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Alzheimer's & Dementia (Amsterdam,... 2024Vascular pathology is known to contribute to dementia and vascular endothelial growth factor (VEGF) is a well-established biomarker associated with vascular alterations....
INTRODUCTION
Vascular pathology is known to contribute to dementia and vascular endothelial growth factor (VEGF) is a well-established biomarker associated with vascular alterations. Nonetheless, research findings on VEGF in Alzheimer's disease (AD) and vascular dementia (VaD) are inconsistent across various studies.
METHODS
We conducted a meta-analysis to elucidate relationships between VEGF and AD/VaD.
RESULTS
Twenty-four studies were included. Pooled data showed that both blood and cerebrospinal fluid (CSF) VEGF levels were higher in VaD patients, whereas no significant difference was found between AD patients and healthy controls. However, the correlation between blood VEGF and AD was found among studies with AD pathology verification. And blood VEGF levels were higher in AD patients than controls in "age difference < 5 years" subgroup and CSF samples for European cohorts.
DISCUSSION
This study highlights that VEGF is more effective for the diagnosis of VaD and vascular factors are also an important contributor in AD.
HIGHLIGHTS
Vascular endothelial growth factor (VEGF) levels were higher in the vascular dementia group, but not in the overall Alzheimer's disease (AD) group.Correlation between VEGF and AD was found among studies with clear AD pathological verification.Elevated VEGF in the cerebrospinal fluid might be a diagnostic marker for AD in European populations.
PubMed: 38912304
DOI: 10.1002/dad2.12612 -
Journal of Inflammation Research 2024Alzheimer's disease (AD) is the most common neurodegenerative illness, characterized by memory loss and cognitive decline, accounting for 60-80% of dementia cases. AD is... (Review)
Review
Alzheimer's disease (AD) is the most common neurodegenerative illness, characterized by memory loss and cognitive decline, accounting for 60-80% of dementia cases. AD is characterized by senile plaques made up of amyloid β (Aβ) protein, intracellular neurofibrillary tangles caused by hyperphosphorylation of tau protein linked with microtubules, and neuronal loss. Currently, therapeutic treatments and nanotechnological developments are effective in treating the symptoms of AD, but a cure for the illness has not yet been found. Recently, the increased study of extracellular vesicles (EVs) has led to a growing awareness of their significant involvement in neurodegenerative disorders, including AD. Exosomes are small extracellular vesicles that transport various components including messenger RNAs, non-coding RNAs, proteins, lipids, DNA, and other bioactive compounds from one cell to another, facilitating information transmission and material movement. There is growing evidence indicating that exosomes have complex functions in AD. Exosomes may have a dual role in Alzheimer's disease by contributing to neuronal death and also helping to alleviate the pathological progression of the disease. Therefore, the primary aim of this review is to outline the updated understandings on exosomes biogenesis and many functions of exosomes in the generation, conveyance, distribution, and elimination of hazardous proteins related to Alzheimer's disease. This review is intended to provide novel insights for understanding the development, specific treatment, and early detection of Alzheimer's disease.
PubMed: 38911990
DOI: 10.2147/JIR.S466821 -
Frontiers in Psychiatry 2024Accompanied by a rapid and effective antidepressant effect, electroconvulsive shock (ECS) can also induce learning and memory impairment. Our previous research reported...
Alteration of hyperpolarization-activated cation current-mediated metaplasticity contributes to electroconvulsive shock-induced learning and memory impairment in depressed rats.
BACKGROUND
Accompanied by a rapid and effective antidepressant effect, electroconvulsive shock (ECS) can also induce learning and memory impairment. Our previous research reported that metaplasticity is involved in this process. However, the mechanisms still remain unclear. This study investigated the role of current in the metaplastic changes and learning and memory impairment induced by ECS in depressive rats.
METHODS
Depressive rats received ECS after modelling using chronic unpredictable. ZD7288, a type of current inhibitor was used to verify the effect of current. The sucrose preference test and Morris water maze were used for behavior testing. Changes in metaplasticity was assessed with the LTD/LTP threshold by stimulation at different frequencies. Spontaneous and evoked action potentials (APs) were measured to confirm difference of neuronal excitability. Additionally, the amplitude of current was analyzed.
RESULTS
ECS exerts antidepressant effect, but also induce spatial learning and memory dysfunction. ECS up-regulates the LTD/LTP threshold. In rats treated with ECS, the frequency of spontaneous and evoked APs is significantly reduced. In addition, ECS induces changes in the intrinsic properties of AP, including a decrease of AP-half width and peak amplitude, and an increase in AP time to peak and post-hyperpolarization potential amplitude. In particular, ECS increases both instantaneous and steady-state currents. However, Inhibition of current with ZD7288 results in a relief of learning and memory impairment and a decrease in threshold, as well as a significant reversal of whole-cell electrophysiological changes.
CONCLUSION
ECS-induced learning and memory impairment is caused by neuronal hypoexcitability mediated metaplasticity, and upregulation of LTD/LTP threshold by an increase in current.
PubMed: 38911706
DOI: 10.3389/fpsyt.2024.1365119 -
Journal of Alzheimer's Disease Reports 2024Despite intense investigations, no effective treatment is yet available to reduce plaques and protect memory and learning in patients with Alzheimer's disease (AD), the...
Identification of Cinnamein, a Component of Balsam of Tolu/Peru, as a New Ligand of PPARα for Plaque Reduction and Memory Protection in a Mouse Model of Alzheimer's Disease.
BACKGROUND
Despite intense investigations, no effective treatment is yet available to reduce plaques and protect memory and learning in patients with Alzheimer's disease (AD), the most common neurodegenerative disorder. Therefore, it is important to identify a non-toxic, but effective, treatment option for AD.
OBJECTIVE
Cinnamein, a nontoxic compound, is naturally available in Balsam of Peru and Tolu Balsam. We examined whether cinnamein treatment could decrease plaques and improve cognitive functions in mouse model of AD.
METHODS
We employed analysis, time-resolved fluorescence energy transfer assay, thermal shift assay, primary neuron isolation, western blot, immunostaining, immunohistochemistry, Barnes maze, T maze, and open field behavior.
RESULTS
Oral administration of cinnamein led to significant reduction in amyloid-β plaque deposits in the brain and protection of spatial learning and memory in mice. Peroxisome proliferator-activated receptor alpha (PPARα), a nuclear hormone receptor, is involved in plaque lowering and increase in hippocampal plasticity. While investigating underlying mechanisms, we found that cinnamein served as a ligand of PPARα. Accordingly, oral cinnamein upregulated the level of PPARα, but not PPARβ, in the hippocampus, and remained unable to decrease plaques from the hippocampus and improve memory and learning in mice lacking PPARα. While A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) is one of the drivers of nonamyloidogenic pathway, transcription factor EB (TFEB) is considered as the master regulator of autophagy. Cinnamein treatment was found to upregulate both ADAM10 and TFEB in the brain of mice via PPARα.
CONCLUSIONS
Our results suggest that this balsam component may have therapeutic importance in AD.
PubMed: 38910936
DOI: 10.3233/ADR-230179 -
Cureus May 2024Objective and background This study aimed to develop a deep convolutional neural network (DCNN) model capable of generating synthetic 4D magnetic resonance angiography...
Objective and background This study aimed to develop a deep convolutional neural network (DCNN) model capable of generating synthetic 4D magnetic resonance angiography (MRA) from 3D time-of-flight (TOF) images, allowing estimation of temporal changes in arterial flow. TOF MRA provides static information about arterial structures through maximum intensity projection (MIP) processing, but it does not capture the dynamic information of contrast agent circulation, which is lost during MIP processing. Considering the principles of TOF, it is hypothesized that dynamic information about arterial blood flow is latent within TOF signals. Although arterial spin labeling (ASL) can extract dynamic arterial information, ASL MRA has drawbacks, such as longer imaging times and lower spatial resolution than TOF MRA. This study's primary aim is to extend the utility of TOF MRA by training a machine-learning model on paired TOF and ASL data to extract latent dynamic information from TOF signals. Methods A DCNN combining a modified U-Net and a long-short-term memory (LSTM) network was trained on a dataset of 13 subjects (11 men and two women, aged 42-77 years) using paired 3D TOF MRA and 4D ASL MRA images. Subjects had no history of cerebral vessel occlusion or significant stenosis. The dataset was acquired using a 3T MRI system with a 32-channel head coil. Preprocessing involved resampling and intensity normalization of TOF and ASL images, followed by data augmentation and arterial mask generation. The model learned to extract flow information from TOF images and generate 8-phase 4D MRA images. The precision of flow estimation was evaluated using the coefficient of determination (R²) and Bland-Altman analysis. A board-certified neuroradiologist validated the quality of the images and the absence of significant stenosis in the major cerebral arteries. Results The generated 4D MRA images closely resembled the ground-truth ASL MRA data, with R² values of 0.92, 0.85, and 0.84 for the internal carotid artery (ICA), proximal middle cerebral artery (MCA), and distal MCA, respectively. Bland-Altman analysis revealed a systematic error of -0.06, with 95% agreement limits ranging from -0.18 to 0.12. Additionally, the model successfully identified flow abnormalities in a subject with left MCA stenosis, displaying a delayed peak and subsequent flattening distal to the stenosis, indicative of reduced blood flow. Visualization of the predicted arterial flow overlaid on the original TOF MRA images highlighted the spatial progression and dynamics of the flow. Conclusions The DCNN model effectively generated synthetic 4D MRA images from TOF images, demonstrating its potential to estimate temporal changes in arterial flow accurately. This non-invasive technique offers a promising alternative to conventional methods for visualizing and evaluating healthy and pathological flow dynamics. It has significant potential to improve the diagnosis and treatment of cerebrovascular diseases by providing detailed temporal flow information without the need for contrast agents or invasive procedures. The practical implementation of this model could enable the extraction of dynamic cerebral blood flow information from routine brain MRI examinations, contributing to the early diagnosis and management of cerebrovascular disorders.
PubMed: 38910733
DOI: 10.7759/cureus.60803 -
Cureus May 2024Alzheimer's disease (AD) stands as one of the predominant neurodegenerative disorders, often culminating in dementia. Taurine, an endogenous amino acid, holds pivotal... (Review)
Review
Alzheimer's disease (AD) stands as one of the predominant neurodegenerative disorders, often culminating in dementia. Taurine, an endogenous amino acid, holds pivotal regulatory functions within the physiological milieu. Emerging evidence suggests that taurine may confer protection against the onset and progression of AD through diverse mechanistic pathways. This systematic review aims to comprehensively elucidate the multifaceted role of taurine in Alzheimer's disease. The primary objective is to assess taurine's potential as a preventative and therapeutic intervention for Alzheimer's, based on studies from 2004 to 2022. A rigorous search strategy was implemented, targeting English-language articles accessible in full text. Eligible studies were meticulously sourced from renowned databases including PubMed, PubMed Central, Science Direct, Cochrane Library, and Medline Plus. Inclusion criteria were limited to studies explicitly investigating the role of taurine in Alzheimer's disease. Our review encompasses a wealth of experimental studies conducted on murine models, collectively indicating taurine's capacity to ameliorate symptomatic presentations of Alzheimer's disease. Encouraged by these promising preclinical findings, the imperative for clinical trials in human subjects emerges. Taurine emerges as a prospective agent, offering potential mitigation of the cognitive and memory-related debility synonymous with Alzheimer's disease. This systematic review delineates a compelling body of evidence underscoring the putative neuroprotective role of taurine in Alzheimer's disease. However, it is incumbent upon the scientific community to bridge the translational gap through robust clinical investigations. Such endeavors hold promise in revolutionizing the therapeutic landscape for individuals grappling with the formidable challenges posed by Alzheimer's disease.
PubMed: 38910611
DOI: 10.7759/cureus.60997 -
Biological Psychiatry. Cognitive... Jun 2024Working memory is a fundamental cognitive process that is critically involved in planning, comprehension, reasoning, or problem-solving. Acute stress has been shown to...
BACKGROUND
Working memory is a fundamental cognitive process that is critically involved in planning, comprehension, reasoning, or problem-solving. Acute stress has been shown to impair working memory. This stress-induced working memory deficit has profound implications for our cognitive functioning in everyday life as well as for stress-related mental disorders. Here, we tested whether a cognitive training intervention can make working memory more resistant to disruptive effects of acute stress.
METHODS
In a pre-registered, fully-crossed between-subjects design with the factors stress (vs. control) and cognitive training (vs. sham), one hundred twenty-three healthy men and women (aged 18-35 years) completed a daily cognitive training program targeting working memory-related processes or a sham training over a period of six weeks. After this six-week training intervention, participants underwent a standardized stress or control manipulation shortly before their working memory performance was tested.
RESULTS
As expected, the exposure to acute stress led to a significant working memory impairment in the sham training group. Critically, although the subjective, autonomic, and endocrine stress responses were comparable in the two training groups, this stress-induced working memory impairment was abolished in the intervention training group.
CONCLUSIONS
These results are the first to show that a cognitive training intervention directed at prefrontal and hippocampal functioning can prevent the detrimental effects of stressful events on working memory performance.
PubMed: 38909897
DOI: 10.1016/j.bpsc.2024.06.006 -
European Neuropsychopharmacology : the... Jun 2024Social dysfunction represents one of the most common signs of neuropsychiatric disorders, such as Schizophrenia (SZ) and Alzheimer's disease (AD). Perturbed...
Social dysfunction represents one of the most common signs of neuropsychiatric disorders, such as Schizophrenia (SZ) and Alzheimer's disease (AD). Perturbed socioaffective neural processing is crucially implicated in SZ/AD and generally linked to social dysfunction. Yet, transdiagnostic properties of social dysfunction and its neurobiological underpinnings remain unknown. As part of the European PRISM project, we examined whether social dysfunction maps onto shifts within socioaffective brain systems across SZ and AD patients. We probed coupling of social dysfunction with socioaffective neural processing, as indexed by an implicit facial emotional processing fMRI task, across SZ (N = 46), AD (N = 40) and two age-matched healthy control (HC) groups (N = 26 HC-younger and N = 27 HC-older). Behavioural (i.e., social withdrawal, interpersonal dysfunction, diminished prosocial or recreational activity) and subjective (i.e., feelings of loneliness) aspects of social dysfunction were assessed using the Social Functioning Scale and De Jong-Gierveld loneliness questionnaire, respectively. Across SZ/AD/HC participants, more severe behavioural social dysfunction related to hyperactivity within fronto-parieto-limbic brain systems in response to sad emotions (P = 0.0078), along with hypoactivity of these brain systems in response to happy emotions (P = 0.0418). Such relationships were not found for subjective experiences of social dysfunction. These effects were independent of diagnosis, and not confounded by clinical and sociodemographic factors. In conclusion, behavioural aspects of social dysfunction across SZ/AD/HC participants are associated with shifts within fronto-parieto-limbic brain systems. These findings pinpoint altered socioaffective neural processing as a putative marker for social dysfunction, and could aid personalized care initiatives grounded in social behaviour.
PubMed: 38909542
DOI: 10.1016/j.euroneuro.2024.05.004 -
Alzheimer's Research & Therapy Jun 2024Studies suggest that cerebrospinal fluid (CSF) levels of amyloid-β (Aβ)42 and Aβ40 present a circadian rhythm. However sustained sampling of large volumes of CSF with...
BACKGROUND
Studies suggest that cerebrospinal fluid (CSF) levels of amyloid-β (Aβ)42 and Aβ40 present a circadian rhythm. However sustained sampling of large volumes of CSF with indwelling intrathecal catheters used in most of these studies might have affected CSF dynamics and thereby confounded the observed fluctuations in the biomarker levels.
METHODS
We included 38 individuals with either normal (N = 20) or abnormal (N = 18) CSF Aβ42/Aβ40 levels at baseline. CSF and plasma were collected at two visits separated by an average of 53 days with lumbar punctures and venipunctures performed either in the morning or evening. At the first visit, sample collection was performed in the morning for 17 participants and the order was reversed for the remaining 21 participants. CSF and plasma samples were analyzed for Alzheimer' disease (AD) biomarkers, including Aβ42, Aβ40, GFAP, NfL p-tau181, p-tau217, p-tau231 and t-tau. CSF samples were also tested using mass spectrometry for 22 synaptic and endo-lysosomal proteins.
RESULTS
CSF Aβ42 (mean difference [MD], 0.21 ng/mL; p = 0.038), CSF Aβ40 (MD, 1.85 ng/mL; p < 0.001), plasma Aβ42 (MD, 1.65 pg/mL; p = 0.002) and plasma Aβ40 (MD, 0.01 ng/mL, p = 0.002) were increased by 4.2-17.0% in evening compared with morning samples. Further, CSF levels of 14 synaptic and endo-lysosomal proteins, including neurogranin and neuronal pentraxin-1, were increased by 4.5-13.3% in the evening samples (MD, 0.02-0.56 fmol/µl; p < 0.042). However, no significant differences were found between morning and evening levels for the Aβ42/Aβ40 ratio, different p-tau variants, GFAP and NfL. There were no significant interaction between sampling time and Aβ status for any of the biomarkers, except that CSF t-tau was increased (by 5.74%) in the evening samples compared to the morning samples in Aβ-positive (MD, 16.46 ng/ml; p = 0.009) but not Aβ-negative participants (MD, 1.89 ng/ml; p = 0.47). There were no significant interactions between sampling time and order in which samples were obtained.
DISCUSSION
Our findings provide evidence for diurnal fluctuations in Aβ peptide levels, both in CSF and plasma, while CSF and plasma p-tau, GFAP and NfL were unaffected. Importantly, Aβ42/Aβ40 ratio remained unaltered, suggesting that it is more suitable for implementation in clinical workup than individual Aβ peptides. Additionally, we show that CSF levels of many synaptic and endo-lysosomal proteins presented a diurnal rhythm, implying a build-up of neuronal activity markers during the day. These results will guide the development of unified sample collection procedures to avoid effects of diurnal variation for future implementation of AD biomarkers in clinical practice and drug trials.
Topics: Humans; Amyloid beta-Peptides; Alzheimer Disease; Female; Biomarkers; Male; Aged; Peptide Fragments; tau Proteins; Middle Aged; Circadian Rhythm; Neurofilament Proteins; Aged, 80 and over; Glial Fibrillary Acidic Protein
PubMed: 38909218
DOI: 10.1186/s13195-024-01503-x -
Scientific Reports Jun 2024Astrocytes play a role in healthy cognitive function and Alzheimer's disease (AD). The transcriptional factor nuclear factor-κB (NF-κB) drives astrocyte diversity, but...
Astrocytes play a role in healthy cognitive function and Alzheimer's disease (AD). The transcriptional factor nuclear factor-κB (NF-κB) drives astrocyte diversity, but the mechanisms are not fully understood. By combining studies in human brains and animal models and selectively manipulating NF-κB function in astrocytes, we deepened the understanding of the role of astrocytic NF-κB in brain health and AD. In silico analysis of bulk and cell-specific transcriptomic data revealed the association of NF-κB and astrocytes in AD. Confocal studies validated the higher level of p50 NF-κB and phosphorylated-p65 NF-κB in glial fibrillary acidic protein (GFAP)-astrocytes in AD versus non-AD subjects. In the healthy mouse brain, chronic activation of astrocytic NF-κB disturbed the proteomic milieu, causing a loss of mitochondrial-associated proteins and the rise of inflammatory-related proteins. Sustained NF-κB signaling also led to microglial reactivity, production of pro-inflammatory mediators, and buildup of senescence-related protein p16 in neurons. However, in an AD mouse model, NF-κB inhibition accelerated β-amyloid and tau accumulation. Molecular biology studies revealed that astrocytic NF-κB activation drives the increase in GFAP and inflammatory proteins and aquaporin-4, a glymphatic system protein that assists in mitigating AD. Our investigation uncovered fundamental mechanisms by which NF-κB enables astrocytes' neuroprotective and neurotoxic responses in the brain.
Topics: Astrocytes; Alzheimer Disease; Animals; Humans; Mice; Brain; NF-kappa B; Disease Models, Animal; Male; Signal Transduction; Female; Glial Fibrillary Acidic Protein; Amyloid beta-Peptides
PubMed: 38906984
DOI: 10.1038/s41598-024-65248-1