bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive Insight Into Electronic Modulation of Rare‐Earth Elements for Enhancing Electrocatalytic Performance of Atomically Dispersed Materials
Authors: Cao Yanhui , Zheng Xuerong , Deng Yida , Hu Wenbin
Published: January 2025

Atomically dispersed materials have been a thriving research field due to their maximum atomic utilization and remarkable performance in energy conversion and storage systems. Owing to the large atomic radius, strong oxophilicity, and unique electronic properties, rare‐earth (RE) elements have been widely investigated as oxide carriers and promoters in atomically dispersed materials to manipulate and regulate the electronic structure of active species. Single‐atom state with an adjustable coordination environment on the N‐doped carbon endows RE metals with special electronic states and outstanding catalytic performances. A thorough comprehension of the electronic modulation mechanism of RE elements paves the way for the construction of advanced RE‐based electrocatalysts with high activity, stability, and selectivity. This review provides a widespread insight into the roles of RE elements in modulating the electronic properties of atomically dispersed materials combined with the structure–performance relationship in electrocatalysis processes. The characteristic physical and chemical properties of RE elements are highlighted, and the synthetic strategy of RE‐based atomically dispersed materials is discussed. Finally, a summary and perspectives for rational design and development of highly efficient RE‐based catalysts are proposed. This review aims to provide a guideline for promoting the rational and effective utilization of RE elements in advanced functional materials.
Microbial DNA Profiles of Bacterial Extracellular Vesicles from 3D Salivary Polymicrobial Biofilms – A Pilot Study
Authors: Liu Chun , Udawatte Nadeeka S. , Liaw Andrew , Staples Reuben , Salomon Carlos , Seneviratne Chaminda Jayampath , Ivanovski Sašo , Han Pingping
Published: January 2025

With the advent of multi‐layered and 3D scaffolds, the understanding of microbiome composition and pathogenic mechanisms within polymicrobial biofilms is continuously evolving. A fundamental component in mediating the microenvironment and bacterial‐host communication within the biofilm are bilayered nanoparticles secreted by bacteria, known as bacterial extracellular vesicles (BEVs), which transport key biomolecules including proteins, nucleic acids, and metabolites. Their characteristics and microbiome profiles are yet to be explored in the context of in vitro salivary polymicrobial biofilm. This pilot study aimed to compare the profiles of BEVs from salivary biofilm cultured on a 2D tissue culture plate and 3D melt electrowritten medical‐grade polycaprolactone (MEW mPCL) scaffold. BEVs derived from MEW mPCL biofilm exhibited enhanced purity and yield without altered EV morphology and lipopolysaccharide (LPS) content, with enriched BEVs‐associated DNA from Capnocytophaga, porphyromonas, and veillonella genus. Moreover, compared to saliva controls, MEW mPCL BEVs showed comparable DNA expression of Tannerella forsythia, and Treponema denticola and significantly higher expression in Porphyromonas gingivalis, Eikenella corrodens and Lactobacillus acidophilus. Together, these findings highlight a more detailed microbial profile with BEVs derived from salivary biofilms cultured on 3D MEW PCL scaffolds, which facilitates an effective in vitro model with a greater resemblance to naturally occurring biofilms.
Generalizability of Graph Neural Network Force Fields for Predicting Solid‐State Properties
Authors: Mohanty Shaswat , Wang Yifan , Cai Wei
Published: January 2025

Machine‐learned force fields (MLFFs) promise to offer a computationally efficient alternative to ab initio simulations for complex molecular systems. However, ensuring their generalizability beyond training data is crucial for their wide application in studying solid materials. This work investigates the ability of a graph neural network (GNN)‐based MLFF, trained on Lennard–Jones Argon, to describe solid‐state phenomena not explicitly included during training. The MLFF's performance is assessed in predicting phonon density of states (PDOS) for a perfect face‐centered cubic (FCC) crystal structure at both zero and finite temperatures. Additionally, vacancy migration rates and energy barriers are evaluated in an imperfect crystal using direct molecular dynamics (MD) simulations and the string method. Notably, vacancy configurations are absent from the training data. These results demonstrate the MLFF's capability to capture essential solid‐state properties with good agreement to reference data, even for unseen configurations. Data engineering strategies are further discussed to enhance the generalizability of MLFFs. The proposed set of benchmark tests and workflow for evaluating MLFF performance in describing perfect and imperfect crystals pave the way for reliable application of MLFFs in studying complex solid‐state materials.
A Multi‐Colored, Structure‐Tolerant Vanadate Cathode for High‐Performance Aqueous Zinc‐Ion Batteries
Authors: Zhang Qian , Ju Shidi , Zhang Shaohua , Xu Shilong , Zhang Zhipan
Published: January 2025

Vanadium‐based cathode materials for aqueous zinc‐ion batteries (AZIBs) have attracted much attention in large‐scale energy storage devices yet their unsatisfactory cyclic stability and slow diffusion rate of Zn2+ ions during insertion and extraction hinder further commercial applications. Therefore, the development of vanadium‐based cathode materials with stable crystal structures and fast Zn2+ storage remains challenging. Herein, Na2CaV4O12 (NCVO) nanowires are reported as a promising cathode of excellent electrochemical performance in AZIBs, simultaneously rendering high specific capacity (443.2 mAh g−1 at 0.1 A g−1) and high average voltage plateau (0.91 V) with impressive energy density (403.3 Wh kg−1) and power density (1533 W kg−1). As NCVO features a unique open crystal structure with alternately arranged inactive layers ([NaO6] and [CaO8] polyhedra) and active layers ([VO4] tetrahedra), the expansion of the [VO4] tetrahedra during Zn2+ insertion is well balanced by the contraction of the inactive layer, thus enabling remarkable long‐term cycling stability (91.9% and 80% capacity retention after 5000 and 10 000 cycles at 10 A g−1, respectively). With the electrochromic property of the NCVO cathode, the AZIB can further be used for adaptive camouflage under a range of scenarios, shedding light on the future development of high‐performance cathodes for AZIBs.
Health shock and indebtedness: Does having access to health insurance reduce the reliance on borrowing as a shock coping strategy?
Authors: Nguyen Linh D. , Nguyen Thanh T. , Nguyen Tung T. , Grote Ulrike
Published: January 2025

Households in developing countries are often impaired in their economic opportunities by major health shocks. In this article, we first investigate the impact of a health shock on rural household consumption and explore the mechanisms how the health shock brings a household into indebtedness. We then examine the role of health insurance in reducing the reliance on borrowing as a shock coping strategy. Our estimations show that while rural households are able to insure non‐health‐related consumption, a health shock pushes them into severe indebtedness by increasing informal borrowing to smooth consumption. Promotion of health insurance is recommended as it helps to protect households from falling into severe indebtedness when a health shock strikes.
Diagnosis of TET3‐Related Beck–Fahrner Syndrome in an Individual With Chorioretinal and Iris Colobomata Using a DNA Methylation Signature
Authors: Man Alice , Di Scipio Matteo , McConkey Haley , Hough Rebecca , Stein Nina , Diehl Eric , Marshall Christian R. , Sadikovic Bekim , Ejaz Resham
Published: January 2025

Disorders of developmental delay can occur from pathogenic variants in genes responsible for epigenetic regulation. Heterozygous and biallelic pathogenic variants in TET3 have recently been described in TET3‐related Beck–Fahrner syndrome (TET3‐BEFAHRS), representing an autosomal dominant disorder with variable expressivity. Typical features include intellectual disability and developmental delay. Patients can also present with facial dysmorphism, seizure disorder, ophthalmic findings, and other neurobehavioral features. As the condition has recently been described and few patients have been reported in literature, the full scope of the phenotypic spectrum and approaches to identify them are still emerging. We report an individual meeting the criteria for TET3‐BEFAHRS confirmed through clinical, genetic, and DNA methylation episignature analysis, who uniquely presents with bilateral chorioretinal and unilateral right iris colobomata. This case suggests a broader ophthalmic phenotype to TET3‐BEFAHRS and demonstrates the utility of episignatures for the diagnosis of Mendelian disorders of epigenetic machinery.
Hajdu–Cheney Syndrome, a Rare Cause of Acro‐Osteolysis and Osteoporosis With Zoledronic Acid Experience
Authors: Buyukyilmaz Gonul , Adiguzel Mehmet , Gurbuz Fatih , Kılıc Esra
Published: January 2025

Hajdu–Cheney syndrome (HCS), caused by a heterozygous gain of function variant of the NOTCH2 gene, is a rare skeletal dysplasia. Although the main presentation is acro‐osteolysis, osteoporosis, and facial dysmorphism, having a wide range of clinical manifestations creates diagnostic difficulties. Here, a 15‐year‐old male patient with HCS who had no complaints until this age except for two short bone fractures and one vertebral collapse fracture due to a fall was reported. The patient presented with acro‐osteolysis, facial anomalies, skull deformity, and osteoporosis. The clinical diagnosis of HCS was supported by a positive genetic test of a novel de novo heterozygous pathogenic variant in exon 34 of NOTCH2 c.6614dupAfs*. Zoledronic acid treatment was applied for 2 years, and the patient responded well to the treatment, showing signs of improved bone density and improvement in vertebral height. We identified a novel NOTCH2 gene variant related to HCS. Our findings could extend phenotypic spectrum and genotype–phenotype correlations. The results of this case report support that antiresorptive treatment with zoledronic acid increased bone mineral density. Nevertheless, because of the low prevalence of the syndrome and the small number of reported cases, further studies are required to understand the syndrome better and establish treatment guidelines.
Exerkines and brain rejuvenation
Authors: Leiter Odette , Lowe Joshua , Brici David , Walker Tara L
Published: January 2025

Ageing changes the adult brain at the molecular, cellular and functional levels, driving regenerative decline, inflammation, cognitive impairments and susceptibility to dementia‐related neurodegenerative disorders, such as Alzheimer’s disease (AD). There is overwhelming evidence that regular physical exercise can counteract cognitive decline in both healthy ageing and in neurodegenerative conditions such as AD, with exerkines, the circulating humoral factors that are secreted into the blood stream in response to exercise, emerging as likely mediators of this response. However, the source and identity of these exerkines remain unclear. We have recently found that platelets, the small immune cells that primarily regulate haemostasis, are activated after acute periods of running and release factors, including the chemokine platelet factor 4 (PF4), that promote neurogenesis and cognitive rejuvenation.

This presentation will highlight the key role that platelet‐derived exerkines play in mediating cognitive rejuvenation and suggest that platelets represent a unique and underexplored therapeutic approach to counteract age‐related cognitive decline.
Faster DunedinPACE, an epigenetic clock for pace of biological aging, is associated with accelerated cognitive aging among older adults in the Framingham Heart Study
Authors: Savin Micah J.
Published: January 2025

Background

Biomarkers that predict the heterogenous nature and late onset of cognitive decline are needed to evaluate geroscience interventions designed to delay or prevent the progression of Alzheimer’s Disease and related dementias (ADRD). The DunedinPACE epigenetic clock is designed to measure pace of biological aging, and is therefore a promising candidate biomarker. Here we (1) investigate if DunedinPACE is associated with cognitive aging, and (2) the extent to which these associations are independent of education.

Method

We analyzed data from the Framingham Heart Study Offspring Cohort. Our analysis sample included participants with neuropsychological testing data and blood DNA methylation data collected within 14 months of their baseline cognitive assessment (n = 2,296 non‐Hispanic White adults, 46% male; M age = 61.6 ± 9.0 [25‐101y]). A series of growth curve models tested the interactive effects of DundeinPACE and education upon baseline and longitudinal changes in global unadjusted T scores. All models included covariates to adjust for cellular composition of blood samples, smoking status, sex, age at baseline (specified as a quadratic term), and date of blood draw.

Result

A faster DunedinPACE was associated with worse global cognition, and steeper decline in cognition over time (Bs = ‐.37 ‐ ‐.45; ps< .001). After adjusting for education, DunedinPACE remained robustly associated with global cognition and steeper decline in cognition over time (Bs = ‐.33 ‐ ‐38; ps<.01). In effect modification analyses, higher education buffered the effect of faster DunedinPACE upon global cognition at baseline (B = ‐.21; p<.01), but did not significantly modify the effect of DunedinPACE upon cognitive decline over time (p = .95).

Conclusion

The presented findings support prior work that highlight the role of systemic biological aging in cognitive decline, and further validates the utility of the epigenetic clock, DunedinPACE, as a potential biomarker for decline in cognitive aging. Further validation of DunedinPACE and its clinical utility as a biomarker for geroscience interventions targeting ADRD is warranted. Greater years of education appears to mitigate some of the deleterious effect of biological aging upon cognition. Future studies should critically examine these relationships among nationally representative samples and diverse samples disproportionately impacted by ADRD.
Neuroimmune regulation of Alzheimer’s pathology by age‐related blood‐borne factors
Authors: Hemmer Brittany M. , Grau‐Perales Alejandro B. , Ferreira Ana Catarina , Pallikunnath Ralphyn , Rosenstadt Jacob L. , Castellano Joseph M.
Published: January 2025

Background

Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by hallmark pathologies that affect many brain regions, including the cellular microenvironment with the hippocampus, ultimately leading to profound deficits in cognition. Surprising recent work has shown that factors in the systemic environment regulate the hippocampal cellular niche; age‐associated blood‐borne factors exacerbate brain aging phenotypes, whereas youth‐associated blood‐borne factors, including tissue inhibitor of metalloproteinases 2 (TIMP2), reverse or ameliorate features of brain aging. As aging serves as the major risk factor for AD, and recent work shows that systemic factors can regulate AD pathology, we sought to characterize mechanisms by which the systemic environment regulates CNS phenotypes relevant to AD pathology through changes in neuroinflammation.

Method

We used both global and conditional deletion approaches in wildtype and APP‐knockin (NL‐F) or 5XFAD mice to target sources of TIMP2, a youth‐associated systemic factor previously shown to rejuvenate the aged hippocampus. We applied conventional and super‐resolution confocal microscopy approaches to characterize the impact on amyloid pathology and neuroinflammation. Changes in microglial morphology and state in the setting of TIMP2 modulation were characterized using a variety of approaches, including in vivo microdialysis and snRNA‐sequencing. We also restored levels of TIMP2 in aged APP‐KI mice to examine the impact on cognitive deficits. Conversely, we systemically injected APP‐KI mice with proteins associated with advanced age to examine the impact of age‐accumulating blood‐borne factors on amyloid accumulation and microglial state.

Result

Deletion of TIMP2 from specific sources is associated with significant changes in microglial state. Its loss is associated with dysfunctional activation state, senescence, and perturbed morphology. We also find that TIMP2 deletion exacerbates accumulation of amyloid in various brain regions associated with accumulated extracellular matrix and its rescue in aged APP‐KI mice improves memory. Conversely, injecting specific factors present in aged blood significantly exacerbates amyloid pathology and alters microglial state while impairing adult neurogenesis in the hippocampus.

Conclusion

Together our results highlight mechanisms by which both youth‐associated and age‐associated blood‐borne factors regulate AD pathology. Factors in the systemic environment appear to interact with microglia, cells that are intimately involved in modulation of canonical AD pathology.
A Preliminary Validation of the Details of Function of Everyday Life Scale for the Detection of Early‐Stage Alzheimer’s Disease
Authors: Calia Clara , O'Donald Freddie , Parra‐Rodriguez Mario A
Published: January 2025

Background

Assessments for early‐stage Alzheimer’s disease (AD) aim to identify neuropsychological and functional impairments, which rarely correlate with early disease stages. We need to enhance our understanding of the cognitive aspects contributing to functional decline to improve sensitivity in functional assessment. The ability to bind information in memory declines in preclinical AD stages. However, it is unclear whether such cognitive deficits underlie functional impairment in prodromal AD stages. To explore this, the Details of Function of Everyday Life (DoFEL) has been developed, aiming to link the cognitive constructs of memory‐binding to specific impairments in activities of daily living.

Method

The DoFEL underwent revision and latent structure exploration through Exploratory Factor Analysis in a non‐clinical sample (N = 559). This revised DoFEL was subjected to content validity review by eight dementia professionals, and factor structure was reassessed with Confirmatory Factor Analysis in a different sample (N = 135). Forty‐nine participants with MCI and thirty‐three healthy controls completed the DoFEL, Addenbrookes Cognitive Examination‐Revised (ACE‐R), and a Visual Short‐Term Memory Binding Task (VSTMBT). The correlation of revised DoFEL scores was examined in relation to ACE‐R and VSTMBT. Binomial regression was used to establish whether the revised DoFEL could differentiate healthy controls from MCI.

Result

(1) Conjunctive and relational binding appeared to be represented as dimensions within DoFEL subscales. However, the factor structure was not replicated across all subscales, suggesting further scale revision would be of benefit. (2) Dementia professionals considered the revised DoFEL useful for detecting functional impairment in early‐stage AD. However, the relevance of some items to binding was questionable due to their broad nature. (3) Performance on the revised DoFEL (higher score indicating impairment) strongly correlated with performance on the ACE‐R, r(82) = ‐0.663, p < .001, and moderately correlated with performance on the VSTMBT, r(82) = ‐0.518, p = 0.003. (4) The revised DoFEL differentiated those on a healthy ageing trajectory from individuals diagnosed with MCI, demonstrating comparability with the ACE‐R.

Conclusion

These findings offer initial evidence for the validity of the DoFEL. It indicates that the connection between binding and performance in functional activities could offer a valuable avenue for improving functional assessment during early‐stage AD.
Tangle distribution is differentially influenced by age at onset, APOE ε4, and MAPT H1 along the corticolimbic axis
Authors: Boon Baayla D. C.
Published: January 2025

Background

Alzheimer’s disease (AD) is heterogeneous in both its clinical and neuropathologic course. Age at onset and distribution of corticolimbic tangles can vary widely among individuals. Genetic risk factors APOE ε4 and MAPT H1 increase AD risk. However, the association with the spatial distribution of pathology remains a key gap in knowledge. We investigated the effects of age at onset, APOE ε4, MAPT H1, and family history of cognitive symptoms on corticolimbic tangle density variability to better distinguish how each factor contributes.

Method

The FLorida Autopsied Multi‐Ethnic (FLAME) cohort was queried for neuropathologically confirmed AD cases (n = 1233). Tangle density (count per 0.125mm2) was quantified using thioflavin‐S staining in nucleus basalis of Meynert (nbM), hippocampal CA1 and subiculum, association cortices, and primary cortices. Cortical thickness was measured using digital pathology on hematoxylin‐eosin‐stained sections. We employed univariate and multivariate negative binomial regression models to evaluate the association of each factor on tangle density across the corticolimbic axis. Multivariate analysis was adjusted for significant variables from univariate analyses.

Result

Donors with young‐onset (<65) AD (YOAD; n = 314) had more tangles than those with late‐onset AD (LOAD; n = 919) across most corticolimbic regions (Fig. 1). Except for CA1, younger age at onset was associated with a higher expected tangle density with an increase ranging from 8% in subiculum up to 99% in motor cortex (Table 1). Male sex was associated with lower expected tangle density throughout all corticolimbic regions. Being male associated the strongest in visual cortex with a 41% tangle density decrease. The APOE ε4 allele associated with an increase of tangle density in the nbM, CA1, subiculum, and visual cortex, whereas the MAPT H1 haplotype associated with a decrease in association and motor cortices. A positive family history for cognitive problems was associated with a 16% decrease of tangle density in visual cortex. Tangle density correlated closely with (sub)cortical thickness in the CA1+subiculum, superior temporal, inferior parietal, and middle frontal cortex (Spearman Rho = ‐0.39 ‐ ‐0.58, p<0.001).

Conclusion

These data contribute to the concept that brain regions may experience aging and genetics differentially, underlining the need to distinguish these aspects when investigating AD disease mechanisms.
Clinical criteria for a limbic‐predominant amnestic neurodegenerative syndrome highly associated with TDP‐43 and slow clinical progression
Authors: Corriveau‐Lecavalier Nick , Botha Hugo , Graff‐Radford Jonathan , Switzer Aaron , Przybelski Scott A. , Wiste Heather J. , Murray Melissa E. , Reichard Ross R. , Dickson Dennis W. , Nguyen Aivi T. , Ramanan Vijay K. , McCarter Stuart J. , Boeve Brad , Machulda Mary M. , Fields Julie A. , Stricker Nikki H. , Nelson Peter T , Grothe Michel J. , Knopman David S. , Lowe Val J. , Petersen Ronald C. , Jack Clifford R. , Jones David T.
Published: January 2025

Background

Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) is a neuropathologically‐defined disease, and it is frequently comorbid with Alzheimer’s disease neuropathological change (ADNC). However, the neurological syndrome associated with LATE neuropathological change (LATE‐NC) is not defined. We propose a set of clinical criteria for a limbic‐predominant amnestic neurodegenerative syndrome (LANS) that is highly associated with LATE‐NC. These criteria assess degree of certainty (highest, high, moderate, low) based on features that are measurable in vivo, including older age at evaluation, a mild clinical syndrome, impaired semantic knowledge, disproportionate hippocampal atrophy, limbic hypometabolism, absence of neocortical degeneration patterns and low likelihood of neocortical tau. We operationalized these criteria using two large datasets with clinical and pathologic outcomes.

Method

We screened autopsied patients from Mayo Clinic and ADNI cohorts and applied the LANS criteria to those with an antemortem predominant amnestic syndrome (Mayo, n = 165; ADNI, n = 53). We compared frequencies of neuropathological diagnoses across LANS likelihoods, compared longitudinal CDR‐SB trajectories across LANS likelihoods, and stratified ADNC/LATE‐NC patients according to their LANS likelihood and compared their longitudinal CDR‐SB trajectories to those with ADNC or LATE‐NC.

Result

ADNC, ADNC/LATE‐NC and LATE‐NC accounted for 35%, 37% and 4% of cases in the Mayo cohort, respectively, and 30%, 22%, and 9% of cases in the ADNI cohort, respectively (Fig. 1). ADNC cases had the lowest LANS likelihoods, LATE‐NC patients had the highest likelihoods, and ADNC/LATE‐NC patients had intermediate likelihoods. Patients with high LANS likelihoods had a milder and slower clinical course and more severe temporo‐limbic degeneration compared to those with low likelihoods (Fig. 2). ADNC/LATE‐NC patients with higher likelihoods had more temporo‐limbic degeneration and a slower rate of cognitive decline, and those with lower likelihoods had more lateral temporo‐parietal degeneration and a faster rate of cognitive decline (Fig. 3).

Conclusion

The implementation of LANS criteria has implications for disambiguating the different driving etiologies of progressive amnestic presentations in older age to guide prognosis, treatment, and clinical trial design and enrollment. The development of in vivo biomarkers specific to TDP‐43 pathology are needed to further refine molecular associations between LANS and LATE‐NC and precise antemortem diagnoses of LATE.
The association of body mass index with the mesolimbic system and cognition in Alzheimer’s disease
Authors: Li Qin , Li Xiaofeng
Published: January 2025

Background

The mesolimbic system plays a crucial role in weight regulation and cognition. Previous studies suggest that the pathology of Alzheimer’s disease (AD) can lead to the atrophy of the mesolimbic system and body mass index (BMI) decline. It remains unknown whether BMI is associated with the the mesolimbic system in AD.

Method

The data used in this study was obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. All participants underwent at least one Aβ PET imaging. PET imaging was carried out concurrently with brain MRI data and comprehensive neuropsychological assessments. Follow‐up data were collected at 2, 4, and 6 years. Hippocampus, amygdala, accumbens, caudate, and putamen were selected as regions of interest (ROIs) in the mesolimbic system. Linear regression was conducted to assess the relationship between BMI and cognition, and the volume of the ROIs. Linear mixed‐effects models were employed for longitudinal data analysis.

Result

A total of 1182 participants were included in this study, including 608 cases of Aβ positive and 574 cases of Aβ negative. (1) Compared with the Aβ negative group, the Aβ positive group exhibited a decreased volume of hippocampus, amygdala, accumbens, and putamen and lower BMI (P < 0.01); (2) BMI was associated with baseline hippocampal volume (β = 0.12, P < 0.001), amygdala volume (β = 0.12, P < 0.001), accumbens volume (β = 0.07, P = 0.046), caudate volume (β = 0.09, P = 0.021), and putamen volume (β = 0.09, P = 0.023) in Aβ positive group, whereas, in the Aβ negative group, BMI was not associated with the volume of ROIs; (3) BMI was associated with baseline Mini‐Mental State Examination (MMSE) z‐score (β = 0.09, P = 0.002) and memory composite score (β = 0.07, P = 0.015), whereas, in the Aβ negative group, BMI was not associated with cognition; (4) longitudinal data analyses involving Aβ positive participants indicated that BMI was associated with the volume of hippocampus, amygdala, accumbens, putamen, MMSE z‐score, and memory score.

Conclusion

A lower BMI was associated with smaller volume of mesolimbic system and poorer cognition in AD patients.
Prostaglandin D2 synthase is differentially methylated specifically in Huntington’s Disease
Authors: Wheildon Greg , Weymouth Luke , Smith Adam , Smith Rebecca G. , Troakes Claire , Al‐Sarraj Safa , Lunnon Katie
Published: January 2025

Background

Huntington’s disease (HD) is an autosomal dominant condition causing severe neurodegeneration in the striatum and the entorhinal cortex (EC). An epigenome wide association study of DNA methylation in HD by our group, identified potential hypomethylation at the PTGDS gene in the striatum. We aimed to validate this result through pyrosequencing, examining the locus in fine detail, and to assess the signal specificity by profiling multiple neurodegenerative diseases.

Method

379 EC and striatal DNA samples from 85 control, 73 Alzheimer’s disease (AD), 90 dementia with Lewy bodies (DLB), 20 HD, 34 Parkinson’s disease (PD) and 24 vascular dementia (VaD) subjects were matched for sex and age. DNA was bisulfite converted, before PTGDS target region amplification and subsequent pyrosequencing. Samples were analysed using linear models comparing the control group to each disease, controlling for sex, age, and batch effects. Average methylation levels across the amplicon were also compared. Additional analysis stratifying DLB and VaD cases by co‐existing AD pathology was also performed.

Result

We confirmed our previous findings of DNA hypomethylation at PTGDS in the striatum in HD. Furthermore, we found significant hypomethylation in the targeted region, both at the level of individual CpG sites, and across the amplicon in the EC. We also observed nominally significant changes in PD and DLB with co‐existing AD pathology across the amplicon, but these did not pass multiple correction.

Conclusion

This study validates our previous findings of PTGDS hypomethylation in HD in the striatum and presents novel associations at the EC. Together, these findings suggest further investigation of PTGDS, given others report differential expression in HD oligodendrocytes. Future studies should address the cell‐specific profile of PTGDS methylation and its transcriptional regulation in HD through fluorescent activated cell sorting.
Glymphatic system dysfunction predicts amyloid deposition, neurodegeneration, and clinical progression in Alzheimer’s disease
Authors: Huang Shu‐Yi
Published: January 2025

Background

Although glymphatic function is involved in Alzheimer’s disease (AD), its potential for tracking the pathological and clinical progression of AD and its sequential association with core AD biomarkers is poorly understood.

Method

Whole‐brain glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI‐ALPS) in participants with AD (n = 47), mild cognitive impairment (n = 137), and normal controls (n = 235) from the Alzheimer’s Disease Neuroimaging Initiative.

Result

Decreased ALPS‐index was observed in AD dementia, prodromal AD, and preclinical AD patients. Lower ALPS‐index was significantly associated with faster changes in amyloid PET burden (AV45 PET) and AD‐signature ROI volume, higher risk of amyloid‐positive transition and clinical progression, and faster rates of amyloid‐ and neurodegeneration‐related cognitive decline. Furthermore, the associations of ALPS‐index with cognitive decline were fully mediated by amyloid PET and brain atrophy.

Conclusion

Glymphatic failure may precede amyloid pathology, and predicts amyloid deposition, neurodegeneration, and clinical progression in AD.
The Dark Side of STING Signaling In Niemann‐Pick Disease Type C And Other Neurodegenerative Diseases
Authors: Chu Ting‐Ting
Published: January 2025

Background

The classic mode of STING activation is through binding the cyclic dinucleotide 2′3′‐cyclic GMP–AMP (cGAMP), produced by the DNA sensor cyclic GMP–AMP synthase (cGAS), which is important for the innate immune response to microbial infection and autoimmune disease. Modes of STING activation that are independent of cGAS are much less well understood. We wanted to explore the interactome of STING on the organelles during its trafficking route and to understand the regulatory network of STING signaling.

Method

To achieve this, we conducted an unbiased spatiotemporally resolved proximity labeling screen, followed by quantitative proteomics. This led us to discover a novel regulator of STING, NPC1, which is a lysosomal membrane protein that plays a role in cholesterol efflux. Mutations in NPC1 can cause Niemann Pick disease Type C, a neurodegenerative disease. Genetic deletion of Sting1 (the gene that encodes STING) or Irf3, but not that of Cgas, significantly reduced the activation of microglia and relieved the loss of Purkinje neurons in the cerebellum of Npc1−/− mice, leading to improved motor function.

Result

We found that NPC1 interacts with STING and recruits it to the lysosome for degradation in both human and mouse cells. Our findings also revealed that knockout of Npc1 ‘primes’STING signaling by physically linking or ‘tethering’ STING to SREBP2 trafficking. Loss of NPC1 protein also ‘boosts’ STING signaling by blocking lysosomal degradation. Both priming and boosting of STING signaling are required for severe neurological disease in the Npc1−/− mouse

Conclusion

Both priming and boosting of STING signaling are required for severe neurological disease in the Npc1−/− mouse. This study provides a comprehensive understanding of the STING interactomes and its regulatory network, shedding light on potential therapeutic targets for neurological diseases.
Computational Docking Analysis of APOE‐TREM2 Crosstalk with Therapeutic implications in Alzheimer’s disease (AD)
Authors: Basha SK Chand , Mekala Janaki Ramaiah
Published: January 2025

Background

Apolipoprotein E (APOE) and Triggering receptor expressed on myeloid cells 2 (TREM2) are the foremost genetic risk factors for late onset Alzheimer’s disease (LOAD). Recent findings suggests that crosstalk of APOE‐TREM2 has immunomodulatory effect on microglial phagocytosis, which have pathological implications in Alzheimer’s disease (AD). APOE has three isoforms: APOE (ε) 2, 3 and 4, with highest AD risk is attributed to APOE 4. R47H, a mutational variant of TREM2 increases the AD risk. The current work is done as a corroborating study, which is an extension of our work on computational investigation of TREM2 – Aβ ligands interaction.

Method

The coordinates of the APOE ligands‐isoforms: 2 and 4 were imported from the PDB database. I‐TASSER server was used for the structural prediction of TREM2 and R47H TREM2 proteins. HawkDock Server was utilised for the docking of TREM2‐APOE and R47H TREM2‐ APOE.

Result

The top model of TREM2 – APOE 2 docking exhibited a score of ‐ 5290.01 (Fig. 1). GBSA analysis reveals the binding free energy of the complex: ‐ 20.09 (kcal/mol). The top ranked docking model of TREM2 – APOE 4 exhibited a docking score of ‐ 5693.83 (Fig. 2) and binding free energy of the complex: ‐ 39.76 (kcal/mol). The top model of R47H TREM2 – APOE 2 docking exhibited a score of ‐ 4101.03. GBSA analysis reveals the binding free energy of the complex: ‐ 1.02 (kcal/mol). The top ranked docking model of R47H TREM2 – APOE 4 exhibited a docking score of ‐ 4969.52 and binding free energy of the complex: ‐ 10.03 (kcal/mol).

Conclusion

Computational docking analysis suggests that, TREM2 exhibited highest docking scores than R47H TREM2 which signify the latter’s role in increasing AD risk. Interestingly, both TREM2 and R47H TREM2 exhibited highest docking scores against APOE 4 in comparison with APOE 2. Our computational docking analysis has therapeutic implications in AD which requires further experimental verification.
ZNF653 transcription factor activity is associated with FDG‐PET changes in AD brain‐vulnerable regions
Authors: De Bastiani Marco , Povala Guilherme , Bellaver Bruna , Ferreira Pamela C.L. , Ferrari‐Souza João Pedro , Rosa‐Neto Pedro , Zatt Bruno , Pascoal Tharick A. , Zimmer Eduardo R.
Published: January 2025

Background

Positron emission tomography (PET) imaging greatly impacted Alzheimer’s disease (AD) research and diagnosis. which makes predicting PET brain imaging alterations using blood data is of high interest. Additionally, integrating PET and omics data can provide new insights into AD pathophysiology. Here, we implemented a module‐based framework combining blood transcriptomics with PET to search transcription factors (TFs) activities associated with brain metabolic changes in AD. We hypothesized that integrating omics and PET data will help advance our understanding of AD neurobiology and may reveal relevant new peripheral biomarkers.

Methods

[18F]Fluorodeoxyglucose ([18F]FDG)‐PET imaging and transcriptomics data were acquired from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Blood microarray gene expression from ADNI, GSE63063 and GSE97760 (https://www.ncbi.nlm.nih.gov/geo/) datasets were submitted to differential expression (DE) analysis. Regulatory units (regulons) of TFs and their predicted target genes were reconstructed using the ARACNe method. Altered regulons in AD submitted gene set variation analysis to infer their TF activity prior to neuroimaging integration with [18F]FDG‐PET images using voxel‐wise eneralized linear regression (GLR) models adjusted for age, gender, years of education, and APOEε4 (RMINC package).

Results

Sixty‐one regulatory units were significantly enriched with altered genes in at least ⅔ of the datasets explored, and 12 were altered in all three (Figure A‐B). The voxel‐wise correlation between [18F]FDG‐PET and regulons resulted in t‐statistical maps, where uncorrected t‐value > 2.0 was used as the threshol. We observed that ZNF653 has a positive correlation with [18F]FDG‐PET in the precuneus (24.24% left, 39.51% right), medial frontal gyrus (17.26% left), medial frontal‐orbital gyrus (12.50% left) and precentral gyrus (9.08% left, 8.28% right). Interestingly, the ZNF653 regulatory unit is composed majoritarily by genes related to energetic metabolism and protein kinase activity (Figure 1C‐D).

Conclusion

We identified the activity of the ZNF653 regulatory unit associated with [18 F]FDG‐PET metabolism in the brain of AD individuals. Furthermore, ZNF653 activity could be modulating metabolic and protein kinase activity‐related genes, highlighting a potential role of this TF in AD.
Assessing Short‐term Memory with Different Memory Modalities in Mild Cognitive Impairment
Authors: Smith Elaina , Cortez Christopher , Wiechmann April R , Davis Sandra , Dyson Hannah , Kucharski Krystyn , Ross Sarah M , Kline Geoffrey P , Mallet Robert T , Shi Xiangrong
Published: January 2025

Background

Mild cognitive function (MCI) is associated with a declined short‐term memory (STM). This study compared STM between adults with MCI and normal cognition assessed by verbal memory vs visuospatial memory.

Methods

Sixteen subjects with MCI and 11 subjects with normal cognition gave their written consent to participate in the study which was approved by the North Texas Regional IRB. Subjects having a self‐ or family member‐reported memory complaint, whose clinical dementia rating was ≤0.5, and/or whose testing scores in two or more cognitive domains were below the age‐/education‐adjusted group averages, were determined to have MCI. Digit‐Span‐Test (DST) and California‐Verbal‐Learning‐Test (CVLT‐II) were assessed for digit‐verbal memory and word‐verbal memory, respectively. Brief‐Visuospatial‐Memory‐Test–Revised (BVMT‐R) was performed for visuospatial memory. Values from the MCI and normal groups were compared using t‐tests. Two‐factor ANOVA was applied to test the significance of the group factor (i.e., MCI vs normal) and the trial factor (i.e., trials 1‐4 in CVLT‐II and trials 1‐3 in BVMT‐R).

Results

Neither group age nor education attainment was different in MCI vs normal (71.3±1.6 vs 67.9±1.7 years old). Although MMSE scores were not different between the groups, Trail‐Making‐Test performance was significantly poorer in the MCI. DST‐Sequencing scores were lower (P = 0.011) in the MCI (4.8±0.4) vs normal (6.4±0.3) subjects. However, neither DST‐Forward nor DST‐Backward scores differed between the groups. CVLT‐II immediate free‐recall and BVMT‐R recall scores were consistently superior in the normal vs MCI subjects (group factor P<0.001) and improved significantly with trial repetitions (trial factor P<0.001) in both groups. The rates of performance improvement with repeated CVLT‐II and BVMT‐R trials were similar in the groups, indicating similar learning effects. Both 30‐s short‐delayed and 10‐min long‐delayed free‐recall scores in CVLT‐II and 30‐min delayed recall scores in BVMT‐R were significantly lower in the MCI vs normal subjects (CVLT‐II short‐delayed: 6.9±0.3 vs 8.4±0.2 [P<0.001]; long‐delayed: 5.9±0.4 vs 8.2±0.3 [P<0.001], and BVMT‐R delayed recall: 5.1±0.9 vs 7.9±0.5, [P = 0.021]).

Conclusions

Both the verbal memory and visuospatial memory are significantly diminished, but learning ability may be preserved in MCI. CVLT‐II seems to be more specific and/or sensitive for detecting MCI‐related difference in STM.
Red Light Therapy Attenuates Prolonged LED light Exposure‐Associated Neuropathology and Mediates Circadian Clock Genes ‐ Per1 and Bmal1 Expression in Rats' Basal Ganglia
Authors: Obajuluwa Adejoke Olukayode , Babafemi Laoye John , Ndianefo Ogochukwu Jessica , Obajuluwa Tiwalola Madoc , Lech James Chrystopher , Okiki Pius Abimbola
Published: January 2025

Background

Prolonged exposure to LED‐light has been associated with impaired sleep quality and pathogenesis of various diseases, including Alzheimer’s Disease (AD). Red light therapy has been indicated as a non‐invasive way of reducing anxiety, mood and sleep optimization in neurodegenerative disorders but its endogenous mechanisms are insufficiently comprehended. Hence, we assessed the effects of scheduled red‐light exposure on clock genes‐Bmal1 and Per 1 expression, feacal boli frequency, and anxiety‐like responses in prolonged LED‐light exposed rats.

Method

Anxiety‐like indices of male rats was assessed using standard neurobehavioural methods under various light settings exposures (n = 5) in groups: I) 12‐hour light/12‐hour dark (NC), II) 12‐hour light and 12‐hour dark + scheduled red light (PC), III) 24‐hour LED light, and IV) 24‐hour LED light + scheduled red light; every two weeks for a total of 60 days. Total RNA was isolated from the rats' basal ganglia and reverse transcription was performed with the ProtoScript cDNA synthesis kit. Quantification and purity of cDNA were assessed using 1μl in a DeNovix spectrometer. Sequenced primers were utilized for the analysis of mRNA expression levels of Bmal1, Per1, and the housekeeping gene (GAPDH) through real‐time PCR. The PCR products were resolved by electrophoresis on 1.5% agarose gels and visualized by SafeView staining.

Result

Feacal bolus frequency (p<0.001), closed arm entries (p<0.05), and time spent in the dark area of the light‐dark box (p<0.001) were significantly reduced in the 24‐h LED light+scheduled red light and control groups rats compared to the 24‐h LED light. Real‐time gene expression analyses of Per1 showed a significant decline in the 24‐hour LED‐exposed rats, as indicated by decreased mRNA expression levels (p<0.05), when compared to other groups. Bmal1 gene expression remained unchanged in groups I and II while AGE revealed 100bp and 150 bp banding patterns for Bmal1 and Per1, respectively.

Conclusion

The findings from this study revealed that red light therapy attenuates LED light‐exposure‐induced anxiogenic responses and Per1 gene expression impairment. Consequently, these findings have the potential to inform the development of non‐invasive treatment strategies targeting the improvement of sleep quality in the management of neurodegenerative disorders. However, safety assessments should be ensured for its validation.
Cognitive Disparities in the Wayuu Indigenous Population: Insights from Neuropsychological Assessment
Authors: Preciado Jose Hernandez , Torres Wanda , Vargas Alex Dominguez , Pianneta Yesenia , Medina Mauricio , Sinisterra Marybel , Vargas José
Published: January 2025

Background

The neuropsychological profile within indigenous communities is a complex interplay of cultural, social, and environmental factors that significantly influence cognitive functioning and distinct neuropsychological patterns. The aim of this study was to assess the neuropsychological profile in the Wayuu indigenous population.

Methods

A cross‐sectional study. Wayuu indigenous individuals (n = 100) and non‐indigenous individuals (n = 100) from the northern coast of the Colombian Caribbean were included. The neuropsychological profile was assessed using the following tests: Hopkins Verbal Learning Test‐Revised (HVLT‐R), Clue Recall, Delayed Recall, Memory Complaint Scale (MCS), Trail Making Test Part A and B (TMT‐A/B), Symbol‐Digit test, Lawton & Brody, Yesavage, and Montreal Cognitive Assessment (MoCA). The Wilcoxon test was applied to compare median scores between Wayuu indigenous and non‐indigenous individuals. Additionally, the Spearman test was utilized to assess the correlation between the scores obtained for each test.

Results

The Wayuu population exhibited significantly lower scores in neuropsychological tests related to memory, learning, autonomy, depression, and cognitive function in comparison to non‐indigenous individuals (p<0.01) (Figure 1). Significant positive correlations were observed between Clue Recall and HLVT‐R (Spearman r = 0.82, p<0.001), Clue Recall and Delayed Recall (Spearman r = 0.69, p<0.001), and between Lawton & Brody and MOCA (Spearman r = 0.42, p<0.001). In contrast, significant negative correlations were found between Yesavage and MOCA (Spearman r = ‐0.45, p < 0.001), and between Yesavage and Lawton/Brody (Spearman r = ‐0.45, p < 0.001).

Conclusions

Our study emphasizes significant cognitive gaps within the Wayuu indigenous community. The neuropsychological landscape of this indigenous population reveals the impact of historical and contemporary factors on cognitive health, emphasizing the necessity of culturally tailored interventions to improve neurocognitive well‐being in these communities.