bluuebunny/crossref_metadata_2025 huggingface dataset:
Chlamydia pneumoniae infection and inflammasome activation in Alzheimer’s retina: Correlations with disease status
Authors: Gaire Bhakta Prasad , Koronyo Yosef , Subedi Lalita , Rentsendorj Altan , Fuchs Dieu‐Trang , Swerdlow Natalie , Black Keith L , Arditi Moshe , Crother Timothy R , Koronyo‐Hamaoui Maya
Published: January 2025

Background

An emerging theory suggests a link between Alzheimer’s disease (AD) and microbial infection. Notably, various microbes have been detected in the post‐mortem brains of AD patients and murine models. However, there exists a gap in research concerning the presence and role of microbial infection in the AD retina, which shares common pathogenesis with the brain. Focusing on Chlamydia pneumoniae (Cp), a gram‐negative respiratory pathogen, we assessed the presence and severity of infection and inflammasome activation in retinas and paired brains from individuals with mild cognitive impairment (MCI) or AD, comparing them to age‐ and sex‐matched counterparts with normal cognition (NC). This investigation provides critical insights into the potential microbial involvement in AD pathology.

Method

Employing diverse histological and biochemical techniques, we identified and quantified Cp and related biomarkers in retinas and brains of MCI and AD patients vs NC controls. We determined the relationships between retinal and brain Cp infection and gliosis, inflammasome activation, pyroptosis, and disease status.

Result

Cp inclusions were identified in the postmortem retina of individuals with MCI and AD, correlating with Cp burden in the corresponding brain tissues. Notably, a threefold increase in retinal and brain Cp infection was observed in AD, not in MCI, compared to NC, suggesting a predilection of Cp infection at later AD stages. Live Cp was successfully isolated from AD retinal lysates, confirming active Cp infection. Retinal Cp infection correlated with retinal amyloidosis and synaptic damage, but not with brain amyloidosis. Additionally, it was associated with brain tauopathy markers as well as the cognitive status. Cp‐infected cells were engulfed by retinal microglia. Furthermore, Cp infection triggered NLRP3‐inflammasome activation, gliosis, pyroptosis, and apoptosis. While retinal NLRP3 inflammasome increased earlier in MCI, Cp‐induced retinal ASC, Capase‐1 and ‐3, and cleaved‐GSDMD rose later in AD‐dementia stage. These findings unveil the intricate relationship between Cp infection, retinal pathology, and AD progression.

Conclusion

Our findings reveal Cp infection in both AD retina and brain, coupled with inflammasome markers. This highlights a potential link to neurodegeneration in AD, offering avenues for therapeutic exploration, involving early antibiotic treatment or inflammasome attenuation.
To study the correlation between cognitive decline and Parkinson’s disease with sarcopenia in Qinghai‐Tibet Plateau
Authors: Zhu Aiqin , Liu Jiangang
Published: January 2025

Background

To investigate the correlation between cognitive decline and gait speed and grip strength in patients with Parkinson’s disease (PD) and sarcopenia in the hypoxic environment.

Method

From October 2022 to December 2023, a cross‐sectional study was conducted to collect 134 patients (65 males and 69 females) of Parkinson’s disease (age 68.59±10.20 years), who had lived in a Qinghai‐Tibet Plateau area (Qinghai province, an average altitude of 2,500m) for more than 30 years. Skeletal muscle mass index (SMI) was measured using InBody S10 Biospace device from Korea. Grip strength(GS) and six‐meter gait speed test(GST) were measured by JAMAR handgrip dynamometer and Tsinghua Tongfang 6‐meter walking test instrument. PD related scales were used to assess motor and cognitive function.

Result

The prevalence of PD with sarcopenia was 32.8%, including 59.1% (female) and 40.9% (male). Compared with the PD without sarcopenia group, the PD with sarcopenia group showed an increased in age(65.17±8.80 vs 75.50±9.36 years), MDS Unified‐Parkinson Disease Rating Scale‐III (MDS‐UPDRS III) and Hoehn‐Yahr stage (H‐Y) grading (which were used to assess the severity of PD), while Body Mass Index (BMI), GST, SMI, GS, Mini‐mental state Examination (MMSE) and Montreal Cognitive Assessment (MOCA) scores were significantly decreased (P < 0.001). Correlation analysis showed that the GS and GST of PD patients were negatively correlated with UPDRS III (r = ‐0.461; r = ‐0.410), H‐Y grading (r = ‐0.347, r = ‐0.399), and Activities of Daily Living (ADL) (r = ‐0.558, r = ‐0.344) (P<0.001), and positively correlated with MMSE (r = 0.452, r = 0.506), MOCA (r = 0.267, r = 0.453) (P <0.001), and language ability (r = 0.177, r = 0.208; P <0.05). GS was positively correlated with orientation (r = 0.302), attention and calculation (r = 0.262)(P<0.002). Binary regression analysis showed that BMI (OR = 0.682,95%CI: 0.495‐0.940, P<0.05) and MMSE (OR = 0.695,95%CI: 0.557‐0.866, P < 0.001) were protective factors for PD with sarcopenia. H‐Y stage (OR = 4.942,95%CI: 1.567‐15.896, P < 0.006) was a risk factor for PD with sarcopenia.

Conclusion

Cognitive decline is the main risk factor for Parkinson’s disease with sarcopenia in the Qinghai Tibet Plateau region. It may be related to slow gait speed and decreased grip strength. The processing speed and executive dysfunction are mainly related to weak grip strength.
Exploring the Relationship Between Brain Structural and Antipsychotic Drug Dosage in BPSD
Authors: Hong Bo , Tao Tianli , Zhang Han , Li Xia , Chen Jianhua , Yue Ling
Published: January 2025

Background

Psychotropic medications are commonly prescribed for behavioral and psychological symptoms of dementia (BPSD). However, the safety of antipsychotic drugs has always been a concern. The study aims to investigate the relationship between brain structural and the effective dosage of antipsychotic drugs.

Method

All the subjects were from Shanghai Mental Health Center. On baseline, the BPSD patients completed a 3D T1 MRI scan and evaluated by MMSE and Neuropsychiatric Inventory (NPI). Patients who underwent standardized clinical treatment were followed up until BPSD remission. Drug treatment procedures were recorded, with the antipsychotic drugs being converted using a defined daily doses (DDDs) method to obtain the final daily doses. We divided the patients into three groups: DDDs = 0, 0<DDDs<0.3, and DDDs≥0.3, representing a non‐antipsychotic group (NAP), a low‐dose group (LAP), and a high‐dose group (HAP). The relationship between the altered brain regions and the DDDs were investigated.

Result

A total of 86 BPSD patients were enrolled (NAP = 28, LAP = 26, HAP = 32). Among the three groups, NAP group showed less NPI score, while no difference was observed in age, gender, education level, and MMSE (Tab. 1). ANCOVA analysis showed significant differences in the cortical thickness of pars orbitalis on the left (F = 3.277, p = 0.003) and the volume of thalamus on the left (F = 4.279, p<0.001) among three groups. Post hoc analysis indicated that HAP group had thinner cortex in the left pars orbitalis compared to NAP group (Fig. 1). Ordinal logistic regression analysis revealed that NPI (p = 0.014) and cortical thickness at the left pars orbitalis (p = 0.037) were independent predictors of DDDs. Further association analysis revealed a significant negative correlation between cortical thickness of left pars orbitalis and DDDs (r = ‐0.229, p = 0.04), even after adjusting for gender, age, education, MMSE, and NPI. (Fig. 2).

Conclusion

This study provides the first‐ever evidence that brain anatomical changes may serve as valuable biomarkers in the prediction of antipsychotic drug dosage for BPSD. The result has significant implications for optimizing clinical management strategies and offers insights into the intricate neuropathological mechanisms of BPSD.
Effects of Memantine on okadaic acid induced neurotoxicity at the systemic and molecular level in rats
Authors: Rusadze Khatuna , CHIGHLADZE MARIAM , Dashniani Manana , Burjanadze Maia , Chkhikvishvili Nino , Beselia Gela
Published: January 2025

Background

Alzheimer’s disease (AD) is a neurodegenerative disease that causes progressive cognitive decline over age 65. Individuals suffering from this disease suffer memory loss, and histological examination of the brains. Okadaic acid (OA), is a potent and selective inhibitor of protein phosphatases 1 and 2A. Intracerebroventricular (ICV) administration of OA can produce an Alzheimer‐like hyperphosphorylation of tau protein. Therefore, it was suggested that intracerebral injection of OA can affect the activity of neurotransmitters and their receptors in brain areas. Central cholinergic and glutamatergic activity together are known to be crucial for the acquisition and consolidation performance of a variety of learned behaviors. The present study was designed to investigate the effects of okadaic acid (OA) intracerebroventricular (ICV) injection on memory function and expression level of α7 subunit of nicotinic acetylcholine receptor (nAChR) and NR2B subunit of NMDA glutamate receptors in the hippocampus, as well as effect of the antidementic drug memantine on OA induced changes at systemic and molecular level in rats.

Method

OA was dissolved in artificial cerebrospinal fluid (aCSF) and injected ICV 200 ng/10 μl. Vehicle control received 10 μl of aCSF ICV. Control and OA injected rats were divided into 2 subgroups: treated i.p. with saline or memantine (5 mg/kg daily for 13 days starting from the day of OA injection). Rats were trained in the dual‐solution plus‐maze task that can be solved by using place or response strategies. The Western immunoblotting was used to determine relative amount of hippocampal receptors protein levels.

Result

Obtained data revealed that OA ICV injected rats were severely impaired at acquiring the place version of the maze accompanied by significant decline in hippocampal α7 subunit of nACh receptors protein levels. Memantine treatment can prevent OA induced impairment of hippocampal‐dependent spatial memory and accompanied by modulation of the expression level of α7 subunit of nACh and NR2B subunit of NMDA receptors in the hippocampus.

Conclusion

Thus, our results support the presumption that α7 nACh receptors may play an important role in the cognitive enhancer effects of memantine and emphasize the role of cholinergic‐glutamatergic interactions in memory.
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

Background

Alzheimer’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.

Method

We 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.

Result

Amyloid 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.

Conclusion

This 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

Background

Neuropsychiatric 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.

Method

We 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.

Result

We 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.

Conclusion

NPS 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

Background

Cognitive 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.

Methods

Forty‐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.

Results

No 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.

Conclusion

Our 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

Background

The 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‐).

Method

Participants (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.

Result

The 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.

Conclusion

Results 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

Background

Many 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.

Method

We 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.

Result

We 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).

Conclusion

In 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

Background

DNA 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.

Method

We 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.

Result

Mitochondrial‐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.

Conclusion

Disordered 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

Background

Accumulation 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.

Method

In 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.

Result

5xFAD 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.

Conclusion

Collectively, 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

Background

White 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.

Methods

A 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.

Results

Four 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.

Conclusion

These 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

Background

Alzheimer’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.

Method

We 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.

Result

Our 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.

Conclusion

This 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.
XBP‐1s transcriptional targets in the endoplasmic reticulum unfolded protein response ameliorate tauopathy
Authors: Kraemer Brian C. , Han Marina
Published: January 2025

Background

Protein homeostasis (proteostasis) mechanisms fail with aging and disease, promoting toxic protein accumulation. Neurons are particularly vulnerable to proteostatic disruption leading to aging related neurodegeneration. Abnormal activation of the endoplasmic reticulum unfolded protein response (UPRER) is implicated in tauopathies, a group of neurodegenerative diseases characterized by pathological accumulation of the microtubule‐associated protein tau. Previous work showed neuronal overexpression of IRE1a branch UPRER transcription factor XBP‐1s suppresses tauopathy in C. elegans.

Methods

We conducted RNA sequencing of mRNAs to analyze the transcriptome of xbp‐1s and tau transgenic animals to identify genes required for XBP‐1s mediate protection from tauopathy.

Results

Transcriptomic analysis of XBP‐1s animals showed upregulation of the following genes with human homologs: csp‐1, F42G8.7, F41E7.6, Y19D10A.16, C01B4.6, dnj‐28, hsp‐4, ckb‐2, mct‐2, lipl‐3, and eol‐1. Surprisingly, each one of these genes is required for xbp‐1s‐mediated suppression of tauopathy, suggesting that XBP‐1s activates a broad and non‐redundant network of cellular mechanisms to reduce tau pathology. Of these, we examined the critical UPRER regulator BiP/hsp‐4, the ER resident HSP70 homolog. Hsp‐4 loss of function, but not loss of the cognate ER resident DNAJ protein dnj‐28, eliminates xbp‐1s‐mediated suppression of tauopathy. While hsp‐4 loss of function exacerbates tau‐induced behavioral deficits, tau protein level and phosphorylation are unaffected. High level overexpression of hsp‐4 exacerbates tau‐induced behavioral deficits and protein accumulation, while moderated hsp‐4 overexpression ameliorates this phenotype. Furthermore, caspases also appear to play an important role downstream of XBP‐1s: both the XBP‐1s target csp‐1 and its non‐XBP‐1s target gene family member ced‐3 are required for xbp‐1s‐mediated suppression of tauopathy.

Conclusions

We present a dataset illuminating the mechanism of xbp‐1s‐mediated suppression of tauopathy involving a suite of diverse transcriptional targets.
APOE rare missense variants in Japan
Authors: Miyashita Akinori , Hara Norikazu , Obinata Ai , Tsukie Tamao , Hasegawa Mai , Kikuchi Masataka , Kasuga Kensaku , Ikeuchi Takeshi
Published: January 2025

Background

APOE is well recognized to be the most influential susceptibility gene for Alzheimer’s disease (AD). For the wild‐type allele, e3, it is known that the e4 allele is a risk for AD, while the e2 allele is protective. Recently, genetic analyses with Caucasians have reported the critical associations between APOE rare missense variants (RMVs) and AD, and their importance has been pointed out in terms of disease pathogenesis of AD. For example, the Christchurch (rs121918393, p.R136S [CGC > AGC]) and the Jacksonville (rs199768005, p.V236E [GTG > GAG]) variants can be mentioned. Since there have been no such analyses or reports yet in East Asians, including Japanese, we designed this study.

Objective

To identify APOE RMVs in a Japanese population.

Method

Through the Tohoku Medical Megabank Organization (ToMMo) with a cohort of healthy Japanese community residents, APOE variant data were obtained from 3,307 subjects (1,810 females, and 1,497 males; mean age 55.9 years [standard deviation 14.1]) over 20 years old. Rare variants with amino acid substitutions were selected from them. The human genome database, Ensemble Human (GRCh38.p14), was searched to obtain the allelic frequency data of identified RMVs by populations. We also investigated the association with APOE common alleles, e2, e3, and e4, in the background of RMV carriers.

Result

A total of 176 variants were identified in and around APOE in an approximately 7.2 kb genomic region in the ToMMo cohort. Of these, 14 were RMVs, including those previously reported. Four RMVs were found to be very rare, which were not found in the 1000 Genomes or gnomAD exomes/genomes databases. The 13 RMVs were inferred to be under the wild‐type allele, e3, as background.

Conclusion

Through this survey, it became clear that there are RMVs of APOE that are unique to the Japanese population. In the future, we will expand the analysis to a discovery project on a scale of tens of thousands of individuals, including our subjects (n = approx. 2,500) collected so far. For the newly discovered RMVs, we plan to investigate their effects on the metabolism of amyloid beta and tau proteins in relation to AD.
Evaluation of feasibility, added value and satisfaction of remote digital self‐assessment for mild cognitive impairment in primary and specialized routine care with the app neotivCare
Authors: Düzel Emrah , Schoettler Michael , Sommer Harriet , Griebe Martin
Published: January 2025

Background

Timely diagnosis of mild cognitive impairment (MCI) in Alzheimer’s disease (AD) is crucial for early interventions, but its implementation is often challenging due to the complexity and time burden of required cognitive assessments. Remote unsupervised self‐testing of cognition can potentially addres this health care challenge. We conducted the to date largest evaluation of feasibility and experienced added value of unsupervised digital remote assessment in primary and specialized health care in Germany.

Method

This is a prospective, multicentric health care research evaluation survey called “re.cogni.ze”. Its goal is to evaluate physician satisfaction with a remote digital assessment solution (neotivCare) in primary and specialized routine care in Germany. Physicians in different regions of Germany have been recommending the app to approximately 1000 patients for a 12‐week self‐assessment of cognition. Last patient out is on 31st January 2024. The primary endpoint is the evaluation of physicians’ and patients’ overall satisfaction with neotivCare in comparison to neuropsychological questionnaires / standard procedures using a Likert scale. Secondary endpoints include user‐friendliness, qualitative assessment of acceptance, and potential improvements on medical routine services.

Result

This is first large scale assessment of feasibility, satisfaction and experienced added value of remote digital self‐assessment of MCI in routine care. The data will be analysed according to prespecified endpoints after data closure on the 31st January 2024.

Conclusion

The study results will provide insights into the feasibility, efficiency, and acceptance of new digital tools for MCI diagnosis in routine care. The re.cogni.ze survey will thus provide proof‐of‐concept information for the implementation of remote digital cognitive assessment apps for MCI into medical routine care.
Physiological β‐amyloid clearance by the liver and its therapeutic potential for Alzheimer’s disease
Authors: Cheng Yuan
Published: January 2025

Background

To investigate the physiological clearance of circulating Aβ by the liver and its role in the pathogenesis of Alzheimer’s disease (AD).

Method

Immunostaining, near‐infrared imaging, and flow cytometry were used to explore the physiological clearance of Aβ by the liver and the impact of aging on Aβ clearance. Liver‐specific LRP‐1 knockdown and functional LRP‐1 minigene (mLRP‐1) expression in mice with AD were used to explore the effects of hepatic Aβ clearance on AD pathogenesis and treatment.

Result

Aβ was detected in hepatocytes of both humans and APP/PS1 mice, and Aβ40 and Aβ42 levels in the outflow blood of the liver (hepatic vein) were 13.9% and 8.9% lower than those in the inflow blood (composites of hepatic artery and portal vein), respectively, suggesting that circulating Aβ is removed when flowing through the liver. The hepatic Aβ uptake was lower in aged mice than in young mice. In addition, specific knockdown of the LRP‐1 gene in hepatocytes reduced hepatic Aβ clearance and increased Aβ levels in both plasma and interstitial fluid in the brain, as well as AD‐type pathologies and behavioral deficits in APP/PS1 mice. Furthermore, enhancing liver Aβ clearance by expressing functional mLRP‐1 in hepatocytes reduced brain Aβ deposition, ameliorated AD‐type pathologies, including neuroinflammation, neuronal loss, and tau hyperphosphorylation, and improved behavioral performance.

Conclusion

Our findings demonstrate that the liver physiologically clears brain‐derived Aβ, providing novel insights into the disease pathogenesis of AD and suggesting new interventional strategies.
Genome‐wide DNA methylation in early‐onset dementias brain tissue and lymphoblastoid cell lines
Authors: Comas‐Albertí Aina , Ramos‐Campoy Oscar , Fort‐Aznar Laura , Hervás‐Marín David , Borrego‐Écija Sergi , Bosch Bea , Sandoval Juan , Moreno Fermin , Fernandez‐Villullas Guadalupe , Molina Laura , Balasa Mircea , Lladó Albert , Sanchez‐Valle Raquel , Antonell Anna
Published: January 2025

Background

Epigenetic mechanisms as a potential underlying pathogenic mechanism of neurodegenerative diseases have been the scope of several studies performed so far. However, there is a gap in analyzing different forms of early‐onset dementia to minimize the effect of aging and the use of Lymphoblastoid cell lines (LCLs) as a possible disease model for earlier clinical phases.

Method

We performed a genome‐wide DNA methylation analysis in 64 samples (from prefrontal cortex and lymphoblastoid cell lines) from Alzheimer’s Disease (AD) and Frontotemporal dementia (FTD) using the Illumina Infinium MethylationEPIC V2.0 array. The studied cohort included sporadic early‐onset (sEOAD, sFTD‐TP43, sFTD‐Tau) and genetic subgroups of AD (PSEN1) and FTD (MAPT, GRN, C9orf72), with n = 5 subjects/group. We analyzed the differentially methylated positions (DMPs) using the Beta regression model, with age and sex as covariates, and all p‐values adjusted by False Discovery Rate (FDR). Venn diagrams to visualize common genes between pairwise comparisons and heatmaps were performed to further explore the most important DMPs. Elastic Net logistic regression was used to obtain epigenetic diagnostic signatures. We also performed a correlation analysis of DNA methylation levels with Clariom D array gene expression data for the same cohort.

Result

Results showed hypermethylation in patients’ groups as the most frequent finding in both tissues studied (Fig. 1). We identified common DMPs when comparing patients with healthy controls (CTRL) for each respective disease (Fig. 2, 3). Biological significance analysis revealed common pathways altered in AD and FTD affecting neuron development, metabolism, signal transduction and immune system pathways. These alterations were also found in LCLs, even some related to neuron development. We obtained diagnostic signatures to differentiate patients from CTRL. In the brain, CpG methylation presented an inverse correlation with gene expression, while in LCLs we observed mainly a positive correlation.

Conclusion

This study enhances our understanding about the biological pathways that are associated with neurodegeneration, describes differential methylation patterns, and suggests LCLs are a potential cell model for studying neurodegenerative diseases in early clinical phases.
Advanced modeling of Alzheimer’s disease using human iPSC‐derived microglia and neurons carrying disease‐related mutations
Authors: Morello Berta Sanz , Shatri Elin Byman , Frandsen Sofie , Schmid Benjamin , Thirstrup Kenneth , Holst Bjørn
Published: January 2025

Background

Microglia are the primary immune cells of the brain and represent the main line of defense against brain environmental insults. In recent years, microglia have been implicated in Alzheimer’s disease (AD) pathogenesis by having interconnected yet opposing roles: beneficial as they clear amyloid beta (Aβ) and amyloid plaques, and detrimental as being responsible for synaptic and neuronal loss. These activities are tightly regulated by microglia receptors CD33 and TREM2. Microglial expression of both CD33 and TREM2 is upregulated and correlates with Aβ plaque load in the brain of AD patients, and genome‐wide association studies have associated genetic variants of CD33 and TREM2 with AD progression. Interestingly, humans carrying the polymorphic allele rs12459419(T) of CD33, which results in the loss of exon 2 in the CD33 transcript giving rise to a shorter isoform of CD33 (CD33‐D2), show higher CD33 expression in microglia and decreased Aβ deposition, lowering AD risk. In contrast, the heterozygous variant R47H TREM2 increases AD risk by four‐fold.

Method

We characterized the phagocytic and surveillance activity of human iPSC‐derived microglia carrying R47H TREM2 or Exon 2‐deleted CD33 (CD33ΔE2) in monoculture. Moreover, we analyzed how these microglia genotypes impact Aβ accumulation and neuronal integrity in a robust AD in‐vitro model represented by iPSC‐derived neurogenin‐2 (NGN2) neurons carrying the PSEN1 E280A mutation.

Result

iPSC‐derived microglia carrying R47H TREM2 or CD33ΔE2 show altered phagocytic and migratory activities. When co‐cultured with NGN2 neurons carrying PSEN1 E280A, R47H TREM2 microglia and CD33ΔE2 microglia affect Aβ40 and Aβ42 levels and neuronal integrity.

Conclusion

Insights into how CD33ΔE2 and R47H TREM2 mutations regulate microglial activity in an AD context can help to characterize them as potential therapeutic targets to arrest AD progression.