bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synaptic proteasome is inhibited in Alzheimer’s disease models and associates with memory impairment in mice
Authors: Ribeiro Felipe C , Ferreira Danielle Cozachenco , Heimfarth Luana , Fortuna Juliana , de Freitas Guilherme B. , Souza Jorge M , Alves‐Leon Soniza , Leite Renata Elaine Paraizo , Suemoto Claudia Kimie , Grinberg Lea T. , De Felice Fernanda G , Lourenco Mychael V , Ferreira Sergio T 
Published: January 2025

AbstractBackgroundThe proteasome plays key roles in synaptic plasticity and memory by regulating protein turnover, quality control, and elimination of oxidized/misfolded proteins. Here, we investigate proteasome function and localization at synapses in Alzheimer’s disease (AD) post‐mortem brain tissue and in experimental models.MethodWe used primary hippocampal cultures, amyloid‐β oligomers (AβO)‐injected or transgenic animal models, and human brain tissue to determine brain proteasome function and subcellular localization. We further induced proteasome inhibition in vitro and in vivo to determine AD‐like phenotypes and memory in mice.ResultWe found a marked increase in ubiquitinylated proteins in post‐mortem AD hippocampi compared to controls. Using several experimental models, we show that AβO inhibit synaptic proteasome activity and trigger a reduction in synaptic proteasome content. We further show proteasome inhibition specifically in hippocampal synaptic fractions derived from APPswePS1ΔE9 mice. Reduced synaptic proteasome activity instigated by AβOs is corrected by treatment with rolipram, a phosphodiesterase‐4 inhibitor, in mice. Results further show that dynein inhibition blocks AβO‐induced reduction in dendritic proteasome content in hippocampal neurons. Finally, proteasome inhibition induces AD‐like pathological features, including reactive oxygen species and dendritic spine loss in hippocampal neurons, inhibition of hippocampal mRNA translation, and memory impairment in mice.ConclusionResults suggest that proteasome inhibition may contribute to synaptic and memory deficits in AD.
Correlation between Cognitive Function and Time‐Series Variation in Eyelid Opening and Closing from Facial Videos During Neuropsychological Tests
Authors: Umematsu Terumi , Tsugawa Akito , Takenoshita Naoto , Sato Tomohiko , Shimizu Soichiro 
Published: January 2025

AbstractBackgroundThe application of image recognition technology has been spreading to dementia screening. However, cognitive function fluctuates due to mental and physical conditions. Therefore, we believe that it may be necessary to evaluate facial information over time after considering these factors. This study evaluated the correlation between cognitive function and features acquired from facial videos during neuropsychological tests.MethodOutpatients who complained of memory loss from a single memory clinic between March 2022 and April 2023 were recruited in the study. All patients underwent standard clinical tests, and facial videos were obtained during an approximately 1‐hour neuropsychological test. Cognitive function was evaluated by Mini‐Mental State Examination (MMSE). Facial feature points were calculated from the videos, then facial pose, gaze, and time‐series variation in eyelid opening and closing, such as the percentage of eyelid closure (PERCLOS), blink‐movement speed, number of blinks, eyelid time variability, and eyelid left‐right variability, were analyzed to evaluate their relationship to MMSE using the Pearson’s correlation coefficients. During neuropsychological tests, under concentration conditions, we evaluate a relationship between MMSE and the facial analysis results, particularly time‐series data of eyelid opening and closing.ResultA total of 91 patients (31 males and 60 females, age: 80.5±5.7 years, years of education: 12.8±2.7years, MMSE: 22.2±4.9 points) were included in the study. The results showed a correlation between MMSE and the time‐series variation in eyelid opening and closing, with a correlation of 0.17 with PERCLOS, 0.26 with blink‐movement speed, and 0.15 with blink counts. The correlation coefficient between blink‐movement speed and MMSE was significant, with a 95% confidence interval.ConclusionThis study showed a weak correlation between MMSE and some features of eyelid opening and closing. These results suggest that, during neuropsychological tests, when subjects are considered to be concentrating on their answers, i.e., not drowsy, an increase in the PERCLOS may be seen as one of the physical responses due to cognitive function decline.
Lung function and plasma biomarkers: Unraveling the interplay with Alzheimer’s Disease and Related Dementias
Authors: Vivek Sithara , Crimmins Eileen M. , Guan Weihua , Faul Jessica D , Thyagarajan Bharat 
Published: January 2025

AbstractBackgroundWith the emerging role of the blood biomarkers in Alzheimer’s Disease (AD) clinical practice and trials, it is crucial to identify and address factors influencing the concentrations of these biomarkers in circulation for enhanced clinical utility. We aim to assess the impact of lung function on plasma AD biomarker levels and elucidate the relationship between lung function and Alzheimer’s Disease and Related Dementias (ADRD).MethodWe used the Peak Expiratory Flow (PEF), plasma biomarkers of AD (Amyloid beta 42/40 (Aβ42/40) ratio, phosphorylated‐tau181 (p‐tau181), Neurofilament light chain (NfL) and Glial fibrillary acidic protein (GFAP)) measured in the Health and Retirement Study (HRS) 2016 survey participants (n = 3801) and incident dementia (n = 142) over 4 years. Participants were categorized into sex‐specific standardized residual percentiles (SRP) of PEF adjusted for age and height based on previously published method. We created 3 categories using SRP with cut points at: ≥50%, 10%–50%, and <10% (poor lung function). Multiple linear regressions assessed the association between PEF and AD biomarkers, adjusting for sample weights, age, race, education, body mass index, smoking status, comorbidity index, composite inflammatory score, estimated glomerular filtration rate and APOE ε4 allele. Separate analysis were conducted for men and women. We applied causal mediation analysis to determine how plasma biomarkers mediate the association between PEF and incident dementia.ResultIn models adjusted for covariates, men (β = 0.11 p = 0.09) and women ( = 0.06, p = 0.09) in SRP <10% show elevated GFAP levels compared to those in SRP ≥50%. Women in SRP <10% exhibit higher NfL levels (β = 0.13, p = 0.001) compared to those in SRP ≥50%. PEF showed no association with plasma levels of Aβ42/40 and p‐tau 181 in both sexes. In women, the association between lung function and incident dementia was mediated by plasma levels of NfL (proportion mediated = 20%, 95% CI = [1.2, 39], p = 0.04).ConclusionIndividuals with poor lung function exhibit elevated levels of NfL and GFAP in their blood, with discernible sex‐specific variations in the association. These findings suggest a potential connection between lung health and cognitive function in older women, and providing a basis for future hypotheses to explore the pathological mechanisms of AD/ADRD.
Brain‐targeting liposome‐based APOE2 gene delivery exacerbates soluble amyloid‐β accumulation in AppNL‐G‐F mice
Authors: Wang Ni , Parsons Tammee M , Ren Yingxue , Pan Yining , Starling Skylar C , Muolokwu Chinenye , Singh Jagdish , Kanekiyo Takahisa 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disease and the most prevalent form of late‐life dementia. The ε2 allele of the APOE gene encoding apolipoprotein E (APOE2) is associated with lower susceptibility to AD among the three genotypes (ε2, ε3, ε4), while APOE4 is the strongest genetic risk factor for late‐onset AD. APOE plays a critical role in maintaining synaptic plasticity and neuronal function by controlling lipid homeostasis, with APOE2 having a superior function. Gene therapy that increases APOE2 levels in the brain has, therefore, emerged as a potential therapeutic strategy to treat AD.MethodWe conjugated PEGylated liposomes with transferrin and Penetratin, a cell‐penetrating peptide, sufficiently deliver chitosan‐APOE2 cDNA plasmid complex into amyloid model AppNL‐G‐F knockin mice at 12‐month‐old. Biochemical studies and brain transcriptome analysis were employed to investigate how brain‐targeting liposome‐based APOE2 gene delivery influences amyloid‐β (Aβ)‐related pathologies in AppNL‐G‐F knockin mice.ResultOne month after APOE2 gene therapy, there was a trend of reduced insoluble Aβ levels in the mouse cortices. Furthermore, in the AppNL‐G‐F knockin mice that received the APOE2 gene therapy, brain transcriptome analysis through RNA‐sequencing identified the upregulation of genes/pathways related to neuronal development. This was supported by increases of Dlg4 and Syp mRNAs coding synaptic proteins in the experimental group. On the other hand, we found that APOE2 gene delivery increased soluble Aβ levels, including oligomers, as well as exacerbated neurite dystrophy and decreased synaptophysin.ConclusionOur results suggest that brain‐targeting liposome‐based APOE2 gene therapy is potentially beneficial for synaptic formation at the transcriptional level. Forced APOE2 expressions, however, may exacerbate Aβ toxicity by increasing the dissociation of Aβ oligomers from aggregates in the presence of considerable amyloid burden.
The regulation of working memory by rTMS target on cerebellum with different frequencies in healthy adults
Authors: Song Bo , Shi Jingping , Tian Minjie 
Published: January 2025

AbstractBackgroundThe study of the involvement of the cerebellum in learning and memory has become one of the recent hot topics in the field of cognitive neuroscience. Transcranial magnetic stimulation (TMS) of the cerebellum has gained increasing interest in the treatment of cognition‐related disorders, making it necessary to determine the optimal parameters for cerebellar TMS. In this study, we aim to explore the effects of different frequencies of cerebellar repetitive TMS (rTMS) on working memory regulation and the associated electrophysiological changes. Through this research, we hope to provide objective bioinformatic guiding evidence for parameter optimization of cerebellar TMS.MethodWe recruited 75 healthy university students or graduate students as participants and divided them into five groups: 1Hz rTMS group, 5Hz rTMS group, 10Hz rTMS group, 20Hz rTMS group, and sham stimulation group. Each group received rTMS at different frequencies (1Hz, 5Hz, 10Hz, and 20Hz) over the cerebellar Crus II region, while a control group received sham stimulation. We assessed working memory performance using a 2‐back task and recorded electroencephalographic (EEG) signals during the 2‐back task and resting state before and after the stimulation. Cluster‐based permutation statistics and One‐way analysis of variance were used for the analysis of both neurophysiological and behavioral data.ResultThe 5Hz rTMS significantly increased the induced ERP activity of N100, P150, and N200, showed greater theta and alpha oscillatory activity, and significantly improved working memory performance. Furthermore, using phase locking value to construct brain networks and conduct analysis, we found that 5Hz rTMS significantly enhanced the whole‐brain local and global efficiency of brain networks in the theta frequency band, while 20Hz rTMS improved the local efficiency of the occipital and parietal lobes in the beta frequency band, with no significant differences observed in other frequency bands.ConclusionOur results demonstrate that 5Hz rTMS stimulation can significantly improve subjects' neurophysiological changes and working memory performance, showing a certain frequency‐dependent effect. These findings contribute to providing scientific evidence for the application of cerebellar TMS in memory improvement and offer valuable references for future related research.
Exploring Homeostasis Restoration as a Potential Therapeutic Avenue for Addressing Obesity and Sleep Disorders
Authors: Bhaskar Rakesh , Singh Krishna Kumar , Ghosh Shampa , Mahapatra Madhumita , Sinha Jitendra Kumar 
Published: January 2025

AbstractBackgroundObesity is caused by the buildup of excess body fat, which upsets homeostasis. Genetic, epigenetic, and behavioural variables all have a role in the pathophysiology of obesity. In turn, obesity throws off the sleep cycle, leading to sleep problems. Sleep is essential for preserving homeostasis, adjusting to environmental changes, and saving energy. The contemporary way of living frequently disrupts sleep cycles, which is bad for health. Many pathophysiological disorders are caused by changes in homeostasis, and obesity is one important consequence.MethodThis study examines the complex connection between fat and sleep, focusing on how sleep disturbances affect energy homeostasis. The study explores the significance of sleep in evolution, as well as its anabolic properties and role in restoring glycogen stores that are used up during waking hours. It also looks at how modern lifestyles affect sleep, establishing a connection between energy balance, obesity, and sleep behaviour.ResultReduced sleep length and poor quality of sleep are important obesity risk factors that negatively impact energy homeostasis. The review emphasises the necessity of interventions aimed at managing obesity and sleep disorders in order to enhance both the quantity and quality of sleep. People who are at a higher risk of obesity should maintain good sleep hygiene and sleep discipline.ConclusionComprehending the relationship between fat and sleep is crucial, given the noteworthy overlap between disorders such as sleep apnea and imbalanced energy. The review underscores the significance of addressing obesity and sleep disorders together in order to lessen related health effects. To find evidence that such therapies are effective in decreasing obesity‐related health outcomes, more study is required.
Purpose‐in‐life associates with later onset and lower hazard for cognitive impairment in a population‐based, longitudinal cohort of diverse participants
Authors: Howard Nicholas C , Gerasimov Ekaterina S , Wingo Thomas S. , Wingo Aliza P. 
Published: January 2025

AbstractBackgroundPurpose‐in‐life (PiL) refers to the tendency to derive purpose and meaning in life. Higher PiL was associated with lower risk for developing Alzheimer’s dementia in older white participants (age 70s‐80s). It is unclear, however, whether the protective effect of PiL can be observed as early as in the 50s and 60s, and whether PiL is associated with a delay in onset age of cognitive impairment. Here, we investigated these questions in the population‐based cohort of diverse participants recruited by the Health and Retirement Study.Method13,689 participants (10,114 White, 1837 Black, 1335 Hispanic, 405 Other) with normal cognitive status at baseline, PiL assessment, longitudinal depression and cognitive test scores, and genetic data were included. Cognitive performance was assessed biennially with the modified Telephone Interview for Cognitive Status (mTICS) over 15 follow‐up years. The mTICS includes immediate and delay recall, working memory, attention, and processing speed. Cognitive impairment was defined as having mTICS<12, which is a psychometrically validated threshold. Ethnicity‐stratified Cox proportional hazards was performed to assess the association between baseline PiL and incident of cognitive impairment. Linear regressions were performed to examine the association between PiL and onset age of cognitive impairment. APOE e4 allele was additionally adjusted for in the above regression models.ResultWithin each of the ethnicity groups, higher PiL was associated with lower hazard for developing cognitive impairment after adjusting for sex, age at baseline, education, and longitudinal depression (HR = 0.86, p<0.001). This association remained significant after we adjusted for APOE e4 in addition to the above covariates. APOE e4 was not associated with PiL. Furthermore, higher PiL was associated with a later onset age of cognitive impairment after adjusting for sex, age at baseline, education, and longitudinal depression (b = 0.19, p = 0.02).ConclusionHigher PiL was associated with lower risk for developing cognitive impairment in diverse populations. Furthermore, this is the first study to show that higher PiL was associated with a later onset age of cognitive impairment in different ethnicities. Interventions that foster PiL can potentially reduce the risk of cognitive impairment and delay its onset age.
Clinical manifestations of sporadic Creutzfeldt‐Jakob disease in public neurological center in Thailand
Authors: Khieukhajee Jedsada , Suanprasert Narupat , Apiwattanakul Metha , Rojana‐Udomsart Arada , Tantirittisak Tasanee 
Published: January 2025

AbstractBackgroundSporadic Creutzfeldt‐Jakob disease (sCJD) is one of common causes of rapidly progressive dementia worldwide. However, because of the variety of its clinical presentations that mimic other cognitive disorders, the certain diagnosis in public hospitals is still limited. Therefore, this study provides more information about disease manifestations and clinical courses of probable sCJD cases in Thailand.MethodThe retrospective cross‐sectional study of probable sCJD patients visited Neurological Institute of Thailand during 2018‐2023 was conducted. Probable sCJD cases were diagnosed according to 2017 International CJD Surveillance Network Diagnostic Criteria. Demographic data, clinical presentations, brain MRI, EEG, CSF analyses, and clinical course were reviewed.ResultThe total of 17 probable sCJD cases were studied. There was 11 female (64.71%) with the median age of 62 (IQR 14.5) years. The median onset of symptom was 2 months (IQR 2) before hospital visit, which cognitive impairment is the most common first presentation (29.41%) followed by ataxia (23.53%) and visual disturbances (17.65%). Myoclonus was found in most patients during the disease course at 2 weeks prior to diagnosis. Most patients had typical high signal intensities at both caudate/putamen and cortical regions (76.47%). Generalized periodic discharges with triphasic morphology of 1‐1.5 Hz were found in 11/14 patients with EEG results (78.57%). Most patients progressed to akinetic mutism and bed‐bound within 1 month after hospital visit.ConclusionsCJD has diverse clinical presentations that resemble other cognitive disorders. Detailed assessment of signs and symptoms together with proper investigations could help to differentiate this condition in resource‐limit setting.
Polygenic risk score analysis suggests hypothyroidism as a risk factor for Alzheimer’s disease
Authors: Piras Ignazio , Naymik Marcus , Don Janith , Schork Nicholas J. , Saner Don , Huentelman Matthew J. 
Published: January 2025

AbstractBackgroundAlzheimer’s Disease (AD) is characterized by cognitive decline due to synaptic loss and neuron death, with amyloid‐β plaques and neurofibrillary tau tangles as key pathological hallmarks. Although genetics account for about 70% of AD risk, modifiable factors also significantly contribute to AD and dementia onset and AD‐resilience. Utilizing the All of Us (AoU) cohort, this study explores the relationship between clinical conditions, quantitative phenotypes (including lab tests and anthropometric measurements), and AD risk, shedding light on potential preventative measures.MethodWe selected a subset of non‐AD affected individuals from the AoU Controlled Tier Dataset v7 for analyzing medical conditions and measurements related to AD. Polygenic Risk Scores (PRS) were calculated to assess AD risk, which were then associated with medical conditions and measurements using linear regression models and accounting for biological sex and age. A replication study was conducted in the UK Biobank to validate the findings, particularly focusing on the association between AD‐PRS and hypothyroidism prevalence.ResultWe found significant association between AD‐PRS and nine conditions, with the most significant hypothyroidism and acquired hypothyroidism (adj‐p < 1.3‐06). The AD‐PRS was significantly lower in participants with these conditions. Additionally, an investigation into 355 measurement variables revealed a significant association for eighteen variables, with height and blood pressure showing a positive correlation with AD‐PRS. Thyrotropin level (TSH) exhibited a negative correlation, aligning with hypothyroidism’s association with lower PRS. This association remained significant even after accounting for hypothyroidism medications in the analysis, and was further confirmed in a replication study using the UK Biobank data (n = 390,543; p = 1.3‐23)ConclusionOur results seem to demonstrate that the absence of HPT might be a factor enhancing AD resilience since it can balance the genetic risk factors, as non‐affected individuals exhibited a significantly higher AD‐PRS than HPT‐affected individuals.
Alzheimer’s Disease: Because Amyloid‐β Cannot Differentiate Between Bacteria and Neurons
Authors: Neal Matthew P , Meek Autumn , Weaver Donald F 
Published: January 2025

AbstractBackgroundAn explicit molecular level understanding of Alzheimer’s Disease (AD) remains elusive. What initiates the disease and why does it progress? Answering these questions will be crucial to the development of much needed new diagnostics and therapeutics. Though the amyloid hypothesis is often debated, recent biologic trial results support a role for Aβ in AD pathogenesis. However, there are other tenable hypotheses, most notably neuroinflammation, but also gliopathy, synaptopathy, mitochondriopathy, and oxidative stress. Is it possible to formulate a model of AD that incorporates multiple proposed hypotheses into a single unifying conceptual approach? We seek to answer this question.MethodWe performed a comprehensive series of in silico, in vitro and in vivo studies explicitly evaluating the atomistic‐molecular mechanisms of Aβ‐mediated neurotoxicities as well as Aβ’s antimicrobial and immunomodulatory effects. The molecular effects of Aβ and various cytokines on mitochondria, neuronal membranes and synapses were also explicitly studied.ResultMembranes are a mosaic of lipophilic and hydrophilic (negatively‐charged) regions organized in specific geometric patterns. Our studies show that bacterial membranes and neuronal membranes have essentially identical patterns, making neurons inadvertently susceptible to molecules targeting bacterial membranes. From this, a new model of AD emerges: In response to various immunostimulatory events (infection, trauma, ischemia, diabetes, air pollution), Aβ is released as an immunopeptide (kinocidin‐type cytokine) which exhibits both immunomodulatory and antimicrobial properties (whether bacteria are present, or not); this inflicts a misdirected attack upon ‘self’ neurons, arising from the essentially identical membrane surface electrotopologies between neurons (especially at the synapse) and bacteria – causing neuronal death by mistaken identity. Following this self‐attack, the resulting necrotic neuronal breakdown products diffuse to adjacent neurons eliciting further release of Aβ, leading to a self‐perpetuating cycle.ConclusionWe propose that AD occurs because Aβ is an immunopeptide that cannot differentiate neurons from bacteria – a case of mistaken identity that leads to an innate autoimmune response in which Aβ extracellularly attacks neuronal membranes, particularly at the synapse, while also intracellularly attacking mitochondria.