR‐PVC), or (ii) the three‐way interaction between LC integrity, LFPN‐FC, and PiB (DVR‐PVC). All analyses were adjusted for age, sex, and years of education.ResultAt baseline, lower LFPN‐FC (p = 0.001) was related to worse performance on the DSST, while no such association was found for LC integrity (p = 0.26). Longitudinally, both, lower LC integrity (p<0.001) and LFPN‐FC (p = 0.026) were associated with faster DSST decline, especially at higher PiB levels (Figure 1). The modulating effect of LFPN‐FC is most prominent under lower LC structural integrity values, where higher levels of LFPN‐FC were associated with less steep decline on the DSST, in particular in individuals with higher PiB (p = 0.036, Figure 2).ConclusionOur findings demonstrate that when LC structural health is poor, higher LFPN‐FC can maintain cognitive performance even at higher levels of Aβ deposition in preclinical AD. These results provide critical insights and targets to support specific brain mechanisms that delay symptom progression in the early stages of the disease.
Selective targeting and protection against toxic amyloid‐beta oligomers by PMN310, a monoclonal antibody rationally designed for greater therapeutic potency in Alzheimer’s disease
Authors: Cashman Neil R , Gibbs Ebrima , Silverman Judith M , Zhao Beibei , Coutts Juliane , Peng Xubiao , Plotkin Steven S , Kaplan Johanne 
Published: December 2023

AbstractBackgroundA large body of evidence indicates that the most pathogenic species of amyloid‐beta (Aß) in Alzheimer’s disease (AD) consists of soluble toxic oligomers (AßO) as opposed to insoluble fibrils and monomers. Clinical results to date indicate that non‐selective antibodies that bind Aß monomers, oligomers and plaque fail to provide a therapeutic benefit. Partially selective antibodies that bind AßO and plaque have shown improved success but are associated with dose‐limiting adverse events (amyloid‐related imaging abnormalities; ARIA). These findings suggest that antibodies capable of selectively neutralizing toxic AßO may achieve improved efficacy and safety. Monoclonal antibody PMN310 was raised against a conformational epitope predicted by computational modeling to be exposed on toxic AßO but not monomers or fibrils. A summary of the selectivity and protective activity of PMN310 against toxic AßO in vitro and in vivo is presented.MethodThe binding selectivity of PMN310 was characterized and compared to that of other Aß‐directed antibodies by surface plasmon resonance (SPR) and immunohistochemistry (IHC). Its ability to neutralize the propagation and toxicity of AßO was assessed in vitro in a thioflavin‐T propagation assay and in cultures of primary rodent neurons, respectively. In vivo protective activity was tested in wild‐type mice injected intracerebroventricularly (ICV) with AßO and in the APP/L transgenic mouse model of AD.ResultIn SPR analysis, PMN310 showed selective binding to AßO over monomers and, compared to otherAß‐directed antibodies, was minimally impacted by monomer competition in binding to toxic oligomers from AD brain extract. In addition, PMN310 did not bind to Aß plaque or vascular deposits as determined by IHC suggesting a potentially reduced risk of ARIA compared to other Aß‐directed antibodies. In vitro, PMN310 inhibited AßO propagation and neuronal toxicity. In vivo, PMN310 prevented AßO‐induced loss of memory formation after ICV injection. Systemic administration to APP/L transgenic mice preserved memory and learning in the water maze task.ConclusionThe antibody PMN310 was shown to selectively bind toxic AßO and protect against their pathogenic activity in vitro. In two rodent models of AD, PMN310 protected memory function, suggesting that PMN310 may offer a new therapeutic option for the treatment or prevention of AD.
A Multivariate Genome‐Wide Association Study of the Shared Genetic Architecture Among Modifiable Risk Factors for Dementia: 590 Loci Associated with Brain Health
Authors: Foote Isabelle F , Bandres‐Ciga Sara , Kim Jonggeol Jeff , Alvarado Chelsea X , Leonard Hampton L , Bothongo Phazha LK , Grotzinger Andrew D , Jacobs Benjamin M , Waters Sheena , Dobson Ruth , Noyce Alastair J , Bhui Kamaldeep S , Korszun Ania , Marshall Charles R 
Published: December 2023

AbstractBackgroundTargeting modifiable risk factors may prevent or delay dementia. The mechanisms by which some risk factors influence dementia remain unclear and commonality between risk factors is often overlooked. We aimed to characterize the shared genetic architecture of modifiable risk factors for dementia, and use this to explore whether shared pathways influence dementia pathogenesis and brain health.MethodWe performed two multivariate genome‐wide association studies (GWAS) to characterize the shared genetic architecture of 12 modifiable risk factors for dementia using genomic structural equation modeling (GSEM). One GWAS measured genetic associations with 3 latent subgroups of closely correlated risk factors, whereas our second GWAS measured genetic associations shared across all 12 risk factors (Figure 1). We tested whether the associated variants were enriched in neuronal/glial subtypes and epigenetic marks found in different brain regions using stratified‐GSEM and identified potentially causal genes for each of the latent factors using gene mapping techniques and summary‐data‐based Mendelian randomization. Pathway analysis was conducted to examine whether the prioritized genes were implicated in dementia‐related biological pathways.ResultWe identified 305 genome‐wide significant loci for the 3‐factor model of modifiable dementia risk and 285 genome‐wide significant loci for the Common Factor. Thirty‐four of these loci were novel (not previously associated with any phenotype by GWAS). Post‐GWAS analyses uncovered multiple links between the shared risk factor loci and dementia pathogenesis. Stratified‐GSEM showed that shared risk factor variants are significantly enriched in regions of the brain that degenerate in dementia, including the hippocampus and prefrontal cortex. Gene mapping identified potentially shared causal genes between risk factor loci and Alzheimer’s disease (AD) loci. Pathway analysis indicated that our prioritized genes were enriched in AD pathways, protein aggregation and neuronal cell signaling. Mendelian randomization provided evidence for a causal role of the shared risk factor variants in AD pathogenesis.ConclusionWe highlight multiple genomic regions where genetic overlap between modifiable risk factors seems to directly influence dementia‐related pathways in regions of the brain that are known to degenerate in dementia. Our findings provide novel insights into the potential biological mechanisms by which modifiable risk factors may increase risk for dementia.
Spatiotemporal Assessment of Locus Coeruleus Integrity Predicting Cortical Tau and Cognition
Authors: Bueichekú Elisenda , Diez Ibai Palacio , Kim Chan‐Mi , Becker Alex , Koops Elouise A. , Kwong Kenneth , Papp Kathryn V. , Salat David H , Bennett David A. A , Rentz Dorene M. , Sperling Reisa A. , Johnson Keith A. , Sepulcre Jorge , Jacobs Heidi I.L. 
Published: December 2023

AbstractBackgroundMisfolded tau protein, an Alzheimer’s Disease (AD) hallmark, accumulates decades before the emergence of cognitive decline. Autopsy and neuroimaging studies support the locus coeruleus (LC) as an early site of tau and its contribution to disease progression. However, whether tau in LC precedes cortical tau deposition remains unclear. Understanding the topography of tau progression and the biological factors making specific neuronal systems prone to AD‐related pathology is essential to target interventions appropriately. We examined the spatiotemporal relationships between LC integrity and cortical tau accumulation and its relevance to cognition.,MethodsWe combined longitudinal LC‐integrity (T1‐TSE‐imaging) and tau pathology (18F‐FTP‐PET) data from 77 adults (Fig1A). We used whole‐brain voxel‐wise GLM analysis to investigate the relationship between baseline LC‐integrity (inverted signal) and longitudinal tau accumulation and compared the correlation distributions in both directions. Robust regression analysis was used to examine whether the observed tau spreading pathway predicts PACC5 performance at follow‐up. We used neuropathological measures from 160 cognitively unimpaired or MCI/AD adults (Fig1B) to support the in‐vivo neuroimaging data. Spearman‐rank partial correlations were used to relate LC tangle density to tangles in temporal cortex areas. Using AHBA, the biological backgrounds underlying the connectomic‐genetic relationships related to LC were explored using a whole‐brain region‐wise transcriptomic similarity analysis.,ResultsCorrelations between baseline LC‐integrity and follow‐up tau were stronger than the inverse correlations, indicative of lower LC‐integrity preceding tau accumulation in MTL (Fig1C‐D). LC tangle density was strongly related to tangles in MTL structures (Fig1E). Longitudinal tau accumulation in the LC‐MTL axis is associated with lower cognitive performance (Fig2). Common neurogenetic profiles exist between LC and MTL/limbic regions, supporting a shared connectomic‐transcriptomic substrate. The genetic profile displays specific biological functions in protein transport regulation and lipid biosynthetic processes (Fig3).,ConclusionOur results suggest that changes in LC‐integrity may occur before tau spreads into the MTL, which jointly contributes to lower cognitive performance. The neurogenetic profiles can provide a biological framework for identifying individuals more likely to be at risk for AD disease progression. Future developments could examine the intersection between amyloid and LC‐related tau progression in the context of AD.
Cerebral perfusion is not altered after 24 weeks of daily anthocyanin consumption in a population population of individuals at increased risk for dementia
Authors: Kallevag Oystein 
Published: December 2023

AbstractBackgroundPreliminary research suggests that anthocyanin‐consumption may improve memory, with a positive influence on the blood vessels as a possible contributing factor to these effects (1). We investigate the potential of long‐term consumption of anthocyanins to improve regional cerebral perfusion in a population of individuals at increased risk for dementia.MethodFrom 2018 to 2020 we performed a 24‐week randomised, doubleblind, placebo‐controlled study on 87 cognitively healthy, defined by Mini‐Mental State Exam (MMSE) and clinical dementia rating (CDR) (2. Anthocyanins were given in Medox® capsules that contained 80 mg natural purified anthocyanins, and the dosage was 4 capsules daily (i.e., 320mg/d of anthocyanins). Cerebral perfusion was measured non‐invasively with ASL‐MRI at baseline and after 24 weeks of daily anthocyanin‐consumption. The MRI‐scans analyzed using the FMRIB Software Library (FSL v 6.0.1; Analysis Group, Oxford, UK).ResultThe mean age in the anthocyanins group was 69.8 (± 5.5) years and the placebo group was 69.1 (± 6.0) years. When corrected for FWER, the anthocyanin > placebo analysis did not reveal any significant increased regional cerebral perfusion. There were no clusters found. When extracting maximum intensity, the lowest p‐value present was 0.839. When corrected for FWER, the placebo > anthocyanin analysis did not reveal any significant increased regional cerebral perfusion. The lowest p‐value present was 0.889 located in the right temporal pole.ConclusionOur results show no significant differences in cerebral perfusion found between the control and experimental group after 24 weeks. The data does not provide evidence for, in a population of older adults with risk of developing dementia, a daily dose of 320 mg anthocyanin ingested over a period of 24 weeks to affect cerebral perfusion to a level measureable by ASL‐MRI.1. Kent K, Charlton K, Roodenrys S, Batterham M, Potter J, Traynor V, et al. Consumption of anthocyanin‐rich cherry juice for 12 weeks improves memory and cognition 23 in older adults with mild‐to‐moderate dementia. Eur J Nutr. 2017;56(1):333‐41.2. Khalifa K, Bergland AK, Soennesyn H, Oppedal K, Oesterhus R, Dalen I, et al. Effects of Purified Anthocyanins in People at Risk for Dementia: Study Protocol for a Phase II Randomized Controlled Trial. Front Neurol. 2020;11:916.
Inadequate sleep associated with increased odds of subjective cognitive decline among transgender and gender nonbinary adults in the U.S., 2016‐2018
Authors: Lambrou Nickolas H. , Flatt Jason D. , Cicero Ethan C. 
Published: December 2023

AbstractBackgroundInadequate sleep (<7 hours/night) and subjective cognitive decline (SCD), a self‐reported experience of worsening memory or thinking, are independently associated with an increased risk for Alzheimer’s disease and related dementias (ADRD) and cognitive impairment. Transgender and nonbinary (TNB) adults report significantly poorer sleep quality and are more likely to report SCD compared to cisgender adults. However, little is known about ADRD risk or how inadequate sleep is associated with SCD among TNB adults.Method2016‐2018 Behavioral Risk Factor Surveillance System data, representing 14 U.S. states that assessed sleep duration, SCD, and TNB status from adults ages 45+, were analyzed to examine differences in inadequate sleep prevalence and SCD among TNB adults (n = 394) and cisgender adults (n = 120,688). Odds ratios (OR) along with 95% confidence intervals (CI) were calculated to investigate group differences in inadequate sleep prevalence. A separate analysis compared the prevalence of SCD among TNB and cisgender adults with inadequate sleep.ResultInadequate sleep was highest among TNB adults (37.9%) compared to cisgender adults (31.34%). TNB adults were 34% more likely to report inadequate sleep compared to cisgender adults (95% CI: 1.1‐1.7, p = 0.0180). Inadequate sleep significantly increases the likelihood of SCD by 1.3 times (95% CL: 1.2, 1.3) compared to sleeping ≥7 hours/night. Among those with inadequate sleep, TNB adults were 2.3 times more likely to report SCD compared to cisgender adults (95% CI: 1.2‐3.6, p = <0.0001).ConclusionInadequate sleep and its relationship with SCD is not uniformly experienced among TNB and cisgender adults. It is important to explore and address modifiable risk factors affecting sleep duration among TNB adults. Given the literature linking sleep duration, SCD, and ADRD risk, these data highlight the need for additional research focused on better understanding TNB cognitive health. The use of objective measures to assess sleep and cognition will provide more precision, which is needed to develop tailored interventions for TNB adults.