bluuebunny/crossref_metadata_2025 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

Background

Very 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.

Method

Clinical 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.

Result

A 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.

Conclusion

Late‐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

Background

APOE 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.

Method

To 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.

Result

Significant 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.

Conclusion

The 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

Background

Alzheimer’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.

Method

We 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.

Result

For 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.

Conclusion

Our 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

Background

Autopsy 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.

Method

143 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.

Result

At 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).

Conclusion

Our 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

Background

A 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.

Method

The 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.

Result

In 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.

Conclusion

The 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

Background

Targeting 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.

Method

We 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.

Result

We 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.

Conclusion

We 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

Background

Misfolded 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.,

Methods

We 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.,

Results

Correlations 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).,

Conclusion

Our 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

Background

Preliminary 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.

Method

From 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).

Result

The 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.

Conclusion

Our 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

Background

Inadequate 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.

Method

2016‐2018 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.

Result

Inadequate 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).

Conclusion

Inadequate 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.
Biomarker analyses from the phase 2, randomized, placebo‐controlled ACT‐AD and open‐label extension clinical trials of fosgonimeton in patients with mild‐to‐moderate Alzheimer’s disease
Authors: Moebius Hans J. , Ooi Kai‐Bin C. , Hale Michael D. , Setti Sharay E. , Kleist Kayla N. , Pan Josh , Church Kevin J. , Sabbagh Marwan
Published: December 2023

Background

Despite the multifactorial nature of Alzheimer’s disease (AD), research has primarily targeted amyloid‐beta and tau; other approaches are needed. Fosgonimeton, a small‐molecule positive modulator of the hepatocyte growth factor (HGF)/MET system, was evaluated in a randomized, double‐blind, placebo‐controlled, 6‐month, exploratory phase 2 trial (ACT‐AD; NCT04491006)a and an open‐label extension trial (NCT04886063)a.

Method

To evaluate fosgonimeton in participants with mild‐to‐moderate AD, changes from baseline (CFB) in plasma biomarkers were compared with placebo in post hoc analyses. Multifactorial correlations were assessed against the global statistical test (GST), a composite score of cognition (ADAS‐Cog11) and activities of daily living (ADCS‐ADL23) assessments. Blood samples from baseline (n = 59‐61) and week 26 were assessed for biomarkers of neurodegeneration (NfL), neuroinflammation (GFAP; YKL‐40), and proteinopathy (Aβ42/40 ratio; p‐Tau181).

Result

Baseline biomarker levels were similar between treatments. An ANOVA, including baseline levels, yielded a statistically significant CFB in NfL (−6.49 pg/mL; SE, 2.79; p = 0.0241) and numerical improvements in GFAP (−35.17 pg/mL; SE, 30.0; p = 0.2469), YKL‐40 (−47.37 ng/L; SE, 27.5; p = 0.0916), Aβ42/40 ratio (0.006; SE, 0.0035; p = 0.0938), and p‐Tau181 (−0.67 pg/mL; SE 0.60; p = 0.2715) were observed in fosgonimeton‐treated participants versus placebo, each without background therapy. APOE4 genotype, baseline Mini‐Mental State Examination score, sex, or age did not affect results. Additional biomarker and correlation analyses are being conducted. The potential association of biomarkers with clinical outcomes is supported by the CFB relative to GST, which significantly correlated with changes in NfL (r = 0.40; p = 0.0023) and GFAP (r = 0.35; p = 0.0408).

Conclusion

In this first randomized, placebo‐controlled, 6‐month trial of fosgonimeton, a statistically significant reduction in NfL and numerical improvements in GFAP, YKL‐40, Aβ42/40, and p‐Tau181 plasma concentrations were observed, suggesting a multimodal neuroprotective mechanism of action of fosgonimeton and potential to impact AD‐specific proteinopathies. The significant correlation of NfL and GFAP reduction with the composite endpoint further supports potential clinical relevance.

aThe ACT‐AD trial and open‐label extension thereof are supported by a grant from the National Institute on Aging of the National Institutes of Health (award number R01AG06268). The information presented herein is solely the responsibility of Athira and does not necessarily represent the official views of the National Institutes of Health.
Investigation of neighborhood disadvantage in the context of APOE‐associated amyloid onset age risk
Authors: Irizarry‐Pagan Erica E , Teague Jordan P , Buckingham William R. , Cody Karly Alex , Langhough Rebecca E , De Chavez Elena Ruiz , Navaratna Ruvini , Okonkwo Ozioma , Asthana Sanjay , Johnson Sterling C. , Kind Amy J. , Bendlin Barbara B , Powell W. Ryan , Zuelsdorff Megan , Betthauser Tobey J
Published: December 2023

Background

Exposome social determinants of health (SDoH), such as neighborhood disadvantage, have shown associations with accelerated cognitive decline, brain volume loss, and postmortem AD pathology. However, associations between neighborhood disadvantage and amyloid biomarker positivity (A+) onset remain understudied. This study uses estimated A+ onset age (EAOA) and the Area Deprivation Index (ADI; an exposome SDoH) to investigate associations between neighborhood disadvantage and A+ risk.

Methods

Participants (n = 599, Table 1) from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) and the Wisconsin Alzheimer’s Disease Research Center (WADRC) with available amyloid PET, address, and APOE genotype were included. EAOA was estimated using sampled iterative local approximation. Neighborhood disadvantage was categorized by national‐rank 2020 ADI (most disadvantaged ≥80th percentile; least disadvantaged <80th percentile). APOE groups were established based on the number of e4 alleles. Cox proportional hazard models assessed A+ risk associated with APOE, ADI, and their interaction. Secondary Cox models used continuous ADI and a lower 70th ADI percentile for neighborhood groups. Kaplan‐Meier curves were generated to depict A‐ probability vs. age for combinations of APOE and ADI groups. A‐ were right censored.

Results

A significant interaction (p = 0.015) between ADI and APOE groups was observed such that APOE‐e4 homozygotes who resided within a highly disadvantaged neighborhood had higher risk of becoming A+, but this group was limited to two participants. Secondary analyses indicated no significant effect of ADI or interaction with APOE on A+ risk (p>0.49). Plots of A+/‐ and EAOA by ADI and APOE group (Figure 1) and Kaplan‐Meier EAOA curves indicated EAOA overlap of ADI groups within APOE strata. A+ risk was significantly higher for APOE‐e4 homozygotes, followed by APOE‐e4 heterozygotes, and then APOE‐e4 non‐carriers.

Conclusions

In this mostly unimpaired, highly educated sample, higher number of APOE‐e4 alleles was associated with higher A+ risk and earlier A+ onset. APOE‐associated A+ risk was similar for all ADI groups, but representation across APOE genotypes for individuals residing within highly disadvantaged neighborhoods was limited. Further work is needed in more diverse samples to investigate the possible influence of ADI and other exposome SDoH factors on AD biomarker timing and trajectories.
Differential sex associations of regional adiposity with cognition and brain pathology in Israeli older adults with Type II Diabetes
Authors: Boccara Ethel , Golan Sapir , Ganmore Ithamar , Ravona‐Springer Ramit , Ben‐Meir Mery , Livny Abigail , Inbar Yael , Heymann Anthony , Beeri Michal S
Published: December 2023

Background

Adiposity and Type II diabetes (T2D) are consistently associated with cognitive impairment and dementia. Body mass index (BMI) is the most common measure of global adiposity, but its associations with cognition in old age are inconsistent. BMI does not represent regional fat distribution, which might differ between the sexes. In this study, we examined sex differences in the relationships of regional adiposity with cognition and AD‐related brain volumes in older adults participating in the Israel Diabetes and Cognitive Decline study.

Methods

Regional adiposity was measured by abdominal MRI in 89 participants (32.6% women), including hepatic and pancreatic fat, visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT). Participants were assessed for global cognition, episodic memory (EP), working memory (WM), executive function (EF), and language. A subsample (N = 50) underwent brain MRI assessing total gray matter [GM], hippocampus, inferior, middle, and superior frontal gyrus [IFG, MFG, and SFG, respectively]. Linear regressions examined associations of regional adiposity with cognition and AD‐related brain volumes adjusting for age, sex, education, and BMI (and intracranial volume for MRI measures).

Results

In the whole sample, higher pancreatic fat was associated with lower EF (r = ‐0.369, p = 0.024). In men, high pancreatic fat was associated with lower global cognition (Men: r = ‐0.311; p = 0.048; Women: r = ‐0.122; p = 0.706), EF (Men: r = ‐0.384; p = 0.033; Women: r = ‐0.508; p = 0.661) and language (Men: r = ‐0.309; p = 0.049; Women: r = 0.082; p = 0.798). In the whole sample, no associations were found between pancreatic fat % and AD‐related brain volumes. Surprisingly, in men, higher pancreatic fat was associated with greater GM volume (Men: r = 0.411; p = 0.046; Women: r = ‐0.231; p = 0.521). In women, higher pancreatic fat was associated with smaller IFG (Men: r = ‐0.185, p = 0.386; Women: r = ‐0.642, p = 0.045). Hepatic fat %, VAT, and SAT did not associate with AD‐related brain volumes or cognitive measures.

Conclusion

In Israeli older adults with T2D, different regional fat depots are linked to different cognitive and brain outcomes in men and women. Specifically, more pancreatic fat, but not other fat depots, is associated with poorer cognition. These findings highlight the value of examining distinct fat depots rather than global obesity concerning brain and cognition, and the need to account for sex differences in these associations.
Exploring the involvement of oligodendrocytes in Alzheimer’s disease using human iPSCs
Authors: McQuade Courtney A ,   Research Group of Dr. Sarah Jäkel ‐ ISD Munich ‐ Oligodendrocyte Pathology
Published: December 2023

Background

Alzheimer’s disease (AD) is a chronic neurodegenerative disease, characterized clinically by cognitive and neuropsychiatric impairments, and pathologically by extracellular amyloid plaques, intracellular neurofibrillary tangles, and neuroinflammation which ultimately leads to neurodegeneration and dementia. Despite extensive research, no effective treatments have been identified to date, and many clinical trials have failed. This is due, in part, to a lack of human‐specific models for evaluating the contribution of non‐neuronal cell types to the disease pathogenesis; an issue we aim to address with our research into the pathogenic contributions of oligodendrocytes to AD.

Method

To investigate the role of OLs in AD, we are analyzing post‐mortem human brain tissue of AD and appropriate control samples to assess OL distribution between cortical areas with different disease burdens within the same patient using transcriptomic and immunohistochemical approaches. To complement our observations in the human brain, we are using human iPSC‐derived oligodendrocyte model systems in 2D and 3D to study how AD‐associated mutations, as well as exposure to AD‐related environmental stress may impact OL physiology.

Result

Thus far, our analysis of post‐mortem human brain tissue has revealed region and layer‐specific loss of oligodendrocytes in AD. With our in‐vitro models, we have seen morphological differences between human iPSC‐derived OLs carrying AD‐related mutations and isogenic wild‐type controls. We study OL/neuronal interactions in our in‐vitro model systems, as well as in‐vivo via transplantation of iPSC‐derived OL‐precursors into myelin‐deficient mice to allow visualization of their myelination capacity.

Conclusion

Oligodendrocytes (OLs) are known primarily as the myelinating cells of the central nervous system, but have other important functions as well, including providing trophic support to neurons. Accumulating evidence suggests that OLs play an active pathogenic role in AD ‐ historically considered a neuronal disease ‐ but this role has not yet been investigated. The methods we are implementing will help us to identify OL‐mediated mechanisms which may contribute to the pathogenesis and progression of AD, to shed new light on a prevalent neurodegenerative disorder, and to identify novel therapeutic approaches in the future.
Life course exposure to air pollution and the risk of mild cognitive impairment and dementia in the Lothian Birth Cohort 1936
Authors: Jutila Otto‐Emil Ilmari , Welstead Miles , Mullin Donncha S , Tomlinson Samuel , Vieno Massimo , Cox Simon R , Baranyi Gergo , Russ Tom C , Luciano Michelle , Karlsson Ida K
Published: December 2023

Background

Air pollution has been associated with the risk of pathological cognitive decline and dementia (Chandra et al., 2022). Past research has focused on cross‐sectional associations or short‐term exposure measurement, and there is a lack of studies investigating the impact of air pollution throughout the life course of the individual which examines sensitive periods. In this study, the relationship of air pollution exposure at different periods across the life course and the risk of dementia and mild cognitive impairment (MCI) was investigated.

Method

Historic fine particulate matter (PM2.5) was modeled using the EMEP4UK atmospheric chemistry transport model for several time periods (1935, 1950, 1970, 1980, and 1990) was combined with contemporary data for time period 2001 and 2007 to calculate the lifetime exposure for 576 participants of the Lothian Birth Cohort (LBC) 1936 who had information about lifetime residential history.

There were 69 individuals with all‐cause dementia from age 70 years (baseline) onwards were clinically ascertained and 156 individuals with MCI derived at the ages 76, 79, and 82 years according to the NIA‐AA workgroups guidelines. A multivariable Cox proportional hazards model was developed to investigate associations between PM2.5 exposure at each time period with both cognitive outcomes, adjusting for sex, parental occupational social class (OSC) and of Apolipoprotein e4 allele (APOE4) status, childhood smoking (<16 years), years of education, adulthood OSC, smoking status at age 70, and early retirement (<60 years) dependent on time period.

Result

Higher exposure (1SD [0.25µg/m3]) of PM2.5 in later life (2007, age 71 years) had a statistically significant (P = 0.0262) association with increased risk of MCI (HR 1.25, 95% CI 1.02‐1.54) and other time periods were positively associated but not statistically significant (P>0.05). There was no statistically significant (P>0.05) association between PM2.5 exposure at any time period and risk of all cause dementia.

Conclusion

Later life exposure to PM2.5 had a positive association with MCI which could suggest that this is a sensitive period in the life course model. This could indicate that people in later life are more susceptible to the impact of air pollution on cognitive decline and therefore risk of MCI.
Effects of binge alcohol administration on tauopathy and neuroinflammation in PS19 mice
Authors: Colin Samantha , Lee‐Gosselin Audrey , Perkins Abigail , McKinzie David , Oblak Adrian L
Published: December 2023

Background

It is estimated that 50 million people worldwide are suffering from dementia, the most common being Alzheimer’s disease (AD). Even as the population ages and the incidence of AD increases, there are limited disease‐modifying treatments to date. Alcohol use disorders (AUD) have been identified as a modifiable risk factors for developing AD. Heavy alcohol intake in elderly individuals is associated with more rapid progression of AD pathology and an elevated neuroinflammatory state. The objective of this study was to investigate the interaction of high ethanol ‘binge’ treatments in a mouse model of tauopathy.

Method

PS19 mice, a widely used tauopathy model, were subjected to a 5‐week binge paradigm of IP ethanol administration, 3.0g/kg, three times per week, beginning at 6 months of age. Prior to initiation of the binge ethanol regimen, mice received subcutaneous biotransponder implantations to record body temperature changes in response to ethanol. Blood ethanol concentrations were determined in a subset of mice at 30 minutes following the last ethanol administration. Frailty measures were completed one week after ethanol administration. NanoString unbiased gene expression, MesoScale Discovery ELISA, Western blotting, and Immunohistochemistry were performed to examine neuroimmune changes and markers of tau pathology.

Result

Overall, ethanol treatment resulted in reduced body weight, which was further exacerbated in female PS19 mice.. Measures of frailty (i.e. cerebellar ataxia and grip strength) were impaired in PS19 mice, however, female PS19 mice receiving ethanol treatment had the greatest impairments compared to WT controls. Alterations in inflammatory signaling pathways were observed in the PS19 animals receiving alcohol treatment compared to PS19 or WT mice.

Conclusion

We have examined the result of intermittent alcohol exposure on tau pathogenesis. In the present study we found that alcohol can induce biometric and behavioral changes in mice, which are further exacerbated by alcohol. Transcriptomic analysis indicated changes in both innate and inflammatory signaling, suggesting a increased inflammatory response in the ethanol treated animals. Taken together, these results suggest that intermittent environmental influences, such as ethanol, can result in more rapid progression of AD pathogenesis.
Screening older adults for potential deficits in IADL using the Menu Task and Medi‐Cog‐R
Authors: Marks Timothy S , Giles Gordon Muir , Kehl‐Floberg Kristen E , Edwards Dorothy F.
Published: December 2023

Background

The identification of deficits in functional performance is critical to sustaining the community independence of older adults. Screening for difficulties in the performance of cognitively demanding instrumental activities of daily living (IADL) can facilitate earlier identification of and intervention for people with impairment (Rodakowski et al., 2014). We examined whether two brief performance‐based screening measures ‐ the Menu Task and the Medi‐Cog‐R ‐ can identify those at risk of functional cognitive deficits as indicated by poor performance on the Weekly Calendar Planning Activity (WCPA).

Method

Using a cross‐sectional design we administered the Menu Task, Medi‐Cog‐R, and the WCPA to community dwelling adults 55 years of age and older (N = 280). Using established cut scores, we examined the sensitivity and specificity of the two screening measures to poor performance on WCPA Accuracy (≤ 20th percentile). Known‐group construct validity were examined by comparing impaired and unimpaired groups on the screening measures on subtests of the WCPA.

Result

The sample was 73.57% female and 73.57% white. Mean age was 69.72 (SD = 8.81) and mean education was 15.61 (SD = 3.30) years. The Menu Task demonstrated a sensitivity of .84 and a specificity of .62 and the Medi‐Cog‐R demonstrated a sensitivity of .77 and a specificity of .66 in correctly classifying individuals with potential for impaired IADL as indicated by a score at or below the 20th percentile on the WCPA. The impaired groups on both screening measures scored significantly lower on WCPA subtests of Accuracy, Appointments Entered, Efficiency, Rules, and Strategies than the unimpaired group (p < .001).

Conclusion

The Menu Task and the Medi‐Cog‐R could both alert clinicians to the potential for functional cognitive deficits and need for IADL support in community dwelling older adults. Performance‐based screening measures of functional cognition can be used to prompt further assessment and intervention to promote community independence.
Modifications in the perceptions about the use of mobile phones in old people after an interplay program using technological devices
Authors: Sarmiento Elsa Araceli Revollo , Vivas Leticia , Moreno Maria Celeste López
Published: December 2023

Background

In the elderly the management of technology has a great impact to nurture their autonomy (Camacho Coronel et al., 2019). In this work, we propose to study whether perceptions change after people´s exposure to the use of technology through a general technology program or a more specific mobile‐phone use program. Sample: 28 elderly people (between 65 and 90 years) without cognitive impairment.

Method

An experimental study was carried out with two groups (experimental GE and active control GC) matched in age (p = .620), educational level (p = .757) and experience in the use of technologies (p = .321). Both groups received training (3 months) through the use of tablets. Subsequently, the GE received an additional two‐week training on the use of cell phones. The Technology Acceptance Questionnaire (Chen & Chan, 2014) oriented to cell phone use was administered before and after the intervention.

Result

By means of the Friedman test, comparisons were established between the pre and post intervention measures with all the participants on the variables of acceptance of the technology. Significant differences were observed in Self‐efficacy (p<0.05), Utility (p<0.05) and Anxiety (p<0.05). Subsequently, the analysis was divided into groups and it was observed that the EG presented significant values in Anxiety (p = 0.03), Utility (p = 0.02) and Self‐efficacy (p = 0.08), while the CG presented significant values in Self‐efficacy (p = 0.08) and values that were not significant, although they were close in usefulness (p = 0.096) and anxiety (p = 0.059). The variables conditions of Facilitation and Attitude toward use did not present significant changes in any group.

Conclusion

The results indicate that the measure of Self‐efficacy in the use of technology improves in older people after using a technological product for a while. However, the group that received training in the use of the cell phone also increased the Perceived Utility and Anxiety in the use of technology. In old age, knowing the usefulness of technology and self‐perceiving how effectively it can be used can generate benefits such as greater security and decreased anxiety in the face of technology.
Mechanistic insights into the therapeutic potential of Angiotensin type 2 receptors (AT2R) in shaping behavior of astrocytes and microglia during hypertensive state
Authors: Bhat Shahnawaz A
Published: December 2023

Background

Astrocytes are the major glial cell type in the central nervous system (CNS) and play a critical role in the pathogenesis of neuroinflammatory and neurodegenerative diseases. In particular, astrocytic activation during neuroinflammatory conditions perpetuates the inflammatory response and brain damage and neurodegeneration. Conversely, Angiotensin type 2 receptor (AT2R) activation is known to promote neuroprotection.

Method

Therefore, the present study evaluated the role of AT2R in astrocytic activation in vitro in primary astrocytes and in vivo in hypertensive rats.

Result

Here, we demonstrated that Ang II‐induced astrogliosis in primary astrocytes as apparent from increased expression of GFAP and iNOS, ROS generation, inflammatory imbalance and mitochondrial dysfunction in the primary astrocytes. On the contrary, AT2R activation by CGP42112A (CGP) abrogated Ang II induced astrocytic activation by inhibition of ROS production, mitochondrial dysfunction and inflammatory imbalance. However, this anti‐inflammatory action of AT2R activation by CGP was reversed by AT2R antagonist, PD123319 in both in vitro and in vivo conditions. Mechanistically, we found that AT2R via protein phosphatase‐2A (PP2A) activation abrogated the Ang II induced NFкB activation, ROS generation and consequent pro‐inflammatory activation of astrocytes. Importantly, PP2A antagonist, okadaic acid, reversed the anti‐inflammatory action of CGP to the comparable level as that by AT2R antagonist PD123319.

Conclusion

Thus, the present study suggests that AT2R by the activation of PP2A abrogates the NFкB inflammatory signalling and inflammatory activation of astrocytes. Therefore, the therapeutic strategies targeting AT2R might be advantageous for neuroinflammatory or degenerative diseases perpetuated by astrocytic activation.