bluuebunny/crossref_metadata_2025_split huggingface dataset:
Temporal Progression of Pathophysiological Changes in hAPP‐J20 Transgenic Alzheimer’s Mice: Insights from Longitudinal Analysis
Authors: Hsin Yue Loong , Liao Keng Ying , Han Xu , Chen Wen‐Ying , Liu Wentai 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is characterized by cognitive decline and increased seizure susceptibility due to brain damage and neural disruptions. This study examines the relationship between cognitive deterioration and seizure pathology in hAPP‐J20 transgenic Alzheimer’s mice, a model known for amyloid plaque deposition and heightened seizure activity.MethodWe observed hAPP‐J20 mice aged 8 to 28 weeks using long‐term wireless telemetry to assess hippocampal local field potential, sampled at 2 kHz. This allowed categorization of high‐frequency oscillations (HFOs) into ripples (80‐200 Hz) and fast ripples (250‐600 Hz). We conducted the Morris water maze test for spatial learning assessment, analyzed amyloid plaque deposition, seizure‐related deaths, neuropeptide Y (NPY) concentration, quantified glutamatergic pyramidal cells and GABAergic parvalbumin (PV) interneurons, and measured the excitatory/inhibitory cell ratio.ResultAmyloid plaque deposition commenced post‐18 weeks, marking a pivotal phase in disease progression. This period correlated with a peak in seizure‐related deaths, which reached its zenith at 15 weeks and subsequently declined gradually. In parallel, the NPY concentration surged, peaking concurrently with the peak in seizure‐related deaths at 15 weeks before tapering off. Meanwhile, the count of pyramidal cells showed a mild upward trend. In contrast, the population of PV interneurons demonstrated a discernible decrease starting from 15 weeks, with a significant reduction post‐18 weeks, aligning with the initiation of amyloid plaque staining in the hippocampus. The ratio of excitatory to inhibitory cells began increasing from 9 weeks, peaking after 15 weeks. The rates of HFOs, encompassing both ripples and fast ripples, exhibited an upward trajectory preceding the 18‐week mark, reflecting an increase in neural network excitability during this critical period.ConclusionThis study outlines the progression of pathophysiological changes in the AD mouse model, linking amyloid plaque deposition to seizure activity, NPY levels, neuronal cell density changes, and increased neural network excitability. The rise in HFO rates, especially fast ripples, suggests their potential as biomarkers for seizure onset or epileptogenesis, linking amyloid pathology with seizure pathology. These findings provide crucial insights for the development and timing of therapeutic strategies in AD.
Neuropsychiatric Symptoms in Patients with Early‐onset Dementia from a Memory Clinic in India
Authors: Chatterjee Atri , Laskar Sanghamitra , Abhinav Ankur Arvind , Aggarwal Sonali , Kathait Aparna 
Published: January 2025

AbstractBackgroundNeuropsychiatric symptoms (NPS) are common in patients who develop dementia before the age of 65 years, defined as early‐onset dementia (EoD). NPS are a major source of morbidity and caregiver distress in patients living with EoD. The prevalence, severity and types of NPS in different populations are unclear. Therefore, we investigated the frequency and characteristics of NPS in EoD patients attending a memory clinic in India.MethodWe recruited participants with a clinical diagnosis of EoD from a subspecialty cognitive neurology clinic. NPS were assessed using Neuropsychiatric Inventory‐Questionnaire (NPI‐Q). In addition, we collected information regarding age at onset, gender, diagnosis and duration of disease. We analyzed the frequency and severity of NPS among the participants present at the baseline assessment.ResultWe report data from 31 patients diagnosed with EoD. The average age at baseline assessment was 57.1 years (SD ± 7.9) and the mean age at onset of symptoms was 54 years (SD ± 6.6). 61.3% patients were male. 38.7% patients were diagnosed with vascular cognitive impairment; 32.3% and 9.7% patients were diagnosed with Alzheimer’s disease and frontotemporal dementia respectively. 96.8% patients reported at least one NPS with a mean NPI‐Q total score of 13.6 (SD ± 15.2). Irritability stood as the most frequent symptom (61.3%), followed by agitation (58.1%) and apathy (45.2%). Notably, 12.9% of patients reported psychotic symptoms at baseline.ConclusionNPS were nearly ubiquitous in this Indian EoD cohort at baseline. Irritability, agitation, and apathy, associated with significant caregiver burden, emerged as the dominant NPS. Further research is crucial to explore the efficacy of pharmacotherapy and culturally relevant non‐pharmacological interventions for managing NPS in diverse populations.
Gait Speed as a Marker of Superior Physical Performance in SuperAgers: Cognitive and Neuroanatomical Correlates
Authors: Kim Bori. R. , Park Kee Hyung , Jeong Jee Hyang , Kim Geon Ha 
Published: January 2025

AbstractBackgroundCognitive abilities, notably memory, typically decline with age, but a subset of individuals known as superagers defy this trend by exhibiting memory functions akin to those 20‐30 years younger in late life. Recognizing the interconnection between physical performance, health outcomes, and cognitive function in older adults, our aim was to explore whether superagers demonstrate superior physical performance compared to typical agers.MethodsForty‐nine cognitively unimpaired older adults underwent comprehensive assessments, including cognitive function tests using the Seoul Neuropsychological Screening Battery, Brain MRI, and the Short Physical Performance Battery (SPPB), a prominent tool for evaluating physical function. Normal cognitive function was defined by scores above ‐1.0 SD of population norms for memory tests and above ‐1.5 SD for language, attention, visuospatial, and executive function tests. FreeSurfer software processed T1 images to obtain anatomical parcellations, including the hippocampus. The SPPB, consisting of standing balance, repeated chair stands, and gait speed measures, was conducted using an automated physical performance test instrument (AndanteFit, DYPHI Inc., South Korea). Superagers were identified based on their performance compared to middle‐aged adults (45 years old) in delayed recall scores from the Seoul Verbal Learning Test and the Rey‐Osterrieth Complex Figure test. Among the 49 participants, 26 were classified as superagers.ResultsNo significant differences in age (72.6 ± 7.4 vs. 71.2 ± 5.7, P = 0.465), sex (69.6% female vs. 80.8% female, P = 0.363), and education level (10.5 ± 4.2 vs. 11.1 ± 3.8, P = 0.582) were observed between typical agers and superagers. While total SPPB scores showed no significant difference, gait speed scores were notably higher in superagers (3.7 ± 0.6 vs. 4 ± 0, P = 0.008). Raw gait speed analysis confirmed a faster gait speed in superagers, and intriguingly, gait speed correlated significantly with memory function (r = 0.4182, P = 0.03) and left hippocampal volume (r = 0.6103, P = 0.04) in superagers.ConclusionOur study suggests that superior physical performance, including gait speed, in superagers is associated with enhanced memory function and greater left hippocampal volume. This reinforces the importance of assessing physical function in clinical practice, particularly gait speed, as it may serve as a marker for cognitive health.
COVID‐19 Mobile Brain Health
Authors: Gurnani Ashita S. , Li Stephanie , Hwang Phillip H 
Published: January 2025

AbstractBackgroundThe long‐term neurological impact of the SARS‐CoV‐2 virus is unknown and it remains to be seen whether it would create a surge in cases of dementia and cognitive decline years later, which is already a global public health challenge. Our group has previously shown that participants cognitive functioning as measured via mobile‐based assessments using smartphone‐based cognitive tests did not differ based on their COVID status. The goal of the present study was to examine participants longitudinal cognitive performance with the hypothesis that participants with a previous COVID‐19 diagnosis (COVID+) will have worse cognitive performance over time than those without COVID‐19 (COVID‐).MethodParticipants (n = 45) with self‐reported positive (n = 25) or negative COVID‐19 (n = 20) statuses based on polymerase chain reaction or antigen testing were recruited from the Boston area. Inclusion criteria included access to a smartphone with an Android or iOS operation system and to internet connectivity, along with proficiency in English. Cognitive performance was measured using Defense Automated Neurobehavioral Assessment (DANA) from AnthroTronix. Participants were asked to complete DANA monthly over six months. Generalized estimating equations (GEE) were used to compare longitudinal cognitive performance among those with and without COVID‐19.ResultThe sample was, on average, 53 years of age and comprised primarily of COVID+ (56%), female (78%), and Caucasian (50%) participants that were generally well educated (42% with at least a bachelor’s degree), and had ≥1 COVID vaccination (95%). Participants completed an average of 5.5 DANA assessments over the six‐month period. Results indicated that after adjusting for age, sex, and education, COVID+ group had significantly greater decline in performance on the Code Substitution (β = ‐2.14, 95% CI = ‐4.05 – ‐0.24, p = 0.028) and Match to Sample tasks (β = ‐2.01, 95% CI = ‐3.80 – ‐0.25, p = 0.026) in comparison to the COVID‐ group.ConclusionResults indicate that while cognitive performance at baseline does not differ based on COVID status, having COVID may impact working memory and sensory processing abilities over time. Future directions include examining the impact of COVID disease severity and reinfection on cognition.
Sex‐stratified genome‐wide meta‐analysis identifies novel loci for cognitive decline in older adults
Authors: Acharya Vibha , Fan Kang‐Hsien , Snitz Beth E. , Ganguli Mary , DeKosky Steven T. , Feingold Eleanor , Kamboh M. Ilyas 
Published: January 2025

AbstractBackgroundMany complex traits and diseases show sex‐specific biases in clinical presentation and prevalence. For instance, two‐thirds of AD cases are female. Studies suggest that women might have higher cognitive reserve but steeper cognitive decline in older age. Cognitive traits have substantial genetic influence. Cognitive impairment could vary among sexes due to sex‐specific genetic factors. To understand the sex‐specific genetic architecture of cognitive decline, we performed genome‐wide association study (GWAS) on sex‐stratified data and assessed a SNP‐sex interaction.MethodWe derived inter‐individual specific slopes using linear mixed effect model adjusting for age, education, and sex across five cognitive domains (attention, memory, executive function, language, visuospatial function) and global cognitive function in 3021 older adults aged ≥65 years (females = 1545, males = 1476) belonging to three prospective cohorts: Gingko Evaluation of Memory (GEM), Monongahela‐Youghiogheny Heathy Aging Team (MYHAT), and Monongahela Valley Independent Elders Survey (MoVIES). GWAS was conducted on each cognitive phenotype in each cohort adjusting for the first four genetic principal components. Gene‐based analysis was also conducted to discover genes specific to biological sexes.ResultWe identified a novel genome‐wide significant (GWS) intergenic locus for decline of memory in males near RPS23P3 on chromosome 4 (top SNP: rs6851574; MAF = 0.39; Pmale = 4.10E‐08, bmale = ‐0.19; Pfemale = 6.13E‐01, bfemale = ‐0.017; Pinteraction = 3.76E‐04). This intergenic region has previously been associated with other cognitive related traits such as educational attainment, anatomical brain aging and brain shape. We also identified a subthreshold GWS locus for decline of executive function in females near NDUFA12 on chromosome 12 (top SNP: rs11107823; MAF = 0.12; Pfemale = 9.35E‐08, bfemale = 0.28; Pmale = 0.151, bmale = ‐0.077; Pinteraction = 7.42E‐06). NDUFA12/rs11107823 is cis‐eQTL for NDUFA12, NTN4 and VETZ in blood and brain tissues. NDUFA12 codes for a gene involved in oxidative phosphorylation in mitochondria and was also found to be suggestively associated with decline of executive function in gene‐based analysis in females (P = 1.40E‐04).ConclusionIn this sex‐stratified analysis of cognitive decline, we identified two novel loci affecting cognition. Our study illustrates that sex‐aware genetic studies can help in the identification of novel genetic loci and enhance sex‐specific understanding of cognitive aging.
Whole genome methylation sequencing in blood reveals differential DNA methylation in pathways associated with mitochondrial function in persons with late‐onset dementia due to Alzheimer’s disease (AD)
Authors: Boruch Alexander E , Renteria Isabelle , Madrid Andy , Breen Coleman E , Papale Ligia A , Clark Lindsay R. , Bergmann Phillip E , Asthana Sanjay , Johnson Sterling C. , Keles Sündüz , Cook Dane B. , Hogan Kirk J. , Alisch Reid S 
Published: January 2025

AbstractBackgroundDNA microarray‐based studies report differentially methylated positions (DMPs) in blood between cognitively unimpaired persons (CU) and persons with late‐onset dementia due to Alzheimer’s disease (AD) or Mild Cognitive Impairment (MCI) but interrogate less than 4% of the human genome. Whole genome methylation sequencing (WGMS) quantifies DNA methylation levels across the entire human genome (>25 million CpG loci). Using WGMS, we previously reported 28,038 DMPs within 2,707 genes between persons with and without AD.MethodWe used WGMS to measure DNA methylation levels in nuclear genes encoding proteins that participate in mitochondrial function as cataloged in the Human Protein Atlas in blood samples from participants with AD (N = 109) and MCI (N = 99) compared to CU (N = 174). DNA methylation levels were compared cross‐sectionally in the Wisconsin Alzheimer’s Disease Research Center (WADRC) and the Wisconsin Registry for Alzheimer’s Prevention (WRAP) cohorts. ParticipantAPOE allele and demographic information are provided in Table 1.ResultMitochondrial‐related genes (N = 1,121) were differentially methylated (local false discovery rate [lFDR] < 0.01) in persons with AD (N = 218) and MCI (N = 421) compared to CU controls. Gene ontology pathway analyses of differentially methylated genes observed in both AD and MCI groups (N = 142) are enriched for multiple terms, including myristoyl‐CoA hydrolase, palmitoyl‐CoA hydrolase, and thiolester hydrolase activity (Figure 1). Differentially methylated genes align with differentially expressed genes that support beta‐oxidation (acyl‐CoA dehydrogenase family member 9 [ACAD9]) and fatty acid transport into mitochondria (carnitine palmitoyl transferase I [CPT1A]) in blood from persons with AD.ConclusionDisordered pathways that participate in beta‐oxidation and fatty acid metabolism have been identified in large‐scale multi‐omic reports of AD histopathology. Present data indicate that corresponding changes in the methylome play a role in mitochondrial pathways known to contribute to the pathogenesis of AD and may serve as candidates for diagnosis and intervention.
Mild Magnetic Hyperthermia Stimulation Attenuates b‐Amyloid Deposition in the Hippocampus of Alzheimer’s Disease Mouse Model
Authors: Jeon Byeong Tak , Kim Min‐Ho 
Published: January 2025

AbstractBackgroundAccumulation of β‐amyloid (Aβ) plaque in the brain is a pathological hallmark of Alzheimer’s Disease (AD). We recently reported that the application of mild magnetic hyperthermia is feasible to target and disrupt Aβ plaques by means of generating localized heat on the surface of magnetic nanoparticles (MNPs) targeted to Aβ aggregates in response to a remotely applied alternating magnetic field (AMF) (Nanomedicine:NBM, 2021). The objective of the current study is to demonstrate the feasibility of mild magnetic hyperthermia stimulation (MNP/AMF) in clearing Aβ deposits in vivo using 5xFAD mice, a well‐established transgenic AD mouse model.MethodIn this study, 5xFAD mice (9‐10 months old, males and females) were administered with MNPs (2 mg in 1 mL PBS, 20 nm size, Ocean Nanotech) or vehicle (1 mL PBS) via intracranial injection to the hippocampus using stereotaxic surgery. At day 7 post‐MNP injection, mice were stimulated with a single session of AMF (375kHz at 60 kA/m) for 15 min. At day 14 post‐MNP injection, brain samples containing the hippocampus were harvested and immunostained for Aβ burden (6E10 antibody) and microglial activation (Iba antibody). The number and size of Aβ plaques as well as changes in microglial morphology were assessed in the hippocampus area.Result5xFAD mice treated with a single session of MNP/AMF showed enhanced clearance of Aβ plaques compared with the vehicle‐treated 5xFAD mice. The size of Aβ plaques in MNP/AMF‐treated mice decreased by 47.6% compared with the size in control mice. However, the number of Aβ plaques was not significantly reduced. MNP/AMF‐treated mice revealed an increased number of microglia in the proximity of Aβ plaques in the hippocampus by 37.8% compared with control mice. Additionally, the coverage of microglia in Aβ plaques increased by 44.8% under the MNP/AMF condition. Interestingly, this change was associated with a transition of microglia morphology from the ramified‐like into the phagocytic ameboid‐like shape in MNP/AMF‐treated mice, suggesting that MNP/AMF stimulation might skew microglial activation towards enhanced clearance.ConclusionCollectively, our findings suggest that MNP/AMF stimulation could not only mediate the fragmentation of Aβ plaques but also activate microglia to clear Aβ.
Validation of machine learning models to detect neuropathologies
Authors: Kamal Farooq , Morrison Cassandra , Oliver Michael , Dadar Mahsa 
Published: January 2025

AbstractBackgroundWhite matter hyperintensities (WMHs) are increasingly recognized for their role in cognitive decline and the progression of neurodegenerative conditions including Alzheimer’s disease (AD). Despite advances in imaging technologies, the exact contribution of WMHs to disease processes remains a subject of ongoing research. This study aims to apply machine learning approaches to determine critical features of AD‐related neuropathologies in vivo.MethodsA total of 65 participants (17 females, mean age = 79.0) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were included. In the ADNI dataset, machine learning models were applied towards feature selection of MRI, clinical, and demographic data to identify the best performing set of variables that could predict neuropathology outcomes [e.g., Braak neurofibrillary tangle stage, Consortium to Establish a Registry for AD (CERAD) neuritic plaque, etc.]. The best‐performing neuropathology predictors using the top seven MRI, clinical, and demographic features were selected. For continuous measures, gradient boosting, bagging, support vector regression, and linear regression were implemented. For binary outcomes, logistic regression, gradient boosting, support vector machine, and bagging classifiers were utilized.ResultsFour machine learning models applying feature ranking methods using similar information criteria consistently ranked WMHs as important features in predicting all neuropathology measures. In the ADNI dataset, prediction accuracy was highest for Braak stage, CERAD neuritic palques, and diffuse plaques (i.e., cross‐validated correlation between actual measures and predictions was above 0.8). The best‐performing model achieved over r = 0.85 correlation in predicting Braak.ConclusionThese results highlight the importance of WMHs as core features of AD and the benefits of using machine learning models that incorporate WMH burden in predicting AD‐related neuropathologies. The use of machine learning may prove beneficial in early detection of AD.
Unveiling the Pathogenic Influence of TDP‐43 on Tau‐Mediated Neurotoxicity in an Alzheimer’s Disease Mouse Model
Authors: Toscano Laura Garcia , Hincks Joshua C. , McMillan Pamela J. , Baum Misa , Waldherr Sarah M. , Kraemer Brian C. , Liachko Nicole F 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is the leading cause of dementia and one of the most devastating neurodegenerative diseases. In the last decades, a large proportion of AD patients have been described as having aberrant accumulation of TDP‐43 protein, a well‐established driver of neurodegeneration. This TDP‐43 proteinopathy in AD can co‐occur in neurons with the main hallmarks of the disease, toxic amyloid oligomers and neurofibrillary tangles containing hyperphosphorylated Tau, and correlates with rapid progression and worse prognosis. However, the underlying mechanisms of pathogenic TDP‐43 contributing to AD and its possible involvement as a trigger of neurotoxicity remain unclear.MethodWe aimed to explore the role of TDP‐43 in a mouse model of tau‐mediated toxicity. To this end, we created a new mouse model of tau and TDP‐43 co‐pathology that combines the constitutive transgenic expression of wild‐type human tau with adeno‐associated virus (AAV) driven expression of wild‐type human TDP‐43. Using a stereotaxic device, we performed a unilateral intrahippocampal injection of AAV‐9 carrying the human TDP‐43 cDNA (or green fluorescent protein as a control) into 3‐month‐old transgenic mice expressing the most abundant brain isoform (1N4R) of Tau in neurons. Animals were then perfused 2, 4, and 12 weeks after injection, and brains were collected for immunohistochemistry.ResultOur results showed that although TDP 43 overexpression was similar in both transgenic and control mice, the presence of hTDP‐43 promoted an increase in phosphorylated tau species. These data suggest a possible interaction between human tau protein and TDP‐43 proteins leading to the spread of phosphorylated Tau species, thus contributing to the pathology in our mouse model of the disease. Additionally, the co‐expression of both TDP‐43 and Tau proteins induced a transient inflammatory state in transgenic animals, sustained 4 weeks after injury. However, 12 weeks after injury, inflammation was resolved, and the presence of phosphorylated Tau species was significantly reduced.ConclusionThis new mouse model provides a vehicle to explore causes and consequences of co‐pathological tau and TDP‐43. Further studies will be necessary to determine mechanisms underlying TDP‐43 promotion of pathological accumulation of toxic Tau species and neuroinflammation in this experimental model of TDP‐43‐ Tau co‐expression.