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Brain : a Journal of Neurology Jun 2024Increasing evidence shows that neuroinflammation is a possible modulator of tau spread effects on cognitive impairment in Alzheimer's disease. In this context, plasma...
Increasing evidence shows that neuroinflammation is a possible modulator of tau spread effects on cognitive impairment in Alzheimer's disease. In this context, plasma levels of the glial fibrillary acidic protein (GFAP) have been suggested to have a robust association with Alzheimer's disease pathophysiology. This study aims to assess the correlation between plasma GFAP and Alzheimer's disease pathology, and their synergistic effect on cognitive performance and decline. A cohort of 122 memory clinic subjects with amyloid and tau positron emission tomography, MRI scans, plasma GFAP, and Mini-Mental State Examination (MMSE) was included in the study. A subsample of 94 subjects had a follow-up MMSE score at least one year after baseline. Regional and voxel-based correlations between Alzheimer's disease biomarkers and plasma GFAP were assessed. Mediation analyses were performed to evaluate the effects of plasma GFAP on the association between amyloid and tau PET, and tau PET and cognitive impairment and decline. GFAP was associated with increased tau PET ligand uptake in the lateral temporal and inferior temporal lobes in a strong left-sided pattern independently of age, gender, education, amyloid, and APOE status (β=0.001, p < 0.01). The annual rate of MMSE change was significantly and independently correlated with both GFAP (β=0.006, p < 0.01) and global tau SUVR (β=4.33, p < 0.01), but not with amyloid burden. Partial mediation effects of GFAP were found on the association between amyloid and tau pathology (13.7%), and between tau pathology and cognitive decline (17.4%), but not on global cognition at baseline. Neuroinflammation measured by circulating GFAP is independently associated with tau Alzheimer's disease pathology and with cognitive decline, suggesting neuroinflammation as a potential target for future disease-modifying trials targeting tau pathology. Peretti et al. show that a circulatory marker of neuroinflammation-glial fibrillary acidic protein-is associated with tau pathology in lateral temporal and frontal regions in patients with Alzheimer's disease, independent of amyloid load. Neuroinflammation appears to modulate the association between amyloid and tau biomarkers.
PubMed: 38940331
DOI: 10.1093/brain/awae211 -
Alzheimer's & Dementia : the Journal of... Jun 2024Blood-based biomarkers are a cost-effective and minimally invasive method for diagnosing the early and preclinical stages of amyloid positivity (AP). Our study aims to...
INTRODUCTION
Blood-based biomarkers are a cost-effective and minimally invasive method for diagnosing the early and preclinical stages of amyloid positivity (AP). Our study aims to investigate our novel immunoprecipitation-immunoassay (IP-IA) as a test for predicting cognitive decline.
METHODS
We measured levels of amyloid beta (Aβ)X-40 and AβX-42 in immunoprecipitated eluates from the DELCODE cohort. Receiver-operating characteristic (ROC) curves, regression analyses, and Cox proportional hazard regression models were constructed to predict AP by Aβ42/40 classification in cerebrospinal fluid (CSF) and conversion to mild cognitive impairment (MCI) or dementia.
RESULTS
We detected a significant correlation between AßX-42/X-40 in plasma and CSF (r = 0.473). Mixed-modeling analysis revealed a substantial prediction of AßX-42/X-40 with an area under the curve (AUC) of 0.81 for AP (sensitivity: 0.79, specificity: 0.74, positive predictive value [PPV]: 0.71, negative predictive value [NPV]: 0.81). In addition, lower AβX-42/X-40 ratios were associated with negative PACC5 slopes, suggesting cognitive decline.
DISCUSSION
Our results suggest that assessing the plasma AβX-42/X-40 ratio via our semiautomated IP-IA is a promising biomarker when examining patients with early or preclinical AD.
HIGHLIGHTS
New plasma Aβ42/Aβ40 measurement using immunoprecipitation-immunoassay Plasma Aβ42/Aβ40 associated with longitudinal cognitive decline Promising biomarker to detect subjective cognitive decline at-risk for brain amyloid positivity.
PubMed: 38940303
DOI: 10.1002/alz.13909 -
American Journal of Human Biology : the... Jun 2024Black people had the highest prevalence of Alzheimer's disease and related dementias (ADRD) of any racial/ethnic group in the United States (US) as of 2020. As racial...
INTRODUCTION
Black people had the highest prevalence of Alzheimer's disease and related dementias (ADRD) of any racial/ethnic group in the United States (US) as of 2020. As racial disparities in the prevalence of ADRD are being investigated, more evidence is necessary to determine the pathways and mechanisms that either slow ADRD progression or improve quality of life for those affected. Religion/spirituality (R/S) has been shown to affect health outcomes but has rarely been studied as a possible pathway for reducing ADRD risk. Crucially, Black people also report higher levels of R/S than other racial/ethnic groups in the United States. This research asks if R/S affects ADRD risk among Black adults and if any effects persist after controlling for hypertension.
METHODS
We conducted a secondary data analysis drawing from the Health and Retirement Study (HRS), a nationally representative longitudinal dataset with an oversampling of Black adults.
RESULTS
We used logistic regression analysis to demonstrate how R/S has an ameliorating impact on ADRD risk among Black people, even after controlling for hypertension. Those who never attended religious services had 2.37 higher odds of being diagnosed with ADRD than those who attended more than once a week. Further, as R/S attendance increased, ADRD risk decreased linearly.
CONCLUSION
These findings demonstrate the importance that existing cultural networks (e.g., R/S) can have for reducing ADRD burden for Black people and has important implications for the role of R/S in shaping ADRD symptomatology.
PubMed: 38940191
DOI: 10.1002/ajhb.24125 -
Bioinformatics (Oxford, England) Jun 2024Electronic health records (EHRs) represent a comprehensive resource of a patient's medical history. EHRs are essential for utilizing advanced technologies such as deep...
MOTIVATION
Electronic health records (EHRs) represent a comprehensive resource of a patient's medical history. EHRs are essential for utilizing advanced technologies such as deep learning (DL), enabling healthcare providers to analyze extensive data, extract valuable insights, and make precise and data-driven clinical decisions. DL methods such as recurrent neural networks (RNN) have been utilized to analyze EHR to model disease progression and predict diagnosis. However, these methods do not address some inherent irregularities in EHR data such as irregular time intervals between clinical visits. Furthermore, most DL models are not interpretable. In this study, we propose two interpretable DL architectures based on RNN, namely time-aware RNN (TA-RNN) and TA-RNN-autoencoder (TA-RNN-AE) to predict patient's clinical outcome in EHR at the next visit and multiple visits ahead, respectively. To mitigate the impact of irregular time intervals, we propose incorporating time embedding of the elapsed times between visits. For interpretability, we propose employing a dual-level attention mechanism that operates between visits and features within each visit.
RESULTS
The results of the experiments conducted on Alzheimer's Disease Neuroimaging Initiative (ADNI) and National Alzheimer's Coordinating Center (NACC) datasets indicated the superior performance of proposed models for predicting Alzheimer's Disease (AD) compared to state-of-the-art and baseline approaches based on F2 and sensitivity. Additionally, TA-RNN showed superior performance on the Medical Information Mart for Intensive Care (MIMIC-III) dataset for mortality prediction. In our ablation study, we observed enhanced predictive performance by incorporating time embedding and attention mechanisms. Finally, investigating attention weights helped identify influential visits and features in predictions.
AVAILABILITY AND IMPLEMENTATION
https://github.com/bozdaglab/TA-RNN.
Topics: Electronic Health Records; Neural Networks, Computer; Humans; Deep Learning; Alzheimer Disease
PubMed: 38940180
DOI: 10.1093/bioinformatics/btae264 -
Frontiers in Bioscience (Landmark... Jun 2024
Topics: Humans; Biomarkers; Dementia; Proteostasis Deficiencies; Protein Folding; Alzheimer Disease
PubMed: 38940055
DOI: 10.31083/j.fbl2906227 -
Frontiers in Bioscience (Landmark... Jun 2024Alzheimer's disease is characterized by extracellular beta-amyloid plaques, intraneuronal tau neurofibrillary tangles and excessive neurodegeneration. The mechanisms of...
BACKGROUND
Alzheimer's disease is characterized by extracellular beta-amyloid plaques, intraneuronal tau neurofibrillary tangles and excessive neurodegeneration. The mechanisms of neuron degeneration and the potential of these neurons to form new nerve fibers for compensation remain elusive. The present study aimed to evaluate the impact of beta-amyloid and tau on new formations of nerve fibers from mouse organotypic brain slices connected to collagen-based microcontact prints.
METHODS
Organotypic brain slices of postnatal day 8-10 wild-type mice were connected to established collagen-based microcontact prints loaded with polyornithine to enhance nerve fiber outgrowth. Human beta-amyloid(42) or P301S mutated aggregated tau was co-loaded to the prints. Nerve fibers were immunohistochemically stained with neurofilament antibodies. The physiological activity of outgrown neurites was tested with neurotracer MiniRuby, voltage-sensitive dye FluoVolt, and calcium-sensitive dye Rhod-4.
RESULTS
Immunohistochemical staining revealed newly formed nerve fibers extending along the prints derived from the brain slices. While collagen-only microcontact prints stimulated nerve fiber growth, those loaded with polyornithine significantly enhanced nerve fiber outgrowth. Beta-amyloid(42) significantly increased the neurofilament-positive nerve fibers, while tau had only a weak effect. MiniRuby crystals, retrogradely transported along these newly formed nerve fibers, reached the hippocampus, while FluoVolt and Rhod-4 monitored electrical activity in newly formed nerve fibers.
CONCLUSIONS
Our data provide evidence that intact nerve fibers can form along collagen-based microcontact prints from mouse brain slices. The Alzheimer's peptide beta-amyloid(42) stimulates this growth, hinting at a neuroprotective function when physiologically active. This "brain-on-chip" model may offer a platform for screening bioactive factors or testing drug effects on nerve fiber growth.
Topics: Animals; Amyloid beta-Peptides; Mice; Nerve Fibers; Brain; tau Proteins; Humans; Immunohistochemistry; Peptide Fragments; Alzheimer Disease; Mice, Inbred C57BL
PubMed: 38940051
DOI: 10.31083/j.fbl2906232 -
Central Nervous System Agents in... Jun 2024More than 20 million people worldwide have Alzheimer's disease (AD), making it the most prevalent disease. Patients with AD may live for at least a decade after...
More than 20 million people worldwide have Alzheimer's disease (AD), making it the most prevalent disease. Patients with AD may live for at least a decade after diagnosis, making it the most common cause of disability in the elderly. Each year, 1% to 4% of the population is affected by AD, with prevalence peaking between ages 65 and 70 and declining to 6% among those over 85. Researchers have accumulated evidence on medicinal herbs that may reverse the pathogenesis of Alzheimer's disease. Alzheimer's disease (AD) is associated with severe memory loss, which can negatively impact social and professional life. The first neurotransmitter linked to Alzheimer's was acetylcholine (ACh). There is no known cure, and the available treatments are ineffective. Multiple studies indicate that Ayurvedic restorative herbs and their constituents may be effective in treating Alzheimer's disease. This technique emphasizes the fact that delaying or preventing Alzheimer's disease with the help of natural bio-actives could reduce the number of cases over the next half-century. To provide detailed information, the pathology and pathophysiology of Alzheimer's Disease are discussed in the text of this review, along with an overview of the neurotransmitters involved in the progression of the disease. The importance of different natural bioactives for the treatment of Alzheimer's disease is also outlined in the paper. The information contained in this paper can serve as a template for future research expressing the more beneficial role of other bioactive in acting as an adjuvant in the prevention and treatment of this disease, facing certain challenges and gaps with conventional drugs used to treat Alzheimer's disease.
PubMed: 38939998
DOI: 10.2174/0118715249307525240614073143 -
Current Neuropharmacology Jun 2024The human central nervous system (CNS) has a limited capacity for regeneration and repair, as many other organs do. Partly as a result, neurological diseases are the...
The human central nervous system (CNS) has a limited capacity for regeneration and repair, as many other organs do. Partly as a result, neurological diseases are the leading cause of medical burden globally. Most neurological disorders cannot be cured, and primary treatments focus on managing their symptoms and slowing down their progression. Cell therapy for neurological disorders offers several therapeutic potentials and provides hope for many patients. Here we provide a general overview of cell therapy in neurological disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Wilson's disease (WD), stroke and traumatic brain injury (TBI), involving many forms of stem cells, including embryonic stem cells and induced pluripotent stem cells. We also address the current concerns and perspectives for the future. Most studies for cell therapy in neurological diseases are in the pre-clinical stage, and there is still a great need for further research to translate neural replacement and regenerative therapies into clinical settings.
PubMed: 38939990
DOI: 10.2174/1570159X22666240509092903 -
Annals of Clinical and Translational... Jun 2024Amyloid-related imaging abnormalities, were originally described by dementia care experts. The wider use of aducanumab and now lecanemab warrant broader understanding by... (Review)
Review
Amyloid-related imaging abnormalities, were originally described by dementia care experts. The wider use of aducanumab and now lecanemab warrant broader understanding by the health care provider continuum. The optimal care approach for patients with Alzheimer's dementia, treated with amyloid-targeted therapy, includes proper clinical diagnosis, complication surveillance, specific imaging protocols, expert specialty consultation, integrated treatment strategies, and proper facility system planning. Improved awareness and understanding of amyloid-modifying therapy, both benefits and potential complications, among the health care provider continuum is paramount to the success of complex care programs. Specifically, recognition of treatment high risk, high benefit groups, and the interface of concurrent antiplatelet and anticoagulation. This integrated acute, specialty, and primary care approach should improve patient care quality and outcome.
PubMed: 38939962
DOI: 10.1002/acn3.52042 -
Sheng Li Xue Bao : [Acta Physiologica... Jun 2024The purpose of the study was to investigate the mechanism of TFEB activator 1 (TA1) improving the autophagic degradation of oligomeric amyloid-β (oAβ) in microglia,...
The purpose of the study was to investigate the mechanism of TFEB activator 1 (TA1) improving the autophagic degradation of oligomeric amyloid-β (oAβ) in microglia, and to explore the therapeutic effect of TA1 on an in vitro model of microglia in Alzheimer's disease (AD). Primary microglia were exposed to 1 μmol/L oAβ for 0, 3, 12, and 24 h respectively to construct the in vitro model of microglia in AD. In order to explore the therapeutic effect of TA1, primary microglia were co-treated with 1 μmol/L oAβ and 1 μmol/L TA1 for 12 h. To determine the autophagy flux, the above cells were further treated with 100 nmol/L Bafilomycin A1 for 1 h before fixation. Fluorescent probes were used to detect the endocytosis or degradation of oAβ by microglia. The autophagic flux was determined by infection of lentivirus mCherry-EGFP-LC3. The nuclear TFEB intensity, the autophagosomes number, and the colocalization ratio of oAβ with lysosome-associated membrane protein 1 (LAMP1) or microtubule-associated protein light chain 3 (LC3), were detected by immunofluorescence assay. Expressions of autophagy-related-genes, including Lamp1, Atg5, and Map1lc3b, were detected by qRT-PCR. Results showed that prolonged oAβ exposure inhibited the endocytosis and degradation of oAβ by microglia. Meanwhile, the number of autophagosomes and autophagy flux in microglia decreased after 12 h of oAβ treatment. We further found that the nuclear expression of autophagy regulator TFEB decreased after 12 h of oAβ exposure, resulting in the decrease of autophagy genes, thus leading to the damage of autophagic degradation of oAβ. Therefore, long-term oAβ exposure was considered to construct the in vitro model of microglia in AD. After TA1 treatment, the nuclear expression of TFEB in cells was obviously upregulated. TA1 treatment upregulated the expressions of autophagy-related genes, leading to the recovery of autophagy flux. TA1 also recovered the endocytosis and degradation of oAβ by microglia. In conclusion, TA1 could improve oAβ clearance by microglia in AD by upregulating microglial TFEB-mediated autophagy, suggesting TA1 as a potential therapeutic drug for AD.
Topics: Microglia; Amyloid beta-Peptides; Autophagy; Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Alzheimer Disease; Cells, Cultured; Mice
PubMed: 38939931
DOI: No ID Found