@article {pmid36750318, year = {2022}, author = {Bohlson, SS and Tenner, AJ}, title = {Complement in the Brain: Contributions to Neuroprotection, Neuronal Plasticity, and Neuroinflammation.}, journal = {Annual review of immunology}, volume = {}, number = {}, pages = {}, doi = {10.1146/annurev-immunol-101921-035639}, pmid = {36750318}, issn = {1545-3278}, abstract = {The complement system is an ancient collection of proteolytic cascades with well-described roles in regulation of innate and adaptive immunity. With the convergence of a revolution in complement-directed clinical therapeutics, the discovery of specific complement-associated targetable pathways in the central nervous system, and the development of integrated multi-omic technologies that have all emerged over the last 15 years, precision therapeutic targeting in Alzheimer disease and other neurodegenerative diseases and processes appears to be within reach. As a sensor of tissue distress, the complement system protects the brain from microbial challenge as well as the accumulation of dead and/or damaged molecules and cells. Additional more recently discovered diverse functions of complement make it of paramount importance to design complement-directed neurotherapeutics such that the beneficial roles in neurodevelopment, adult neural plasticity, and neuroprotective functions of the complement system are retained. Expected final online publication date for the Annual Review of Immunology, Volume 41 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.}, } @article {pmid36748965, year = {2022}, author = {Guntipalli, P and Gara, S and Poudel, S and Hans, A and Usman, MA and Dhar, D and Pakala, R and Shah, S and Thapa, S and Acharya, S and Nedd, KJ and Kara, S}, title = {Impact of COVID‑19 infection in patients with neurodegenerative diseases with particular focus on Alzheimer's and Parkinson's disease.}, journal = {Acta neurobiologiae experimentalis}, volume = {82}, number = {4}, pages = {424-432}, doi = {10.55782/ane-2022-040}, pmid = {36748965}, issn = {1689-0035}, abstract = {Neurodegenerative disorders (NDD) are chronic neurological diseases characterized by loss and/or damage to neurons along with the myelin sheath, and patients are at higher risk of severe infection with the SARS‑CoV‑2. A comprehensive literature search was performed using relevant terms and inclusion‑exclusion criteria. Recent articles, subjects older than 50 years, and articles written in the English language were included, whereas letters to the editor and articles related to pregnant women were excluded from the review study. COVID‑19 appears to damage angiotensin‑II receptors which cause natural killer cells to lose the ability to clear virus‑infected cells, owing to worse outcomes in patients with NDD. COVID‑19 can worsen the symptoms of Alzheimer's disease. In addition, COVID‑19 worsens drug‑responsive motor symptoms in Parkinson's disease (PD) and other symptoms like fatigue and urinary complaints. Vitamin D is essential in decreasing pro‑inflammatory and increasing anti‑inflammatory cytokines in ongoing COVID‑19 infections and reducing angiotensin receptors and, hence, decreasing COVID‑19 infection severity. Telemedicine shows promise for patients with NDD but is yet to overcome legal issues and personal barriers. COVID‑19 has a significant effect on neurodegenerative conditions, which appears partly to the nature of the NDD and the neuro‑invasive capabilities of the SARS‑CoV‑2. The protective role of vitamin D in patients with NDD further supports this hypothesis. Modifications in current health care, like the telemedicine platform, are required to address the increased risk of serious infection in this population. Further studies will be required to clarify conflicting reports in many fields.}, } @article {pmid36745142, year = {2022}, author = {Hosseini, M and Pierre, K and Felisma, P and Mampre, D and Stein, A and Fusco, A and Reddy, R and Chandra, V and Lucke-Wold, B}, title = {Focused ultrasound: Innovation in use for neurologic conditions.}, journal = {Trauma and emergency medicine}, volume = {1}, number = {1}, pages = {1-12}, pmid = {36745142}, abstract = {Focused ultrasound has emerged as a key tool for neurologic disorders. In this focused review, we discuss the utility in disrupting the blood brain barrier to maximize treatment. This can facilitate creating direct coagulative lesions and aid in the administration of chemotherapy. Furthermore, it can facilitate neuromodulation when used in pulse sequencing. The current literature regarding brain tumors, essential tremor, and obsessive-compulsive disorder is reviewed. Additionally, concepts and experimental outcomes for neurodegenerative disease such as Alzheimer's is presented. Focused ultrasound as a tool is still in its infancy but the potential for adjuvant and direct therapy is promising. More clinical uses will become apparent in coming decades.}, } @article {pmid36743910, year = {2022}, author = {Alamro, H and Bajic, V and Macvanin, MT and Isenovic, ER and Gojobori, T and Essack, M and Gao, X}, title = {Type 2 Diabetes Mellitus and its comorbidity, Alzheimer's disease: Identifying critical microRNA using machine learning.}, journal = {Frontiers in endocrinology}, volume = {13}, number = {}, pages = {1084656}, pmid = {36743910}, issn = {1664-2392}, mesh = {Humans ; *Diabetes Mellitus, Type 2/epidemiology/genetics ; *Alzheimer Disease/diagnosis/epidemiology/genetics ; *MicroRNAs/genetics/metabolism ; Comorbidity ; Machine Learning ; }, abstract = {MicroRNAs (miRNAs) are critical regulators of gene expression in healthy and diseased states, and numerous studies have established their tremendous potential as a tool for improving the diagnosis of Type 2 Diabetes Mellitus (T2D) and its comorbidities. In this regard, we computationally identify novel top-ranked hub miRNAs that might be involved in T2D. We accomplish this via two strategies: 1) by ranking miRNAs based on the number of T2D differentially expressed genes (DEGs) they target, and 2) using only the common DEGs between T2D and its comorbidity, Alzheimer's disease (AD) to predict and rank miRNA. Then classifier models are built using the DEGs targeted by each miRNA as features. Here, we show the T2D DEGs targeted by hsa-mir-1-3p, hsa-mir-16-5p, hsa-mir-124-3p, hsa-mir-34a-5p, hsa-let-7b-5p, hsa-mir-155-5p, hsa-mir-107, hsa-mir-27a-3p, hsa-mir-129-2-3p, and hsa-mir-146a-5p are capable of distinguishing T2D samples from the controls, which serves as a measure of confidence in the miRNAs' potential role in T2D progression. Moreover, for the second strategy, we show other critical miRNAs can be made apparent through the disease's comorbidities, and in this case, overall, the hsa-mir-103a-3p models work well for all the datasets, especially in T2D, while the hsa-mir-124-3p models achieved the best scores for the AD datasets. To the best of our knowledge, this is the first study that used predicted miRNAs to determine the features that can separate the diseased samples (T2D or AD) from the normal ones, instead of using conventional non-biology-based feature selection methods.}, } @article {pmid36743825, year = {2022}, author = {Mehkri, Y and McDonald, B and Sriram, S and Reddy, R and Kounelis-Wuillaume, S and Roberts, JA and Lucke-Wold, B}, title = {Recent Treatment Strategies in Alzheimer's Disease and Chronic Traumatic Encephalopathy.}, journal = {Biomedical research and clinical reviews}, volume = {7}, number = {3}, pages = {}, pmid = {36743825}, issn = {2692-9406}, abstract = {Neurotrauma has been well linked to the progression of neurodegenerative disease. Much work has been done characterizing chronic traumatic encephalopathy, but less has been done regarding the contribution to Alzheimer's Disease. This review focuses on AD and its association with neurotrauma. Emerging clinical trials are discussed as well as novel mechanisms. We then address how some of these mechanisms are shared with CTE and emerging pre-clinical studies. This paper is a user-friendly resource that summarizes the emerging findings and proposes further investigation into key areas of interest. It is intended to serve as a catalyst for both research teams and clinicians in the quest to improve effective treatment and diagnostic options.}, } @article {pmid36743783, year = {2022}, author = {Statz, TL and Peterson, CM and Birkeland, RW and McCarron, HR and Finlay, JM and Rosebush, CE and Baker, ZG and Gaugler, JE}, title = {"We Moved Her Too Soon": Navigating Guilt Among Adult Child and Spousal Caregivers of Persons Living with Dementia Following a Move into Residential Long-Term Care.}, journal = {Couple & family psychology}, volume = {11}, number = {4}, pages = {300-314}, pmid = {36743783}, issn = {2160-4096}, abstract = {Guilt is a complex and multifaceted emotion navigated by many family caregivers. Guilt is sometimes experienced following a transition into a residential long-term care facility, even when the move is necessary given high care needs related to Alzheimer's disease and related dementias. This mixed methods study identifies and compares areas of guilt most frequently experienced by spouse and adult child caregivers (N=83) of a family member with dementia following transition into residential long-term care. Nearly half of caregivers reported experiencing guilt from their care recipient, other family members, or facility staff. Quantitative analyses explored variables that predict heightened feelings of guilt, and qualitative thematic analyses provided rich insight into subjective experiences of guilt. Person-specific and situational characteristics influenced caregiver guilt, including level of involvement in care, frequency and quality of visits, and perceptions of the residential long-term care facility. We identify specific opportunities for tailored couple and family psychology interventions including communication strategies, decision-making approaches, focusing on positives, psychoeducation, self-forgiveness exercises, stress management and self-care activities, and validation. The present work informs how counseling interventions can provide practical support by highlighting specific clinical mechanisms that help to alleviate common facets of caregiver guilt following a transition into residential long-term care. Critically, we distinguish variation between spouses and adult children to design treatment plans that best support clients who are caring for a person living with dementia in residential long-term care.}, } @article {pmid36742045, year = {2022}, author = {Vogler, EC and Mahavongtrakul, M and Sarkan, K and Bohannan, RC and Catuara-Solarz, S and Busciglio, J}, title = {Genetic removal of synaptic Zn[2+] impairs cognition, alters neurotrophic signaling and induces neuronal hyperactivity.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {882635}, pmid = {36742045}, issn = {1664-2295}, abstract = {Vesicular Zn[2+] (zinc) is released at synapses and has been demonstrated to modulate neuronal responses. However, mechanisms through which dysregulation of zinc homeostasis may potentiate neuronal dysfunction and neurodegeneration are not well-understood. We previously reported that accumulation of soluble amyloid beta oligomers (AβO) at synapses correlates with synaptic loss and that AβO localization at synapses is regulated by synaptic activity and enhanced by the release of vesicular Zn[2+] in the hippocampus, a brain region that deteriorates early in Alzheimer's disease (AD). Significantly, drugs regulating zinc homeostasis inhibit AβO accumulation and improve cognition in mouse models of AD. We used both sexes of a transgenic mouse model lacking synaptic Zn[2+] (ZnT3KO) that develops AD-like cognitive impairment and neurodegeneration to study the effects of disruption of Zn[2+] modulation of neurotransmission in cognition, protein expression and activation, and neuronal excitability. Here we report that the genetic removal of synaptic Zn[2+] results in progressive impairment of hippocampal-dependent memory, reduces activity-dependent increase in Erk phosphorylation and BDNF mRNA, alters regulation of Erk activation by NMDAR subunits, increases neuronal spiking, and induces biochemical and morphological alterations consistent with increasing epileptiform activity and neurodegeneration as ZnT3KO mice age. Our study shows that disruption of synaptic Zn[2+] triggers neurodegenerative processes and is a potential pathway through which AβO trigger altered expression of neurotrophic proteins, along with reduced hippocampal synaptic density and degenerating neurons, neuronal spiking activity, and cognitive impairment and supports efforts to develop therapeutics to preserve synaptic zinc homeostasis in the brain as potential treatments for AD.}, } @article {pmid36741918, year = {2022}, author = {Shukla, R and Kumar, A and Kelvin, DJ and Singh, TR}, title = {Disruption of DYRK1A-induced hyperphosphorylation of amyloid-beta and tau protein in Alzheimer's disease: An integrative molecular modeling approach.}, journal = {Frontiers in molecular biosciences}, volume = {9}, number = {}, pages = {1078987}, pmid = {36741918}, issn = {2296-889X}, abstract = {Alzheimer's disease (AD) is a neurological disorder caused by the abnormal accumulation of hyperphosphorylated proteins. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a dual phosphorylation enzyme which phosphorylates the amyloid-β (Aβ) and neurofibrillary tangles (NFTs). A high throughput virtual screening approach was applied to screen a library of 98,071 compounds against DYRK1A using different programs including AutoDock Vina, Smina, and idock. Based on the binding affinities, we selected 330 compounds for absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis. Various pharmacokinetics parameters were predicted using the admetSAR server, and based on the pharmacokinetics results, 14 compounds were selected for cross-docking analysis using AutoDock. Cross-docking analysis revealed four compounds, namely, ZINC3843365 (-11.07 kcal/mol[-1]), ZINC2123081 (-10.93 kcal/mol[-1]), ZINC5220992 (-10.63 kcal/mol[-1]), and ZINC68569602 (-10.35 kcal/mol[-1]), which had the highest negative affinity scores compared to the 10 other molecules analyzed. Density functional theory (DFT) analysis was conducted for all the four top-ranked compounds. The molecular interaction stability of these four compounds with DYRK1A has been evaluated using molecular dynamics (MD) simulations on 100 nanoseconds followed by principal component analysis (PCA) and binding free energy calculations. The Gibbs free energy landscape analysis suggested the metastable state and folding pattern of selected docking complexes. Based on the present study outcome, we propose four antagonists, viz., ZINC3843365, ZINC2123081, ZINC5220992, and ZINC68569602 as potential inhibitors against DYRK1A and to reduce the amyloid-β and neurofibrillary tangle burden. These screened molecules can be further investigated using a number of in vitro and in vivo experiments.}, } @article {pmid36741774, year = {2022}, author = {Shuken, SR and Rutledge, J and Iram, T and Losada, PM and Wilson, EN and Andreasson, KI and Leib, RD and Wyss-Coray, T}, title = {Limited Proteolysis-Mass Spectrometry Reveals Aging-Associated Changes in Cerebrospinal Fluid Protein Abundances and Structures.}, journal = {Nature aging}, volume = {2}, number = {5}, pages = {379-388}, pmid = {36741774}, issn = {2662-8465}, abstract = {Cerebrospinal fluid (CSF) proteins and their structures have been implicated repeatedly in aging and neurodegenerative diseases. Limited proteolysis-mass spectrometry (LiP-MS) is a method that enables proteome-wide screening for changes in both protein abundance and structure. To screen for novel aging-associated changes in the CSF proteome, we performed LiP-MS on CSF from young and old mice with a modified analysis pipeline. We found 38 protein groups change in abundance with aging, most dominantly immunoglobulins of the IgM subclass. We discovered six high-confidence candidates that appeared to change in structure with aging, of which Kng1, Itih2, Lp-PLA2, and 14-3-3 proteins have binding partners or proteoforms known previously to change in the brain with Alzheimer's disease. Intriguingly, using orthogonal validation by Western blot we found the LiP-MS hit Cd5l forms a covalent complex with IgM in mouse and human CSF whose abundance increases with aging. SOMAmer probe signals for all six LiP-MS hits in human CSF, especially 14-3-3 proteins, significantly associate with several clinical features relevant to cognitive function and neurodegeneration. Together, our findings show that LiP-MS can uncover age-related structural changes in CSF with relevance to neurodegeneration.}, } @article {pmid36741545, year = {2022}, author = {Mittal, KR and Pharasi, N and Sarna, B and Singh, M and Rachana, and Haider, S and Singh, SK and Dua, K and Jha, SK and Dey, A and Ojha, S and Mani, S and Jha, NK}, title = {Nanotechnology-based drug delivery for the treatment of CNS disorders.}, journal = {Translational neuroscience}, volume = {13}, number = {1}, pages = {527-546}, pmid = {36741545}, issn = {2081-3856}, abstract = {Approximately 6.8 million people die annually because of problems related to the central nervous system (CNS), and out of them, approximately 1 million people are affected by neurodegenerative diseases that include Alzheimer's disease, multiple sclerosis, epilepsy, and Parkinson's disease. CNS problems are a primary concern because of the complexity of the brain. There are various drugs available to treat CNS disorders and overcome problems with toxicity, specificity, and delivery. Barriers like the blood-brain barrier (BBB) are a challenge, as they do not allow therapeutic drugs to cross and reach their target. Researchers have been searching for ways to allow drugs to pass through the BBB and reach the target sites. These problems highlight the need of nanotechnology to alter or manipulate various processes at the cellular level to achieve the desired attributes. Due to their nanosize, nanoparticles are able to pass through the BBB and are an effective alternative to drug administration and other approaches. Nanotechnology has the potential to improve treatment and diagnostic techniques for CNS disorders and facilitate effective drug transfer. With the aid of nanoengineering, drugs could be modified to perform functions like transference across the BBB, altering signaling pathways, targeting specific cells, effective gene transfer, and promoting regeneration and preservation of nerve cells. The involvement of a nanocarrier framework inside the delivery of several neurotherapeutic agents used in the treatment of neurological diseases is reviewed in this study.}, } @article {pmid36741518, year = {2023}, author = {Du, Z and Liu, C and Liu, Z and Song, H and Scott, P and Du, X and Ren, J and Qu, X}, title = {In vivo visualization of enantioselective targeting of amyloid and improvement of cognitive function by clickable chiral metallohelices.}, journal = {Chemical science}, volume = {14}, number = {3}, pages = {506-513}, pmid = {36741518}, issn = {2041-6520}, abstract = {The pathogenesis of Alzheimer's disease (AD) is closely related to several contributing factors, especially amyloid-β (Aβ) aggregation. Bioorthogonal reactions provide a general, facile, and robust route for the localization and derivatization of Aβ-targeted agents. Herein, a pair of chiral alkyne-containing metallohelices (ΛA and ΔA) were demonstrated to enantioselectively target and modulate Aβ aggregation, which has been monitored in triple-transgenic AD model mice and proved to improve cognitive function. Compared with its enantiomer ΔA, ΛA performed better in blocking Aβ fibrillation, relieving Aβ-triggered toxicity, and recovering memory deficits in vivo. Moreover, clickable ΛA could act as a functional module for subsequent visualization and versatile modification of amyloid via bioorthogonal reaction. As a proof-of-concept, thioflavin T, tacrine, and magnetic nanoparticles were conjugated with ΛA to realize Aβ photo-oxygenation, acetylcholinesterase inhibition, and Aβ clearance, respectively. This proof-of-principle work provided new insights into the biolabeling and bioconjugation of multifunctional metallosupramolecules through click reactions for AD therapy.}, } @article {pmid36741417, year = {2022}, author = {Burgelman, M and Dujardin, P and Vandendriessche, C and Vandenbroucke, RE}, title = {Free complement and complement containing extracellular vesicles as potential biomarkers for neuroinflammatory and neurodegenerative disorders.}, journal = {Frontiers in immunology}, volume = {13}, number = {}, pages = {1055050}, pmid = {36741417}, issn = {1664-3224}, mesh = {Humans ; Neuroinflammatory Diseases ; *Neurodegenerative Diseases/diagnosis/metabolism ; *Extracellular Vesicles/metabolism ; Complement System Proteins/metabolism ; Biomarkers/metabolism ; }, abstract = {The complement system is implicated in a broad range of neuroinflammatory disorders such as Alzheimer's disease (AD) and multiple sclerosis (MS). Consequently, measuring complement levels in biofluids could serve as a potential biomarker for these diseases. Indeed, complement levels are shown to be altered in patients compared to controls, and some studies reported a correlation between the level of free complement in biofluids and disease progression, severity or the response to therapeutics. Overall, they are not (yet) suitable as a diagnostic tool due to heterogeneity of reported results. Moreover, measurement of free complement proteins has the disadvantage that information on their origin is lost, which might be of value in a multi-parameter approach for disease prediction and stratification. In light of this, extracellular vesicles (EVs) could provide a platform to improve the diagnostic power of complement proteins. EVs are nanosized double membrane particles that are secreted by essentially every cell type and resemble the (status of the) cell of origin. Interestingly, EVs can contain complement proteins, while the cellular origin can still be determined by the presence of EV surface markers. In this review, we summarize the current knowledge and future opportunities on the use of free and EV-associated complement proteins as biomarkers for neuroinflammatory and neurodegenerative disorders.}, } @article {pmid36741058, year = {2022}, author = {Sun, X and Guo, W and Shen, J}, title = {Toward attention-based learning to predict the risk of brain degeneration with multimodal medical data.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {1043626}, pmid = {36741058}, issn = {1662-4548}, abstract = {INTRODUCTION: Brain degeneration is commonly caused by some chronic diseases, such as Alzheimer's disease (AD) and diabetes mellitus (DM). The risk prediction of brain degeneration aims to forecast the situation of disease progression of patients in the near future based on their historical health records. It is beneficial for patients to make an accurate clinical diagnosis and early prevention of disease. Current risk predictions of brain degeneration mainly rely on single-modality medical data, such as Electronic Health Records (EHR) or magnetic resonance imaging (MRI). However, only leveraging EHR or MRI data for the pertinent and accurate prediction is insufficient because of single-modality information (e.g., pixel or volume information of image data or clinical context information of non-image data).

METHODS: Several deep learning-based methods have used multimodal data to predict the risks of specified diseases. However, most of them simply integrate different modalities in an early, intermediate, or late fusion structure and do not care about the intra-modal and intermodal dependencies. A lack of these dependencies would lead to sub-optimal prediction performance. Thus, we propose an encoder-decoder framework for better risk prediction of brain degeneration by using MRI and EHR. An encoder module is one of the key components and mainly focuses on feature extraction of input data. Specifically, we introduce an encoder module, which integrates intra-modal and inter-modal dependencies with the spatial-temporal attention and cross-attention mechanism. The corresponding decoder module is another key component and mainly parses the features from the encoder. In the decoder module, a disease-oriented module is used to extract the most relevant disease representation features. We take advantage of a multi-head attention module followed by a fully connected layer to produce the predicted results.

RESULTS: As different types of AD and DM influence the nature and severity of brain degeneration, we evaluate the proposed method for three-class prediction of AD and three-class prediction of DM. Our results show that the proposed method with integrated MRI and EHR data achieves an accuracy of 0.859 and 0.899 for the risk prediction of AD and DM, respectively.

DISCUSSION: The prediction performance is significantly better than the benchmarks, including MRI-only, EHR-only, and state-of-the-art multimodal fusion methods.}, } @article {pmid36741048, year = {2022}, author = {Chen, Z and Zheng, W and Pang, K and Xia, D and Guo, L and Chen, X and Wu, F and Wang, H}, title = {Weakly supervised learning analysis of Aβ plaque distribution in the whole rat brain.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {1097019}, pmid = {36741048}, issn = {1662-4548}, abstract = {Alzheimer's disease (AD) is a great challenge for the world and hardly to be cured, partly because of the lack of animal models that fully mimic pathological progress. Recently, a rat model exhibiting the most pathological symptoms of AD has been reported. However, high-resolution imaging and accurate quantification of beta-amyloid (Aβ) plaques in the whole rat brain have not been fulfilled due to substantial technical challenges. In this paper, a high-efficiency data analysis pipeline is proposed to quantify Aβ plaques in whole rat brain through several terabytes of image data acquired by a high-speed volumetric imaging approach we have developed previously. A novel segmentation framework applying a high-performance weakly supervised learning method which can dramatically reduce the human labeling consumption is described in this study. The effectiveness of our segmentation framework is validated with different metrics. The segmented Aβ plaques were mapped to a standard rat brain atlas for quantitative analysis of the Aβ distribution in each brain area. This pipeline may also be applied to the segmentation and accurate quantification of other non-specific morphology objects.}, } @article {pmid36740554, year = {2022}, author = {Qiao, J and Wang, T and Shao, Z and Zhu, Y and Zhang, M and Huang, S and Zeng, P}, title = {Genetic correlation and gene-based pleiotropy analysis for four major neurodegenerative diseases with summary statistics.}, journal = {Neurobiology of aging}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neurobiolaging.2022.12.012}, pmid = {36740554}, issn = {1558-1497}, abstract = {Recent genome-wide association studies suggested shared genetic components between neurodegenerative diseases. However, pleiotropic association patterns among them remain poorly understood. We here analyzed 4 major neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), and found suggestively positive genetic correlation. We next implemented a gene-centric pleiotropy analysis with a powerful method called PLACO and detected 280 pleiotropic associations (226 unique genes) with these diseases. Functional analyses demonstrated that these genes were enriched in the pancreas, liver, heart, blood, brain, and muscle tissues; and that 42 pleiotropic genes exhibited drug-gene interactions with 341 drugs. Using Mendelian randomization, we discovered that AD and PD can increase the risk of developing ALS, and that AD and ALS can also increase the risk of developing FTD, respectively. Overall, this study provides in-depth insights into shared genetic components and causal relationship among the 4 major neurodegenerative diseases, indicating genetic overlap and causality commonly drive their co-occurrence. It also has important implications on the etiology understanding, drug development and therapeutic targets for neurodegenerative diseases.}, } @article {pmid36739619, year = {2022}, author = {Tetlow, AM and Jackman, BM and Alhadidy, MM and Muskus, P and Morgan, DG and Gordon, MN}, title = {Neural atrophy produced by AAV tau injections into hippocampus and anterior cortex of middle-aged mice.}, journal = {Neurobiology of aging}, volume = {124}, number = {}, pages = {39-50}, doi = {10.1016/j.neurobiolaging.2022.06.014}, pmid = {36739619}, issn = {1558-1497}, abstract = {Animal models of tauopathy help in understanding the role of mutations in tau pathobiology. Here, we used adeno-associated viral (AAV) vectors to administer three tau genetic variants (tau[wild-type], tau[P301L], and tau[R406W]) intracranially into 12-month-old C57BL/6Nia mice and collected tissue at 16 months. Vectors designed to express green fluorescent protein controlled for surgical procedures and exogenous protein expression by AAV. The tau genetic variants produced considerably different phenotypes. Tau[wild-type] and tau[P301L] caused memory impairments. The tau[P301L] caused increased amounts of aggregated tau, measured both neurochemically and histologically. Tau[wild-type] produced elevated levels of soluble tau and phosphorylated tau by ELISA and increased staining for phosphorylated forms of tau histologically. However, only the tau[wild-type] caused localized atrophy of brain tissue at the sites near the injection. The tau[R406W] had low protein expression and produced no atrophy or memory impairments. This supports the potential use of AAV expressing tau[wild-type] in aged mice to examine events leading to neurodegeneration in Alzheimer's disease pathology.}, } @article {pmid36739557, year = {2023}, author = {Aguirre, A and Hilsabeck, RC and O'Mahar, K and Carberry, KE and Ayers, G and Bertelson, J and Rousseau, JF and Paydarfar, D}, title = {Designing an interprofessional dementia specialty clinic: Conceptualization and evaluation of a patient-centered model.}, journal = {Journal of interprofessional care}, volume = {37}, number = {2}, pages = {254-261}, doi = {10.1080/13561820.2022.2060194}, pmid = {36739557}, issn = {1469-9567}, mesh = {Humans ; Aged ; *Interprofessional Relations ; Concept Formation ; Focus Groups ; *Dementia/diagnosis/therapy ; Patient-Centered Care ; Cooperative Behavior ; Patient Care Team ; }, abstract = {The need for blueprints to design specialty care interprofessional collaboration (IPC) models is urgent, given the expanding aging population and current challenges in dementia diagnosis and treatment. We describe key steps creating an interprofessional outpatient dementia specialty clinic, efforts to sustain the model, and evaluation of interprofessional effectiveness and clinician satisfaction. The conception for the Comprehensive Memory Center was informed by qualitative research methodologies including focus groups, interviews, and literature reviews. Quantitative evaluation included satisfaction surveys and team effectiveness measures. The IPC model diverges from typical dementia practices through its interprofessional team, visit structure, approach to decision-making, in-house services, and community collaborations. Team retreats and workshops helped build clinician knowledge of interprofessional values and practices to sustain the IPC model. In the first 3.5 years, we served nearly 750 patients and their caregivers. Team evaluation results revealed that increased access to consultation and sharing the workload and emotional burden were beneficial. The majority of team members preferred the IPC model to traditional models of clinical care.}, } @article {pmid36734383, year = {2022}, author = {Lu, J and Liu, L and Chen, J and Zhi, J and Li, J and Li, L and Jiang, Z}, title = {LncRNA HOTAIR in exercise-induced neuro-protective function in Alzheimer's disease.}, journal = {Folia neuropathologica}, volume = {60}, number = {4}, pages = {414-420}, doi = {10.5114/fn.2022.118961}, pmid = {36734383}, issn = {1509-572X}, mesh = {Humans ; *Alzheimer Disease/diagnosis/genetics ; *RNA, Long Noncoding/genetics ; Neuropsychological Tests ; *Cognitive Dysfunction ; Biomarkers ; }, abstract = {INTRODUCTION: Exercise is effective in Alzheimer's disease (AD), which is characterized by neuro-degenerative progress with increasing morbidity. The present study aimed to explore whether HOTAIR participated in the regulation of exercise in AD.

MATERIAL AND METHODS: A relative expression of serum HOTAIR was detected using quantitative real-time polymerase chain reaction (PCR). The diagnostic significance of HOTAIR on distinguishing AD patients was evaluated by receiver operating characteristic (ROC) curve. Correlations between HOTAIR expression and Mini-Mental State Examination (MMSE) score or Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score were analyzed with Pearson's test. Logistic regression analysis was applied to investigate factors as independent indicators for HOTAIR expression.

RESULTS: In AD patients, the expression of HOTAIR was increased, and it could function as a diagnostic marker in AD patients. The expression of HOTAIR was associated with MMSE score and ADAS-Cog score in AD patients before exercise. Exercise ameliorated the cognitive impairment and reduced the relative serum expression of HOTAIR. Exercise was proved to be an independent indicator of HOTAIR expression.

CONCLUSIONS: HOTAIR was a possible biomarker for indicating AD patients, and it was correlated with MMSE scores and ADAS-Cog results. Exercise might moderate AD progress via controlling HOTAIR.}, } @article {pmid36733665, year = {2022}, author = {Alich, TC and Röderer, P and Szalontai, B and Golcuk, K and Tariq, S and Peitz, M and Brüstle, O and Mody, I}, title = {Bringing to light the physiological and pathological firing patterns of human induced pluripotent stem cell-derived neurons using optical recordings.}, journal = {Frontiers in cellular neuroscience}, volume = {16}, number = {}, pages = {1039957}, pmid = {36733665}, issn = {1662-5102}, abstract = {Human induced pluripotent stem cells (hiPSCs) are a promising approach to study neurological and neuropsychiatric diseases. Most methods to record the activity of these cells have major drawbacks as they are invasive or they do not allow single cell resolution. Genetically encoded voltage indicators (GEVIs) open the path to high throughput visualization of undisturbed neuronal activity. However, conventional GEVIs perturb membrane integrity through inserting multiple copies of transmembrane domains into the plasma membrane. To circumvent large add-ons to the plasma membrane, we used a minimally invasive novel hybrid dark quencher GEVI to record the physiological and pathological firing patterns of hiPSCs-derived sensory neurons from patients with inherited erythromelalgia, a chronic pain condition associated with recurrent attacks of redness and swelling in the distal extremities. We observed considerable differences in action potential firing patterns between patient and control neurons that were previously overlooked with other recording methods. Our system also performed well in hiPSC-derived forebrain neurons where it detected spontaneous synchronous bursting behavior, thus opening the path to future applications in other cell types and disease models including Parkinson's disease, Alzheimer's disease, epilepsy, and schizophrenia, conditions associated with disturbances of neuronal activity and synchrony.}, } @article {pmid36733500, year = {2022}, author = {Kong, W and Zang, Y}, title = {Alzheimer's disease biomarkers in patients with obstructive sleep apnea hypopnea syndrome and effects of surgery: A prospective cohort study.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {959472}, pmid = {36733500}, issn = {1663-4365}, abstract = {BACKGROUND: Obstructive sleep apnea hypopnea syndrome (OSAHS) may cause Alzheimer's disease (AD), t-tau, p-tau, Aβ42, and Aβ40 are important elements in the process of AD, and changes in the levels of these biomarkers may affect the cognitive functioning of patients. Our objective was to investigate whether uvulopalatopharyngoplasty could reduce the plasma levels of AD biomarkers in OSAHS patients and the potential correlations of AD biomarkers with cognitive impairment and sleepiness, and explore the independent influencing factors of cognitive function.

METHODS: Alzheimer's disease biomarkers were measured in the plasma of 35 patients with severe OSAHS requiring surgical treatment and 16 healthy controls without OSAHS. The cognitive function and sleepiness of OSAHS patients was also evaluated. The case group was given uvulopalatopharyngoplasty and followed at the postoperative sixth month, the follow-up cases were 27, and plasma AD biomarker levels, cognitive function, and sleepiness were re-evaluated. The preoperative and postoperative AD biomarker levels OSAHS patients were compared with each other and those of the control group. Linear stepwise regression and lasso regression were used to explore the relationships of AD biomarkers with cognitive impairment and sleepiness.

RESULTS: Significantly higher Aβ40, t-tau, p-tau in plasma were observed preoperatively in OSAHS patients comparing to controls (29.24 ± 32.52 vs. 13.18 ± 10.78, p = 0.049; 11.88 ± 7.05 vs. 7.64 ± 4.17, p = 0.037; 26.31 ± 14.41 vs. 17.34 ± 9.12, p = 0.027). The sixth month of postoperation, the plasma AD biomarkers (Aβ42, Aβ40, t-tau, p-tau) in plasma levels decreased significantly (0.23 ± 0.17 vs. 0.20 ± 0.16, p = 0.0001; 29.24 ± 32.52 vs. 23.52 ± 24.46, p = 0.0046; 11.88 ± 7.05 vs. 8.88 ± 6.21, p = 0.0001;26.31 ± 14.41 vs. 20.43 ± 10.50, p = 0.0001). A comparison of MMSE and ESS scores from before to after surgery revealed obvious differences (27.14 ± 1.65 vs. 29.07 ± 1.78, p = 0.0001; 11.91 ± 4.84 vs. 5.89 ± 2.83, p = 0.0001). Changes in cognitive function and sleepiness scores from before to after uvulopalatopharyngoplasty were significantly correlated with AD biomarkers. Body mass index and t-tau were potential influencing factors cognitive function.

CONCLUSION: Obstructive sleep apnea hypopnea syndrome can increase plasma AD biomarkers levels. Uvulopalatopharyngoplasty can improve patients' cognition and sleepiness, and the mechanism may be related to changes in plasma AD biomarkers. Higher AHI and higher t-tau level were identified as independent risk factors for cognitive decline.}, } @article {pmid36733450, year = {2022}, author = {Ouyang, Y and Zhang, Y and Guo, X and Li, J and Ao, Q and Guo, S and Zhang, M and Sun, J}, title = {An analysis of neurovascular disease markers in the hippocampus of Tupaia chinensis at different growth stages.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {1083182}, pmid = {36733450}, issn = {1664-2295}, abstract = {INTRODUCTION: It is considered that Tupaia chinensis can replace laboratory primates in the study of nervous system diseases. To date, however, protein expression in the brain of Tupaia chinensis has not been fully understood.

METHOD: Three age groups of T. chinensis-15 days, 3 months and 1.5 years-were selected to study their hippocampal protein expression profiles.

RESULTS: A significant difference was observed between the 15-day group and the other two age groups, where as there were no significant differences between the 3-month and 1.5-year age groups. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis found that differentially expressed proteins could be enriched in several pathways related to neurovascular diseases, such as metabolic pathways for Alzheimer's disease (AD), Huntington's disease, Parkinson's disease, and other diseases. The KEGG enrichment also showed that relevant protein involved in oxidative phosphorylation in the hippocampus of T. chinensis for 15days were downregulated, and ribosomal proteins (RPs) were upregulated, compared to those in the hippocampus of the other two age groups.

DISCUSSION: It was suggested that when the hippocampus of T. chinensis developed from day 15 to 3 months, the expression of oxidatively phosphorylated proteins and RPs would vary over time. Meanwhile, the hippocamppal protein expression profile of T. chinensis after 3 months had become stable. Moreover, the study underlines that, during the early development of the hippocampus of T. chinensis, energy demand increases while protein synthesis decreases. The mitochondria of T. chinensis changes with age, and the oxidative phosphorylation metabolic pathway of mitochondria is closely related to neurovascular diseases, such as stroke and cerebral ischemia.}, } @article {pmid36733447, year = {2022}, author = {Luo, N and Guo, Y and Peng, L and Deng, F}, title = {High-fiber-diet-related metabolites improve neurodegenerative symptoms in patients with obesity with diabetes mellitus by modulating the hippocampal-hypothalamic endocrine axis.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {1026904}, pmid = {36733447}, issn = {1664-2295}, abstract = {OBJECTIVE: Through transcriptomic and metabolomic analyses, this study examined the role of high-fiber diet in obesity complicated by diabetes and neurodegenerative symptoms.

METHOD: The expression matrix of high-fiber-diet-related metabolites, blood methylation profile associated with pre-symptomatic dementia in elderly patients with type 2 diabetes mellitus (T2DM), and high-throughput single-cell sequencing data of hippocampal samples from patients with Alzheimer's disease (AD) were retrieved from the Gene Expression Omnibus (GEO) database and through a literature search. Data were analyzed using principal component analysis (PCA) after quality control and data filtering to identify different cell clusters and candidate markers. A protein-protein interaction network was mapped using the STRING database. To further investigate the interaction among high-fiber-diet-related metabolites, methylation-related DEGs related to T2DM, and single-cell marker genes related to AD, AutoDock was used for semi-flexible molecular docking.

RESULT: Based on GEO database data and previous studies, 24 marker genes associated with high-fiber diet, T2DM, and AD were identified. Top 10 core genes include SYNE1, ANK2, SPEG, PDZD2, KALRN, PTPRM, PTPRK, BIN1, DOCK9, and NPNT, and their functions are primarily related to autophagy. According to molecular docking analysis, acetamidobenzoic acid, the most substantially altered metabolic marker associated with a high-fiber diet, had the strongest binding affinity for SPEG.

CONCLUSION: By targeting the SPEG protein in the hippocampus, acetamidobenzoic acid, a metabolite associated with high-fiber diet, may improve diabetic and neurodegenerative diseases in obese people.}, } @article {pmid36733444, year = {2022}, author = {Pyun, JM and Youn, YC and Park, YH and Kim, S}, title = {Integration of amyloid-β oligomerization tendency as a plasma biomarker in Alzheimer's disease diagnosis.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {1028448}, pmid = {36733444}, issn = {1664-2295}, abstract = {INTRODUCTION: There has been significant development in blood-based biomarkers targeting amyloidopathy of Alzheimer's disease (AD). However, the guidelines for integrating such biomarkers into AD diagnosis are still inadequate. Multimer Detection System-Oligomeric Amyloid-β (MDS-OAβ) as a plasma biomarker detecting oligomerization tendency is available in the clinical practice.

MAIN TEXT: We suggest how to interpret the results of plasma biomarker for amyloidopathy using MDS-OAβ with neuropsychological test, brain magnetic resonance imaging (MRI), and amyloid PET for AD diagnosis. Combination of each test result differentiates various stages of AD, other neurodegenerative diseases, or cognitive impairment due to the causes other than neurodegeneration.

DISCUSSION: A systematic interpretation strategy could support accurate diagnosis and staging of AD. Moreover, comprehensive use of biomarkers that target amyloidopathy such as amyloid PET on brain amyloid plaque and MDS-OAβ on amyloid-β oligomerization tendency can complement to gain advanced insights on amyloid-β dynamics in AD.}, } @article {pmid36727091, year = {2022}, author = {Basri, R and Awan, FM and Yang, BB and Awan, UA and Obaid, A and Naz, A and Ikram, A and Khan, S and Haq, IU and Khan, SN and Aqeel, MB}, title = {Brain-protective mechanisms of autophagy associated circRNAs: Kick starting self-cleaning mode in brain cells via circRNAs as a potential therapeutic approach for neurodegenerative diseases.}, journal = {Frontiers in molecular neuroscience}, volume = {15}, number = {}, pages = {1078441}, pmid = {36727091}, issn = {1662-5099}, abstract = {Altered autophagy is a hallmark of neurodegeneration but how autophagy is regulated in the brain and dysfunctional autophagy leads to neuronal death has remained cryptic. Being a key cellular waste-recycling and housekeeping system, autophagy is implicated in a range of brain disorders and altering autophagy flux could be an effective therapeutic strategy and has the potential for clinical applications down the road. Tight regulation of proteins and organelles in order to meet the needs of complex neuronal physiology suggests that there is distinct regulatory pattern of neuronal autophagy as compared to non-neuronal cells and nervous system might have its own separate regulator of autophagy. Evidence has shown that circRNAs participates in the biological processes of autophagosome assembly. The regulatory networks between circRNAs, autophagy, and neurodegeneration remains unknown and warrants further investigation. Understanding the interplay between autophagy, circRNAs and neurodegeneration requires a knowledge of the multiple steps and regulatory interactions involved in the autophagy pathway which might provide a valuable resource for the diagnosis and therapy of neurodegenerative diseases. In this review, we aimed to summarize the latest studies on the role of brain-protective mechanisms of autophagy associated circRNAs in neurodegenerative diseases (including Alzheimer's disease, Parkinson's disease, Huntington's disease, Spinal Muscular Atrophy, Amyotrophic Lateral Sclerosis, and Friedreich's ataxia) and how this knowledge can be leveraged for the development of novel therapeutics against them. Autophagy stimulation might be potential one-size-fits-all therapy for neurodegenerative disease as per considerable body of evidence, therefore future research on brain-protective mechanisms of autophagy associated circRNAs will illuminate an important feature of nervous system biology and will open the door to new approaches for treating neurodegenerative diseases.}, } @article {pmid36726800, year = {2022}, author = {Zhou, K and Piao, S and Liu, X and Luo, X and Chen, H and Xiang, R and Geng, D}, title = {A novel cascade machine learning pipeline for Alzheimer's disease identification and prediction.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1073909}, pmid = {36726800}, issn = {1663-4365}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive and irreversible brain degenerative disorder early. Among all diagnostic strategies, hippocampal atrophy is considered a promising diagnostic method. In order to proactively detect patients with early Alzheimer's disease, we built an Alzheimer's segmentation and classification (AL-SCF) pipeline based on machine learning.

METHODS: In our study, we collected coronal T1 weighted images that include 187 patients with AD and 230 normal controls (NCs). Our pipeline began with the segmentation of the hippocampus by using a modified U2-net. Subsequently, we extracted 851 radiomics features and selected 37 features most relevant to AD by the Hierarchical clustering method and Least Absolute Shrinkage and Selection Operator (LASSO) algorithm. At last, four classifiers were implemented to distinguish AD from NCs, and the performance of the models was evaluated by accuracy, specificity, sensitivity, and area under the curve.

RESULTS: Our proposed pipeline showed excellent discriminative performance of classification with AD vs NC in the training set (AUC=0.97, 95% CI: (0.96-0.98)). The model was also verified in the validation set with Dice=0.93 for segmentation and accuracy=0.95 for classification.

DISCUSSION: The AL-SCF pipeline can automate the process from segmentation to classification, which may assist doctors with AD diagnosis and develop individualized medical plans for AD in clinical practice.}, } @article {pmid36726477, year = {2022}, author = {Han, AH and Burroughs, CR and Falgoust, EP and Hasoon, J and Hunt, G and Kakazu, J and Lee, T and Kaye, AM and Kaye, AD and Ganti, L}, title = {Suvorexant, a Novel Dual Orexin Receptor Antagonist, for the Management of Insomnia.}, journal = {Health psychology research}, volume = {10}, number = {5}, pages = {67898}, pmid = {36726477}, issn = {2420-8124}, abstract = {PURPOSE OF REVIEW: The present investigation is a comprehensive review regarding the use of Suvorexant for insomnia treatment. It covers the background, pathophysiology, and significance of addressing insomnia, the pharmaceutical details of Suvorexant, and its safety, efficacy, and implications in treating insomnia. We further discuss Suvorexant's role in targeting insomnia with other comorbidities.

RECENT FINDINGS: Insomnia refers to poor quality and/or quantity of sleep. While there are many existing treatments such as benzodiazepines, melatonin agonists, TCAs, and atypical antipsychotics used to target various receptors involved in normal induction and maintenance of sleep, Suvorexant is an antagonist that specifically targets orexin receptors. Recent clinical studies suggest that Suvorexant is both clinically safe and effective. Quantity and quality of sleep are measured in various ways, yet the consensus points towards Suvorexant's effectiveness in improving sleep time, onset, latency, and quality compared to placebo. In addition to helping improve isolated insomnia, Suvorexant helps improve sleep in patients that have other comorbidities such as obstructive sleep apnea, Alzheimer's disease, dementia, acute stroke, and delirium. While Suvorexant is safe, there are still adverse effects associated with the drug that needs to be considered. The most common adverse effects include dizziness, somnolence, headaches, and cognitive impairment.

SUMMARY: Insomnia is a major public health concern that affects many people worldwide and has been linked to many adverse health outcomes. While there are existing treatments that target different receptors and pathways of normal sleep induction and maintenance, Suvorexant is a novel drug that targets dual orexin receptors. Its safety and efficacy, mechanism of action, pharmacokinetic parameters, and relative lack of rebound and withdrawal effects render suvorexant a reliable choice for the treatment of insomnia.}, } @article {pmid36724611, year = {2022}, author = {Zhang, RL and Lei, BX and Wu, GY and Wang, YY and Huang, QH}, title = {Protective effects of berberine against β-amyloid-induced neurotoxicity in HT22 cells via the Nrf2/HO-1 pathway.}, journal = {Bioorganic chemistry}, volume = {133}, number = {}, pages = {106210}, doi = {10.1016/j.bioorg.2022.106210}, pmid = {36724611}, issn = {1090-2120}, abstract = {Neuronal apoptosis has been found to have a pivotal role in the course of Alzheimer's disease (AD). Berberine (BBR), a potent antioxidant, occurs in plants such as Berberis, Phellodendron chinense, and Hydrastis canadensis. In this study, a neuronal apoptotic model was established in vitro using HT22 cells induced by Aβ25-35 to explore whether BBR contributes to protecting neurons against Aβ25-35-induced neurotoxicity, as well as its potential mechanisms. BBR was applied to HT22 cells for 1 h prior to exposing the cells to Aβ25-35 for 24 h. A CCK-8 assay was utilized to assess cell viability, and Annexin V - fluorescein isothiocyanate (FITC)/propidium iodide and Hoechst 33342 fluorescence staining were used to measure the rate of cell apoptosis. Existing scientific literature was also reviewed to further determine the effects of BBR on ROS production and mitochondrial function in HT22 cells. Furthermore, the expressions of proteins, including cytochrome C, cleaved caspase-3, p-p65, p65, and Nrf2/HO-1 antioxidant axis were assessed by Western blotting. The data indicated that BBR markedly improved cell viability, inhibited apoptosis and intracellular ROS levels, improved mitochondrial membrane potentials, decreased the rate of p-p65/p65, cytochrome C, and cleaved caspase-3, and intensified the activity of Nrf2/HO-1 antioxidants in HT22 cells. Overall, the findings indicated that BBR provides a certain level of neuroprotectiveness in HT22 cells exposed to Aβ25-35 via relieving oxidative stress, as well as by restraining the mitochondrial pathway of cellular apoptosis. In addition, the restraint of NF-κB activity and sensitization of the Nrf2/HO-1 antioxidant axis, which together are intimately involved in the neuroprotection of BBR, may be possible mechanisms accounting for its effectiveness against Aβ25-35in vitro.}, } @article {pmid36722236, year = {2022}, author = {Zhao, J and Yang, J and Ding, L and Wang, F and Lin, L}, title = {A Review of the Pathogenesis and Chinese Medicine Intervention of Alzheimer's Disease.}, journal = {Journal of integrative neuroscience}, volume = {22}, number = {1}, pages = {2}, doi = {10.31083/j.jin2201002}, pmid = {36722236}, issn = {0219-6352}, mesh = {Humans ; *Alzheimer Disease/etiology/therapy ; Medicine, Chinese Traditional ; *Neurodegenerative Diseases ; Amyloid beta-Peptides ; *Brain Injuries ; }, abstract = {Alzheimer's disease (AD) is an age-related neurodegenerative disease that is primary characterized as a cognitive disorder. Its pathology is characterized by the formation of senile plaques in the brain from amyloid-beta (Aβ) aggregation, neuronal fibrillary tangles from hyperphosphorylated tau protein aggregation, prolonged inflammatory responses, and neuronal death. The pathogenesis and clinical manifestations of AD are complex, but aging is generally accepted as one of the most important contributing factors. In addition, there are several hypotheses, including the Aβ hypothesis based on amyloid plaques, the tau hypothesis based on neuronal fiber entanglement, the inflammation hypothesis based on long-term inflammatory responses causing brain damage, and the neuroprotection hypothesis based on synaptic dysfunction and neuronal death. Although the pathogenesis of AD has been broadly classified into four major hypotheses, there are multiple forms of interactions, which is one of the reasons for its complex pathogenesis. Numerous epidemiological studies have shown the important role of genes in AD, followed by brain damage, hyperlipidemia, diabetes, hypertension, and obesity as risk factors for the disease. Despite years of research, several mysteries in AD remain unsolved. Drugs based on various pathogenetic hypotheses are being investigated in large numbers, but the effects are unsatisfactory. In recent years, traditional Chinese medicine (TCM) has made excellent progress and is expected to provide a new possibility for AD treatment. In this review, we focus on the latest developments in studies on the risk factors-Aβ aggregates and related factors such as apolipoprotein E, synaptic loss, and fatty acids, and then present the progress in the research of TCM based on the above pathogenesis, intended to provide a research reference and treatment for AD.}, } @article {pmid36721488, year = {2022}, author = {Kanagasingam, S and von Ruhland, C and Welbury, R and Singhrao, SK}, title = {Ex vivo Detection of Amyloid-β in Naturally Formed Oral Biofilm.}, journal = {Journal of Alzheimer's disease reports}, volume = {6}, number = {1}, pages = {757-773}, pmid = {36721488}, issn = {2542-4823}, abstract = {BACKGROUND: Oral infection has been implicated in the possible etiology of Alzheimer's disease.

OBJECTIVE: To detect amyloid-β (Aβ) within microbial biofilms.

METHODS: Freshly extracted teeth (N = 87) with periodontal disease were separated into Group A (N = 11), with primary root canal infection and Group B (N = 21) with failed endodontic treatment identified by the presence of, gutta percha root filling. Biofilm characteristics were observed by scanning electron microscopy (SEM). Demineralized paraffin wax embedded tooth sections and mineralized calculus biofilm were immunostained with the anti-Aβ antibody. The gutta perchas were processed either for on-section acrylic resin tissue immunocolloidal gold silver staining (IGSS) using the anti-Aβ antibody or in Araldite resin for ultrastructure.

RESULTS: SEM demonstrated calculus and gutta percha in situ harboring a polymicrobial biofilm featuring extracellular polymeric substance (EPS) and water channels. Immunohistochemistry on rehydrated paraffin wax tooth sections from Group A, demonstrated Aβ staining on external (calculus and plaque) and all intracanal infected regions. In Group B, the gutta percha biofilm IGSS gave an inconclusive result for Aβ. Transmission electron microscopy of selected teeth with infected intra-canals (Group A) and 20% of gutta percha biofilm (Group B) EPS contained electron dense fibrils of variable sizes, some of which were typical of human Aβ fibrils.

CONCLUSION: This study detected both soluble and insoluble Aβ fibrils within the EPS of periodontal and endodontic natural biofilm, strongly suggesting its role as an antimicrobial peptide in combatting local infection, with potential risk for cross-seeding into the brain for AD development.}, } @article {pmid36721487, year = {2022}, author = {Mozdbar, S and Petersen, M and Zhang, F and Johnson, L and Tolman, A and Nyalakonda, R and Gutierrez, A and O'Bryant, S}, title = {Application of Structural Retinal Biomarkers to Detect Cognitive Impairment in a Primary Care Setting.}, journal = {Journal of Alzheimer's disease reports}, volume = {6}, number = {1}, pages = {749-755}, pmid = {36721487}, issn = {2542-4823}, abstract = {BACKGROUND: Despite the diagnostic accuracy of advanced neurodiagnostic procedures, the detection of Alzheimer's disease (AD) remains poor in primary care. There is an urgent need for screening tools to aid in the detection of early AD.

OBJECTIVE: This study examines the predictive ability of structural retinal biomarkers in detecting cognitive impairment in a primary care setting.

METHODS: Participants were recruited from Alzheimer's Disease in Primary Care (ADPC) study. As part of the ADPC Retinal Biomarker Study (ADPC RBS), visual acuity, an ocular history questionnaire, eye pressure, optical coherence tomography (OCT) imaging, and fundus imaging was performed.

RESULTS: Data were examined on n = 91 participants. The top biomarkers for predicting cognitive impairment included the inferior quadrant of the outer retinal layers, all four quadrants of the peripapillary retinal nerve fiber layer, and the inferior quadrant of the macular retinal nerve fiber layer.

CONCLUSION: The current data provides strong support for continued investigation into structural retinal biomarkers, particularly the retinal nerve fiber layer, as screening tools for AD.}, } @article {pmid36721486, year = {2022}, author = {El Haj, M and Boudoukha, AH and Moustafa, AA and Gallouj, K and Altintas, E}, title = {"I Will Be Healthy": Ideal Self in Patients with Alzheimer's Disease.}, journal = {Journal of Alzheimer's disease reports}, volume = {6}, number = {1}, pages = {775-781}, pmid = {36721486}, issn = {2542-4823}, abstract = {BACKGROUND: Within the concept of the self, a distinction can be made between ideal self (i.e., what would like to become) and feared self (i.e., what would not like to become in the future).

OBJECTIVE: We investigated ideal self and feared self in patients with mild Alzheimer's disease (AD). We have also measured these self-related processes in relation to depression and anxiety.

METHODS: We invited 31 patients with mild AD and 35 control participants to decide whether they would consider the statement (e.g., I will be healthy) as a representation that they would like to acquire (i.e., ideal self) or to avoid (i.e., feared self).

RESULTS: Analysis demonstrated that more participants assigned the "I will be healthy" statement to ideal self than to feared self, and this tendency was observed in both AD participants and controls. Less depression and anxiety were observed in participants who have assigned the "I will be healthy" statement to their ideal self compared to those who assigned this statement to their feared self, and this was observed in both AD participant and control groups.

CONCLUSION: Our study demonstrates that AD patients tend to endorse positive health traits and to integrate these traits into their ideal self. AD patients tend to endorse health-related images that are associated with hopes when projecting into their future self. This positive projection into the self may create a motivational force (e.g., aspirations and hopes) to embody the "healthy" self that AD patients desire to be.}, } @article {pmid36721403, year = {2023}, author = {Solomon, ED and Mozersky, J and Goodman, M and Parsons, MV and Baldwin, KA and Friedrich, AB and Harris, JK and DuBois, JM}, title = {A randomized implementation trial to increase adoption of evidence-informed consent practices.}, journal = {Journal of clinical and translational science}, volume = {7}, number = {1}, pages = {e28}, pmid = {36721403}, issn = {2059-8661}, abstract = {INTRODUCTION: Several evidence-informed consent practices (ECPs) have been shown to improve informed consent in clinical trials but are not routinely used. These include optimizing consent formatting, using plain language, using validated instruments to assess understanding, and involving legally authorized representatives when appropriate. We hypothesized that participants receiving an implementation science toolkit and a social media push would have increased adoption of ECPs and other outcomes.

METHODS: We conducted a 1-year trial with clinical research professionals in the USA (n = 1284) who have trials open to older adults or focus on Alzheimer's disease. We randomized participants to receive information on ECPs via receiving a toolkit with a social media push (intervention) or receiving an online learning module (active control). Participants completed a baseline survey and a follow-up survey after 1 year. A subset of participants was interviewed (n = 43).

RESULTS: Participants who engaged more with the toolkit were more likely to have tried to implement an ECP during the trial than participants less engaged with the toolkit or the active control group. However, there were no significant differences in the adoption of ECPs, intention to adopt, or positive attitudes. Participants reported the toolkit and social media push were satisfactory, and participating increased their awareness of ECPs. However, they reported lacking the time needed to engage with the toolkit more fully.

CONCLUSIONS: Using an implementation science approach to increase the use of ECPs was only modestly successful. Data suggest that having institutional review boards recommend or require ECPs may be an effective way to increase their use.}, } @article {pmid36721393, year = {2022}, author = {Barnes, JN and Burns, JM and Bamman, MM and Billinger, SA and Bodine, SC and Booth, FW and Brassard, P and Clemons, TA and Fadel, PJ and Geiger, PC and Gujral, S and Haus, JM and Kanoski, SE and Miller, BF and Morris, JK and O'Connell, KMS and Poole, DC and Sandoval, DA and Smith, JC and Swerdlow, RH and Whitehead, SN and Vidoni, ED and van Praag, H}, title = {Proceedings from the Albert Charitable Trust Inaugural Workshop on 'Understanding the Acute Effects of Exercise on the Brain'.}, journal = {Brain plasticity (Amsterdam, Netherlands)}, volume = {8}, number = {2}, pages = {153-168}, pmid = {36721393}, issn = {2213-6312}, abstract = {An inaugural workshop supported by "The Leo and Anne Albert Charitable Trust," was held October 4-7, 2019 in Scottsdale, Arizona, to focus on the effects of exercise on the brain and to discuss how physical activity may prevent or delay the onset of aging-related neurodegenerative conditions. The Scientific Program Committee (led by Dr. Jeff Burns) assembled translational, clinical, and basic scientists who research various aspects of the effects of exercise on the body and brain, with the overall goal of gaining a better understanding as to how to delay or prevent neurodegenerative diseases. In particular, research topics included the links between cardiorespiratory fitness, the cerebrovasculature, energy metabolism, peripheral organs, and cognitive function, which are all highly relevant to understanding the effects of acute and chronic exercise on the brain. The Albert Trust workshop participants addressed these and related topics, as well as how other lifestyle interventions, such as diet, affect age-related cognitive decline associated with Alzheimer's and other neurodegenerative diseases. This report provides a synopsis of the presentations and discussions by the participants, and a delineation of the next steps towards advancing our understanding of the effects of exercise on the aging brain.}, } @article {pmid36721391, year = {2022}, author = {Fang, EF and Bergersen, LH and Storm-Mathisen, J}, title = {Professors Henriette van Praag and David Gems give the 2022 Nansen Neuroscience Lectures on "Is ageing inevitable?" in the Norwegian Academy of Science and Letters, Norway.}, journal = {Brain plasticity (Amsterdam, Netherlands)}, volume = {8}, number = {2}, pages = {169-172}, doi = {10.3233/BPL-220145}, pmid = {36721391}, issn = {2213-6312}, abstract = {This is a summary of the 2022 Nansen Neuroscience Lectures. On 10 October 2022, Professors Henriette van Praag and David Gems gave the 2022 Nansen Neuroscience Lectures on the theme "Is ageing inevitable?" in the Norwegian Academy of Science and Letters, Oslo, Norway. While van Praag gave a lecture entitled "The benefits of exercise for brain function", Gems gave the 2[nd] lecture discussing "What causes ageing? Lessons from The Worm". Understanding the fundamental mechanisms of ageing will pave the way to the development of future interventions to pre-empt the development of the diseases, including Alzheimer's disease and other dementias, of later life.}, } @article {pmid36719337, year = {2023}, author = {Haussmann, R and Donix, M}, title = {Pharmacologic treatment of depression in Alzheimer's disease.}, journal = {International clinical psychopharmacology}, volume = {38}, number = {2}, pages = {81-88}, doi = {10.1097/YIC.0000000000000439}, pmid = {36719337}, issn = {1473-5857}, mesh = {Humans ; Aged ; *Depressive Disorder, Major/diagnosis/drug therapy ; Depression/drug therapy ; *Alzheimer Disease/drug therapy ; *Neurodegenerative Diseases ; Quality of Life ; }, abstract = {Major depressive disorder and Alzheimer's disease are common among older people, frequently co-occur and severely impact the quality of life. Unfortunately, data on the efficacy of pharmacologic treatment of depressive symptoms in patients with the neurodegenerative disease remain inconclusive. The heterogeneity of treatment study designs, from varying diagnostic specificity to diverse outcome measures, contributes to conflicting evidence across single trials and meta-analyses. In this literature review, we focus on commercially available products for antidepressant treatment in demented individuals and show how insights from randomized controlled trials could still guide and be aligned with common clinical practice.}, } @article {pmid36717446, year = {2022}, author = {Kolosova, NG and Kozhevnikova, OS and Muraleva, NA and Rudnitskaya, EA and Rumyantseva, YV and Stefanova, NA and Telegina, DV and Tyumentsev, MA and Fursova, AZ}, title = {SkQ1 as a Tool for Controlling Accelerated Senescence Program: Experiments with OXYS Rats.}, journal = {Biochemistry. Biokhimiia}, volume = {87}, number = {12}, pages = {1552-1562}, doi = {10.1134/S0006297922120124}, pmid = {36717446}, issn = {1608-3040}, mesh = {Animals ; Rats ; *Aging/physiology ; *Antioxidants/pharmacology ; Mitochondria/metabolism ; Oxidative Stress ; }, abstract = {According to the concept suggested by V. P. Skulachev and co-authors, aging of living organisms can be considered as a special case of programmed death of an organism - phenoptosis, and mitochondrial antioxidant SkQ1 is capable of inhibiting both acute and chronic phenoptosis (aging). The authors of the concept associate effects of SkQ1 with suppression of the enhanced generation of ROS in mitochondria. Numerous studies have confirmed the ability of SkQ1 to inhibit manifestations of the "healthy", or physiological, aging. According to the results of our studies, SkQ1 is especially effective in suppressing the program of genetically determined accelerated senescence in OXYS rats, which appears as an early development of a complex of age-related diseases: cataracts, retinopathy (similar to the age-related macular degeneration in humans), osteoporosis, and signs of Alzheimer's disease. Accelerated senescence in OXYS rats is associated with mitochondrial dysfunction, but no direct associations with oxidative stress have been identified. Nevertheless, SkQ1 is able to prevent and/or suppress development of all manifestations of accelerated senescence in OXYS rats. Its effects are due to impact on the activity of many signaling pathways and processes, but first of all they are associated with restoration of the structural and functional parameters of mitochondria. It could be suggested that the use of SkQ1 could represent a promising strategy in prevention of accelerated phenoptosis - early development of a complex of age-related diseases (multimorbidity) in people predisposed to it.}, } @article {pmid36714789, year = {2022}, author = {Mitchell, C and Gaitán, JM and Pewowaruk, RJ and Gepner, AD and Hess, T and Wilbrand, SM and Dempsey, RJ and Dougherty, RJ and Cook, DB and Okonkwo, O}, title = {Transcranial Color-Coded Doppler Cerebral Hemodynamics Following Aerobic Exercise Training: Outcomes From a Pilot Randomized Clinical Trial.}, journal = {Journal for vascular ultrasound : JVU}, volume = {46}, number = {3}, pages = {110-117}, pmid = {36714789}, issn = {1544-3175}, support = {T32 HL007936/HL/NHLBI NIH HHS/United States ; R01 AG062167/AG/NIA NIH HHS/United States ; R01 AG027161/AG/NIA NIH HHS/United States ; F31 AG062009/AG/NIA NIH HHS/United States ; P50 AG033514/AG/NIA NIH HHS/United States ; R01 AA019511/AA/NIAAA NIH HHS/United States ; K23 AG045957/AG/NIA NIH HHS/United States ; UL1 RR025011/RR/NCRR NIH HHS/United States ; }, abstract = {INTRODUCTION: An active lifestyle with regular exercise is thought to decrease or delay the onset of Alzheimer dementia through increasing blood flow to the brain. We examined the mean flow velocity (MFV) and pulsatility index (PI) in the middle cerebral arteries of individuals randomized into two groups-a Usual Physical Activity (UPA) group and an Enhanced Physical Activity (EPA) exercise intervention group-to determine if exercise training is related to changes in cerebral blood flow.

METHODS: We examined 23 participants, randomized into a UPA group (n=12) and an EPA group (n=11), with transcranial color-coded Doppler (TCCD) and cardiorespiratory fitness (VO2peak, mL/kg/min) testing at baseline and following a 26-week intervention. TCCD was used to measure MFV and PI. Participants in the EPA group completed supervised aerobic exercise training for 26 weeks. Kendall's tau b correlation was used to examine relationships between variables. The Wilcoxon Rank Sum tests were used to examine changes between the UPA and EPA groups.

RESULTS: There was no significant change in MFV or PI in the UPA group or the EPA group (p-values >0.05) between baseline and 26 weeks; the change between the UPA and EPA groups was also not significant (p=0.603). There was no evidence of an association between change in VO2peak and change in MFV or PI (all p-values >0.05). Participants in the EPA group significantly increased their VO2peak compared to the UPA group (p=0.027).

CONCLUSION: This study did not demonstrate evidence of a significant change in the MFV in the middle cerebral arteries or evidence of a significant change in the PI between UPA and EPA groups. Future studies should be performed in larger cohorts and should consider use of personalized exercise programs to maximize understanding of how cerebrovascular hemodynamics change in structure and function with exercise for adults at risk for Alzheimer dementia.}, } @article {pmid36714670, year = {2022}, author = {Ghosh, SK and Sarkar, S and Mondal, S and Das, S}, title = {Clinical profile of dermatitis neglecta with special emphasis on psychiatric comorbidities: A case series of 22 patients from Eastern India.}, journal = {Indian journal of psychiatry}, volume = {64}, number = {6}, pages = {599-604}, pmid = {36714670}, issn = {0019-5545}, abstract = {Dermatitis neglecta (DN), first described by Poskitt et al. in 1995, is a dermatosis resulting from insufficient frictional cleansing of the skin. Lesions result from self-neglect and may have several underlying etiologies, including psychiatric conditions. There is a dearth of any formal study or large case series on this subject. Moreover, the psychological aspects of DN mostly remain unexplored. We report here the clinical profile and psychiatric comorbidities of a group of patients with DN from eastern India. Sporadic cases of underlying psychological problems like cognitive deficit and executive dysfunction, schizophrenia, severe anxiety disorder, and depression have been reported in the existing literature. Associated psychiatric disorder was present in 72.7% of the patients of this case series that include several underlying psychiatric disorders like depression, schizophrenia, somatic symptom disorder, social anxiety disorder, intellectual disability, bipolar disorder, Alzheimer's disease, and alcohol dependence. In this article we would like to emphasize that DN is frequently associated with psychiatric disorder and management of the underlying psychiatric condition with psychotropic medications; psychotherapy is of immense importance.}, } @article {pmid36714669, year = {2022}, author = {Liu, Z and Liu, Y and Zhao, X and Zhang, H and Feng, T and Pang, J and Li, H}, title = {Correlation between Aβ1-42, Dnmt3a2, urinary AD7c-NTP and cognitive dysfunction in first-episode and recurrent MDD: A case-control study.}, journal = {Indian journal of psychiatry}, volume = {64}, number = {6}, pages = {560-566}, pmid = {36714669}, issn = {0019-5545}, abstract = {BACKGROUND AND AIM: Major depressive disorder (MDD) is one of the most prevalent mental illnesses worldwide and involves cognitive dysfunction that may negatively impact clinical and social outcomes. Previous studies have suggested that beta-amyloid peptide (Aβ1-42), DNA methyltransferase (Dnmt3a2), and urinary Alzheimer-associated neuronal thread protein (AD7c-NTP) are associated with cognitive impairment. However, there are no relevant studies in MDD. The aim of this study was to assess the correlation between serum Aβ1-42, Dnmt3a2, and urinary AD7c-NTP and cognitive dysfunction in MDD.

MATERIALS AND METHODS: A total of 59 eligible patients were included in the study, including 29 patients with first-episode MDD (FEDs) and 30 patients with recurrent MDD (RMDDs), and 30 matched healthy controls (HCs) were selected. Participants' cognitive functioning was evaluated using the MATRICS consensus cognitive battery (MCCB). The enzyme-linked immunosorbent assay (ELISA) method was used to measure the concentrations of the three proteins. Statistical analysis was completed using Statistical Package for the Social Sciences (SPSS) 20.0. The statistical significance was set as P < 0.05.

RESULTS: Serum Dnmt3a2 and urinary AD7c-NTP showed significant differences among the three groups (both P < 0.001), but there were no significant differences in Aβ1-42 levels. Upon examining the results of cognitive testing, we found that serum Aβ1-42 was negatively associated with working memory scores in RMDDs (P = 0.020), but Dnmt3a2 was positively associated with working memory and verbal learning scores in the same cohort (P = 0.012 and P = 0.037, respectively). In contrast, urinary AD7c-NTP was negatively correlated with verbal learning scores in FEDs (P = 0.013).

CONCLUSIONS: Serum Dnmt3a2 and Aβ1-42 levels may be associated with cognitive impairment in RMDDs and may act as potential biomarkers of cognitive impairment. Although urinary AD7c-NTP was closely related to cognitive dysfunction in FEDs, this relationship did not hold in RMDDs.}, } @article {pmid36713907, year = {2022}, author = {Gaubert, M and Dell'Orco, A and Lange, C and Garnier-Crussard, A and Zimmermann, I and Dyrba, M and Duering, M and Ziegler, G and Peters, O and Preis, L and Priller, J and Spruth, EJ and Schneider, A and Fliessbach, K and Wiltfang, J and Schott, BH and Maier, F and Glanz, W and Buerger, K and Janowitz, D and Perneczky, R and Rauchmann, BS and Teipel, S and Kilimann, I and Laske, C and Munk, MH and Spottke, A and Roy, N and Dobisch, L and Ewers, M and Dechent, P and Haynes, JD and Scheffler, K and Düzel, E and Jessen, F and Wirth, M and , }, title = {Performance evaluation of automated white matter hyperintensity segmentation algorithms in a multicenter cohort on cognitive impairment and dementia.}, journal = {Frontiers in psychiatry}, volume = {13}, number = {}, pages = {1010273}, pmid = {36713907}, issn = {1664-0640}, abstract = {BACKGROUND: White matter hyperintensities (WMH), a biomarker of small vessel disease, are often found in Alzheimer's disease (AD) and their advanced detection and quantification can be beneficial for research and clinical applications. To investigate WMH in large-scale multicenter studies on cognitive impairment and AD, appropriate automated WMH segmentation algorithms are required. This study aimed to compare the performance of segmentation tools and provide information on their application in multicenter research.

METHODS: We used a pseudo-randomly selected dataset (n = 50) from the DZNE-multicenter observational Longitudinal Cognitive Impairment and Dementia Study (DELCODE) that included 3D fluid-attenuated inversion recovery (FLAIR) images from participants across the cognitive continuum. Performances of top-rated algorithms for automated WMH segmentation [Brain Intensity Abnormality Classification Algorithm (BIANCA), lesion segmentation toolbox (LST), lesion growth algorithm (LGA), LST lesion prediction algorithm (LPA), pgs, and sysu_media] were compared to manual reference segmentation (RS).

RESULTS: Across tools, segmentation performance was moderate for global WMH volume and number of detected lesions. After retraining on a DELCODE subset, the deep learning algorithm sysu_media showed the highest performances with an average Dice's coefficient of 0.702 (±0.109 SD) for volume and a mean F1-score of 0.642 (±0.109 SD) for the number of lesions. The intra-class correlation was excellent for all algorithms (>0.9) but BIANCA (0.835). Performance improved with high WMH burden and varied across brain regions.

CONCLUSION: To conclude, the deep learning algorithm, when retrained, performed well in the multicenter context. Nevertheless, the performance was close to traditional methods. We provide methodological recommendations for future studies using automated WMH segmentation to quantify and assess WMH along the continuum of cognitive impairment and AD dementia.}, } @article {pmid36712694, year = {2022}, author = {Zhu, J and Liang, Q and He, S and Wang, C and Lin, X and Wu, D and Lin, G and Wang, Z}, title = {Research trends and hotspots of neurodegenerative diseases employing network pharmacology: A bibliometric analysis.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1109400}, pmid = {36712694}, issn = {1663-9812}, abstract = {Background: Employing network pharmacology in neurodegenerative diseases (NDs) has been extensively studied recently. However, no comprehensive study has conducted on this subject employing bibliometrics so far. The purpose of this study was to find out the developmental trends and hotspots, and to predict potential research directions in this filed. Methods: Relevant research were collected from the Web of Science Core Collection Bibliometrics and visual analysis were executed using CiteSpace, VOSviewer, Histcite and R-bibliometrix. Results: A total of 420 English articles on network pharmacology in NDs published in 2008-2022 were obtained from the WOSCC database. From 2008 to 2022, annual publications showed a steady growing trend, especially in 2014-2022. China, Beijing Univ Chinese Med, Frontiers in Pharmacology, and Geerts H are the most prolific country, institution, journal, and author, respectively. China, Nucleic Acids Research, and Hopkins AL are the most highly cited country, journal, and author, respectively. Moreover, network pharmacology and Alzheimer's disease are the focal areas of current researches according to analysis of co-cited references and keywords. Finally, in the detection of burst keywords, systems pharmacology and database are new approaches to disease and drug research, while traditional Chinese medicine (TCM) and Alzheimer's disease are hot research directions. The above keywords are speculated to be the research frontiers. Conclusion: Network pharmacology and Alzheimers' disease are the main topics of researches on network pharmacology in NDs. Network pharmacology and the TCM treatment of Alzheimer's disease have been the recent research hotspots. To sum up, the potential for exploring TCM treatment of AD with network pharmacology is huge.}, } @article {pmid36712678, year = {2022}, author = {Zhou, S and Liu, L and Zhang, Y and Zhang, Z and Li, H and Fan, F and He, J and Kang, J and Zuo, L}, title = {Integrated untargeted and targeted metabolomics to reveal therapeutic effect and mechanism of Alpiniae oxyphyllae fructus on Alzheimer's disease in APP/PS1 mice.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1104954}, pmid = {36712678}, issn = {1663-9812}, abstract = {Introduction: Alpiniae oxyphyllae Fructus (AOF) has been abundantly utilized for the treatment of diarrhea, dyspepsia, kidney asthenia, and abdominal pain in China. AOF is effective for treating AD in clinical trials, but its exact mode of action is yet unknown. Methods: In this study, metabolomics was combined to ascertain the alterations in plasma metabolism in APP/PS1 transgenic mice, the therapy of AOF on model mice, and the dynamic variations in 15 bile acids (BAs) concentration. Results: 31 differential biomarkers were finally identified in APP/PS1 group vs. the WT group. The levels of 16 metabolites like sphinganine (Sa), lyso PE (20:2), lysoPC (17:0), glycocholic acid (GCA), deoxycholicacid (DCA) were increased in APP/PS1 group, and those of 15 metabolites like phytosphingosine, cer (d18:0/14:0), and fumaric acid were reduced in APP/PS1 group. After AOF treatment, 29 of the 31 differential metabolites showed a tendency to be back-regulated, and 15 metabolites were significantly back-regulated, including sphinganine (Sa), lyso PE (20:2), glycocholic acid (GCA), deoxycholic acid (DCA). The relationship between BAs level and AD had been received increasing attention in recent years, and we also found notable differences between DCA and GCA in different groups. Therefore, a BAs-targeted metabonomic way was established to determine the level of 15 bile acids in different groups. The consequence demonstrated that primary BAs (CA, CDCA) declined in APP/PS1 model mice. After 3 months of AOF administration, CA and CDCA levels showed an upward trend. Conjugated primary bile acids (TCA, GCA, TCDCA, GCDCA), and secondary bile acids (DCA, LCA, GDCA, TDCA, TLCA GLCA) ascended in APP/PS1 group. After 3 months of AOF treatment, the levels of most BAs decreased to varying degrees. Notably, the metabolic performance of DCA and GCA in different groups was consistent with the predictions of untargeted metabolomics, validating the correctness of untargeted metabolomics. Discussion: According to metabolic pathways of regulated metabolites, it was prompted that AOF ameliorated the symptom of AD mice probably by regulating bile acids metabolism. This study offers a solid foundation for further research into the AOF mechanism for the therapy of AD.}, } @article {pmid36712676, year = {2022}, author = {Huang, XY and Xue, LL and Chen, TB and Huangfu, LR and Wang, TH and Xiong, LL and Yu, CY}, title = {Miracle fruit seed as a potential supplement for the treatment of learning and memory disorders in Alzheimer's disease.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1080753}, pmid = {36712676}, issn = {1663-9812}, abstract = {Currently, the treatment of Alzheimer's disease (AD) is still at the stage of symptomatic treatment due to lack of effective drugs. The research on miracle fruit seeds (MFSs) has focused on lipid-lowering and antidiabetic effects, but no therapeutic effects have been reported in AD. The purpose of this study was to provide data resources and a potential drug for treatment of AD. An AD mouse model was established and treated with MFSs for 1 month. The Morris water maze test was used to assess learning memory function in mice. Nissl staining was used to demonstrate histopathological changes. MFSs were found to have therapeutic implications in the AD mouse model, as evidenced by improved learning memory function and an increase in surviving neurons. To explore the mechanism of MFSs in treating AD, network pharmacological approaches, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and molecular docking studies were carried out. Based on the network pharmacology strategy, 74 components from MFS corresponded to 293 targets related to the AD pathology. Among these targets, AKT1, MAPK3, ESR1, PPARG, PTGS2, EGFR, PPARA, CNR1, ABCB1, and MAPT were identified as the core targets. According to the relevant number of core targets, cis-8-octadecenoic acid, cis-10-octadecenoic acid, 2-dodecenal, and tetradecane are likely to be highly correlated with MFS for AD. Enrichment analysis indicated the common targets mainly enriched in AD and the neurodegeneration-multiple disease signaling pathway. The molecular docking predictions showed that MFSs were stably bound to core targets, specifically AKT1, EGFR, ESR1, PPARA, and PPARG. MFSs may play a therapeutic role in AD by affecting the insulin signaling pathway and the Wnt pathway. The findings of this study provide potential possibilities and drug candidates for the treatment of AD.}, } @article {pmid36712655, year = {2022}, author = {Yao, J and Chen, SRW}, title = {Corrigendum: R-carvedilol, a potential new therapy for Alzheimer's disease.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1125890}, doi = {10.3389/fphar.2022.1125890}, pmid = {36712655}, issn = {1663-9812}, abstract = {[This corrects the article DOI: 10.3389/fphar.2022.1062495.].}, } @article {pmid36712573, year = {2023}, author = {Strikwerda-Brown, C and Ozlen, H and Pichet Binette, A and Chapleau, M and Marchant, NL and Breitner, JCS and Villeneuve, S}, title = {Trait Mindfulness Is Associated With Less Amyloid, Tau, and Cognitive Decline in Individuals at Risk for Alzheimer's Disease.}, journal = {Biological psychiatry global open science}, volume = {3}, number = {1}, pages = {130-138}, pmid = {36712573}, issn = {2667-1743}, abstract = {BACKGROUND: Mindfulness, defined as nonjudgmental awareness of the present moment, has been associated with an array of mental and physical health benefits. Mindfulness may also represent a protective factor for Alzheimer's disease (AD). Here, we tested the potential protective effect of trait mindfulness on cognitive decline and AD pathology in older adults at risk for AD dementia.

METHODS: Measures of trait mindfulness, longitudinal cognitive assessments, and amyloid-β (Aβ) and tau positron emission tomography scans were collected in 261 nondemented older adults with a family history of AD dementia from the PREVENT-AD (Pre-symptomatic Evaluation of Experimental or Novel Treatments for AD) observational cohort study. Multivariate partial least squares analyses were used to examine relationships between combinations of different facets of trait mindfulness and 1) cognitive decline, 2) Aβ, and 3) tau.

RESULTS: Higher levels of mindful nonjudgment, describing, and nonreactivity were associated with less cognitive decline in attention, global cognition, and immediate and delayed memory. Higher levels of mindful nonjudgment and nonreactivity were related to less Aβ positron emission tomography signal in bilateral medial and lateral temporoparietal and frontal regions. Higher levels of mindful acting with awareness, describing, nonjudgment, and nonreactivity were associated with less tau positron emission tomography signal in bilateral medial and lateral temporal regions.

CONCLUSIONS: Trait mindfulness was associated with less cognitive decline and less Aβ and tau in the brain in older adults at risk for AD dementia. Longitudinal studies examining the temporal relationship between trait mindfulness and AD markers, along with mindfulness intervention studies, will be important for further clarifying the potential protective benefits of mindfulness on AD risk.}, } @article {pmid36712428, year = {2022}, author = {Sáiz-Vazquez, O and Puente-Martínez, A and Pacheco-Bonrostro, J and Ubillos-Landa, S}, title = {Blood pressure and Alzheimer's disease: A review of meta-analysis.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {1065335}, pmid = {36712428}, issn = {1664-2295}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurological disorder of unknown cause, resulting in the death of brain cells. Identifying some of the modifiable risk factors for AD could be crucial for primary prevention and could lead to a reduction in the incidence of AD.

OBJECTIVE: This study aimed to perform a meta-meta-analysis of studies in order to assess the effect of blood pressure (BP) on the diagnosis of AD.

METHOD: The search was restricted to meta-analyses assessing high systolic BP (SBP) and diastolic BP (DBP) and AD. We applied the PRISMA guidelines.

RESULTS: A total of 214 studies were identified from major databases. Finally, five meta-analyses (52 studies) were analyzed in this review. Results confirm that high SBP is associated with AD. The exploration of parameters (sex, age, study design, region, and BP measurements) shows that only region significantly moderates the relationship between BP and AD. Asian people are those whose SBP levels >140 mmHg are associated with AD. BP is associated with AD in both people aged ≤65 years and those aged ≥65 years and in cross-sectional and longitudinal studies. In the case of DBP, only women are at a higher risk of AD, particularly when its levels are >90.

CONCLUSION: SBP is associated with both cerebrovascular disease and AD. Therefore, future studies should use other uncontrolled factors, such as cardiovascular diseases, diabetes, and stroke, to explain the relationship between SBP and AD.}, } @article {pmid36711310, year = {2023}, author = {Afzal, M and Alharbi, KS and Alzarea, SI and Alyamani, NM and Kazmi, I and Güven, E}, title = {Revealing genetic links of Type 2 diabetes that lead to the development of Alzheimer's disease.}, journal = {Heliyon}, volume = {9}, number = {1}, pages = {e12202}, pmid = {36711310}, issn = {2405-8440}, abstract = {BACKGROUND: A factor leading to Alzheimer's Disease (AD), portrayed by peripheral insulin resistance, is Type 2 diabetes mellitus (T2D). The likelihood of T2D cases would be at boosted danger in alternating AD cases has severe social consequences. Several genes have been detected via gene expression profiling or different techniques; despite the consideration of the utility of numerous of these genes stays insufficient.

METHODS: This project is designed to uncover the mutual genomics motifs between AD and T2D via non-negative matrix factorization (NMF) of differentially expressed genes (DEGs) of T2D Mellitus of human cortical neurons of the neurovascular unit gene expression data. A rank factorization value is calculated by employing the combination of the NMF model with the unit invariant knee (UIK) point method. The metagenes are further determined by remarking the enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and gene ontology (GO) enrichment tools. In this study, the most highly expressed genes of metagenes are subjected to protein-protein interaction (PPI) network study to discover the most significant biomarkers of T2D Mellitus in the ageing brain.

RESULTS: We screened the most important shared genes (CDKN1A, COL22A1, EIF4A, GFAP, SLC1A1, and VIM) and essential human molecular pathways that motivate these diseases. The study aimed to validate the most significant hub genes using network-based methods which detected the corresponding relationship between AD and T2D.

CONCLUSIONS: Using in silico tools, the computational pipeline has broadly examined transformed pathways and discovered promising biomarkers and drug targets. We validated the most significant hub genes using network-based methods which detected the corresponding relationship between AD and T2D. These consequences on brain cells hypothetically reserve to diabetic Alzheimer's so-called type 3 diabetes (T3D) and may offer promising methodologies for curative intrusion.}, } @article {pmid36711231, year = {2022}, author = {Britt, KC and Richards, KC and Acton, G and Hamilton, J and Radhakrishnan, K}, title = {Older Adults with Dementia: Association of Prayer with Neuropsychiatric Symptoms, Cognitive Function, and Sleep Disturbances.}, journal = {Religions}, volume = {13}, number = {10}, pages = {}, pmid = {36711231}, issn = {2077-1444}, support = {T32 NR009356/NR/NINR NIH HHS/United States ; }, abstract = {Protective factors that slow dementia progression and improve quality of life are needed. Neuropsychiatric symptoms (NPS), cognitive decline, and sleep disturbances are commonly found in dementia, indicate progression, and increase caregiver distress. The purpose of this study was to examine the association of private prayer with NPS, cognitive function, and sleep disturbances in older adults with dementia. We analyzed data from the Health and Retirement Study in 2000, 2006, and 2008 and Aging, Demographics, and Memory Sub study in 2001-2003, 2006-2007, and 2008-2009 among 40 older adults (age 70-100 years, mean age = 84.67, 29 females and 11 males, 73.9% non-Hispanic White, and 19.2% Non-Hispanic Black, and 3% Hispanic, cognitive function = 1.169 indicating mild cognitive impairment) using correlational analysis. The results indicated that increased frequency of private prayer was significantly associated with lower NPS, better cognitive function, and lower sleep disturbances. In total, 100% of Non-Hispanic Black and Hispanic participants reported praying at least once per week. Findings could be due to use of cognitive processes used in prayer during supplication, requesting aid, and through communication with the divine, reducing loneliness. Longitudinal studies including historically underrepresented populations are needed to examine these associations over time.}, } @article {pmid36711209, year = {2022}, author = {Morrissey, ZD and Gao, J and Zhan, L and Li, W and Fortel, I and Saido, T and Saito, T and Bakker, A and Mackin, S and Ajilore, O and Lazarov, O and Leow, AD}, title = {Hippocampal functional connectivity across age in an App knock-in mouse model of Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1085989}, pmid = {36711209}, issn = {1663-4365}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disease. The early processes of AD, however, are not fully understood and likely begin years before symptoms manifest. Importantly, disruption of the default mode network, including the hippocampus, has been implicated in AD.

METHODS: To examine the role of functional network connectivity changes in the early stages of AD, we performed resting-state functional magnetic resonance imaging (rs-fMRI) using a mouse model harboring three familial AD mutations (App [NL-G-F/NL-G-F] knock-in, APPKI) in female mice in early, middle, and late age groups. The interhemispheric and intrahemispheric functional connectivity (FC) of the hippocampus was modeled across age.

RESULTS: We observed higher interhemispheric functional connectivity (FC) in the hippocampus across age. This was reduced, however, in APPKI mice in later age. Further, we observed loss of hemispheric asymmetry in FC in APPKI mice.

DISCUSSION: Together, this suggests that there are early changes in hippocampal FC prior to heavy onset of amyloid β plaques, and which may be clinically relevant as an early biomarker of AD.}, } @article {pmid36711203, year = {2022}, author = {Xing, Y and Li, P and Jia, Y and Zhang, K and Liu, M and Jiang, J}, title = {Association of inflammatory bowel disease and related medication exposure with risk of Alzheimer's disease: An updated meta-analysis.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1082575}, pmid = {36711203}, issn = {1663-4365}, abstract = {BACKGROUND: Chronic systemic inflammation may be associated with neurocognitive decline, but the relationships between inflammatory bowel disease and related medications and the risk of Alzheimer's disease remain unclear.

METHODS: We performed a meta-analysis to evaluate the associations of ulcerative colitis, Crohn's disease and related medications with risk of Alzheimer's disease. We identified cohort and case-control studies by searching PubMed, Embase and Web of Science up to August 2022.

RESULTS: Seven eligible studies with 20,174 cases of Alzheimer's disease were included in the meta-analysis. Six studies reported the association between ulcerative colitis and risk of Alzheimer's disease; five studies reported the association between Crohn's disease and risk of Alzheimer's disease. Meta-analysis combining these studies did not reveal any significant association of ulcerative colitis or Crohn's disease with risk of Alzheimer's disease. The pooled relative risks were 1.16 (95%CI: 0.96, 1.41) and 1.17 (95%CI: 0.84, 1.62) for ulcerative colitis and Crohn's disease, respectively. High heterogeneity was detected across the studies. Of note, there was an inverse association between inflammatory bowel disease related medication exposure and risk of Alzheimer's disease. The pooled relative risk of three studies for Alzheimer's disease was 0.86 (95%CI: 0.75, 0.99). No publication bias was detected.

CONCLUSION: This study does not support the association of ulcerative colitis and Crohn's disease with the risk of Alzheimer's disease. However, medications for the treatment of inflammatory bowel disease might be associated with a lower risk of Alzheimer's disease.}, } @article {pmid36711200, year = {2022}, author = {Rogojin, A and Gorbet, DJ and Hawkins, KM and Sergio, LE}, title = {Differences in structural MRI and diffusion tensor imaging underlie visuomotor performance declines in older adults with an increased risk for Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1054516}, pmid = {36711200}, issn = {1663-4365}, abstract = {INTRODUCTION: Visuomotor impairments have been demonstrated in preclinical AD in individuals with a positive family history of dementia and APOE e4 carriers. Previous behavioral findings have also reported sex-differences in performance of visuomotor tasks involving a visual feedback reversal. The current study investigated the relationship between grey and white matter changes and non-standard visuomotor performance, as well as the effects of APOE status, family history of dementia, and sex on these brain-behavior relationships.

METHODS: Older adults (n = 49) with no cognitive impairments completed non-standard visuomotor tasks involving a visual feedback reversal, plane-change, or combination of the two. Participants with a family history of dementia or who were APOE e4 carriers were considered at an increased risk for AD. T1-weighted anatomical scans were used to quantify grey matter volume and thickness, and diffusion tensor imaging measures were used to quantify white matter integrity.

RESULTS: In APOE e4 carriers, grey and white matter structural measures were associated with visuomotor performance. Regression analyses showed that visuomotor deficits were predicted by lower grey matter thickness and volume in areas of the medial temporal lobe previously implicated in visuomotor control (entorhinal and parahippocampal cortices). This finding was replicated in the diffusion data, where regression analyses revealed that lower white matter integrity (lower FA, higher MD, higher RD, higher AxD) was a significant predictor of worse visuomotor performance in the forceps minor, forceps major, cingulum, inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), and uncinate fasciculus (UF). Some of these tracts overlap with those important for visuomotor integration, namely the forceps minor, forceps major, SLF, IFOF, and ILF.

CONCLUSION: These findings suggest that measuring the dysfunction of brain networks underlying visuomotor control in early-stage AD may provide a novel behavioral target for dementia risk detection that is easily accessible, non-invasive, and cost-effective. The results also provide insight into the structural differences in inferior parietal lobule that may underlie previously reported sex-differences in performance of the visual feedback reversal task.}, } @article {pmid36711126, year = {2022}, author = {Ueno, D and Ohira, H and Narumoto, J}, title = {Editorial: Interoception and the autonomic nervous system: Investigating affect, decision-making, and mental health.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {1130324}, pmid = {36711126}, issn = {1662-4548}, } @article {pmid36710967, year = {2022}, author = {Xiao, QY and Ye, TY and Wang, XL and Qi, DM and Cheng, XR}, title = {Effects of Qi-Fu-Yin on aging of APP/PS1 transgenic mice by regulating the intestinal microbiome.}, journal = {Frontiers in cellular and infection microbiology}, volume = {12}, number = {}, pages = {1048513}, pmid = {36710967}, issn = {2235-2988}, mesh = {Mice ; Animals ; Mice, Transgenic ; *Gastrointestinal Microbiome ; Amyloid beta-Protein Precursor/genetics ; *Alzheimer Disease ; Aging/metabolism ; Carbohydrates ; Disease Models, Animal ; }, abstract = {INTRODUCTION: Alzheimer's disease is the most common form of dementia and closely related to aging. Qi-Fu-Yin is widely used to treat dementia, but its anti-aging effects is unknown.

METHODS: We used 11-month-old APP/PS1 transgenic mice for behavioral tests to observe the changes in cognitive function and age-related symptoms after Qi-Fu-Yin treatment. Fecal samples were collected for 16sRNA sequencing and metagenomic sequencing. Differences among the groups of intestinal microbiota and the associations with aging and intestinal microbiota were analyzed based on the results.

RESULTS: Here we found that Qi-Fu-Yin improved the ability of motor coordination, raised survival rate and prolonged the survival days under cold stress stimulation in aged APP/ PS1 transgenic mice. Our data from 16sRNA and metagenomic sequencing showed that at the Family level, the intestinal microbiota was significantly different among wild-type mice, APP/PS1 transgenic mice and the Qi-Fu-Yin group by PCA analysis. Importantly, Qi-Fu-Yin improved the functional diversity of the major KEGG pathways, carbohydrate-active enzymes, and major virulence factors in the intestinal flora of APP/PS1 transgenic mice. Among them, the functions of eight carbohydrate-active enzymes (GT2_Glycos_transf_2, GT4, GT41, GH2, CE1, CE10, CE3, and GH24) and the functions of top three virulence factors (defensive virulence factors, offensive virulence factors and nonspecific virulence factors) were significantly and positively correlated with the level of grasping ability. We further indicated that the Qi-Fu-Yin significantly reduced the plasma levels of IL-6.

CONCLUSION: Our results indicated that the effects of Qi-Fu-Yin anti-aging of APP/PS1 transgenic mice might be through the regulation of intestinal flora diversity, species richness and the function of major active enzymes.}, } @article {pmid36710956, year = {2022}, author = {Silva, A and Martínez, MC}, title = {Spatial memory deficits in Alzheimer's disease and their connection to cognitive maps' formation by place cells and grid cells.}, journal = {Frontiers in behavioral neuroscience}, volume = {16}, number = {}, pages = {1082158}, pmid = {36710956}, issn = {1662-5153}, abstract = {Whenever we navigate through different contexts, we build a cognitive map: an internal representation of the territory. Spatial navigation is a complex skill that involves multiple types of information processing and integration. Place cells and grid cells, collectively with other hippocampal and medial entorhinal cortex neurons (MEC), form a neural network whose activity is critical for the representation of self-position and orientation along with spatial memory retrieval. Furthermore, this activity generates new representations adapting to changes in the environment. Though there is a normal decline in spatial memory related to aging, this is dramatically increased in pathological conditions such as Alzheimer's disease (AD). AD is a multi-factorial neurodegenerative disorder affecting mainly the hippocampus-entorhinal cortex (HP-EC) circuit. Consequently, the initial stages of the disease have disorientation and wandering behavior as two of its hallmarks. Recent electrophysiological studies have linked spatial memory deficits to difficulties in spatial information encoding. Here we will discuss map impairment and remapping disruption in the HP-EC network, as a possible circuit mechanism involved in the spatial memory and navigation deficits observed in AD, pointing out the benefits of virtual reality as a tool for early diagnosis and rehabilitation.}, } @article {pmid36707184, year = {2023}, author = {Takahashi, N and Akaike, N and Nagamatsu, T and Uchino, H and Kudo, Y}, title = {Effects of TND1128 (a 5-deazaflavin derivative), with self-redox ability, as a mitochondria activator on the mouse brain slice and its comparison with β-NMN.}, journal = {Journal of pharmacological sciences}, volume = {151}, number = {2}, pages = {93-109}, doi = {10.1016/j.jphs.2022.11.005}, pmid = {36707184}, issn = {1347-8648}, mesh = {Mice ; Animals ; *Mitochondria/metabolism ; Brain/metabolism ; *Alzheimer Disease/metabolism ; Oxidation-Reduction ; }, abstract = {We have no definitive treatment for dementia characterized by prolonged neuronal death due to the enormous accumulation of foreign matter, such as β-amyloid. Since Alzheimer's type dementia develops slowly, we may be able to delay the onset and improve neuronal dysfunction by enhancing the energy metabolism of individual neurons. TND1128, a derivative of 5-deazaflavin, is a chemical known to have an efficient self-redox ability. We expected TND1128 as an activator for mitochondrial energy synthesis. We used brain slices prepared from mice 22 ± 2 h pretreated with TND1128 or β-NMN. We measured Ca[2+] concentrations in the cytoplasm ([Ca[2+]]cyt) and mitochondria ([Ca[2+]]mit) by using fluorescence Ca[2+] indicators, Fura-4F, and X-Rhod-1, respectively, and examined the protective effects of drugs on [Ca[2+]]cyt and [Ca[2+]]mit overloading by repeating 80K exposure. TND1128 (0.01, 0.1, and 1 mg/kg s.c.) mitigates the dynamics of both [Ca[2+]]cyt and [Ca[2+]]mit in a dose-dependent manner. β-NMN (10, 30, and 100 mg/kg s.c.) also showed significant dose-dependent mitigating effects on [Ca[2+]]cyt, but the effect on the [Ca[2+]]mit dynamics was insignificant. We confirmed the mitochondria-activating potential of TND1128 in the present study. We expect TND1128 as a drug that rescues deteriorating neurons with aging or disease.}, } @article {pmid36707176, year = {2023}, author = {Sun, R and Wu, T and Xing, S and Wei, S and Bielicki, JK and Pan, X and Zhou, M and Chen, J}, title = {Caffeic acid protects against atherosclerotic lesions and cognitive decline in ApoE[-/-] mice.}, journal = {Journal of pharmacological sciences}, volume = {151}, number = {2}, pages = {110-118}, doi = {10.1016/j.jphs.2022.12.006}, pmid = {36707176}, issn = {1347-8648}, mesh = {Female ; Animals ; Mice ; *Alzheimer Disease/prevention & control ; *Atherosclerosis/drug therapy/genetics/prevention & control ; Inflammation/drug therapy/prevention & control/pathology ; Apolipoproteins E/genetics ; *Cognitive Dysfunction/drug therapy/prevention & control ; Mice, Knockout ; *Plaque, Atherosclerotic ; }, abstract = {Caffeic acid has been indicated to benefit cholesterol balance, but the effect of pure caffeic acid on atherosclerosis in vivo has not been tested. Given that atherosclerosis and Alzheimer's disease share common features including distracted lipid balance and chronic inflammation, the concurrent effects of caffeic acid on atherosclerotic lesions and cognitive decline were explored here by using the ApoE[-/-] mice model. A two months' administration of 20 mg/kg caffeic acid or saline was given once two days intraperitoneally to 5-month-old female ApoE[-/-] mice. We found that the caffeic acid treatment reduced the atherosclerotic lesions in the whole aorta and aortic sinus of the resulting 7-month-old ApoE[-/-] mice by roughly 50%, compared with the saline control. Meanwhile, the cognitive decline of treated mice were significantly alleviated, as measured by Y-maze and Morris water maze tasks. A reduced accumulation of β-amyloid in the hippocampus was also observed. These effects were associated with elevated serum HDL-c concentration, upregulated ABCA1 and ABCG1 mRNA levels, as well as decrease local inflammation and reduced levels of serum pro-inflammatory cytokines including TNF-α, IL-6 and MCP-1. These obtained results suggested the preventive and therapeutic potential of caffeic acid against atherosclerosis and Alzheimer's disease during aging.}, } @article {pmid36705622, year = {2022}, author = {Perus, L and Mangin, JF and Deverdun, J and Gutierrez, LA and Gourieux, E and Fischer, C and Van Dokkum, LEH and Manesco, C and Busto, G and Guyonnet, S and Vellas, B and Gabelle, A and Le Bars, E and , }, title = {Impact of multidomain preventive strategies on functional brain connectivity in older adults with cognitive complaint: Subset from the Montpellier center of the ancillary MAPT-MRI study.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {971220}, pmid = {36705622}, issn = {1663-4365}, abstract = {INTRODUCTION: The impact of multi-domain preventive interventions on older adults, in particular on those with higher risk to develop Alzheimer's disease (AD), could be beneficial, as it may delay cognitive decline. However, the precise mechanism of such positive impact is not fully understood and may involve brain reserve and adaptability of brain functional connectivity (FC).

METHODS: To determine the effect of multidomain interventions (involving physical activity, cognitive training, nutritional counseling alone or in combination with omega-3 fatty acid supplementation and vs. a placebo) on the brain, longitudinal FC changes were assessed after 36 months of intervention on 100 older adults (above 70 year-old) with subjective cognitive complaints.

RESULTS: No global change in FC was detected after uni or multidomain preventive interventions. However, an effect of omega-3 fatty acid supplementation dependent on cognitive decline status was underlined for frontoparietal, salience, visual and sensorimotor networks FC. These findings were independent of the cortical thickness and vascular burden.

DISCUSSION: These results emphasize the importance of patient stratification, based on risk factors, for preventive interventions.}, } @article {pmid36705011, year = {2023}, author = {Loi, SM and Pijnenberg, Y and Velakoulis, D}, title = {Recent research advances in young-onset dementia.}, journal = {Current opinion in psychiatry}, volume = {36}, number = {2}, pages = {126-133}, doi = {10.1097/YCO.0000000000000843}, pmid = {36705011}, issn = {1473-6578}, mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Frontotemporal Dementia/diagnosis ; Age of Onset ; }, abstract = {PURPOSE OF REVIEW: Young-onset dementia (YOD) refers to a dementia for which symptom onset occurs below the age of 65. This review summarizes the recent literature in this area, focusing on updates in epidemiology, diagnosis and service provision.

RECENT FINDINGS: In the last year, internationally, the prevalence of YOD was reported as 119 per 100 000, but this may vary according to population types. Although the commonest causes of YOD are Alzheimer's disease (AD) and frontotemporal dementia (FTD), there is increasing recognition that YOD is diagnostically and phenotypically broader than AD and FTD. YOD may be due to many other diseases (e.g. Huntington's disease, vascular dementia) whereas accumulation of the same protein (e.g. amyloid protein) may lead to different phenotypes of Alzheimer's disease (such as posterior cortical atrophy and behavioural-variant/frontal-variant AD). This heterogeneity of phenotypic presentation is also seen in YOD due to known genetic mutations. Biomarkers such as plasma and cerebrospinal fluid proteins, neuroimaging and genetics have shown promise in the early identification of YOD as well as providing further understanding behind the overlap between psychiatric and neurodegenerative conditions occurring in younger people. The management of YOD needs to consider age-specific issues for younger people with dementia and their family networks together with better integration with other health services such as aged, disability and improved access to services and financial assistance.

SUMMARY: These findings emphasize the need for early identification and appropriate age-specific and person-centred management for people with young-onset dementia.}, } @article {pmid36704658, year = {2023}, author = {Bathini, P and Dupanloup, I and Zenaro, E and Terrabuio, E and Fischer, A and Ballabani, E and Doucey, MA and Alberi, L}, title = {Systemic Inflammation Causes Microglial Dysfunction With a Vascular AD phenotype.}, journal = {Brain, behavior, & immunity - health}, volume = {28}, number = {}, pages = {100568}, pmid = {36704658}, issn = {2666-3546}, abstract = {BACKGROUND: Studies in rodents and humans have indicated that inflammation outside CNS (systemic inflammation) affects brain homeostasis contributing to neurodevelopmental disorders. Itis becoming increasingly evident that such early insults may also belinked to neurodegenerative diseases like late-onset Alzheimer's disease (AD). Importantly, lifestyle and stress, such as viral or bacterial infection causing chronic inflammation, may contribute to neurodegenerative dementia. Systemic inflammatory response triggers a cascade of neuroinflammatory responses, altering brain transcriptome, cell death characteristic of AD, and vascular dementia. Our study aimed to assess the temporal evolution of the pathological impact of systemic inflammation evoked by prenatal and early postnatal peripheral exposure of viral mimetic Polyinosinic:polycytidylic acid (PolyI:C) and compare the hippocampal transcriptomic changes with the profiles of human post-mortem AD and vascular dementia brain specimens.

METHODS: We have engineered the PolyI:C sterile infection model in wildtype C57BL6 mice to achieve chronic low-grade systemic inflammation. We have conducted a cross-sectional analysis of aging PolyI:C and Saline control mice (3 months, 6 months, 9 months, and 16 months), taking the hippocampus as a reference brain region, and compared the brain aging phenotype to AD progression in humans with mild AD, severe AD, and Controls (CTL), in parallel to Vascular dementia (VaD) patients' specimens.

RESULTS: We found that PolyI:C mice display both peripheral and central inflammation with a peak at 6 months, associated with memory deficits. The hippocampus is characterized by a pronounced and progressive tauopathy. In PolyI:C brains, microglia undergo aging-dependent morphological shifts progressively adopting a phagocytic phenotype. Transcriptomic analysis reveals a profound change in gene expression throughout aging, with a peak in differential expression at 9 months. We show that the proinflammatory marker Lcn2 is one of the genes with the strongest upregulation in PolyI:C mice upon aging. Validation in brains from patients with increasing severity of AD and VaD shows the reproducibility of some gene targets in vascular dementia specimens as compared to AD ones.

CONCLUSIONS: The PolyI:C model of sterile infection demonstrates that peripheral chronic inflammation causes progressive tau hyperphosphorylation, changes in microglia morphology, astrogliosis and gene reprogramming reflecting increased neuroinflammation, vascular remodeling, and the loss of neuronal functionality seen to some extent in human AD and Vascular dementia suggesting early immune insults could be crucial in neurodegenerative diseases.}, } @article {pmid36704637, year = {2023}, author = {Pawar, A and Pardasani, KR}, title = {Effect of disturbances in neuronal calcium and IP3 dynamics on β-amyloid production and degradation.}, journal = {Cognitive neurodynamics}, volume = {17}, number = {1}, pages = {239-256}, pmid = {36704637}, issn = {1871-4080}, abstract = {Overproduction and accumulation of β-amyloid and its improper clearance can cause neurotoxicity leading to Alzheimer's disease. The production and degradation of β-amyloid depend on the calcium ([Ca[2+]]) and IP3 dynamics in the nerve cells. Thus, there is a need to understand the impacts of disturbances in the processes of [Ca[2+]] and IP3 dynamics on β-amyloid production and its degradation. Here, a model is proposed to investigate the role of [Ca[2+]] and IP3 dynamics on β-amyloid production and degradation. The problem is formulated in terms of the initial boundary value problem involving the system of two reaction-diffusion equations respectively for [Ca[2+]] and IP3 in the nerve cell. The solution is obtained by employing the Finite element approach. The numerical results are used to analyze the impact of various mechanisms of calcium and IP3 dynamics on β-amyloid production and degradation in a neuron cell. The results indicate that disturbances in any of the constitutive processes of interdependent calcium and IP3 dynamics like source influx, buffering, serca pump, and IP3 dynamics, etc. can cause dynamic changes in β-amyloid production and degradation, which in turn can be the cause of neurotoxicity and neuronal disorders like Alzheimer's disease. Thus, the relationships obtained by the proposed model among various mechanisms can be useful in addressing the challenges of identifying specific constitutive processes causing neuronal disorders like Alzheimer's disease, etc., and developing the framework for their diagnosis and treatment.}, } @article {pmid36704634, year = {2023}, author = {Budak, M and Bayraktaroglu, Z and Hanoglu, L}, title = {The effects of repetitive transcranial magnetic stimulation and aerobic exercise on cognition, balance and functional brain networks in patients with Alzheimer's disease.}, journal = {Cognitive neurodynamics}, volume = {17}, number = {1}, pages = {39-61}, pmid = {36704634}, issn = {1871-4080}, abstract = {The purpose of this study was to investigate the effects of high-frequency repetitive Transcranial Magnetic Stimulation (rTMS) and aerobic exercises (AE) in addition to the pharmacological therapy (PT) in Alzheimer's Disease (AD). Twenty-seven patients with AD aged ≥ 60 years were included in the study and divided into 3 groups (rTMS, AE and control). All groups received PT. rTMS group (n = 10) received 20 Hz rTMS over dorsolateral prefrontal cortex (dlPFC) bilaterally and AE group (n = 9) received the structured moderate-intensity AE for 5 consecutive days/week over 2 weeks. Control group (n = 8) only received PT. Cognition, balance, mobility, quality of life (QoL), and resting state functional brain activity were evaluated one week before and one week after the interventions. (ClinicalTrials.gov ID:NCT05102045). Significant improvements were found in executive functions, behavior, and QoL in the rTMS group, in balance and mobility in the AE group, and in the visual memory and behavior in the control group (p < 0.05). Significant differences were found in the behavior in favor of the rTMS group, and balance in favor of the AE group (p < 0.05). There was a significant increase in activation on middle temporal gyrus, intra calcarine, central opercular cortex, superior parietal lobule, and paracingulate cortex in Default Mode Network (DMN) in the rTMS group (p < 0.05). High-frequency rTMS over bilateral dlPFC may improve executive functions and behavior and lead to increased activation in DMN, structured moderate-intensity AE may improve balance and mobility, and PT may improve memory and behaviour compared to pretreatment in AD.}, } @article {pmid36704504, year = {2022}, author = {Wang, Z and Wang, Q and Li, S and Li, XJ and Yang, W and He, D}, title = {Microglial autophagy in Alzheimer's disease and Parkinson's disease.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1065183}, pmid = {36704504}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases, characterized by gradual and selective loss of neurons in the central nervous system. They affect more than 50 million people worldwide, and their incidence increases with age. Although most cases of AD and PD are sporadic, some are caused by genetic mutations that are inherited. Both sporadic and familial cases display complex neuropathology and represent the most perplexing neurological disorders. Because of the undefined pathogenesis and complex clinical manifestations, there is still no effective treatment for both AD and PD. Understanding the pathogenesis of these important neurodegenerative diseases is important for developing successful therapies. Increasing evidence suggests that microglial autophagy is associated with the pathogenesis of AD and PD, and its dysfunction has been implicated in disease progression. In this review, we focus on the autophagy function in microglia and its dysfunction in AD and PD disease models in an attempt to help our understanding of the pathogenesis and identifying new therapeutic targets of AD and PD.}, } @article {pmid36704501, year = {2022}, author = {Guo, L and Yang, X and Zhang, Y and Xu, X and Li, Y}, title = {Effect of exercise on cognitive function and synaptic plasticity in Alzheimer's disease models: A systematic review and meta-analysis.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1077732}, pmid = {36704501}, issn = {1663-4365}, abstract = {INTRODUCTION: Cognitive decline is a central manifestation of Alzheimer's disease (AD), and its process is inseparable from changes in synaptic plasticity. The aim of this review was to summarize and evaluate the effectiveness of exercise on cognitive function and synaptic plasticity in AD animal models.

MATERIALS AND METHODS: Eligible studies were searched from PubMed, MEDLINE, EMBASE, Web of Science, and Cochrane Library from April to May 2022. The risk of bias was evaluated by Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE). The Morris water maze (MWM) test and synaptic plasticity were considered outcome measures. Data were analyzed using random-effects meta-analyses using the software Stata. Heterogeneity was examined by using I2 test. Sensitivity analysis and publication bias were also assessed.

RESULTS: A total of 20 randomized controlled studies were eligible for study inclusion. Compared with controls, exercise decreased escape latency (SMD = -0.86, 95% CI: -1.21 to -0.50, P < 0.001), increased platform crossover numbers (SMD = 1.34, 95% CI: 0.57-2.11, P = 0.001) and time in the target quadrant (SMD = 1.65, 95% CI: 0.95-2.36, P < 0.001) and the expression of PSD95 (SMD = 0.73, 95% CI: 0.25-1.21, P = 0.003) in AD animals. The results of the subgroup analysis showed that exercise before AD had a greater effect on escape latency (SMD = -0.88, 95% CI: -1.25 to -0.52, P < 0.001), platform crossover numbers (SMD = 1.71, 95% CI: 1.23-2.18, P < 0.001), time in the target quadrant (SMD = 2.03, 95% CI: 1.19-2.87, P < 0.001) and the expression of PSD95 (SMD = 0.94, 95% CI: 0.19-1.69, P = 0.014) than exercise after AD. The results of the subgroup analysis also showed that treadmill running might be an appropriate exercise type.

CONCLUSION: Our findings suggested that exercise had a potential effect on improving cognitive function and synaptic plasticity. It can play a better neuroprotective role before AD.

PROSPERO, identifier: CRD42022328438.}, } @article {pmid36704351, year = {2022}, author = {Ma, X and Feng, Y and Quan, X and Geng, B and Li, G and Fu, X and Zeng, L}, title = {Multi-omics analysis revealed the role of CCT2 in the induction of autophagy in Alzheimer's disease.}, journal = {Frontiers in genetics}, volume = {13}, number = {}, pages = {967730}, pmid = {36704351}, issn = {1664-8021}, abstract = {Chaperonin containing TCP1 subunit 2 (CCT2) is essential in various neurodegenerative diseases, albeit its role in the pathogenesis of Alzheimer's disease (AD) remains elusive. This study aimed to evaluate the role of CCT2 in Alzheimer's disease. First, bioinformatics database analysis revealed that CCT2 was significantly downregulated in patients with Alzheimer's disease and associated with autophagic clearance of β-amyloid. The 789 differentially expressed genes overlapped in AD-group and CCT2-low/high group, and the CCT2-high-associated genes screened by Pearson coefficients were enriched in protein folding, autophagy, and messenger RNA stability regulation pathways. These results suggest that CCT2 is significantly and positively associated with multiple pathways linked to autophagy and negatively associated with neuronal death. The logistic prediction model with 13 key genes, such as CCT2, screened in this study better predicts Alzheimer's disease occurrence (AUC = 0.9671) and is a favorable candidate for predicting potential biological targets of Alzheimer's disease. Additionally, this study predicts reciprocal micro RNAs and small molecule drugs for hub genes. Our findings suggest that low CCT2 expression may be responsible for the autophagy suppression in Alzheimer's disease, providing an accurate explanation for its pathogenesis and new targets and small molecule inhibitors for its treatment.}, } @article {pmid36704327, year = {2022}, author = {Alves Conceição, C and Assis de Lemos, G and Barros, CA and Vieira, TCRG}, title = {What is the role of lipids in prion conversion and disease?.}, journal = {Frontiers in molecular neuroscience}, volume = {15}, number = {}, pages = {1032541}, pmid = {36704327}, issn = {1662-5099}, abstract = {The molecular cause of transmissible spongiform encephalopathies (TSEs) involves the conversion of the cellular prion protein (PrP[C]) into its pathogenic form, called prion scrapie (PrP[Sc]), which is prone to the formation of amorphous and amyloid aggregates found in TSE patients. Although the mechanisms of conversion of PrP[C] into PrP[Sc] are not entirely understood, two key points are currently accepted: (i) PrP[Sc] acts as a seed for the recruitment of native PrP[C], inducing the latter's conversion to PrP[Sc]; and (ii) other biomolecules, such as DNA, RNA, or lipids, can act as cofactors, mediating the conversion from PrP[C] to PrP[Sc]. Interestingly, PrP[C] is anchored by a glycosylphosphatidylinositol molecule in the outer cell membrane. Therefore, interactions with lipid membranes or alterations in the membranes themselves have been widely investigated as possible factors for conversion. Alone or in combination with RNA molecules, lipids can induce the formation of PrP in vitro-produced aggregates capable of infecting animal models. Here, we discuss the role of lipids in prion conversion and infectivity, highlighting the structural and cytotoxic aspects of lipid-prion interactions. Strikingly, disorders like Alzheimer's and Parkinson's disease also seem to be caused by changes in protein structure and share pathogenic mechanisms with TSEs. Thus, we posit that comprehending the process of PrP conversion is relevant to understanding critical events involved in a variety of neurodegenerative disorders and will contribute to developing future therapeutic strategies for these devastating conditions.}, } @article {pmid36704265, year = {2022}, author = {Wang, WT and Chang, WL and Cheng, HM}, title = {The Relationship of Vascular Aging to Reduced Cognitive Function: Pulsatile and Steady State Arterial Hemodynamics.}, journal = {Pulse (Basel, Switzerland)}, volume = {10}, number = {1-4}, pages = {19-25}, pmid = {36704265}, issn = {2235-8676}, abstract = {Aortic stiffness increases with age and is a robust predictor of cerebrovascular events and cognitive decline including Alzheimer's disease and other forms of dementia. Recent clinical studies have investigated the association between proximal aortic stiffness and pulsatile energy transmission that has deleterious effects on the cerebrovascular network in order to identify potential therapeutic targets. Aging causes disproportionate stiffening of the aorta compared with the carotid arteries, reducing protective impedance mismatches at their interface, increasing the transmission of destructive pulsatile pressure and energy to the cerebral circulation, and leading to cerebral small vessel disease. Thus, aortic stiffening and high-flow pulsatility are associated with alterations in the microvasculature of the brain, vascular endothelial dysfunction, and white matter damage, which contribute to impaired memory function with advancing age. Previous studies have also shown that silent lacunar infarcts and white matter hyperintensities are strongly associated with arterial stiffness. More and more evidence suggests that vascular etiologies, including aortic stiffness, impedance match, and microvascular damage, are associated with cognitive impairment and the pathogenesis of dementia. The measurement of arterial flow and pressure can help understand pulsatile hemodynamics and its impact on vital organs. Interventions that reduce aortic stiffness, such as improvement of the living environment, management of risk factors, and innovation and development of novel drugs, may reduce the risk for dementia.}, } @article {pmid36704097, year = {2022}, author = {Ayanampudi, V and Kumar, V and Krishnan, A and Walker, MP and Ivry, RB and Knight, RT and Gurumoorthy, R}, title = {Personalized transcranial alternating current stimulation improves sleep quality: Initial findings.}, journal = {Frontiers in human neuroscience}, volume = {16}, number = {}, pages = {1066453}, pmid = {36704097}, issn = {1662-5161}, abstract = {Insufficient sleep is a major health issue. Inadequate sleep is associated with an array of poor health outcomes, including cardiovascular disease, diabetes, obesity, certain forms of cancer, Alzheimer's disease, depression, anxiety, and suicidality. Given concerns with typical sedative hypnotic drugs for treating sleep difficulties, there is a compelling need for alternative interventions. Here, we report results of a non-invasive electrical brain stimulation approach to optimizing sleep involving transcranial alternating current stimulation (tACS). A total of 25 participants (mean age: 46.3, S.D. ± 12.4, 15 females) were recruited for a null-stimulation controlled (Control condition), within subjects, randomized crossed design, that included two variants of an active condition involving 15 min pre-sleep tACS stimulation. To evaluate the impact on sleep quality, the two active tACS stimulation conditions were designed to modulate sleep-dependent neural activity in the theta/alpha frequency bands, with both stimulation types applied to all subjects in separate sessions. The first tACS condition used a fixed stimulation pattern across all participants, a pattern composed of stimulation at 5 and 10 Hz. The second tACS condition used a personalized stimulation approach with the stimulation frequencies determined by each individual's peak EEG frequencies in the 4-6 Hz and 9-11 Hz bands. Personalized tACS stimulation increased sleep quantity (duration) by 22 min compared to a Control condition (p = 0.04), and 19 min compared to Fixed tACS stimulation (p = 0.03). Fixed stimulation did not significantly increase sleep duration compared to Control (mean: 3 min; p = 0.75). For sleep onset, the Personalized tACS stimulation resulted in reducing the onset by 28% compared to the Fixed tACS stimulation (6 min faster, p = 0.02). For a Poor Sleep sub-group (n = 13) categorized with Clinical Insomnia and a high insomnia severity, Personalized tACS stimulation improved sleep duration by 33 min compared to Fixed stimulation (p = 0.02), and 30 min compared to Control condition (p < 0.1). Together, these results suggest that Personalized stimulation improves sleep quantity and time taken to fall asleep relative to Control and Fixed stimulation providing motivation for larger-scale trials for Personalized tACS as a sleep therapeutic, including for those with insomnia.}, } @article {pmid36704008, year = {2022}, author = {Kamal, MA and Alexiou, A and Perveen, A}, title = {Editorial: The Alzheimer's disease challenge, volume II.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {1127189}, doi = {10.3389/fnins.2022.1127189}, pmid = {36704008}, issn = {1662-4548}, } @article {pmid36704003, year = {2022}, author = {Anwar, MM and Özkan, E and Shomalizadeh, N and Sapancı, S and Özler, C and Kesibi, J and Gürsoy-Özdemir, Y}, title = {Assessing the role of primary healthy microglia and gap junction blocker in hindering Alzheimer's disease neuroinflammatory type: Early approaches for therapeutic intervention.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {1041461}, pmid = {36704003}, issn = {1662-4548}, abstract = {Alzheimer's disease (AD) is a predominantly heterogeneous disease with a highly complex pathobiology. The presence of amyloid-beta (Aβ) depositions and the accumulation of hyperphosphorylated tau protein remain the characteristic hallmarks of AD. These hallmarks can be detected throughout the brain and other regions, including cerebrospinal fluid (CSF) and the spinal cord. Microglia cells, the brain-resident macrophage type of the brain, are implicated in maintaining healthy brain homeostasis. The localized administration of primary healthy microglia (PHM) is suggested to play a role in mitigating AD hallmark depositions and associated cognitive dysfunction. Carbenoxolone (CBX) is the most common gap junction blocker. It cannot effectively cross the blood-brain barrier (BBB) under systemic administration. Therefore, localized administration of CBX may be a recommended intervention against AD by acting as an antioxidant and anti-inflammatory agent. This study aims to determine whether the localized intracerebroventricular (ICV) administration of PHM and CBX may act as an effective therapeutic intervention for AD neuroinflammatory type. In addition, this study also aims to reveal whether detecting AD hallmarks in the spinal cord and CSF can be considered functional and effective during AD early diagnosis. Male albino rats were divided into four groups: control (group 1), lipopolysaccharide (LPS)-induced AD neuroinflammatory type (group 2), ICV injection of LPS + isolated PHM (group 3), and ICV injection of LPS + CBX (group 4). Morris water maze (MWM) was conducted to evaluate spatial working memory. The brain and spinal cord were isolated from each rat with the collection of CSF. Our findings demonstrate that the localized administration of PHM and CBX can act as promising therapeutic approaches against AD. Additionally, Aβ and tau toxic aggregates were detected in the spinal cord and the CSF of the induced AD model concomitant with the brain tissues. Overall, it is suggested that the ICV administration of PHM and CBX can restore normal brain functions and alleviate AD hallmark depositions. Detecting these depositions in the spinal cord and CSF may be considered in AD early diagnosis. As such, conducting clinical research is recommended to reveal the benefits of related therapeutic approaches compared with preclinical findings.}, } @article {pmid36703981, year = {2022}, author = {Daini, E and Vandini, E and Bodria, M and Liao, W and Baraldi, C and Secco, V and Ottani, A and Zoli, M and Giuliani, D and Vilella, A}, title = {Melanocortin receptor agonist NDP-α-MSH improves cognitive deficits and microgliosis but not amyloidosis in advanced stages of AD progression in 5XFAD and 3xTg mice.}, journal = {Frontiers in immunology}, volume = {13}, number = {}, pages = {1082036}, pmid = {36703981}, issn = {1664-3224}, mesh = {Animals ; Mice ; *Alzheimer Disease/drug therapy/metabolism ; Cognition ; *Cognitive Dysfunction/drug therapy/etiology ; Mice, Transgenic ; *Receptor, Melanocortin, Type 4/agonists ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is the most frequent cause of dementia and still lacks effective therapy. Clinical signs of AD include low levels of endogenous melanocortins (MCs) and previous studies have shown that treatment with MC analogs induces neuroprotection in the early stages of AD.

METHODS: We investigated the neuroprotective role of MCs in two transgenic mouse models of severe AD using 5 and 7 month-old (mo) 5XFAD mice and 9 and 12 mo 3xTg mice. These mice were subjected to a chronic stimulation of MC receptors (MCRs) with MC analogue Nle4-D-Phe7-α-melanocyte stimulating hormone (NDP-α-MSH, 340 μg/kg, i.p.). Mouse behavior and ex-vivo histological and biochemical analyses were performed after 50 days of treatment.

RESULTS: Our analysis demonstrated an improvement in cognitive abilities of AD mice at late stage of AD progression. We also showed that these protective effects are associated with decreased levels of hyperphosphorylated Tau but not with Aβ burden, that was unaffected in the hippocampus and in the cortex of AD mice. In addition, an age-dependent NDP effect on glial reactivity was observed only in 3xTg mice whereas a global downregulation of p38 mitogen-activated protein kinase was selectively observed in 7 mo 5XFAD and 14 mo 3xTg mice.

CONCLUSION: Our results suggest that MCR stimulation by NDP-α-MSH could represent a promising therapeutic strategy in managing cognitive decline also at late stage of AD, whereas the effects on neuroinflammation may be restricted to specific stages of AD progression.}, } @article {pmid36703722, year = {2022}, author = {Murdy, TJ and Dunn, AR and Singh, S and Telpoukhovskaia, MA and Zhang, S and White, JK and Kahn, I and Febo, M and Kaczorowski, CC}, title = {Leveraging genetic diversity in mice to inform individual differences in brain microstructure and memory.}, journal = {Frontiers in behavioral neuroscience}, volume = {16}, number = {}, pages = {1033975}, pmid = {36703722}, issn = {1662-5153}, abstract = {In human Alzheimer's disease (AD) patients and AD mouse models, both differential pre-disease brain features and differential disease-associated memory decline are observed, suggesting that certain neurological features may protect against AD-related cognitive decline. The combination of these features is known as brain reserve, and understanding the genetic underpinnings of brain reserve may advance AD treatment in genetically diverse human populations. One potential source of brain reserve is brain microstructure, which is genetically influenced and can be measured with diffusion MRI (dMRI). To investigate variation of dMRI metrics in pre-disease-onset, genetically diverse AD mouse models, we utilized a population of genetically distinct AD mice produced by crossing the 5XFAD transgenic mouse model of AD to 3 inbred strains (C57BL/6J, DBA/2J, FVB/NJ) and two wild-derived strains (CAST/EiJ, WSB/EiJ). At 3 months of age, these mice underwent diffusion magnetic resonance imaging (dMRI) to probe neural microanatomy in 83 regions of interest (ROIs). At 5 months of age, these mice underwent contextual fear conditioning (CFC). Strain had a significant effect on dMRI measures in most ROIs tested, while far fewer effects of sex, sex*strain interactions, or strain*sex*5XFAD genotype interactions were observed. A main effect of 5XFAD genotype was observed in only 1 ROI, suggesting that the 5XFAD transgene does not strongly disrupt neural development or microstructure of mice in early adulthood. Strain also explained the most variance in mouse baseline motor activity and long-term fear memory. Additionally, significant effects of sex and strain*sex interaction were observed on baseline motor activity, and significant strain*sex and sex*5XFAD genotype interactions were observed on long-term memory. We are the first to study the genetic influences of brain microanatomy in genetically diverse AD mice. Thus, we demonstrated that strain is the primary factor influencing brain microstructure in young adult AD mice and that neural development and early adult microstructure are not strongly altered by the 5XFAD transgene. We also demonstrated that strain, sex, and 5XFAD genotype interact to influence memory in genetically diverse adult mice. Our results support the usefulness of the 5XFAD mouse model and convey strong relationships between natural genetic variation, brain microstructure, and memory.}, } @article {pmid36700443, year = {2022}, author = {Joubert, S and Tannou, T and Maquestiaux, F}, title = {[Errorless learning in cognitive rehabilitation of Alzheimer’s disease and primary progressive aphasia].}, journal = {Geriatrie et psychologie neuropsychiatrie du vieillissement}, volume = {20}, number = {4}, pages = {506-514}, doi = {10.1684/pnv.2022.1071}, pmid = {36700443}, issn = {2115-7863}, mesh = {Humans ; *Alzheimer Disease/psychology ; Cognitive Training ; Activities of Daily Living ; Quality of Life ; *Aphasia, Primary Progressive ; }, abstract = {Alzheimer’s disease (AD) and primary progressive aphasia (PPA) are age-related neurodegenerative diseases characterized by a slowly progressive cognitive decline that significantly impacts functional autonomy. Cognitive interventions remain one of the most useful management perspectives to help patients compensate for their cognitive and functional deficits in everyday life. Errorless learning represents a set of principles and methods aimed at eliminating or minimizing errors in a learning context, which was initially applied to patients with an amnesic syndrome. In this article, we examine the effectiveness of this learning principle in the context of AD and PPA. Based on current data from the literature, errorless learning appears to be useful in (re)learning new information or procedural skills in AD and APP, such as relearning names or certain independent activities of daily living. In addition, the benefits of errorless learning are maintained at follow-up. There are, however, discrepancies in the results between studies which could reflect differences in the learning methods employed and in the parameters of the interventions. In conclusion, such interventions should primarily target learning that is useful for patients and that allows them to preserve their autonomy longer and improve their quality of life.}, } @article {pmid36699540, year = {2022}, author = {Ge, S and Pan, W and Wu, B and Plassman, BL and Dong, X and McConnell, ES}, title = {Sensory impairment and cognitive decline among older adults: An analysis of mediation and moderation effects of loneliness.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {1092297}, pmid = {36699540}, issn = {1662-4548}, abstract = {BACKGROUND: Multiple studies have reported that hearing and vision impairment are linked to cognitive decline. Yet little is known about factors that may influence the association between sensory impairment and cognitive decline. This study examined if loneliness mediates or moderates the impact of sensory impairment on cognitive decline as individuals age.

METHODS: This was a longitudinal study using data from the Health and Retirement Study (HRS) and The Aging, Demographics, and Memory Study (ADAMS) (N = 243). We used one timepoint of hearing and vision (ADAMS 2006-2008), one timepoint of loneliness (HRS 2006-2008), and five waves of cognition (HRS 2006-2014). Hearing impairment was defined by an inability to hear pure-tone stimuli of 25 dB at frequencies between 0.5 and 4.0 kHz in either ear. Visual impairment was defined as having corrected binocular vision worse than 20/40. Longitudinal parallel-process (LPP) analysis was conducted at a significance level of α = 0.05 (one-tailed).

RESULTS: Loneliness moderated but did not mediate the association between visual impairment and the rate of cognitive decline (standardized β =-0.108, p < 0.05). No moderation or mediation effect of loneliness was found for the association between hearing impairment and cognitive decline. Both vision and hearing impairment were significantly associated with increased severity of loneliness.

CONCLUSION: Visual impairment combined with an elevated level of loneliness may produce a more synergistic, deleterious impact on older adults' cognitive function than visual impairment alone. This study highlights the importance of promoting a healthy social and psychological status for older adults with sensory impairment.}, } @article {pmid36699527, year = {2022}, author = {Khan, R and Akbar, S and Mehmood, A and Shahid, F and Munir, K and Ilyas, N and Asif, M and Zheng, Z}, title = {A transfer learning approach for multiclass classification of Alzheimer's disease using MRI images.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {1050777}, pmid = {36699527}, issn = {1662-4548}, abstract = {Alzheimer's is an acute degenerative disease affecting the elderly population all over the world. The detection of disease at an early stage in the absence of a large-scale annotated dataset is crucial to the clinical treatment for the prevention and early detection of Alzheimer's disease (AD). In this study, we propose a transfer learning base approach to classify various stages of AD. The proposed model can distinguish between normal control (NC), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI), and AD. In this regard, we apply tissue segmentation to extract the gray matter from the MRI scans obtained from the Alzheimer's Disease National Initiative (ADNI) database. We utilize this gray matter to tune the pre-trained VGG architecture while freezing the features of the ImageNet database. It is achieved through the addition of a layer with step-wise freezing of the existing blocks in the network. It not only assists transfer learning but also contributes to learning new features efficiently. Extensive experiments are conducted and results demonstrate the superiority of the proposed approach.}, } @article {pmid36699514, year = {2022}, author = {Sacchetti, P and Jain, S and Yadav, H and Paoli, A}, title = {Editorial: Impact of ketogenic diet on metabolic and brain health.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {1107741}, pmid = {36699514}, issn = {1662-4548}, } @article {pmid36699496, year = {2022}, author = {Bosworth, A and Loh, V and Stranahan, BN and Palmer, CM}, title = {Case report: Ketogenic diet acutely improves cognitive function in patient with Down syndrome and Alzheimer's disease.}, journal = {Frontiers in psychiatry}, volume = {13}, number = {}, pages = {1085512}, pmid = {36699496}, issn = {1664-0640}, abstract = {Ketogenic diets have a century-long history as a therapeutic tool to treat intractable epilepsy. Recently, a renewed interest in neuroketotherapeutics has arisen, with ketogenic diets being explored for the treatment of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, as well as mental health conditions. Herein, we present a case report of a 47-year-old woman with Down syndrome diagnosed with Alzheimer's disease and absence seizures with accelerated cognitive decline over 6 years. A ketogenic diet restored her cognitive function over 6 weeks, with an increase in Activities of Daily Living Scale score from 34 to 58. A therapeutic ketogenic diet was associated with significant cognitive improvement in this patient with concurrent Down syndrome and dementia.}, } @article {pmid36699460, year = {2022}, author = {Schultheis, N and Becker, R and Berhanu, G and Kapral, A and Roseman, M and Shah, S and Connell, A and Selleck, S}, title = {Regulation of autophagy, lipid metabolism, and neurodegenerative pathology by heparan sulfate proteoglycans.}, journal = {Frontiers in genetics}, volume = {13}, number = {}, pages = {1012706}, pmid = {36699460}, issn = {1664-8021}, abstract = {Heparan sulfate modified proteins or proteoglycans (HSPGs) are an abundant class of cell surface and extracellular matrix molecules. They serve important co-receptor functions in the regulation of signaling as well as membrane trafficking. Many of these activities directly affect processes associated with neurodegeneration including uptake and export of Tau protein, disposition of Amyloid Precursor Protein-derived peptides, and regulation of autophagy. In this review we focus on the impact of HSPGs on autophagy, membrane trafficking, mitochondrial quality control and biogenesis, and lipid metabolism. Disruption of these processes are a hallmark of Alzheimer's disease (AD) and there is evidence that altering heparan sulfate structure and function could counter AD-associated pathological processes. Compromising presenilin function in several systems has provided instructive models for understanding the molecular and cellular underpinnings of AD. Disrupting presenilin function produces a constellation of cellular deficits including accumulation of lipid, disruption of autophagosome to lysosome traffic and reduction in mitochondrial size and number. Inhibition of heparan sulfate biosynthesis has opposing effects on all these cellular phenotypes, increasing mitochondrial size, stimulating autophagy flux to lysosomes, and reducing the level of intracellular lipid. These findings suggest a potential mechanism for countering pathology found in AD and related disorders by altering heparan sulfate structure and influencing cellular processes disrupted broadly in neurodegenerative disease. Vertebrate and invertebrate model systems, where the cellular machinery of autophagy and lipid metabolism are conserved, continue to provide important translational guideposts for designing interventions that address the root cause of neurodegenerative pathology.}, } @article {pmid36699095, year = {2022}, author = {Yang, Z and Liu, J and Wei, S and Deng, J and Feng, X and Liu, S and Liu, M}, title = {A novel strategy for bioactive natural products targeting NLRP3 inflammasome in Alzheimer's disease.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1077222}, pmid = {36699095}, issn = {1663-9812}, abstract = {Alzheimer's disease (AD), the most common type of dementia, is an ageing-related progressive neurodegenerative brain disorder. Extracellular neuritic plaques composed of misfolded amyloid β (Aβ) proteins and intracellular neurofibrillary tangles formed by hyperphosphorylated tau protein are the two classical characteristics of AD. Aβ and tau pathologies induce neurite atrophy and neuronal apoptosis, leading to cognitive, language, and behavioral deficits. For decades, researchers have made great efforts to explore the pathogens and therapeutics of AD; however, its intrinsic mechanism remains unclear and there are still no well-established strategies to restore or even prevent this disease. Therefore, it would be beneficial for the establishment of novel therapeutic strategy to determine the intrinsic molecular mechanism that is interrelated with the initiation and progression of AD. A variety of evidence indicates that neuroinflammation plays a crucial role in the pathogenesis of AD. Nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) is a key inflammasome sensor of cellular stress and infection that is involved in the innate immune system. In response to a wide range of stimuli like Aβ, NLRP3 assembles apoptosis-associated speck-like protein (ASC) and procaspase-1 into an inflammasome complex to induce the caspase-1 mediated secretion of interleukin (IL)-1β/IL-18 in M1 polarized microglia, triggering the pathophysiological changes and cognitive decline of AD. Therefore, targeting NLRP3 inflammasome seems an efficient path for AD treatment via regulating brain immune microenvironment. Furthermore, accumulating evidence indicates that traditional Chinese medicine (TCM) exerts beneficial effects on AD via NLRP3 inflammasome inactivation. In this review, we summarize current reports on the role and activated mechanisms of the NLRP3 inflammasome in the pathogenesis of AD. We also review the natural products for attenuating neuroinflammation by targeting NLRP3 inflammasome activation, which provides useful clues for developing novel AD treatments.}, } @article {pmid36699002, year = {2023}, author = {Muñoz, E and Jodar, M and Guerrero, J and Compta, Y and Perissinotti, A and Álvarez-Mora, MI and Falgàs, N and Rodríguez-Revenga, L and Sánchez-Valle, R}, title = {Spastic Paraplegia and Cognitive Impairment Due to a De Novo Pathogenic Variant in Presenilin-1.}, journal = {Movement disorders clinical practice}, volume = {10}, number = {1}, pages = {148-150}, pmid = {36699002}, issn = {2330-1619}, } @article {pmid36698965, year = {2023}, author = {Semyachkina-Glushkovskaya, OV and Karavaev, AS and Prokhorov, MD and Runnova, AE and Borovkova, EI and Yu M, I and Hramkov, AN and Kulminskiy, DD and Semenova, NI and Sergeev, KS and Slepnev, AV and Yu, SE and Zhuravlev, MO and Fedosov, IV and Shirokov, AA and Blokhina, IA and Dubrovski, AI and Terskov, AV and Khorovodov, AP and Ageev, VB and Elovenko, DA and Evsukova, AS and Adushkina, VV and Telnova, VV and Postnov, DE and Penzel, TU and Kurths, JG}, title = {EEG biomarkers of activation of the lymphatic drainage system of the brain during sleep and opening of the blood-brain barrier.}, journal = {Computational and structural biotechnology journal}, volume = {21}, number = {}, pages = {758-768}, pmid = {36698965}, issn = {2001-0370}, abstract = {The lymphatic drainage system of the brain (LDSB) is the removal of metabolites and wastes from its tissues. A dysfunction of LDSB is an important sign of aging, brain oncology, the Alzheimer's and Parkinson's diseases. The development of new strategies for diagnosis of LDSB injuries can improve prevention of age-related cerebral amyloid angiopathy, neurodegenerative and cerebrovascular diseases. There are two conditions, such as deep sleep and opening of the blood-brain-barrier (OBBB) associated with the LDSB activation. A promising candidate for measurement of LDSB could be electroencephalography (EEG). In this pilot study on rats, we tested the hypothesis, whether deep sleep and OBBB can be an informative platform for an effective extracting of information about the LDSB functions. Using the nonlinear analysis of EEG dynamics and machine learning technology, we discovered that the LDSB activation during OBBB and sleep is associated with similar changes in the EEG θ-activity. The OBBB causes the higher LDSB activation vs. sleep that is accompanied by specific changes in the low frequency EEG activity extracted by the power spectra analysis of the EEG dynamics combined with the coherence function. Thus, our findings demonstrate a link between neural activity associated with the LDSB activation during sleep and OBBB that is an important informative platform for extraction of the EEG-biomarkers of the LDSB activity. These results open new perspectives for the development of technology for the LDSB diagnostics that would open a novel era in the prognosis of brain diseases caused by the LDSB disorders, including OBBB.}, } @article {pmid36698894, year = {2022}, author = {Qiu, G and Cao, L and Chen, YJ}, title = {Novel heterozygous mutation in alpha-2-macroglobulin (A2M) suppressing the binding of amyloid-β (Aβ).}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {1090900}, pmid = {36698894}, issn = {1664-2295}, abstract = {INTRODUCTION: Many studies have suggested that the alpha-2-macroglobulin (A2M) gene may be involved in the pathogenesis of Alzheimer's disease (AD). A2M encoded by the A2M gene can specifically bind to the β-amyloid peptide and prevent fiber formation.

METHODS: The patient in this study had progressive memory loss at the age of 60 years and underwent a series of neuropsychological tests, cranial magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) biomarker analysis, and whole-exome sequencing (WES) to evaluate possible mutations. We used in silico tools and three-dimensional (3D) protein structure prediction to analyze the pathogenicity of the mutation and used a co-immunoprecipitation experiment to study the effect of mutations on amyloid-β (Aβ) binding.

RESULTS: Based on neuropsychological tests, cranial MRI, and CSF biomarker analysis, the patient was diagnosed with AD. WES showed that there was a missense mutation in A2M (c.1229A>C, p.N410T). Bioinformatics analysis showed that this mutation was pathogenic. Moreover, 3D protein structure analysis showed that the A2M Asn410 residue was an N-glycosylation site, which was necessary for A2M activation to bind to Aβ. Missense mutations led to the loss of glycosylation at this site, which suppressed the binding of Aβ. The functional experiment also confirmed the prediction: the interaction between A2M and Aβ from the patient's plasma was weakened.

CONCLUSIONS: Our results demonstrate that this novel A2M p.N410T mutation may have a pathogenic role in AD, by altering the binding interactions between A2M and Aβ.}, } @article {pmid36698871, year = {2022}, author = {Lei, D and Mao, C and Li, J and Huang, X and Sha, L and Liu, C and Dong, L and Xu, Q and Gao, J}, title = {CSF biomarkers for early-onset Alzheimer's disease in Chinese population from PUMCH dementia cohort.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {1030019}, pmid = {36698871}, issn = {1664-2295}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is one of the highly concerned degenerative disorders in recent decades. Though vast amount of researches has been done in various aspects, early-onset subtype, however, needs more investigation in diagnosis for its atypical manifestations and progression process. Fundamental CSF biomarkers of early-onset AD are explored in PUMCH dementia cohort to depict its laboratory characteristics.

MATERIALS AND METHODS: A total of 125 individuals (age of onset <65 years old) from PUMCH dementia cohort were recruited consecutively and classified into AD, non-AD dementia, and control groups. Levels of amyloid-β 42 (Aβ42), total tau (t-tau) and phosphorylated tau (p-tau) were measured using ELISA INNOTEST (Fujirebio, Ghent, Belgium). Students' t-test or non-parametric test are used to evaluate the differences between groups. Area under curve (AUC) of receiver operating characteristic (ROC) curve was introduced to prove the diagnostic powers of corresponding markers. Logistic regression is used to establish diagnostic model to combine several markers together to promote the diagnostic power.

RESULTS: The average of all three biomarkers and two calculated ratios (t-tau/Aβ42, p-tau/Aβ42) were statistically different in the AD group compared with the other two groups (Ps < 0.01). From our data, we were able to provide cutoff values (Aβ42 < 570.9 pg/mL; p-tau > 56.49 pg/mL; t-tau > 241.6 pg/mL; t-tau/Aβ42 > 0.529; p-tau/Aβ42 > 0.0846) with acceptable diagnostic accuracy compared to other studies. Using a combination of biomarkers and logistic regression (area under curve 0.951), we were able to further improve diagnostic efficacy.

DISCUSSION: Our study supports the diagnostic usefulness of biomarkers and defined cutoff values to diagnose early-onset AD. We showed that the ratios of t-tau/Aβ42 and p-tau/Aβ42 are more sensitive than relying on Aβ42 levels alone, and that we can further improve diagnostic accuracy by combining biomarkers.}, } @article {pmid36698863, year = {2022}, author = {Chiariello, A and Valente, S and Pasquinelli, G and Baracca, A and Sgarbi, G and Solaini, G and Medici, V and Fantini, V and Poloni, TE and Tognocchi, M and Arcaro, M and Galimberti, D and Franceschi, C and Capri, M and Salvioli, S and Conte, M}, title = {The expression pattern of GDF15 in human brain changes during aging and in Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1058665}, pmid = {36698863}, issn = {1663-4365}, abstract = {INTRODUCTION: Growth Differentiation Factor 15 (GDF15) is a mitochondrial-stress-responsive molecule whose expression strongly increases with aging and age-related diseases. However, its role in neurodegenerative diseases, including Alzheimer's disease (AD), is still debated.

METHODS: We have characterized the expression of GDF15 in brain samples from AD patients and non-demented subjects (controls) of different ages.

RESULTS: Although no difference in CSF levels of GDF15 was found between AD patients and controls, GDF15 was expressed in different brain areas and seems to be predominantly localized in neurons. The ratio between its mature and precursor form was higher in the frontal cortex of AD patients compared to age-matched controls (p < 0.05). Moreover, this ratio was even higher for centenarians (p < 0.01), indicating that aging also affects GDF15 expression and maturation. A lower expression of OXPHOS complexes I, III, and V in AD patients compared to controls was also noticed, and a positive correlation between GDF15 and IL-6 mRNA levels was observed. Finally, when GDF15 was silenced in vitro in dermal fibroblasts, a decrease in OXPHOS complexes transcript levels and an increase in IL-6 levels were observed.

DISCUSSION: Although GDF15 seems not to be a reliable CSF marker for AD, it is highly expressed in aging and AD brains, likely as a part of stress response aimed at counteracting mitochondrial dysfunction and neuroinflammation.}, } @article {pmid36698862, year = {2022}, author = {Liu, Y and Liu, S and Tang, C and Tang, K and Liu, D and Chen, M and Mao, Z and Xia, X}, title = {Transcranial alternating current stimulation combined with sound stimulation improves cognitive function in patients with Alzheimer's disease: Study protocol for a randomized controlled trial.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1068175}, pmid = {36698862}, issn = {1663-4365}, abstract = {BACKGROUND: The number of patients with Alzheimer's disease (AD) worldwide is increasing yearly, but the existing treatment methods have poor efficacy. Transcranial alternating current stimulation (tACS) is a new treatment for AD, but the offline effect of tACS is insufficient. To prolong the offline effect, we designed to combine tACS with sound stimulation to maintain the long-term post-effect.

MATERIALS AND METHODS: To explore the safety and effectiveness of tACS combined with sound stimulation and its impact on the cognition of AD patients. This trial will recruit 87 patients with mild to moderate AD. All patients were randomly divided into three groups. The change in Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) scores from the day before treatment to the end of treatment and 3 months after treatment was used as the main evaluation index. We will also explore the changes in the brain structural network, functional network, and metabolic network of AD patients in each group after treatment.

DISCUSSION: We hope to conclude that tACS combined with sound stimulation is safe and tolerable in 87 patients with mild to moderate AD under three standardized treatment regimens. Compared with tACS alone or sound alone, the combination group had a significant long-term effect on cognitive improvement. To screen out a better treatment plan for AD patients. tACS combined with sound stimulation is a previously unexplored, non-invasive joint intervention to improve patients' cognitive status. This study may also identify the potential mechanism of tACS combined with sound stimulation in treating mild to moderate AD patients.

CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT05251649. Registered on February 22, 2022.}, } @article {pmid36698861, year = {2022}, author = {Penalba-Sánchez, L and Oliveira-Silva, P and Sumich, AL and Cifre, I}, title = {Increased functional connectivity patterns in mild Alzheimer's disease: A rsfMRI study.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1037347}, pmid = {36698861}, issn = {1663-4365}, abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. In view of our rapidly aging population, there is an urgent need to identify Alzheimer's disease (AD) at an early stage. A potential way to do so is by assessing the functional connectivity (FC), i.e., the statistical dependency between two or more brain regions, through novel analysis techniques.

METHODS: In the present study, we assessed the static and dynamic FC using different approaches. A resting state (rs)fMRI dataset from the Alzheimer's disease neuroimaging initiative (ADNI) was used (n = 128). The blood-oxygen-level-dependent (BOLD) signals from 116 regions of 4 groups of participants, i.e., healthy controls (HC; n = 35), early mild cognitive impairment (EMCI; n = 29), late mild cognitive impairment (LMCI; n = 30), and Alzheimer's disease (AD; n = 34) were extracted and analyzed. FC and dynamic FC were extracted using Pearson's correlation, sliding-windows correlation analysis (SWA), and the point process analysis (PPA). Additionally, graph theory measures to explore network segregation and integration were computed.

RESULTS: Our results showed a longer characteristic path length and a decreased degree of EMCI in comparison to the other groups. Additionally, an increased FC in several regions in LMCI and AD in contrast to HC and EMCI was detected. These results suggest a maladaptive short-term mechanism to maintain cognition.

CONCLUSION: The increased pattern of FC in several regions in LMCI and AD is observable in all the analyses; however, the PPA enabled us to reduce the computational demands and offered new specific dynamic FC findings.}, } @article {pmid36698860, year = {2022}, author = {Cumbo, E and Adair, M and Åstrom, DO and Christensen, MC}, title = {Effectiveness of vortioxetine in patients with major depressive disorder and comorbid Alzheimer's disease in routine clinical practice: An analysis of a post-marketing surveillance study in South Korea.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1037816}, pmid = {36698860}, issn = {1663-4365}, abstract = {BACKGROUND: Vortioxetine has demonstrated procognitive effects in patients with major depressive disorder (MDD). We assessed the effectiveness and safety of vortioxetine in a cohort of patients with MDD and comorbid Alzheimer's disease participating in a large post-marketing surveillance study in South Korea.

METHODS: Subgroup analysis of a 6-month, prospective, multicenter, non-interventional cohort study in outpatients with MDD with a pre-baseline diagnosis of Alzheimer's disease receiving vortioxetine in routine care settings (n = 207). Patients were assessed at baseline and after 8 weeks; a subset of patients was also assessed after 24 weeks. Depression severity was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) and Clinical Global Impression (CGI) scale, cognitive symptoms using the Perceived Deficits Questionnaire-Depression, Korean version (PDQ-K), and cognitive performance using the Digit Symbol Substitution Test (DSST).

RESULTS: Most patients were receiving a mean daily vortioxetine dose of 5 mg/day (174/190 patients; 91.6%). After 24 weeks of vortioxetine treatment, 71.4% of patients (40/56) had experienced overall clinical improvement (i.e., CGI-Improvement score ≤3) and 51.9% (28/54) had achieved remission from depressive symptoms (i.e., MADRS total score ≤10 points). Respective mean changes in MADRS, PDQ-K, and DSST total scores from baseline to week 24 were -11.5 (p < 0.0001), -5.1 (p = 0.03), and +3.8 points (p = 0.0524). Adverse events were reported by 27 patients (13.0%) and were mostly mild (89.2%).

CONCLUSION: Patients with MDD and comorbid Alzheimer's disease receiving vortioxetine in routine care settings in South Korea demonstrated clinically meaningful improvements in depressive symptoms, cognitive symptoms, and objective cognitive performance over the 6-month treatment period. Treatment with vortioxetine was well tolerated in this patient cohort, with reported adverse events consistent with the established tolerability profile of vortioxetine.}, } @article {pmid36698780, year = {2022}, author = {Pang, S and Li, S and Cheng, H and Luo, Z and Qi, X and Guan, F and Dong, W and Gao, S and Liu, N and Gao, X and Pan, S and Zhang, X and Zhang, L and Yang, Y and Zhang, L}, title = {Discovery of an evodiamine derivative for PI3K/AKT/GSK3β pathway activation and AD pathology improvement in mouse models.}, journal = {Frontiers in molecular neuroscience}, volume = {15}, number = {}, pages = {1025066}, pmid = {36698780}, issn = {1662-5099}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive neurodegeneration and cognitive decline. Evodiamine, a main component in Chinese medicine, was found to improve cognitive impairment in AD model mice based on several intensive studies. However, evodiamine has high cytotoxicity and poor bioactivity. In this study, several evodiamine derivatives were synthesized via heterocyclic substitution and amide introduction and screened for cytotoxicity and antioxidant capacity. Under the same concentrations, compound 4c was found to exhibit lower cytotoxicity and higher activity against H2O2 and amyloid β oligomers (AβOs) than evodiamine in vitro and significantly improve the working memory and spatial memory of 3 x Tg and APP/PS1 AD mice. Subsequent RNA sequencing and pathway enrichment analysis showed that 4c affected AD-related genes and the AMPK and insulin signaling pathways. Furthermore, we confirmed that 4c recovered PI3K/AKT/GSK3β/Tau dysfunction in vivo and in vitro. In conclusion, 4c represents a potential lead compound for AD therapy based on the recovery of PI3K/AKT/GSK3β pathway dysfunction.}, } @article {pmid36698693, year = {2022}, author = {Poudineh, M and Ghotbi, T and Azizi, F and Karami, N and Zolfaghari, Z and Gheisari, F and Hormozi, M and Poudineh, S}, title = {Neuropharmaceutical Properties of Naringin Against Alzheimer's and Parkinson's Diseases: Naringin Protection Against AD and PD.}, journal = {Galen medical journal}, volume = {11}, number = {}, pages = {e2337}, pmid = {36698693}, issn = {2322-2379}, abstract = {Neurological complications are considered the leading cause of disability and the second cause of death worldwide. Although the most common neurological disorders affecting a large population are Alzheimer's (AD) and Parkinson's diseases (PD), no definitive treatment has been propounded in the clinic. As in recent years, special attention has been paid to medicinal herbal products as one of the ways to meet the challenges of treating diseases. This review study aimed to introduce the naringin neuroprotective effects as an abundant flavonoid in grapes and citrus fruits on the most common neurological disorders, including AD and PD. For this purpose, the specified keywords were searched in PubMed, Web of Science, Scopus, Embase, and Google Scholar, and the results were entered into the study after a concise overview. The findings show naringin can confront neurological disorders through several mechanisms such as modulating stress response pathways, preventing apoptosis, oxidative stress, and neuroinflammation, excessive chelating amounts of metal ions, thereby improving cognitive impairment and memory loss induced by neurological disorders. However, further studies, particularly on human, are critical for the final confirmation of obtained findings. [GMJ.2022;11:e2337].}, } @article {pmid36698629, year = {2022}, author = {Qian, H and Shan, Y and Gong, R and Lin, D and Zhang, M and Wang, C and Wang, L}, title = {Mechanism of action and therapeutic effects of oxidative stress and stem cell-based materials in skin aging: Current evidence and future perspectives.}, journal = {Frontiers in bioengineering and biotechnology}, volume = {10}, number = {}, pages = {1082403}, pmid = {36698629}, issn = {2296-4185}, abstract = {Aging is associated with multiple degenerative diseases, including atherosclerosis, osteoporosis, and Alzheimer's disease. As the most intuitive manifestation of aging, skin aging has received the most significant attention. Skin aging results from various intrinsic and extrinsic factors. Aged skin is characterized by wrinkles, laxity, elastosis, telangiectasia, and aberrant pigmentation. The underlying mechanism is complex and may involve cellular senescence, DNA damage, oxidative stress (OS), inflammation, and genetic mutations, among other factors. Among them, OS plays an important role in skin aging, and multiple antioxidants (e.g., vitamin C, glutathione, and melatonin) are considered to promote skin rejuvenation. In addition, stem cells that exhibit self-replication, multi-directional differentiation, and a strong paracrine function can exert anti-aging effects by inhibiting OS. With the further development of stem cell technology, treatments related to OS mitigation and involving stem cell use may have a promising future in anti-skin aging therapy.}, } @article {pmid36698474, year = {2022}, author = {Liang, S and Wang, L and Wu, X and Hu, X and Wang, T and Jin, F}, title = {The different trends in the burden of neurological and mental disorders following dietary transition in China, the USA, and the world: An extension analysis for the Global Burden of Disease Study 2019.}, journal = {Frontiers in nutrition}, volume = {9}, number = {}, pages = {957688}, pmid = {36698474}, issn = {2296-861X}, abstract = {INTRODUCTION: The highly processed western diet is substituting the low-processed traditional diet in the last decades globally. Increasing research found that a diet with poor quality such as western diet disrupts gut microbiota and increases the susceptibility to various neurological and mental disorders, while a balanced diet regulates gut microbiota and prevents and alleviates the neurological and mental disorders. Yet, there is limited research on the association between the disease burden expanding of neurological and mental disorders with a dietary transition.

METHODS: We compared the disability-adjusted life-years (DALYs) trend by age for neurological and mental disorders in China, in the United States of America (USA), and across the world from 1990 to 2019, evaluated the dietary transition in the past 60 years, and analyzed the association between the burden trend of the two disorders with the changes in diet composition and food production.

RESULTS: We identified an age-related upward pattern in disease burden in China. Compared with the USA and the world, the Chinese neurological and mental disorders DALY percent was least in the generation over 75 but rapidly increased in younger generations and surpassed the USA and/or the world in the last decades. The age-related upward pattern in Chinese disease burdens had not only shown in the presence of cardiovascular diseases, neoplasms, and diabetes mellitus but also appeared in the presence of depressive disorders, Parkinson's disease, Alzheimer's disease and other dementias, schizophrenia, headache disorders, anxiety disorders, conduct disorders, autism spectrum disorders, and eating disorders, successively. Additionally, the upward trend was associated with the dramatic dietary transition including a reduction in dietary quality and food production sustainability, during which the younger generation is more affected than the older. Following the increase in total calorie intake, alcohol intake, ratios of animal to vegetal foods, and poultry meat to pulses, the burdens of the above diseases continuously rose. Then, following the rise of the ratios of meat to pulses, eggs to pulses, and pork to pulses, the usage of fertilizers, the farming density of pigs, and the burdens of the above disease except diabetes mellitus were also ever-increasing. Even the usage of pesticides was positively correlated with the burdens of Parkinson's disease, schizophrenia, cardiovascular diseases, and neoplasms. Contrary to China, the corresponding burdens of the USA trended to reduce with the improvements in diet quality and food production sustainability.

DISCUSSION: Our results suggest that improving diet quality and food production sustainability might be a promising way to stop the expanding burdens of neurological and mental disorders.}, } @article {pmid36697708, year = {2022}, author = {Wang, H and Wu, J and Sternke-Hoffmann, R and Zheng, W and Mörman, C and Luo, J}, title = {Multivariate effects of pH, salt, and Zn[2+] ions on Aβ40 fibrillation.}, journal = {Communications chemistry}, volume = {5}, number = {1}, pages = {171}, pmid = {36697708}, issn = {2399-3669}, abstract = {Amyloid-β (Aβ) peptide aggregation plays a central role in the progress of Alzheimer's disease (AD), of which Aβ-deposited extracellular amyloid plaques are a major hallmark. The brain micro-environmental variation in AD patients, like local acidification, increased ionic strength, or changed metal ion levels, cooperatively modulates the aggregation of the Aβ peptides. Here, we investigate the multivariate effects of varied pH, ionic strength and Zn[2+] on Aβ40 fibrillation kinetics. Our results reveal that Aβ fibrillation kinetics are strongly affected by pH and ionic strength suggesting the importance of electrostatic interactions in regulating Aβ40 fibrillation. More interestingly, the presence of Zn[2+] ions can further alter or even reserve the role of pH and ionic strength on the amyloid fibril kinetics, suggesting the importance of amino acids like Histidine that can interact with Zn[2+] ions. Both pH and ionic strength regulate the secondary nucleation processes, however regardless of pH and Zn[2+] ions, ionic strength can also modulate the morphology of Aβ40 aggregates. These multivariate effects in bulk solution provide insights into the correlation of pH-, ionic strength- or Zn[2+] ions changes with amyloid deposits in AD brain and will deepen our understanding of the molecular pathology in the local brain microenvironment.}, } @article {pmid36696249, year = {2022}, author = {Scherrer, J and Salas, J and Jacobs, C and Wiemken, T}, title = {Lower dementia risk in patients vaccinated against herpes zoster.}, journal = {Annals of family medicine}, volume = {}, number = {20 Suppl 1}, pages = {}, doi = {10.1370/afm.20.s1.2680}, pmid = {36696249}, issn = {1544-1717}, mesh = {Humans ; Female ; Aged ; United States/epidemiology ; Male ; Retrospective Studies ; Medicare ; *Herpes Zoster/epidemiology/prevention & control ; *Dementia/epidemiology/prevention & control ; Antiviral Agents ; *Herpes Zoster Vaccine ; }, abstract = {Context: Herpes zoster (HZ) infection increases dementia risk but it is not known if HZ vaccination is associated with lower risk for dementia. Objective: Determine if patients with HZ vaccination vs. those who remain unvaccinated, have a lower risk for dementia in a cohort of Veterans Health Administration (VHA) patients. Replicate results in a private sector, medical claims patient cohort. Study Design: Retrospective cohort. Competing risk (VHA) and Cox proportional hazard (MarketScan) models estimated the association between HZ vaccination and incident dementia in all patients and in age (65-69, 70-74, ≥75) and race (White, Black, Other) sub-groups. Expanded models accounted for the effect of antivirals and HZ infection between index and end of follow-up. Sensitivity analysis measured the association between HZ vaccination and incident Alzheimer's dementia (AD). E-values computed to test for bias due to unmeasured confounding and selection bias. Setting/Data set: VHA cohort (10/1/2008 - 9/30/2019) with replication in MarketScan® commercial and Medicare claims (1/1/2009-12/31/2018). Population studied: Eligible patients (VHA n=136,016; MarketScan n=172,790) were ≥65 years of age and free of dementia for two years prior to baseline. All patients had 3 or more 'well visits' to control for confounding related to use of preventive health care services. Outcome measures: Incident dementia. Results: VHA patients were 75.6 (SD±7.5) years of age, 4% female, and 91.2% were white race. MarketScan patients were 69.8 (SD±5.6) years of age, on average and 65.4% were female. years of age on average, 65.0% were female. After controlling for confounding, HZ vaccination compared with no vaccination, was significantly associated with lower dementia risk (VHA HR= 0.69; 95%CI: 0.67-0.72; MarketScan HR=0.65; 95%CI:0.57-0.74). No difference in outcomes were observed by race and HZ vaccination was associated with lower AD risk. Results were stable after adjusting for antivirals and HZ infection. E-values indicated results are not explained by selection bias or unmeasured confounding. Conclusions: Among patients ≥65 years of age, HZ vaccination is associated with a 31-35% reduced risk of dementia. Confirmation in other study designs is warranted. Results may be explained by nonspecific neuroprotection and vaccination training the immune system to limit damaging inflammation. Results highlight the importance of HZ vaccination.}, } @article {pmid36694902, year = {2022}, author = {Povarnina, PY and Volkova, AA and Vorontsova, ON and Kamensky, AA and Gudasheva, TA and Seredenin, SB}, title = {A Low-Molecular-Weight BDNF Mimetic, Dipeptide GSB-214, Prevents Memory Impairment in Rat Models of Alzheimer's Disease.}, journal = {Acta naturae}, volume = {14}, number = {4}, pages = {94-100}, pmid = {36694902}, issn = {2075-8251}, abstract = {Brain-derived neurotrophic factor (BDNF) is known to be involved in the pathogenesis of Alzheimer's disease (AD). However, the pharmacological use of full-length neurotrophin is limited, because of its macromolecular protein nature. A dimeric dipeptide mimetic of the BDNF loop 1, bis-(N-monosuccinyl-L-methionyl-L-serine) heptamethylene diamide (GSB-214), was designed at the Zakusov Research Institute of Pharmacology. GSB-214 activates TrkB, PI3K/AKT, and PLC-γ1 in vitro. GSB-214 exhibited a neuroprotective activity during middle cerebral artery occlusion in rats when administered intraperitoneally (i.p.) at a dose of 0.1 mg/kg and improved memory in the novel object recognition test (0.1 and 1.0 mg/kg, i.p.). In the present study, we investigated the effects of GSB-214 on memory in the scopolamine- and steptozotocin-induced AD models, with reference to activation of TrkB receptors. AD was modeled in rats using a chronic i.p. scopolamine injection or a single streptozotocin injection into the cerebral ventricles. GSB-214 was administered within 10 days after the exposure to scopolamine at doses of 0.05, 0.1, and 1 mg/kg (i.p.) or within 14 days after the exposure to streptozotocin at a dose of 0.1 mg/kg (i.p.). The effect of the dipeptide was evaluated in the novel object recognition test; K252A, a selective inhibitor of tyrosine kinase receptors, was used to reveal a dependence between the mnemotropic action and Trk receptors. GSB-214 at doses of 0.05 and 0.1 mg/kg statistically significantly prevented scopolamine-induced long-term memory impairment, while not affecting short-term memory. In the streptozotocin-induced model, GSB-214 completely eliminated the impairment of short-term memory. No mnemotropic effect of GSB-214 was registered when Trk receptors were inhibited by K252A.}, } @article {pmid36692779, year = {2022}, author = {Mark, RE and Brehmer, Y}, title = {Preclinical Alzheimer's dementia: a useful concept or another dead end?.}, journal = {European journal of ageing}, volume = {19}, number = {4}, pages = {997-1004}, pmid = {36692779}, issn = {1613-9372}, abstract = {The term, preclinical dementia, was introduced in 2011 when new guidelines for the diagnosis of Alzheimer's dementia (AD) were published. In the intervening 11 years, many studies have appeared in the literature focusing on this early stage. A search conducted in English on Google Scholar on 06.23.2022 using the term "preclinical (Alzheimer's) dementia" produced 121, 000 results. However, the label is arguably more relevant for research purposes, and it is possible that the knowledge gained may lead to a cure for AD. The term has not been widely adopted by clinical practitioners. Furthermore, it is still not possible to predict who, after a diagnosis of preclinical dementia, will go on to develop AD, and if so, what the risk factors (modifiable and non-modifiable) might be. This Review/Theoretical article will focus on preclinical Alzheimer's dementia (hereafter called preclinical AD). We outline how preclinical AD is currently defined, explain how it is diagnosed and explore why this is problematic at a number of different levels. We also ask the question: Is the concept 'preclinical AD' useful in clinical practice or is it just another dead end in the Holy Grail to find a treatment for AD? Specific recommendations for research and clinical practice are provided.}, } @article {pmid36692743, year = {2022}, author = {Dewitte, L and Hill, PL and Vandenbulcke, M and Dezutter, J}, title = {The longitudinal relationship between meaning in life, depressive symptoms, life satisfaction, and cognitive functioning for older adults with Alzheimer's disease.}, journal = {European journal of ageing}, volume = {19}, number = {4}, pages = {1155-1166}, pmid = {36692743}, issn = {1613-9372}, abstract = {Studies show the importance of the personal experience of meaning in life for older adults, but adults with dementia have been largely excluded from this research. The current study examined the longitudinal predictive effect of meaning in life for the psychological and cognitive functioning of older adults with Alzheimer's disease and whether cognitive decline predicted presence of meaning in life. On three yearly measurement occasions, presence of meaning in life, depressive symptoms, life satisfaction, and cognitive functioning were assessed in structured interviews with a convenience sample of 140 older adults with Alzheimer's disease from nine nursing homes in Belgium. Cross-lagged panel and latent growth curve models were used to analyze the longitudinal relationships between the variables. Over the three measurement waves, participants with higher presence of meaning reported lower depressive symptoms one year later. Presence of meaning and life satisfaction predicted each other over time, but only between the first and second wave. The analyses showed no strong evidence for a longitudinal association between meaning in life and cognitive functioning in either direction. The findings emphasize the importance of the experience of meaning in life for the psychological functioning of older adults with Alzheimer's disease. The lack of evidence for associations between meaning and cognitive functioning questions the prevailing view that intact cognitive abilities are a necessity for experiencing meaning. More attention to the potential of meaning interventions for persons with dementia is warranted.}, } @article {pmid36689720, year = {2022}, author = {Hamadyanova, AU and Kuznetsov, KO and Gaifullina, EI and Kalandin, DA and Khamidullina, RR and Khalitova, IF and Faizov, RM and Kamaletdinova, NO and Aslanova, BF and Nakieva, AG and Burangulova, LE and Gaisina, GO}, title = {[Androgens and Parkinson's disease: the role in humans and in experiment].}, journal = {Problemy endokrinologii}, volume = {68}, number = {6}, pages = {146-156}, doi = {10.14341/probl13148}, pmid = {36689720}, issn = {2308-1430}, mesh = {Female ; Humans ; Male ; 5-alpha Reductase Inhibitors/pharmacology/therapeutic use ; Androgens ; Dutasteride/pharmacology/therapeutic use ; *Neurodegenerative Diseases ; *Parkinson Disease/drug therapy ; }, abstract = {Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. There is evidence that PD has a wider prevalence among men, which indicates the existing role of sex hormones in the pathogenesis of the disease. The article presents an overview of studies devoted to the study of sex differences in the incidence and symptoms of PD. Drug therapy with androgens, androgen precursors, antiandrogens and drugs that modify androgen metabolism is available for the treatment of various endocrine conditions, having translational significance for PD, but none of these drugs has yet shown sufficient effectiveness. Although PD has now been proven to be more common in men than in women, androgens do not always have any effect on the symptoms or progression of the disease. 5α-reductase inhibitors have shown neuroprotective and anti-dyskinetic activity and need further investigation. Despite the fact that the neuroprotective effect of dutasteride was observed only before damage to DA neurons, the absence of a negative effect makes it an attractive drug for use in patients with PD due to its anti-dyskinetic properties.}, } @article {pmid36688174, year = {2022}, author = {Kabir, F and Atkinson, R and Cook, AL and Phipps, AJ and King, AE}, title = {The role of altered protein acetylation in neurodegenerative disease.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1025473}, pmid = {36688174}, issn = {1663-4365}, abstract = {Acetylation is a key post-translational modification (PTM) involved in the regulation of both histone and non-histone proteins. It controls cellular processes such as DNA transcription, RNA modifications, proteostasis, aging, autophagy, regulation of cytoskeletal structures, and metabolism. Acetylation is essential to maintain neuronal plasticity and therefore essential for memory and learning. Homeostasis of acetylation is maintained through the activities of histone acetyltransferases (HAT) and histone deacetylase (HDAC) enzymes, with alterations to these tightly regulated processes reported in several neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Both hyperacetylation and hypoacetylation can impair neuronal physiological homeostasis and increase the accumulation of pathophysiological proteins such as tau, α-synuclein, and Huntingtin protein implicated in AD, PD, and HD, respectively. Additionally, dysregulation of acetylation is linked to impaired axonal transport, a key pathological mechanism in ALS. This review article will discuss the physiological roles of protein acetylation and examine the current literature that describes altered protein acetylation in neurodegenerative disorders.}, } @article {pmid36688173, year = {2022}, author = {Turner, AD and Locklear, CE and Oruru, D and Briggs, AQ and Bubu, OM and Seixas, A}, title = {Exploring the combined effects of sleep apnea and APOE-e4 on biomarkers of Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1017521}, pmid = {36688173}, issn = {1663-4365}, abstract = {OBJECTIVE: We determined the interactive associations of apolipoprotein e4 (APOE-e4), and obstructive sleep apnea (OSA) on biomarkers of Alzheimer's disease and examined for racial/ethnic differences of this association.

METHODS: We used data from the National Alzheimer's Coordinating Center Uniform Dataset (NACC UDS). All participants undergo annual observations, including demographic survey, battery of neuropsychological tests, blood draw (with genotyping), and a clinical evaluation with medical and cognitive/dementia status assessment, while a subset of participants have cerebrospinal fluid (CSF) biomarkers and neuroimaging data. Biomarkers of AD were characterized as the presence of abnormally low amyloid in CSF, via validated Aβ42 cut off protocols, and total segmented hippocampal volume, and volume of white matter hyper intensities (WMH). While clinical markers (to preview cognitive relationships) were characterized via the Montreal Cognitive Assessment (MOCA).

RESULTS: Biomarker and clinical marker data were derived from 1,387 participants at baseline (mean age = 69.73 ± 8.32; 58.6% female; 13.7% Black/African American), 18.4% of the sample had sleep apnea, and 37.9% were APOE-e4 carriers. Our results confirmed previous reports that OSA and APOE-e4 were independently associated with AD through abnormal levels of amyloid (F (1,306) = 4.27; p = 0.040; F (1,285) = 60.88; p < 0.000, respectively), WMH volume (F (1,306) = 4.27; p = 0.040; F (1,285) = 60.88; p < 0.000, respectively), and MOCA scores (F (1,306) = 4.27; p = 0.040; F (1,285) = 60.88; p < 0.000, respectively). No significant interaction between OSA and APOE-e4 relative to amyloid emerged, however, race stratified analyses indicated the interaction of OSA and APOE-e4 and was significantly associated with WMH and hippocampal volume in Black/African American, but not white participants.

CONCLUSION: OSA and APOE-e4 are interactively associated with WHM in Black/African Americans. This interaction may partially explicate increased levels of risk in this population.}, } @article {pmid36688172, year = {2022}, author = {Zhang, S and Liu, L and Zhang, L and Ma, L and Wu, H and He, X and Cao, M and Li, R}, title = {Evaluating the treatment outcomes of repetitive transcranial magnetic stimulation in patients with moderate-to-severe Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1070535}, pmid = {36688172}, issn = {1663-4365}, abstract = {The repetitive transcranial magnetic stimulation (rTMS) shows great potential in the treatment of Alzheimer's disease (AD). However, its treatment efficacy for AD patients in moderate to severe stage is relatively evaluated. Here, we proposed a randomized, sham-controlled, clinical trial of rTMS among 35 moderate-to-severe AD patients. A high frequency (10 Hz) stimulation of the left dorsal lateral prefrontal cortex (DLPFC), 60-session long treatment lasting for 3 months procedure was adopted in the trial. Each participant completed a battery of neuropsychological tests at baseline and post-treatment for evaluation of the rTMS therapeutic effect. Twelve of them completed baseline resting-state functional magnetic resonance imaging (fMRI) for exploration of the underlying neural contribution to individual difference in treatment outcomes. The result showed that the rTMS treatment significantly improved cognitive performance on the severe impairment battery (SIB), reduced psychiatric symptoms on the neuropsychiatric inventory (NPI), and improved the clinician's global impression of change (CIBIC-Plus). Furthermore, the result preliminarily proposed resting-state multivariate functional connectivity in the (para) hippocampal region as well as two clusters in the frontal and occipital cortices as a pre-treatment neuroimaging marker for predicting individual differences in treatment outcomes. The finding could brought some enlightenment and reference for the rTMS treatment of moderate and severe AD patients.}, } @article {pmid36688166, year = {2022}, author = {Ishiguro, H}, title = {Editorial: Targeting the endocannabinoidome in neurodegenerative disorders.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1116635}, pmid = {36688166}, issn = {1663-4365}, } @article {pmid36688162, year = {2022}, author = {Yoon, EJ and Lee, JY and Kwak, S and Kim, YK}, title = {Mild behavioral impairment linked to progression to Alzheimer's disease and cortical thinning in amnestic mild cognitive impairment.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1051621}, pmid = {36688162}, issn = {1663-4365}, abstract = {BACKGROUND: Mild behavioral impairment (MBI) is a neurobehavioral syndrome characterized by later life emergence of sustained neuropsychiatric symptoms, as an at-risk state for dementia. However, the associations between MBI and a risk of progression to Alzheimer's disease (AD) and its neuroanatomical correlates in mild cognitive impairment (MCI) are still unclear.

METHOD: A total 1,184 older adults with amnestic MCI was followed for a mean of 3.1 ± 2.0 years. MBI was approximated using a transformation algorithm for the Neuropsychiatric Inventory at baseline. A two-step cluster analysis was used to identify subgroups of individuals with amnestic MCI based on profiles of 5 MBI domain symptoms (decreased motivation, affective dysregulation, impulse dyscontrol, social inappropriateness, abnormal perception/thought content). A Cox regression analysis was applied to investigate differences in the risk of progression to AD between subgroups. A subset of participants (n = 202) underwent 3D T1-weighted MRI scans at baseline and cortical thickness was compared between the subgroups of amnestic MCI patients.

RESULT: The cluster analysis classified the patients into 3 groups: (1) patients without any MBI domain symptoms (47.4%, asymptomatic group); (2) those with only affective dysregulation (29.4%, affective dysregulation group); (3) those with multiple MBI domain symptoms, particularly affective dysregulation, decreased motivation and impulse dyscontrol (23.2%, complex group). Compared to the asymptomatic group, the complex group was associated with a higher risk of progression to AD (hazard ratio = 2.541 [1.904-3.392], p < 0.001), but the affective dysregulation group was not (1.214 [0.883-1.670], p = 0.232). In cortical thickness analysis, the complex group revealed cortical thinning bilaterally in the inferior parietal, lateral occipital, lateral superior temporal, and frontopolar regions compared with the affective dysregulation group.

CONCLUSION: The multiple co-occuring MBI domains in individuals with amnestic MCI are associated with a higher risk of progression to AD and cortical thinning in temporal, parietal and frontal areas. These results suggest that evaluation of MBI could be useful for risk stratification for AD and appropriate intervention in MCI individuals.}, } @article {pmid36688156, year = {2022}, author = {Liu, G and Li, T and Yang, A and Zhang, X and Qi, S and Feng, W}, title = {Knowledge domains and emerging trends of microglia research from 2002 to 2021: A bibliometric analysis and visualization study.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1057214}, pmid = {36688156}, issn = {1663-4365}, abstract = {BACKGROUND: Microglia have been identified for a century. In this period, their ontogeny and functions have come to light thanks to the tireless efforts of scientists. However, numerous documents are being produced, making it challenging for scholars, especially those new to the field, to understand them thoroughly. Therefore, having a reliable method for quickly grasping a field is crucial.

METHODS: We searched and downloaded articles from the Web of Science Core Collection with "microglia" or "microglial" in the title from 2002 to 2021. Eventually, 12,813 articles were located and, using CiteSpace and VOSviewer, the fundamental data, knowledge domains, hot spots, and emerging trends, as well as the influential literature in the field of microglia research, were analyzed.

RESULTS: Following 2011, microglia publications grew significantly. The two prominent journals are Glia and J Neuroinflamm. The United States and Germany dominated the microglia study. The primary research institutions are Harvard Univ and Univ Freiburg, and the leading authors are Prinz Marco and Kettenmann Helmut. The knowledge domains of microglia include eight directions, namely neuroinflammation, lipopolysaccharide, aging, neuropathic pain, macrophages, Alzheimer's disease, retina, and apoptosis. Microglial phenotype is the focus of research; while RNA-seq, exosome, and glycolysis are emerging topics, a microglial-specific marker is still a hard stone. We also identified 19 influential articles that contributed to the study of microglial origin (Mildner A 2007; Ginhoux F 2010), identity (Butovsky O 2014), homeostasis (Cardona AE 2006; Elmore MRP 2014); microglial function such as surveillance (Nimmerjahn A 2005), movement (Davalos D 2005; Haynes SE 2006), phagocytosis (Simard AR 2006), and synapse pruning (Wake H 2009; Paolicelli RC 2011; Schafer DP 2012; Parkhurst CN 2013); and microglial state/phenotype associated with disease (Keren-Shaul H 2017), as well as 5 review articles represented by Kettenmann H 2011.

CONCLUSION: Using bibliometrics, we have investigated the fundamental data, knowledge structure, and dynamic evolution of microglia research over the previous 20 years. We hope this study can provide some inspiration and a reference for researchers studying microglia in neuroscience.}, } @article {pmid36688151, year = {2022}, author = {Huguenard, CJC and Cseresznye, A and Darcey, T and Nkiliza, A and Evans, JE and Hazen, SL and Mullan, M and Crawford, F and Abdullah, L}, title = {Age and APOE affect L-carnitine system metabolites in the brain in the APOE-TR model.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1059017}, pmid = {36688151}, issn = {1663-4365}, abstract = {With age the apolipoprotein E (APOE) E4 allele (involved in lipid homeostasis) is associated with perturbation of bioenergetics pathways in Alzheimer's disease (AD). We therefore hypothesized that in aging mice APOE genotype would affect the L-carnitine system (central to lipid bioenergetics), in the brain and in the periphery. Using liquid chromatography-mass spectrometry, levels of L-carnitine and associated metabolites: γ-butyrobetaine (GBB), crotonobetaine, as well as acylcarnitines, were evaluated at 10-, 25-, and 50-weeks, in the brain and the periphery, in a targeted replacement mouse model of human APOE (APOE-TR). Aged APOE-TR mice were also orally administered 125 mg/kg of L-carnitine daily for 7 days followed by evaluation of brain, liver, and plasma L-carnitine system metabolites. Compared to E4-TR, an age-dependent increase among E2- and E3-TR mice was detected for medium- and long-chain acylcarnitines (MCA and LCA, respectively) within the cerebrovasculature and brain parenchyma. While following L-carnitine oral challenge, E4-TR mice had higher increases in the L-carnitine metabolites, GBB and crotonobetaine in the brain and a reduction of plasma to brain total acylcarnitine ratios compared to other genotypes. These studies suggest that with aging, the presence of the E4 allele may contribute to alterations in the L-carnitine bioenergetic system and to the generation of L-carnitine metabolites that could have detrimental effects on the vascular system. Collectively the E4 allele and aging may therefore contribute to AD pathogenesis through aging-related lipid bioenergetics as well as cerebrovascular dysfunctions.}, } @article {pmid36688149, year = {2022}, author = {Chen, PH and Lin, SI and Liao, YY and Hsu, WL and Cheng, FY}, title = {Corrigendum: Associations between blood-based biomarkers of Alzheimer's disease with cognition in motoric cognitive risk syndrome: A pilot study using plasma Aβ42 and total tau.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1125201}, doi = {10.3389/fnagi.2022.1125201}, pmid = {36688149}, issn = {1663-4365}, abstract = {[This corrects the article DOI: 10.3389/fnagi.2022.981632.].}, } @article {pmid36688148, year = {2022}, author = {Xiao, Y and Wang, J and Huang, K and Gao, L and Yao, S and , }, title = {Progressive structural and covariance connectivity abnormalities in patients with Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1064667}, pmid = {36688148}, issn = {1663-4365}, abstract = {BACKGROUND: Alzheimer's disease (AD) is one of most prevalent neurodegenerative diseases worldwide and characterized by cognitive decline and brain structure atrophy. While studies have reported substantial grey matter atrophy related to progression of AD, it remains unclear about brain regions with progressive grey matter atrophy, covariance connectivity, and the associations with cognitive decline in AD patients.

OBJECTIVE: This study aims to investigate the grey matter atrophy, structural covariance connectivity abnormalities, and the correlations between grey matter atrophy and cognitive decline during AD progression.

MATERIALS: We analyzed neuroimaging data of healthy controls (HC, n = 45) and AD patients (n = 40) at baseline (AD-T1) and one-year follow-up (AD-T2) obtained from the Alzheimer's Disease Neuroimaging Initiative. We investigated AD-related progressive changes of grey matter volume, covariance connectivity, and the clinical relevance to further understand the pathological progression of AD.

RESULTS: The results showed clear patterns of grey matter atrophy in inferior frontal gyrus, prefrontal cortex, lateral temporal gyrus, posterior cingulate cortex, insula, hippocampus, caudate, and thalamus in AD patients. There was significant atrophy in bilateral superior temporal gyrus (STG) and left caudate in AD patients over a one-year period, and the grey matter volume decrease in right STG and left caudate was correlated with cognitive decline. Additionally, we found reduced structural covariance connectivity between right STG and left caudate in AD patients. Using AD-related grey matter atrophy as features, there was high discrimination accuracy of AD patients from HC, and AD patients at different time points.}, } @article {pmid36687822, year = {2022}, author = {Delgado-Álvarez, A and Delgado-Alonso, C and Goudsmit, M and García-Ramos, R and Gil-Moreno, MJ and Valles-Salgado, M and Díez-Cirarda, M and Zamarrón-Cassinello, MD and Matías-Guiu, J and Matias-Guiu, JA}, title = {Validation of the cross-cultural dementia screening test in Alzheimer's disease and Parkinson's disease.}, journal = {Frontiers in psychology}, volume = {13}, number = {}, pages = {1043721}, pmid = {36687822}, issn = {1664-1078}, abstract = {OBJECTIVE: The Cross-Cultural Dementia (CCD) is a new screening tool to evaluate cognitive impairment based on a cross-cultural perspective to reduce the bias of education, and language and cultural differences. We aimed to evaluate the diagnostic properties of the CCD in Spaniards for the assessment of patients with Alzheimer's disease in mild cognitive impairment (AD-MCI) and mild dementia stages (AD-D) and patients with mild cognitive impairment associated with Parkinson's disease (PD-MCI).

METHODS: Sixty participants with AD (50% MCI) and thirty with PD-MCI were enrolled. Each clinical group was compared against a healthy control group (HC) with the same number of participants and no significant differences in age, education, and sex. A comprehensive neuropsychological test battery and CCD were completed. Intergroup comparisons, ROC curves, and cut-off scores were calculated for the study of diagnostic properties.

RESULTS: Intergroup differences were found in accordance with the cognitive profile of each clinical condition. Memory measures (Objects test) were especially relevant for the classification between AD and HC. Memory and executive function scores (Sun-Moon and Dots tests) were useful in the case of PD-MCI and HC. Furthermore, CCD described differences in executive functions and speed scores comparing AD-MCI and PD-MCI. Correlations between standardized neuropsychological tests and CCD measures supported the convergent validity of the test.

CONCLUSION: CCD showed good discrimination properties and cut-off scores for dementia and extended its application to a sample of prodromal stages of AD and PD with mild cognitive impairment.}, } @article {pmid36687769, year = {2022}, author = {Li, Y and Sadiq, A and Wang, Z}, title = {Arterial Spin Labelling-Based Blood-Brain Barrier Assessment and Its Applications.}, journal = {Investigative magnetic resonance imaging}, volume = {26}, number = {4}, pages = {229-236}, pmid = {36687769}, issn = {2384-1095}, support = {R01 AG060054/AG/NIA NIH HHS/United States ; R21 AG082345/AG/NIA NIH HHS/United States ; R01 AG070227/AG/NIA NIH HHS/United States ; P41 EB029460/EB/NIBIB NIH HHS/United States ; R01 EB031080/EB/NIBIB NIH HHS/United States ; UL1 TR003098/TR/NCATS NIH HHS/United States ; }, abstract = {The brain relies on the blood-brain barrier (BBB) for the selective absorption of nutrients and the exclusion of other big molecules from the circulating blood. Therefore, the integrity of BBB is critical to brain health, and assessing BBB condition is of great clinical importance. BBB is often examined using exogenous tracers that can travel across the BBB, but the tracers might cause severe side effects. To avoid the use of external tracers, researchers have used magnetically labeled arterial blood as the endogenous tracer to assess the water permeability of BBB as a surrogate index of BBB. This paper reviews the three major types of Arterial Spin Labelling (ASL) based BBB water permeability assessment techniques and their applications in brain diseases such as Alzheimer's Disease.}, } @article {pmid36687397, year = {2023}, author = {Willumsen, N and Arber, C and Lovejoy, C and Toombs, J and Alatza, A and Weston, PSJ and Chávez-Gutiérrez, L and Hardy, J and Zetterberg, H and Fox, NC and Ryan, NS and Lashley, T and Wray, S}, title = {The PSEN1 E280G mutation leads to increased amyloid-β43 production in induced pluripotent stem cell neurons and deposition in brain tissue.}, journal = {Brain communications}, volume = {5}, number = {1}, pages = {fcac321}, pmid = {36687397}, issn = {2632-1297}, abstract = {Mutations in the presenilin 1 gene, PSEN1, which cause familial Alzheimer's disease alter the processing of amyloid precursor protein, leading to the generation of various amyloid-β peptide species. These species differ in their potential for aggregation. Mutation-specific amyloid-β peptide profiles may thereby influence pathogenicity and clinical heterogeneity. There is particular interest in comparing mutations with typical and atypical clinical presentations, such as E280G. We generated PSEN1 E280G mutation induced pluripotent stem cells from two patients and differentiated them into cortical neurons, along with previously reported PSEN1 M146I, PSEN1 R278I and two control lines. We assessed both the amyloid-β peptide profiles and presenilin 1 protein maturity. We also compared amyloid-β peptide profiles in human post-mortem brain tissue from cases with matched mutations. Amyloid-β ratios significantly differed compared with controls and between different patients, implicating mutation-specific alterations in amyloid-β ratios. Amyloid-β42:40 was increased in the M146I and both E280G lines compared with controls. Amyloid-β42:40 was not increased in the R278I line compared with controls. The amyloid-β43:40 ratio was increased in R278I and both E280G lines compared with controls, but not in M146I cells. Distinct amyloid-β peptide patterns were also observed in human brain tissue from individuals with these mutations, showing some similar patterns to cell line observations. Reduced presenilin 1 maturation was observed in neurons with the PSEN1 R278I and E280G mutations, but not the M146I mutation. These results suggest that mutation location can differentially alter the presenilin 1 protein and affect its autoendoproteolysis and processivity, contributing to the pathological phenotype. Investigating differences in underlying molecular mechanisms of familial Alzheimer's disease may inform our understanding of clinical heterogeneity.}, } @article {pmid36686717, year = {2022}, author = {Das, B and Bhardwaj, PK and Sharma, N and Sarkar, A and Haldar, PK and Mukherjee, PK}, title = {Evaluation of Mollugo oppositifolia Linn. as cholinesterase and β-secretase enzymes inhibitor.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {990926}, pmid = {36686717}, issn = {1663-9812}, abstract = {Mollugo oppositifolia Linn. is traditionally used in neurological complications. The study aimed to investigate in-vitro neuroprotective effect of the plant extracts through testing against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-secretase linked to Alzheimer's disease (AD). To understand the safety aspects, the extracts were tested for CYP450 isozymes and human hepatocellular carcinoma cell (HepG2) inhibitory potential. The heavy metal contents were estimated using atomic absorption spectroscopy (AAS). Further, the antioxidant capacities as well as total phenolic content and total flavonoid content (TFC) were measured spectrophotometrically. UPLC-QTOF-MS/MS analysis was employed to identify phytometabolites present in the extract. The interactions of the ligands with the target proteins (AChE, BChE, and BACE-1) were studied using AutoDockTools 1.5.6. The results showed that M. oppositifolia extract has more selectivity towards BChE (IC50 = 278.23 ± 1.89 μg/ml) as compared to AChE (IC50 = 322.87 ± 2.05 μg/ml). The IC50 value against β-secretase was 173.93 μg/ml. The extract showed a CC50 value of 965.45 ± 3.07 μg/ml against HepG2 cells and the AAS analysis showed traces of lead 0.02 ± 0.001 which was found to be within the WHO prescribed limits. Moreover, the IC50 values against CYP3A4 (477.03 ± 2.01 μg/ml) and CYP2D6 (249.65 ± 2.46 μg/ml) isozymes justify the safety aspects of the extract. The in silico molecular docking analysis of the target enzymes showed that the compound menthoside was found to be the most stable and showed a good docking score among all the identified metabolites. Keeping in mind the multi-targeted drug approach, the present findings suggested that M. oppositifolia extract have anti-Alzheimer's potential.}, } @article {pmid36686687, year = {2022}, author = {Gáspár, A and Hutka, B and Ernyey, AJ and Tajti, BT and Varga, BT and Zádori, ZS and Gyertyán, I}, title = {Corrigendum: Intracerebroventricularly Injected Streptozotocin Exerts Subtle Effects on the Cognitive Performance of Long-Evans Rats.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1122260}, doi = {10.3389/fphar.2022.1122260}, pmid = {36686687}, issn = {1663-9812}, abstract = {[This corrects the article DOI: 10.3389/fphar.2021.662173.].}, } @article {pmid36686668, year = {2022}, author = {Azlan, UK and Khairul Annuar, NA and Mediani, A and Aizat, WM and Damanhuri, HA and Tong, X and Yanagisawa, D and Tooyama, I and Wan Ngah, WZ and Jantan, I and Hamezah, HS}, title = {An insight into the neuroprotective and anti-neuroinflammatory effects and mechanisms of Moringa oleifera.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1035220}, pmid = {36686668}, issn = {1663-9812}, abstract = {Neurodegenerative diseases (NDs) are sporadic maladies that affect patients' lives with progressive neurological disabilities and reduced quality of life. Neuroinflammation and oxidative reaction are among the pivotal factors for neurodegenerative conditions, contributing to the progression of NDs, such as Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS) and Huntington's disease (HD). Management of NDs is still less than optimum due to its wide range of causative factors and influences, such as lifestyle, genetic variants, and environmental aspects. The neuroprotective and anti-neuroinflammatory activities of Moringa oleifera have been documented in numerous studies due to its richness of phytochemicals with antioxidant and anti-inflammatory properties. This review highlights up-to-date research findings on the anti-neuroinflammatory and neuroprotective effects of M. oleifera, including mechanisms against NDs. The information was gathered from databases, which include Scopus, Science Direct, Ovid-MEDLINE, Springer, and Elsevier. Neuroprotective effects of M. oleifera were mainly assessed by using the crude extracts in vitro and in vivo experiments. Isolated compounds from M. oleifera such as moringin, astragalin, and isoquercitrin, and identified compounds of M. oleifera such as phenolic acids and flavonoids (chlorogenic acid, gallic acid, ferulic acid, caffeic acid, kaempferol, quercetin, myricetin, (-)-epicatechin, and isoquercitrin) have been reported to have neuropharmacological activities. Therefore, these compounds may potentially contribute to the neuroprotective and anti-neuroinflammatory effects. More in-depth studies using in vivo animal models of neurological-related disorders and extensive preclinical investigations, such as pharmacokinetics, toxicity, and bioavailability studies are necessary before clinical trials can be carried out to develop M. oleifera constituents into neuroprotective agents.}, } @article {pmid36686657, year = {2022}, author = {Qu, Y and Wu, Y and Cheng, W and Wang, D and Zeng, L and Wang, Y and Li, T and Zhang, L and Yang, J and Sun, L and Ai, J}, title = {Amelioration of cognitive impairment using epigallocatechin-3-gallate in ovariectomized mice fed a high-fat diet involves remodeling with Prevotella and Bifidobacteriales.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1079313}, pmid = {36686657}, issn = {1663-9812}, abstract = {Background: Estrogen deficiency and a high-fat diet (HFD) are both risk factors for Alzheimer's disease (AD). HFD can accelerate cognitive impairment in estrogen-deficient patients, but there is currently no effective treatment. Epigallocatechin-3-galate (EGCG) is widely studied for its anti-inflammatory, anti-cancer, and anti-neurodegeneration effects. Nevertheless, whether EGCG can ameliorate cognitive impairment in HFD-fed estrogen-deficient mice has not been studied. Methods and Results: Ovariectomized (OVX) mice fed an HFD (HFOVX) for 8 weeks experienced impaired object recognition and spatial memory, but this damage was significantly attenuated by the administration of EGCG at a dose of 45 mg/kg. Through 16S rRNA gene sequencing, we found that HFOVX changed the diversity and structure of the gut microbiota in mice, which could be restored with EGCG. Further analysis showed that HFOVX exposure not only resulted in a decrease of Alloprevotella in Bacteroidetes, Lactobacillaceae in Firmicutes, and Prevotella in Bacteroidetes but also in an increase of Bifidobacteriales in Actinobacteria. EGCG effectively reversed the decrease of Prevotella and inhibited the increase of Bifidobacteriales but had no effect on the decrease of Alloprevotella or Lactobacillaceae or on the increase of Enterorhabdus in HFOVX mice. Additionally, using Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, we found that EGCG significantly reversed the five functional gut microbiota genes elevated by HFOVX, including iron complex transport system substrate-binding protein, iron complex transport system permease protein, 3-oxoacyl- [acyl-carrier protein] reductase, transketolase, and 8-oxo-dGTP diphosphatase. Conclusions: We concluded that EGCG improved cognitive impairment in mice with estrogen deficiency exacerbated by an HFD involved a rebuilding of the disrupted gut microbiota composition.}, } @article {pmid36686482, year = {2022}, author = {Wang, Y and Zhang, J and Zhang, Y and Yao, J}, title = {Bibliometric analysis of global research profile on ketogenic diet therapies in neurological diseases: Beneficial diet therapies deserve more attention.}, journal = {Frontiers in endocrinology}, volume = {13}, number = {}, pages = {1066785}, pmid = {36686482}, issn = {1664-2392}, mesh = {Humans ; *Nervous System Diseases ; Ketones ; *Diet, Ketogenic ; *Alzheimer Disease ; Bibliometrics ; }, abstract = {BACKGROUND: The protective effects of Ketogenic Diet Therapies (KDTs) on neurological diseases have been extensively studied over the past two decades. The purpose of this study was to quantitatively and qualitatively analyze the publication of KDTs in the neurological field from 2000 to 2021.

METHODS: A literature search was performed on June 7th, 2022, using the search terms: (("ketone" OR "ketogenic" OR "*hydroxybuty*") AND ("neuro*")) in the WoSCC database. Collected data were further analyzed using VOSviewer, CiteSpace and other online bibliometric websites. The annual publication volume and citation trends were summarized. The collaborations among highly cited countries, institutions, authors and journals were visualized. The co-citation analysis of highly cited references and journals were also visualized. Moreover, the research focuses and fronts were revealed by co-occurrence analysis and burst keywords detection.

RESULTS: A total of 2808 publications with 88,119 citations were identified. From 2000-2021, the number of publications and citations presented rising trends. The United States was the country with an overwhelming number of publications and cited times. Johns Hopkins University was the most contributory institution. Kossoff Eric H was the author with the largest number of publications. And Epilepsia was both the largest publisher and the most frequently cited journal. The keywords of intense interest involved "Modified Atkins Diet", "Temporal Lobe Epilepsy", "Alzheimer's Disease", "Parkinson's Disease", "Cerebral Blood Flow", "Neuroinflammation", "Oxidative Stress", "Metabolism" and "Mitochondria".

CONCLUSION: We presented the global trend of KDTs in neurological diseases and provided important information for relevant researchers in a bibliometric way. This bibliometric study revealed that treating epilepsy, neuroprotection and functional effects of KDTs on mitochondria and oxidative stress have been the spotlight from 2000 to 2021. These have emerged as the basis for transformation from basic research to clinical application of KDTs.}, } @article {pmid36685865, year = {2022}, author = {Tang, C and Deng, L and Luo, Q and He, G}, title = {Identification of oxidative stress-related genes and potential mechanisms in atherosclerosis.}, journal = {Frontiers in genetics}, volume = {13}, number = {}, pages = {998954}, pmid = {36685865}, issn = {1664-8021}, abstract = {Atherosclerosis (AS) is the main cause of death in individuals with cardiovascular and cerebrovascular diseases. A growing body of evidence suggests that oxidative stress plays an essential role in Atherosclerosis pathology. The aim of this study was to determine genetic mechanisms associated with Atherosclerosis and oxidative stress, as well as to construct a diagnostic model and to investigate its immune microenvironment. Seventeen oxidative stress-related genes were identified. A four-gene diagnostic model was constructed using the least absolute shrinkage and selection operator (LASSO) algorithm based on these 17 genes. The area under the Receiver Operating Characteristic (ROC) curve (AUC) was 0.967. Based on the GO analysis, cell-substrate adherens junction and focal adhesion were the most enriched terms. KEGG analysis revealed that these overlapping genes were enriched in pathways associated with Alzheimer's disease and Parkinson's disease, as well as with prion disease pathways and ribosomes. Immune cell infiltration correlation analysis showed that the immune cells with significant differences were CD4 memory activated T cells and follicular helper T cells in the GSE43292 dataset and CD4 naïve T cells and CD4 memory resting T cells in the GSE57691 dataset. We identified 17 hub genes that were closely associated with oxidative stress in AS and constructed a four-gene (aldehyde dehydrogenase six family member A1 (ALDH6A1), eukaryotic elongation factor 2 kinase (EEF2K), glutaredoxin (GLRX) and l-lactate dehydrogenase B (LDHB)) diagnostic model with good accuracy. The four-gene diagnostic model was also found to have good discriminatory efficacy for the immune cell infiltration microenvironment of AS. Overall, these findings provide valuable information and directions for future research into Atherosclerosis diagnosis and aid in the discovery of biological mechanisms underlying AS with oxidative stress.}, } @article {pmid36685766, year = {2022}, author = {Tiwari, D and Mittal, N and Jha, HC}, title = {Unraveling the links between neurodegeneration and Epstein-Barr virus-mediated cell cycle dysregulation.}, journal = {Current research in neurobiology}, volume = {3}, number = {}, pages = {100046}, pmid = {36685766}, issn = {2665-945X}, abstract = {The Epstein-Barr virus is a well-known cell cycle modulator. To establish successful infection in the host, EBV alters the cell cycle at multiple steps via antigens such as EBNAs, LMPs, and certain other EBV-encoded transcripts. Interestingly, several recent studies have indicated the possibility of EBV's neurotrophic potential. However, the effects and outcomes of EBV infection in the CNS are under-explored. Additionally, more and more epidemiological evidence implicates the cell-cycle dysregulation in neurodegeneration. Numerous hypotheses which describe the triggers that force post-mitotic neurons to re-enter the cell cycle are prevalent. Apart from the known genetic and epigenetic factors responsible, several reports have shown the association of microbial infections with neurodegenerative pathology. Although, studies implicating the herpesvirus family members in neurodegeneration exist, the involvement of Epstein-Barr virus (EBV), in particular, is under-evaluated. Interestingly, a few clinical studies have reported patients of AD or PD to be seropositive for EBV. Based on the findings mentioned above, in this review, we propose that EBV infection in neurons could drive it towards neurodegeneration through dysregulation of cell-cycle events and induction of apoptosis.}, } @article {pmid36685605, year = {2022}, author = {Chen, J and Dai, AX and Tang, HL and Lu, CH and Liu, HX and Hou, T and Lu, ZJ and Kong, N and Peng, XY and Lin, KX and Zheng, ZD and Xu, SL and Ying, XF and Ji, XY and Pan, H and Wu, J and Zeng, X and Wei, NL}, title = {Increase of ALCAM and VCAM-1 in the plasma predicts the Alzheimer's disease.}, journal = {Frontiers in immunology}, volume = {13}, number = {}, pages = {1097409}, pmid = {36685605}, issn = {1664-3224}, mesh = {Humans ; *Alzheimer Disease/pathology ; Vascular Cell Adhesion Molecule-1 ; Intercellular Adhesion Molecule-1 ; Activated-Leukocyte Cell Adhesion Molecule ; Neural Cell Adhesion Molecules ; }, abstract = {Cell adhesion molecules (CAM) are crucial in several pathological inflammation processes in Alzheimer's disease (AD). However, their potential for clinical diagnostics remains unknown. The present investigation evaluated the clinical significance of ALCAM, VCAM-1, NCAM, and ICAM-1 levels in the plasma of participants with cognitive impairment (44 patients with mild cognitive impairment, 71 patients with Alzheimer's dementia, and 18 patients with other dementia) and 28 controls with normal cognitive ability. We also detected plasma levels of multiple inflammatory factors (IFN-gamma, IL-18, IL-1beta, IL-13, IL-8, IL-7, CCL11, MCP-1, TSLP, IL-10, BDNF, IL-17, IL-5, TREM-1) using Multiplex liquid chip and plasma levels of Abeta1-42 and Abeta1-40 using liquid-phase flow cytometry (FCM). Our findings demonstrated a correlation of ALCAM and VCAM-1 with age, the severity of cognitive decline, and MTA, but no significant difference between groups for NCAM and ICAM-1. ALCAM and VCAM-1 both demonstrated a positive correlation with the degree of atrophy in the medial temporal lobe structure. Further analysis revealed no significant correlation in plasma between VCAM-1, ALCAM and Abeta1-40, Abeta1-42. Nevertheless, there was a significant correlation between VCAM-1, ALCAM and many inflammatory factors. Furthermore, the predictive value of ALCAM and VCAM-1 for AD was assessed using a multi-parameter regression model. ALCAM and VCAM-1 in combination with ApoE4, education, age, and MMSE could predict AD with high precision (AUC=0.891; AIC=146.9) without imaging diagnosis. ALCAM and VCAM-1 combination improved the predictive accuracy significantly. In a nutshell, these findings revealed ALCAM and VCAM-1 as reliable indicators of Alzheimer's disease.}, } @article {pmid36685287, year = {2022}, author = {Gelfo, F and Serra, L and Petrosini, L}, title = {New prospects on cerebellar reserve: Remarks on neuroprotective effects of experience in animals and humans.}, journal = {Frontiers in systems neuroscience}, volume = {16}, number = {}, pages = {1088587}, pmid = {36685287}, issn = {1662-5137}, abstract = {The ability of the brain to change structure and function in response to experience accounts for its ability to successfully adapt to the environment in both learning processes and unique phases, such as during development and repair. On this basis, the occurrence of the brain, cognitive, and neural reserves has been advanced to explain the discrepancies between the extent of neurological damage and the severity of clinical manifestations described in patients with different life span experiences. Research on this topic highlighted the neuroprotective role of complex stimulations, allowing the brain to better cope with the damage. This framework was initially developed by observing patients with Alzheimer's disease, and it has since been progressively expanded to multifarious pathological states. The cerebellum is known to be particularly responsive to experience through extensive plastic rearrangements. The neuroprotective value exerted by reserve mechanisms appears to be suitable for basic neuronal plasticity in the cerebellum. Thus, it is of primary interest to deepen our understanding of how life experiences modify individuals' cerebellar morphology and functionality. The present study is aimed at analyzing the evidence provided on this topic by animal and human studies. For animals, we considered the studies in which subjects were submitted to enhanced stimulations before the damage occurred. For humans, we considered studies in which previous lifelong high-level experiences were associated with superior cerebellar abilities to cope with injury. Detailed indications of the processes underlying cerebellar reserves may be important in proposing effective interventions for patients suffering from pathologies that directly or indirectly damage cerebellar functionality.}, } @article {pmid36685284, year = {2022}, author = {Dalmasso, MC and Arán, M and Galeano, P and Perin, S and Giavalisco, P and Martino Adami, PV and Novack, GV and Castaño, EM and Cuello, AC and Scherer, M and Maier, W and Wagner, M and Riedel-Heller, S and Ramirez, A and Morelli, L}, title = {Nicotinamide as potential biomarker for Alzheimer's disease: A translational study based on metabolomics.}, journal = {Frontiers in molecular biosciences}, volume = {9}, number = {}, pages = {1067296}, pmid = {36685284}, issn = {2296-889X}, abstract = {Introduction: The metabolic routes altered in Alzheimer's disease (AD) brain are poorly understood. As the metabolic pathways are evolutionarily conserved, the metabolic profiles carried out in animal models of AD could be directly translated into human studies. Methods: We performed untargeted Nuclear Magnetic Resonance metabolomics in hippocampus of McGill-R-Thy1-APP transgenic (Tg) rats, a model of AD-like cerebral amyloidosis and the translational potential of these findings was assessed by targeted Gas Chromatography-Electron Impact-Mass Spectrometry in plasma of participants in the German longitudinal cohort AgeCoDe. Results: In rat hippocampus 26 metabolites were identified. Of these 26 metabolites, nine showed differences between rat genotypes that were nominally significant. Two of them presented partial least square-discriminant analysis (PLS-DA) loadings with the larger absolute weights and the highest Variable Importance in Projection (VIP) scores and were specifically assigned to nicotinamide adenine dinucleotide (NAD) and nicotinamide (Nam). NAD levels were significantly decreased in Tg rat brains as compared to controls. In agreement with these results, plasma of AD patients showed significantly reduced levels of Nam in respect to cognitively normal participants. In addition, high plasma levels of Nam showed a 27% risk reduction of progressing to AD dementia within the following 2.5 years, this hazard ratio is lost afterwards. Discussion: To our knowledge, this is the first report showing that a decrease of Nam plasma levels is observed couple of years before conversion to AD, thereby suggesting its potential use as biomarker for AD progression.}, } @article {pmid36685247, year = {2022}, author = {Juiz, JM and Fuentes Santamaría, V and Scheper, V and Lenarz, T}, title = {Editorial: Deafness, aging and Alzheimer's disease: Neurobiological links and therapy options.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {1114383}, pmid = {36685247}, issn = {1662-4548}, } @article {pmid36685238, year = {2022}, author = {Zhang, G and Nie, X and Liu, B and Yuan, H and Li, J and Sun, W and Huang, S}, title = {A multimodal fusion method for Alzheimer's disease based on DCT convolutional sparse representation.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {1100812}, pmid = {36685238}, issn = {1662-4548}, abstract = {INTRODUCTION: The medical information contained in magnetic resonance imaging (MRI) and positron emission tomography (PET) has driven the development of intelligent diagnosis of Alzheimer's disease (AD) and multimodal medical imaging. To solve the problems of severe energy loss, low contrast of fused images and spatial inconsistency in the traditional multimodal medical image fusion methods based on sparse representation. A multimodal fusion algorithm for Alzheimer' s disease based on the discrete cosine transform (DCT) convolutional sparse representation is proposed.

METHODS: The algorithm first performs a multi-scale DCT decomposition of the source medical images and uses the sub-images of different scales as training images, respectively. Different sparse coefficients are obtained by optimally solving the sub-dictionaries at different scales using alternating directional multiplication method (ADMM). Secondly, the coefficients of high-frequency and low-frequency subimages are inverse DCTed using an improved L1 parametric rule combined with improved spatial frequency novel sum-modified SF (NMSF) to obtain the final fused images.

RESULTS AND DISCUSSION: Through extensive experimental results, we show that our proposed method has good performance in contrast enhancement, texture and contour information retention.}, } @article {pmid36685237, year = {2022}, author = {Piñol-Ripoll, G and Lima, MMS and Li, SB and Targa, ADS}, title = {Editorial: The underlying relationship between sleep and neurodegenerative diseases.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {1117265}, pmid = {36685237}, issn = {1662-4548}, } @article {pmid36685078, year = {2023}, author = {Kleawyothatis, W and Jattujan, P and Chumphoochai, K and Chalorak, P and Sobhon, P and Meemon, K}, title = {Holothuria scabra extracts confer neuroprotective effect in C. elegans model of Alzheimer's disease by attenuating amyloid-β aggregation and toxicity.}, journal = {Journal of traditional and complementary medicine}, volume = {13}, number = {1}, pages = {93-104}, pmid = {36685078}, issn = {2225-4110}, abstract = {BACKGROUND AND AIM: Alzheimer's disease (AD) is the most common aged-related neurodegenerative disorder that is associated with the toxic amyloid-β (Aβ) aggregation in the brain. While the efficacies of available drugs against AD are still limited, natural products have been shown to possess neuroprotective potential for prevention and therapy of AD. This study aimed to investigate the neuroprotective effects of H. scabra extracts against Aβ aggregation and proteotoxicity in C. elegans model of Alzheimer's diseases.

EXPERIMENTAL PROCEDURE: Whole bodies (WB) and body wall (BW) of H. scabra were extracted and fractionated into ethyl acetate (WBEA, BWEA), butanol (WBBU, BWBU), and ethanol (BWET). Then C. elegans AD models were treated with these fractions and investigated for Aβ aggregation and polymerization, biochemical and behavioral changes, and level of oxidative stress, as well as lifespan extension.

RESULTS AND CONCLUSION: C. elegans AD model treated with H. scabra extracts, especially triterpene glycoside-rich ethyl acetate and butanol fractions, exhibited significant reduction of Aβ deposition. These H. scabra extracts also attenuated the paralysis behavior and improved the neurological defects in chemotaxis caused by Aβ aggregation. Immunoblot analysis revealed decreased level of Aβ oligomeric forms and the increased level of Aβ monomers after treatments with H. scabra extracts. In addition, H. scabra extracts reduced reactive oxygen species and increased the mean lifespan of the treated AD worms. In conclusion, this study demonstrated strong evidence of anti-Alzheimer effects by H. scabra extracts, implying that these extracts can potentially be applied as natural preventive and therapeutic agents for AD.

Alzheimer's disease, Neurodegenerative disorder, Traditional medicine, Experimental model systems, Molecular biology.}, } @article {pmid36684988, year = {2022}, author = {Toro-Devia, O and Leyton, G}, title = {COVID-19 pandemic and mental healthcare: Impact on health insurance with guaranteed universal access in Chile.}, journal = {Frontiers in public health}, volume = {10}, number = {}, pages = {1005033}, pmid = {36684988}, issn = {2296-2565}, mesh = {Humans ; Chile/epidemiology ; Pandemics ; *COVID-19/epidemiology ; Insurance, Health ; *Mental Health Services ; }, abstract = {BACKGROUND: Universal health coverage (UHC) is a goal of the member states of the United Nations. The negative impact of the COVID-19 pandemic on mental health, inequalities in access to care, and financing gaps set a problematic scenario for universal mental health coverage. In Latin America, depression and anxiety disorders have increased by more than 30%. Chile implemented a reform for UHC in 2005 generating a mandatory guaranteed plan for health insurance (GES) that covers schizophrenia, depression, bipolar disorders, and Alzheimer's disease. We assume that the pandemic increased cases of mental illness in GES of public and private insurance.

OBJECTIVES: This study aimed to explore the effects of the pandemic on the use of the GES mental health plan of public and private insurance.

METHODS: A descriptive analysis of secondary data from public and private insurance on the use and expenditure of the GES plan in mental illness between 2005 and 2020 was carried out. An aggregate analysis of the use of psychiatric consultations without a guaranteed plan and sick leave was performed.

RESULTS: Between 2005 and 2020, 18.5% of GES cases corresponded to four mental health illnesses (1,682,021 cases). Public insurance covered 80% of cases. In the pandemic, cases of mental illness fell by 10.5% in public insurance and 28.7% in private ones, reducing spending by 33 and 6.2%, respectively. Psychiatric consultations without using the GES plan doubled in 2020 in private insurance, and medical discharges due to mental illness also increased. Leave due to mental illness increased by 20% in both types of insurance.

CONCLUSION: The results suggest that the demand for mental healthcare increased during the pandemic, but public and private health insurance reduced admissions to the GES universal plan for schizophrenia, depression, and bipolar disorder. A universal guaranteed plan in an individual contribution system can have essential weaknesses for people when the principles of social security are not complied with, especially concerning the solidarity of the health insurance system.}, } @article {pmid36684932, year = {2022}, author = {Lu, K and Xiong, X and Li, M and Yuan, J and Luo, Y and Friedman, DB}, title = {Trends in prevalence, health disparities, and early detection of dementia: A 10-year nationally representative serial cross-sectional and cohort study.}, journal = {Frontiers in public health}, volume = {10}, number = {}, pages = {1021010}, pmid = {36684932}, issn = {2296-2565}, mesh = {Middle Aged ; Humans ; Male ; Female ; Aged ; *Dementia/diagnosis/epidemiology ; Cohort Studies ; Prevalence ; Cross-Sectional Studies ; *Cognitive Dysfunction/diagnosis/epidemiology ; }, abstract = {OBJECTIVE: To identify trends in the prevalence of mild cognitive impairment (MCI) and dementia, and to determine risk factors associated with the early detection of dementia among U.S. middle-aged and older adults.

METHODS: We used 10-year nationally representative longitudinal data from the Health and Retirement Study (HRS) (2006-2016). Adults aged 55 years or older were included to examine the trend. To identify the associated factors, adults aged 55 years or older in 2006 who developed MCI or dementia in subsequent waves until the 2016 wave were included. Early and late detection of dementia were identified using the Langa-Weir classification of cognitive function. Multivariate logistic regression models were used to identify factors associated with the early detection of dementia.

RESULTS: The sample size for the analysis of the prevalence of MCI and dementia ranged from 14,935 to 16,115 in the six survey years, and 3,729 individuals were identified to determine associated factors of the early detection of dementia. Among them, participants aged 65 years or older accounted for 77.9%, and male participants accounted for 37.2%. The 10-year prevalence of MCI and dementia was 14.5 and 6.6%, respectively. We also found decreasing prevalence trends in MCI (from 14.9 to 13.6%) and dementia (from 7.4 to 6.0%) overall in the past decade. Using logistic regression controlling for the year, non-Hispanic black (MCI: OR = 2.83, P < 0.001; dementia: OR = 2.53, P < 0.001) and Hispanic (MCI: OR = 2.52, P < 0.001; dementia: OR = 2.62, P < 0.001) had a higher prevalence of both MCI and dementia than non-Hispanic white participants. In addition, men had a lower prevalence of MCI (OR = 0.94, P = 0.035) and dementia (OR = 0.84, P < 0.001) compared to women. Associated factors of the early detection of dementia include age, gender, race, educational attainment, stroke, arthritis diseases, heart problems, and pensions.

CONCLUSION: This study found a decreasing trend in the prevalence of MCI and dementia in the past decade and associated racial/ethnic and gender disparities among U.S. middle-aged and older adults. Healthcare policies and strategies may be needed to address health disparities in the prevalence and take the associated factors of the early detection of dementia into account in clinical settings.}, } @article {pmid36684491, year = {2023}, author = {Singh, V and Mishra, VN and Thakur, MK}, title = {Identification of Plasma Proteomic Biomarkers in Patients with Mild Cognitive Impairment.}, journal = {Indian journal of clinical biochemistry : IJCB}, volume = {38}, number = {1}, pages = {33-41}, pmid = {36684491}, issn = {0970-1915}, abstract = {Plasma proteomic profiling may provide novel biomarkers for the identification of mild cognitive impairment (MCI). The early diagnosis of MCI still remains a challenging task due to its diverse origin. Currently, molecular approaches have been used to identify MCI diversified origin as its onset is governed by a variety of molecular changes. Therefore, we aimed to find out molecular alteration in plasma using proteomics in patients with MCI for early detection of prodromal Alzheimer's disease (AD). To achieve this, we performed two-dimensional (2-D) gel electrophoresis coupled with MALDI-TOF/MS, which is used to analyze the differentially expressed proteins. In our study, we found three significantly altered proteins. Out of three differentially expressed proteins, one was downregulated and two were upregulated in MCI individuals as compared to control. Further, In silico analysis showed that identified proteins are involved in pathways such as complement and coagulation cascades, platelet activation and AD. STRING interaction network analysis revealed that the majority of proteins including apolipoprotein E (APO-E) have a common association with Transthyretin (TTR) and fibrinogen chain beta (FGB) protein. This suggests that APO-E, TTR and FGB are the key proteins with which other proteins interact to exert other biological functions. Conclusively, these proteins showing differential expression in the plasma might be used as a potent signature in blood for the diagnosis of MCI individuals.}, } @article {pmid36684422, year = {2022}, author = {Giovenale, AMG and Ruotolo, G and Soriano, AA and Turco, EM and Rotundo, G and Casamassa, A and D'Anzi, A and Vescovi, AL and Rosati, J}, title = {Deepening the understanding of CNVs on chromosome 15q11-13 by using hiPSCs: An overview.}, journal = {Frontiers in cell and developmental biology}, volume = {10}, number = {}, pages = {1107881}, pmid = {36684422}, issn = {2296-634X}, abstract = {The human α7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is widely expressed in the central and peripheral nervous systems. This receptor is implicated in both brain development and adult neurogenesis thanks to its ability to mediate acetylcholine stimulus (Ach). Copy number variations (CNVs) of CHRNA7 gene have been identified in humans and are genetically linked to cognitive impairments associated with multiple disorders, including schizophrenia, bipolar disorder, epilepsy, Alzheimer's disease, and others. Currently, α7 receptor analysis has been commonly performed in animal models due to the impossibility of direct investigation of the living human brain. But the use of model systems has shown that there are very large differences between humans and mice when researchers must study the CNVs and, in particular, the CNV of chromosome 15q13.3 where the CHRNA7 gene is present. In fact, human beings present genomic alterations as well as the presence of genes of recent origin that are not present in other model systems as well as they show a very heterogeneous symptomatology that is associated with both their genetic background and the environment where they live. To date, the induced pluripotent stem cells, obtained from patients carrying CNV in CHRNA7 gene, are a good in vitro model for studying the association of the α7 receptor to human diseases. In this review, we will outline the current state of hiPSCs technology applications in neurological diseases caused by CNVs in CHRNA7 gene. Furthermore, we will discuss some weaknesses that emerge from the overall analysis of the published articles.}, } @article {pmid36684104, year = {2023}, author = {Manero, A and Crawford, KE and Prock-Gibbs, H and Shah, N and Gandhi, D and Coathup, MJ}, title = {Improving disease prevention, diagnosis, and treatment using novel bionic technologies.}, journal = {Bioengineering & translational medicine}, volume = {8}, number = {1}, pages = {e10359}, pmid = {36684104}, issn = {2380-6761}, abstract = {Increased human life expectancy, due in part to improvements in infant and childhood survival, more active lifestyles, in combination with higher patient expectations for better health outcomes, is leading to an extensive change in the number, type and manner in which health conditions are treated. Over the next decades as the global population rapidly progresses toward a super-aging society, meeting the long-term quality of care needs is forecast to present a major healthcare challenge. The goal is to ensure longer periods of good health, a sustained sense of well-being, with extended periods of activity, social engagement, and productivity. To accomplish these goals, multifunctionalized interfaces are an indispensable component of next generation medical technologies. The development of more sophisticated materials and devices as well as an improved understanding of human disease is forecast to revolutionize the diagnosis and treatment of conditions ranging from osteoarthritis to Alzheimer's disease and will impact disease prevention. This review examines emerging cutting-edge bionic materials, devices and technologies developed to advance disease prevention, and medical care and treatment in our elderly population including developments in smart bandages, cochlear implants, and the increasing role of artificial intelligence and nanorobotics in medicine.}, } @article {pmid36684089, year = {2023}, author = {Leinenga, G and Bodea, LG and Schröder, J and Sun, G and Zhou, Y and Song, J and Grubman, A and Polo, JM and Götz, J}, title = {Transcriptional signature in microglia isolated from an Alzheimer's disease mouse model treated with scanning ultrasound.}, journal = {Bioengineering & translational medicine}, volume = {8}, number = {1}, pages = {e10329}, pmid = {36684089}, issn = {2380-6761}, abstract = {Transcranial scanning ultrasound combined with intravenously injected microbubbles (SUS[+MB]) has been shown to transiently open the blood-brain barrier and reduce the amyloid-β (Aβ) pathology in the APP23 mouse model of Alzheimer's disease (AD). This has been accomplished through the activation of microglial cells; however, their response to the SUS treatment is incompletely understood. Here, wild-type (WT) and APP23 mice were subjected to SUS[+MB], using nonsonicated mice as sham controls. After 48 h, the APP23 mice were injected with methoxy-XO4 to label Aβ aggregates, followed by microglial isolation into XO4[+] and XO4[-] populations using flow cytometry. Both XO4[+] and XO4[-] cells were subjected to RNA sequencing and transcriptome profiling. The analysis of the microglial cells revealed a clear segregation depending on genotype (AD model vs. WT mice) and Aβ internalization (XO4[+] vs. XO4[-] microglia), but interestingly, no differences were found between SUS[+MB] and sham in WT mice. Differential gene expression analysis in APP23 mice detected 278 genes that were significantly changed by SUS[+MB] in the XO4[+] cells (248 up/30 down) and 242 in XO[-] cells (225 up/17 down). Pathway analysis highlighted differential expression of genes related to the phagosome pathway and marked upregulation of cell cycle-related transcripts in XO4[+] and XO4- microglia isolated from SUS[+MB]-treated APP23 mice. Together, this highlights the complexity of the microglial response to transcranial ultrasound, with potential applications for the treatment of AD.}, } @article {pmid36684083, year = {2023}, author = {Chopade, P and Chopade, N and Zhao, Z and Mitragotri, S and Liao, R and Chandran Suja, V}, title = {Alzheimer's and Parkinson's disease therapies in the clinic.}, journal = {Bioengineering & translational medicine}, volume = {8}, number = {1}, pages = {e10367}, pmid = {36684083}, issn = {2380-6761}, abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are the most prevalent neurodegenerative diseases, affecting millions and costing billions each year in the United States alone. Despite tremendous progress in developing therapeutics that manage the symptoms of these two diseases, the scientific community has yet to develop a treatment that effectively slows down, inhibits, or cures neurodegeneration. To gain a better understanding of the current therapeutic frontier for the treatment of AD and PD, we provide a review on past and present therapeutic strategies for these two major neurodegenerative disorders in the clinical trial process. We briefly recap currently US Food and Drug Administration-approved therapies, and then explore trends in clinical trials across the variables of therapy mechanism of disease intervention, administration route, use of delivery vehicle, and outcome measures, across the clinical phases over time for "Drug" and "Biologic" therapeutics. We then present the success rate of past clinical trials and analyze the intersections in therapeutic approaches for AD and PD, revealing the shift in clinical trials away from therapies targeting neurotransmitter systems that provide symptomatic relief, and towards anti-aggregation, anti-inflammatory, anti-oxidant, and regeneration strategies that aim to inhibit the root causes of disease progression. We also highlight the evolving distribution of the types of "Biologic" therapies investigated, and the slowly increasing yet still severe under-utilization of delivery vehicles for AD and PD therapeutics. We then briefly discuss novel preclinical strategies for treating AD and PD. Overall, this review aims to provide a succinct overview of the clinical landscape of AD and PD therapies to better understand the field's therapeutic strategy in the past and the field's evolution in approach to the present, to better inform how to effectively treat AD and PD in the future.}, } @article {pmid36684015, year = {2022}, author = {Rodriguez, G and Fisher, DW and McClarty, B and Montalvo-Ortiz, J and Cui, Q and Chan, CS and Dong, H}, title = {Histone deacetylase inhibitors mitigate antipsychotic risperidone-induced motor side effects in aged mice and in a mouse model of Alzheimer's disease.}, journal = {Frontiers in psychiatry}, volume = {13}, number = {}, pages = {1020831}, pmid = {36684015}, issn = {1664-0640}, support = {R01 MH109466/MH/NIMH NIH HHS/United States ; R21 MH100919/MH/NIMH NIH HHS/United States ; }, abstract = {Antipsychotic drugs are still widely prescribed to control various severe neuropsychiatric symptoms in the elderly and dementia patients although they are off-label use in the United States. However, clinical practice shows greater side effects and lower efficacy of antipsychotics for this vulnerable population and the mechanisms surrounding this aged-related sensitivity are not well understood. Our previous studies have shown that aging-induced epigenetic alterations may be involved in the increasing severity of typical antipsychotic haloperidol induced side effects in aged mice. Still, it is unknown if similar epigenetic mechanisms extend to atypical antipsychotics, which are most often prescribed to dementia patients combined with severe neuropsychiatric symptoms. In this study, we report that atypical antipsychotic risperidone also causes increased motor side effect behaviors in aged mice and 5xFAD mice. Histone deacetylase (HDAC) inhibitor Valproic Acid and Entinostat can mitigate the risperidone induced motor side effects. We further showed besides D2R, reduced expression of 5-HT2A, one of the primary atypical antipsychotic targets in the striatum of aged mice that are also mitigated by HDAC inhibitors. Finally, we demonstrate that specific histone acetylation mark H3K27 is hypoacetylated at the 5htr2a and Drd2 promoters in aged mice and can be reversed with HDAC inhibitors. Our work here establishes evidence for a mechanism where aging reduces expression of 5-HT2A and D2R, the key atypical antipsychotic drug targets through epigenetic alteration. HDAC inhibitors can restore 5-HT2A and D2R expression in aged mice and decrease the motor side effects in aged and 5xFAD mice.}, } @article {pmid36684006, year = {2022}, author = {Bellou, E and Escott-Price, V}, title = {Are Alzheimer's and coronary artery diseases genetically related to longevity?.}, journal = {Frontiers in psychiatry}, volume = {13}, number = {}, pages = {1102347}, pmid = {36684006}, issn = {1664-0640}, abstract = {INTRODUCTION: In the last decade researchers have attempted to investigate the shared genetic architecture of longevity and age-related diseases and assess whether the increased longevity in certain people is due to protective alleles in the risk genes for a particular condition or whether there are specific "longevity" genes increasing the lifespan independently of age-related conditions' risk genes. The aim of this study was to investigate the shared genetic component between longevity and two age-related conditions.

METHODS: We performed a cross-trait meta-analysis of publicly available genome-wide data for Alzheimer's disease, coronary artery disease and longevity using a subset-based approach provided by the R package ASSET.

RESULTS: Despite the lack of strong genetic correlation between longevity and the two diseases, we identified 38 genome-wide significant lead SNPs across 22 independent genomic loci. Of them 6 were found to be potentially shared among the three traits mapping to genes including DAB2IP, DNM2, FCHO1, CLPTM1, and SNRPD2. We also identified 19 novel genome-wide associations for the individual traits in this study. Functional annotations and biological pathway enrichment analyses suggested that pleiotropic variants are involved in clathrin-mediated endocytosis and plasma lipoprotein and neurotransmitter clearance processes.

DISCUSSION: In summary, we have been able to advance in the knowledge of the genetic overlap existing among longevity and the two most common age-related disorders.}, } @article {pmid36683856, year = {2022}, author = {Xie, D and Deng, T and Zhai, Z and Sun, T and Xu, Y}, title = {The cellular model for Alzheimer's disease research: PC12 cells.}, journal = {Frontiers in molecular neuroscience}, volume = {15}, number = {}, pages = {1016559}, pmid = {36683856}, issn = {1662-5099}, abstract = {Alzheimer's disease (AD) is a common age-related neurodegenerative disease characterized by progressive cognitive decline and irreversible memory impairment. Currently, several studies have failed to fully elucidate AD's cellular and molecular mechanisms. For this purpose, research on related cellular models may propose potential predictive models for the drug development of AD. Therefore, many cells characterized by neuronal properties are widely used to mimic the pathological process of AD, such as PC12, SH-SY5Y, and N2a, especially the PC12 pheochromocytoma cell line. Thus, this review covers the most systematic essay that used PC12 cells to study AD. We depict the cellular source, culture condition, differentiation methods, transfection methods, drugs inducing AD, general approaches (evaluation methods and metrics), and in vitro cellular models used in parallel with PC12 cells.}, } @article {pmid36683855, year = {2022}, author = {Ramamurthy, E and Welch, G and Cheng, J and Yuan, Y and Gunsalus, L and Bennett, DA and Tsai, LH and Pfenning, AR}, title = {Cell type-specific histone acetylation profiling of Alzheimer's disease subjects and integration with genetics.}, journal = {Frontiers in molecular neuroscience}, volume = {15}, number = {}, pages = {948456}, pmid = {36683855}, issn = {1662-5099}, abstract = {We profile genome-wide histone 3 lysine 27 acetylation (H3K27ac) of 3 major brain cell types from hippocampus and dorsolateral prefrontal cortex (dlPFC) of subjects with and without Alzheimer's Disease (AD). We confirm that single nucleotide polymorphisms (SNPs) associated with late onset AD (LOAD) show a strong tendency to reside in microglia-specific gene regulatory elements. Despite this significant colocalization, we find that microglia harbor more acetylation changes associated with age than with amyloid-β (Aβ) load. In contrast, we detect that an oligodendrocyte-enriched glial (OEG) population contains the majority of differentially acetylated peaks associated with Aβ load. These differential peaks reside near both early onset risk genes (APP, PSEN1, PSEN2) and late onset AD risk loci (including BIN1, PICALM, CLU, ADAM10, ADAMTS4, SORL1, FERMT2), Aβ processing genes (BACE1), as well as genes involved in myelinating and oligodendrocyte development processes. Interestingly, a number of LOAD risk loci associated with differentially acetylated risk genes contain H3K27ac peaks that are specifically enriched in OEG. These findings implicate oligodendrocyte gene regulation as a potential mechanism by which early onset and late onset risk genes mediate their effects, and highlight the deregulation of myelinating processes in AD. More broadly, our dataset serves as a resource for the study of functional effects of genetic variants and cell type specific gene regulation in AD.}, } @article {pmid36683852, year = {2022}, author = {Kamikubo, Y and Jin, H and Zhou, Y and Niisato, K and Hashimoto, Y and Takasugi, N and Sakurai, T}, title = {Ex vivo analysis platforms for monitoring amyloid precursor protein cleavage.}, journal = {Frontiers in molecular neuroscience}, volume = {15}, number = {}, pages = {1068990}, pmid = {36683852}, issn = {1662-5099}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder and the most common cause of dementia in the elderly. The presence of large numbers of senile plaques, neurofibrillary tangles, and cerebral atrophy is the characteristic feature of AD. Amyloid β peptide (Aβ), derived from the amyloid precursor protein (APP), is the main component of senile plaques. AD has been extensively studied using methods involving cell lines, primary cultures of neural cells, and animal models; however, discrepancies have been observed between these methods. Dissociated cultures lose the brain's tissue architecture, including neural circuits, glial cells, and extracellular matrix. Experiments with animal models are lengthy and require laborious monitoring of multiple parameters. Therefore, it is necessary to combine these experimental models to understand the pathology of AD. An experimental platform amenable to continuous observation and experimental manipulation is required to analyze long-term neuronal development, plasticity, and progressive neurodegenerative diseases. In the current study, we provide a practical method to slice and cultivate rodent hippocampus to investigate the cleavage of APP and secretion of Aβ in an ex vivo model. Furthermore, we provide basic information on Aβ secretion using slice cultures. Using our optimized method, dozens to hundreds of long-term stable slice cultures can be coordinated simultaneously. Our findings are valuable for analyses of AD mouse models and senile plaque formation culture models.}, } @article {pmid36683586, year = {2022}, author = {van den Bos, MAJ and Menon, P and Vucic, S}, title = {Cortical hyperexcitability and plasticity in Alzheimer's disease: developments in understanding and management.}, journal = {Expert review of neurotherapeutics}, volume = {22}, number = {11-12}, pages = {981-993}, doi = {10.1080/14737175.2022.2170784}, pmid = {36683586}, issn = {1744-8360}, mesh = {Humans ; *Alzheimer Disease/therapy ; Transcranial Magnetic Stimulation/methods ; Anxiety ; }, abstract = {INTRODUCTION: Transcranial magnetic stimulation (TMS) is a non-invasive neurophysiological tool that provides important insights into Alzheimer's Disease (AD). A significant body of work utilizing TMS techniques has explored the pathophysiological relevance of cortical hyperexcitability and plasticity in AD and their modulation in novel therapies.

AREAS COVERED: This review examines the technique of TMS, the use of TMS to examine specific features of cortical excitability and the use of TMS techniques to modulate cortical function. A search was performed utilizing the PubMed database to identify key studies utilizing TMS to examine cortical hyperexcitability and plasticity in Alzheimer's dementia. We then translate this understanding to the study of Alzheimer's disease pathophysiology, examining the underlying neurophysiologic links contributing to these twin signatures, cortical hyperexcitability and abnormal plasticity, in the cortical dysfunction characterizing AD. Finally, we examine utilization of TMS excitability to guide targeted therapies and, through the use of repetitive TMS (rTMS), modulate cortical plasticity.

EXPERT OPINION: The examination of cortical hyperexcitability and plasticity with TMS has potential to optimize and expand the window of therapeutic interventions in AD, though remains at relatively early stage of development.}, } @article {pmid36678724, year = {2022}, author = {Gupta, SM and Behera, A and Jain, NK and Kumar, D and Tripathi, A and Tripathi, SM and Mujwar, S and Patra, J and Negi, A}, title = {Indene-Derived Hydrazides Targeting Acetylcholinesterase Enzyme in Alzheimer's: Design, Synthesis, and Biological Evaluation.}, journal = {Pharmaceutics}, volume = {15}, number = {1}, pages = {}, pmid = {36678724}, issn = {1999-4923}, abstract = {As acetylcholinesterase (AChE) plays a crucial role in advancing Alzheimer's disease (AD), its inhibition is a promising approach for treating AD. Sulindac is an NSAID of the aryl alkanoic acid class, consisting of a indene moiety, which showed neuroprotective behavior in recent studies. In this study, newer Indene analogs were synthesized and evaluated for their in vitro AChE inhibition. Additionally, compared with donepezil as the standard drug, these Indene analogs were accessed for their cell line-based toxicity study on SH-SY5Y cell line. The molecule SD-30, having hydrogen bond donor (HBD) at para-position, showed maximum AChE inhibition potential (IC50 13.86 ± 0.163 µM) in the indene series. Further, the SD-30 showed maximum BuChE inhibition potential (IC50 = 48.55 ± 0.136 µM) with a selectivity ratio of 3.50 and reasonable antioxidant properties compared to ascorbic acid (using DPPH assay). SD-30 (at a dose level: of 10 µM, 20 µM) effectively inhibited AChE-induced Aβ aggregation and showed no significant toxicity up to 30 mM against SH-SY5Y cell lines.}, } @article {pmid36678710, year = {2022}, author = {Badesso, S and Cartas-Cejudo, P and Espelosin, M and Santamaria, E and Cuadrado-Tejedor, M and Garcia-Osta, A}, title = {Docosahexaenoic Acid Ameliorates Contextual Fear Memory Deficits in the Tg2576 Alzheimer's Disease Mouse Model: Cellular and Molecular Correlates.}, journal = {Pharmaceutics}, volume = {15}, number = {1}, pages = {}, pmid = {36678710}, issn = {1999-4923}, abstract = {Docosahexaenoic acid (DHA), the most abundant polyunsaturated fatty acid in the brain, is essential for successful aging. In fact, epidemiological studies have demonstrated that increased intake of DHA might lower the risk for developing Alzheimer's disease (AD). These observations are supported by studies in animal models showing that DHA reduces synaptic pathology and memory deficits. Different mechanisms to explain these beneficial effects have been proposed; however, the molecular pathways involved are still unknown. In this study, to unravel the main underlying molecular mechanisms activated upon DHA treatment, the effect of a high dose of DHA on cognitive function and AD pathology was analyzed in aged Tg2576 mice and their wild-type littermates. Transcriptomic analysis of mice hippocampi using RNA sequencing was subsequently performed. Our results revealed that, through an amyloid-independent mechanism, DHA enhanced memory function and increased synapse formation only in the Tg2576 mice. Likewise, the IPA analysis demonstrated that essential neuronal functions related to synaptogenesis, neuritogenesis, the branching of neurites, the density of dendritic spines and the outgrowth of axons were upregulated upon-DHA treatment in Tg2576 mice. Our results suggest that memory function in APP mice is influenced by DHA intake; therefore, a high dose of daily DHA should be tested as a dietary supplement for AD dementia prevention.}, } @article {pmid36678660, year = {2022}, author = {Lee, CH and Hung, SY}, title = {Physiologic Functions and Therapeutic Applications of α7 Nicotinic Acetylcholine Receptor in Brain Disorders.}, journal = {Pharmaceutics}, volume = {15}, number = {1}, pages = {}, pmid = {36678660}, issn = {1999-4923}, abstract = {Accumulating data suggest that α7 nicotinic acetylcholine receptors (α7nAChRs) are an important therapeutic target for the treatment of Alzheimer's disease (AD) and schizophrenia. The homopentameric ligand-gated ion channel α7nAChR consists of five identical α7 subunits that are encoded by the CHRNA7 (cholinergic receptor nicotinic alpha7 subunit) gene. Moreover, α7nAChRs are densely distributed throughout the hippocampus, cortex, and thalamus brain regions, but sparsely in the striatum, forebrain, and medulla. Compared with other nAChRs, α7nAChR binds with low affinity to the naturally occurring neurotransmitter acetylcholine and the non-specific exogenous agonist nicotine, and with high affinity to the specific antagonists α-bungarotoxin and methyllycaconitine. Reports indicate that α7nAChR plays important roles in neurotransmitter release, cognitive functioning, and the cholinergic anti-inflammatory response. Genetic variations that alter CHRNA7 mRNA and protein expression or cause α7nAChR dysfunction are associated with many brain disorders. Our previous studies revealed that α7nAChR exerts neuroprotection in AD by acting as a cargo receptor for binding the autophagosomal marker protein LC3 and engulfing extracellular neurotoxic Aβ1-42 during autophagic degradation of the α7nAChR-Aβ1-42 complex. However, the role of α7nAChRs in other diseases remains unknown. Here, we review and summarize the essential characteristics and current findings concerning α7nAChRs in four common brain diseases (AD, Parkinson's disease, schizophrenia, and depression), which may elucidate the role of α7nAChRs and inform innovative research and novel treatments that target α7nAChRs in brain disease.}, } @article {pmid36678552, year = {2022}, author = {Schino, I and Cantore, M and de Candia, M and Altomare, CD and Maria, C and Barros, J and Cachatra, V and Calado, P and Shimizu, K and Freitas, AA and Oliveira, MC and Ferreira, MJ and Lopes, JNC and Colabufo, NA and Rauter, AP}, title = {Exploring Mannosylpurines as Copper Chelators and Cholinesterase Inhibitors with Potential for Alzheimer's Disease.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {16}, number = {1}, pages = {}, pmid = {36678552}, issn = {1424-8247}, abstract = {Alzheimer's Disease (AD) is characterized by a progressive cholinergic neurotransmission imbalance, with a decrease of acetylcholinesterase (AChE) activity followed by a significant increase of butyrylcholinesterase (BChE) in the later AD stages. BChE activity is also crucial for the development of Aβ plaques, the main hallmarks of this pathology. Moreover, systemic copper dyshomeostasis alters neurotransmission leading to AD. In the search for structures targeting both events, a set of novel 6-benzamide purine nucleosides was synthesized, differing in glycone configuration and N[7]/N[9] linkage to the purine. Their AChE/BChE inhibitory activity and metal ion chelating properties were evaluated. Selectivity for human BChE inhibition required N[9]-linked 6-deoxy-α-d-mannosylpurine structure, while all three tested β-d-derivatives appeared as non-selective inhibitors. The N[9]-linked l-nucleosides were cholinesterase inhibitors except the one embodying either the acetylated sugar or the N-benzyl-protected nucleobase. These findings highlight that sugar-enriched molecular entities can tune bioactivity and selectivity against cholinesterases. In addition, selective copper chelating properties over zinc, aluminum, and iron were found for the benzyl and acetyl-protected 6-deoxy-α-l-mannosyl N[9-]linked purine nucleosides. Computational studies highlight molecular conformations and the chelating molecular site. The first dual target compounds were disclosed with the perspective of generating drug candidates by improving water solubility.}, } @article {pmid36678527, year = {2022}, author = {Yang, L and Liang, J and Zheng, Q and Zhou, L and Xiong, Y and Wang, H and Yuan, J}, title = {A Comparative Study of Serum Pharmacochemistry of Kai-Xin-San in Normal and AD Rats Using UPLC-LTQ-Orbitrap-MS.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {16}, number = {1}, pages = {}, pmid = {36678527}, issn = {1424-8247}, abstract = {Kai-Xin-San (KXS) is a classic formula for the treatment of Alzheimer's disease (AD). KXS has been widely used to treat emotional diseases; however, its active components remain unknown. There have been some reports about the efficacy and metabolic analysis of KXS, which are mainly based on studying normal animals. The current work first established an AD rat model by injecting D-galactose into the abdominal cavity and injecting Aβ25-35 into the hippocampus on both sides, followed by intragastric administration of KXS for a consecutive week; then, the analytical method for ethanol extraction from the serum of normal and model rats was developed using UPLC-LTQ-Orbitrap-MS; finally, the transitional components in the blood were systematically compared and analyzed by multivariate statistical analysis. A total of 36 components of KXS were identified in the rat serum of the normal group, including 24 prototype components (including ginsenosides, triterpenoid acids of Poria cocos, polygala saponins, polygala xanthones and polygala ester) and 13 metabolites (including desugar, hydration and oxidation products of ginsenosides, triterpenoid acid hydroxylation, deoxygenation, demethylation, desaturation, and glycine-conjugated products of Poria cocos). Twenty KXS-relevant components were detected in the rat serum of the model group, including 11 prototypes and 9 metabolites. The normal group and the model group shared 12 common components, including 9 prototypes and 3 metabolites. The intestinal microecological balance of the model rats probably was destroyed, affecting the absorption/metabolism of saponins by the body, which resulted in fewer transitional components in the model group. This study reflected the drug-body interaction from an objective and accurate perspective, offering references and insights for elucidating the basis of active components and mechanism of action of KXS for treating AD.}, } @article {pmid36678510, year = {2022}, author = {Abd El-Aziz, NM and Shehata, MG and Alsulami, T and Badr, AN and Elbakatoshy, MR and Ali, HS and El-Sohaimy, SA}, title = {Characterization of Orange Peel Extract and Its Potential Protective Effect against Aluminum Chloride-Induced Alzheimer's Disease.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {16}, number = {1}, pages = {}, pmid = {36678510}, issn = {1424-8247}, abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative disorder without a cure. Hence, developing an effective treatment or protective agent is crucial for public health. The present study aims to characterize orange peel extract (OPE) through in vitro and in silico studies. Furthermore, it examines the protective effect of OPE against experimentally-induced Alzheimer's disease in rats. The total phenolic and flavonoid content of OPE was 255.86 ± 1.77 and 52.06 ± 1.74 (mg/100 g), respectively. Gallic acid, the common polyphenol in OPE detected by HPLC was 3388.60 μg/100 g. OPE antioxidant IC50 was 67.90 ± 1.05, 60.48 ± 0.91, and 63.70 ± 0.30 by DPPH, ABTS and Hydroxyl radical scavenging activity methods, respectively. In vitro anti-acetylcholinesterase (AChE) IC50 was 0.87 ± 0.025 mg/mL for OPE and 2.45 ± 0.001 mg/mL for gallic acid. Molecular docking analysis for human AChE (4EY7) with donepezil, gallic acid, and acetylcholine showed binding energy ΔG values of -9.47, -3.72, and -5.69 Kcal/mol, respectively. Aluminum chloride injection (70 mg/Kg/day for 6 weeks) induced Alzheimer's-like disease in male rats. OPE (100 and 200 mg/kg/d) and gallic acid (50 mg/kg/d) were administered orally to experimental animals for 6 weeks in addition to aluminum chloride injection (as protective). OPE was found to protect against aluminum chloride-induced neuronal damage by decreasing both gene expression and activity of acetylcholinesterase (AChE) and a decrease in amyloid beta (Aβ42) protein level, thiobarbituric acid-reactive substances (TBARS), and nitric oxide (NO), and increased reduced glutathione (GSH) level and activity of the antioxidant enzymes in the brain tissues. Additionally, gene expressions for amyloid precursor protein (APP) and beta secretase enzyme (BACE1) were downregulated, whereas those for presinilin-2 (PSEN2) and beta cell lymphoma-2 (BCL2) were upregulated. Furthermore, the reverse of mitochondrial alternation and restored brain ultrastructure might underlie neuronal dysfunction in AD. In conclusion, our exploration of the neuroprotective effect of OPE in vivo reveals that OPE may be helpful in ameliorating brain oxidative stress, hence protecting from Alzheimer's disease progression.}, } @article {pmid36678507, year = {2022}, author = {Khan, BA and Hamdani, SS and Jalil, S and Ejaz, SA and Iqbal, J and Shawky, AM and Alqahtani, AM and Gabr, GA and Ibrahim, MAA and Sidhom, PA}, title = {Synthesis and Evaluation of Novel S-alkyl Phthalimide- and S-benzyl-oxadiazole-quinoline Hybrids as Inhibitors of Monoamine Oxidase and Acetylcholinesterase.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {16}, number = {1}, pages = {}, pmid = {36678507}, issn = {1424-8247}, abstract = {New S-alkyl phthalimide 5a-f and S-benzyl 6a-d analogs of 5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazole-2-thiol (4) were prepared by reacting 4 with N-bromoalkylphthalimide and CF3-substituted benzyl bromides in excellent yields. Spectroscopic techniques were employed to elucidate the structures of the synthesized molecules. The inhibition activity of newly synthesized molecules toward MAO-A, MAO-B, and AChE enzymes, was also assessed. All these compounds showed activity in the submicromolar range against all enzymes. Compounds 5a and 5f were found to be the most potent compounds against MAO-A (IC50 = 0.91 ± 0.15 nM) and MAO-B (IC50 = 0.84 ± 0.06 nM), while compound 5c showed the most efficient acetylcholinesterase inhibition (IC50 = 1.02± 0.65 μM). Docking predictions disclosed the docking poses of the synthesized molecules with all enzymes and demonstrated the outstanding potency of compounds 5a, 5f, and 5c (docking scores = -11.6, -15.3, and -14.0 kcal/mol against MAO-A, MAO-B, and AChE, respectively). These newly synthesized analogs act as up-and-coming candidates for the creation of safer curative use against Alzheimer's illness.}, } @article {pmid36676672, year = {2022}, author = {Hellis, E and Mukaetova-Ladinska, EB}, title = {Informal Caregiving and Alzheimer's Disease: The Psychological Effect.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {59}, number = {1}, pages = {}, pmid = {36676672}, issn = {1648-9144}, mesh = {Humans ; Aged ; *Alzheimer Disease ; Quality of Life/psychology ; Caregivers/psychology ; *Home Care Services ; }, abstract = {Background and Objectives: People with Alzheimer's disease and dementia in general benefit from home-based care as demonstrated via their better quality of life, increased lifespan, and delayed disease progression. Since currently nearly half of the dementia care is being provided by informal and unpaid caregiving, the health, wellbeing and quality of life of informal dementia caregivers is extremely important. Materials and Methods: We used a systematic review process with searches based upon the six elements from the "Quality of Life Scale for Informal Carers of Older Adults" with additional items on traditional and non-traditional caregiving ideologies, as well as caregivers' experiences. Results: We identified 19 studies with primary data. Informal caregivers of older adults with Alzheimer's Disease experience significant emotional strain, documented through increased levels of anxiety and depression, as well as increased caregiver burden and poorer quality of life, primarily due to caregiving ideologies, financial strain and a lack of support. Conclusions: Our findings suggest that caregiving should be a normative component of adult education to better prepare individuals with the mental and physical skills required for undertaking informal caregiving. They should also help inform policy makers to develop novel programs and services to both assist and reduce informal caregivers' strain, whilst considering their different social and cultural contexts.}, } @article {pmid36676048, year = {2022}, author = {Emran, TB and Islam, F and Nath, N and Sutradhar, H and Das, R and Mitra, S and Alshahrani, MM and Alhasaniah, AH and Sharma, R}, title = {Naringin and Naringenin Polyphenols in Neurological Diseases: Understandings from a Therapeutic Viewpoint.}, journal = {Life (Basel, Switzerland)}, volume = {13}, number = {1}, pages = {}, pmid = {36676048}, issn = {2075-1729}, abstract = {The glycosides of two flavonoids, naringin and naringenin, are found in various citrus fruits, bergamots, tomatoes, and other fruits. These phytochemicals are associated with multiple biological functions, including neuroprotective, antioxidant, anticancer, antiviral, antibacterial, anti-inflammatory, antiadipogenic, and cardioprotective effects. The higher glutathione/oxidized glutathione ratio in 3-NP-induced rats is attributed to the ability of naringin to reduce hydroxyl radical, hydroperoxide, and nitrite. However, although progress has been made in treating these diseases, there are still global concerns about how to obtain a solution. Thus, natural compounds can provide a promising strategy for treating many neurological conditions. Possible therapeutics for neurodegenerative disorders include naringin and naringenin polyphenols. New experimental evidence shows that these polyphenols exert a wide range of pharmacological activity; particular attention was paid to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, as well as other neurological conditions such as anxiety, depression, schizophrenia, and chronic hyperglycemic peripheral neuropathy. Several preliminary investigations have shown promising evidence of neuroprotection. The main objective of this review was to reflect on developments in understanding the molecular mechanisms underlying the development of naringin and naringenin as potential neuroprotective medications. Furthermore, the configuration relationships between naringin and naringenin are discussed, as well as their plant sources and extraction methods.}, } @article {pmid36676033, year = {2022}, author = {Mosabbir, A}, title = {Mechanisms behind the Development of Chronic Low Back Pain and Its Neurodegenerative Features.}, journal = {Life (Basel, Switzerland)}, volume = {13}, number = {1}, pages = {}, pmid = {36676033}, issn = {2075-1729}, abstract = {Chronic back pain is complex and there is no guarantee that treating its potential causes will cause the pain to go away. Therefore, rather than attempting to "cure" chronic pain, many clinicians, caregivers and researchers aim to help educate patients about their pain and try to help them live a better quality of life despite their condition. A systematic review has demonstrated that patient education has a large effect on pain and pain related disability when done in conjunction with treatments. Therefore, understanding and updating our current state of knowledge of the pathophysiology of back pain is important in educating patients as well as guiding the development of novel therapeutics. Growing evidence suggests that back pain causes morphological changes in the central nervous system and that these changes have significant overlap with those seen in common neurodegenerative disorders. These similarities in mechanisms may explain the associations between chronic low back pain and cognitive decline and brain fog. The neurodegenerative underpinnings of chronic low back pain demonstrate a new layer of understanding for this condition, which may help inspire new strategies in pain education and management, as well as potentially improve current treatment.}, } @article {pmid36675988, year = {2022}, author = {Obrenovich, M and Singh, SK and Li, Y and Perry, G and Siddiqui, B and Haq, W and Reddy, VP}, title = {Natural Product Co-Metabolism and the Microbiota-Gut-Brain Axis in Age-Related Diseases.}, journal = {Life (Basel, Switzerland)}, volume = {13}, number = {1}, pages = {}, pmid = {36675988}, issn = {2075-1729}, abstract = {Complementary alternative medicine approaches are growing treatments of diseases to standard medicine practice. Many of these concepts are being adopted into standard practice and orthomolecular medicine. Age-related diseases, in particular neurodegenerative disorders, are particularly difficult to treat and a cure is likely a distant expectation for many of them. Shifting attention from pharmaceuticals to phytoceuticals and "bugs as drugs" represents a paradigm shift and novel approaches to intervention and management of age-related diseases and downstream effects of aging. Although they have their own unique pathologies, a growing body of evidence suggests Alzheimer's disease (AD) and vascular dementia (VaD) share common pathology and features. Moreover, normal metabolic processes contribute to detrimental aging and age-related diseases such as AD. Recognizing the role that the cerebral and cardiovascular pathways play in AD and age-related diseases represents a common denominator in their pathobiology. Understanding how prosaic foods and medications are co-metabolized with the gut microbiota (GMB) would advance personalized medicine and represents a paradigm shift in our view of human physiology and biochemistry. Extending that advance to include a new physiology for the advanced age-related diseases would provide new treatment targets for mild cognitive impairment, dementia, and neurodegeneration and may speed up medical advancements for these particularly devastating and debilitating diseases. Here, we explore selected foods and their derivatives and suggest new dementia treatment approaches for age-related diseases that focus on reexamining the role of the GMB.}, } @article {pmid36675950, year = {2022}, author = {Rasheed, A and Zaheer, AB and Munawwar, A and Sarfraz, Z and Sarfraz, A and Robles-Velasco, K and Cherrez-Ojeda, I}, title = {The Allosteric Antagonist of the Sigma-2 Receptors-Elayta (CT1812) as a Therapeutic Candidate for Mild to Moderate Alzheimer's Disease: A Scoping Systematic Review.}, journal = {Life (Basel, Switzerland)}, volume = {13}, number = {1}, pages = {}, pmid = {36675950}, issn = {2075-1729}, abstract = {Nearly 35 million people worldwide live with Alzheimer's disease (AD). The prevalence of the disease is expected to rise two-fold by 2050. With only symptomatic treatment options available, it is essential to understand the developments and existing evidence that aims to target brain pathology and dementia outcomes. This scoping systematic review aimed to collate existing evidence of CT1812 for use in patients with AD and summarize the methodologies of ongoing trials. Adhering to PRISMA Statement 2020 guidelines, PubMed/MEDLINE, Embase, Cochrane, and ClinicalTrials.gov were systematically searched through up to 15 November 2022 by applying the following keywords: CT1812, Alzheimer's disease, dementia, and/or sigma-2 receptor. Three completed clinical trials were included along with three ongoing records of clinical trials. The three completed trials were in Phases I and II of testing. The sample size across all three trials was 135. CT1812 reached endpoints across the trials and obtained a maximum concentration in the cerebrospinal fluid with 97-98% receptor occupancy. The findings of this systematic review must be used with caution as the results, while mostly favorable so far, must be replicated in higher-powered, placebo-controlled Phase II-III trials.}, } @article {pmid36672812, year = {2022}, author = {Raza, A and Rustam, F and Siddiqui, HUR and Diez, IT and Garcia-Zapirain, B and Lee, E and Ashraf, I}, title = {Predicting Genetic Disorder and Types of Disorder Using Chain Classifier Approach.}, journal = {Genes}, volume = {14}, number = {1}, pages = {}, pmid = {36672812}, issn = {2073-4425}, mesh = {Humans ; *Artificial Intelligence ; *Neoplasms ; Prognosis ; Random Forest ; }, abstract = {Genetic disorders are the result of mutation in the deoxyribonucleic acid (DNA) sequence which can be developed or inherited from parents. Such mutations may lead to fatal diseases such as Alzheimer's, cancer, Hemochromatosis, etc. Recently, the use of artificial intelligence-based methods has shown superb success in the prediction and prognosis of different diseases. The potential of such methods can be utilized to predict genetic disorders at an early stage using the genome data for timely treatment. This study focuses on the multi-label multi-class problem and makes two major contributions to genetic disorder prediction. A novel feature engineering approach is proposed where the class probabilities from an extra tree (ET) and random forest (RF) are joined to make a feature set for model training. Secondly, the study utilizes the classifier chain approach where multiple classifiers are joined in a chain and the predictions from all the preceding classifiers are used by the conceding classifiers to make the final prediction. Because of the multi-label multi-class data, macro accuracy, Hamming loss, and α-evaluation score are used to evaluate the performance. Results suggest that extreme gradient boosting (XGB) produces the best scores with a 92% α-evaluation score and a 84% macro accuracy score. The performance of XGB is much better than state-of-the-art approaches, in terms of both performance and computational complexity.}, } @article {pmid36672595, year = {2022}, author = {Brogna, C and Cristoni, S and Brogna, B and Bisaccia, DR and Marino, G and Viduto, V and Montano, L and Piscopo, M}, title = {Toxin-like Peptides from the Bacterial Cultures Derived from Gut Microbiome Infected by SARS-CoV-2-New Data for a Possible Role in the Long COVID Pattern.}, journal = {Biomedicines}, volume = {11}, number = {1}, pages = {}, pmid = {36672595}, issn = {2227-9059}, abstract = {It has been 3 years since the beginning of the SARS-CoV-2 outbreak, however it is as yet little known how to care for the acute COVID-19 and long COVID patients. COVID-19 clinical manifestations are of both pulmonary and extra-pulmonary types. Extra-pulmonary ones include extreme tiredness (fatigue), shortness of breath, muscle aches, hyposmia, dysgeusia, and other neurological manifestations. In other autoimmune diseases, such as Parkinson's disease (PD) or Alzheimer's Disease (AD), it is well known that role of acetylcholine is crucial in olfactory dysfunction. We have already observed the presence of toxin-like peptides in plasma, urine, and faecal samples from COVID-19 patients, which are very similar to molecules known to alter acetylcholine signaling. After observing the production of these peptides in bacterial cultures, we have performed additional proteomics analyses to better understand their behavior and reported the extended data from our latest in vitro experiment. It seems that the gut microbiome continues to produce toxin-like peptides also after the decrease of RNA SARS-CoV-2 viral load at molecular tests. These toxicological interactions between the gut/human microbiome bacteria and the virus suggest a new scenario in the study of the clinical symptoms in long COVID and also in acute COVID-19 patients. It is discussed that in the bacteriophage similar behavior, the presence of toxins produced by bacteria continuously after viral aggression can be blocked using an appropriate combination of certain drugs.}, } @article {pmid36672558, year = {2022}, author = {Shibly, AZ and Sheikh, AM and Michikawa, M and Tabassum, S and Azad, AK and Zhou, X and Zhang, Y and Yano, S and Nagai, A}, title = {Analysis of Cerebral Small Vessel Changes in AD Model Mice.}, journal = {Biomedicines}, volume = {11}, number = {1}, pages = {}, pmid = {36672558}, issn = {2227-9059}, abstract = {Amyloid β (Aβ) peptide is deposited in the brains of sporadic Alzheimer's disease (AD) due to impaired vessel-dependent clearance. To understand the mechanisms, we investigated time-dependent cerebrovascular changes in AD model mice. Cerebrovascular and other pathological changes were analyzed in AD model mice (J20 strain) aging from 2 to 9 months by immunostaining. At 2 months, Aβ was only intraneuronal, whereas vessels were positive from 3 months in J20 mice. Compared to wild-type (WT), vessel density was increased at 2 months but decreased at 9 months in J20 mice, claudin-5 levels were decreased, and vascular endothelial growth factor (VEGF) levels were increased in the cortex and hippocampus of J20 mice brain at all time points. Albumin extravasation was evident from 3 months in J20 brains. Collagen 4 was increased at 2 and 3 months. Aquaporin 4 was spread beyond the vessels starting from 3 months in J20, which was restricted around the vessel in wild-type mice. In conclusion, the study showed that an early decrease in claudin-5 was associated with VEGF expression, indicating dysfunction of the blood-brain barrier. Decreased claudin-5 might cause the leakage of blood constituents into the parenchyma that alters astrocyte polarity and its functions.}, } @article {pmid36672138, year = {2022}, author = {Valcic, M and Khoury, MA and Kim, J and Fornazzari, L and Churchill, NW and Ismail, Z and De Luca, V and Tsuang, D and Schweizer, TA and Munoz, DG and Fischer, CE}, title = {Correction: Valcic et al. Determining Whether Sex and Zygosity Modulates the Association between APOE4 and Psychosis in a Neuropathologically-Confirmed Alzheimer's Disease Cohort. Brain Sci. 2022, 12, 1266.}, journal = {Brain sciences}, volume = {13}, number = {1}, pages = {}, pmid = {36672138}, issn = {2076-3425}, abstract = {In the original publication [...].}, } @article {pmid36672010, year = {2022}, author = {Agbavor, F and Liang, H}, title = {Artificial Intelligence-Enabled End-To-End Detection and Assessment of Alzheimer's Disease Using Voice.}, journal = {Brain sciences}, volume = {13}, number = {1}, pages = {}, pmid = {36672010}, issn = {2076-3425}, abstract = {There is currently no simple, widely available screening method for Alzheimer's disease (AD), partly because the diagnosis of AD is complex and typically involves expensive and sometimes invasive tests not commonly available outside highly specialized clinical settings. Here, we developed an artificial intelligence (AI)-powered end-to-end system to detect AD and predict its severity directly from voice recordings. At the core of our system is the pre-trained data2vec model, the first high-performance self-supervised algorithm that works for speech, vision, and text. Our model was internally evaluated on the ADReSSo (Alzheimer's Dementia Recognition through Spontaneous Speech only) dataset containing voice recordings of subjects describing the Cookie Theft picture, and externally validated on a test dataset from DementiaBank. The AI model can detect AD with average area under the curve (AUC) of 0.846 and 0.835 on held-out and external test set, respectively. The model was well-calibrated (Hosmer-Lemeshow goodness-of-fit p-value = 0.9616). Moreover, the model can reliably predict the subject's cognitive testing score solely based on raw voice recordings. Our study demonstrates the feasibility of using the AI-powered end-to-end model for early AD diagnosis and severity prediction directly based on voice, showing its potential for screening Alzheimer's disease in a community setting.}, } @article {pmid36671907, year = {2022}, author = {Prieto-Avalos, G and Sánchez-Morales, LN and Alor-Hernández, G and Sánchez-Cervantes, JL}, title = {A Review of Commercial and Non-Commercial Wearables Devices for Monitoring Motor Impairments Caused by Neurodegenerative Diseases.}, journal = {Biosensors}, volume = {13}, number = {1}, pages = {}, pmid = {36671907}, issn = {2079-6374}, mesh = {Humans ; *Neurodegenerative Diseases ; *Motor Disorders ; *Wearable Electronic Devices ; *Parkinson Disease ; Tremor ; }, abstract = {Neurodegenerative diseases (NDDs) are among the 10 causes of death worldwide. The effects of NDDs, including irreversible motor impairments, have an impact not only on patients themselves but also on their families and social environments. One strategy to mitigate the pain of NDDs is to early identify and remotely monitor related motor impairments using wearable devices. Technological progress has contributed to reducing the hardware complexity of mobile devices while simultaneously improving their efficiency in terms of data collection and processing and energy consumption. However, perhaps the greatest challenges of current mobile devices are to successfully manage the security and privacy of patient medical data and maintain reasonable costs with respect to the traditional patient consultation scheme. In this work, we conclude: (1) Falls are most monitored for Parkinson's disease, while tremors predominate in epilepsy and Alzheimer's disease. These findings will provide guidance for wearable device manufacturers to strengthen areas of opportunity that need to be addressed, and (2) Of the total universe of commercial wearables devices that are available on the market, only a few have FDA approval, which means that there is a large number of devices that do not safeguard the integrity of the users who use them.}, } @article {pmid36671742, year = {2022}, author = {Montserrat-de la Paz, S and Carrillo-Berdasco, G and Rivero-Pino, F and Villanueva-Lazo, A and Millan-Linares, MC}, title = {Hemp Protein Hydrolysates Modulate Inflammasome-Related Genes in Microglial Cells.}, journal = {Biology}, volume = {12}, number = {1}, pages = {}, pmid = {36671742}, issn = {2079-7737}, abstract = {A prolonged inflammatory response can lead to the development of neurodegenerative diseases such as Alzheimer's disease. Enzymatic hydrolysis is a sustainable way to increase the value of protein sources by obtaining peptides that can exert bioactivity. Hemp (Cannabis sativa L.) protein hydrolysates have been proven to exert anti-inflammatory activity. In this study, two hemp protein hydrolysate (HPHs), obtained with Alcalase as sole catalyst, or with Alcalase followed by Flavourzyme, were evaluated as inflammatory mediators (TNFα, IL-1β, IL-6, and IL-10), microglial polarization markers (Ccr7, iNos, Arg1, and Ym1), and genes related to inflammasome activation (Nlrp3, Asc, Casp1, and Il18), employing the lipopolysaccharide (LPS)-induced neuroinflammation model in murine BV-2 microglial cells. A significant decrease of the expression of proinflammatory genes (e.g., Tnfα, Ccr7, inos, and Nlrp3, among others) and increase of the expression anti-inflammatory cytokines in microglial cells was observed after treatment with the test HPHs. This result in the cell model suggests a polarization toward an anti-inflammatory M2 phenotype. Our results show that the evaluated HPHs show potential neuroprotective activity in microglial cells via the inflammasome.}, } @article {pmid36671411, year = {2022}, author = {Zalewska, T and Pawelec, P and Ziabska, K and Ziemka-Nalecz, M}, title = {Sexual Dimorphism in Neurodegenerative Diseases and in Brain Ischemia.}, journal = {Biomolecules}, volume = {13}, number = {1}, pages = {}, pmid = {36671411}, issn = {2218-273X}, mesh = {Male ; Female ; Humans ; *Neurodegenerative Diseases/genetics ; Sex Characteristics ; Brain ; *Brain Diseases ; *Brain Ischemia ; }, abstract = {Epidemiological studies and clinical observations show evidence of sexual dimorphism in brain responses to several neurological conditions. It is suggested that sex-related differences between men and women may have profound effects on disease susceptibility, pathophysiology, and progression. Sexual differences of the brain are achieved through the complex interplay of several factors contributing to this phenomenon, such as sex hormones, as well as genetic and epigenetic differences. Despite recent advances, the precise link between these factors and brain disorders is incompletely understood. This review aims to briefly outline the most relevant aspects that differ between men and women in ischemia and neurodegenerative disorders (AD, PD, HD, ALS, and SM). Recognition of disparities between both sexes could aid the development of individual approaches to ameliorate or slow the progression of intractable disorders.}, } @article {pmid36660683, year = {2022}, author = {Li, L and Su, H and Yang, Y and Yang, P and Zhang, X and Su, S}, title = {Screening key genes related to neuropathic pain-induced depression through an integrative bioinformatics analysis.}, journal = {Annals of translational medicine}, volume = {10}, number = {24}, pages = {1348}, pmid = {36660683}, issn = {2305-5839}, abstract = {BACKGROUND: Neuropathic pain (NP) is often accompanied by sleep disorders, anxiety, depression and other complications, and the pathogenesis is still unclear. Some drugs can relieve patients' pain, but the overall effect is not good. We screened for the key genes related to NP-induced depression based on bioinformatics.

METHODS: The dataset of GSE92718 was obtained from the Gene Expression Omnibus database, data mining was conducted based on R language, the genes modules were screened by weighted correlation network analysis, Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed, a protein-protein interaction (PPI) network was constructed in the STRING database, and hub genes were screened according to degree value.

RESULTS: Seven modules were obtained and built to identify the relationships between the NP-induced depression and the modules, weighted gene co-expression network analysis (WGCNA) was used to identify gene modules closely related to the experimental group. The GO annotations of depression-related genes mainly enriched in protein polyubiquitination, regulation of chromosome organization, mitochondrial matrix, mitochondrial protein-containing complex, etc. KEGG enrichment analysis results were: Alzheimer's disease, Huntington's disease, ribosome, thermogenesis, prion disease, non-alcoholic fatty liver disease, diabetic cardiomyopathy, oxidative phosphorylation, retrograde endocannabinoid signaling, 2-oxocarboxylic acid metabolism. PPI network analysis showed that Polr2f, Rps13, Mrpl2, Mrpl40, Mrpl34, and Ndufs8 were more highly expressed in NP-induced depression. Functional analysis of key genes showed that these genes were related to mitochondrial translation termination, respiratory chain complex I, mitochondrial, mRNA Splicing (minor pathway), and of rRNA processing in the nucleolus and cytosol (major pathway).

CONCLUSIONS: The key genes of depression induced by NP are Polr2f, Rps13, Mrpl2, Mrpl40, Mrpl34, and Ndufs8.}, } @article {pmid36660588, year = {2023}, author = {Kaokaen, P and Sorraksa, N and Phonchai, R and Chaicharoenaudomrung, N and Kunhorm, P and Noisa, P}, title = {Enhancing Neurological Competence of Nanoencapsulated Cordyceps/Turmeric Extracts in Human Neuroblastoma SH-SY5Y Cells.}, journal = {Cellular and molecular bioengineering}, volume = {16}, number = {1}, pages = {81-93}, pmid = {36660588}, issn = {1865-5025}, abstract = {INTRODUCTION: Neurological diseases, including Alzheimer's, Parkinson's diseases, and brain cancers, are reportedly caused by genetic aberration and cellular malfunction. Herbs with bioactive compounds that have anti-oxidant effects such as cordyceps and turmeric, are of interest to clinical applications due to their minimal adverse effects. The aim of study is to develop the nanoencapsulated cordyceps and turmeric extracts and investigate their capability to enhance the biological activity and improve neuronal function.

METHODS: Human neuroblastoma SH-SY5Y cells were utilized as a neuronal model to investigate the properties of nanoencapsulated cordyceps or turmeric extracts, called CMP and TEP, respectively. SH-SY5Y cells were treated with either CMP or TEP and examined the biological consequences, including neuronal maturation and neuronal function.

RESULTS: The results showed that both CMP and TEP improved cellular uptake efficiency within 6 h by 2.3 and 2.8 times, respectively. Besides, they were able to inhibit cellular proliferation of SH-SY5Y cells up to 153- and 218-fold changes, and increase the expression of mature neuronal markers (TUJ1, PAX6, and NESTIN). Upon the treatment of CMP and TEP, the expression of dopaminergic-specific genes (LMX1B, FOXA2, EN1, and NURR1), and the secretion level of dopamine were significantly improved up to 3.3-fold and 3.0-fold, respectively, while the expression of Alzheimer genes (PSEN1, PSEN2, and APP), and the secretion of amyloid precursor protein were significantly reduced by 32-fold and 108-fold, respectively. Importantly, the autophagy activity was upregulated by CMP and TEP at 6.3- and 5.5-fold changes, respectively.

CONCLUSIONS: This finding suggested that the nanoencapsulated cordyceps and turmeric extracts accelerated neuronal maturation and alleviated neuronal pathology in human neural cells. This paves the way for nanotechnology-driven drug delivery systems that could potentially be used as an alternative medicine in the future for neurological diseases.}, } @article {pmid36660381, year = {2022}, author = {Cinar, N and Sahin, S and Karsidag, S and Karali, FS and Ates, MF and Gonul, O and Okluoglu, T and Eren, F and Bulbul, NG and Okuyan, DY and Totuk, O and Demirel, EA and Golen, MK and Yildirim, Z and Erhan, H and Polat, BSA and Ergin, N and Tur, EK and Akdogan, O}, title = {Neuropsychiatric Effects of COVID-19 Pandemic on Alzheimer's Disease: A Comparative Study of Total and Partial Lockdown.}, journal = {Sisli Etfal Hastanesi tip bulteni}, volume = {56}, number = {4}, pages = {453-460}, pmid = {36660381}, issn = {1302-7123}, abstract = {OBJECTIVES: Coronavirus disease 2019 (COVID-19)-related lockdown may have a negative effect on the neuropsychiatric status of Alzheimer's disease (AD) cases. In this study, it was aimed to find future implications by evaluating the neuropsychiatric conditions of AD cases during total and partial lockdown periods.

METHODS: It is a prospective, cross-sectional, and multicenter study that includes AD cases which have been followed for at least 1 year by outpatient clinics from different regions of Turkey. Sociodemographic data, comorbidities, mobility, existence of social interactions, clinical dementia rating (CDR) scale, and neuropsychiatric inventory (NPI) for total and partial lockdown were questioned by the caregivers with the help of case files of the patients.

RESULTS: A total of 302 AD cases were enrolled to the study (mean age: 78±8 years, mean duration of education: 5.8±9 years). The total comorbidity ratio was found to be 84%, with the most frequent comorbidity being hypertension. The mean NPI score was 22.9±21 in total lockdown and 17.7±15 in partial lockdown, which is statistically significantly different. When lockdown periods were compared with the total scores of NPI scores according to gender, existence of social interactions, mobility, and comorbidities were found higher in the total lockdown than the partial lockdown. When switching from total lockdown to partial lockdown, the presence of comorbidities, mobility, and CDR were found to be factors that had a significant effect on NPI scores. In regression analysis, CDR score was found as the most effective parameter on the neuropsychiatric status of AD cases for both lockdown periods.

CONCLUSION: When lockdown-related restrictions were reduced, the neuropsychological conditions of AD cases were significantly improved. Lockdown rules should be considered with these data in mind.}, } @article {pmid36660288, year = {2022}, author = {Satorres, E and Escudero Torrella, J and Real, E and Pitarque, A and Delhom, I and Melendez, JC}, title = {Home-based transcranial direct current stimulation in mild neurocognitive disorder due to possible Alzheimer's disease. A randomised, single-blind, controlled-placebo study.}, journal = {Frontiers in psychology}, volume = {13}, number = {}, pages = {1071737}, pmid = {36660288}, issn = {1664-1078}, abstract = {INTRODUCTION: Mild neurocognitive disorder (mNCD), a pre-dementia stage close to Mild Cognitive Impairment, shows a progressive and constant decline in the memory domain. Of the non-pharmacological therapeutic interventions that may help to decelerate the neurodegenerative progress, transcranial direct current stimulation (tDCS) shows beneficial effects on the learning curve, immediate recall, immediate verbal memory and executive functions. The purpose of this research was to study the effect of tDCS on general cognition, immediate and delayed memory and executive functions by comparing an active group with a placebo group of mNCD patients.

METHODS: Participants were 33 mNCD due to possible AD, randomly assigned to two groups: 17 active tDCS and 16 placebo tDCS. Ten sessions of tDCS were conducted over the left dorsolateral prefrontal cortex. Several neuropsychological scales were administered to assess the primary outcome measures of general cognitive function, immediate and delayed memory and learning ability, whereas the secondary outcome measures included executive function tests. All participants were evaluated at baseline and at the end of the intervention. Mixed ANOVAs were performed.

RESULTS: Significant effects were obtained on general cognitive function, immediate and delayed memory and learning ability, with increases in scores in the active tDCS group. However, there were no significant effects on executive function performance.

CONCLUSION: The present study demonstrated the effectiveness of tDCS in an active tDCS group, compared to a placebo group, in improving general cognition and immediate and delayed memory, as previous studies found. Taken together, our data suggest that tDCS is a simple, painless, reproducible and easy technique that is useful for treating cognitive alterations found in neurodegenerative diseases.}, } @article {pmid36657371, year = {2023}, author = {Bac, B and Hicheri, C and Weiss, C and Buell, A and Vilcek, N and Spaeni, C and Geula, C and Savas, JN and Disterhoft, JF}, title = {The TgF344-AD rat: behavioral and proteomic changes associated with aging and protein expression in a transgenic rat model of Alzheimer's disease.}, journal = {Neurobiology of aging}, volume = {123}, number = {}, pages = {98-110}, doi = {10.1016/j.neurobiolaging.2022.12.015}, pmid = {36657371}, issn = {1558-1497}, support = {R01 AG078796/AG/NIA NIH HHS/United States ; R01 AG061787/AG/NIA NIH HHS/United States ; P30 AG013854/AG/NIA NIH HHS/United States ; P30 CA060553/CA/NCI NIH HHS/United States ; R01 NS113804/NS/NINDS NIH HHS/United States ; RF1 AG017139/AG/NIA NIH HHS/United States ; R37 AG008796/AG/NIA NIH HHS/United States ; }, mesh = {Rats ; Animals ; Female ; Mice ; *Alzheimer Disease/metabolism ; Rats, Transgenic ; Proteomics ; *Cognition Disorders/complications ; *Cognitive Dysfunction/genetics/complications ; Disease Models, Animal ; Maze Learning ; Mice, Transgenic ; Amyloid beta-Peptides ; Membrane Glycoproteins ; Receptors, Immunologic ; }, abstract = {Animal models of Alzheimer's Disease (AD) are attractive tools for preclinical, prodromal drug testing. The TgF344-AD (Tg) rat exhibits cognitive deficits and 5 major hallmarks of AD. Here we show that spatial water maze (WMZ) memory deficits and proteomic differences in dorsal CA1 were present in young Tg rats. Aged learning-unimpaired (AU) and aged learning-impaired (AI) proteome associated changes were identified and differed by sex. Levels of phosphorylated tau, reactive astrocytes and microglia were significantly increased in aged Tg rats and correlated with the WMZ learning index (LI); in contrast, no significant correlation was present between amyloid plaques or insoluble Aβ levels and LI. Neuroinflammatory markers were also significantly correlated with LI and increased in female Tg rats. The anti-inflammatory marker, triggering receptor expressed on myeloid cells-2 (TREM2), was significantly reduced in aged impaired Tg rats and correlated with LI. Identifying and understanding mechanisms that allow for healthy aging by overcoming genetic drivers for AD, and/or promoting drivers for successful aging, are important for developing successful therapeutics against AD.}, } @article {pmid36654924, year = {2022}, author = {Arthur, P and Li, CY and , }, title = {Living with Dementia During the COVID-19 Pandemic: A Nationwide Survey Informing the American Experience.}, journal = {Journal of Alzheimer's disease reports}, volume = {6}, number = {1}, pages = {733-737}, pmid = {36654924}, issn = {2542-4823}, abstract = {Persons living with dementia and their caregivers are among society's most vulnerable, a condition exacerbated by the COVID-19 pandemic. This national survey was conducted with dementia caregivers in the US. Primary outcomes targeted pandemic-related changes in cognitive, behavioral, and motors systems. 113 dementia caregivers from 30 US states completed the survey. The impact of the COVID-19 pandemic on persons living with dementia and their caregivers is substantial in comparison to society at large. A marked public health and preventative role signals opportunity for practitioners to fill the void and prepare for future public health emergencies.}, } @article {pmid36654748, year = {2023}, author = {Patil, G and Kulsange, S and Kazi, R and Chirmade, T and Kale, V and Mote, C and Aswar, M and Koratkar, S and Agawane, S and Kulkarni, M}, title = {Behavioral and Proteomic Studies Reveal Methylglyoxal Activate Pathways Associated with Alzheimer's Disease.}, journal = {ACS pharmacology & translational science}, volume = {6}, number = {1}, pages = {65-75}, pmid = {36654748}, issn = {2575-9108}, abstract = {Diabetes is one of the major risk factors for Alzheimer's disease (AD) development. The role of elevated levels of glucose, methylglyoxal (MGO), and advanced glycation end products (AGEs) in the pathogenesis of AD is not well understood. In this pursuit, we studied the role of methylglyoxal in the pathogenesis of AD in rat models. The elevated plus-maze (EPM) behavioral study indicated that MGO induces anxiety. Treatment of telmisartan (RAGE expression inhibitor) and aminoguanidine (MGO quencher) attenuated MGO induced anxiety. Further, hippocampal proteomics demonstrated that MGO treated rats differentially regulate proteins involved in calcium homeostasis, mitochondrial functioning, and apoptosis, which may affect neurotransmission and neuronal plasticity. The hippocampal tau phosphorylation level was increased in MGO treated rats, which was reduced in the presence of aminoguanidine and telmisartan. The plasma fructosamine level was increased upon MGO treatment. Hippocampal histochemistry showed vascular degeneration and neuronal loss upon MGO treatment. This study provides mechanistic insight into the role of MGO in the diabetes-associated development of AD.}, } @article {pmid36649440, year = {2022}, author = {Osborne, OM and Kowalczyk, JM and Louis, KDP and Daftari, MT and Colbert, BM and Naranjo, O and Torices, S and András, IE and Dykxhoorn, DM and Toborek, M}, title = {Brain endothelium-derived extracellular vesicles containing amyloid-beta induce mitochondrial alterations in neural progenitor cells.}, journal = {Extracellular vesicles and circulating nucleic acids}, volume = {3}, number = {4}, pages = {340-362}, pmid = {36649440}, support = {R01 MH128022/MH/NIMH NIH HHS/United States ; R01 DA044579/DA/NIDA NIH HHS/United States ; R01 DA039576/DA/NIDA NIH HHS/United States ; R01 DA050528/DA/NIDA NIH HHS/United States ; R01 DA040537/DA/NIDA NIH HHS/United States ; R21 MH122235/MH/NIMH NIH HHS/United States ; R01 HL126559/HL/NHLBI NIH HHS/United States ; F31 NS125905/NS/NINDS NIH HHS/United States ; R01 DA047157/DA/NIDA NIH HHS/United States ; R01 MH072567/MH/NIMH NIH HHS/United States ; }, abstract = {AIM: Elevated brain deposits of amyloid beta (Aβ40) contribute to neuropathology and cognitive dysfunction in Alzheimer's disease (AD). However, the role of the blood-brain barrier (BBB) as an interface for the transfer of Aβ40 from the periphery into the brain is not well characterized. In addition, a substantial population of neural progenitor cells (NPCs) resides in close proximity to brain capillaries that form the BBB. The aim of this study is to understand the impact of brain endothelium-derived extracellular vesicles (EV) containing Aβ40 on metabolic functions and differentiation of NPCs.

METHODS: Endothelial EVs were derived from an in vitro model of the brain endothelium treated with 100 nM Aβ40 or PBS. We then analyzed the impact of these EVs on mitochondrial morphology and bioenergetic disruption of NPCs. In addition, NPCs were differentiated and neurite development upon exposure to EVs was assessed using the IncuCyte Zoom live cell imaging system.

RESULTS: We demonstrate that physiological concentrations of Aβ40 can be transferred to accumulate in NPCs via endothelial EVs. This transfer results in mitochondrial dysfunction, disrupting crista morphology, metabolic rates, fusion and fission dynamics of NPCs, as well as their neurite development.

CONCLUSION: Intercellular transfer of Aβ40 is carried out by brain endothelium-derived EVs, which can affect NPC differentiation and induce mitochondrial dysfunction, leading to aberrant neurogenesis. This has pathological implications because NPCs growing into neurons are incorporated into cerebral structures involved in learning and memory, two common phenotypes affected in AD and related dementias.}, } @article {pmid36649140, year = {2022}, author = {Białoń, N and Trzęsicki, M and Górka, M and Suszyński, K and Górka, D}, title = {[Cerebral metabolism of glucose and selected glucose transporters in neurodegenerative diseases].}, journal = {Postepy biochemii}, volume = {68}, number = {4}, pages = {375-380}, doi = {10.18388/pb.2021_463}, pmid = {36649140}, issn = {0032-5422}, mesh = {Humans ; *Glucose Transport Proteins, Facilitative/metabolism ; Glucose/metabolism ; *Neurodegenerative Diseases/metabolism ; Brain/metabolism ; }, abstract = {Cerebral glucose metabolism is an issue of researchers’ interest for a long time. Disturbed transport and metabolism of glucose in the brain lead to development of numerous neurological pathologies. Recently, a significant correlation between perturbed cerebral glucose metabolism and development of neurodegenerative diseases has been shown. Glucose, a monosaccharide, is the main source of energy for brain cells. Brain is the organ which is the most sensitive to changes in blood glucose level. Perturbed glucose transport leads to disorders of the central glucose metabolism. Neurodegenerative diseases are defined in the literature as progressive and irreversible degeneration of nerve tissue, causing cell death as a result of degenerative processes. The aim of this article is to discuss the physiology and the role of selected glucose transporters in the development of neurodegenerative diseases: expression of selected GLUT1 and GLUT3 transporters in Alzheimer's and Huntington's diseases. Understanding of the cerebral glucose metabolism may be a crucial factor in fight with central nervous system diseases.}, } @article {pmid36649137, year = {2022}, author = {Sadowska, A and Grzesiak, M}, title = {[The role of steroid hormones in the neurodegenerative diseases].}, journal = {Postepy biochemii}, volume = {68}, number = {4}, pages = {387-398}, doi = {10.18388/pb.2021_468}, pmid = {36649137}, issn = {0032-5422}, mesh = {Male ; Humans ; Female ; Aged ; *Neurodegenerative Diseases/drug therapy ; *Amyotrophic Lateral Sclerosis/drug therapy ; *Alzheimer Disease/drug therapy ; *Parkinson Disease/drug therapy ; Steroids ; Hormones ; }, abstract = {An increasing number of elders in a general population and longer life expectancy have a negative outcome in the growth of dissemination of neurodegenerative diseases (NDs). The NDs like Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) show sex-dependent prevalence. It is considered that sex steroids could influence on the NDs occurrence. Epidemiological studies indicate that women suffer more frequently from AD, whereas men from PD and ALS. Research suggest neuroprotective effects of estrogens and confirm that factors reducing their level may have a contribution to a higher morbidity rate to NDs. Adverse effects of androgens on NDs have been noticed, however some data suggest their beneficial actions. Therefore, the understanding of the potential role of sex steroids and their receptors in the pathogenesis and course of NDs would contribute to broadening the knowledge of molecular mechanisms leading to NDs. Moreover effective prevention and treatment could be assessed in the future.}, } @article {pmid36648909, year = {2022}, author = {Mohanty, M and Kumar, P}, title = {Multi-Component Interventions in Older Adults Having Subjective Cognitive Decline (SCD)-A Review Article.}, journal = {Geriatrics (Basel, Switzerland)}, volume = {8}, number = {1}, pages = {}, pmid = {36648909}, issn = {2308-3417}, abstract = {Subjective cognitive decline (SCD) is one of those significant concerns faced by older individuals. Though it is predominantly self-reported, it is not an event that should be overlooked, considering its significant association with cognitive disorders like Alzheimer's disease, mild cognitive impairment, and so on. This makes it imperative to find ways to manage the event to enhance the cognitive performance of older adults and/or suppress the rate at which cognitive decline results in impairment. While multiple interventions have been used for SCD, multi-component non-pharmacological interventions are beginning to gain more attention among researchers. This is due to how such interventions have effectively contributed to improved cognitive performance across different outcome domains. Against this backdrop, this literature review has been conducted to explore the different multi-component non-pharmacological interventions utilized in managing SCD. Papers from databases such as PubMed, Scopus, and EBSCO were retrieved, with relevant data being extracted on the subject matter to address the objective of this review.}, } @article {pmid36648906, year = {2022}, author = {Papastefanopoulou, V and Stanitsa, E and Koros, C and Simoudis, A and Florou-Hatziyiannidou, C and Beratis, I and Antonelou, R and Andronas, N and Voskou, P and Angelopoulou, E and Papatriantafyllou, JD and Stefanis, L and Kroupis, C and Papageorgiou, SG}, title = {APOE Allele Frequency in Southern Greece: Exploring the Role of Geographical Gradient in the Greek Population.}, journal = {Geriatrics (Basel, Switzerland)}, volume = {8}, number = {1}, pages = {}, pmid = {36648906}, issn = {2308-3417}, abstract = {BACKGROUND: the apolipoprotein e4 allele (APOE4) constitutes an established genetic risk factor for Alzheimer's Disease Dementia (ADD). We aimed to explore the frequency of the APOE isoforms in the Greek population of Southern Greece.

METHODS: peripheral blood from 175 Greek AD patients, 113 with mild cognitive impairment (MCI), and 75 healthy individuals. DNA isolation was performed with a High Pure PCR Template Kit (Roche), followed by amplification with a real-time qPCR kit (TIB MolBiol) in Roche's Light Cycler PCR platform.

RESULTS: APOE4 allele frequency was 20.57% in the ADD group, 17.69% in the MCI group, and 6.67% in the control group. APOE3/3 homozygosity was the most common genotype, while the frequency of APOE4/4 homozygosity was higher in the AD group (8.60%). APOE4 carrier status was associated with higher odds for ADD and MCI (OR: 4.49, 95% CI: [1.90-10.61] and OR: 3.82, 95% CI: [1.59-9.17], respectively).

CONCLUSION: this study examines the APOE isoforms and is the first to report a higher APOE frequency in MCI compared with healthy controls in southern Greece. Importantly, we report the occurrence of the APOE4 allele, related to ADD, as amongst the lowest globally reported, even within the nation, thus enhancing the theory of ethnicity and latitude contribution.}, } @article {pmid36647384, year = {2023}, author = {Seol, S and Kwon, J and Kang, HJ}, title = {Cell type characterization of spatiotemporal gene co-expression modules in Down syndrome brain.}, journal = {iScience}, volume = {26}, number = {1}, pages = {105884}, pmid = {36647384}, issn = {2589-0042}, abstract = {Down syndrome (DS) is the most common genetic cause of intellectual disability and increases the risk of other brain-related dysfunctions, like seizures, early-onset Alzheimer's disease, and autism. To reveal the molecular profiles of DS-associated brain phenotypes, we performed a meta-data analysis of the developmental DS brain transcriptome at cell type and co-expression module levels. In the DS brain, astrocyte-, microglia-, and endothelial cell-associated genes show upregulated patterns, whereas neuron- and oligodendrocyte-associated genes show downregulated patterns. Weighted gene co-expression network analysis identified cell type-enriched co-expressed gene modules. We present eight representative cell-type modules for neurons, astrocytes, oligodendrocytes, and microglia. We classified the neuron modules into glutamatergic and GABAergic neurons and associated them with detailed subtypes. Cell type modules were interpreted by analyzing spatiotemporal expression patterns, functional annotations, and co-expression networks of the modules. This study provides insight into the mechanisms underlying brain abnormalities in DS and related disorders.}, } @article {pmid36647262, year = {2023}, author = {Dang, M and Chen, Q and Zhao, X and Chen, K and Li, X and Zhang, J and Lu, J and Ai, L and Chen, Y and Zhang, Z}, title = {Tau as a biomarker of cognitive impairment and neuropsychiatric symptom in Alzheimer's disease.}, journal = {Human brain mapping}, volume = {44}, number = {2}, pages = {327-340}, pmid = {36647262}, issn = {1097-0193}, mesh = {Humans ; *Alzheimer Disease/complications/diagnostic imaging ; Brain/pathology ; *Cognitive Dysfunction/diagnostic imaging/etiology ; Positron-Emission Tomography/methods ; Biomarkers/metabolism ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; }, abstract = {The A/T/N research framework has been proposed for the diagnosis and prognosis of Alzheimer's disease (AD). However, the spatial distribution of ATN biomarkers and their relationship with cognitive impairment and neuropsychiatric symptoms (NPS) need further clarification in patients with AD. We scanned 83 AD patients and 38 cognitively normal controls who independently completed the mini-mental state examination and Neuropsychiatric Inventory scales. Tau, Aβ, and hypometabolism spatial patterns were characterized using Statistical Parametric Mapping together with [18F]flortaucipir, [18F]florbetapir, and [18F]FDG positron emission tomography. Piecewise linear regression, two-sample t-tests, and support vector machine algorithms were used to explore the relationship between tau, Aβ, and hypometabolism and cognition, NPS, and AD diagnosis. The results showed that regions with tau deposition are region-specific and mainly occurred in inferior temporal lobes in AD, which extensively overlaps with the hypometabolic regions. While the deposition regions of Aβ were unique and the regions affected by hypometabolism were widely distributed. Unlike Aβ, tau and hypometabolism build up monotonically with increasing cognitive impairment in the late stages of AD. In addition, NPS in AD were associated with tau deposition closely, followed by hypometabolism, but not with Aβ. Finally, hypometabolism and tau had higher accuracy in differentiating the AD patients from controls (accuracy = 0.88, accuracy = 0.85) than Aβ (accuracy = 0.81), and the combined three were the highest (accuracy = 0.95). These findings suggest tau pathology is superior over Aβ and glucose metabolism to identify cognitive impairment and NPS. Its results support tau accumulation can be used as a biomarker of clinical impairment in AD.}, } @article {pmid36645688, year = {2022}, author = {Zachara, R and Właszczuk, A and Gorzkowska, A and Jędrzejowska-Szypułka, H}, title = {The influence of hypertension, diabetes, lipid disorders and the presence of the APOE4 allele on the cognitive functions of patients over 65 years of age.}, journal = {Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego}, volume = {50}, number = {300}, pages = {391-394}, pmid = {36645688}, issn = {1426-9686}, mesh = {Adult ; Aged ; Humans ; Middle Aged ; Alleles ; *Alzheimer Disease/genetics ; *Apolipoprotein E4/genetics ; Cognition ; *Diabetes Mellitus/epidemiology/genetics ; *Hypertension/epidemiology/genetics ; }, abstract = {UNLABELLED: Diabetes mellitus (DM) and hypertension (HA) are common diseases in the population of people over 65 years of age. Many studies show the impact of the long-lasting decompensation of these chronic diseases, often diagnosed in middle age, on the cognitive functioning of elderly patients.

RESULTS: There is almost 30% prevalence of cognitive impairment among patients diagnosed with arterial hypertension. Possible explanation includes intensification of inflammatory processes in the central nervous system, influence on cerebral blood flow and acceleration of atherosclerosis. Another analyzed factor is the presence of diabetes. DM impacts the development of Alzheimer's disease. The inflammatory processes are intensified by advanced glycation products promoting atherosclerotic changes in blood vessels. In addition to that, the presence of hypoglycemic episodes significantly increases the risk of dementia. Moreover, approximately 78% of adult diabetic patients are also diagnosed with arterial hypertension, resulting in the coexistence of these CNS damaging mechanisms. The effect of elevated total cholesterol concentration on cognitive performance is still under debate and more research is needed. The role of the presence of ApoE4 in the development of cognitive dysfunctions, including Alzheimer's disease is emphasized.

CONCLUSIONS: In daily medical practice, extraordinary attention should be paid to control of chronic diseases of the patient, especially in the middle age. It improves cognitive functioning, possibly extending the quality-adjusted life year expectancy.}, } @article {pmid36644126, year = {2022}, author = {Banks, WA and Noonan, C and Rhea, EM}, title = {Evidence for an alternative insulin transporter at the blood-brain barrier.}, journal = {Aging pathobiology and therapeutics}, volume = {4}, number = {4}, pages = {100-108}, pmid = {36644126}, issn = {2690-1803}, support = {P30 AG066509/AG/NIA NIH HHS/United States ; RF1 AG059088/AG/NIA NIH HHS/United States ; }, abstract = {Accumulating evidence suggests there is an alternative insulin transporter besides the insulin receptor at the blood-brain barrier (BBB), responsible for shuttling insulin from the circulation into the brain. In this review, we summarize key features of the BBB and what makes it unique compared to other capillary beds; summarize what we know about insulin BBB transport; provide an extensive list of diseases, physiological states, and serum factors tested in modifying insulin BBB transport; and lastly, highlight potential alternative transport systems that may be involved in or have already been tested in mediating insulin BBB transport. Identifying the transport system for insulin at the BBB would aide in controlling central nervous system (CNS) insulin levels in multiple diseases and conditions including Alzheimer's disease (AD) and obesity, where availability of insulin to the CNS is limited.}, } @article {pmid36643555, year = {2023}, author = {Wang, N and Liu, W and Zhou, L and Liu, W and Liang, X and Liu, X and Xu, Z and Zhong, T and Wu, Q and Jiao, X and Chen, J and Ning, X and Jiang, X and Zhao, Q}, title = {Correction to Design, Synthesis, and Biological Evaluation of Notopterol Derivatives as Triple Inhibitors of AChE/BACE1/GSK3β for the Treatment of Alzheimer's Disease.}, journal = {ACS omega}, volume = {8}, number = {1}, pages = {1723}, doi = {10.1021/acsomega.2c07761}, pmid = {36643555}, issn = {2470-1343}, abstract = {[This corrects the article DOI: 10.1021/acsomega.2c03368.].}, } @article {pmid36642997, year = {2022}, author = {Dorris, JL and Chang, K and McLaughlin, DJ and Murray, SS and Schaumburg, S and Rodakowski, J}, title = {Project Unmute: A Digital Music Program Delivered by Adolescent Musicians to Older Adults with Cognitive Decline.}, journal = {Journal of intergenerational relationships}, volume = {20}, number = {4}, pages = {493-501}, pmid = {36642997}, issn = {1535-0770}, support = {R01 AG056351/AG/NIA NIH HHS/United States ; }, abstract = {Effective intergenerational music programming has the power to positively influence the current lives of the millions of older adults who are experiencing Alzheimer's disease and dementia, as well as to support the confidence of the newest generation of young musicians. To explore this potential, we designed a digital, intergenerational music program delivered by adolescent musicians to older adults with cognitive decline. This program utilized songs preferred by the older adults and an interactive activity that engaged the two generations. We believe this type of easily scalable programming could support older adults and young musicians, as well as promote new intergenerational relationships.}, } @article {pmid36642988, year = {2022}, author = {Liao, F and He, D and Vong, CT and Wang, L and Chen, Z and Zhang, T and Luo, H and Wang, Y}, title = {Screening of the active Ingredients in Huanglian Jiedu decoction through amide bond-Immobilized magnetic nanoparticle-assisted cell membrane chromatography.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1087404}, pmid = {36642988}, issn = {1663-9812}, abstract = {Introduction: The Huanglian Jiedu decoction (HLJDD) is a Chinese herbal formula that exerts neuroprotective effects by alleviating oxidative stress injuries and may potentially be prescribed for treating Alzheimer's disease; however, its active ingredients have not yet been identified. Cell membrane chromatography is a high-throughput method for screening active ingredients, but traditional cell membrane chromatography requires multiple centrifugation steps, which affects its separation efficiency. Magnetic nanoparticles are unparalleled in solid-liquid separation and can overcome the shortcomings of traditional cell membrane chromatography. Methods: In this study, the neuroprotective effects of the components of HLJDD were screened through a novel magnetic nanoparticle-assisted cell membrane chromatography method. Magnetic nanoparticles and cell membranes were stably immobilized by amide bonds. Magnetic bead (MB)-immobilized cell membranes of HT-22 cells were incubated with the HLJDD extract to isolate specific binding components. The specific binding components were then identified by ultraperformance liquid chromatography (UPLC)-Orbitrap Fusion Tribrid MS after solid-phase extraction. The bioactivity of these components was analyzed in an HT-22 cellular model of glutamate-induced injury. Results and Discussion: The preparation method of the composite of cell membrane and MBs has the advantages of simple preparation and no introduction of toxic organic reagents. MBs not only provide support for cell membranes, but also greatly improve the separation efficiency compared with traditional cell membrane chromatography. Fifteen of these components were found to specifically bind to the cell membranes, and seven of them were confirmed to reduce varying degrees of glutamate-induced toxicity in HT-22 cells. In conclusion, our findings suggest that the amide bond-based immobilization of magnetic nanoparticles on cell membranes, along with solid-phase extraction and UPLC, is an effective method for isolating and discovering the bioactive components of traditional Chinese medicines.}, } @article {pmid36642915, year = {2022}, author = {Yuan, M and Wang, Y and Huang, Z and Jing, F and Qiao, P and Zou, Q and Li, J and Cai, Z}, title = {Impaired autophagy in amyloid-beta pathology: A traditional review of recent Alzheimer's research.}, journal = {Journal of biomedical research}, volume = {37}, number = {1}, pages = {30-46}, doi = {10.7555/JBR.36.20220145}, pmid = {36642915}, issn = {1674-8301}, abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. The major pathological changes in AD progression are the generation and accumulation of amyloid-beta (Aβ) peptides as well as the presence of abnormally hyperphosphorylated tau proteins in the brain. Autophagy is a conserved degradation pathway that eliminates abnormal protein aggregates and damaged organelles. Previous studies have suggested that autophagy plays a key role in the production and clearance of Aβ peptides to maintain a steady-state of Aβ peptides levels. However, a growing body of evidence suggests that autophagy is significantly impaired in the pathogenesis of AD, especially in Aβ metabolism. Therefore, this article reviews the latest studies concerning the mechanisms of autophagy, the metabolism of Aβ peptides, and the defective autophagy in the production and clearance of Aβ peptides. Here, we also summarize the established and new strategies for targeting autophagy in vivo and through clinical AD trials to identify gaps in our knowledge and to generate further questions.}, } @article {pmid36636477, year = {2022}, author = {Zegarra-Valdivia, J and Fernandez, AM and Martinez-Rachadell, L and Herrero-Labrador, R and Fernandes, J and Torres Aleman, I}, title = {Insulin and insulin-like growth factor-I receptors in astrocytes exert different effects on behavior and Alzheimer´s-like pathology.}, journal = {F1000Research}, volume = {11}, number = {}, pages = {663}, doi = {10.12688/f1000research.121901.3}, pmid = {36636477}, issn = {2046-1402}, mesh = {Animals ; Mice ; *Alzheimer Disease/metabolism ; Astrocytes ; Carrier Proteins/metabolism ; Insulin ; Insulin-Like Growth Factor I/metabolism ; *Receptor, IGF Type 1/metabolism ; }, abstract = {Background: Pleiotropic actions of insulin and insulin-like growth factor I (IGF-I) in the brain are context- and cell-dependent, but whether this holds for their receptors (insulin receptor (IR) and IGF-I receptor (IGF-IR), respectively), is less clear. Methods: We compared mice lacking IR or IGF-IR in glial fibrillary astrocytic protein (GFAP)-expressing astrocytes in a tamoxifen-regulated manner, to clarify their role in this type of glial cells, as the majority of data of their actions in brain have been obtained in neurons. Results: We observed that mice lacking IR in GFAP astrocytes (GFAP IR KO mice) develop mood disturbances and maintained intact cognition, while at the same time show greater pathology when cross-bred with APP/PS1 mice, a model of familial Alzheimer´s disease (AD). Conversely, mice lacking IGF-IR in GFAP astrocytes (GFAP-IGF-IR KO mice) show cognitive disturbances, maintained mood tone, and show control-dependent changes in AD-like pathology. Conclusions: These observations confirm that the role of IR and IGF-IR in the brain is cell-specific and context-dependent.}, } @article {pmid36642485, year = {2023}, author = {Simrén, J and Elmgren, A and Blennow, K and Zetterberg, H}, title = {Fluid biomarkers in Alzheimer's disease.}, journal = {Advances in clinical chemistry}, volume = {112}, number = {}, pages = {249-281}, doi = {10.1016/bs.acc.2022.09.006}, pmid = {36642485}, issn = {2162-9471}, mesh = {Humans ; *Alzheimer Disease/diagnosis ; tau Proteins/cerebrospinal fluid ; Amyloid beta-Peptides ; Biomarkers ; Peptide Fragments ; }, abstract = {Alzheimer's disease (AD) characterization has progressed from being indexed using clinical symptomatology followed by neuropathological examination at autopsy to in vivo signatures using cerebrospinal fluid (CSF) biomarkers and positron emission tomography. The core AD biomarkers reflect amyloid-β plaques (A), tau pathology (T) and neurodegeneration (N), following the ATN schedule, and are now being introduced into clinical routine practice. This is an important development, as disease-modifying treatments are now emerging. Further, there are now reproducible data on CSF biomarkers which reflect synaptic pathology, neuroinflammation and common co-pathologies. In addition, the development of ultrasensitive techniques has enabled the core CSF biomarkers of AD pathophysiology to be translated to blood (e.g., phosphorylated tau, amyloid-β and neurofilament light). In this chapter, we review where we stand with both core and novel CSF biomarkers, as well as the explosion of data on blood biomarkers. Also, we discuss potential applications in research aiming to better understand the disease, as well as possible use in routine clinical practice and therapeutic trials.}, } @article {pmid36641371, year = {2023}, author = {Cheng, HR and Lin, RR and Li, HL and Xue, YY and Gao, PR and Chen, DF and Tao, QQ and Wu, ZY}, title = {Identification and functional characterization of novel variants of MAPT and GRN in Chinese patients with frontotemporal dementia.}, journal = {Neurobiology of aging}, volume = {123}, number = {}, pages = {233-243}, doi = {10.1016/j.neurobiolaging.2022.12.009}, pmid = {36641371}, issn = {1558-1497}, mesh = {Humans ; *Frontotemporal Dementia/genetics/pathology ; Intercellular Signaling Peptides and Proteins/genetics ; Progranulins/genetics ; East Asian People ; Mutation ; tau Proteins/genetics/metabolism ; *Pick Disease of the Brain ; }, abstract = {Frontotemporal dementia (FTD) is the second most common cause of dementia after Alzheimer's disease, characterized by distinct changes in behavior, personality, and language. Our study performed whole exome sequencing and repeat-primed PCR analysis in 29 unrelated FTD patients. Consequently, 2 known pathogenic variants (MAPT: p.P301L; TBK1: p.I450Kfs), and 4 novel variants (MAPT: p.R406Q, p.D430H, p.A330D; GRN: c.350-2A>G) were identified. The functional analysis results showed that phosphorylated tau levels were higher in cells expressing p.R406Q and p.D430H tau than those expressing wild-type tau, especially at the Thr205, Thr231, and Ser396 phosphorylation epitopes. Besides, the p.R406Q and p.D430H variants of MAPT impaired the ability of tau to bind to the microtubules and increased tau self-aggregation. Furthermore, we found that the c.350-2A>G variant caused exon 5 skipping. Our results showed that p.R406Q, p.D430H, and c.350-2A>G variants were classified as pathogenic. Finally, we summarized the clinical characterization of patients carrying pathogenic variants of MAPT in the East Asia populations. Our results broaden the genetic spectrum of FTD with MAPT and GRN variants.}, } @article {pmid36638683, year = {2023}, author = {Bubak, AN and Merle, L and Niemeyer, CS and Baxter, BD and Gentile Polese, A and Ramakrishnan, V and Gomez, J and Madrigal, L and Villegas-Lanau, A and Lopera, F and Macklin, W and Frietze, S and Nagel, MA and Restrepo, D}, title = {Signatures for viral infection and inflammation in the proximal olfactory system in familial Alzheimer's disease.}, journal = {Neurobiology of aging}, volume = {123}, number = {}, pages = {75-82}, pmid = {36638683}, issn = {1558-1497}, support = {R01 DC000566/DC/NIDCD NIH HHS/United States ; R01 DC014253/DC/NIDCD NIH HHS/United States ; RF1 MH128867/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/metabolism ; Proteomics ; Amyloid beta-Peptides/metabolism ; Olfactory Bulb/metabolism ; Inflammation/genetics/pathology ; *Virus Diseases/pathology ; Presenilin-1/genetics/metabolism ; }, abstract = {Alzheimer's disease (AD) is characterized by deficits in olfaction and olfactory pathology preceding diagnosis of dementia. Here we analyzed differential gene and protein expression in the olfactory bulb (OB) and tract (OT) of familial AD (FAD) individuals carrying the autosomal dominant presenilin 1 E280A mutation. Compared to control, FAD OT had increased immunostaining for β-amyloid (Aβ) and CD68 in high and low myelinated regions, as well as increased immunostaining for Iba1 in the high myelinated region. In FAD samples, RNA sequencing showed: (1) viral infection in the OB; (2) inflammation in the OT that carries information via entorhinal cortex from the OB to hippocampus, a brain region essential for learning and memory; and (3) decreased oligodendrocyte deconvolved transcripts. Interestingly, spatial proteomic analysis confirmed altered myelination in the OT of FAD individuals, implying dysfunction of communication between the OB and hippocampus. These findings raise the possibility that viral infection and associated inflammation and dysregulation of myelination of the olfactory system may disrupt hippocampal function, contributing to acceleration of FAD progression.}, } @article {pmid36638682, year = {2023}, author = {Honda, K and Saito, Y and Saito, H and Toyoda, M and Abe, R and Saito, T and Saido, TC and Michikawa, M and Taru, H and Sobu, Y and Hata, S and Nakaya, T and Suzuki, T}, title = {Accumulation of amyloid-β in the brain of mouse models of Alzheimer's disease is modified by altered gene expression in the presence of human apoE isoforms during aging.}, journal = {Neurobiology of aging}, volume = {123}, number = {}, pages = {63-74}, doi = {10.1016/j.neurobiolaging.2022.12.003}, pmid = {36638682}, issn = {1558-1497}, mesh = {Humans ; Mice ; Animals ; *Alzheimer Disease/metabolism ; Apolipoprotein E4/genetics/metabolism ; Apolipoprotein E3/genetics/metabolism ; Mice, Transgenic ; Apolipoproteins E/metabolism ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; Brain/metabolism ; Aging/genetics/metabolism ; Protein Isoforms/genetics/metabolism ; Gene Expression ; }, abstract = {Apolipoprotein E4 (apoE4) is a risk factor for Alzheimer's disease (AD). Here, we investigated brain amyloid-β (Aβ) accumulation throughout the aging process in an amyloid precursor protein (APP) knock-in (KI) mouse model of AD that expresses human APP[NL-G-F] with or without human apoE4 or apoE3. Brain Aβ42 levels were significantly lower in 9-month-old mice that express human isoforms of apoE than in age-matched APP-KI control mice. Linear accumulation of Aβ42 began in 5-month-old apoE4 mice, and a strong increase in Aβ42 levels was observed in 21-month-old apoE3 mice. Aβ42 levels in cerebroventricular fluid were higher in apoE3 than in apoE4 mice at 6-7 months of age, suggesting that apoE3 is more efficient at clearing Aβ42 than apoE4 at these ages. However, apoE3 protein levels were lower than apoE4 protein levels in the brains of 21-month-old apoE3 and apoE4 mice, respectively, which may explain the rapid increase in brain Aβ42 burden in apoE3 mice. We identified genes that were downregulated in a human apoE-dependent (apoE4 > apoE3) and age-dependent (apoE3 = apoE4) manner, which may regulate brain Aβ burden and/or AD progression. Analysis of gene expression in AD mouse models helps identify molecular mechanisms of pleiotropy by the human APOE gene during aging.}, } @article {pmid36638681, year = {2023}, author = {Freire-Cobo, C and Rothwell, ES and Varghese, M and Edwards, M and Janssen, WGM and Lacreuse, A and Hof, PR}, title = {Neuronal vulnerability to brain aging and neurodegeneration in cognitively impaired marmoset monkeys (Callithrix jacchus).}, journal = {Neurobiology of aging}, volume = {123}, number = {}, pages = {49-62}, pmid = {36638681}, issn = {1558-1497}, support = {R01 AG046266/AG/NIA NIH HHS/United States ; F32 AG064925/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Callithrix ; *Amyloid beta-Peptides ; Brain ; Neurons ; Aging/physiology ; }, abstract = {The investigation of neurobiological and neuropathological changes that affect synaptic integrity and function with aging is key to understanding why the aging brain is vulnerable to Alzheimer's disease. We investigated the cellular characteristics in the cerebral cortex of behaviorally characterized marmosets, based on their trajectories of cognitive learning as they transitioned to old age. We found increased astrogliosis, increased phagocytic activity of microglial cells and differences in resting and reactive microglial cell phenotypes in cognitively impaired compared to nonimpaired marmosets. Differences in amyloid beta deposition were not related to cognitive trajectory. However, we found age-related changes in density and morphology of dendritic spines in pyramidal neurons of layer 3 in the dorsolateral prefrontal cortex and the CA1 field of the hippocampus between cohorts. Overall, our data suggest that an accelerated aging process, accompanied by neurodegeneration, that takes place in cognitively impaired aged marmosets and affects the plasticity of dendritic spines in cortical areas involved in cognition and points to mechanisms of neuronal vulnerability to aging.}, } @article {pmid36637075, year = {2023}, author = {Welty, FK}, title = {Omega-3 fatty acids and cognitive function.}, journal = {Current opinion in lipidology}, volume = {34}, number = {1}, pages = {12-21}, doi = {10.1097/MOL.0000000000000862}, pmid = {36637075}, issn = {1473-6535}, mesh = {Animals ; *Alzheimer Disease/drug therapy/prevention & control ; Dietary Supplements ; *Fatty Acids, Omega-3/pharmacology/therapeutic use ; Docosahexaenoic Acids/pharmacology/therapeutic use ; Cognition ; *Cognitive Dysfunction/prevention & control ; *Coronary Artery Disease ; Eicosapentaenoic Acid/pharmacology ; }, abstract = {PURPOSE OF REVIEW: The aim is to provide an update on omega-3 polyunsaturated fatty acids (n-3 PUFA) in preventing cognitive decline and dementia.

RECENT FINDINGS: Prospective studies and three new meta-analyses suggest that fish or n-3 PUFA intake are associated with a reduction in development of mild cognitive decline and Alzheimer's disease. Supplementation with docosahexaenoic acid (DHA) in randomized controlled trials (RCTs) in those with mild cognitive impairment showed benefit on cognitive decline, whereas there was no benefit in Alzheimer's disease. In cognitively healthy individuals with clinical coronary artery disease (CAD), 3.36 g EPA and DHA daily slowed cognitive ageing by 2.5 years. Of 15 RCTs in cognitively healthy individuals age more than 55 years, seven reported benefit, whereas eight did not. Potential mechanisms for differences in outcomes include dose, trial duration, apolipoproteinE genotype, sex, stage and rate of cognitive decline, cognitive testing employed and individual characteristics. The downstream product of DHA, neuroprotectin D1, may be involved in beneficial effects.

SUMMARY: Patients with early memory complaints or a family history of dementia and those with CAD should be counselled on the potential benefits of fish intake and supplementation with n-3 PUFA. ApolipoproteinE4 carriers may especially benefit from DHA supplementation prior to development of cognitive decline.}, } @article {pmid36636325, year = {2022}, author = {Chen, PC and Han, X and Shaw, TI and Fu, Y and Sun, H and Niu, M and Wang, Z and Jiao, Y and Teubner, BJW and Eddins, D and Beloate, LN and Bai, B and Mertz, J and Li, Y and Cho, JH and Wang, X and Wu, Z and Liu, D and Poudel, S and Yuan, ZF and Mancieri, A and Low, J and Lee, HM and Patton, MH and Earls, LR and Stewart, E and Vogel, P and Hui, Y and Wan, S and Bennett, DA and Serrano, GE and Beach, TG and Dyer, MA and Smeyne, RJ and Moldoveanu, T and Chen, T and Wu, G and Zakharenko, SS and Yu, G and Peng, J}, title = {Alzheimer's disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment.}, journal = {Nature aging}, volume = {2}, number = {10}, pages = {923-940}, pmid = {36636325}, issn = {2662-8465}, support = {RF1 AG068581/AG/NIA NIH HHS/United States ; U19 AG069701/AG/NIA NIH HHS/United States ; U24 NS072026/NS/NINDS NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; R01 MH095810/MH/NIMH NIH HHS/United States ; R01 AG047928/AG/NIA NIH HHS/United States ; R01 AG053987/AG/NIA NIH HHS/United States ; P30 AG072980/AG/NIA NIH HHS/United States ; U54 NS110435/NS/NINDS NIH HHS/United States ; RF1 AG064909/AG/NIA NIH HHS/United States ; }, abstract = {Recent proteome and transcriptome profiling of Alzheimer's disease (AD) brains reveals RNA splicing dysfunction and U1 small nuclear ribonucleoprotein (snRNP) pathology containing U1-70K and its N-terminal 40-KDa fragment (N40K). Here we present a causative role of U1 snRNP dysfunction to neurodegeneration in primary neurons and transgenic mice (N40K-Tg), in which N40K expression exerts a dominant-negative effect to downregulate full-length U1-70K. N40K-Tg recapitulates N40K insolubility, erroneous splicing events, neuronal degeneration and cognitive impairment. Specifically, N40K-Tg shows the reduction of GABAergic synapse components (e.g., the GABA receptor subunit of GABRA2), and concomitant postsynaptic hyperexcitability that is rescued by a GABA receptor agonist. Crossing of N40K-Tg and the 5xFAD amyloidosis model indicates that the RNA splicing defect synergizes with the amyloid cascade to remodel the brain transcriptome and proteome, deregulate synaptic proteins, and accelerate cognitive decline. Thus, our results support the contribution of U1 snRNP-mediated splicing dysfunction to AD pathogenesis.}, } @article {pmid36636148, year = {2022}, author = {Reiss, AB and de Levante Raphael, D and Chin, NA and Sinha, V}, title = {The physician's Alzheimer's disease management guide: Early detection and diagnosis of cognitive impairment, Alzheimer's disease and related dementia.}, journal = {AIMS public health}, volume = {9}, number = {4}, pages = {661-689}, pmid = {36636148}, issn = {2327-8994}, abstract = {Primary care professionals play a critical role in the care of their patients. In clinical practice, early detection and diagnosis of Mild Cognitive Impairment, Alzheimer's disease and related dementia are often missed or delayed. Disclosure of diagnosis is not timely or not revealed. Though the methods that could improve early detection and diagnosis have remained the same over the decades with little change, they provide opportunities for early intervention, treatment and improvement in patient care. Emerging research suggests that though the disease process begins years prior to the clinical diagnosis, the healthcare system and health care professionals remain distant and reluctant to provide the service of annual cognitive assessment, which has been recommended by the Medicare program for older adults aged 65 years and older. Findings support that Alzheimer's disease and related cognitive impairments have gone under detected, underdiagnosed and undertreated. This article seeks to provide valuable and equitable information in the form of a clinician's guide for removing the barriers to early detection and diagnosis of cognitive impairments and offers an unprecedented opportunity to improve the clinical outcomes and care of older adults with various levels of cognitive decline, including mild cognitive impairment, Alzheimer's disease, and related dementias. This article provides information on understanding and addressing the challenges faced by health care professionals, including primary care clinicians; removing the barriers to cognitive assessments; educating this professional group on the importance of brain health, early detection, and diagnosis for their older adult patients; and providing these professionals with the ability to transfer their knowledge into more defined care planning. Until cognitive screening has been fully accepted and implemented for the optimal the care of older adults, health-related efforts should include the promotion and education of brain health, early detection, and diagnosis in the education of health care providers.}, } @article {pmid36635241, year = {2022}, author = {Huang, M and Macdonald, J and Lavenir, I and Chen, R and Craxton, M and Slavik-Smith, E and Davies, SW and Goedert, M}, title = {Increase in Tau Pathology in P290S Mapt Knock-In Mice Crossed with App [NL-G-F] Mice.}, journal = {eNeuro}, volume = {9}, number = {6}, pages = {}, pmid = {36635241}, issn = {2373-2822}, mesh = {Animals ; Mice ; *Alzheimer Disease/genetics/pathology ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; Brain/metabolism ; Disease Models, Animal ; Mice, Transgenic ; Plaque, Amyloid/pathology ; tau Proteins/genetics/metabolism ; }, abstract = {Alzheimer's Disease (AD) is characterized by the pathologic assembly of amyloid β (Aβ) peptide, which deposits into extracellular plaques, and tau, which accumulates in intraneuronal inclusions. To investigate the link between Aβ and tau pathologies, experimental models featuring both pathologies are needed. We developed a mouse model featuring both tau and Aβ pathologies by knocking the P290S mutation into murine Mapt and crossing these Mapt [P290S] knock-in (KI) mice with the App [NL-G-F] KI line. Mapt [P290S] KI mice developed a small number of tau inclusions, which increased with age. The amount of tau pathology was significantly larger in App [NL-G-F] xMapt [P290S] KI mice from 18 months of age onward. Tau pathology was higher in limbic areas, including hippocampus, amygdala, and piriform/entorhinal cortex. We also observed AT100-positive and Gallyas-Braak-silver-positive dystrophic neurites containing assembled filamentous tau, as visualized by in situ electron microscopy. Using a cell-based tau seeding assay, we showed that Sarkosyl-insoluble brain extracts from both 18-month-old Mapt [P290S] KI and App [NL-G-F] xMapt [P290S] KI mice were seed competent, with brain extracts from double-KI mice seeding significantly more than those from the Mapt [P290S] KI mice. Finally, we showed that App [NL-G-F] xMapt [P290S] KI mice had neurodegeneration in the piriform cortex from 18 months of age. We suggest that App [NL-G-F] xMapt [P290S] KI mice provide a good model for studying the interactions of aggregation-prone tau, Aβ, neuritic plaques, neurodegeneration, and aging.}, } @article {pmid36634385, year = {2023}, author = {B Szabo, A and Cattaud, V and Bezzina, C and Dard, RF and Sayegh, F and Gauzin, S and Lejards, C and Valton, L and Rampon, C and Verret, L and Dahan, L}, title = {Neuronal hyperexcitability in the Tg2576 mouse model of Alzheimer's disease - the influence of sleep and noradrenergic transmission.}, journal = {Neurobiology of aging}, volume = {123}, number = {}, pages = {35-48}, doi = {10.1016/j.neurobiolaging.2022.11.017}, pmid = {36634385}, issn = {1558-1497}, mesh = {Mice ; Animals ; *Alzheimer Disease/pathology ; Mice, Transgenic ; Sleep/physiology ; Disease Models, Animal ; Sleep, REM ; *Epilepsy ; }, abstract = {The link between Alzheimer's disease (AD) and network hypersynchrony - manifesting as epileptic activities - received considerable attention in the past decade. However, several questions remain unanswered as to its mechanistic underpinnings. Therefore, our objectives were (1) to better characterise epileptic events in the Tg2576 mouse model throughout the sleep-wake cycle and disease progression via electrophysiological recordings and (2) to explore the involvement of noradrenergic transmission in this pathological hypersynchrony. Over and above confirming the previously described early presence and predominance of epileptic events during rapid-eye-movement (REM) sleep, we also show that these events do not worsen with age and are highly phase-locked to the section of the theta cycle during REM sleep where hippocampal pyramidal cells reach their highest firing probability. Finally, we reveal an antiepileptic mechanism of noradrenergic transmission via α1-adrenoreceptors that could explain the intriguing distribution of epileptic events over the sleep-wake cycle in this model, with potential therapeutic implications in the treatment of the epileptic events occurring in many AD patients.}, } @article {pmid36632487, year = {2023}, author = {Lowry, E and Coughlan, G and Morrissey, S and Jeffs, S and Hornberger, M}, title = {Spatial orientation - a stable marker for vascular cognitive impairment?.}, journal = {Cerebral circulation - cognition and behavior}, volume = {4}, number = {}, pages = {100155}, pmid = {36632487}, issn = {2666-2450}, abstract = {Vascular cognitive impairment (VCI) is the second most prevalent form of dementia, but little is known about the early cognitive and neuroimaging markers. Spatial navigation deficits are an emerging marker for Alzheimer's disease (AD), yet less is known about spatial orientation deficits sensitive to VCI. This case report follows up on the first VCI patient identified to have an egocentric orientation deficit. The study aimed to examine the patient's spatial deficits three years on and gain insights from the addition of the patient's MRI brain scan. A battery of spatial navigation tasks were administered following neuropsychological assessment. Results continue to show spatial orientation deficits. Critically, these changes appear stable and are sensitive to novel spatial tests. Whereas conventional screening tools demonstrate patient recovery. MRI DTI analysis indicates a non-significant trend towards loss of structural integrity to the posterior tracts of the longitudinal superior fasciculus (SLF), while the medial temporal lobe, typically implicated in spatial navigation, is unaffected. This finding potentially reflects reduced network connectivity in posterior to anterior white matter tracts co-existing with spatial orientation deficits. Findings have clinical utility and show spatial orientation as a potential sensitive cognitive marker for VCI.}, } @article {pmid36632183, year = {2023}, author = {de Leo, G and Gulino, R and Coradazzi, M and Leanza, G}, title = {Acetylcholine and noradrenaline differentially regulate hippocampus-dependent spatial learning and memory.}, journal = {Brain communications}, volume = {5}, number = {1}, pages = {fcac338}, pmid = {36632183}, issn = {2632-1297}, abstract = {Severe loss of cholinergic neurons in the basal forebrain nuclei and of noradrenergic neurons in the locus coeruleus are almost invariant histopathological hallmarks of Alzheimer's disease. However, the role of these transmitter systems in the spectrum of cognitive dysfunctions typical of the disease is still unclear, nor is it yet fully known whether do these systems interact and how. Selective ablation of either neuronal population, or both of them combined, were produced in developing animals to investigate their respective and/or concurrent contribution to spatial learning and memory, known to be severely affected in Alzheimer's disease. Single or double lesions were created in 4-8 days old rats by bilateral intraventricular infusion of two selective immunotoxins. At about 16 weeks of age, the animals underwent behavioural tests specifically designed to evaluate reference and working memory abilities, and their brains were later processed for quantitative morphological analyses. Animals with lesion to either system alone showed no significant reference memory deficits which, by contrast, were evident in the double-lesioned subjects. These animals could not adopt an efficient search strategy on a given testing day and were unable to transfer all relevant information to the next day, suggesting deficits in acquisition, storage and/or recall. Only animals with single noradrenergic or double lesions exhibited impaired working memory. Interestingly, ablation of cholinergic afferents to the hippocampus stimulated a robust ingrowth of thick fibres from the superior cervical ganglion which, however, did not appear to have contributed to the observed cognitive performance. Ascending cholinergic and noradrenergic afferents to the hippocampus and neocortex appear to be primarily involved in the regulation of different cognitive domains, but they may functionally interact, mainly at hippocampal level, for sustaining normal learning and memory. Moreover, these transmitter systems are likely to compensate for each other, but apparently not via ingrowing sympathetic fibres.}, } @article {pmid36632128, year = {2023}, author = {Lee, JE and Kang, HW and Jung, SA and Lee, SY and Kim, JY and Lee, DE and Jeong, JH and Jung, IC and Cho, E}, title = {The effects of herbal medicine (Jujadokseo-hwan) on quality of life in patients with mild cognitive impairment: Cost-effectiveness analysis alongside randomized controlled trial.}, journal = {Integrative medicine research}, volume = {12}, number = {1}, pages = {100914}, pmid = {36632128}, issn = {2213-4220}, abstract = {BACKGROUND: Mild cognitive impairment (MCI), the early stage of dementia, requires effective intervention for symptom management and improving patients' quality of life (QoL). Jujadokseo-hwan (JDH) is a Korean herbal medicine prescription used to improve MCI symptoms, such as memory deficit. This study evaluates the improvement in QoL through JDH. Alongside a clinical trial, it estimates the cost-effectiveness of JDH, compared to placebo, for MCI over 24 weeks.

METHODS: Changes in QoL were measured using the EuroQol-5 Dimensions (EQ-5D) and Korean version QoL-Alzheimer's Disease (KQOL-AD). Direct medical and non-medical costs were surveyed and incremental cost-effectiveness ratios (ICER) per QALY for JDH were produced.

RESULTS: In total, 64 patients were included in the economic evaluation (n = 35 in JDH, n = 29 in placebo). In the JDH group, EQ-5D and KQOL-AD improved by 0.020 (p = .318) and 3.40 (p = .011) over 24 weeks, respectively. In the placebo group, they increased by 0.001 (p=.920) and 1.07 (p=.130), respectively. The ICER was KRW 76,400,000 per QALY and KRW 108,000 per KQOL-AD for JDH, compared to the placebo group.

CONCLUSION: JDH is not considered a cost-effective treatment option compared with placebo; however, it positively affects QoL improvement in patients with MCI.}, } @article {pmid36632072, year = {2023}, author = {Alhasaniah, AH}, title = {l-carnitine: Nutrition, pathology, and health benefits.}, journal = {Saudi journal of biological sciences}, volume = {30}, number = {2}, pages = {103555}, pmid = {36632072}, issn = {1319-562X}, abstract = {Carnitine is a medically needful nutrient that contributes in the production of energy and the metabolism of fatty acids. Bioavailability is higher in vegetarians than in people who eat meat. Deficits in carnitine transporters occur as a result of genetic mutations or in combination with other illnesses such like hepatic or renal disease. Carnitine deficit can arise in diseases such endocrine maladies, cardiomyopathy, diabetes, malnutrition, aging, sepsis, and cirrhosis due to abnormalities in carnitine regulation. The exogenously provided molecule is obviously useful in people with primary carnitine deficits, which can be life-threatening, and also some secondary deficiencies, including such organic acidurias: by eradicating hypotonia, muscle weakness, motor skills, and wasting are all improved l-carnitine (LC) have reported to improve myocardial functionality and metabolism in ischemic heart disease patients, as well as athletic performance in individuals with angina pectoris. Furthermore, although some intriguing data indicates that LC could be useful in a variety of conditions, including carnitine deficiency caused by long-term total parenteral supplementation or chronic hemodialysis, hyperlipidemias, and the prevention of anthracyclines and valproate-induced toxicity, such findings must be viewed with caution.}, } @article {pmid36631849, year = {2022}, author = {Park, J and Won, J and Jeon, CY and Lim, KS and Choi, WS and Park, SH and Seo, J and Cho, J and Seong, JB and Yeo, HG and Kim, K and Kim, YG and Kim, M and Yi, KS and Lee, Y}, title = {XperCT-guided Intra-cisterna Magna Injection of Streptozotocin for Establishing an Alzheimer's Disease Model Using the Cynomolgus Monkey (Macaca fascicularis).}, journal = {Experimental neurobiology}, volume = {31}, number = {6}, pages = {409-418}, pmid = {36631849}, issn = {1226-2560}, abstract = {Till date, researchers have been developing animal models of Alzheimer's disease (AD) in various species to understand the pathological characterization and molecular mechanistic pathways associated with this condition in humans to identify potential therapeutic treatments. A widely recognized AD model that mimics the pathology of human AD involves the intracerebroventricular (ICV) injection with streptozotocin (STZ). However, ICV injection as an invasive approach has several limitations related to complicated surgical procedures. Therefore, in the present study, we created a customized stereotaxic frame using the XperCT-guided system for injecting STZ in cynomolgus monkeys, aiming to establish an AD model. The anatomical structures surrounding the cisterna magna (CM) were confirmed using CT/MRI fusion images of monkey brain with XperCT, the c-arm cone beam computed tomography. XperCT was used to determine the appropriate direction in which the needle tip should be inserted within the CM region. Cerebrospinal fluid (CSF) was collected to confirm the accurate target site when STZ was injected into the CM. Cynomolgus monkeys were administered STZ dissolved in artificial CSF once every week for 4 weeks via intracisterna magna (ICM) injection using XperCT-guided stereotactic system. The molecular mechanisms underlying the progression of STZ-induced AD pathology were analyzed two weeks after the final injection. The monkeys subjected to XperCT-based STZ injection via the ICM route showed features of AD pathology, including markedly enhanced neuronal loss, synaptic impairment, and tau phosphorylation in the hippocampus. These findings suggest a new approach for the construction of neurodegenerative disease models and development of therapeutic strategies.}, } @article {pmid36631848, year = {2022}, author = {Kim, JE and Lee, DK and Hwang, JH and Kim, CM and Kim, Y and Lee, JH and Lee, JM and Roh, JH and , }, title = {Regional Comparison of Imaging Biomarkers in the Striatum between Early- and Late-onset Alzheimer's Disease.}, journal = {Experimental neurobiology}, volume = {31}, number = {6}, pages = {401-408}, pmid = {36631848}, issn = {1226-2560}, abstract = {Striatal changes in the pathogenesis of Alzheimer's disease (AD) is not fully understood yet. We compared structural and functional image differences in the striatum between patients with early onset AD (EOAD) and late onset AD (LOAD) to investigate whether EOAD harbors autosomal dominant AD like imaging findings. The clinical, neuropsychological and neuroimaging biomarkers of 77 probable AD patients and 107 elderly subjects with normal cognition (NC) from the Alzheimer's Disease Neuroimaging Initiative (ADNI)-2 dataset were analyzed. Enrolled each subject completed a 3-Tesla MRI, baseline 18F-FDG-PET, and baseline 18F-AV-45 (Florbetapir) amyloid PET studies. AD patients were divided into two groups based on the onset age of clinical symptoms (EOAD <65 yrs; LOAD ≥65 yrs). A standardized uptake value ratio of the striatum and subcortical structures was obtained from both amyloid and FDG-PET scans. Structural MR imaging analysis was conducted using a parametric boundary description protocol, SPHARM-PDM. Of the 77 AD patients, 18 were EOAD and 59 were LOAD. Except for age of symptom onset, there were no statistically significant differences between the groups in demographics and detailed neuropsychological test results. 18F-AV-45 amyloid PET showed marked β-amyloid accumulation in the bilateral caudate nucleus and left pallidum in the EOAD group. Intriguingly, the caudate nucleus and putamen showed maintained glucose metabolism in the EOAD group compared to the LOAD group. Our image findings in the striatum of EOAD patients suggest that sporadic EOAD may share some pathophysiological changes noted in autosomal dominant AD.}, } @article {pmid36631200, year = {2023}, author = {Rukavina Mikusic, NL and Gironacci, MM}, title = {Mas receptor endocytosis and signaling in health and disease.}, journal = {Progress in molecular biology and translational science}, volume = {194}, number = {}, pages = {49-65}, doi = {10.1016/bs.pmbts.2022.09.001}, pmid = {36631200}, issn = {1878-0814}, mesh = {Humans ; *Proto-Oncogene Mas ; *Renin-Angiotensin System/physiology ; Angiotensin II/metabolism/pharmacology ; Blood Pressure/physiology ; Receptors, G-Protein-Coupled/metabolism ; Endocytosis ; }, abstract = {The renin angiotensin system (RAS) plays a major role in blood pressure regulation and electrolyte homeostasis and is mainly composed by two axes mediating opposite effects. The pressor axis, constituted by angiotensin (Ang) II and the Ang II type 1 receptor (AT1R), exerts vasoconstrictor, proliferative, hypertensive, oxidative and pro-inflammatory actions, while the depressor/protective axis, represented by Ang-(1-7), its Mas receptor (MasR) and the Ang II type 2 receptor (AT2R), opposes the actions elicited by the pressor arm. The MasR belongs to the G protein-coupled receptor (GPCR) family. To avoid receptor overstimulation, GPCRs undergo internalization and trafficking into the cell after being stimulated. Then, the receptor may induce other signaling cascades or it may even interact with other receptors, generating distinct biological responses. Thus, control of a GPCR regarding space and time affects the specificity of the signals transduced by the receptor and the ultimate cellular response. The present chapter is focused on the signaling and trafficking pathways of MasR under physiological conditions and its participation in the pathogenesis of numerous brain diseases.}, } @article {pmid36630749, year = {2022}, author = {Bruno, D and Jauregi Zinkunegi, A and Kollmorgen, G and Suridjan, I and Wild, N and Carlsson, C and Bendlin, B and Okonkwo, O and Chin, N and Hermann, BP and Asthana, S and Zetterberg, H and Blennow, K and Langhough, R and Johnson, SC and Mueller, KD}, title = {The recency ratio assessed by story recall is associated with cerebrospinal fluid levels of neurodegeneration biomarkers.}, journal = {Cortex; a journal devoted to the study of the nervous system and behavior}, volume = {159}, number = {}, pages = {167-174}, doi = {10.1016/j.cortex.2022.12.004}, pmid = {36630749}, issn = {1973-8102}, abstract = {Recency refers to the information learned at the end of a study list or task. Recency forgetting, as tracked by the ratio between recency recall in immediate and delayed conditions, i.e., the recency ratio (Rr), has been applied to list-learning tasks, demonstrating its efficacy in predicting cognitive decline, conversion to mild cognitive impairment (MCI), and cerebrospinal fluid (CSF) biomarkers of neurodegeneration. However, little is known as to whether Rr can be effectively applied to story recall tasks. To address this question, data were extracted from the database of the Alzheimer's Disease Research Center at the University of Wisconsin - Madison. A total of 212 participants were included in the study. CSF biomarkers were amyloid-beta (Aβ) 40 and 42, phosphorylated (p) and total (t) tau, neurofilament light (NFL), neurogranin (Ng), and α-synuclein (a-syn). Story Recall was measured with the Logical Memory Test (LMT). We carried out Bayesian regression analyses with Rr, and other LMT scores as predictors; and CSF biomarkers (including the Aβ42/40 and p-tau/Aβ42 ratios) as outcomes. Results showed that models including Rr consistently provided best fits with the data, with few exceptions. These findings demonstrate the applicability of Rr to story recall and its sensitivity to CSF biomarkers of neurodegeneration, and encourage its inclusion when evaluating risk of neurodegeneration with story recall.}, } @article {pmid36630558, year = {2023}, author = {Ganoza, LF and Villani, J and Klabunde, CN}, title = {Investment in Prevention Health Care Delivery Research by the National Institutes of Health.}, journal = {Medical care}, volume = {61}, number = {2}, pages = {75-80}, pmid = {36630558}, issn = {1537-1948}, support = {Z99 OD999999/ImNIH/Intramural NIH HHS/United States ; }, mesh = {United States ; Humans ; *Acquired Immunodeficiency Syndrome ; Health Services Research ; Health Care Costs ; National Institutes of Health (U.S.) ; *Substance-Related Disorders ; }, abstract = {BACKGROUND: Research assessing the delivery of preventive health care has considerable potential for improving health outcomes and reducing health care costs for the United States population.

OBJECTIVE: To characterize the prevention health care delivery research grant portfolio supported by the National Institutes of Health (NIH).

MATERIALS AND METHODS: A random sample of 14,523 NIH research projects funded during 2012-2019 was selected and coded for various study topics using a structured taxonomy. We analyzed the subset of prevention research projects, for which health care delivery was identified as an independent or dependent variable, including study characteristics and funding trends.

RESULTS: Overall, 11.2% of NIH-funded prevention research projects were relevant to health care delivery. Of these projects, 68.6% assessed access to care, 53.4% examined quality, and 27.1% assessed costs. Over the study period, the percentage of funded prevention research projects involving health care delivery increased from 10.9%-15.1%. Over half of the projects assessed research related to the prevention of a new health condition, identification of risk factors, or health promotion (55.5%), whereas < half addressed prevention of disease progression/recurrence (40.4%), screening for early disease (20.2%), or screening for risk factors (1.4%). human immunodeficiency virus/acquired immune deficiency syndrome, cancer, and substance use were the most prevalent health topics studied, whereas other topics-such as lung diseases and Alzheimer disease-were less frequently studied.

CONCLUSIONS: Health care delivery research comprises a modest portion of the NIH prevention research portfolio and is mostly focused on access and quality of care; cost-related analyses are less prevalent.human immunodeficiency virus/acquired immune deficiency syndrome, cancer, and substance use are frequently studied health topics in this portfolio.}, } @article {pmid36628782, year = {2023}, author = {Prenkaj, B and Aragona, D and Flaborea, A and Galasso, F and Gravina, S and Podo, L and Reda, E and Velardi, P}, title = {A self-supervised algorithm to detect signs of social isolation in the elderly from daily activity sequences.}, journal = {Artificial intelligence in medicine}, volume = {135}, number = {}, pages = {102454}, doi = {10.1016/j.artmed.2022.102454}, pmid = {36628782}, issn = {1873-2860}, mesh = {Humans ; Aged ; *Activities of Daily Living ; *Algorithms ; Aging ; Independent Living ; Social Isolation ; }, abstract = {Considering the increasing aging of the population, multi-device monitoring of the activities of daily living (ADL) of older people becomes crucial to support independent living and early detection of symptoms of mental illnesses, such as depression and Alzheimer's disease. Anomalies can anticipate the diagnosis of these pathologies in the patient's normal behavior, such as reduced hygiene, changes in sleep habits, and fewer social interactions. These abnormalities are often subtle and hard to detect. Especially using non-intrusive monitoring devices might cause anomaly detectors to generate false alarms or ignore relevant clues. This limitation may hinder their usage by caregivers. Furthermore, the notion of abnormality here is context and patient-dependent, thus requiring untrained approaches. To reduce these problems, we propose a self-supervised model for multi-sensor time series signals based on Hyperbolic uncertainty for Anomaly Detection, which we dub HypAD. HypAD estimates uncertainty end-to-end, thanks to hyperbolic neural networks, and integrates it into the "classic" notion of reconstruction loss in anomaly detection. Based on hyperbolic uncertainty, HypAD introduces the principle of a detectable anomaly. HypAD assesses whether it is sure about the input signal and fails to reconstruct it because it is anomalous or whether the high reconstruction loss is due to the model uncertainty, e.g., a complex but regular signal (cf. this parallels the residual model error upon training). The proposed solution has been incorporated into an end-to-end ADL monitoring system for elderly patients in retirement homes, developed within a funded project leveraging an interdisciplinary consortium of computer scientists, engineers, and geriatricians. Healthcare professionals were involved in the design and verification process to foster trust in the system. In addition, the system has been equipped with explainability features.}, } @article {pmid36628723, year = {2023}, author = {Liang, ZY and Wei, N and Guo, XF and Wang, H}, title = {A new quinoline based probe with large Stokes shift and high sensitivity for formaldehyde and its bioimaging applications.}, journal = {Analytica chimica acta}, volume = {1239}, number = {}, pages = {340723}, doi = {10.1016/j.aca.2022.340723}, pmid = {36628723}, issn = {1873-4324}, mesh = {Animals ; Humans ; *Zebrafish ; Hydrazines/metabolism ; HeLa Cells ; Formaldehyde ; Fluorescent Dyes/metabolism ; *Quinolines ; }, abstract = {As a common reactive metabolite in living organisms, abnormal levels of formaldehyde may cause diseases such as cancer and Alzheimer's disease. Therefore, it is important to develop a sensitive and efficient method to understand the role of formaldehyde in physiology and pathology. Herein, a new fluorescent probe 4-phenyl-2-(trifluoromethyl) quinolin-7-hydrazino (QH-FA) was prepared for the detection of formaldehyde in near-total aqueous media with hydrazine as the reaction site and quinoline derivatives as the fluorophore. After reacting with formaldehyde, the hydrazine group formed methylenehydrazine and the fluorescence was significantly enhanced (223-fold) with large Stokes shift of 140 nm. Furthermore, the response of QH-FA to formaldehyde could be finished with in only 10 min with good selectivity, and can distinguish formaldehyde from other aldehydes. More remarkably, the estimated limit of detection of QH-FA is 8.1 nM, which is superior to those of previously reported formaldehyde fluorescent probes. At the end, we detected formaldehyde in cells and zebrafish using QH-FA in a near-total aqueous system and obtained fluorescence images by confocal microscopy.}, } @article {pmid36628718, year = {2023}, author = {Zou, X and Zhao, Y and Lin, W}, title = {Photoacoustic/fluorescence dual-modality cyanine-based probe for real-time imaging of endogenous cysteine and in situ diagnosis of cervical cancer in vivo.}, journal = {Analytica chimica acta}, volume = {1239}, number = {}, pages = {340713}, doi = {10.1016/j.aca.2022.340713}, pmid = {36628718}, issn = {1873-4324}, mesh = {Humans ; Female ; Mice ; Animals ; *Cysteine ; *Uterine Cervical Neoplasms/diagnostic imaging ; Fluorescent Dyes ; Spectrum Analysis ; Optical Imaging/methods ; }, abstract = {Cysteine (Cys), one of cellular biothiols in the organism, is associated with many diseases, such as Parkinson's disease, Alzheimer's disease, liver damage, rheumatoid arthritis, and cancer. However, activatable fluorescence/photoacoustic (FL/PA) probes for non-invasive, real-time, and deep imaging of Cys in vivo are still lacking, and this hinders the diagnosis of Cys-related diseases. Herein, we designed and synthesized a novel activated FL/PA dual-modality cyanine-base probe (FP700) for real-time detection of Cys. The probe FP700 was established with near-infrared emissive dye cyanin as the fluorophore, linking with 2, 4-dinitrobenzenesulfonyl group as the recognition moiety for Cys. Using the FP700, we found that the FP700 exhibited intensive "turn-on" FL/PA signals under the excitation of 700 nm, which realized noninvasive in vivo detection of exogenous Cys. Significantly, FP700 accurately detected endogenous Cys though the FL/PA dual-mode imaging technology in tumor-bearing mice and obtain 3D PA diagnostic images with deep penetration depth and spatial resolution. Thus, the new dual-modality probe FP700 has advantage of high potential for deep tumor diagnosis of Cys in vivo, which may provide a new approach for the detection of cervical cancer and identification of its potential therapeutic targets.}, } @article {pmid36628348, year = {2022}, author = {Kim, CJ and Kwak, TY and Bae, MH and Shin, HK and Choi, BT}, title = {Therapeutic Potential of Active Components from Acorus gramineus and Acorus tatarinowii in Neurological Disorders and Their Application in Korean Medicine.}, journal = {Journal of pharmacopuncture}, volume = {25}, number = {4}, pages = {326-343}, pmid = {36628348}, issn = {2093-6966}, abstract = {Neurological disorders represent a substantial healthcare burden worldwide due to population aging. Acorus gramineus Solander (AG) and Acorus tatarinowii Schott (AT), whose major component is asarone, have been shown to be effective in neurological disorders. This review summarized current information from preclinical and clinical studies regarding the effects of extracts and active components of AG and AT (e.g., α-asarone and β-asarone) on neurological disorders and biomedical targets, as well as the mechanisms involved. Databases, including PubMed, Embase, and RISS, were searched using the following keywords: asarone, AG, AT, and neurological disorders, including Alzheimer's disease, Parkinson's disease, depression and anxiety, epilepsy, and stroke. Meta-analyses and reviews were excluded. A total of 873 studies were collected. A total of 89 studies were selected after eliminating studies that did not meet the inclusion criteria. Research on neurological disorders widely reported that extracts or active components of AG and AT showed therapeutic efficacy in treating neurological disorders. These components also possessed a wide array of neuroprotective effects, including reduction of pathogenic protein aggregates, antiapoptotic activity, modulation of autophagy, anti-inflammatory and antioxidant activities, regulation of neurotransmitters, activation of neurogenesis, and stimulation of neurotrophic factors. Most of the included studies were preclinical studies that used in vitro and in vivo models, and only a few clinical studies have been performed. Therefore, this review summarizes the current knowledge on AG and AT therapeutic effects as a basis for further clinical studies, and clinical trials are required before these findings can be applied to human neurological disorders.}, } @article {pmid36627944, year = {2022}, author = {Carbone, MG and Pomara, N and Callegari, C and Marazziti, D and Imbimbo, BP}, title = {Type 2 Diabetes Mellitus, Platelet Activation and Alzheimer's Disease: A Possible Connection.}, journal = {Clinical neuropsychiatry}, volume = {19}, number = {6}, pages = {370-378}, pmid = {36627944}, issn = {2385-0787}, abstract = {Type 2 diabetes mellitus DM (T2DM) is associated with a 70% increased risk for dementia, including Alzheimer's disease (AD). Insulin resistance has been proposed to play a pivotal role in both T2DM and AD and the concept of "brain insulin resistance" has been suggested as an interpretation to the growing literature regarding cognitive impairment and T2DM. Subjects with T2DM present an abnormal platelet reactivity that together with insulin resistance, hyperglycaemia and dyslipidaemia effect the vascular wall by a series of events including endothelial dysfunction, oxidative stress and low-grade inflammation. Activated platelets directly contribute to cerebral amyloid angiopathy (CAA) by promoting the formation of β-amyloid (Aβ) aggregates and that Aβ, in turn, activates platelets, creating a feed-forward loop suggesting the involvement of platelets in the AD pathogenesis. Moreover, islet amyloid polypeptide deposition, co-localized with Aβ deposits, is a common finding in the brain of patients with T2DM. These observations raise the intriguing prospect that traditional or novel antiplatelet therapeutic strategies may alleviate fibril formation and could be used in the prevention or treatment of AD subjects with diabetes.}, } @article {pmid36627889, year = {2023}, author = {Kwan, ATH and Arfaie, S and Therriault, J and Azizi, Z and Lussier, FZ and Tissot, C and Chamoun, M and Bezgin, G and Servaes, S and Stevenon, J and Rahmouni, N and Pallen, V and Gauthier, S and Rosa-Neto, P}, title = {Medial temporal tau predicts memory decline in cognitively unimpaired elderly.}, journal = {Brain communications}, volume = {5}, number = {1}, pages = {fcac325}, pmid = {36627889}, issn = {2632-1297}, abstract = {Alzheimer's disease can be detected in living people using in vivo biomarkers of amyloid-β and tau, even in the absence of cognitive impairment during the preclinical phase. [[18]F]-MK-6420 is a high-affinity PET tracer that quantifies tau neurofibrillary tangles, but its ability to predict cognitive changes associated with early Alzheimer's disease symptoms, such as memory decline, is unclear. Here, we assess the prognostic accuracy of baseline [[18]F]-MK-6420 tau-PET for predicting longitudinal memory decline in asymptomatic elderly individuals. In a longitudinal observational study, we evaluated a cohort of cognitively normal elderly participants (n = 111) from the translational biomarkers in ageing and dementia study (data collected between October 2017 and July 2020, with a follow-up period of 12 months). All participants underwent tau-PET with [[18]F]-MK-6420 and amyloid-β PET with [[18]F]-AZD-4694. The exclusion criteria included the presence of head trauma, stroke or other neurological disorders. There were 111 eligible participants selected based on the availability of amyloid-β PET, tau-PET, MRI and APOEɛ4 genotyping. Among these participants, the mean standard deviation age was 70.1 (8.6) years; 20 (18%) were tau-PET-positive and 71 of 111 (63.9%) were women. A significant association between the baseline Braak Stages I-II [[18]F]-MK-6240 standardized uptake value ratio positivity and change in composite memory score were observed at the 12-month follow-up, after correcting for age, sex and years of education [logical memory and Rey Auditory Verbal Learning Test, standardized beta = -0.52 (-0.82-0.21), P < 0.001, for dichotomized tau-PET and -1.22 (-1.84-(-0.61)], P < 0.0001, for continuous tau-PET]. Moderate cognitive decline was observed for A + T + over the follow-up period, whereas no significant change was observed for A-T+, A + T- and A-T-, although it should be noted that the A-T + group was small. Our results indicate that baseline tau neurofibrillary tangle pathology is associated with longitudinal changes in memory function, supporting the use of [[18]F]-MK-6420 PET to predict the likelihood of asymptomatic elderly individuals experiencing future memory decline. Overall, [[18]F]-MK-6420 PET is a promising tool for predicting memory decline in older adults without cognitive impairment at baseline. This is of critical relevance as the field is shifting towards a biological model of Alzheimer's disease defined by the aggregation of pathologic tau. Therefore, early detection of tau pathology using [[18]F]-MK-6420 PET provides us with hope that living patients with Alzheimer's disease may be diagnosed during the preclinical phase before it is too late.}, } @article {pmid36626477, year = {2022}, author = {Liu, Z and Guan, R and Bu, F and Pan, L}, title = {Treatment of Alzheimer's disease by combination of acupuncture and Chinese medicine based on pathophysiological mechanism: A review.}, journal = {Medicine}, volume = {101}, number = {49}, pages = {e32218}, pmid = {36626477}, issn = {1536-5964}, mesh = {Humans ; *Acupuncture Therapy ; *Alzheimer Disease/drug therapy ; Biomarkers ; Medicine, Chinese Traditional ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neurodegeneration, nerve loss, neurofibrillary tangles, and Aβ plaques. In modern medical science, there has been a serious obstacle to the effective treatment of AD. At present, there is no clinically proven and effective western medicine treatment for AD. The reason is that the etiology of AD is not yet fully understood. In 2018, the international community put forward a purely biological definition of AD, but soon this view of biomarkers was widely questioned, because the so-called AD biomarkers are shared with other neurological diseases, the diagnostic accuracy is low, and they face various challenges in the process of clinical diagnosis and treatment. Nowadays, scholars increasingly regard AD as the result of multimechanism and multicenter interaction. Because there is no exact Western medicine treatment for AD, the times call for the comprehensive treatment of AD in traditional Chinese medicine (TCM). AD belongs to the category of "dull disease" in TCM. For thousands of years, TCM has accumulated a lot of relevant treatment experience in the process of diagnosis and treatment. TCM, acupuncture, and the combination of acupuncture and medicine all play an important role in the treatment of AD. Based on the research progress of modern medicine on the pathophysiology of AD, this paper discusses the treatment of this disease with the combination of acupuncture and medicine.}, } @article {pmid36626425, year = {2022}, author = {Bu, F and Guan, R and Wang, W and Liu, Z and Yin, S and Zhao, Y and Chai, J}, title = {Bioinformatics and systems biology approaches to identify the effects of COVID-19 on neurodegenerative diseases: A review.}, journal = {Medicine}, volume = {101}, number = {49}, pages = {e32100}, pmid = {36626425}, issn = {1536-5964}, mesh = {Humans ; *COVID-19 ; SARS-CoV-2 ; Systems Biology ; *Alzheimer Disease ; *Parkinson Disease ; Phosphatidylinositol 3-Kinases ; Computational Biology ; *Neurodegenerative Diseases/epidemiology/genetics ; *Multiple Sclerosis ; }, abstract = {Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease (COVID-19), has been devastated by COVID-19 in an increasing number of countries and health care systems around the world since its announcement of a global pandemic on 11 March 2020. During the pandemic, emerging novel viral mutant variants have caused multiple outbreaks of COVID-19 around the world and are prone to genetic evolution, causing serious damage to human health. As confirmed cases of COVID-19 spread rapidly, there is evidence that SARS-CoV-2 infection involves the central nervous system (CNS) and peripheral nervous system (PNS), directly or indirectly damaging neurons and further leading to neurodegenerative diseases (ND), but the molecular mechanisms of ND and CVOID-19 are unknown. We employed transcriptomic profiling to detect several major diseases of ND: Alzheimer 's disease (AD), Parkinson' s disease (PD), and multiple sclerosis (MS) common pathways and molecular biomarkers in association with COVID-19, helping to understand the link between ND and COVID-19. There were 14, 30 and 19 differentially expressed genes (DEGs) between COVID-19 and Alzheimer 's disease (AD), Parkinson' s disease (PD) and multiple sclerosis (MS), respectively; enrichment analysis showed that MAPK, IL-17, PI3K-Akt and other signaling pathways were significantly expressed; the hub genes (HGs) of DEGs between ND and COVID-19 were CRH, SST, TAC1, SLC32A1, GAD2, GAD1, VIP and SYP. Analysis of transcriptome data suggests multiple co-morbid mechanisms between COVID-19 and AD, PD, and MS, providing new ideas and therapeutic strategies for clinical prevention and treatment of COVID-19 and ND.}, } @article {pmid36625236, year = {2022}, author = {Kawakami, J and Piccolo, SR and Kauwe, JK and Graves, SW}, title = {Gender differences contribute to variability of serum lipid biomarkers for Alzheimer's disease.}, journal = {Biomarkers in medicine}, volume = {16}, number = {15}, pages = {1089-1100}, doi = {10.2217/bmm-2022-0462}, pmid = {36625236}, issn = {1752-0371}, mesh = {Humans ; Male ; Female ; *Alzheimer Disease/diagnosis ; Sex Factors ; Mass Spectrometry/methods ; Biomarkers ; Lipids ; }, abstract = {Background: Alzheimer's disease (AD) cannot currently be diagnosed by a blood test. One reason may be gender differences. Another may be the statistical methods used. The authors evaluate these possibilities. Objective: The authors applied serum lipidomics to find AD biomarkers in men and women. They hypothesized that AD biomarkers would differ between genders and that machine-learning algorithms would improve diagnostic performance. Methods: Serum lipids were analyzed by mass spectrometry for a training set of AD cases and controls and in a blinded test set. Statistical analyses considered gender differences. Results: Lipids best classifying AD subjects differed significantly between men and women. Robust statistical algorithms did not improve diagnostic performance. Conclusion: Poor performance of AD biomarkers appears to be due primarily to inherent variability in AD patients.}, } @article {pmid36623535, year = {2022}, author = {Mastrianni, JA and Seibert, K}, title = {Challenging Cases of Neurocognitive Disorders.}, journal = {Seminars in neurology}, volume = {42}, number = {6}, pages = {742-751}, doi = {10.1055/s-0042-1760378}, pmid = {36623535}, issn = {1098-9021}, mesh = {Humans ; Aged ; *Parkinson Disease/diagnosis ; *Alzheimer Disease/diagnosis ; *Cognitive Dysfunction/diagnosis/etiology ; *Prion Diseases ; *Frontotemporal Dementia ; }, abstract = {Dementia is broadly defined by DSM-V as cognitive decline from a previous level that impacts the patient's functioning at work or play. This broad definition does not provide information about the underlying disease process, an aspect of clinical care that is of increasing importance, as therapeutic development inches closer to effective disease-modifying treatments. The most common neurodegenerative dementias include Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, and Parkinson's disease dementia. Although rare, the prion diseases constitute an important group of dementias that should be routinely considered in the evaluation. Over the last two decades, advances in neuroimaging, biomarker development, and neurogenetics have not only led to a better understanding of the biology of these diseases, but they have improved our awareness of less common clinical subtypes of dementia. As such, to best define the disease process, the evaluation of a patient with cognitive decline requires attention to a myriad of disease aspects, such as the primary symptom at onset (memory, language, visual perception, praxis, etc.), the age at onset (younger or older than 65 years), the rate of disease progression (weeks to months or years), the cognitive and behavioral profile (neuropsychological assessment), and involvement of physical findings. We present here three cases that highlight the decision-making process in the evaluation of patients with atypical presentations of dementia.}, } @article {pmid36620771, year = {2022}, author = {Ma, X and Zhao, Y and Yang, T and Gong, N and Chen, X and Liu, G and Xiao, J}, title = {Integration of network pharmacology and molecular docking to explore the molecular mechanism of Cordycepin in the treatment of Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1058780}, pmid = {36620771}, issn = {1663-4365}, abstract = {BACKGROUND: Cordycepin is a nucleoside adenosine analog and an active ingredient isolated from the liquid fermentation of Cordyceps. This study sought to explore the mechanism underlying the therapeutic effect of Cordycepin against Alzheimer's disease using network pharmacology and molecular docking technology.

METHODS: TCMSP, SYMMAP, CTD, Super-pred, SEA, GeneCards, DisGeNET database, and STRING platform were used to screen and construct the target and protein interaction network of Cordycepin for Alzheimer's disease. The results of Gene Ontology annotation and KEGG pathway enrichment analysis were obtained based on the DAVID database. The Omicshare database was also applied in GO and KEGG pathway enrichment analysis of the key targets. The protein-protein interaction network was constructed using the STRING database, and the potential effective targets for AD were screened based on the degree values. The correlation between the potential targets of Cordycepin in the treatment of AD and APP, MAPT, and PSEN2 was analyzed using (GEPIA) databases. We obtained potential targets related to aging using the Aging Altas database. Molecular docking analysis was performed by AutoDock Vina and Pymol software. Finally, we validated the significant therapeutic targets in the Gene Expression Omnibus (GEO) database.

RESULTS: A total of 74 potential targets of Cordycepin for treating Alzheimer's disease were identified. The potential targets of Cordycepin for the treatment of AD mainly focused on Lipid and atherosclerosis (hsa05417), Platinum drug resistance (hsa01524), Apoptosis (hsa04210), and Pathways in cancer (hsa05200). Our findings suggest that the therapeutic effect of Cordycepin on AD is primarily associated with these biological processes. We obtained 12 potential therapeutic targets for AD using the degree value in Cytoscape. Interestingly, AKT1, MAPK8, BCL2L1, FOXO3, and CTNNB1 were not only significantly associated with pathogenic genes (APP, MAPT, and PSEN2) but also with longevity in Alzheimer's Disease. Thus we speculated that the five target genes were potential core targets mediating the therapeutic effect of Cordycepin against AD. Moreover, molecular docking results analysis showed good binding affinity between Cordycepin and the five core targets. Overall, MAPK8, FOXO3 and CTNNB1 may have significant clinical and treatment implications.

CONCLUSION: Network pharmacology demonstrated that Cordycepin exerts a therapeutic effect against Alzheimer's disease via multiple targets and signaling pathways and has huge prospects for application in treating neurodegenerative diseases.}, } @article {pmid36620769, year = {2022}, author = {Aversano, S and Caiazza, C and Caiazzo, M}, title = {Induced pluripotent stem cell-derived and directly reprogrammed neurons to study neurodegenerative diseases: The impact of aging signatures.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1069482}, pmid = {36620769}, issn = {1663-4365}, abstract = {Many diseases of the central nervous system are age-associated and do not directly result from genetic mutations. These include late-onset neurodegenerative diseases (NDDs), which represent a challenge for biomedical research and drug development due to the impossibility to access to viable human brain specimens. Advancements in reprogramming technologies have allowed to obtain neurons from induced pluripotent stem cells (iPSCs) or directly from somatic cells (iNs), leading to the generation of better models to understand the molecular mechanisms and design of new drugs. Nevertheless, iPSC technology faces some limitations due to reprogramming-associated cellular rejuvenation which resets the aging hallmarks of donor cells. Given the prominent role of aging for the development and manifestation of late-onset NDDs, this suggests that this approach is not the most suitable to accurately model age-related diseases. Direct neuronal reprogramming, by which a neuron is formed via direct conversion from a somatic cell without going through a pluripotent intermediate stage, allows the possibility to generate patient-derived neurons that maintain aging and epigenetic signatures of the donor. This aspect may be advantageous for investigating the role of aging in neurodegeneration and for finely dissecting underlying pathological mechanisms. Here, we will compare iPSC and iN models as regards the aging status and explore how this difference is reported to affect the phenotype of NDD in vitro models.}, } @article {pmid36620768, year = {2022}, author = {Smith, DC and Karahan, H and Wijeratne, HRS and Al-Amin, M and McCord, B and Moon, Y and Kim, J}, title = {Deletion of the Alzheimer's disease risk gene Abi3 locus results in obesity and systemic metabolic disruption in mice.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1035572}, pmid = {36620768}, issn = {1663-4365}, support = {T32 AG071444/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) genetics studies have identified a coding variant within ABI3 gene that increases the risk of developing AD. Recently, we demonstrated that deletion of the Abi3 gene locus dramatically exacerbates AD neuropathology in a transgenic mouse model of amyloidosis. In the course of this AD project, we unexpectedly found that deletion of the Abi3 gene locus resulted in a dramatic obese phenotype in non-transgenic mice. Here, we report our investigation into this serendipitous metabolic finding. Specifically, we demonstrate that mice with deletion of the Abi3 gene locus (Abi3[-/-]) have dramatically increased body weight and body fat. Further, we determined that Abi3[-/-] mice have impaired energy expenditure. Additionally, we found that deletion of the Abi3 gene locus altered gene expression within the hypothalamus, particularly within immune-related pathways. Subsequent immunohistological analysis of the central nervous system (CNS) revealed that microglia number and area were decreased specifically within the mediobasal hypothalamus of Abi3[-/-] mice. Altogether, this investigation establishes the functional importance of the Abi3 gene locus in the regulation of systemic metabolism and maintenance of healthy body weight. While our previous findings indicated the importance of Abi3 in neurodegeneration, this study indicates that Abi3 related functions are also essential for metabolic regulation.}, } @article {pmid36620767, year = {2022}, author = {Miller, A and Desai, A and Roley, LT and Goodwin, RL and Nathaniel, AI and Nathaniel, TI}, title = {The role of ethnicity, biological sex, and psychotropic agents in early and late onset Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1052330}, pmid = {36620767}, issn = {1663-4365}, abstract = {OBJECTIVE: This study investigates differences in pharmacological and demographic factors among male and female patients with Late-onset Alzheimer's disease (LOAD) and Early-onset Alzheimer's disease (EOAD).

METHOD: Data are from 10,126 AD patients, 9,290 were diagnosed with LOAD, while 836 were diagnosed with EOAD. Data were collected from the Prisma Health Upstate Alzheimer's patients' registry between 2016 and 2021. The logistic regression analysis was used to assess the association between pharmacological and demographic factors in males and females with LOAD and EOAD.

RESULTS: In the adjusted analysis for males, patients that were administered memantine [odd ratio (OR) = 1.588, 95% CI, 1.175-2.145, p = 0.003], and buspirone [OR = 1.971, 95% CI, 1.221-3.183, p = 0.006] were more likely to be associated with EOAD, while increasing age [OR = 0.816, 95% CI, 0.799-0.834, p < 0.001] was associated with LOAD. Female patients with a history of alcohol (ETOH) use were more likely to be associated with EOAD while increasing age [OR = 0.845, 95% CI, 0.834-0.857, p < 0.001], treatment with memantine [OR = 0.774, 95% CI, 0.627-0.956, p = 0.017], African Americans [OR = 0.621, 95% CI, 0.462-0.835, p = 0.002] and tobacco use [OR = 0.529, 95% CI, 0.424-0.660, p < 0.001] were associated with LOAD.

CONCLUSION: Our findings identified specific demographic and pharmacological factors associated with males and females with LOAD and EOAD. These findings suggest the need to develop strategies to eliminate disparity in the care of LOAD or EOAD patients.}, } @article {pmid36620766, year = {2022}, author = {Fellows, RP and Bangen, KJ and Graves, LV and Delano-Wood, L and Bondi, MW}, title = {Pathological functional impairment: Neuropsychological correlates of the shared variance between everyday functioning and brain volumetrics.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {952145}, pmid = {36620766}, issn = {1663-4365}, abstract = {OBJECTIVE: Given that several non-cognitive factors can contribute to difficulties with everyday functioning, examining the extent to which cognition is associated with brain-related changes in everyday functioning is critical to accurate characterization of cognitive disorders. In this study, we examined neuropsychological correlates of the shared variance between everyday functioning and pathological indicators of cognitive aging using MRI brain volumetrics.

PARTICIPANTS AND METHODS: Participants were 600 adults aged 55 and older without dementia [432 cognitively normal; 168 mild cognitive impairment (MCI)] from the National Alzheimer's Coordinating Center cohort who underwent neuropsychological testing, informant-rated everyday functioning, and brain MRI scanning at baseline. The shared variance between everyday functioning and brain volumetrics (i.e., hippocampal volume, white matter hyperintensity volume) was extracted using the predicted value from multiple regression. The shared variance was used as an indicator of pathological everyday functional impairment. The residual variance from the regression analysis was used to examine functional reserve.

RESULTS: Larger white matter hyperintensity volumes (p = 0.002) and smaller hippocampal volumes (p < 0.001) were significantly correlated with worse informant-rated everyday functioning. Among individuals with MCI, worse performances on delayed recall (p = 0.013) and category fluency (p = 0.012) were significantly correlated with pathological functional impairment in multiple regression analysis. In the cognitively normal group, only worse auditory working memory (i.e., digit span backward; p = 0.025) significantly correlated with pathological functioning. Functional reserve was inversely related to anxiety (p < 0.001) in the MCI group and was associated with depressive symptoms (p = 0.003) and apathy (p < 0.001) in the cognitively normal group.

CONCLUSION: Subtle brain-related everyday functioning difficulties are evident in MCI and track with expected preclinical Alzheimer's disease cognitive phenotypes in this largely amnestic sample. Our findings indicate that functional changes occur early in the disease process and that interventions to target neuropsychiatric symptoms may help to bolster functional reserve in those at risk.}, } @article {pmid36620763, year = {2022}, author = {Knobel, P and Litke, R and Mobbs, CV}, title = {Biological age and environmental risk factors for dementia and stroke: Molecular mechanisms.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1042488}, pmid = {36620763}, issn = {1663-4365}, abstract = {Since the development of antibiotics and vaccination, as well as major improvements in public hygiene, the main risk factors for morbidity and mortality are age and chronic exposure to environmental factors, both of which can interact with genetic predispositions. As the average age of the population increases, the prevalence and costs of chronic diseases, especially neurological conditions, are rapidly increasing. The deleterious effects of age and environmental risk factors, develop chronically over relatively long periods of time, in contrast to the relatively rapid deleterious effects of infectious diseases or accidents. Of particular interest is the hypothesis that the deleterious effects of environmental factors may be mediated by acceleration of biological age. This hypothesis is supported by evidence that dietary restriction, which universally delays age-related diseases, also ameliorates deleterious effects of environmental factors. Conversely, both age and environmental risk factors are associated with the accumulation of somatic mutations in mitotic cells and epigenetic modifications that are a measure of "biological age", a better predictor of age-related morbidity and mortality than chronological age. Here we review evidence that environmental risk factors such as smoking and air pollution may also drive neurological conditions, including Alzheimer's Disease, by the acceleration of biological age, mediated by cumulative and persistent epigenetic effects as well as somatic mutations. Elucidation of such mechanisms could plausibly allow the development of interventions which delay deleterious effects of both aging and environmental risk factors.}, } @article {pmid36620455, year = {2022}, author = {Wolfrum, P and Fietz, A and Schnichels, S and Hurst, J}, title = {The function of p53 and its role in Alzheimer's and Parkinson's disease compared to age-related macular degeneration.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {1029473}, pmid = {36620455}, issn = {1662-4548}, abstract = {The protein p53 is the main human tumor suppressor. Since its discovery, extensive research has been conducted, which led to the general assumption that the purview of p53 is also essential for additional functions, apart from the prevention of carcinogenesis. In response to cellular stress and DNA damages, p53 constitutes the key point for the induction of various regulatory processes, determining whether the cell induces cell cycle arrest and DNA repair mechanisms or otherwise cell death. As an implication, aberrations from its normal functioning can lead to pathogeneses. To this day, neurodegenerative diseases are considered difficult to treat, which arises from the fact that in general the underlying pathological mechanisms are not well understood. Current research on brain and retina-related neurodegenerative disorders suggests that p53 plays an essential role in the progression of these conditions as well. In this review, we therefore compare the role and similarities of the tumor suppressor protein p53 in the pathogenesis of Alzheimer's (AD) and Parkinson's disease (PD), two of the most prevalent neurological diseases, to the age-related macular degeneration (AMD) which is among the most common forms of retinal degeneration.}, } @article {pmid36620440, year = {2022}, author = {Shmuel, A and Park, H and Rathi, Y and Yang, A}, title = {Editorial: Deep learning techniques and their applications to the healthy and disordered brain - during development through adulthood and beyond.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {1118233}, pmid = {36620440}, issn = {1662-4548}, } @article {pmid36620129, year = {2023}, author = {Guo, XY and Kwon, HJ and Rhee, HY and Park, S and Cho, AR and Ryu, CW and Jahng, GH}, title = {Microvascular morphology alteration using relaxation rate change with gadolinium-based magnetic resonance imaging contrast agent in patients with Alzheimer's disease.}, journal = {Quantitative imaging in medicine and surgery}, volume = {13}, number = {1}, pages = {1-16}, pmid = {36620129}, issn = {2223-4292}, abstract = {BACKGROUND: Conventional magnetic resonance imaging (MRI) techniques cannot demonstrate microvascular alterations in mild Alzheimer's disease (AD). Thus, the diagnosis of microvascular pathology commonly relies on postmortem. The purpose of this study was to evaluate alterations of microvascular structures in patients with AD using a 3T clinical MRI system with a commercially available contrast agent.

METHODS: Eleven patients with AD and 11 cognitively normal (CN) controls were included in this cross-sectional prospective study. R2 and R2* relaxation rate changes (∆R2 and ∆R2*) before and after a Gadolinium (Gd)-based contrast agent injection were calculated from images obtained with a multi-echo turbo spin-echo sequence and multi-echo gradient-echo sequence to obtain microvascular index maps of blood volume fraction (BVf), mean vessel diameter (mVD), vessel size index (VSI), mean vessel density (Q), and microvessel-weighted imaging (MvWI). Two-sample t-test was used to compare those values between the two groups. Correlation analysis was performed to evaluate the relationship between those values and age.

RESULTS: BVfs at the corpus callosum and at the thalamus were significantly increased in the AD group (P=0.024 and P=0.005, respectively). BVf at the gray matter (P=0.020) and white matter area (P=0.012) were also significantly increased in the AD group compared with the CN group. MvWIs at the hippocampus and parahippocampal gyrus were significantly increased in the AD group compared with the CN group (P=0.020 and P=0.006, respectively). Voxel-based analysis showed both mVD and VSI were significantly decreased at the prefrontal lobe in the AD group. Q were not significant difference between CN and AD groups. MvWI were significantly positively correlated with age.

CONCLUSIONS: Microvascular index was a useful non-invasive method to evaluate microvascular morphology alteration. The microvascular morphology of AD was manifested as increasing BVf and microvessel-weighted.}, } @article {pmid36619845, year = {2022}, author = {Mira, A and Gonçalves, R and Rodrigues, IT}, title = {Dysphagia in Alzheimer's disease: a systematic review.}, journal = {Dementia & neuropsychologia}, volume = {16}, number = {3}, pages = {261-269}, pmid = {36619845}, issn = {1980-5764}, abstract = {UNLABELLED: Dysphagia is described as a highly relevant comorbidity of Alzheimer's disease (AD). However, there is a scarcity of studies aiming at the characteristics and progression of dysphagia.

OBJECTIVE: The objective of this study was to identify the specific characteristics, progression, and prevalence of dysphagia in AD.

METHODS: Publications were searched in the PubMed (MEDLINE), EBSCO, ScienceDirect, and BASE databases. Critical appraisal and evidence-level analysis were conducted using the Joanna Briggs Institute and Effective Public Health Practice Project's (EPHPP) tools.

RESULTS: A total of 26 studies were reviewed. Symptoms begin in the early stage of AD, as oral phase impairments, and progress to pharyngeal symptoms and swallowing apraxia in the later stages of AD. Dysphagia progresses, as AD, along a continuum, with severity depending on individual variability. There were no studies found on prevalence.

CONCLUSIONS: Dysphagia is a complex and important comorbidity in AD that impacts the quality of life. No recent publications on prevalence may imply that is not being coded as a potential cause for pneumonia deaths in AD.}, } @article {pmid36619833, year = {2022}, author = {Nora, CD and de Lima, JD and Teixeira, IA and Silva, FO and de Almeida, JS and Monteiro, FC and Marinho, V and Dourado, MCN and Deslandes, AC}, title = {Online physical exercise and the neuropsychiatric symptoms in patients with dementia: a cross-sectional study during the COVID-19 pandemic.}, journal = {Dementia & neuropsychologia}, volume = {16}, number = {3}, pages = {253-260}, pmid = {36619833}, issn = {1980-5764}, abstract = {UNLABELLED: Social isolation is necessary during the COVID-19 pandemic but can be harmful to mental health, especially in people with neurocognitive disorders. Although physical exercise can alleviate neuropsychiatric symptoms and improve quality of life (QoL), sedentary behavior increased during the pandemic. Online interventions can contribute to improving physical activity and mental health.

OBJECTIVE: The objective of this study was to compare the neuropsychiatric symptoms and QoL of older adults with neurocognitive disorders who participated in an online physical exercise program with sedentary patients during the COVID-19 pandemic.

METHODS: In this cross-sectional study, 25 older patients with neurocognitive disorders (control group=11; online exercise group=14) were evaluated based on Neuropsychiatric Inventory (NPI) and the Quality of Life in Alzheimer's Disease (QoL-AD) scale.

RESULTS: There were differences between the two groups in the total NPI (U=36.50, p=0.025) and the nighttime behavior disturbances item (U=38.00, p=0.033), both with large effect sizes (ES=-1.03, 95% confidence interval [CI]:-1.83 to -0.16 and ES=-1.06, 95%CI -1.86 to -0.19, respectively). In terms of QoL-AD, a difference was identified only in the memory subitem (U=20.00, p=0.005), with a large ES (1.59, 95%CI 0.59-2.48).

CONCLUSIONS: Older adults with neurocognitive disorders who participated in an online physical exercise program, during the COVID-19 pandemic, showed fewer neuropsychiatric total symptoms, fewer nighttime disturbances episodes, and better subjective memory, compared to their physically inactive counterparts. Randomized controlled trials should be performed to better understand the effect of physical exercise in neuropsychiatric symptoms in dementia patients during periods of social isolation.}, } @article {pmid36619768, year = {2022}, author = {Vakili, K and Fathi, M and Yaghoobpoor, S and Sayehmiri, F and Nazerian, Y and Nazerian, A and Mohamadkhani, A and Khodabakhsh, P and Réus, GZ and Hajibeygi, R and Rezaei-Tavirani, M}, title = {The contribution of gut-brain axis to development of neurological symptoms in COVID-19 recovered patients: A hypothesis and review of literature.}, journal = {Frontiers in cellular and infection microbiology}, volume = {12}, number = {}, pages = {983089}, pmid = {36619768}, issn = {2235-2988}, mesh = {Humans ; *COVID-19/complications ; Brain-Gut Axis ; Dysbiosis ; SARS-CoV-2 ; *Neurodegenerative Diseases ; Brain ; }, abstract = {The gut microbiota undergoes significant alterations in response to viral infections, particularly the novel SARS-CoV-2. As impaired gut microbiota can trigger numerous neurological disorders, we suggest that the long-term neurological symptoms of COVID-19 may be related to intestinal microbiota disorders in these patients. Thus, we have gathered available information on how the virus can affect the microbiota of gastrointestinal systems, both in the acute and the recovery phase of the disease, and described several mechanisms through which this gut dysbiosis can lead to long-term neurological disorders, such as Guillain-Barre syndrome, chronic fatigue, psychiatric disorders such as depression and anxiety, and even neurodegenerative diseases such as Alzheimer's and Parkinson's disease. These mechanisms may be mediated by inflammatory cytokines, as well as certain chemicals such as gastrointestinal hormones (e.g., CCK), neurotransmitters (e.g., 5-HT), etc. (e.g., short-chain fatty acids), and the autonomic nervous system. In addition to the direct influences of the virus, repurposed medications used for COVID-19 patients can also play a role in gut dysbiosis. In conclusion, although there are many dark spots in our current knowledge of the mechanism of COVID-19-related gut-brain axis disturbance, based on available evidence, we can hypothesize that these two phenomena are more than just a coincidence and highly recommend large-scale epidemiologic studies in the future.}, } @article {pmid36619561, year = {2022}, author = {Alqarni, S and Alsebai, M}, title = {Could VGF and/or its derived peptide act as biomarkers for the diagnosis of neurodegenerative diseases: A systematic review.}, journal = {Frontiers in endocrinology}, volume = {13}, number = {}, pages = {1032192}, pmid = {36619561}, issn = {1664-2392}, mesh = {Adult ; Animals ; Female ; Humans ; Male ; Rats ; *Alzheimer Disease ; Amyloid beta-Peptides ; *Amyotrophic Lateral Sclerosis/diagnosis ; Biomarkers ; Dopamine ; Nerve Growth Factors ; *Neurodegenerative Diseases/diagnosis ; Observational Studies as Topic ; }, abstract = {BACKGROUND: The increasing ageing population has led to an increase in the prevalence of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). However, as yet, there are no simple biomarkers to predict the onset of such diseases. Recently, VGF and its peptides have been highlighted in neurodegenerative diseases. VGF (non-acronymic) is a polypeptide induced in PC12 cells by neurotrophic factors.

OBJECTIVE: This systematic review aimed to determine whether VGF and/or its derived peptides can be used as biomarkers for the diagnosis of ALS, PD, and AD with specific attention to (1) the levels of VGF and/or its derived peptides, (2) amyloid-beta, (3) dopamine, and (4) cognitive score.

METHODOLOGY: A search was undertaken in the Ovid EMBASE, Cochrane Library, PubMed, Scopus, and Web of Science for observational studies. Publications that assessed the level of VGF and/or its derived peptides among people with neurodegenerative diseases and compared them with healthy people were included. The quality of the included studies was assessed using the National Heart, Lung, and Blood Institute Quality Assessment Tool.

RESULT: A search of the databases yielded 834 studies, of which, eight observational studies met the inclusion criteria with a total of 673 participants (51.7% males) aged >18 years. Seven studies showed significant decreases in VGF and its derived peptides in adults with AD, PD, and ALS compared to healthy controls (p<0.05). However, one study showed that there was no significant difference in VGF in AD compared to healthy control(p>0.05). Furthermore, only one study reported that VGF levels were positively correlated with those of tissue dopamine but not with Aβ1-42, and low levels of VGF were associated to cognitive deficits.

CONCLUSION: The use of VGF and its derivatives for the diagnosis of PD, ALS, AD remains unclear, so further investigation of the role of VGF in neurodegenerative diseases and pathophysiology is needed to provide new insights.}, } @article {pmid36619176, year = {2022}, author = {Grycuk, E and Eichenholtz, E and Aarsland, D and Betzhold, S and Daly, G and Folkerts, AK and Kalbe, E and Kane, JP and Kinchin, I and Saldanha, I and Smith, V and Taylor, JP and Thompson, R and Leroi, I}, title = {Developing a core outcome set (COS) for Dementia with Lewy bodies (DLB).}, journal = {HRB open research}, volume = {5}, number = {}, pages = {57}, pmid = {36619176}, issn = {2515-4826}, abstract = {Background: Dementia with Lewy bodies (DLB) is an important cause of dementia with a range of clinical manifestations, including motor, neuropsychiatric, and autonomic symptoms. Compared with more common forms of dementia such as Alzheimer's disease, DLB has been the focus of significantly fewer treatment studies, often with diverse outcome measures, making comparison and clinical implementation difficult. A core outcome set (COS) can address this by ensuring that data are comparable, relevant, useful, and usable for making the best healthcare decisions. Methods: Using a multi-stage approach, development of the DLB-COS will include the following stages: (1) A systematic review, following PRISMA guidelines to create an initial long list of outcomes; (2) A two-round online Delphi including clinicians, scientists, policymakers, and individuals with lived experience of DLB and their representatives; (3) An online consensus meeting to agree on the final core list of outcomes (the final DLB-COS) for use in research and clinical practice; (4) A literature search to identify appropriate measurement instruments for the DLB-COS outcomes; (5) A final consensus meeting of the professional stakeholders who attended the online consensus meeting to agree on the instruments that should be used to measure the outcomes in the DLB-COS; and (6) Global dissemination. Discussion: This is a multi-stage project to develop a COS to be used in treatment trials for DLB. A DLB-COS will ensure the selection of relevant outcomes and will identify the instruments to be used to measure DLB globally.}, } @article {pmid36619150, year = {2022}, author = {Sayehmiri, F and Samadian, M and Mohamadkhani, A and Tafakhori, A and Haghighat, S and Rahmatian, A and Mohammadkhani, MA and Fazli, HR and Rezaei Tavirani, M}, title = {Gut Microbiota Modification via Glucagon-like Peptide-1 with Beneficial Neuroprotective Effects.}, journal = {Middle East journal of digestive diseases}, volume = {14}, number = {2}, pages = {235-243}, pmid = {36619150}, issn = {2008-5230}, abstract = {BACKGROUND: In recent decades, it has been shown that the association between intestinal bacterial imbalance (dysbiosis) and various diseases such as type 2 diabetes can play a role in the development of Alzheimer's and Parkinson's diseases. In this study, the beneficial effects of intestinal microbiota glucagon-like peptide 1 (GLP-1) in cognitive disorders were investigated. METHODS: PubMed-Medline, Web of Science, and Scopus were searched to identify experimental studies based on the bacterial strains along with GLP-1 1 expression in preventing or reducing cognitive impairment. Of the 233 studies, six were eligible for inclusion, and the Systematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk of bias tool was used to evaluate the risk of bias in individual studies. RESULTS: The results showed that intestinal expression of GLP-1 1 could reduce the intestinal pathogenic genus such as Enterobacteriaceae and was obviously associated with a greater number of beneficial genera such as Lactobacillus and Akkermansia. Also, the neuroprotective effects of Clostridium butyricum with GLP-1 1 in a mice were approved. Therefore, the modulation of the intestinal microbiota, mediated by an increase in the intestinal GLP-1 1 level, consequently improved cognitive function. CONCLUSION: In this review, we have indicated that the gut microbiota, by stimulating the expression of the intestinal hormones like GLP-1 1, and also with a beneficial effect in inhibiting some involved genes in inflammation, can declined the development of cognitive disorders.}, } @article {pmid36619039, year = {2022}, author = {Murphy, SA and Chen, L and Doherty, JM and Acharyya, P and Riley, N and Johnson, AM and Walker, A and Domash, H and Jorgensen, M and Bayat, S and Carr, DB and Ances, BM and Babulal, GM}, title = {Cognitive and brain reserve predict decline in adverse driving behaviors among cognitively normal older adults.}, journal = {Frontiers in psychology}, volume = {13}, number = {}, pages = {1076735}, pmid = {36619039}, issn = {1664-1078}, abstract = {Daily driving is a multi-faceted, real-world, behavioral measure of cognitive functioning requiring multiple cognitive domains working synergistically to complete this instrumental activity of daily living. As the global population of older adult continues to grow, motor vehicle crashes become more frequent among this demographic. Cognitive reserve (CR) is the brain's adaptability or functional robustness despite damage, while brain reserve (BR) refers the structural, neuroanatomical resources. This study examined whether CR and BR predicted changes in adverse driving behaviors in cognitively normal older adults. Cognitively normal older adults (Clinical Dementia Rating 0) were enrolled from longitudinal studies at the Knight Alzheimer's Disease Research Center at Washington University. Participants (n = 186) were ≥65 years of age, required to have Magnetic Resonance Imaging (MRI) data, neuropsychological testing data, and at least one full year of naturalistic driving data prior to the beginning of COVID-19 lockdown in the United States (March 2020) as measured by Driving Real World In-vehicle Evaluation System (DRIVES). Findings suggest numerous changes in driving behaviors over time were predicted by increased hippocampal and whole brain atrophy, as well as lower CR scores as proxied by the Wide Range Achievement Test 4. These changes indicate that those with lower BR and CR are more likely to reduce their driving exposure and limit trips as they age and may be more likely to avoid highways where speeding and aggressive maneuvers frequently occur.}, } @article {pmid36618979, year = {2023}, author = {Finney, CA and Delerue, F and Gold, WA and Brown, DA and Shvetcov, A}, title = {Artificial intelligence-driven meta-analysis of brain gene expression identifies novel gene candidates and a role for mitochondria in Alzheimer's disease.}, journal = {Computational and structural biotechnology journal}, volume = {21}, number = {}, pages = {388-400}, pmid = {36618979}, issn = {2001-0370}, abstract = {Alzheimer's disease (AD) is the most common form of dementia. There is no treatment and AD models have focused on a small subset of genes identified in familial AD. Microarray studies have identified thousands of dysregulated genes in the brains of patients with AD yet identifying the best gene candidates to both model and treat AD remains a challenge. We performed a meta-analysis of microarray data from the frontal cortex (n = 697) and cerebellum (n = 230) of AD patients and healthy controls. A two-stage artificial intelligence approach, with both unsupervised and supervised machine learning, combined with a functional network analysis was used to identify functionally connected and biologically relevant novel gene candidates in AD. We found that in the frontal cortex, genes involved in mitochondrial energy, ATP, and oxidative phosphorylation, were the most significant dysregulated genes. In the cerebellum, dysregulated genes were involved in mitochondrial cellular biosynthesis (mitochondrial ribosomes). Although there was little overlap between dysregulated genes between the frontal cortex and cerebellum, machine learning models comprised of this overlap. A further functional network analysis of these genes identified that two downregulated genes, ATP5L and ATP5H, which both encode subunits of ATP synthase (mitochondrial complex V) may play a role in AD. Combined, our results suggest that mitochondrial dysfunction, particularly a deficit in energy homeostasis, may play an important role in AD.}, } @article {pmid36618950, year = {2022}, author = {Liu, LW and Yue, HY and Zou, J and Tang, M and Zou, FM and Li, ZL and Jia, QQ and Li, YB and Kang, J and Zuo, LH}, title = {Comprehensive metabolomics and lipidomics profiling uncovering neuroprotective effects of Ginkgo biloba L. leaf extract on Alzheimer's disease.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1076960}, pmid = {36618950}, issn = {1663-9812}, abstract = {Introduction: Ginkgo biloba L. leaf extract (GBLE) has been reported to be effective for alleviating cognitive and memory impairment in Alzheimer's disease (AD). Nevertheless, the potential mechanism remains unclear. Herein, this study aimed to explore the neuroprotective effects of GBLE on AD and elaborate the underlying therapeutic mechanism. Methods: Donepezil, the most widely prescribed drug for AD, was used as a positive control. An integrated metabolomics and lipidomics approach was adopted to characterize plasma metabolic phenotype of APP/PS1 double transgenic mice and describe the metabolomic and lipidomic fingerprint changes after GBLE intervention. The Morris water maze test and immunohistochemistry were applied to evaluate the efficacy of GBLE. Results: As a result, administration of GBLE significantly improved the cognitive function and alleviated amyloid beta (Aβ) deposition in APP/PS1 mice, showing similar effects to donepezil. Significant alterations were observed in metabolic signatures of APP/PS1 mice compared with wild type (WT) mice by metabolomic analysis. A total of 60 markedly altered differential metabolites were identified, including 28 lipid and lipid-like molecules, 13 organic acids and derivatives, 11 organic nitrogen compounds, and 8 other compounds, indicative of significant changes in lipid metabolism of AD. Further lipidomic profiling showed that the differential expressed lipid metabolites between APP/PS1 and WT mice mainly consisted of phosphatidylcholines, lysophosphatidylcholines, triglycerides, and ceramides. Taking together all the data, the plasma metabolic signature of APP/PS1 mice was primarily characterized by disrupted sphingolipid metabolism, glycerophospholipid metabolism, glycerolipid metabolism, and amino acid metabolism. Most of the disordered metabolites were ameliorated after GBLE treatment, 19 metabolites and 24 lipids of which were significantly reversely regulated (adjusted-p<0.05), which were considered as potential therapeutic targets of GBLE on AD. The response of APP/PS1 mice to GBLE was similar to that of donepezil, which significantly reversed the levels of 23 disturbed metabolites and 30 lipids. Discussion: Our data suggested that lipid metabolism was dramatically perturbed in the plasma of APP/PS1 mice, and GBLE might exert its neuroprotective effects by restoring lipid metabolic balance. This work provided a basis for better understanding the potential pathogenesis of AD and shed new light on the therapeutic mechanism of GBLE in the treatment of AD.}, } @article {pmid36618946, year = {2022}, author = {Subramanian, A and Tamilanban, T and Alsayari, A and Ramachawolran, G and Wong, LS and Sekar, M and Gan, SH and Subramaniyan, V and Chinni, SV and Izzati Mat Rani, NN and Suryadevara, N and Wahab, S}, title = {Trilateral association of autophagy, mTOR and Alzheimer's disease: Potential pathway in the development for Alzheimer's disease therapy.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1094351}, pmid = {36618946}, issn = {1663-9812}, abstract = {The primary and considerable weakening event affecting elderly individuals is age-dependent cognitive decline and dementia. Alzheimer's disease (AD) is the chief cause of progressive dementia, and it is characterized by irreparable loss of cognitive abilities, forming senile plaques having Amyloid Beta (Aβ) aggregates and neurofibrillary tangles with considerable amounts of tau in affected hippocampus and cortex regions of human brains. AD affects millions of people worldwide, and the count is showing an increasing trend. Therefore, it is crucial to understand the underlying mechanisms at molecular levels to generate novel insights into the pathogenesis of AD and other cognitive deficits. A growing body of evidence elicits the regulatory relationship between the mammalian target of rapamycin (mTOR) signaling pathway and AD. In addition, the role of autophagy, a systematic degradation, and recycling of cellular components like accumulated proteins and damaged organelles in AD, is also pivotal. The present review describes different mechanisms and signaling regulations highlighting the trilateral association of autophagy, the mTOR pathway, and AD with a description of inhibiting drugs/molecules of mTOR, a strategic target in AD. Downregulation of mTOR signaling triggers autophagy activation, degrading the misfolded proteins and preventing the further accumulation of misfolded proteins that inhibit the progression of AD. Other target mechanisms such as autophagosome maturation, and autophagy-lysosomal pathway, may initiate a faulty autophagy process resulting in senile plaques due to defective lysosomal acidification and alteration in lysosomal pH. Hence, the strong link between mTOR and autophagy can be explored further as a potential mechanism for AD therapy.}, } @article {pmid36618920, year = {2022}, author = {Mirza, FJ and Zahid, S}, title = {Ursolic acid and rosmarinic acid ameliorate alterations in hippocampal neurogenesis and social memory induced by amyloid beta in mouse model of Alzheimer's disease.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1058358}, pmid = {36618920}, issn = {1663-9812}, abstract = {Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder characterized by substantial neuronal damage which manifests in the form of deficits in memory and cognition. In spite of the debilitating nature of Alzheimer's disease (AD), a dearth of treatment strategies calls for the need to develop therapeutic agents that stimulate neurogenesis and alleviate the associated cognitive deficits. The present study investigates the therapeutic potential of two major phytochemicals, rosmarinic acid (RA) and ursolic acid (UA) in an amyloid beta1-42 (Aβ1-42)-induced model of AD. UA, a natural pentacyclic triterpenoid and RA, a phenolic ester are major bioactive constituents of Rosmarinus officinalis, which is a medicinal herb belonging to family Lamiaceae and exhibiting significant biological properties including neuroprotection. Donepezil, a second generation cholinesterase inhibitor approved for the treatment of mild, moderate and severe Alzheimer's disease (AD) is used as control. Out of eight groups of male BALB/c mice, stereotaxic surgery was performed on four groups (n = 6 each) to introduce Aβ1-42 in the hippocampus followed by treatment with vehicle (phosphate-buffered saline (PBS)), donepezil, UA or RA. The other four groups were given vehicle, donepezil, UA and RA only. Behavior analysis for social interaction was performed which constitutes the social affiliation and the social novelty preference test. Presence of Aβ plaques and expression of neurogenesis markers i.e., doublecortin (DCX) and Ki-67 were also assessed. Results revealed the neuroprotective effect of UA and RA observed through substantial reduction in Aβ plaques as compared to the Aβ1-42- and donepezil-treated groups. The neuronal density was also restored as evident via DCX and Ki-67 immunoreactivity in Aβ1-42 + RA and Aβ1-42+UA-treated groups in comparison to Aβ1-42-treated and Aβ1-42+donepezil-treated groups. The social affiliation was reestablished in the Aβ1-42 administered groups treated with UA and RA. Molecular docking studies further validated the comparable binding of UA and RA with Ki-67 and DCX to that of donepezil. Our findings suggest that UA and RA are potential neuroprotective compounds that reverses the histological hallmarks of AD and ameliorate impaired social memory and hippocampal neurogenesis.}, } @article {pmid36618909, year = {2022}, author = {Ahmad, N and Lesa, KN and Sudarmanto, A and Fakhrudin, N and Ikawati, Z}, title = {The role of Phosphodiesterase-1 and its natural product inhibitors in Alzheimer's disease: A review.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1070677}, pmid = {36618909}, issn = {1663-9812}, abstract = {Phosphodiesterase-1 (PDE1) is a versatile enzyme that has surprisingly received considerable attention as a possible therapeutic target in Alzheimer's disease (AD) because it maintains the homeostasis of 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) in the brain. 3',5'-cyclic adenosine monophosphate and 3',5'-cyclic guanosine monophosphate are the two key second messengers that regulate a broad range of intracellular processes and neurocognitive functions, specifically memory and cognition, associated with Alzheimer's disease. However, the lack of available selective drugs on the market poses challenges to identifying the beneficial effects of natural products. The present review focuses on Phosphodiesterase-1 and its isoforms, splicing variants, location, distribution, and function; the role of Phosphodiesterase-1 inhibitors in Alzheimer's disease; and the use of vinpocetine and natural products as specific Phosphodiesterase-1 inhibitors. Moreover, it aims to provide ongoing updates, identify research gaps, and present future perspectives. This review indicates the potential role of Phosphodiesterase-1 inhibitors in the treatment of neurodegenerative disorders, such as Alzheimer's disease. Certain clinical trials on the alleviation of Alzheimer's disease in patients are still in progress. Among de novo outcomes, the employment of Phosphodiesterase-1 inhibitors to treat Alzheimer's disease is an important advancement given the absence of particular therapies in the pipeline for this highly prevalent disease. To sum up, Phosphodiesterase-1 inhibition has been specifically proposed as a critical therapeutic approach for Alzheimer's disease. This study provides a comprehensive review on the biological and pharmacological aspects of Phosphodiesterase-1, its role on the Alzheimer's diseases and its significance as Alzheimer's disease therapeutic target in drug discovery from natural products. This review will help clinical trials and scientific research exploring new entities for the treatment and prevention of Alzheimer's disease.}, } @article {pmid36618105, year = {2023}, author = {Fleming, CL and Golzan, M and Gunawan, C and McGrath, KC}, title = {Systematic and Bibliometric Analysis of Magnetite Nanoparticles and Their Applications in (Biomedical) Research.}, journal = {Global challenges (Hoboken, NJ)}, volume = {7}, number = {1}, pages = {2200009}, pmid = {36618105}, issn = {2056-6646}, abstract = {Recent reports show air pollutant magnetite nanoparticles (MNPs) in the brains of people with Alzheimer's disease (AD). Considering various field applications of MNPs because of developments in nanotechnology, the aim of this study is to identify major trends and data gaps in research on magnetite to allow for relevant environmental and health risk assessment. Herein, a bibliometric and systematic analysis of the published magnetite literature (n = 31 567) between 1990 to 2020 is completed. Following appraisal, publications (n = 244) are grouped into four time periods with the main research theme identified for each as 1990-1997 "oxides," 1998-2005 "ferric oxide," 2006-2013 "pathology," and 2014-2020 "animal model." Magnetite formation and catalytic activity dominate the first two time periods, with the last two focusing on the exploitation of nanoparticle engineering. Japan and China have the highest number of citations for articles published. Longitudinal analysis indicates that magnetite research for the past 30 years shifted from environmental and industrial applications, to biomedical and its potential toxic effects. Therefore, whilst this study presents the research profile of different countries, the development in research on MNPs, it also reveals that further studies on the effects of MNPs on human health is much needed.}, } @article {pmid36617333, year = {2022}, author = {Kunitskaya, NA and Ariev, AL}, title = {[The role of hyperuricemia in the development of cognitive changes in the elderly.].}, journal = {Advances in gerontology = Uspekhi gerontologii}, volume = {35}, number = {5}, pages = {775-782}, pmid = {36617333}, issn = {1561-9125}, mesh = {Humans ; Aged ; *Dementia/etiology ; *Alzheimer Disease/complications ; *Hyperuricemia/complications/diagnosis ; *Dementia, Vascular ; Uric Acid ; *Parkinson Disease/complications ; *Cognitive Dysfunction/diagnosis/etiology ; Cognition ; }, abstract = {It is known that hyperuricemia is recognized as an independent cardiovascular risk factor. However, uric acid can also perform useful functions due to its antioxidant properties, which may be especially relevant in the context of neurodegenerative diseases. This review examines the currently available data on the relationship between serum uric acid levels and cognitive functions in the elderly, paying special attention to the etiology of cognitive disorders (Alzheimer's disease, Parkinson's dementia and vascular dementia). Despite the high heterogeneity of existing studies due to the different characteristics of the studied populations and methods of assessing cognitive impairment, it was concluded that uric acid can modulate cognitive function in different ways depending on the etiology of dementia. Modern studies demonstrate that uric acid can have a neuroprotective effect in Alzheimer's disease and Parkinson's dementia, while hypouricemia is a risk factor for faster disease progression and is a possible marker of malnutrition. Conversely, a high level of uric acid in the blood serum can negatively affect the course of the disease in vascular dementia. Further studies are needed to clarify the physiopathological role of uric acid in various types of dementia and its clinical and prognostic significance.}, } @article {pmid36616187, year = {2022}, author = {Ahmad, R and Rosandy, AR and Sahidin, I and Ab Ghani, NS and Noor, NM and Baharum, SN}, title = {Bioassay Analysis and Molecular Docking Study Revealed the Potential Medicinal Activities of Active Compounds Polygonumins B, C and D from Polygonum minus (Persicaria minor).}, journal = {Plants (Basel, Switzerland)}, volume = {12}, number = {1}, pages = {}, pmid = {36616187}, issn = {2223-7747}, abstract = {Polygonumins B, C and D, derivative compounds of polygonumins A, were isolated from the stem of Polygonum minus. Based on NMR results, the structure of polygonumins derivatives is comprised of four phenylpropanoid units and a sucrose unit, with a similar structure to polygonumins A. However, the structural differences between polygonumins B (1), C (2) and D (3) can be distinguished based on the existence of methoxy, ethanoyl and hydroxyl groups and protons which bind to C-4, C-4' and C-3″. Interestingly, these bioactive compounds showed various medicinal properties based on our investigation on antioxidant, anticholinesterase and anti-HIV-1 protease activities. The IC50 value of DPPH and ABTS (antioxidant activities) was in the following descending order: polygonumins B > polygonumins C > polygonumins A > polygonumins D. In addition, almost similar pattern of antioxidant activity was observed for anti-acetylcholinesterase activity based on its IC50 value in descending order: polygonumins B > polygonumins C > polygonumins D > polygonumins A. On the other hand, polygonumins C and D showed inhibition of HIV-1 protease activity more than the positive control, pepstatin A. Finally, molecular docking studies on AChE and BChE proteins were carried out in order to gain insight into the mode of interactions between these compounds and the active residues for both enzymes. These remarkable findings indicate that these compounds have potential to be developed as targeted drugs for Alzheimer's disease or as anti-HIV drugs.}, } @article {pmid36615808, year = {2022}, author = {Jiang, H and Chen, C and Gao, J}, title = {Extensive Summary of the Important Roles of Indole Propionic Acid, a Gut Microbial Metabolite in Host Health and Disease.}, journal = {Nutrients}, volume = {15}, number = {1}, pages = {}, pmid = {36615808}, issn = {2072-6643}, mesh = {Humans ; *Gastrointestinal Microbiome ; Propionates/metabolism ; *Non-alcoholic Fatty Liver Disease/metabolism ; Bacteria/metabolism ; Indoles/pharmacology ; }, abstract = {Increasing evidence suggests that metabolites produced by the gut microbiota play a crucial role in host-microbe interactions. Dietary tryptophan ingested by the host enters the gut, where indole-like metabolites such as indole propionic acid (IPA) are produced under deamination by commensal bacteria. Here, we summarize the IPA-producing bacteria, dietary patterns on IPA content, and functional roles of IPA in various diseases. IPA can not only stimulate the expression of tight junction (TJ) proteins to enhance gut barrier function and inhibit the penetration of toxic factors, but also modulate the immune system to exert anti-inflammatory and antioxidant effects to synergistically regulate body physiology. Moreover, IPA can act on target organs through blood circulation to form the gut-organ axis, which helps maintain systemic homeostasis. IPA shows great potential for the diagnosis and treatment of various clinical diseases, such as NAFLD, Alzheimer's disease, and breast cancer. However, the therapeutic effect of IPA depends on dose, target organ, or time. In future studies, further work should be performed to explore the effects and mechanisms of IPA on host health and disease to further improve the existing treatment program.}, } @article {pmid36615790, year = {2022}, author = {Wang, L and Zhou, C and Yu, H and Hao, L and Ju, M and Feng, W and Guo, Z and Sun, X and Fan, Q and Xiao, R}, title = {Vitamin D, Folic Acid and Vitamin B12 Can Reverse Vitamin D Deficiency-Induced Learning and Memory Impairment by Altering 27-Hydroxycholesterol and S-Adenosylmethionine.}, journal = {Nutrients}, volume = {15}, number = {1}, pages = {}, pmid = {36615790}, issn = {2072-6643}, mesh = {Animals ; Mice ; Folic Acid ; Vitamin B 12 ; S-Adenosylmethionine ; Vitamin D ; Mice, Inbred C57BL ; *Vitamin B Complex ; *Vitamin D Deficiency ; Memory Disorders/drug therapy/etiology ; }, abstract = {The cholesterol-oxidized metabolite 27-hydroxycholesterol (27-OHC) is synthesized by CYP27A1, which is a key factor in vitamin D and oxysterol metabolism. Both vitamin D and 27-OHC are considered to play important roles in Alzheimer's disease (AD). The study aims to research the effects of co-supplementation of vitamin D, folic acid, and vitamin B12 on learning and memory ability in vitamin D-deficient mice, and to explore the underlying mechanism. In this study, C57BL/6J mice were fed a vitamin D-deficient diet for 13 weeks to establish a vitamin D-deficient mice model. The vitamin D-deficient mice were then orally gavaged with vitamin D (VD), folic acid (FA), and vitamin B12 (VB12) alone or together for eight weeks. Following the gavage, the learning and memory ability of the mice were evaluated by Morris Water Maze and Novel object recognition test. The CYP27A1-related gene and protein expressions in the liver and brain were determined by qRT-PCR. The serum level of 27-OHC was detected by HPLC-MS. Serum levels of 25(OH)D, homocysteine (Hcy), and S-Adenosylmethionine (SAM) were measured by ELISA. After feeding with the vitamin D-deficient diet, the mice performed longer latency to a platform (p < 0.001), lower average speed (p = 0.026) in the Morris Water Maze, a lower time discrimination index (p = 0.009) in Novel object recognition, and performances were reversed after vitamin D, folic acid and vitamin B12 supplementation alone or together (p < 0.05). The gene expressions of CYP27A1 in the liver and brain were upregulated in the vitamin D-deficiency (VDD) group compared with the control (CON) group (p = 0.015), while it was downregulated in VDD + VD and VDD + VD-FA/VB12 groups compared with the VDD group (p < 0.05), with a similar trend in the protein expression of CYP27A1. The serum levels of 27-OHC were higher in the VDD group, compared with CON, VDD + VD, and VDD + VD-FA/VB12 group (p < 0.05), and a similar trend was found in the brain. The serum 25(OH)D levels were significantly decreased in the vitamin D-deficiency group (p = 0.008), and increased in the vitamin D-supplemented group (p < 0.001). The serum levels of SAM were higher in the B vitamins-supplemented group, compared with CON and VDD groups (p < 0.05). This study suggests that CYP27A1 expression may be involved in the mechanism of learning and memory impairment induced by vitamin D deficiency. Co-supplementation with vitamin D, folic acid, and vitamin B12 significantly reverses this effect by affecting the expression of CYP27A1, which in turn regulates the metabolism of 27-OHC, 25(OH)D, and SAM.}, } @article {pmid36615777, year = {2022}, author = {Li, J and Liao, X and Yin, X and Deng, Z and Hu, G and Zhang, W and Jiang, F and Zhao, L}, title = {Gut Microbiome and Serum Metabolome Profiles of Capsaicin with Cognitive Benefits in APP/PS1 Mice.}, journal = {Nutrients}, volume = {15}, number = {1}, pages = {}, pmid = {36615777}, issn = {2072-6643}, mesh = {Mice ; Animals ; *Gastrointestinal Microbiome ; Capsaicin/pharmacology ; Tryptophan ; Metabolome ; *Alzheimer Disease/microbiology ; Cognition ; }, abstract = {Capsaicin, a natural bioactive component, has been reported to improve cognition and ameliorate the pathology of Alzheimer's disease (AD). Studies have linked AD to alterations in gut microbiota composition and serum metabolites. In the present study, we examined the alterations in serum metabolome and gut microbiome in APPswe/PS1dE9 (APP/PS1) mice treated with capsaicin. Capsaicin treatments resulted in a significant increase in the abundance of Akkermansia, Faecalibaculum, Unclassified_f_Atopobiaceae, and Gordonibacter and a significant decrease in the abundance of Adlercreutzia, Peptococcaceae, Alistipes, Oscillibacter and Erysipelatoclostridium. Furthermore, the species Akkermansia muciniphila (A. muciniphila) was significantly enriched in capsaicin-treated APP/PS1 mice (p = 0.0002). Serum metabolomic analysis showed that capsaicin-treated APP/PS1 mice had a significant higher level of tryptophan (Trp) metabolism and a significantly lower level of lipid metabolism compared with vehicle-treated mice. Capsaicin altered serum metabolites, including Kynurenine (Kyn), 5-Hydroxy-L-tryptophan (5-HIT), 5-Hydroxyindoleacetic acid (5-HIAA), indoxylsulfuric acid, lysophosphatidyl cholines (LysoPCs), and lysophosphatidyl ethanolamine (LysoPE). Significant correlations were observed between the gut bacteria and serum metabolite. With regard to the increased abundance of A. muciniphila and the ensuing rise in tryptophan metabolites, our data show that capsaicin alters both the gut microbiota and blood metabolites. By altering the gut microbiome and serum metabolome, a diet high in capsaicin may reduce the incidence and development of AD.}, } @article {pmid36615767, year = {2022}, author = {Gao, J and Fu, J and Gao, X and Yang, D}, title = {Molecular Mechanism of Cyanidin-3-O-Glucoside Disassembling Aβ Fibril In Silico.}, journal = {Nutrients}, volume = {15}, number = {1}, pages = {}, pmid = {36615767}, issn = {2072-6643}, mesh = {*Peptide Fragments/metabolism ; *Amyloid beta-Peptides/metabolism ; Anthocyanins ; Glucosides ; }, abstract = {The deposition of β-amyloid (Aβ) in the brain leads to neurotoxic effects and subsequent Alzheimer's disease (AD). While AD is becoming more and more prevalent in modern society, therapeutic efforts targeting Aβ could be a promising solution. Currently, two natural products are reported to disintegrate preformed Aβ fibril in vitro. Meanwhile, the chemical driving force behind this phenomenon remains unknown. Taking cyanidin-3-O-glucoside (Cy-3G) as an example, here we studied its interaction with different Aβ polymorphs in silico. Negative charges on different Aβ polymorphs draw the interaction with the flavylium cation on Cy-3G. Our results show that Aβ in a single peptide form in solution exposed more hydrophobic solvent accessible surface area than its fibril structure (per protomer), and Cy-3G interacts more intensively with the single peptide form than fibril as indicated by more hydrogen bonding formed and more amino acid residues involved in their hydrophobic interactions. Thus, the single Aβ peptide aggregation into fibril and fibril dissociation into single peptide equilibrium could be disturbed by the preferential binding of Cy-3G to the monomeric Aβ peptide, which leads to the disassembly of the pathogenic Aβ fibril. This study offers a novel perspective of Cy-3G alleviated AD syndrome beyond its dogmatic antioxidant activity.}, } @article {pmid36615719, year = {2022}, author = {Melo van Lent, D and Egert, S and Wolfsgruber, S and Kleineidam, L and Weinhold, L and Wagner-Thelen, H and Stoffel-Wagner, B and Bickel, H and Wiese, B and Weyerer, S and Pentzek, M and Jessen, F and Schmid, M and Maier, W and Scherer, M and Riedel-Heller, SG and Ramirez, A and Wagner, M}, title = {Low Serum Vitamin D Status Is Associated with Incident Alzheimer's Dementia in the Oldest Old.}, journal = {Nutrients}, volume = {15}, number = {1}, pages = {}, pmid = {36615719}, issn = {2072-6643}, mesh = {Aged, 80 and over ; Humans ; Aged ; *Alzheimer Disease/epidemiology/etiology ; *Dementia/epidemiology/etiology ; beta Carotene ; Prospective Studies ; Vitamins ; Vitamin D ; Vitamin A ; Tocopherols ; *Vitamin D Deficiency/complications/epidemiology ; }, abstract = {BACKGROUND: Vitamins A, D and E and beta-carotene may have a protective function for cognitive health, due to their antioxidant capacities.

METHODS: We analyzed data from 1334 non-demented participants (mean age 84 years) from the AgeCoDe study, a prospective multicenter-cohort of elderly general-practitioner patients in Germany, of whom n = 250 developed all-cause dementia and n = 209 developed Alzheimer's dementia (AD) during 7 years of follow-up. We examined whether concentrations of vitamins A (retinol), D (25-hydroxycholecalciferol) and E (alpha-tocopherol) and beta-carotene, would be associated with incident (AD) dementia.

RESULTS: In our sample, 33.7% had optimum vitamin D concentrations (≥50 nmol/L). Higher concentrations of vitamin D were associated with lower incidence of all-cause dementia and AD (HR 0.99 (95%CI 0.98; 0.99); HR0.99 (95%CI 0.98; 0.99), respectively). In particular, subjects with vitamin D deficiency (25.3%, <25 nmol/L) were at increased risk for all-cause dementia and AD (HR1.91 (95%CI 1.30; 2.81); HR2.28 (95%CI 1.47; 3.53), respectively). Vitamins A and E and beta-carotene were unrelated to (AD) dementia.

CONCLUSIONS: Vitamin D deficiency increased the risk to develop (AD) dementia. Our study supports the advice for monitoring vitamin D status in the elderly and vitamin D supplementation in those with vitamin D deficiency. We observed no relationships between the other vitamins with incident (AD) dementia, which is in line with previous observational studies.}, } @article {pmid36615708, year = {2022}, author = {Shi, S and Zhang, Q and Sang, Y and Ge, S and Wang, Q and Wang, R and He, J}, title = {Probiotic Bifidobacterium longum BB68S Improves Cognitive Functions in Healthy Older Adults: A Randomized, Double-Blind, Placebo-Controlled Trial.}, journal = {Nutrients}, volume = {15}, number = {1}, pages = {}, pmid = {36615708}, issn = {2072-6643}, mesh = {Humans ; Aged ; *Bifidobacterium longum ; *Probiotics/therapeutic use ; Cognition ; Bifidobacterium ; *Cognitive Dysfunction/therapy ; Double-Blind Method ; }, abstract = {Probiotics could improve cognitive functions in patients with neurological disorders such as Alzheimer's disease, but the effects on cognitive function in healthy older adults without cognitive impairment need further study. The purpose of this study was to investigate the effect of Bifidobacterium longum BB68S (BB68S) on cognitive functions among healthy older adults without cognitive impairment. A randomized, double-blind, placebo-controlled trial was conducted with 60 healthy older adults without cognitive impairment who were divided into probiotic or placebo groups and required to consume either a sachet of probiotic (BB68S, 5 × 10[10] CFU/sachet) or placebo once daily for 8 weeks. The Montreal Cognitive Assessment (MoCA) was used as an inclusion screening tool to screen elderly participants with healthy cognitive function in our study, and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was used to assess cognitive function in subjects before and after intervention as an assessment tool. BB68S significantly improved subjects' cognitive functions (total RBANS score increased by 18.89 points after intervention, p < 0.0001), especially immediate memory, visuospatial/constructional, attention, and delayed memory domains. BB68S intervention increased the relative abundances of beneficial bacteria Lachnospira, Bifidobacterium, Dorea, and Cellulosilyticum, while decreasing those of bacteria related to cognition impairment, such as Collinsella, Parabacteroides, Tyzzerella, Bilophila,&nbsp;unclassified_c_Negativicutes, Epulopiscium, Porphyromonas, and Granulicatella. In conclusion, BB68S could improve cognitive functions in healthy elderly adults without cognitive impairment, along with having beneficial regulatory effects on their gut microbiota. This study supports probiotics as a strategy to promote healthy aging and advances cognitive aging research.}, } @article {pmid36615435, year = {2022}, author = {Godyń, J and Zaręba, P and Stary, D and Kaleta, M and Kuder, KJ and Latacz, G and Mogilski, S and Reiner-Link, D and Frank, A and Doroz-Płonka, A and Olejarz-Maciej, A and Sudoł-Tałaj, S and Nolte, T and Handzlik, J and Stark, H and Więckowska, A and Malawska, B and Kieć-Kononowicz, K and Łażewska, D and Bajda, M}, title = {Benzophenone Derivatives with Histamine H3 Receptor Affinity and Cholinesterase Inhibitory Potency as Multitarget-Directed Ligands for Possible Therapy of Alzheimer's Disease.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {1}, pages = {}, pmid = {36615435}, issn = {1420-3049}, mesh = {Mice ; Animals ; Cholinesterases/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; Histamine ; *Receptors, Histamine H3/metabolism ; Cholinesterase Inhibitors/pharmacology ; Receptors, Histamine ; Ligands ; Structure-Activity Relationship ; }, abstract = {The multitarget-directed ligands demonstrating affinity to histamine H3 receptor and additional cholinesterase inhibitory potency represent a promising strategy for research into the effective treatment of Alzheimer's disease. In this study, a novel series of benzophenone derivatives was designed and synthesized. Among these derivatives, we identified compound 6 with a high affinity for H3R (Ki = 8 nM) and significant inhibitory activity toward BuChE (IC50 = 172 nM and 1.16 µM for eqBuChE and hBuChE, respectively). Further in vitro studies revealed that compound 6 (4-fluorophenyl) (4-((5-(piperidin-1-yl)pentyl)oxy)phenyl)methanone) displays moderate metabolic stability in mouse liver microsomes, good permeability with a permeability coefficient value (Pe) of 6.3 × 10[-6] cm/s, and its safety was confirmed in terms of hepatotoxicity in the HepG2 cell line. Therefore, we investigated the in vivo activity of compound 6 in the Passive Avoidance Test and the Formalin Test. While compound 6 did not show a statistically significant influence on memory and learning, it showed analgesic properties in both acute (ED50 = 20.9 mg/kg) and inflammatory (ED50 = 17.5 mg/kg) pain.}, } @article {pmid36615279, year = {2022}, author = {Panchal, SK and Brown, L}, title = {Potential Benefits of Anthocyanins in Chronic Disorders of the Central Nervous System.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {1}, pages = {}, pmid = {36615279}, issn = {1420-3049}, mesh = {Humans ; *Anthocyanins/pharmacology/therapeutic use ; *Autism Spectrum Disorder ; Central Nervous System ; Anxiety ; Chronic Disease ; Brain ; }, abstract = {Anthocyanins have been shown to be effective in chronic diseases because of their antioxidant and anti-inflammatory effects together with changes in the gut microbiota and modulation of neuropeptides such as insulin-like growth factor-1. This review will examine whether these mechanisms may be effective to moderate the symptoms of disorders of the central nervous system in humans, including schizophrenia, Parkinson's disease, Alzheimer's disease, autism spectrum disorder, depression, anxiety, attention-deficit hyperactivity disorder and epilepsy. Thus, anthocyanins from fruits and berries should be considered as complementary interventions to improve these chronic disorders.}, } @article {pmid36615235, year = {2022}, author = {Ţînţaş, ML and Peauger, L and Alix, F and Papamicaël, C and Besson, T and Sopková-de Oliveira Santos, J and Gembus, V and Levacher, V}, title = {Straightforward Access to a New Class of Dual DYRK1A/CLK1 Inhibitors Possessing a Simple Dihydroquinoline Core.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {1}, pages = {}, pmid = {36615235}, issn = {1420-3049}, mesh = {Humans ; Molecular Docking Simulation ; Glycogen Synthase Kinase 3 ; Phosphorylation ; *Alzheimer Disease/drug therapy ; *Down Syndrome ; Protein Kinase Inhibitors/pharmacology/therapeutic use ; }, abstract = {The DYRK (Dual-specificity tyrosine phosphorylation-regulated kinase) family of protein kinases is involved in the pathogenesis of several neurodegenerative diseases. Among them, the DYRK1A protein kinase is thought to be implicated in Alzheimer's disease (AD) and Down syndrome, and as such, has emerged as an appealing therapeutic target. DYRKs are a subset of the CMGC (CDK, MAPKK, GSK3 and CLK) group of kinases. Within this group of kinases, the CDC2-like kinases (CLKs), such as CLK1, are closely related to DYRKs and have also sparked great interest as potential therapeutic targets for AD. Based on inhibitors previously described in the literature (namely TG003 and INDY), we report in this work a new class of dihydroquinolines exhibiting inhibitory activities in the nanomolar range on hDYRK1A and hCLK1. Moreover, there is overwhelming evidence that oxidative stress plays an important role in AD. Pleasingly, the most potent dual kinase inhibitor 1p exhibited antioxidant and radical scavenging properties. Finally, drug-likeness and molecular docking studies of this new class of DYRK1A/CLK1 inhibitors are also discussed in this article.}, } @article {pmid36615218, year = {2022}, author = {Rahim, F and Ullah, H and Taha, M and Hussain, R and Sarfraz, M and Iqbal, R and Iqbal, N and Khan, S and Ali Shah, SA and Albalawi, MA and Abdelaziz, MA and Alatawi, FS and Alasmari, A and Sakran, MI and Zidan, N and Jafri, I and Khan, KM}, title = {Synthesis of New Triazole-Based Thiosemicarbazone Derivatives as Anti-Alzheimer's Disease Candidates: Evidence-Based In Vitro Study.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {1}, pages = {}, pmid = {36615218}, issn = {1420-3049}, mesh = {Humans ; Butyrylcholinesterase/metabolism ; Acetylcholinesterase/metabolism ; Cholinesterase Inhibitors/chemistry ; Molecular Structure ; Molecular Docking Simulation ; *Thiosemicarbazones/pharmacology ; Structure-Activity Relationship ; *Alzheimer Disease/metabolism ; }, abstract = {Triazole-based thiosemicarbazone derivatives (6a-u) were synthesized then characterized by spectroscopic techniques, such as 1HNMR and 13CNMR and HRMS (ESI). Newly synthesized derivatives were screened in vitro for inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. All derivatives (except 6c and 6d, which were found to be completely inactive) demonstrated moderate to good inhibitory effects ranging from 0.10 ± 0.050 to 12.20 ± 0.30 µM (for AChE) and 0.20 ± 0.10 to 14.10 ± 0.40 µM (for BuChE). The analogue 6i (IC50 = 0.10 ± 0.050 for AChE and IC50 = 0.20 ± 0.050 µM for BuChE), which had di-substitutions (2-nitro, 3-hydroxy groups) at ring B and tri-substitutions (2-nitro, 4,5-dichloro groups) at ring C, and analogue 6b (IC50 = 0.20 ± 0.10 µM for AChE and IC50 = 0.30 ± 0.10 µM for BuChE), which had di-Cl at 4,5, -NO2 groups at 2-position of phenyl ring B and hydroxy group at ortho-position of phenyl ring C, emerged as the most potent inhibitors of both targeted enzymes (AChE and BuChE) among the current series. A structure-activity relationship (SAR) was developed based on nature, position, number, electron donating/withdrawing effects of substitution/s on phenyl rings. Molecular docking studies were used to describe binding interactions of the most active inhibitors with active sites of AChE and BuChE.}, } @article {pmid36615197, year = {2022}, author = {Elbandy, M}, title = {Anti-Inflammatory Effects of Marine Bioactive Compounds and Their Potential as Functional Food Ingredients in the Prevention and Treatment of Neuroinflammatory Disorders.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {1}, pages = {}, pmid = {36615197}, issn = {1420-3049}, mesh = {Animals ; *Neuroinflammatory Diseases ; *Functional Food ; Anti-Inflammatory Agents/pharmacology/therapeutic use ; Peptides ; Polysaccharides ; }, abstract = {Functional foods include enhanced, enriched, fortified, or whole foods that impart health benefits beyond their nutritional value, particularly when consumed as part of a varied diet on a regular basis at effective levels. Marine sources can serve as the sources of various healthy foods and numerous functional food ingredients with biological effects can be derived from these sources. Microalgae, macroalgae, crustaceans, fungi, bacteria fish, and fish by-products are the most common marine sources that can provide many potential functional food ingredients including phenolic compounds, proteins and peptides, and polysaccharides. Neuroinflammation is closely linked with the initiation and progression of various neurodegenerative diseases, including Alzheimer's disease, Huntington's disease, and Parkinson's disease. Activation of astrocytes and microglia is a defense mechanism of the brain to counter damaged tissues and detrimental pathogens, wherein their chronic activation triggers neuroinflammation that can further exacerbate or induce neurodegeneration. Currently, available therapeutic agents only provide symptomatic relief from these disorders and no therapies are available to stop or slow down the advancement of neurodegeneration. Thereffore, natural compounds that can exert a protective effect against these disorders have therapeutic potential. Numerous chemical compounds, including bioactive peptides, fatty acids, pigments, alkaloids, and polysaccharides, have already been isolated from marine sources that show anti-inflammatory properties, which can be effective in the treatment and prevention of neuroinflammatory disorders. The anti-inflammatory potential of marine-derived compounds as functional food ingredients in the prevention and treatment of neurological disorders is covered in this review.}, } @article {pmid36614829, year = {2022}, author = {Cheng, J and Ji, X and He, L and Zhang, Y and Xiao, T and Geng, Q and Wang, Z and Qi, S and Zhou, F and Zhan, J}, title = {Epidemiological Characteristics and Factors Associated with Alzheimer's Disease and Mild Cognitive Impairment among the Elderly in Urban and Rural Areas of Hubei Province.}, journal = {Journal of clinical medicine}, volume = {12}, number = {1}, pages = {}, pmid = {36614829}, issn = {2077-0383}, abstract = {Utilize the prevalence, associated factors and population distribution of AD and MCI among residents of the Hubei province aged 60 years or over to prove that elderly people who study and communicate with others, take part in regular physical exercise and choose a healthy lifestyle, will prevent or slow the decline in cognitive ability. If elderly people study and communicate with others, take part in regular physical exercise and choose a healthy lifestyle, can prevent or slow the decline in cognitive ability. A cross-sectional study was used for the recruitment of subjects. The screened patients with AD and MCI were then selected as patients in a case-control study. A total of 4314 subjects were recruited into the study. The prevalence of AD and MCI was 1.44% and 10.04%, respectively. The prevalence of AD and MCI differed significantly as a function of age and gender (p < 0.05). The preventative factors for AD and MCI, separately, included a happy marriage (OR = 0.69, 95%CI: 0.36-1.35) and higher education (OR = 0.65, 95%CI: 0.55-0.78). The risk factors for AD and MCI, separately, included infrequent participation in social activities (OR = 1.00, 95%CI: 0.60-1.66) and infrequent communication with children (OR = 1.35, 95%CI: 1.09-1.69). The prevalence of AD for people aged 60 or over in the Hubei province was lower than the national average of 3.06%. The prevalence of MCI was within the national range (5.2-23.4%). The influencing factors of AD and MCI were associated with the participants' social connections, lifestyle behaviors, somatic diseases and so on. The elderly people who study and communicate with others, take part in regular physical exercise and choose a healthy lifestyle will prevent or slow the decline in cognitive ability. The conclusion section has been replaced.}, } @article {pmid36614151, year = {2022}, author = {Ubeda, C and Vázquez-Carretero, MD and Luque-Tirado, A and Ríos-Reina, R and Rubio-Sánchez, R and Franco-Macías, E and García-Miranda, P and Calonge, ML and Peral, MJ}, title = {Fecal Volatile Organic Compounds and Microbiota Associated with the Progression of Cognitive Impairment in Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36614151}, issn = {1422-0067}, mesh = {Humans ; *Volatile Organic Compounds/metabolism ; *Alzheimer Disease/metabolism ; *Microbiota ; *Cognitive Dysfunction/microbiology ; Feces/microbiology ; Fatty Acids, Volatile/metabolism ; Bacteria/metabolism ; Biomarkers/metabolism ; }, abstract = {Metabolites produced by an altered gut microbiota might mediate the effects in the brain. Among metabolites, the fecal volatile organic compounds (VOCs) are considered to be potential biomarkers. In this study, we examined both the VOCs and bacterial taxa in the feces from healthy subjects and Alzheimer's disease (AD) patients at early and middle stages. Remarkably, 29 fecal VOCs and 13 bacterial genera were differentiated from the healthy subjects and the AD patients. In general, higher amounts of acids and esters were found in in the feces of the AD patients and terpenes, sulfur compounds and aldehydes in the healthy subjects. At the early stage of AD, the most relevant VOCs with a higher abundance were short-chain fatty acids and their producing bacteria, Faecalibacterium and Lachnoclostridium. Coinciding with the development of dementia in the AD patients, parallel rises of heptanoic acid and Peptococcus were observed. At a more advanced stage of AD, the microbiota and volatiles shifted towards a profile in the feces with increases in hexanoic acid, Ruminococcus and Blautia. The most remarkable VOCs that were associated with the healthy subjects were 4-ethyl-phenol and dodecanol, together with their possible producers Clostridium and Coprococcus. Our results revealed a VOCs and microbiota crosstalk in AD development and their profiles in the feces were specific depending on the stage of AD. Additionally, some of the most significant fecal VOCs identified in our study could be used as potential biomarkers for the initiation and progression of AD.}, } @article {pmid36614120, year = {2022}, author = {Bok, J and Ha, J and Ahn, BJ and Jang, Y}, title = {Disease-Modifying Effects of Non-Invasive Electroceuticals on β-Amyloid Plaques and Tau Tangles for Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36614120}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/therapy/pathology ; Amyloid beta-Peptides/pharmacology ; tau Proteins ; Plaque, Amyloid/pathology ; *Transcranial Direct Current Stimulation ; Neurofibrillary Tangles/pathology ; }, abstract = {Electroceuticals refer to various forms of electronic neurostimulators used for therapy. Interdisciplinary advances in medical engineering and science have led to the development of the electroceutical approach, which involves therapeutic agents that specifically target neural circuits, to realize precision therapy for Alzheimer's disease (AD). To date, extensive studies have attempted to elucidate the disease-modifying effects of electroceuticals on areas in the brain of a patient with AD by the use of various physical stimuli, including electric, magnetic, and electromagnetic waves as well as ultrasound. Herein, we review non-invasive stimulatory systems and their effects on β-amyloid plaques and tau tangles, which are pathological molecular markers of AD. Therefore, this review will aid in better understanding the recent technological developments, applicable methods, and therapeutic effects of electronic stimulatory systems, including transcranial direct current stimulation, 40-Hz gamma oscillations, transcranial magnetic stimulation, electromagnetic field stimulation, infrared light stimulation and ionizing radiation therapy, and focused ultrasound for AD.}, } @article {pmid36614118, year = {2022}, author = {Tsou, YS and Lai, JH and Chen, KY and Chang, CF and Huang, CC}, title = {Therapeutic Effect of Rapamycin on TDP-43-Related Pathogenesis in Ischemic Stroke.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36614118}, issn = {1422-0067}, mesh = {Animals ; Rats ; Sirolimus/pharmacology/therapeutic use ; *Ischemic Stroke/drug therapy ; DNA-Binding Proteins/genetics/metabolism ; *Stroke/drug therapy ; Apoptosis ; *Amyotrophic Lateral Sclerosis/pathology ; }, abstract = {Stroke is a major cause of death and disability across the world, and its detrimental impact should not be underestimated. Therapies are available and effective for ischemic stroke (e.g., thrombolytic recanalization and mechanical thrombectomy); however, there are limitations to therapeutic interventions. Recanalization therapy has developed dramatically, while the use of adjunct neuroprotective agents as complementary therapies remains deficient. Pathological TAR DNA-binding protein (TDP-43) has been identified as a major component of insoluble aggregates in numerous neurodegenerative pathologies, including ALS, FTLD and Alzheimer's disease. Here, we show that increased pathological TDP-43 fractions accompanied by impaired mitochondrial function and increased gliosis were observed in an ischemic stroke rat model, suggesting a pathological role of TDP-43 in ischemic stroke. In ischemic rats administered rapamycin, the insoluble TDP-43 fraction was significantly decreased in the ischemic cortex region, accompanied by a recovery of mitochondrial function, the attenuation of cellular apoptosis, a reduction in infarct areas and improvements in motor defects. Accordingly, our results suggest that rapamycin provides neuroprotective benefits not only by ameliorating pathological TDP-43 levels, but also by reversing mitochondrial function and attenuating cell apoptosis in ischemic stroke.}, } @article {pmid36614117, year = {2022}, author = {Kim, YK and Jung, YS and Song, J}, title = {Transcriptome Profile in the Mouse Brain of Hepatic Encephalopathy and Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36614117}, issn = {1422-0067}, mesh = {Mice ; Animals ; *Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; *Hepatic Encephalopathy/metabolism ; *Neurodegenerative Diseases/metabolism ; Transcriptome ; Brain/metabolism ; Disease Models, Animal ; Mice, Transgenic ; }, abstract = {Hepatic encephalopathy (HE) is a chronic metabolic disease accompanied by neuropathological and neuropsychiatric features, including memory deficits, psychomotor dysfunction, depression, and anxiety. Alzheimer's disease (AD), the most common neurodegenerative disease, is characterized by tau hyperphosphorylation, excessive amyloid beta (Aβ) accumulation, the formation of fibrillary tangles, hippocampus atrophy, and neuroinflammation. Recent studies have suggested a positive correlation between HE and AD. Some studies reported that an impaired cholesterol pathway, abnormal bile acid secretion, excessive ammonia level, impaired Aβ clearance, astrocytic dysfunction, and abnormal γ-aminobutyric acid GABAergic neuronal signaling in HE may also be involved in AD pathology. However, the mechanisms and related genes involved in AD-like pathology in the HE brain are unclear. Thus, we compared the cortical transcriptome profile between an HE mouse model, bile duct ligation (BDL), and an AD mouse model, the 5×FAD. Our study showed that the expression of many genes implicated in HE is associated with neuronal dysfunction in AD mice. We found changes in various protein-coding RNAs, implicated in synapses, neurogenesis, neuron projection, neuron differentiation, and neurite outgrowth, and non-coding RNAs possibly associated with neuropathology. Our data provide an important resource for further studies to elucidate AD-like pathophysiology in HE patients.}, } @article {pmid36614115, year = {2022}, author = {Zhou, X and Sheikh, AM and Matsumoto, KI and Mitaki, S and Shibly, AZ and Zhang, Y and A, G and Yano, S and Nagai, A}, title = {iTRAQ-Based Proteomic Analysis of APP Transgenic Mouse Urine Exosomes.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36614115}, issn = {1422-0067}, mesh = {Mice ; Animals ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; Clusterin/metabolism ; *Exosomes/metabolism ; Tandem Mass Spectrometry ; Proteomics ; *Alzheimer Disease/metabolism ; Apolipoproteins E/metabolism ; Disease Models, Animal ; Amyloid beta-Protein Precursor/metabolism ; }, abstract = {Alzheimer's disease (AD) is a common dementia disease in the elderly. To get a better understanding of the pathophysiology, we performed a proteomic analysis of the urine exosomes (U-exo) in AD model mice (J20). The polymer precipitation method was used to isolate U-exo from the urine of 3-month-old J20 and wild-type (WT) mice. Neuron-derived exosome (N-exo) was isolated from U-exo by immunoprecipitation. iTRAQ-based MALDI TOF MS/MS was used for proteomic analysis. The results showed that compared to WT, the levels of 61 and 92 proteins were increased in the J20 U-exo and N-exo, respectively. Gene ontology enrichment analysis demonstrated that the sphingolipid catabolic process, ceramide catabolic process, membrane lipid catabolic process, Aβ clearance, and Aβ metabolic process were highly enriched in U-exo and N-exo. Among these, Asah1 was shown to be the key protein in lipid metabolism, and clusterin, ApoE, neprilysin, and ACE were related to Aβ metabolism and clearance. Furthermore, protein-protein interaction analysis identified four protein complexes where clusterin and ApoE participated as partner proteins. Thus, J20 U-exo and N-exo contain proteins related to lipid- and Aβ-metabolism in the early stages of AD, providing a new insight into the underlying pathological mechanism of early AD.}, } @article {pmid36614107, year = {2022}, author = {Naz, N and Naqvi, SF and Hohn, N and Whelan, K and Littler, P and Roncaroli, F and Robinson, AC and Miyan, JA}, title = {Cerebral Folate Metabolism in Post-Mortem Alzheimer's Disease Tissues: A Small Cohort Study.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36614107}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid ; Cohort Studies ; Brain/metabolism ; Astrocytes/metabolism ; Folic Acid/metabolism ; Glial Fibrillary Acidic Protein/metabolism ; }, abstract = {We investigated the cerebral folate system in post-mortem brains and matched cerebrospinal fluid (CSF) samples from subjects with definite Alzheimer's disease (AD) (n = 21) and neuropathologically normal brains (n = 21) using immunohistochemistry, Western blot and dot blot. In AD the CSF showed a significant decrease in 10-formyl tetrahydrofolate dehydrogenase (FDH), a critical folate binding protein and enzyme in the CSF, as well as in the main folate transporter, folate receptor alpha (FRα) and folate. In tissue, we found a switch in the pathway of folate supply to the cerebral cortex in AD compared to neurologically normal brains. FRα switched from entry through FDH-positive astrocytes in normal, to entry through glial fibrillary acidic protein (GFAP)-positive astrocytes in the AD cortex. Moreover, this switch correlated with an apparent change in metabolic direction to hypermethylation of neurons in AD. Our data suggest that the reduction in FDH in CSF prohibits FRα-folate entry via FDH-positive astrocytes and promotes entry through the GFAP pathway directly to neurons for hypermethylation. This data may explain some of the cognitive decline not attributable to the loss of neurons alone and presents a target for potential treatment.}, } @article {pmid36614069, year = {2022}, author = {Kim, DY and Shim, KH and Bagyinszky, E and An, SSA}, title = {Prion Mutations in Republic of Republic of Korea, China, and Japan.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36614069}, issn = {1422-0067}, mesh = {Humans ; *Prions/genetics ; *Prion Diseases/genetics/diagnosis ; Japan/epidemiology ; Prion Proteins/genetics ; *Gerstmann-Straussler-Scheinker Disease/genetics ; *Creutzfeldt-Jakob Syndrome/genetics ; Mutation ; }, abstract = {Prion gene (PRNP) mutations are associated with diverse disease phenotypes, including familiar Creutzfeldt-Jakob Disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), and fatal familial insomnia (FFI). Interestingly, PRNP mutations have been reported in patients diagnosed with Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease, and frontotemporal dementia. In this review, we describe prion mutations in Asian countries, including Republic of Republic of Korea, China, and Japan. Clinical phenotypes and imaging data related to these mutations have also been introduced in detail. Several prion mutations are specific to Asians and have rarely been reported in countries outside Asia. For example, PRNP V180I and M232R, which are rare in other countries, are frequently detected in Republic of Korea and Japan. PRNP T188K is common in China, and E200K is significantly more common among Libyan Jews in Israel. The A117V mutation has not been detected in any Asian population, although it is commonly reported among European GSS patients. In addition, V210I or octapeptide insertion is common among European CJD patients, but relatively rare among Asian patients. The reason for these differences may be geographical or ethical isolation. In terms of clinical phenotypes, V180I, P102L, and E200K present diverse clinical symptoms with disease duration, which could be due to other genetic and environmental influences. For example, rs189305274 in the ACO1 gene may be associated with neuroprotective effects in cases of V180I mutation, leading to longer disease survival. Additional neuroprotective variants may be possible in cases featuring the E200K mutation, such as KLKB1, KARS, NRXN2, LAMA3, or CYP4X1. E219K has been suggested to modify the disease course in cases featuring the P102L mutation, as it may result in the absence of prion protein-positive plaques in tissue stained with Congo red. However, these studies analyzed only a few patients and may be too preliminary. The findings need to be verified in studies with larger sample sizes or in other populations. It would be interesting to probe additional genetic factors that cause disease progression or act as neuroprotective factors. Further studies are needed on genetic modifiers working with prions and alterations from mutations.}, } @article {pmid36614030, year = {2022}, author = {Pavlíková, N}, title = {Caffeic Acid and Diseases-Mechanisms of Action.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36614030}, issn = {1422-0067}, mesh = {Humans ; *Caffeic Acids/pharmacology ; *Phenylethyl Alcohol/pharmacology ; }, abstract = {Caffeic acid belongs to the polyphenol compounds we consume daily, often in the form of coffee. Even though it is less explored than caffeic acid phenethyl ester, it still has many positive effects on human health. Caffeic acid can affect cancer, diabetes, atherosclerosis, Alzheimer's disease, or bacterial and viral infections. This review focuses on the molecular mechanisms of how caffeic acid achieves its effects.}, } @article {pmid36613988, year = {2022}, author = {Błaszczyk, JW}, title = {Pathogenesis of Dementia.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36613988}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/metabolism ; *Cognitive Dysfunction/complications ; Brain/metabolism ; *Cognition Disorders/complications ; }, abstract = {According to Alzheimer's Disease International, 55 million people worldwide are living with dementia. Dementia is a disorder that manifests as a set of related symptoms, which usually result from the brain being damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, usually accompanied by emotional problems, difficulties with language, and decreased motivation. The most common variant of dementia is Alzheimer's disease with symptoms dominated by cognitive disorders, particularly memory loss, impaired personality, and judgmental disorders. So far, all attempts to treat dementias by removing their symptoms rather than their causes have failed. Therefore, in the presented narrative review, I will attempt to explain the etiology of dementia and Alzheimer's disease from the perspective of energy and cognitive metabolism dysfunction in an aging brain. I hope that this perspective, though perhaps too simplified, will bring us closer to the essence of aging-related neurodegenerative disorders and will soon allow us to develop new preventive/therapeutic strategies in our struggle with dementia, Alzheimer's disease, and Parkinson's disease.}, } @article {pmid36613951, year = {2022}, author = {Szczurowska, E and Szánti-Pintér, E and Chetverikov, N and Randáková, A and Kudová, E and Jakubík, J}, title = {Modulation of Muscarinic Signalling in the Central Nervous System by Steroid Hormones and Neurosteroids.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36613951}, issn = {1422-0067}, mesh = {*Neurosteroids/pharmacology ; Central Nervous System ; Steroids/pharmacology/physiology ; Hormones ; Receptors, Muscarinic ; Cholinergic Agents ; }, abstract = {Muscarinic acetylcholine receptors expressed in the central nervous system mediate various functions, including cognition, memory, or reward. Therefore, muscarinic receptors represent potential pharmacological targets for various diseases and conditions, such as Alzheimer's disease, schizophrenia, addiction, epilepsy, or depression. Muscarinic receptors are allosterically modulated by neurosteroids and steroid hormones at physiologically relevant concentrations. In this review, we focus on the modulation of muscarinic receptors by neurosteroids and steroid hormones in the context of diseases and disorders of the central nervous system. Further, we propose the potential use of neuroactive steroids in the development of pharmacotherapeutics for these diseases and conditions.}, } @article {pmid36613911, year = {2022}, author = {Babić Leko, M and Mihelčić, M and Jurasović, J and Nikolac Perković, M and Španić, E and Sekovanić, A and Orct, T and Zubčić, K and Langer Horvat, L and Pleić, N and Kiđemet-Piskač, S and Vogrinc, Ž and Pivac, N and Diana, A and Borovečki, F and Hof, PR and Šimić, G}, title = {Heavy Metals and Essential Metals Are Associated with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36613911}, issn = {1422-0067}, support = {P30 AG066514/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Chitinase-3-Like Protein 1 ; *Alzheimer Disease/cerebrospinal fluid ; Cadmium ; Amyloid beta-Peptides ; Lead ; *Metals, Heavy/metabolism ; *Mercury ; Biomarkers/cerebrospinal fluid ; }, abstract = {Various metals have been associated with the pathogenesis of Alzheimer's disease (AD), principally heavy metals that are environmental pollutants (such as As, Cd, Hg, and Pb) and essential metals whose homeostasis is disturbed in AD (such as Cu, Fe, and Zn). Although there is evidence of the involvement of these metals in AD, further research is needed on their mechanisms of toxicity. To further assess the involvement of heavy and essential metals in AD pathogenesis, we compared cerebrospinal fluid (CSF) AD biomarkers to macro- and microelements measured in CSF and plasma. We tested if macro- and microelements' concentrations (heavy metals (As, Cd, Hg, Ni, Pb, and Tl), essential metals (Na, Mg, K, Ca, Fe, Co, Mn, Cu, Zn, and Mo), essential non-metals (B, P, S, and Se), and other non-essential metals (Al, Ba, Li, and Sr)) are associated with CSF AD biomarkers that reflect pathological changes in the AD brain (amyloid β1-42, total tau, phosphorylated tau isoforms, NFL, S100B, VILIP-1, YKL-40, PAPP-A, and albumin). We used inductively coupled plasma mass spectroscopy (ICP-MS) to determine macro- and microelements in CSF and plasma, and enzyme-linked immunosorbent assays (ELISA) to determine protein biomarkers of AD in CSF. This study included 193 participants (124 with AD, 50 with mild cognitive impairment, and 19 healthy controls). Simple correlation, as well as machine learning algorithms (redescription mining and principal component analysis (PCA)), demonstrated that levels of heavy metals (As, Cd, Hg, Ni, Pb, and Tl), essential metals (Ca, Co, Cu, Fe, Mg, Mn, Mo, Na, K, and Zn), and essential non-metals (P, S, and Se) are positively associated with CSF phosphorylated tau isoforms, VILIP-1, S100B, NFL, and YKL-40 in AD.}, } @article {pmid36613883, year = {2022}, author = {Collins, AE and Saleh, TM and Kalisch, BE}, title = {VANL-100 Attenuates Beta-Amyloid-Induced Toxicity in SH-SY5Y Cells.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36613883}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; Amyloid beta-Peptides/toxicity ; *Antioxidants/pharmacology ; Cell Line, Tumor ; *Neuroprotective Agents/pharmacology ; Peptide Fragments/toxicity ; *Thioctic Acid/pharmacology ; }, abstract = {Antioxidants are being explored as novel therapeutics for the treatment of neurodegenerative diseases such as Alzheimer's disease (AD) through strategies such as chemically linking antioxidants to synthesize novel co-drugs. The main objective of this study was to assess the cytoprotective effects of the novel antioxidant compound VANL-100 in a cellular model of beta-amyloid (Aβ)-induced toxicity. The cytotoxic effects of Aβ in the presence and absence of all antioxidant compounds were measured using the 3-(4,5-dimethylthiazol-2-yl)2-5-diphenyl-2H-tetrazolium bromide (MTT) assay in SH-SY5Y cells in both pre-treatment and co-treatment experiments. In pre-treatment experiments, VANL-100, or one of its parent compounds, naringenin (NAR), alpha-lipoic acid (ALA), or naringenin + alpha-lipoic acid (NAR + ALA), was administrated 24 h prior to an additional 24-h incubation with 20 μM non-fibril or fibril Aβ25-35. Co-treatment experiments consisted of simultaneous treatment with Aβ and antioxidants. Pre-treatment and co-treatment with VANL-100 significantly attenuated Aβ-induced cell death. There were no significant differences between the protective effects of VANL-100, NAR, ALA, and NAR + ALA with either form of Aβ, or in the effect of VANL-100 between 24-h pre-treatment and co-treatment. These results demonstrate that the novel co-drug VANL-100 is capable of eliciting cytoprotective effects against Aβ-induced toxicity.}, } @article {pmid36613801, year = {2022}, author = {Pieńkowska, N and Fahnestock, M and Mahadeo, C and Zaborniak, I and Chmielarz, P and Bartosz, G and Sadowska-Bartosz, I}, title = {Induction of Oxidative Stress in SH-SY5Y Cells by Overexpression of hTau40 and Its Mitigation by Redox-Active Nanoparticles.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36613801}, issn = {1422-0067}, mesh = {Humans ; Reactive Oxygen Species/metabolism ; tau Proteins/genetics/metabolism ; *Neuroblastoma/metabolism ; Oxidative Stress ; Oxidation-Reduction ; *Nanoparticles ; Cell Line, Tumor ; }, abstract = {Abnormally phosphorylated tau protein is the principal component of neurofibrillary tangles, accumulating in the brain in many neurodegenerative diseases, including Alzheimer's disease. The aim of this study was to examine whether overexpression of tau protein leads to changes in the redox status of human neuroblastoma SH-SY5Y cells. The level of reactive oxygen species (ROS) was elevated in tau-overexpressing cells (TAU cells) as compared with cells transfected with the empty vector (EP cells). The level of glutathione was increased in TAU cells, apparently due to overproduction as an adaptation to oxidative stress. The TAU cells had elevated mitochondrial mass. They were more sensitive to 6-hydroxydopamine, delphinidin, 4-amino-TEMPO, and nitroxide-containing nanoparticles (NPs) compared to EP controls. These results indicate that overexpression of the tau protein imposes oxidative stress on the cells. The nitroxide 4-amino-TEMPO and nitroxide-containing nanoparticles (NPs) mitigated oxidative stress in TAU cells, decreasing the level of ROS. Nitroxide-containing nanoparticles lowered the level of lipid peroxidation in both TAU and EP cells, suggesting that nitroxides and NPs may mitigate tau-protein-induced oxidative stress.}, } @article {pmid36613679, year = {2022}, author = {Krasnovskaya, O and Kononova, A and Erofeev, A and Gorelkin, P and Majouga, A and Beloglazkina, E}, title = {Aβ-Targeting Bifunctional Chelators (BFCs) for Potential Therapeutic and PET Imaging Applications.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36613679}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/drug therapy ; *Neurodegenerative Diseases ; Chelating Agents ; Positron-Emission Tomography/methods ; Tomography, Emission-Computed, Single-Photon/methods ; Amyloid beta-Peptides ; }, abstract = {Currently, more than 55 million people live with dementia worldwide, and there are nearly 10 million new cases every year. Alzheimer's disease (AD) is the most common neurodegenerative disease resulting in personality changes, cognitive impairment, memory loss, and physical disability. Diagnosis of AD is often missed or delayed in clinical practice due to the fact that cognitive deterioration occurs already in the later stages of the disease. Thus, methods to improve early detection would provide opportunities for early treatment of disease. All FDA-approved PET imaging agents for Aβ plaques use short-lived radioisotopes such as [11]C (t1/2 = 20.4 min) and [18]F (t1/2 = 109.8 min), which limit their widespread use. Thus, a novel metal-based imaging agent for visualization of Aβ plaques is of interest, due to the simplicity of its synthesis and the longer lifetimes of its constituent isotopes. We have previously summarized a metal-containing drug for positron emission tomography (PET), magnetic resonance imaging (MRI), and single-photon emission computed tomography (SPECT) imaging of Alzheimer's disease. In this review, we have summarized a recent advance in design of Aβ-targeting bifunctional chelators for potential therapeutic and PET imaging applications, reported after our previous review.}, } @article {pmid36613677, year = {2022}, author = {Palavicini, JP and Ding, L and Pan, M and Qiu, S and Wang, H and Shen, Q and Dupree, JL and Han, X}, title = {Sulfatide Deficiency, an Early Alzheimer's Lipidomic Signature, Causes Brain Ventricular Enlargement in the Absence of Classical Neuropathological Hallmarks.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36613677}, issn = {1422-0067}, support = {RF1 AG061729/AG/NIA NIH HHS/United States ; P30 AG066546-02/AG/NIA NIH HHS/United States ; P30 AG044271/AG/NIA NIH HHS/United States ; P30 AG013319/AG/NIA NIH HHS/United States ; RF1 AG061872/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Animals ; Mice ; Sulfoglycosphingolipids ; *Alzheimer Disease/pathology ; *Neurodegenerative Diseases ; Lipidomics ; Brain/pathology ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory loss and a decline in activities of daily life. Ventricular enlargement has been associated with worse performance on global cognitive tests and AD. Our previous studies demonstrated that brain sulfatides, myelin-enriched lipids, are dramatically reduced in subjects at the earliest clinically recognizable AD stages via an apolipoprotein E (APOE)-dependent and isoform-specific process. Herein, we provided pre-clinical evidence that sulfatide deficiency is causally associated with brain ventricular enlargement. Specifically, taking advantage of genetic mouse models of global and adult-onset sulfatide deficiency, we demonstrated that sulfatide losses cause ventricular enlargement without significantly affecting hippocampal or whole brain volumes using histological and magnetic resonance imaging approaches. Mild decreases in sulfatide content and mild increases in ventricular areas were also observed in human APOE4 compared to APOE2 knock-in mice. Finally, we provided Western blot and immunofluorescence evidence that aquaporin-4, the most prevalent aquaporin channel in the central nervous system (CNS) that provides fast water transportation and regulates cerebrospinal fluid in the ventricles, is significantly increased under sulfatide-deficient conditions, while other major brain aquaporins (e.g., aquaporin-1) are not altered. In short, we unraveled a novel and causal association between sulfatide deficiency and ventricular enlargement. Finally, we propose putative mechanisms by which sulfatide deficiency may induce ventricular enlargement.}, } @article {pmid36613667, year = {2022}, author = {Maier, JAM and Locatelli, L and Fedele, G and Cazzaniga, A and Mazur, A}, title = {Magnesium and the Brain: A Focus on Neuroinflammation and Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36613667}, issn = {1422-0067}, mesh = {Humans ; *Magnesium ; Neuroinflammatory Diseases ; Brain/metabolism ; Blood-Brain Barrier/metabolism ; *Neurodegenerative Diseases/metabolism ; Inflammation ; }, abstract = {Magnesium (Mg) is involved in the regulation of metabolism and in the maintenance of the homeostasis of all the tissues, including the brain, where it harmonizes nerve signal transmission and preserves the integrity of the blood-brain barrier. Mg deficiency contributes to systemic low-grade inflammation, the common denominator of most diseases. In particular, neuroinflammation is the hallmark of neurodegenerative disorders. Starting from a rapid overview on the role of magnesium in the brain, this narrative review provides evidences linking the derangement of magnesium balance with multiple sclerosis, Alzheimer's, and Parkinson's diseases.}, } @article {pmid36613623, year = {2022}, author = {Petrovskaya, AV and Tverskoi, AM and Barykin, EP and Varshavskaya, KB and Dalina, AA and Mitkevich, VA and Makarov, AA and Petrushanko, IY}, title = {Distinct Effects of Beta-Amyloid, Its Isomerized and Phosphorylated Forms on the Redox Status and Mitochondrial Functioning of the Blood-Brain Barrier Endothelium.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36613623}, issn = {1422-0067}, mesh = {Animals ; Mice ; *Amyloid beta-Peptides/metabolism ; Blood-Brain Barrier/metabolism ; Endothelial Cells/metabolism ; *Alzheimer Disease/metabolism ; Oxidation-Reduction ; Endothelium/metabolism ; Peptide Fragments/metabolism ; }, abstract = {The Alzheimer's disease (AD)-associated breakdown of the blood-brain barrier (BBB) promotes the accumulation of beta-amyloid peptide (Aβ) in the brain as the BBB cells provide Aβ transport from the brain parenchyma to the blood, and vice versa. The breakdown of the BBB during AD may be caused by the emergence of blood-borne Aβ pathogenic forms, such as structurally and chemically modified Aβ species; their effect on the BBB cells has not yet been studied. Here, we report that the effects of Aβ42, Aβ42, containing isomerized Asp7 residue (iso-Aβ42) or phosphorylated Ser8 residue (p-Aβ42) on the mitochondrial potential and respiration are closely related to the redox status changes in the mouse brain endothelial cells bEnd.3. Aβ42 and iso-Aβ42 cause a significant increase in nitric oxide, reactive oxygen species, glutathione, cytosolic calcium and the mitochondrial potential after 4 h of incubation. P-Aβ42 either does not affect or its effect develops after 24 h of incubation. Aβ42 and iso-Aβ42 activate mitochondrial respiration compared to p-Aβ42. The isomerized form promotes a greater cytotoxicity and mitochondrial dysfunction, causing maximum oxidative stress. Thus, Aβ42, p-Aβ42 and iso-Aβ42 isoforms differently affect the BBBs' cell redox parameters, significantly modulating the functioning of the mitochondria. The changes in the level of modified Aβ forms can contribute to the BBBs' breakdown during AD.}, } @article {pmid36613586, year = {2022}, author = {Un-Nisa, A and Khan, A and Zakria, M and Siraj, S and Ullah, S and Tipu, MK and Ikram, M and Kim, MO}, title = {Updates on the Role of Probiotics against Different Health Issues: Focus on Lactobacillus.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36613586}, issn = {1422-0067}, mesh = {Animals ; Humans ; Mice ; Lactobacillus ; *Gastrointestinal Microbiome ; *Central Nervous System Diseases ; *Probiotics/pharmacology/therapeutic use ; }, abstract = {This review article is built on the beneficial effects of Lactobacillus against different diseases, and a special focus has been made on its effects against neurological disorders, such as depression, multiple sclerosis, Alzheimer's, and Parkinson's disease. Probiotics are live microbes, which are found in fermented foods, beverages, and cultured milk and, when administered in an adequate dose, confer health benefits to the host. They are known as "health-friendly bacteria", normally residing in the human gut and involved in maintaining homeostatic conditions. Imbalance in gut microbiota results in the pathophysiology of several diseases entailing the GIT tract, skin, immune system, inflammation, and gut-brain axis. Recently, the use of probiotics has gained tremendous interest, because of their profound effects on the management of these disease conditions. Recent findings suggest that probiotics enrichment in different human and mouse disease models showed promising beneficial effects and results in the amelioration of disease symptoms. Thus, this review focuses on the current probiotics-based products, different disease models, variable markers measured during trials, and evidence obtained from past studies on the use of probiotics in the prevention and treatment of different diseases, covering the skin to the central nervous system diseases.}, } @article {pmid36613555, year = {2022}, author = {Bae, H and Gurinovich, A and Karagiannis, TT and Song, Z and Leshchyk, A and Li, M and Andersen, SL and Arbeev, K and Yashin, A and Zmuda, J and An, P and Feitosa, M and Giuliani, C and Franceschi, C and Garagnani, P and Mengel-From, J and Atzmon, G and Barzilai, N and Puca, A and Schork, NJ and Perls, TT and Sebastiani, P}, title = {A Genome-Wide Association Study of 2304 Extreme Longevity Cases Identifies Novel Longevity Variants.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36613555}, issn = {1422-0067}, support = {R01AG061844/AG/NIA NIH HHS/United States ; U19AG023122/NH/NIH HHS/United States ; U19AG063893/NH/NIH HHS/United States ; UH2AG064704/AG/NIA NIH HHS/United States ; }, mesh = {Aged, 80 and over ; Humans ; *Longevity/genetics ; *Genome-Wide Association Study ; Proteomics ; Polymorphism, Single Nucleotide ; Alleles ; Genetic Predisposition to Disease ; }, abstract = {We performed a genome-wide association study (GWAS) of human extreme longevity (EL), defined as surviving past the 99th survival percentile, by aggregating data from four centenarian studies. The combined data included 2304 EL cases and 5879 controls. The analysis identified a locus in CDKN2B-AS1 (rs6475609, p = 7.13 × 10[-8]) that almost reached genome-wide significance and four additional loci that were suggestively significant. Among these, a novel rare variant (rs145265196) on chromosome 11 had much higher longevity allele frequencies in cases of Ashkenazi Jewish and Southern Italian ancestry compared to cases of other European ancestries. We also correlated EL-associated SNPs with serum proteins to link our findings to potential biological mechanisms that may be related to EL and are under genetic regulation. The findings from the proteomic analyses suggested that longevity-promoting alleles of significant genetic variants either provided EL cases with more youthful molecular profiles compared to controls or provided some form of protection from other illnesses, such as Alzheimer's disease, and disease progressions.}, } @article {pmid36613544, year = {2022}, author = {Rostagno, AA}, title = {Pathogenesis of Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36613544}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/etiology/pathology ; }, abstract = {Alzheimer's disease (AD) is the most common type of dementia, accounting for 60% to 80% of all cases [...].}, } @article {pmid36613538, year = {2022}, author = {Giacconi, R and D'Aquila, P and Balietti, M and Giuli, C and Malavolta, M and Piacenza, F and Costarelli, L and Postacchini, D and Passarino, G and Bellizzi, D and Provinciali, M}, title = {Bacterial DNAemia in Alzheimer's Disease and Mild Cognitive Impairment: Association with Cognitive Decline, Plasma BDNF Levels, and Inflammatory Response.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36613538}, issn = {1422-0067}, mesh = {Humans ; Aged ; Brain-Derived Neurotrophic Factor ; Interleukin-10 ; *Alzheimer Disease/diagnosis ; Tumor Necrosis Factor-alpha ; Biomarkers ; *Cognitive Dysfunction ; DNA ; }, abstract = {Microbial dysbiosis (MD) provokes gut barrier alterations and bacterial translocation in the bloodstream. The increased blood bacterial DNA (BB-DNA) may promote peripheral- and neuro-inflammation, contributing to cognitive impairment. MD also influences brain-derived neurotrophic factor (BDNF) production, whose alterations contribute to the etiopathogenesis of Alzheimer's disease (AD). The purpose of this study is to measure BB-DNA in healthy elderly controls (EC), and in patients with mild cognitive impairment (MCI) and AD to explore the effect on plasma BDNF levels (pBDNF), the inflammatory response, and the association with cognitive decline during a two-year follow-up. Baseline BB-DNA and pBDNF were significantly higher in MCI and AD than in EC. BB-DNA was positively correlated with pBDNF in AD, plasma Tumor necrosis factor-alpha (TNF-α), and Interleukin-10 (IL-10) levels in MCI. AD patients with BB-DNA values above the 50th percentile had lower baseline Mini-Mental State Examination (MMSE). After a two-year follow-up, AD patients with the highest BB-DNA tertile had a worse cognitive decline, while higher BB-DNA levels were associated with higher TNF-α and lower IL-10 in MCI. Our study demonstrates that, in early AD, the higher the BB-DNA levels, the higher the pBDNF levels, suggesting a defensive attempt; BB-DNA seems to play a role in the AD severity/progression; in MCI, higher BB-DNA may trigger an increased inflammatory response.}, } @article {pmid36613531, year = {2022}, author = {Plantone, D and Primiano, G and Manco, C and Locci, S and Servidei, S and De Stefano, N}, title = {Vitamin D in Neurological Diseases.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36613531}, issn = {1422-0067}, mesh = {Humans ; Vitamin D/metabolism ; Vitamins/therapeutic use ; *Multiple Sclerosis/drug therapy ; *Parkinson Disease/drug therapy ; *Vitamin D Deficiency/complications/drug therapy/metabolism ; *Diabetic Neuropathies/drug therapy ; }, abstract = {Vitamin D may have multiple effects on the nervous system and its deficiency can represent a possible risk factor for the development of many neurological diseases. Recent studies are also trying to clarify the different effects of vitamin D supplementation over the course of progressive neurological diseases. In this narrative review, we summarise vitamin D chemistry, metabolism, mechanisms of action, and the recommended daily intake. The role of vitamin D on gene transcription and the immune response is also reviewed. Finally, we discuss the scientific evidence that links low 25-hydroxyvitamin D concentrations to the onset and progression of severe neurological diseases, such as multiple sclerosis, Parkinson's disease, Alzheimer's disease, migraine, diabetic neuropathy and amyotrophic lateral sclerosis. Completed and ongoing clinical trials on vitamin D supplementation in neurological diseases are listed.}, } @article {pmid36613480, year = {2022}, author = {Kumar, M and Li, G}, title = {Emerging Role of MicroRNA-30c in Neurological Disorders.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36613480}, issn = {1422-0067}, support = {NS119538/NH/NIH HHS/United States ; }, mesh = {Humans ; *MicroRNAs/metabolism ; Gene Expression Regulation ; RNA, Messenger ; *Nervous System Diseases/genetics ; }, abstract = {MicroRNAs (miRNAs or miRs) are a class of small non-coding RNAs that negatively regulate the expression of target genes by interacting with 3' untranslated regions of target mRNAs to induce mRNA degradation and translational repression. The miR-30 family members are involved in the development of many tissues and organs and participate in the pathogenesis of human diseases. As a key member of the miR-30 family, miR-30c has been implicated in neurological disorders such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and stroke. Mechanistically, miR-30c may act as a multi-functional regulator of different pathogenic processes such as autophagy, apoptosis, endoplasmic reticulum stress, inflammation, oxidative stress, thrombosis, and neurovascular function, thereby contributing to different disease states. Here, we review and discuss the biogenesis, gene regulation, and the role and mechanisms of action of miR-30c in several neurological disorders and therapeutic potential in clinics.}, } @article {pmid36613460, year = {2022}, author = {Matuszewska, M and Cieślik, M and Wilkaniec, A and Strawski, M and Czapski, GA}, title = {The Role of Bromodomain and Extraterminal (BET) Proteins in Controlling the Phagocytic Activity of Microglia In Vitro: Relevance to Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {24}, number = {1}, pages = {}, pmid = {36613460}, issn = {1422-0067}, mesh = {Mice ; Animals ; *Microglia/metabolism ; Transcription Factors/genetics/metabolism ; Nuclear Proteins/genetics/metabolism ; *Alzheimer Disease/genetics/metabolism ; Phagocytes/metabolism ; Membrane Glycoproteins/metabolism ; Receptors, Immunologic/metabolism ; }, abstract = {The correct phagocytic activity of microglia is a prerequisite for maintaining homeostasis in the brain. In the analysis of mechanisms regulating microglial phagocytosis, we focused on the bromodomain and extraterminal domain (BET) proteins: Brd2, Brd3, and Brd4, the acetylation code readers that control gene expression in cooperation with transcription factors. We used pharmacological (JQ1) and genetic (siRNA) inhibition of BET proteins in murine microglial cell line BV2. Inhibition of BET proteins reduced the phagocytic activity of BV2, as determined by using a fluorescent microspheres-based assay and fluorescently labelled amyloid-beta peptides. Gene silencing experiments demonstrated that all brain-existing BET isoforms control phagocytosis in microglia. From a set of 84 phagocytosis-related genes, we have found the attenuation of the expression of 14: Siglec1, Sirpb1a, Cd36, Clec7a, Itgam, Tlr3, Fcgr1, Cd14, Marco, Pld1, Fcgr2b, Anxa1, Tnf, Nod1, upon BET inhibition. Further analysis of the mRNA level of other phagocytosis-related genes which were involved in the pathomechanism of Alzheimer's disease demonstrated that JQ1 significantly reduced the expression of Cd33, Trem2, and Zyx. Our results indicate the important role of BET proteins in controlling microglial phagocytosis; therefore, targeting BET may be the efficient method of modulating microglial activity.}, } @article {pmid36613315, year = {2022}, author = {Antunes, IC and Bexiga, R and Pinto, C and Roseiro, LC and Quaresma, MAG}, title = {Cow's Milk in Human Nutrition and the Emergence of Plant-Based Milk Alternatives.}, journal = {Foods (Basel, Switzerland)}, volume = {12}, number = {1}, pages = {}, pmid = {36613315}, issn = {2304-8158}, abstract = {Cow's milk is considered a complete food, providing high-quality protein and essential micronutrients, including vitamins and minerals. For medical reasons or as a lifestyle choice, consumers are replacing cow's milk with plant-based milk alternatives (PBMA); some perceive them as healthier alternatives to cow's milk due to their low saturated fatty acid content and no cholesterol content. However, the nutritional composition of PBMA is quite variable between different types and even within, which makes a comparison with cow's milk a complex issue. Furthermore, the consumption of PBMA has been associated with the development of some diseases in infants and children. Meanwhile, the consumption of cow's milk in human health is a controversial issue since it has been associated with a favorable effect in some diseases (such as obesity, type 2 diabetes, and Alzheimer's) and a negative effect in others (such as prostate cancer risk and Parkinson's disease); while in some diseases, there is no consensus in the cow's milk consumption effect. The aim of this review is to make a nutritional comparison of cow's milk with PBMA and to clarify the potential health issues related to their consumption.}, } @article {pmid36613080, year = {2022}, author = {Goldberg, A}, title = {Filial Maturity, Resolution of a Parent's Disease, and Well-Being in Offspring of Parents Diagnosed with Alzheimer's Disease.}, journal = {International journal of environmental research and public health}, volume = {20}, number = {1}, pages = {}, pmid = {36613080}, issn = {1660-4601}, mesh = {Adult ; Humans ; *Alzheimer Disease/diagnosis ; Cross-Sectional Studies ; Parent-Child Relations ; Adult Children/psychology ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: Alzheimer's Disease (AD) is one of the most common forms of dementia. However, research dealing with the experience of adult children of a parent diagnosed with AD, regardless of whether the offspring is a caregiver, is not well developed.

OBJECTIVE: The current research is a cross-sectional study that examines the associations between filial maturity, offspring's coming to terms with their parent's AD, and the well-being of the offspring.

METHOD: one hundred and forty Israeli adult children of parents with AD participated in the study and completed self-report questionnaires assessing their filial maturity, resolution of their parent's diagnosis with AD, the adult children's well-being, and the severity of the parent's AD according neurologist's report.

RESULTS: Results showed that higher resolution of the parent's disease was positively associated with well-being. In addition, filial maturity was negatively associated with resolution of the parent's disease, and resolution of the parent's disease mediated the association between filial maturity and well-being.

CONCLUSION: Resolution of a parent's AD is highly challenging for offspring with high filial maturity, and the lack of resolution affects their well-being. Offering prolonged emotional support for offspring of parents diagnosed with AD may improve their ability to integrate the new reality into their lives and foster their well-being.}, } @article {pmid36612244, year = {2022}, author = {Xia, S and Yu, X and Chen, G}, title = {Pain as a Protective Factor for Alzheimer Disease in Patients with Cancer.}, journal = {Cancers}, volume = {15}, number = {1}, pages = {}, pmid = {36612244}, issn = {2072-6694}, abstract = {OBJECTIVE: Alzheimer disease (AD) and cancer have been reported to be inversely correlated in incidence, but the mechanism remains elusive.

METHODS: A case-control study was conducted, based on the SEER (Surveillance, Epidemiology, and End Results) Research Plus data, to evaluate 12 factors in patients with cancer.

RESULTS: Severe pain was related to reduced AD risk, while older age at cancer diagnosis, female, longer survival years after tumor diagnosis, more benign/borderline tumors, less cancer-directed surgery, and more chemotherapy were associated with higher AD risk. In addition, patients of different races or with different cancer sites were associated with different risks of getting AD. Cases had a higher prevalence of severe pain than controls in all race and cancer site subgroups, except for in digestive cancer, where the result was the opposite.

CONCLUSIONS: This study indicated pain as a novel protective factor for AD in patients with cancer. The mechanism behind it may provide new perspective on AD pathogenesis and AD-cancer association, which we discussed in our own hypothesis of the mechanism of pain action. In addition, digestive cancer pain had an opposite impact on AD risk from other cancer pains, which suggests the uniqueness of digestive system in interacting with the central nervous system.}, } @article {pmid36612076, year = {2022}, author = {Laurent, O and Samson, E and Caër-Lorho, S and Fournier, L and Laurier, D and Leuraud, K}, title = {Updated Mortality Analysis of SELTINE, the French Cohort of Nuclear Workers, 1968-2014.}, journal = {Cancers}, volume = {15}, number = {1}, pages = {}, pmid = {36612076}, issn = {2072-6694}, abstract = {Cohorts of nuclear workers are particularly relevant to study the health effects of protracted exposures to low doses at low dose-rates of ionizing radiation (IR). In France, a cohort of nuclear workers badge-monitored for external IR exposure has been followed-up for several decades. Its size and follow-up period have recently been extended. The present paper focuses on mortality from both cancer and non-cancer diseases in this cohort. The SELTINE cohort of nuclear workers employed by CEA, Orano, and EDF companies was followed-up for mortality from 1968 to 2014. Mortality in the cohort was compared to that in the French general population. Poisson regression methods were used to estimate excess relative rates of mortality per unit of cumulative dose of IR, adjusted for calendar year, age, company, duration of employment, and socioeconomic status. The cohort included 80,348 workers. At the end of the follow-up, the mean attained age was 63 years, and 15,695 deaths were observed. A strong healthy worker effect was observed overall. A significant excess of pleural cancer mortality was observed but not associated with IR dose. Death from solid cancers was positively but non-significantly associated with radiation. Death from leukaemia (excluding chronic lymphocytic leukaemia), dementia, and Alzheimer's disease were positively and significantly associated with IR dose. Estimated dose-risk relationships were consistent with those from other nuclear worker studies for all solid cancers and leukaemia but remained associated with large uncertainty. The association between IR dose and dementia mortality risk should be interpreted with caution and requires further investigation by other studies.}, } @article {pmid36611925, year = {2022}, author = {Miculas, DC and Negru, PA and Bungau, SG and Behl, T and Hassan, SSU and Tit, DM}, title = {Pharmacotherapy Evolution in Alzheimer's Disease: Current Framework and Relevant Directions.}, journal = {Cells}, volume = {12}, number = {1}, pages = {}, pmid = {36611925}, issn = {2073-4409}, mesh = {Humans ; Aged ; *Alzheimer Disease/drug therapy/diagnosis ; Molecular Docking Simulation ; Cholinesterase Inhibitors/pharmacology/therapeutic use ; }, abstract = {Alzheimer's disease (AD), once considered a rare disease, is now the most common form of dementia in the elderly population. Current drugs (cholinesterase inhibitors and glutamate antagonists) are safe but of limited benefit to most patients, offering symptomatic relief without successful cure of the disease. Since the last several decades, there has been a great need for the development of a treatment that might cure the underlying causes of AD and thereby slow its progression in vulnerable individuals. That is why phase I, II, and III studies that act on several fronts, such as cognitive improvement, symptom reduction, and enhancing the basic biology of AD, are imperative to stop the disease. This review discusses current treatment strategies, summarizing the clinical features and pharmacological properties, along with molecular docking analyses of the existing medications.}, } @article {pmid36611911, year = {2022}, author = {Elangovan, S and Borody, TJ and Holsinger, RMD}, title = {Fecal Microbiota Transplantation Reduces Pathology and Improves Cognition in a Mouse Model of Alzheimer's Disease.}, journal = {Cells}, volume = {12}, number = {1}, pages = {}, pmid = {36611911}, issn = {2073-4409}, mesh = {Humans ; Mice ; Animals ; Fecal Microbiota Transplantation ; *Alzheimer Disease/therapy ; *Clostridioides difficile ; *Clostridium Infections/therapy ; Disease Models, Animal ; Cognition ; }, abstract = {Characterized by the presence of amyloid plaques, neurofibrillary tangles and neuroinflammation, Alzheimer's disease (AD) is a progressive neurodegenerative disorder with no known treatment or cure. Global disease projections warrant an urgent and rapid therapeutic for the treatment of this devastating disease. Fecal microbiota transplantation (FMT) is a widely accepted and safely used treatment for recurrent Clostridium difficile infection and other metabolic diseases such as diabetes mellitus. FMT has also been demonstrated to be a possible AD therapeutic. We examined the potential of FMT for the treatment of AD in a robust, mouse model of the disease and report that a brief, 7-day treatment regimen demonstrated 'plaque-busting' and behavior-modifying effects in treated 5xFAD mice. Importantly, we show that donor age plays an important role in the efficacy of the treatment and these findings warrant further investigation in human trials.}, } @article {pmid36611872, year = {2022}, author = {Rudan Njavro, J and Vukicevic, M and Fiorini, E and Dinkel, L and Müller, SA and Berghofer, A and Bordier, C and Kozlov, S and Halle, A and Buschmann, K and Capell, A and Giudici, C and Willem, M and Feederle, R and Lichtenthaler, SF and Babolin, C and Montanari, P and Pfeifer, A and Kosco-Vilbois, M and Tahirovic, S}, title = {Beneficial Effect of ACI-24 Vaccination on Aβ Plaque Pathology and Microglial Phenotypes in an Amyloidosis Mouse Model.}, journal = {Cells}, volume = {12}, number = {1}, pages = {}, pmid = {36611872}, issn = {2073-4409}, mesh = {Mice ; Animals ; Microglia/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/genetics/therapy/metabolism ; *Amyloidosis/metabolism ; Plaque, Amyloid/metabolism ; Phenotype ; Vaccination ; }, abstract = {Amyloid-β (Aβ) deposition is an initiating factor in Alzheimer's disease (AD). Microglia are the brain immune cells that surround and phagocytose Aβ plaques, but their phagocytic capacity declines in AD. This is in agreement with studies that associate AD risk loci with genes regulating the phagocytic function of immune cells. Immunotherapies are currently pursued as strategies against AD and there are increased efforts to understand the role of the immune system in ameliorating AD pathology. Here, we evaluated the effect of the Aβ targeting ACI-24 vaccine in reducing AD pathology in an amyloidosis mouse model. ACI-24 vaccination elicited a robust and sustained antibody response in APPPS1 mice with an accompanying reduction of Aβ plaque load, Aβ plaque-associated ApoE and dystrophic neurites as compared to non-vaccinated controls. Furthermore, an increased number of NLRP3-positive plaque-associated microglia was observed following ACI-24 vaccination. In contrast to this local microglial activation at Aβ plaques, we observed a more ramified morphology of Aβ plaque-distant microglia compared to non-vaccinated controls. Accordingly, bulk transcriptomic analysis revealed a trend towards the reduced expression of several disease-associated microglia (DAM) signatures that is in line with the reduced Aβ plaque load triggered by ACI-24 vaccination. Our study demonstrates that administration of the Aβ targeting vaccine ACI-24 reduces AD pathology, suggesting its use as a safe and cost-effective AD therapeutic intervention.}, } @article {pmid36611856, year = {2022}, author = {Gabrielli, M and Tozzi, F and Verderio, C and Origlia, N}, title = {Emerging Roles of Extracellular Vesicles in Alzheimer's Disease: Focus on Synaptic Dysfunction and Vesicle-Neuron Interaction.}, journal = {Cells}, volume = {12}, number = {1}, pages = {}, pmid = {36611856}, issn = {2073-4409}, mesh = {Humans ; *Alzheimer Disease ; Amyloid beta-Peptides/metabolism ; *Extracellular Vesicles/metabolism ; Neurons/metabolism ; Brain/metabolism ; }, abstract = {Alzheimer's disease (AD) is considered by many to be a synaptic failure. Synaptic function is in fact deeply affected in the very early disease phases and recognized as the main cause of AD-related cognitive impairment. While the reciprocal involvement of amyloid beta (Aβ) and tau peptides in these processes is under intense investigation, the crucial role of extracellular vesicles (EVs) released by different brain cells as vehicles for these molecules and as mediators of early synaptic alterations is gaining more and more ground in the field. In this review, we will summarize the current literature on the contribution of EVs derived from distinct brain cells to neuronal alterations and build a working model for EV-mediated propagation of synaptic dysfunction in early AD. A deeper understanding of EV-neuron interaction will provide useful targets for the development of novel therapeutic approaches aimed at hampering AD progression.}, } @article {pmid36611808, year = {2022}, author = {Zhu, Y and Guo, X and Zhu, F and Zhang, Q and Yang, Y and For The Alzheimer's Disease Neuroimaging Initiative, }, title = {Association of CSF GAP-43 and APOE ε4 with Cognition in Mild Cognitive Impairment and Alzheimer's Disease.}, journal = {Cells}, volume = {12}, number = {1}, pages = {}, pmid = {36611808}, issn = {2073-4409}, mesh = {Humans ; *Alzheimer Disease/etiology ; Apolipoprotein E4/genetics ; GAP-43 Protein ; *Cognitive Dysfunction/complications ; Cognition ; }, abstract = {The growth-associated protein 43 (GAP-43) is a presynaptic phosphoprotein in cerebrospinal fluid (CSF). The ε4 allele of apolipoprotein E (APOE) is an important genetic risk factor for Alzheimer's disease (AD). We aimed to evaluate the association of CSF GAP-43 with cognition and whether this correlation was related to the APOE ε4 status. We recruited participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, and they were divided into cognitively normal (CN) ε4 negative (CN ε4-), CN ε4 positive (CN ε4+), mild cognitive impairment (MCI) ε4 negative (MCI ε4-), MCI ε4 positive (MCI ε4+), AD ε4 negative (AD ε4-), and AD ε4 positive (AD ε4+) groups. Spearman's correlation was utilized to evaluate the relationship between CSF GAP-43 and core AD biomarkers at the baseline. We performed receiver-operating characteristic (ROC) curve analyses to investigate the diagnostic accuracy of CSF GAP-43. The correlations between CSF GAP-43 and the Mini-Mental State Examination (MMSE) scores and brain atrophy at baseline were assessed by using multiple linear regression, while the association between CSF GAP-43 and MMSE scores at the follow-up was tested by performing the generalized estimating equation (GEE). The role of CSF GAP-43 in the conversion from MCI to AD was evaluated using the Cox proportional hazard model. We found that the CSF GAP-43 level was significantly increased in MCI ε4+, AD ε4- and AD ε4+ groups compared with CN ε4- or MCI ε4- group. The negative associations between the CSF GAP-43 and MMSE scores at the baseline and follow-up were found in MCI ε4- and MCI ε4+ groups. In addition, baseline CSF GAP-43 was able to predict the clinical progression from MCI to AD. CSF GAP-43 may be a promising biomarker to screen cognition for AD. The effects of CSF GAP-43 on cognition were suspected to be relevant to APOE ε4 status.}, } @article {pmid36611492, year = {2022}, author = {Rashad, A and Rasool, A and Shaheryar, M and Sarfraz, A and Sarfraz, Z and Robles-Velasco, K and Cherrez-Ojeda, I}, title = {Donanemab for Alzheimer's Disease: A Systematic Review of Clinical Trials.}, journal = {Healthcare (Basel, Switzerland)}, volume = {11}, number = {1}, pages = {}, pmid = {36611492}, issn = {2227-9032}, abstract = {Amyloid-β (Aβ) plaques and aggregated tau are two core mechanisms that contribute to the clinical deterioration of Alzheimer's disease (AD). Recently, targeted-Aβ plaque reduction immunotherapies have been explored for their efficacy and safety as AD treatment. This systematic review critically reviews the latest evidence of Donanemab, a humanized antibody that targets the reduction in Aβ plaques, in AD patients. Comprehensive systematic search was conducted across PubMed/MEDLINE, CINAHL Plus, Web of Science, Cochrane, and Scopus. This study adhered to PRISMA Statement 2020 guidelines. Adult patients with Alzheimer's disease being intervened with Donanemab compared to placebo or standard of care in the clinical trial setting were included. A total of 396 patients across four studies received either Donanemab or a placebo (228 and 168 participants, respectively). The Aβ-plaque reduction was found to be dependent upon baseline levels, such that lower baseline levels had complete amyloid clearance (<24.1 Centiloids). There was a slowing of overall tau levels accumulation as well as relatively reduced functional and cognitive decline noted on the Integrated Alzheimer's Disease Rating Scale by 32% in the Donanemab arm. The safety of Donanemab was established with key adverse events related to Amyloid-Related Imaging Abnormalities (ARIA), ranging between 26.1 and 30.5% across the trials. There is preliminary support for delayed cognitive and functional decline with Donanemab among patients with mild-to-moderate AD. It remains unclear whether Donenameb extends therapeutic benefits that can modify and improve the clinical status of AD patients. Further trials can explore the interplay between Aβ-plaque reduction and toxic tau levels to derive meaningful clinical benefits in AD patients suffering from cognitive impairment.}, } @article {pmid36610398, year = {2022}, author = {Kim, J and de Haro, M and Al-Ramahi, I and Garaicoechea, LL and Jeong, HH and Sonn, JY and Tadros, B and Liu, Z and Botas, J and Zoghbi, HY}, title = {Evolutionarily conserved regulators of tau identify targets for new therapies.}, journal = {Neuron}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuron.2022.12.012}, pmid = {36610398}, issn = {1097-4199}, abstract = {Tauopathies are neurodegenerative diseases that involve the pathological accumulation of tau proteins; in this family are Alzheimer disease, corticobasal degeneration, and chronic traumatic encephalopathy, among others. Hypothesizing that reducing this accumulation could mitigate pathogenesis, we performed a cross-species genetic screen targeting 6,600 potentially druggable genes in human cells and Drosophila. We found and validated 83 hits in cells and further validated 11 hits in the mouse brain. Three of these hits (USP7, RNF130, and RNF149) converge on the C terminus of Hsc70-interacting protein (CHIP) to regulate tau levels, highlighting the role of CHIP in maintaining tau proteostasis in the brain. Knockdown of each of these three genes in adult tauopathy mice reduced tau levels and rescued the disease phenotypes. This study thus identifies several points of intervention to reduce tau levels and demonstrates that reduction of tau levels via regulation of this pathway is a viable therapeutic strategy for Alzheimer disease and other tauopathies.}, } @article {pmid36610198, year = {2023}, author = {Madsen, LS and Parbo, P and Ismail, R and Gottrup, H and Østergaard, L and Brooks, DJ and Eskildsen, SF}, title = {Capillary dysfunction correlates with cortical amyloid load in early Alzheimer's disease.}, journal = {Neurobiology of aging}, volume = {123}, number = {}, pages = {1-9}, doi = {10.1016/j.neurobiolaging.2022.12.006}, pmid = {36610198}, issn = {1558-1497}, mesh = {Humans ; *Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Amyloid ; Amyloidogenic Proteins ; Brain/metabolism ; }, abstract = {Alterations in cerebral perfusion is increasingly considered to play a crucial role in Alzheimer's disease (AD) and together with accumulated amyloid-β, deficiencies in the brain microvascular circulation may result in local hypoxia. Here, we studied alterations in cerebral circulation and the correlation between amyloid-β load and cerebral perfusion in prodromal AD (pAD). Using dynamic susceptibility contrast MRI and PET, we evaluated cerebral perfusion and amyloid-β levels in 19 individuals with mild cognitive impairment (MCI) and high amyloid-β load (pAD-MCI), 13 MCI individuals without AD pathology and 21 healthy controls. The pAD-MCI group showed significantly lower microvascular blood flow and significantly higher heterogeneity of microvascular blood transit times (p < 0.01) compared with the other 2 groups. Additionally, in the pAD-MCI group raised amyloid-β levels correlated with decreased microvascular blood flow and increased heterogeneity of microvascular blood flow in frontal and temporal areas (p < 0.01). These results indicate a close connection between levels of amyloid-β deposition and brain microvascular perfusion in pAD. A vicious cycle may be established where amyloid-β load and deficiencies in brain perfusion may reinforce each other.}, } @article {pmid36610160, year = {2023}, author = {He, Z and Zhang, H and Li, X and Tu, S and Wang, Z and Han, S and Du, X and Shen, L and Li, N and Liu, Q}, title = {The protective effects of Esculentoside A through AMPK in the triple transgenic mouse model of Alzheimer's disease.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {109}, number = {}, pages = {154555}, doi = {10.1016/j.phymed.2022.154555}, pmid = {36610160}, issn = {1618-095X}, mesh = {Mice ; Animals ; *Alzheimer Disease/metabolism ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; AMP-Activated Protein Kinases/metabolism ; Glycogen Synthase Kinase 3 beta/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Proteomics ; tau Proteins/metabolism ; Phosphorylation ; Disease Models, Animal ; Hippocampus ; }, abstract = {BACKGROUND: Neurofibrillary tangles comprising hyperphosphorylated tau are vital factors associated with the pathogenesis of Alzheimer's disease (AD). The elimination or reduction of hyperphosphorylated and abnormally aggregated tau is a valuable measure in AD therapy. Esculentoside A (EsA), isolated from Phytolacca esculenta, exhibits pharmacotherapeutic efficacy in mice with amyloid beta-induced AD. However, whether EsA affects tau pathology and its specific mechanism of action in AD mice remains unclear.

PURPOSE: To investigate the roles and mechanisms of EsA in cognitive decline and tau pathology in a triple transgenic AD (3 × Tg-AD) mouse model.

METHODS: EsA (5 and 10 mg/kg) was administered via intraperitoneal injection to 8-month-old AD mice for eight consecutive weeks. Y-maze and novel object recognition tasks were used to evaluate the cognitive abilities of mice. Potential signaling pathways and targets in EsA-treated AD mice were assessed using quantitative proteomic analysis. The NFT levels and hippocampal synapse numbers were investigated using Gallyas-Braak silver staining and transmission electron microscopy, respectively. Western blotting and immunofluorescence assays were used to measure the expression of tau-associated proteins.

RESULTS: EsA administration attenuated memory and recognition deficits and synaptic damage in AD mice. Isobaric tags for relative and absolute quantitation proteomic analysis of the mouse hippocampus revealed that EsA modulated the expression of some critical proteins, including brain-specific angiogenesis inhibitor 3, galectin-1, and Ras-related protein 24, whose biological roles are relevant to synaptic function and autophagy. Further research revealed that EsA upregulated AKT/GSK3β activity, in turn, inhibited tau hyperphosphorylation and promoted autophagy to clear abnormally phosphorylated tau. In hippocampus-derived primary neurons, inhibiting AMP-activated protein kinase (AMPK) activity through dorsomorphin could eliminate the effect of EsA, as revealed by increased tau hyperphosphorylation, downregulated activity AKT/GSK3β, and blocked autophagy.

CONCLUSIONS: To our knowledge, this study is the first to demonstrate that EsA attenuates cognitive decline by targeting the pathways of both tau hyperphosphorylation and autophagic clearance in an AMPK-dependent manner and it shows a high reference value in AD pharmacotherapy research.}, } @article {pmid36610144, year = {2023}, author = {Yang, M and Zhang, X and Qiao, O and Ji, H and Zhang, Y and Han, X and Wang, W and Li, X and Wang, J and Guo, L and Huang, L and Gao, W}, title = {Rosmarinic acid potentiates and detoxifies tacrine in combination for Alzheimer's disease.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {109}, number = {}, pages = {154600}, doi = {10.1016/j.phymed.2022.154600}, pmid = {36610144}, issn = {1618-095X}, mesh = {Mice ; Animals ; *Alzheimer Disease/metabolism ; Tacrine/pharmacology/therapeutic use ; Acetylcholinesterase/metabolism ; Mice, Transgenic ; *Chemical and Drug Induced Liver Injury ; Disease Models, Animal ; Amyloid beta-Peptides ; }, abstract = {BACKGROUND: There is no doubt that Alzheimer's disease (AD) is one of the greatest threats facing mankind today. Within the next few decades, Acetylcholinesterase inhibitors (AChEIs) will be the most widely used treatment for Alzheimer's disease. The withdrawal of the first generation AChEIs drug Tacrine (TAC)/ Cognex from the market as a result of hepatotoxicity has always been an interesting case study. Rosmarinic acid (RA) is a natural compound of phenolic acids that has pharmacological activity for inhibiting Alzheimer's disease, as well as liver protection.

PURPOSE AND STUDY DESIGN: In this study, we determined that RA can reduce the hepatotoxicity of TAC, and both of them act synergistically to inhibit the progression of AD in mice.

METHODS: In addition to the wild type mice (WT) group, the 6-month-old APP/PS1 (APPswe/PSEN1dE9) double-transgenic (Tg) mice were randomly divided into 6 groups: Tg group, TAC group, RA group, TAC+Silymarin (SIL) group, TAC+RA-L (Rosmarinic Acid Low Dose) goup and TAC+RA-H (Rosmarinic Acid High Dose) group. A series of experiments were carried out, including open field test, Morris water maze test, Hematoxylin - Eosin (HE) staining, Nissl staining, biochemical analysis, immunofluorescence analysis, western blotting analysis and so on.

RESULTS: RA combined with TAC could enter the brain tissue of AD mice, and the combination of drugs could better improve the cognitive behavior and brain pathological damage of AD mice, reduce the expression of A β oligomer, inhibit the deposition of A β, inhibit the activity of AChE and enhance the level of Ach in hippocampus. Both in vivo and in vitro experiments showed that RA could alleviate the hepatotoxicity or liver injury induced by TAC. The Western blot analysis of the liver of AD mice showed that RA combined with TAC might inhibit the apoptosis of Bcl-2/Bax, reduce the programmed apoptosis mediated by caspase-3 and reduce the burden of liver induced by TAC, could inhibit the development of liver apoptosis by alleviating the hepatotoxicity of TAC and inhibiting the phosphorylation of JNK.

CONCLUSION: The potential drug combination that combines rosmarinic acid with tacrine could reduce tacrine's hepatotoxicity as well as enhance its therapeutic effect on Alzheimer's disease.}, } @article {pmid36610130, year = {2023}, author = {Bai, X and Bian, Z and Zhang, M}, title = {Targeting the Nrf2 signaling pathway using phytochemical ingredients: A novel therapeutic road map to combat neurodegenerative diseases.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {109}, number = {}, pages = {154582}, doi = {10.1016/j.phymed.2022.154582}, pmid = {36610130}, issn = {1618-095X}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; NF-E2-Related Factor 2/metabolism ; *Alzheimer Disease/drug therapy ; *Parkinson Disease ; Signal Transduction ; Antioxidants/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a classical nuclear transcription factor that regulates the system's anti-oxidative stress response. The activation of Nrf2 induces the expression of antioxidant proteins and improves the system's anti-oxidative stress ability. Accumulating evidence suggests that Nrf2-centered signaling pathways may be a key pharmacological target for the treatment of neurodegenerative diseases (NDDs). However, phytochemicals as new therapeutic agents against NDDs have not been clearly delineated.

PURPOSE: To review the therapeutic effects of phytochemical ingredients on NDDs by activating Nrf2 and reducing oxidative stress injury.

METHODS: A comprehensive search of published articles was performed using various literature databases including PubMed, Google Scholar, and China National Knowledge Infrastructure. The search terms included "Nrf2", "phytochemical ingredients", "natural bioactive agents", "neurodegenerative diseases", "Antioxidant", "Alzheimer's disease", "Parkinson's disease", "Huntington's disease", "amyotrophic lateral sclerosis" "multiple sclerosis", "toxicity", and combinations of these keywords. A total of 769 preclinical studies were retrieved until August 2022, and we included 39 of these articless on phytochemistry, pharmacology, toxicology and other fields.

RESULTS: Numerous in vivo and in vitro studies showed that phytochemical ingredients could act as an Nrf2 activator in the treatment of NDDs through the antioxidant defense mechanism. These phytochemical ingredients, such as salidroside, naringenin, resveratrol, sesaminol, ellagic acid, ginsenoside Re, tanshinone I, sulforaphane, curcumin, naringin, tetramethylpyrazine, withametelin, magnolol, piperine, and myricetin, had the potential to improve Nrf2 signaling, thereby combatting NDDs.

CONCLUSION: As Nrf2 activators, phytochemical ingredients may provide a novel potential strategy for the treatment of NDDs. Here, we reviewed the interaction between phytochemical ingredients, Nrf2, and its antioxidant damaging pathway in NDDs and explored the advantages of phytochemical ingredients in anti-oxidative stress, which provides a reliable basis for improving the treatment of NDDs. However, further clinical trials are needed to determine the safety and efficacy of Nrf2 activators for NDDs.}, } @article {pmid36610115, year = {2023}, author = {Liu, P and Wang, C and Chen, W and Kang, Y and Liu, W and Qiu, Z and Hayashi, T and Mizuno, K and Hattori, S and Fujisaki, H and Ikejima, T}, title = {Inhibition of GluN2B pathway is involved in the neuroprotective effect of silibinin on streptozotocin-induced Alzheimer's disease models.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {109}, number = {}, pages = {154594}, doi = {10.1016/j.phymed.2022.154594}, pmid = {36610115}, issn = {1618-095X}, mesh = {Rats ; Mice ; Animals ; *Alzheimer Disease/chemically induced/drug therapy ; Receptors, N-Methyl-D-Aspartate/metabolism ; Amyloid beta-Peptides/metabolism ; Silybin/pharmacology ; *Neuroprotective Agents/pharmacology/therapeutic use ; Streptozocin ; Brain-Derived Neurotrophic Factor/metabolism ; Molecular Docking Simulation ; Disease Models, Animal ; }, abstract = {BACKGROUND: Over-activation of N-methyl-D-aspartate receptors (NMDARs) is involved in sporadic Alzheimer's disease. Silibinin, a natural flavonoid gained from the seeds of Silybum marianum, exerts neuroprotective effects on sporadic AD models, but its impacts on NMDARs remain unknown.

PURPOSE: To study silibinin's regulatory effects on NMDARs pathway in sporadic AD models.

METHODS: MTT assay, western blotting, confocal microscopy, flow cytometry, RT-PCR, and siRNA transfection etc. were used for cellular and molecular studies. The direct interactions between silibinin and NMDAR subunits were evaluated by computational molecular docking, drug affinity responsive target stability (DARTS) assay and cellular thermal shift assay (CETSA). Y maze test, novel objects recognition test and Morris water maze test were conducted to examine the learning and memory ability of rats.

RESULTS: An in vitro AD model was established by treating HT22 murine hippocampal neurons with streptozotocin (STZ), as evidenced by the amyloid β (Aβ) deposition and hyperphosphorylation of tau proteins. Silibinin shows protection of neurons against STZ-induced cell damage. It is noteworthy that STZ-induced cellular calcium influx is inhibited by silibinin-treatment, indicating the possible modulation of calcium channels. Studies on NMDARs, the most widely distributed calcium channel, by using molecular docking, DARTS and CESTA, reveal that the GluN2B subunit, but not GluN2A, is the potential target of silibinin. Further studies using the pharmacological agonist (NMDA) and the GluN2B-specific inhibitor (Ifenprodil) or siRNA, indicate that the protection by silibinin treatment from STZ-induced cytotoxicity is medicated through interference with GluN2B-containing NMDARs, followed by the upregulation of CaMKIIα/ BDNF/ TrkB signaling pathway and improved levels of synaptic proteins (SYP and PSD-95). The results in vivo using rats intracerebroventricularly injected with STZ (ICV-STZ), a well-established sporadic AD model, confirm that silibinin improves learning and memory ability in association with modulation of the GluN2B/CaMKIIα/ BDNF/TrkB signaling pathway.

CONCLUSION: Inhibiting over-activation of GluN2B-containing NMDARs is involved in the neuroprotective effect of silibinin on STZ-induced sporadic AD models.}, } @article {pmid36608589, year = {2023}, author = {Xi, Y and Zhang, Y and Zhou, Y and Liu, Q and Chen, X and Liu, X and Grune, T and Shi, L and Hou, M and Liu, Z}, title = {Effects of methionine intake on cognitive function in mild cognitive impairment patients and APP/PS1 Alzheimer's Disease model mice: Role of the cystathionine-β-synthase/H2S pathway.}, journal = {Redox biology}, volume = {59}, number = {}, pages = {102595}, pmid = {36608589}, issn = {2213-2317}, mesh = {Animals ; Female ; Male ; Mice ; *Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; Cognition ; *Cognitive Dysfunction/etiology ; Cystathionine ; Cystathionine beta-Synthase/genetics ; Disease Models, Animal ; Mice, Transgenic ; Racemethionine ; Methionine/pharmacology ; }, abstract = {As a dietary intervention, methionine restriction (MR) has been reported to increase longevity and improve metabolism disorders. However, the effects of MR on alleviating neurodegenerative diseases such as Alzheimer's disease (AD) are largely unexplored. Here we sought to investigate the neuroprotective effects of low methionine intake in mild cognitive impairment (MCI) patients and APP/PS1 AD model mice, and to uncover the underlying mechanisms. In a cohort composed of 45 individuals diagnosed with MCI and 61 healthy controls without cognitive impairment, methionine intake was found to be positively associated with the increased risk of MCI, where no sex differences were observed. We further conducted a 16-week MR intervention (0.17% methionine, w/w) on APP/PS1 AD model mice. Although MR reduced Aβ accumulation in the brain of both male and female APP/PS1 mice, MR improved cognitive function only in male mice, as assessed by the Morris water maze test. Consistently, MR restored synapse ultrastructure and alleviated mitochondrial dysfunction by enhancing mitochondrial biogenesis in the brain of male APP/PS1 mice. Importantly, MR effectively balanced the redox status and activated cystathionine-β-synthase (CBS)/H2S pathway in the brain of male APP/PS1 mice. Together, our study indicated that lower dietary methionine intake is associated with improved cognitive function, in which CBS/H2S pathway plays an essential role. MR could be a promising nutritional intervention for preventing AD development.}, } @article {pmid36607365, year = {2023}, author = {Wassef, HR and Colletti, PM}, title = {Re: Aducanumab-Related ARIA: Paean or Lament?.}, journal = {Clinical nuclear medicine}, volume = {48}, number = {2}, pages = {168-169}, doi = {10.1097/RLU.0000000000004490}, pmid = {36607365}, issn = {1536-0229}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; Reproducibility of Results ; Antibodies, Monoclonal, Humanized/adverse effects ; Amyloid ; Amyloid beta-Peptides ; }, abstract = {Høilund-Carlsen and colleagues raise concern regarding the reliability of amyloid PET to exclude Alzheimer disease. We present additional studies of amyloid PET and discuss the diagnostic challenges in Alzheimer disease. We discuss the limitations of amyloid in diagnosis and evaluation of therapy response in AD.}, } @article {pmid36606272, year = {2022}, author = {Ahmad, F and Sachdeva, P}, title = {Critical appraisal on mitochondrial dysfunction in Alzheimer's disease.}, journal = {Aging medicine (Milton (N.S.W))}, volume = {5}, number = {4}, pages = {272-280}, pmid = {36606272}, issn = {2475-0360}, abstract = {It is widely recognized that Alzheimer's disease (AD) is a common type of progressive neurodegenerative disorder that results in cognitive impairment over time. Approximately 152 million cases of AD are predicted to be reported by 2050. Amyloid plaques and tau proteins are two major hallmarks of AD which can be seen under electron microscope. Mitochondria plays a vital role in the pathogenesis of AD and mitochondria disruption leads to mitochondrial DNA (mtDNA) dysfunction, alteration of mitochondria dependent Ca2+ homeostasis, copper dysfunction, immune cell dysfunction, etc. In this review, we try to cover all the mechanisms related with mitochondrial dysfunction and mitochondrial pathogenesis that may help us to better understand AD as well as open a new era for therapeutic target of AD and treat this progressive disease.}, } @article {pmid36606270, year = {2022}, author = {Liu, J and Chang, D and Cordato, D and Lee, K and Dixson, H and Bensoussan, A and Chan, DKY}, title = {A pilot randomized controlled trial of WeiNaoKang (SaiLuoTong) in treating vascular dementia.}, journal = {Aging medicine (Milton (N.S.W))}, volume = {5}, number = {4}, pages = {246-256}, pmid = {36606270}, issn = {2475-0360}, abstract = {OBJECTIVE: WeiNaoKang (or SaiLuoTong) is an herbal formula consisting of ginkgo, ginseng, and saffron. Our objective was to investigate if WeiNaoKang could improve cognitive function and cerebral perfusion in patients suffering from vascular dementia.

METHODS: A 16-week randomized double-blind, placebo-controlled trial was carried out in the setting of a memory disorder clinic at a single center. Patients with vascular dementia diagnosed clinically but supported by imaging and other investigations were invited to participate. The diagnoses were based on the National Institute of Neurological Disorders and Stroke/Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) criteria. An independent blinded assessor evaluated the effects of the formula. Intervention group was compared to the control group. A subgroup of participants was randomly chosen for further evaluation of cerebral perfusion by single photon emission computed tomography scans post-treatment.

RESULTS: Both groups were comparable in age (mean = 74 ± 7.2 years in the placebo group and 75 ± 7.4 in the intervention group) and in other demographics. Sixty-two participants were included in final analysis. Alzheimer's Disease Assessment Scale - Cognitive Portion (ADAS-cog) was the primary outcome. By week 16, the mean ADAS-cog reduced from 24.48 to 20.30 (mean reduction = 4.18) for those in the treatment group, and from 18.98 to 17.81 (mean reduction = 1.18) for those in the placebo group. The difference in mean reduction of ADAS-cog was -3.00 (95% confidence interval [CI] = -4.910 to -1.100) in favor of the treatment group. Secondary outcomes of activities of daily living and quality of life measures also showed significant difference. In the perfusion scan analysis, the difference in the change in cerebral blood flow (t-scores) pre- and post-treatment between the intervention group (n = 7) and the placebo group (n = 11) was statistically significant (P < 0.001).

CONCLUSION: In this randomized, double-blind placebo-controlled trial, we demonstrated significant differences in improvement in cognitive function and activities of daily living. The clinical improvement is corroborated with improvement in cerebral perfusion in a subset of participants.}, } @article {pmid36606209, year = {2022}, author = {Kandiah, N and Choi, SH and Hu, CJ and Ishii, K and Kasuga, K and Mok, VCT}, title = {Current and Future Trends in Biomarkers for the Early Detection of Alzheimer's Disease in Asia: Expert Opinion.}, journal = {Journal of Alzheimer's disease reports}, volume = {6}, number = {1}, pages = {699-710}, pmid = {36606209}, issn = {2542-4823}, abstract = {Alzheimer's disease (AD) poses a substantial healthcare burden in the rapidly aging Asian population. Early diagnosis of AD, by means of biomarkers, can lead to interventions that might alter the course of the disease. The amyloid, tau, and neurodegeneration (AT[N]) framework, which classifies biomarkers by their core pathophysiological features, is a biomarker measure of amyloid plaques and neurofibrillary tangles. Our current AD biomarker armamentarium, comprising neuroimaging biomarkers and cerebrospinal fluid biomarkers, while clinically useful, may be invasive and expensive and hence not readily available to patients. Several studies have also investigated the use of blood-based measures of established core markers for detection of AD, such as amyloid-β and phosphorylated tau. Furthermore, novel non-invasive peripheral biomarkers and digital biomarkers could potentially expand access to early AD diagnosis to patients in Asia. Despite the multiplicity of established and potential biomarkers in AD, a regional framework for their optimal use to guide early AD diagnosis remains lacking. A group of experts from five regions in Asia gathered at a meeting in March 2021 to review the current evidence on biomarkers in AD diagnosis and discuss best practice around their use, with the goal of developing practical guidance that can be implemented easily by clinicians in Asia to support the early diagnosis of AD. This article summarizes recent key evidence on AD biomarkers and consolidates the experts' insights into the current and future use of these biomarkers for the screening and early diagnosis of AD in Asia.}, } @article {pmid36606207, year = {2022}, author = {Santiago-Mujika, E and Luthi-Carter, R and Giorgini, F and Mukaetova-Ladinska, EB}, title = {Tubulin Isotypes and Posttranslational Modifications in Vascular Dementia and Alzheimer's Disease.}, journal = {Journal of Alzheimer's disease reports}, volume = {6}, number = {1}, pages = {739-748}, pmid = {36606207}, issn = {2542-4823}, abstract = {BACKGROUND: Vascular dementia (VaD) and Alzheimer's disease (AD) are the two most common forms of dementia. Although these two types of dementia have different etiologies, they share some similarities in their pathophysiology, such as neuronal loss and decreased levels of tau protein. We hypothesize that these can have an impact upon the molecular changes in tubulin, precede the neuronal cell loss, and lead to changes in cytoskeletal associated proteins, as documented in both VaD and AD.

OBJECTIVE: We characterized different isotypes of tubulin together with their posttranslational modifications, as well as several microtubule associated proteins (MAPs), such as tau protein, MAP2 and MAP6, all together known as the tubulin code.

METHODS: We performed western blotting in human brain homogenates of controls and AD and VaD subjects.

RESULTS: We report that the levels of different tubulin isotypes differ depending on the dementia type and the brain area being studied: whereas α-tubulin is increased in the temporal lobe of VaD patients, it is decreased in the frontal lobe of AD patients. In VaD patients, the frontal lobe had a decrease in tyrosinated tubulin, which was accompanied by a decrease in tau protein and a tendency for lower levels of MAP2.

CONCLUSION: Our findings highlight distinct changes in the tubulin code in VaD and AD, suggesting a therapeutic opportunity for different dementia subtypes in the future.}, } @article {pmid36606073, year = {2022}, author = {Hegazy, EM and Sabry, A and Khalil, WKB}, title = {Neuroprotective effects of onion and garlic root extracts against Alzheimer's disease in rats: antimicrobial, histopathological, and molecular studies.}, journal = {Biotechnologia}, volume = {103}, number = {2}, pages = {153-167}, pmid = {36606073}, issn = {2353-9461}, abstract = {Alzheimer's disease (AD) is a brain disorder and the main reason for dementia. In this regard, there is a need to understand the alterations that occur during aging to develop treatment strategies to mitigate or prevent neurodegenerative consequences. Onion and garlic root extracts contain natural polyphenols with high antioxidant capacity; therefore, the present study aimed to investigate the protective effect of these extracts free from mycotoxin contamination on a rat model of AD. Antifungal and antibacterial assays were performed for onion and garlic extracts. Several groups of AD-induced rats were administered 1, 2, and 3 mg/kg onion or garlic extract through intragastric intubation for 30 days. After treatment, histopathological analysis, expression of apoptosis-related genes, and analyses of DNA damage and reactive oxygen species (ROS) generation were conducted in the brain tissues. The results indicate that treatment of AD-induced rats with several doses of onion and garlic root extracts decreased histopathological lesions, the expression levels of apoptotic genes, and the rate of DNA damage and inhibited intracellular ROS generation in the brain tissues. The results suggest that the protective role of onion root extract could be attributed to its content of flavonoids and flavonoid compounds through the improvement of antioxidant capacity and regulation of gene expression patterns. The higher activity levels of free radical scavenging of azino-bis (3-ethylbenzothiazoline-6-sulphonic acid (ABTS) and antioxidant ferric reducing antioxidant power (FRAP) levels found in garlic root extract are most probably responsible for its protective effect against neurodegenerative damage.}, } @article {pmid36605893, year = {2022}, author = {Methods In Medicine, CAM}, title = {Retracted: Influence of MRI on Diagnostic Efficacy and Satisfaction of Patients with Alzheimer's Disease.}, journal = {Computational and mathematical methods in medicine}, volume = {2022}, number = {}, pages = {9761394}, pmid = {36605893}, issn = {1748-6718}, abstract = {[This retracts the article DOI: 10.1155/2021/9038784.].}, } @article {pmid36605889, year = {2022}, author = {Kotlarz, P and Nino, JC and Febo, M}, title = {Connectomic analysis of Alzheimer's disease using percolation theory.}, journal = {Network neuroscience (Cambridge, Mass.)}, volume = {6}, number = {1}, pages = {213-233}, pmid = {36605889}, issn = {2472-1751}, abstract = {Alzheimer's disease (AD) is a severe neurodegenerative disorder that affects a growing worldwide elderly population. Identification of brain functional biomarkers is expected to help determine preclinical stages for targeted mechanistic studies and development of therapeutic interventions to deter disease progression. Connectomic analysis, a graph theory-based methodology used in the analysis of brain-derived connectivity matrices was used in conjunction with percolation theory targeted attack model to investigate the network effects of AD-related amyloid deposition. We used matrices derived from resting-state functional magnetic resonance imaging collected on mice with extracellular amyloidosis (TgCRND8 mice, n = 17) and control littermates (n = 17). Global, nodal, spatial, and percolation-based analysis was performed comparing AD and control mice. These data indicate a short-term compensatory response to neurodegeneration in the AD brain via a strongly connected core network with highly vulnerable or disconnected hubs. Targeted attacks demonstrated a greater vulnerability of AD brains to all types of attacks and identified progression models to mimic AD brain functional connectivity through betweenness centrality and collective influence metrics. Furthermore, both spatial analysis and percolation theory identified a key disconnect between the anterior brain of the AD mice to the rest of the brain network.}, } @article {pmid36605800, year = {2022}, author = {Shao, X and Yan, C and Wang, C and Wang, C and Cao, Y and Zhou, Y and Guan, P and Hu, X and Zhu, W and Ding, S}, title = {Advanced nanomaterials for modulating Alzheimer's related amyloid aggregation.}, journal = {Nanoscale advances}, volume = {5}, number = {1}, pages = {46-80}, pmid = {36605800}, issn = {2516-0230}, abstract = {Alzheimer's disease (AD) is a common neurodegenerative disease that brings about enormous economic pressure to families and society. Inhibiting abnormal aggregation of Aβ and accelerating the dissociation of aggregates is treated as an effective method to prevent and treat AD. Recently, nanomaterials have been applied in AD treatment due to their excellent physicochemical properties and drug activity. As a drug delivery platform or inhibitor, various excellent nanomaterials have exhibited potential in inhibiting Aβ fibrillation, disaggregating, and clearing mature amyloid plaques by enhancing the performance of drugs. This review comprehensively summarizes the advantages and disadvantages of nanomaterials in modulating amyloid aggregation and AD treatment. The design of various functional nanomaterials is discussed, and the strategies for improved properties toward AD treatment are analyzed. Finally, the challenges faced by nanomaterials with different dimensions in AD-related amyloid aggregate modulation are expounded, and the prospects of nanomaterials are proposed.}, } @article {pmid36605616, year = {2022}, author = {Han, S and Gim, Y and Jang, EH and Hur, EM}, title = {Functions and dysfunctions of oligodendrocytes in neurodegenerative diseases.}, journal = {Frontiers in cellular neuroscience}, volume = {16}, number = {}, pages = {1083159}, pmid = {36605616}, issn = {1662-5102}, abstract = {Neurodegenerative diseases (NDDs) are characterized by the progressive loss of selectively vulnerable populations of neurons, which is responsible for the clinical symptoms. Although degeneration of neurons is a prominent feature that undoubtedly contributes to and defines NDD pathology, it is now clear that neuronal cell death is by no means mediated solely by cell-autonomous mechanisms. Oligodendrocytes (OLs), the myelinating cells of the central nervous system (CNS), enable rapid transmission of electrical signals and provide metabolic and trophic support to neurons. Recent evidence suggests that OLs and their progenitor population play a role in the onset and progression of NDDs. In this review, we discuss emerging evidence suggesting a role of OL lineage cells in the pathogenesis of age-related NDDs. We start with multiple system atrophy, an NDD with a well-known oligodendroglial pathology, and then discuss Alzheimer's disease (AD) and Parkinson's disease (PD), NDDs which have been thought of as neuronal origins. Understanding the functions and dysfunctions of OLs might lead to the advent of disease-modifying strategies against NDDs.}, } @article {pmid36605589, year = {2022}, author = {Jeon, KB and Lee, SH and Kwon, YS and Beak, JH and Lee, H and Ma, CJ}, title = {Protective effect of fermented aloe extract on glutamate-induced cytotoxicity in HT22 cells.}, journal = {Animal cells and systems}, volume = {26}, number = {6}, pages = {318-327}, pmid = {36605589}, issn = {1976-8354}, abstract = {Excessive glutamate can cause oxidative stress in neuronal cells and this can significantly contribute to the etiology of neurodegenerative disease. The present study mainly aims to investigate that aloe extract (AE) and fermented aloe extract (FAE) could protect against glutamate-induced cytotoxicity by modulating oxidative stress. In this study, both AE and FAE showed potent neuroprotective activity by inhibiting ROS and Ca[2+] concentration, increasing mitochondria membrane potential, and activating glutathione-related enzymes against glutamate-insulted neurotoxicity in HT22 cells. In addition, the neuroprotective activity of FAE was more potent than that of AE. HPLC analysis reveals that the chemical composition of FAE is different from that of AE. Especially, the contents of aloin A, aloin B and aloenin were higher in FAE than in AE. In conclusion, this study indicates that both AE and FAE may have effective neuroprotective activity in glutamate-insulted pathological conditions such as Alzheimer's disease by managing oxidative stress.}, } @article {pmid36605552, year = {2022}, author = {Liao, W and Luo, H and Ruan, Y and Mai, Y and Liu, C and Chen, J and Yang, S and Xuan, A and Liu, J}, title = {Identification of candidate genes associated with clinical onset of Alzheimer's disease.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {1060111}, pmid = {36605552}, issn = {1662-4548}, abstract = {BACKGROUND AND OBJECTIVE: Alzheimer's disease (AD) is the most common type of dementia, with its pathology like beta-amyloid and phosphorylated tau beginning several years before the clinical onset. The aim is to identify genetic risk factors associated with the onset of AD.

METHODS: We collected three microarray data of post-mortem brains of AD patients and the healthy from the GEO database and screened differentially expressed genes between AD and healthy control. GO/KEGG analysis was applied to identify AD-related pathways. Then we distinguished differential expressed genes between symptomatic and asymptomatic AD. Feature importance with logistic regression analysis is adopted to identify the most critical genes with symptomatic AD.

RESULTS: Data was collected from three datasets, including 184 AD patients and 132 healthy controls. We found 66 genes to be differently expressed between AD and the control. The pathway enriched in the process of exocytosis, synapse, and metabolism and identified 19 candidate genes, four of which (VSNL1, RTN1, FGF12, and ENC1) are vital.

CONCLUSION: VSNL1, RTN1, FGF12, and ENC1 may be the essential genes that progress asymptomatic AD to symptomatic AD. Moreover, they may serve as genetic risk factors to identify high-risk individuals showing an earlier onset of AD.}, } @article {pmid36605392, year = {2022}, author = {Li, Y and Lan, X and Wang, S and Cui, Y and Song, S and Zhou, H and Li, Q and Dai, L and Zhang, J}, title = {Serial five-membered lactone ring ions in the treatment of Alzheimer's diseases-comprehensive profiling of arctigenin metabolites and network analysis.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1065654}, pmid = {36605392}, issn = {1663-9812}, abstract = {Arctigenin is a phenylpropanoid dibenzylbutyro lactone lignan compound with multiple biological functions. Previous studies have shown that arctigenin have neuroprotective effects in Alzheimer's disease (AD) models both in vivo and in vitro; however, its metabolism in vivo has not been studied. Most traditional analytical methods only partially characterize drug metabolite prototypes, so there is an urgent need for a research strategy that can fully characterize drug metabolites. In the present study, ions fishing with a serial five-membered lactone ring as a fishhook strategy based on ultrahigh-performance liquid chromatography-Q-Exactive Orbitrap mass spectrometry (UHPLC-Q-Exactive Orbitrap MS) was utilised to characterise the metabolism of arctigenin, and the establishment of this strategy also solved the challenge of creating a comprehensive metabolic profile of neolignan. Based on the proposed strategy, a total of 105 metabolites were detected and characterised, 76 metabolites of which were found in rats and 49 metabolites in liver microsomes. These metabolites were postulated to be produced through oxidation, reduction, hydrolysis, and complex reactions. Subsequently, network pharmacology was utilized to elucidate the mechanism of arctigenin and its main metabolites against Alzheimer's disease, screening 381 potential targets and 20 major signaling pathways. The study on the comprehensive metabolism of arctigenin provides a holistic metabolic profile, which will help to better understand the mechanism of arctigenin in the treatment of Alzheimer's disease (AD) and also provide a basis for the safe administration of arctigenin.}, } @article {pmid36604922, year = {2022}, author = {Guo, YX and Zhang, SH and Wang, AQ and Zhu, XX and Li, YJ and Chen, Y and Yang, Q and Wang, YJ and Li, Q and Cai, WY and Chen, LN and Sun, Y and Weng, XG}, title = {[Pharmacodynamic substances and therapeutic potential of Wuji Pills:based on UPLC-Q-TOF-MS/MS and network pharmacology].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {47}, number = {24}, pages = {6720-6729}, doi = {10.19540/j.cnki.cjcmm.20220727.702}, pmid = {36604922}, issn = {1001-5302}, mesh = {Animals ; Rats ; *Drugs, Chinese Herbal/pharmacology ; Tandem Mass Spectrometry ; Network Pharmacology ; Vascular Endothelial Growth Factor A ; Molecular Docking Simulation ; }, abstract = {As a classic prescription, Wuji Pills is composed of Coptidis Rhizoma, Euodiae Fructus Preparata, and stir-fried Paeo-niae Radix Alba at the ratio of 6∶1∶6. The practical application of it is limited compared with other famous Chinese medicine prescriptions. Only one company produces Wuji Pills in China. In this study, ultra-performance liquid chromatography quadrupole time of flight mass spectrometry(UPLC-Q-TOF-MS/MS) was used to analyze and identify 26 identical compounds from Wuji Pills and drug-containing plasma of rats. Based on these components, 46 potential targets were screened out with network pharmacology methods, followed by the component-target network construction, Gene Ontology(GO) term enrichment, Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment, and disease prediction. It was concluded that Wuji Pills acted on core targets such as PTGS2, PTSG1, NCOA2, HSP9 OAD1, and RXRA through magnoflorine, hydroxyevodiamine, daucosterol, and berberine and exerted pharmacodynamic effects through various pathways such as calcium ion signaling pathway, phosphatidylinositol-3-kinase-protein kinase B(PI3 K-Akt) signaling pathway, and vascular endothelial growth factor(VEGF) signaling pathway. Thus, Wuji Pills has therapeutic potential for Alzheimer's disease, diabetes mellitus, myocardial ischemia, and other diseases in addition to the conventional disease(irritable bowel syndrome, IBS). The above research results can provide a reference for the comprehensive interpretation of the pharmacodynamic basis of Wuji Pills and the expansion of clinical application. At the same time, a lot of components in serum and the in vivo transformed and metabolized components of Wuji Pills have similar structure and relative molecular weight. In theory, these components may show additive effects and the competitive/antagonistic effects on the same target. According to the hypothesis of "additive effect of multiple components for a single target" in traditional Chinese medicine, multiple similar components may exert the additive effects on local targets. This study can partly prove the scientificity of this hypothesis and provide laboratory evidence.}, } @article {pmid36604022, year = {2022}, author = {Liu, W and Gauthier, S and Jia, J}, title = {Alzheimer's disease: current status and perspective.}, journal = {Science bulletin}, volume = {67}, number = {24}, pages = {2494-2497}, doi = {10.1016/j.scib.2022.12.006}, pmid = {36604022}, issn = {2095-9281}, mesh = {Humans ; *Alzheimer Disease/diagnosis ; }, } @article {pmid36603328, year = {2023}, author = {Jellinger, KA}, title = {Morphological differences between the two major subtypes of multiple system atrophy with cognitive impairment.}, journal = {Parkinsonism & related disorders}, volume = {107}, number = {}, pages = {105273}, doi = {10.1016/j.parkreldis.2022.105273}, pmid = {36603328}, issn = {1873-5126}, mesh = {Humans ; *Multiple System Atrophy ; *Alzheimer Disease/pathology ; *Cognitive Dysfunction/etiology/pathology ; *Dementia ; Neurons/pathology ; }, abstract = {OBJECTIVE: To compare the neuropathology between two types of multiple system atrophy - parkinsonism-predominant (MSA-P) and cerebellar ataxia-predominant (MSA-C) with cognitive impairment.

MATERIAL & METHODS: 35 cases of MSA-P (mean age at death 60.5 ± 7.8 years) and 15 cases of MSA-C (mean age at death 61.3 ± 6.8 years), 35.% of which associated with mild to moderate cognitive impairment and one with severe dementia, were examined neuropathologically with semiquantitative evaluation of both α-synuclein and Alzheimer pathologies, including cerebral amyloid angiopathy (CAA) and other co-pathologies.

RESULTS: While the mean age at death of both MSA subgroups was similar, the age at onset and duration of disease were slightly higher in the MSA-C group. In line with the classification, the αSyn pathology glial and neuronal inclusions in both the cortex and brainstem were significantly higher in the MSA-P group. With regard to the Alzheimer disease pathology, tau load in cases with mild to moderate cognitive impairment was slightly but not significantly higher in the MSA-P group, one with severe dementia showing fully developed Alzheimer co-pathology, while the amyloid-β (Aβ) load including the CAA was higher in the MSA-C group. The presence of Lewy co-pathology in this series (20%), being similar to that of other MSA cohorts, was more frequent in MSA cases with mild to severe cognitive impairment, but did not differ between the two subgroups and seems not essentially important for MCI in MSA.

CONCLUSIONS: In agreement with previous clinical studies that reported more severe cognitive dysfunction in patients with MSA-P, the present neuropathological study showed increased tau pathology in MSA-P and one with severe Alzheimer co-pathology, but only slightly increased amyloid pathology in the MSA-C group. Lewy co-pathology was more frequent in MSA-P cases with cognitive decline. In view of the limited data about the pathobiological basis of cognitive impairment in MSA, further studies to elucidate the differences between the two phenotypes are urgently needed.}, } @article {pmid36601621, year = {2023}, author = {Dickson, JR and Frosch, MP and Hyman, BT}, title = {Altered localization of nucleoporin 98 in primary tauopathies.}, journal = {Brain communications}, volume = {5}, number = {1}, pages = {fcac334}, pmid = {36601621}, issn = {2632-1297}, abstract = {Nucleoporin 98 is a nuclear pore complex component that is mislocalized in Alzheimer's disease and the alteration in nucleoporin 98 has been attributed to tau. In order to determine if nucleoporin 98 mislocalization is a general feature of tauopathies, we assessed the localization of nucleoporin 98 in neurons in primary tauopathies, including frontotemporal lobar degeneration-tau, corticobasal degeneration and progressive supranuclear palsy. Immunofluorescence staining was performed on frontal cortex and occipital cortex tissue from cases of primary tauopathies and controls without neurodegenerative disease using antibodies to identify nucleoporin 98, phospho-tau (Ser202, Thr205) monoclonal antibody and neuronal marker microtubule-associated protein 2. The stained tissue was imaged by fluorescence microscopy and the number of neurons with mislocalized nucleoporin 98 and phospho-tau (Ser202, Thr205) monoclonal antibody staining was quantified. In frontal cortex tissue, all primary tauopathies examined demonstrated significantly increased numbers of neurons with abnormal localization of nucleoporin 98 along the nuclear envelope compared with control tissue. Additionally, frontotemporal lobar degeneration-tau and corticobasal degeneration in the frontal cortex demonstrated significantly increased numbers of neurons with a cytoplasmic mislocalization of nucleoporin 98 compared with control tissue. The number of neurons with mislocalized nucleoporin 98 was significantly correlated with the number of neurons with phospho-tau (Ser202, Thr205) monoclonal antibody-positive tau staining. In the occipital cortex, which is relatively spared from pathological tau accumulations in these primary tauopathies, the localization of nucleoporin 98 was not significantly altered. This study demonstrates that nucleoporin 98 mislocalization is a feature of primary tauopathies and is associated with pathological tau accumulation. In the context of prior research demonstrating nucleoporin 98 mislocalization in Alzheimer's disease and an interaction between tau and nucleoporin 98, these results further support the hypothesis that pathological tau may contribute to nucleoporin 98 mislocalization. Given the critical role of the nuclear pore complex in nucleocytoplasmic transport, the identification of nucleoporin 98 mislocalization in primary tauopathies highlights a potential pathophysiological disruption in these disorders.}, } @article {pmid36601596, year = {2022}, author = {Zhang, X and Shams, SP and Yu, H and Wang, Z and Zhang, Q}, title = {A pairwise functional connectivity similarity measure method based on few-shot learning for early MCI detection.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {1081788}, pmid = {36601596}, issn = {1662-4548}, abstract = {Alzheimer's disease is an irreversible neurological disease, therefore prompt diagnosis during its early stage, i.e., early mild cognitive impairment (MCI), is crucial for effective treatment. In this paper, we propose an automatic diagnosis method, a few-shot learning-based pairwise functional connectivity (FC) similarity measure method, to detect early MCI. We first employ a sliding window strategy to generate a dynamic functional connectivity network (FCN) using each subject's rs-fMRI data. Then, normal controls (NCs) and early MCI patients are distinguished by measuring the similarity between the dynamic FC series of corresponding brain regions of interest (ROIs) pairs in different subjects. However, previous studies have shown that FC patterns in different ROI-pairs contribute differently to disease classification. To enable the FCs of different ROI-pairs to make corresponding contributions to disease classification, we adopt a self-attention mechanism to weight the FC features. We evaluated the suggested strategy using rs-fMRI data obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, and the results point to the viability of our approach for detecting MCI at an early stage.}, } @article {pmid36601514, year = {2022}, author = {Ittiyavirah, SP and Ramalingam, K and Sathyan, A and Rajasree, RS and Kuruniyan, MS and Quadri, SA and Elayadeth-Meethal, M and Naseef, PP}, title = {Thymoquinone-rich black cumin oil attenuates ibotenic acid-induced excitotoxicity through glutamate receptors in Wistar rats.}, journal = {Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society}, volume = {30}, number = {12}, pages = {1781-1790}, pmid = {36601514}, issn = {1319-0164}, abstract = {Inflammation-mediated alterations in glutamate neurotransmission constitute the most important pathway in the pathophysiology of various brain disorders. The excessive signalling of glutamate results in excitotoxicity, neuronal degeneration, and neuronal cell death. In the present study, we investigated the relative efficacy of black cumin (Nigella sativa) oil with high (5 % w/w) and low (2 % w/w) thymoquinone content (BCO-5 and BCO-2, respectively) in alleviating ibotenic acid-induced excitotoxicity and neuroinflammation in Wistar rats. It was found that BCO-5 reversed the abnormal behavioural patterns and the key inflammatory mediators (TNF-α and NF-κB) when treated at 5 mg/kg body weight. Immunohistochemical studies showed the potential of BCO-5 to attenuate the glutamate receptor subunits NMDA and GluR-2 along with increased glutamate decarboxylase levels in the brain tissues. Histopathological studies revealed the neuroprotection of BCO-5 against the inflammatory lesions, as evidenced by the normal cerebellum, astrocytes, and glial cells. BCO-2 on the other hand showed either a poor protective effect or no effect even at a 4-fold higher concentration of 20 mg/kg body weight indicating a very significant role of thymoquinone content on the neuroprotective effect of black cumin oil and its plausible clinical efficacy in counteracting the anxiety and stress-related neurological disorders under conditions such as depression and Alzheimer's disease.}, } @article {pmid36601504, year = {2022}, author = {Alhazmi, HA and Albratty, M}, title = {An update on the novel and approved drugs for Alzheimer disease.}, journal = {Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society}, volume = {30}, number = {12}, pages = {1755-1764}, pmid = {36601504}, issn = {1319-0164}, abstract = {INTRODUCTION: Given the severity of the condition and the increasing number of patients, developing effective therapies for Alzheimer's disease has become a significant necessity. Aggregation of Amyloid-Beta (Aβ) plaques and Tau Protein Tangles in the brain's nerve tissue are two of the most histopathological/pathophysiological symptoms. Another important element involved in the etiology of Alzheimer's disease is the reduction in acetylcholine (ACh) levels in the brain. Currently available medications for Alzheimer's disease treatment, such as cholinesterase inhibitors and an antagonist of the N-methyl-d-aspartate receptor, can temporarily reduce dementia symptoms but not stop or reverse disease development. In addition, several medicinal plants have been shown to diminish the degenerative characteristics associated with Alzheimer's disease, either in its crude form or as isolated chemicals.

AIM: This review summarises the results from previous studies that reflect an array of novel therapies underway in various phases of clinical trials. Many are discontinued due to non-adherence to the designed endpoints or the surfacing of unavoidable side effects. The present piece of article focuses on the approved drugs for the treatment of Alzheimer's disease and their related mode of action as well as the promising therapies for the treatment of the said disease. Special attention has been placed on the researched herbal drugs, with the pipeline of novel therapies underway in various phases of clinical trials.

RESULT: The current article includes a list of approved pharmaceuticals for treating Alzheimer's disease, prospective therapies for the illness's treatment, and a pipeline of novel therapies in various stages of clinical trials.

CONCLUSION: The results suggest that the drugs under clinical trials may open new pathways for the effective treatment of patients with Alzheimer's disease while improving their quality of life.}, } @article {pmid36601055, year = {2022}, author = {Behl, T and Arora, A and Singla, RK and Sehgal, A and Makeen, HA and Albratty, M and Meraya, AM and Najmi, A and Bungau, SG}, title = {Understanding the role of "sunshine vitamin D" in Parkinson's disease: A review.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {993033}, pmid = {36601055}, issn = {1663-9812}, abstract = {Next to Alzheimer's disease, Parkinson's disease constitutes the second most widespread neurological disorder, primarily affecting the older population. Its symptoms are noticeable with advancing age including tremors, postural imbalance, and slow movements, and over time, these symptoms get aggravated, progressing to osteoporosis, osteopenia, and risk of fractures. These symptoms correlate to low bone density and hence weakened bones; thus, vitamin D proves to be an intricate component of the pathogenesis of the disease. Moreover, lower serum concentrations of vitamin D have been found in diseased subjects. Supplementation with vitamin D can retard the aggravation of non-motor as well as motor symptoms of Parkinson's disease that include cognitive improvement along with the decline in risk of fractures. Also, vitamin D is extremely crucial for brain functioning, targeting dopaminergic neurons, and almost the entire functioning of the brain is affected. However, further exploration is required to determine the toxic dose of vitamin D in Parkinson's subjects. This "sunshine vitamin" surely can be a ray of sunshine for neurologically diseased subjects.}, } @article {pmid36600949, year = {2022}, author = {Zheng, Z and Wu, K and Ruan, Q and Li, D and Liu, W and Wang, M and Li, Y and Xia, J and Yang, D and Guo, J}, title = {Suppression of Selective Voltage-Gated Calcium Channels Alleviates Neuronal Degeneration and Dysfunction through Glutathione S-Transferase-Mediated Oxidative Stress Resistance in a Caenorhabditis elegans Model of Alzheimer's Disease.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {8287633}, pmid = {36600949}, issn = {1942-0994}, mesh = {Animals ; *Alzheimer Disease/metabolism ; Caenorhabditis elegans ; Calcium/metabolism ; Nimodipine/pharmacology/therapeutic use ; Egtazic Acid/metabolism/pharmacology ; Oxidative Stress ; Amyloid beta-Peptides/metabolism ; Calcium Channels/metabolism ; Ryanodine Receptor Calcium Release Channel/metabolism ; *Caenorhabditis elegans Proteins/metabolism ; }, abstract = {Calcium homeostasis plays a vital role in protecting against Alzheimer's disease (AD). In this study, amyloid-β (Aβ)-induced C. elegans models of AD were used to elucidate the mechanisms underlying calcium homeostasis in AD. Calcium acetate increased the intracellular calcium content, exacerbated Aβ 1-42 aggregation, which is closely associated with oxidative stress, aggravated neuronal degeneration and dysfunction, and shortened the lifespan of the C. elegans models. Ethylene glycol tetraacetic acid (EGTA) and nimodipine were used to decrease the intracellular calcium content. Both EGTA and nimodipine showed remarkable inhibitory effects on Aβ 1-42 aggregations by increasing oxidative stress resistance. Moreover, both compounds significantly delayed the onset of Aβ-induced paralysis, rescued memory deficits, ameliorated behavioral dysfunction, decreased the vulnerability of two major (GABAergic and dopaminergic) neurons and synapses, and extended the lifespan of the C. elegans AD models. Furthermore, RNA sequencing of nimodipine-treated worms revealed numerous downstream differentially expressed genes related to calcium signaling. Nimodipine-induced inhibition of selective voltage-gated calcium channels was shown to activate other calcium channels of the plasma membrane (clhm-1) and endoplasmic reticulum (unc-68), in addition to sodium-calcium exchanger channels (ncx-1). These channels collaborated to activate downstream events to resist oxidative stress through glutathione S-transferase activity mediated by HPGD and skn-1, as verified by RNA interference. These results may be applied for the treatment of Alzheimer's disease.}, } @article {pmid36600570, year = {2023}, author = {Husain, M}, title = {Noradrenergic therapies for apathy in Alzheimer's disease?.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {94}, number = {2}, pages = {93}, pmid = {36600570}, issn = {1468-330X}, support = {206330/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Apathy ; Psychiatric Status Rating Scales ; }, } @article {pmid36599749, year = {2023}, author = {Li, Z and Min, S and Alliey-Rodriguez, N and Giase, G and Cheng, L and Craig, DW and Faulkner, GJ and Asif, H and Liu, C and Gershon, ES}, title = {Single-neuron whole genome sequencing identifies increased somatic mutation burden in Alzheimer's disease related genes.}, journal = {Neurobiology of aging}, volume = {123}, number = {}, pages = {222-232}, doi = {10.1016/j.neurobiolaging.2022.12.002}, pmid = {36599749}, issn = {1558-1497}, support = {R21 AG045789/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Aged ; *Alzheimer Disease/genetics/metabolism ; Whole Genome Sequencing ; Aging/genetics ; Neurons/metabolism ; INDEL Mutation ; Mutation/genetics ; Polymorphism, Single Nucleotide/genetics ; }, abstract = {Accumulation of somatic mutations in human neurons is associated with aging and neurodegeneration. To shed light on the somatic mutational burden in Alzheimer's disease (AD) neurons and get more insight into the role of somatic mutations in AD pathogenesis, we performed single-neuron whole genome sequencing to detect genome-wide somatic mutations (single nucleotide variants (SNVs) and Indels) in 96 single prefrontal cortex neurons from 8 AD patients and 8 elderly controls. We found that the mutational burden is ∼3000 somatic mutations per neuron genome in elderly subjects. AD patients have increased somatic mutation burden in AD-related annotation categories, including AD risk genes and differentially expressed genes in AD neurons. Mutational signature analysis showed somatic SNVs (sSNVs) primarily caused by aging and oxidative DNA damage processes but no significant difference was detected between AD and controls. Additionally, functional somatic mutations identified in AD patients showed significant enrichment in several AD-related pathways, including AD pathway, Notch-signaling pathway and Calcium-signaling pathway. These findings provide genetic insights into how somatic mutations may alter the function of single neurons and exert their potential roles in the pathogenesis of AD.}, } @article {pmid36595373, year = {2023}, author = {Liu, S and Xiao, C and Wang, F}, title = {Comparison of Two Varieties Fig (Peggy Red and Green) Peel Extracts by Liquid Chromatography-Tandem Mass Spectrometry Analysis and for Neuroprotective Efficacy in Caenorhabditis elegans.}, journal = {Journal of medicinal food}, volume = {26}, number = {1}, pages = {14-26}, doi = {10.1089/jmf.2021.K.0190}, pmid = {36595373}, issn = {1557-7600}, mesh = {Animals ; *Antioxidants/pharmacology/analysis ; Caenorhabditis elegans ; *Ficus/chemistry ; Anthocyanins/analysis ; Chromatography, Liquid ; Tandem Mass Spectrometry ; Plant Extracts/chemistry ; Flavonoids/pharmacology/analysis ; Phenols/pharmacology/analysis ; Gallic Acid/analysis ; }, abstract = {Previous reports revealed that peel extracts of Ficus carica (fig) have a wide range of pharmacological and biological activities. The current study aimed to determine the phytochemical components of the ethanol extracts of Peggy Red fig (PRF) and Green fig (GF) peels by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, along with its antioxidant properties and neuroprotective effect in Caenorhabditis elegans. LC-MS/MS analysis confirmed 50 compounds in the extract, which revealed the presence of phenols, flavonoids, and anthocyanins, and exhibited in vitro antioxidant activity. PRF and GF peel had 163.25 (mg gallic acid equivalent [mg GAE]) g[-1], 125.32 (mg GAE) g[-1] of total phenolic content, 62.52 (mg rutin equivalent [mg RE]) g[-1], and 43.36 (mg RE) g[-1] flavonoids content, respectively. In all antioxidant assays, the extract of PRF peel showed higher antioxidant activity than the GF peel, and the extract of PRF peel could effectively reduce the aggregation of amyloid-beta (Aβ), decrease the paralysis of the body, and increase the antioxidant enzyme activities to reduce the toxicity of Aβ1-42 in Alzheimer's disease (AD) transgenic C. elegans CL4176. Therefore, PRF peel extract may have potential applications as a new source for drug development against AD.}, } @article {pmid36594931, year = {2023}, author = {Yılmaz, ŞG and Almasri, S and Karabulut, YY and Korkmaz, M and Bucak, Ö and Balcı, SO}, title = {Okadaic Acid-Induced Alzheimer's in Rat Brain: Phytochemical Cucurbitacin E Contributes to Memory Gain by Reducing TAU Protein Accumulation.}, journal = {Omics : a journal of integrative biology}, volume = {27}, number = {1}, pages = {34-44}, doi = {10.1089/omi.2022.0175}, pmid = {36594931}, issn = {1557-8100}, mesh = {Rats ; Female ; Animals ; tau Proteins/metabolism ; Okadaic Acid/pharmacology ; *Alzheimer Disease/chemically induced/drug therapy/metabolism ; Rats, Sprague-Dawley ; Amyloid beta-Peptides/metabolism/pharmacology ; *Neurodegenerative Diseases/metabolism ; Brain/metabolism ; Disease Models, Animal ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory loss and cognitive decline, with hallmark pathologies related to amyloid beta (Aβ) and TAU. Natural phytochemicals show promise for drug discovery to fill the current therapeutic innovation gap in AD. This study investigated the effect of cucurbitacin E (CuE), one of the bioactive components of Ecballium elaterium, on TAU fibril formation in okadaic acid-induced AD in rats. In a randomized design, we assigned 30 female Sprague Dawley rats to one of five experimental groups: (1) control, (2) stereotaxic surgery, (3) stereotaxic surgery + artificial cerebrospinal fluid, (4) stereotaxic surgery + okadaic acid (AD model), and (5) stereotaxic surgery + okadaic acid + CuE treatment. For experimental groups 4 and 5, rats were administered OKA-ICV (200 ng/kg) followed by CuE (4 mg/[kg·day], intraperitoneally) for 20 days. Expression of the MAPK1/3 and MAPK14 genes associated with TAU metabolism, hippocampal protein levels of these genes, cognitive functions of the rats, and histological accumulation of TAU in the brain were evaluated. Our findings in this preclinical model collectively suggest that phytochemical CuE contributes to memory gain by reducing TAU protein accumulation, which warrants further evaluation in future in vitro and in vivo studies.}, } @article {pmid36594904, year = {2022}, author = {Zhang, L and Yu, M and Wang, L and Steffens, DC and Wu, R and Potter, GG and Liu, M}, title = {Understanding Clinical Progression of Late-Life Depression to Alzheimer's Disease Over 5 Years with Structural MRI.}, journal = {Machine learning in medical imaging. MLMI (Workshop)}, volume = {13583}, number = {}, pages = {259-268}, pmid = {36594904}, support = {R01 AG041721/AG/NIA NIH HHS/United States ; RF1 AG073297/AG/NIA NIH HHS/United States ; }, abstract = {Previous studies have shown that late-life depression (LLD) may be a precursor of neurodegenerative diseases and may increase the risk of dementia. At present, the pathological relationship between LLD and dementia, in particularly Alzheimer's disease (AD) is unclear. Structural MRI (sMRI) can provide objective biomarkers for the computer-aided diagnosis of LLD and AD, providing a promising solution to understand the clinical progression of brain disorders. But few studies have focused on sMRI-based predictive analysis of clinical progression from LLD to AD. In this paper, we develop a deep learning method to predict the clinical progression of LLD to AD up to 5 years after baseline time using T1-weighted structural MRIs. We also analyze several important factors that limit the diagnostic performance of learning-based methods, including data imbalance, small-sample-size, and multi-site data heterogeneity, by leveraging a relatively large-scale database to aid model training. Experimental results on 308 subjects with sMRIs acquired from 2 imaging sites and the publicly available ADNI database demonstrate the potential of deep learning in predicting the clinical progression of LLD to AD. To the best of our knowledge, this is among the first attempts to explore the complex pathophysiological relationship between LLD and AD based on structural MRI using a deep learning method.}, } @article {pmid36594024, year = {2023}, author = {Hsieh, KL and Plascencia-Villa, G and Lin, KH and Perry, G and Jiang, X and Kim, Y}, title = {Synthesize heterogeneous biological knowledge via representation learning for Alzheimer's disease drug repurposing.}, journal = {iScience}, volume = {26}, number = {1}, pages = {105678}, pmid = {36594024}, issn = {2589-0042}, abstract = {Developing drugs for treating Alzheimer's disease has been extremely challenging and costly due to limited knowledge of underlying mechanisms and therapeutic targets. To address the challenge in AD drug development, we developed a multi-task deep learning pipeline that learns biological interactions and AD risk genes, then utilizes multi-level evidence on drug efficacy to identify repurposable drug candidates. Using the embedding derived from the model, we ranked drug candidates based on evidence from post-treatment transcriptomic patterns, efficacy in preclinical models, population-based treatment effects, and clinical trials. We mechanistically validated the top-ranked candidates in neuronal cells, identifying drug combinations with efficacy in reducing oxidative stress and safety in maintaining neuronal viability and morphology. Our neuronal response experiments confirmed several biologically efficacious drug combinations. This pipeline showed that harmonizing heterogeneous and complementary data/knowledge, including human interactome, transcriptome patterns, experimental efficacy, and real-world patient data shed light on the drug development of complex diseases.}, } @article {pmid36593925, year = {2023}, author = {Rani, V and Verma, R and Kumar, K and Chawla, R}, title = {Role of pro-inflammatory cytokines in Alzheimer's disease and neuroprotective effects of pegylated self-assembled nanoscaffolds.}, journal = {Current research in pharmacology and drug discovery}, volume = {4}, number = {}, pages = {100149}, pmid = {36593925}, issn = {2590-2571}, abstract = {Neurodegeneration and synaptic loss in Alzheimer's disease (AD) lead to impairment in memory functions. Neuroinflammation causes activation of microglia and astrocytes cells that locally and systemically produces inflammatory cytokines which can serve as early diagnostic markers or therapeutic targets in AD. Pro-inflammatory cytokines (Interleukins (IL-1β, IL-6 and IL-10) and tumor necrosis factor (TNF α)) levels were estimated in serum, cerebral tissue, hepatic tissue, and renal tissue in treatment groups of scopolamine-induced amnesia mice model using ELISA protocol. The results showed that cerebral tissue of AD mice exhibited elevated levels of IL1β, IL6, IL10 and TNFα which indicate contribution of pro-inflammatory cytokines in the progression of AD. A significant reduction in the concentration of IL1β, IL-10 and TNF-α were noticed in serum, cerebral tissue and hepatic tissue of animal group treated with marketed memantine tablet (Admenta), pure memantine drug (MEMp), memantine-poly (lactic-co-glycolic acid) self-assembled nanoscaffolds (MEM-PLGA) SANs, Polyethylene Glycol coated memantine-poly (lactic-co-glycolic acid) self-assembled nanoscaffolds [(PEG-MEM-PLGA) SANs] and Polyethylene Glycol coated memantine-poly [(lactic-co-glycolic acid)] self-assembled nanoscaffolds grafted with Bone Marrow Derived Stem Cell ((PEG-MEM-PLGA) SANs-BMSc), whereas a high level of IL-6 was observed in hepatic tissue, cerebral tissue and renal tissues of normal and AD induced mice which showed the emerging potential of IL-6 cytokines that can trigger either neurons survival after injury or causing neurodegeneration and cell apoptosis. The Neuroregenerative potential of stem cells helps in the proliferation of neuronal cell and thus improves cognition in AD animal model.}, } @article {pmid36593897, year = {2023}, author = {Ajenikoko, MK and Ajagbe, AO and Onigbinde, OA and Okesina, AA and Tijani, AA}, title = {Review of Alzheimer's disease drugs and their relationship with neuron-glia interaction.}, journal = {IBRO neuroscience reports}, volume = {14}, number = {}, pages = {64-76}, pmid = {36593897}, issn = {2667-2421}, abstract = {Alzheimer's disease (AD) is the most common cause of dementia worldwide. Because Alzheimer's disease has no known treatment, sufferers and their caregivers must concentrate on symptom management. Astrocytes and microglia are now known to play distinct physiological roles in synaptic function, the blood-brain barrier, and neurovascular coupling. Consequently, the search for drugs that can slow the degenerative process in dementia sufferers continues because existing drugs are designed to alleviate the symptoms of Alzheimer's disease. Drugs that address pathological changes without interfering with the normal function of glia, such as eliminating amyloid-beta deposits, are prospective treatments for neuroinflammatory illnesses. Because neuron-astrocytes-microglia interactions are so complex, developing effective, preventive, and therapeutic medications for AD will necessitate novel methodologies and strategic targets. This review focused on existing medications used in treating AD amongst which include Donepezil, Choline Alphoscerate, Galantamine, Dextromethorphan, palmitoylethanolamide, citalopram, resveratrol, and solanezumab. This review summarizes the effects of these drugs on neurons, astrocytes, and microglia interactions based on their pharmacokinetic properties, mechanism of action, dosing, and clinical presentations.}, } @article {pmid36593834, year = {2022}, author = {Ngai, DN and Kibiti, CM and Ngugi, MP}, title = {Cognitive enhancing effects and anticholinesterase activity of stem bark and leaf extracts of Prunus africana.}, journal = {Heliyon}, volume = {8}, number = {12}, pages = {e12289}, pmid = {36593834}, issn = {2405-8440}, abstract = {Alzheimer's disease is ranked among the top five causes of death for old people. Globally, it is approximated that there are 7.7 million new cases of Alzheimer's disease per annum and it is expected that by the year 2050, as many as 1.5% of people will be victims of Alzheimers or other types of dementia. Currently there is no cure for Alzheimer's disease and the conventional therapeutics agents available either have low efficacy or are associated with serious side effects. In the current study, in vivo cognitive advancing and anticholinesterase effects of crude methanol extracts of stem bark and leaf of Prunus africana were investigated in scopolamine treated mice. Passive avoidance task was used to evaluate cognitive enhancing effects of the two plant extracts. Donepezil was used as the standard drug. Scopolamine butylbromide (5 mg/kg bw) was administered intraperitoneally to induce Alzheimer's disease in mice during the study. A completely controlled randomised experimental design was employed in the current study. The two extracts displayed significant anticholinesterase activities and improved cognition in a dose dependent fashion as indicated by escape latency trends. From the current study, it is concluded that methanol extracts of stem bark and leaf of P. africana contain phytochemicals with anticholinesterase activity and cognitive enhancing effects in scopolamine treated mice. The study therefore supports use of leaf and stem bark extracts of P. africana for management of dementia by traditional herbal practitioners.}, } @article {pmid36593774, year = {2022}, author = {Sharma, A and Singh, T and Pathak, D and Virmani, T and Kumar, G and Alhalmi, A}, title = {Antidepressive-Like Effect of Aegle marmelos Leaf Extract in Chronic Unpredictable Mild Stress-Induced Depression-Like Behaviour in Rats.}, journal = {BioMed research international}, volume = {2022}, number = {}, pages = {6479953}, pmid = {36593774}, issn = {2314-6141}, mesh = {Rats ; Animals ; *Depression/psychology ; *Aegle/metabolism ; Anhedonia ; Serotonin/metabolism ; Corticosterone/metabolism ; Hydroxyindoleacetic Acid/metabolism/pharmacology ; Hypothalamo-Hypophyseal System ; Pituitary-Adrenal System ; Antidepressive Agents/pharmacology/therapeutic use ; Hippocampus/metabolism ; Plant Extracts/therapeutic use ; Sucrose/metabolism ; Stress, Psychological/complications/drug therapy/metabolism ; Disease Models, Animal ; }, abstract = {BACKGROUND: Depression is a psychiatric disorder leading to anhedonia and lack of interest and motivation. Depressive symptoms are triggered by stressful life events, and patients with major depression are at significantly increased risk of attempting suicide. The crucial concern in depression treatment with antidepressant medications is that few weeks are required to show the therapeutic effect along with moderate side effects. The use of herbal medications is a new strategy for the treatment of depression which is often based on medicinal plants.Aegle marmelos (L.) Corr. (family: Rutaceae) is reported to have several actions on the central nervous system producing beneficial effects in anxiety, Alzheimer's disease, Parkinson's disease, epilepsy, and convulsion. Thus, the current investigation designed to assess the antidepressant activity of the standardized hydroethanolic extract of Aegle marmelos (EAM) leaves in male rats exposed to the chronic unpredictable mild stress (CUMS) paradigm.

METHODS: Rats were divided in 5 groups. The control group was not subjected to experimental CUMS paradigm, while 4 other groups were subjected to CUMS paradigm to induce depression-like behaviour from day 1 to day 28. Following the CUMS paradigm, 4 groups were divided as CUMS disease control, CUMS+EAM (150 mg/kg, p.o.), CUMS+EAM (300 mg/kg, p.o.), and CUMS+imipramine (15 mg/kg, p.o.), and treatment was given for seven consecutive days to the respective groups (day 29 to day 35). Behavioural parameters such as open field test, forced swim test, sucrose feeding test, and tail suspension test on day 1, day 28, and day 35 were measured, and biochemical parameters such as plasma corticosterone level, serotonergic system (5-HT, 5-HIAA, and 5-HT/5-HIAA), mitochondrial function, and proinflammatory mediators (TNF-α, IL-1β, and IL-6) were estimated in hippocampus (HIP) and prefrontal cortex (PFC) regions of the brain on day 35, after the behavioural observations. On the other hand, phytochemical profile of Aegle marmelos was done.

RESULTS: On day 35, EAM (300 mg/kg) significantly reduced the immobility time during the tail suspension test from 208.66 ± 4.72 s to 108.83 ± 4.81 s and forced swim test from 200.16 ± 4.12 s to 148.5 ± 4.58 s. It also enhanced the behavioural parameters in the open field test such as ambulation from 26.5 ± 2.14 to 56.5 ± 1.80, rearing from 8.33 ± 0.71 to 19 ± 0.57, time spent in centre from 9.16 ± 0.9 to 17.16 ± 0.79 s, total distance travelled from 2.36 ± 0.12 to 4.68 ± 0.10 m, and anhedonia in the sucrose feeding test from 109.33 ± 1.08 to 135.83 ± 3.91 mL. The stimulation of the HPA axis resulting elevated corticosterone level caused by CUMS was reduced by EAM (300 mg/kg) from 80.12 ± 2.020 to 48.25 ± 2.407 μg/dL. Furthermore, EAM (300 mg/kg) increase CUMS-induced changes in serotonin (5-HT) level in HIP and PFC from 3.132 ± 0.09586 to 4.518 ± 0.1812 and 4.308 ± 0.1593 to 5.262 ± 0.1014 ng/mg protein, respectively. EAM (300 mg/kg) significantly attenuated the CUMS-induced changes in proinflammatory cytokine production and mitochondrial function in HIP and PFC. One group used to determine the acute toxicity as per OECD-23 standard protocol which resulted that 300 mg/kg EAM has no significant acute toxicity. Total phenolic content and total flavonoid content of standardized hydroalcoholic extract of AM was found 95.024 ± 2.431 and 36.820 ± 3.41, respectively, and additional identification tests showed the presence of alkaloids, tannins, saponins, cardiac glycosides, flavonoids, and terpenoids.

CONCLUSION: On the basis of findings, EAM can be inferred as a potential antidepressant-like effect of this plan in preclinical research.}, } @article {pmid36593772, year = {2022}, author = {Simayi, J and Bayinsang, and Nuermaimaiti, M and Hailati, S and Han, M and Reheman, Z and Wumaier, A and Zhou, W}, title = {A Network Pharmacology-Based Study on the Mechanism of Dibutyl Phthalate of Ocimum basilicum L. against Alzheimer's Disease through the AKT/GSK-3β Pathway.}, journal = {BioMed research international}, volume = {2022}, number = {}, pages = {9494548}, pmid = {36593772}, issn = {2314-6141}, mesh = {Dibutyl Phthalate ; Glycogen Synthase Kinase 3 beta ; *Ocimum basilicum ; Proto-Oncogene Proteins c-akt ; *Alzheimer Disease/drug therapy ; Molecular Docking Simulation ; Network Pharmacology ; *Drugs, Chinese Herbal ; }, abstract = {BACKGROUND: Ocimum basilicum L. (OBL) is mainly used to treat neurological diseases in China. The preliminary work of this group showed that OBL improves cognitive impairment in Alzheimer's disease (AD). However, the underlying pharmacological mechanism remains unclear.

METHODS: The components of OBL were compiled by literature search, and their active ingredients were screened by online database. The drug targets of OBL in the treatment of AD were predicted and analyzed using information derived from sources such as the SwissTargetPrediction tool. And through the network visual analysis function of Cytoscape software and protein-protein interaction analysis (PPI), the core targets of OBL treatment of AD are predicted. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were employed to analyze the related signaling pathways affected by OBL. Moreover, AutoDock software was used to assess the potential binding affinity between the core targets and the active compounds. Subsequently, in vivo experiment was conducted to verify the findings of network pharmacology.

RESULTS: A total of 35 active compounds and 188 targets of OBL were screened, of which 43 common targets were related to AD. The active compounds of 35 OBLs induced 118 GO and 78 KEGG. The results of PPI and network topology parameter analysis show that targets such as MAPK1, GSK3B, NR3C2, ESR1, and EGFR are known as the core targets for the treatment of AD by OBL and are docked with the active ingredients of OBL. Molecular docking results suggest that diterbutyl phthalate (DBP) may be the main active component of OBL for the treatment of AD. Flow cytometry analysis results showed that apoptosis decreased with increasing DBP dose. In addition, DBP significantly decreased the levels of lactate dehydrogenase (LDH) and reactive oxygen species (ROS) in the supernatant of Aβ 25-35-induced injury HT22 cell cultures, and it can be speculated that DBP has the ability to protect the stability of injured neuronal cells and improve the permeability of cell membranes, thus stabilizing the intracellular environment. Mechanistically, DBP may increase the mRNA levels of AKT, GSK-3β, etc. in AD cell models and regulate the phosphorylation of AKT/GSK-3β pathway-related.

CONCLUSIONS: Conclusively, our study suggests that DBP, the main active component of OBL, has potential in the prevention or treatment of AD.}, } @article {pmid36592944, year = {2022}, author = {Rossini, PM and Miraglia, F and Vecchio, F}, title = {Commentary on Comparison of Machine Learning-based Approaches to Predict the Conversion to Alzheimer's Disease from Mild Cognitive Impairment.}, journal = {Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuroscience.2022.12.018}, pmid = {36592944}, issn = {1873-7544}, } @article {pmid36592872, year = {2022}, author = {Trouche, SG and Boutajangout, A and Asuni, A and Fontés, P and Sigurdsson, EM and Verdier, JM and Mestre-Francés, N}, title = {Amyloid-β targeting immunisation in aged non-human primate (Microcebus murinus).}, journal = {Brain, behavior, and immunity}, volume = {109}, number = {}, pages = {63-77}, doi = {10.1016/j.bbi.2022.12.021}, pmid = {36592872}, issn = {1090-2139}, abstract = {Non-human primates have an important translational value given their close phylogenetic relationship to humans. Studies in these animals remain essential for evaluating efficacy and safety of new therapeutic approaches, particularly in aging primates that display Alzheimer's disease (AD) -like pathology. With the objective to improve amyloid-β (Aβ) targeting immunotherapy, we investigated the safety and efficacy of an active immunisation with an Aβ derivative, K6Aβ1-30-NH2, in old non-human primates. Thirty-two aged (4-10 year-old) mouse lemurs were enrolled in the study, and received up to four subcutaneous injections of the vaccine in alum adjuvant or adjuvant alone. Even though antibody titres to Aβ were not high, pathological examination of the mouse lemur brains showed a significant reduction in intraneuronal Aβ that was associated with reduced microgliosis, and the vaccination did not lead to microhemorrhages. Moreover, a subtle cognitive improvement was observed in the vaccinated primates, which was probably linked to Aβ clearance. This Aβ derivative vaccine appeared to be safe as a prophylactic measure based on the brain analyses and because it did not appear to have detrimental effects on the general health of these old animals.}, } @article {pmid36592871, year = {2023}, author = {Milani, A and Morawski, M and Bechmann, I}, title = {Inter-hemispherical comparison of tau-pathology in the human temporal lobe.}, journal = {Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft}, volume = {246}, number = {}, pages = {152042}, doi = {10.1016/j.aanat.2022.152042}, pmid = {36592871}, issn = {1618-0402}, mesh = {Humans ; *tau Proteins/metabolism ; *Alzheimer Disease/pathology ; Brain/metabolism ; Temporal Lobe/metabolism/pathology ; }, abstract = {Alzheimer's disease (AD) is characterized histopathologically by hyperphosphorylated and aggregated Tau and amyloid plaques. While the latter appear in a less stringent way throughout the brain in the course of the disease, the former evolve in a highly predictable pattern as described by Braak and Braak (1991). It is, however, not clear if this pattern develops simultaneously in both hemispheres. In this study, we therefore compared Tau-pathology of both hemispheres of the same individual in 36 consecutive brain donations as they arrived in our brain bank. 26 exhibited little differences, in eight cases left hemisphere was clearly more affected and in two cases the right hemisphere. Thus, cases with evident interhemispheric Tau-pathology do exist and interhemispheric comparison in such cases may help to identify driving forces in the progression of AD.}, } @article {pmid36592816, year = {2023}, author = {Kumar, A and Verma, A and Chaurasia, RN}, title = {Vitamin D and inflammatory cytokines association in mild cognitive impaired subjects.}, journal = {Neuroscience letters}, volume = {795}, number = {}, pages = {137044}, doi = {10.1016/j.neulet.2022.137044}, pmid = {36592816}, issn = {1872-7972}, mesh = {Humans ; Male ; Female ; Aged ; Vitamin D ; Cytokines ; Tumor Necrosis Factor-alpha ; Interleukin-6 ; Prodromal Symptoms ; *Cognitive Dysfunction/psychology ; *Alzheimer Disease/psychology ; Inflammation ; Cognition ; }, abstract = {BACKGROUND: Mild cognitive impairment (MCI) is a prodromal stage of Alzheimer's disease (AD). The association of low Vitamin D and chronic inflammation in the onset of cognitive decline in the elderly population has been established but the variable population-based study is still lacking.

METHODOLOGY: The present study aims to investigate the level of plasma Vitamin D, pro-inflammatory cytokines IL-1β, IL-6, TNF-α, cognitive performance, and white matter changes in the elderly population in the North-Eastern part of Uttar Pradesh, India.

RESULTS: 70 participants with (Mean age- 75.14 ± 1.24, Male/Female- 50/20) with an Mini Mental State Examination (MMSE) score of (24.82 ± 1.82) and Montreal Cognitive Assessment Test (MOCA) score (21.83 ± 1.75), were cognitive decline, against the 70 healthy controls (Mean Age-73.18 ± 1.43; Male/Female- 50/20) with MMSE score (28.1 ± 1.5) and MOCA (28.5 ± 1.65), White matter variable Fractional Anisotropy (FA) and Apparent Diffusion Coefficient (ADC) values in MCI subject was found significantly altered in Right temporal lobe, Corpus Callosum (Right) and Hippocampus body (Right), Hippocampus body (left), Hippocampus head (Right) and Hippocampus head (Left)as compared with healthy controls. The level of cytokines IL-1β, IL-6, TNF-α, was significantly high in MCI subjects as compared with controls. Further lower Vitamin D level in plasma was detected in MCI as compared with healthy controls.

CONCLUSION: The result from the present study depicts that chronic inflammation and lower Vitamin D level influences neurodegeneration and decline in cognitive performance in the elderly population. These variables can be used as biomarkers for early identification of AD and interventional strategies can be designed for prevention at the prodromal stage of AD.}, } @article {pmid36592800, year = {2022}, author = {Wenzel, TJ and Murray, TE and Noyovitz, B and Narayana, K and Gray, TE and Le, J and He, J and Simtchouk, S and Gibon, J and Alcorn, J and Mousseau, DD and Zandberg, WF and Klegeris, A}, title = {Cardiolipin released by microglia can act on neighboring glial cells to facilitate the uptake of amyloid-β (1-42).}, journal = {Molecular and cellular neurosciences}, volume = {124}, number = {}, pages = {103804}, doi = {10.1016/j.mcn.2022.103804}, pmid = {36592800}, issn = {1095-9327}, abstract = {Cardiolipin is a mitochondrial phospholipid that is also detected in serum inferring its extracellular release; however, this process has not been directly demonstrated for any of the brain cell types. Nevertheless, extracellular cardiolipin has been shown to modulate several neuroimmune functions of microglia and astrocytes, including upregulation of their endocytic activity. Low cardiolipin levels are associated with brain aging, and may thus hinder uptake of amyloid-β (Αβ) in Alzheimer's disease. We hypothesized that glial cells are one of the sources of extracellular cardiolipin in the brain parenchyma where this phospholipid interacts with neighboring cells to upregulate the endocytosis of Αβ. Liquid chromatography-mass spectrophotometry identified 31 different species of cardiolipin released from murine BV-2 microglial cells and revealed this process was accelerated by exposure to Aβ42. Extracellular cardiolipin upregulated internalization of fluorescently-labeled Aβ42 by primary murine astrocytes, human U118 MG astrocytic cells, and murine BV-2 microglia. Increased endocytic activity in the presence of extracellular cardiolipin was also demonstrated by studying uptake of Aβ42 and pHrodo™ Bioparticles™ by human induced pluripotent stem cells (iPSCs)-derived microglia, as well as iPSC-derived human brain organoids containing microglia, astrocytes, oligodendrocytes and neurons. Our observations indicate that Aβ42 augments the release of cardiolipin from microglia into the extracellular space, where it can act on microglia and astrocytes to enhance their endocytosis of Aβ42. Our observations suggest that the reduced glial uptake of Aβ due to the decreased levels of cardiolipin could be at least partially responsible for the extracellular accumulation of Aβ in aging and Alzheimer's disease.}, } @article {pmid36591860, year = {2022}, author = {Niu, TT and Yuan, BY and Liu, GZ}, title = {Ginkgolides and bilobalide for treatment of Alzheimer's disease and COVID-19: potential mechanisms of action.}, journal = {European review for medical and pharmacological sciences}, volume = {26}, number = {24}, pages = {9502-9510}, doi = {10.26355/eurrev_202212_30702}, pmid = {36591860}, issn = {2284-0729}, mesh = {Humans ; *Bilobalides ; *Alzheimer Disease/drug therapy ; Plaque, Amyloid/drug therapy ; *COVID-19 ; SARS-CoV-2 ; Ginkgolides/pharmacology/therapeutic use ; Plant Extracts/pharmacology ; Ginkgo biloba ; }, abstract = {Alzheimer's disease (AD) is an irreversible degenerative illness of the central nervous system with characteristic histological alterations, known as amyloid plaques and neurofibrillary tangles (NFT). Aggregation of plaques and tangles in the brain induces neurotoxicity and synaptic dysfunction, eventually contributing to neuronal cell death and neurodegeneration. Recent studies have revealed that COVID-19 has a great impact on the development of AD, directly or indirectly, by facilitating the accumulation of amyloid plaques, causing altered functional brain integrity or increasing the phosphorylation rate of tau protein. As two important bioactive components of Ginkgo biloba extract (GbE), ginkgolides and bilobalide (BB) have been reported to show neuroprotective effects in AD via multiple mechanisms such as anti-excitotoxicity, anti-inflammatory and anti-oxidative activities. Intriguingly, ginkgolides and BB also seem to demonstrate antiviral properties against COVID-19 by inhibiting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease. Herein, we review studies on the neuroprotective and antiviral mechanisms of ginkgolides and bilobalide, as well as their therapeutic potential against AD and COVID-19.}, } @article {pmid36591656, year = {2022}, author = {Itzhaki, RF}, title = {COVID-19 and Alzheimer's Disease: What Is the Connection?.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {}, doi = {10.3233/JAD-220955}, pmid = {36591656}, issn = {1875-8908}, abstract = {Wang et al. found that elderly COVID-19 patients were at risk of AD. The following facts suggest a possible explanation: reactivation of herpes simplex virus type 1 (HSV1) and other herpesviruses can occur in SARS-CoV-2 patients; in cell cultures, HSV1 infection causes occurrence of many AD-like features, as does reactivation of latent HSV1 after addition of certain infectious agents; recurrent experimental reactivation of HSV1-infected mice leads to formation of the main features of AD brains, and to cognitive decline. These suggest that COVID-19 results in repeated reactivation of HSV1 in brain, with subsequent accumulation of damage and eventual development of AD.}, } @article {pmid36591549, year = {2022}, author = {Singh, A}, title = {Xanomeline and Trospium: A Potential Fixed Drug Combination (FDC) for Schizophrenia-A Brief Review of Current Data.}, journal = {Innovations in clinical neuroscience}, volume = {19}, number = {10-12}, pages = {43-47}, pmid = {36591549}, issn = {2158-8333}, abstract = {Xanomeline, a cholinergic agonist, was initially evaluated for the treatment of Alzheimer's disease and schizophrenia. However, drug development was stopped due to the severe cholinergic adverse effects. In recent years, xanomeline has been explored, along with trospium, a peripheral cholinergic antagonist, for schizophrenia. Xanomeline acts primarily as an M1/M4 agonist and might lead to improvement in all symptom types of schizophrenia. Due to its role as an antimuscarinic agent, trospium is expected to reduce the adverse effects of xanomeline. In initial studies, this combination seems to be promising in the treatment of schizophrenia. The most common side effects of this combination included constipation, dry mouth, and nausea. This article summarizes the present status of combination xanomeline and trospium in schizophrenia.}, } @article {pmid36591205, year = {2022}, author = {Akhtar, A and Gupta, SM and Dwivedi, S and Kumar, D and Shaikh, MF and Negi, A}, title = {Preclinical Models for Alzheimer's Disease: Past, Present, and Future Approaches.}, journal = {ACS omega}, volume = {7}, number = {51}, pages = {47504-47517}, pmid = {36591205}, issn = {2470-1343}, abstract = {A robust preclinical disease model is a primary requirement to understand the underlying mechanisms, signaling pathways, and drug screening for human diseases. Although various preclinical models are available for several diseases, clinical models for Alzheimer's disease (AD) remain underdeveloped and inaccurate. The pathophysiology of AD mainly includes the presence of amyloid plaques and neurofibrillary tangles (NFT). Furthermore, neuroinflammation and free radical generation also contribute to AD. Currently, there is a wide gap in scientific approaches to preventing AD progression. Most of the available drugs are limited to symptomatic relief and improve deteriorating cognitive functions. To mimic the pathogenesis of human AD, animal models like 3XTg-AD and 5XFAD are the primarily used mice models in AD therapeutics. Animal models for AD include intracerebroventricular-streptozotocin (ICV-STZ), amyloid beta-induced, colchicine-induced, etc., focusing on parameters such as cognitive decline and dementia. Unfortunately, the translational rate of the potential drug candidates in clinical trials is poor due to limitations in imitating human AD pathology in animal models. Therefore, the available preclinical models possess a gap in AD modeling. This paper presents an outline that critically assesses the applicability and limitations of the current approaches in disease modeling for AD. Also, we attempted to provide key suggestions for the best-fit model to evaluate potential therapies, which might improve therapy translation from preclinical studies to patients with AD.}, } @article {pmid36591187, year = {2022}, author = {Zhang, N and Yan, C and Yin, C and Hu, X and Guan, P and Cheng, Y}, title = {Structural Remodeling Mechanism of the Toxic Amyloid Fibrillary Mediated by Epigallocatechin-3-gallate.}, journal = {ACS omega}, volume = {7}, number = {51}, pages = {48047-48058}, pmid = {36591187}, issn = {2470-1343}, abstract = {Numerous therapeutic agents and strategies were designed targeting the therapies of Alzheimer's disease, but many have been suspended due to their severe clinical side effects (such as encephalopathy) on patients. The attractiveness for small molecules with good biocompatibility is therefore restarted. Epigallocatechin-3-gallate (EGCG), extracted from green tea, is expected to be a promising small-molecule drug candidate, which can remodel the structure of preformed β-sheet-rich oligomers/fibrils and then effectively interfere with neurodegenerative processes. However, as the structure of non-fibrillary aggregates cannot be directly characterized, the atomic details of the underlying inhibitory and destructive mechanisms still remain elusive to date. Here, all-atom molecular dynamics simulations and experiments were carried out to elucidate the EGCG-induced remodeling mechanism of amyloid β (Aβ) fibrils. We showed that EGCG was indeed an effective Aβ fibril inhibitor. EGCG was capable of mediating conformational rearrangement of Aβ1-42 fibrils (from a β-sheet to a random coil structure) and triggering the disintegration of fibrils in a dose-dependent manner. EGCG redirected the structure of Aβ by breaking the β-sheet structure and hydrogen bonds between peptide chains within the Aβ protofibrils, especially the parallel β-strand (L17VFFAEDVGS26). Moreover, reduced solvent exposure and multisite binding patterns all tended to induce the conformation conversion of Aβ17-42 pentameric protofibrils, destroying pre-formed fibrils and inhibiting continued fibril growth. Detailed data analysis revealed that structural features of EGCG with abundant benzene ring and phenolic hydroxyl moieties preferentially interact with the parallel β-strands to effectually hinder the interaction of the interpeptide chain and the growth of the ordered β-sheet structure. Furthermore, experimental studies confirmed that EGCG was able to disaggregate the preformed fibrils and alter the protein structure. This study will enable a deeper understanding of fundamental principles for design of structural-based inhibitors.}, } @article {pmid36591070, year = {2022}, author = {Park, J and Yoo, YR and Lim, Y and Sung, JE}, title = {Phonological and semantic strategies in a letter fluency task for people with Alzheimer's disease.}, journal = {Frontiers in psychology}, volume = {13}, number = {}, pages = {1053272}, pmid = {36591070}, issn = {1664-1078}, abstract = {OBJECTIVES: This study investigated whether employing a phonological or semantic strategy elicited a better performance on a letter fluency task for people with Alzheimer's disease (AD).

METHODS: Sixty participants with probable AD were extracted from the DementiaBank database. After applying exclusion criteria, 47 participants were included in the final analysis. We used phonological and semantic strategies to analyze participants' responses to the letter fluency task. The phonological strategy analysis was based on the number of switches and the mean cluster size, and the semantic strategy analysis was based on semantic relatedness, which quantified word-similarity change by adapting the concept of persistence length from analyses of DNA and protein structures. We employed Pearson correlation coefficients to determine whether any strategy indexes were significantly related to the number of correct responses and used stepwise multiple regression analyses to determine the best predictor.

RESULTS: Participants who relied on phonological strategy performed better on the letter fluency task. The number of correct responses was significantly positively correlated with phonological strategy but significantly negatively correlated with semantic strategy. The number of switches, mean cluster size, and semantic relatedness were all significant predictors, explaining 68.1% of the variance.

CONCLUSION: Our results suggested that individuals with AD who engaged in phonological strategy performed better on the letter fluency task than those who relied on semantic strategy.}, } @article {pmid36590612, year = {2022}, author = {Miao, D and Zhou, X and Wu, X and Chen, C and Tian, L}, title = {Distinct profiles of functional connectivity density aberrance in Alzheimer's disease and mild cognitive impairment.}, journal = {Frontiers in psychiatry}, volume = {13}, number = {}, pages = {1079149}, pmid = {36590612}, issn = {1664-0640}, abstract = {INTRODUCTION: Investigating the neuroimaging changes from mild cognitive impairment (MCI) to Alzheimer's disease (AD) is of great significance. However, the details about the distinct functional characteristics of AD and MCI remain unknown.

METHODS: In this study, we investigated distinct profiles of functional connectivity density (FCD) differences between AD and MCI compared with the normal population, aiming to depict the progressive brain changes from MCI to AD. As a data-driven method, FCD measures the profiles of FC for the given voxel at different scales. Resting-state functional magnetic resonance imaging (fMRI) images were obtained from patients with AD and MCI and matched healthy controls (HCs). One-way ANCOVA was used to investigate (global, long-range, and local) FCD differences among the three groups followed by post-hoc analysis controlling age, sex, and head motion.

RESULTS: The three groups exhibited significant global FCD differences in the superior frontal gyrus. The post-hoc results further showed that patients with AD had a significant increase in global FCD values than those with MCI and HCs. Patients with MCI exhibited an increased trend compared with HCs. We further identified brain regions contributing to the observed global FCD differences by conducting seed-based FC analysis. We also identified that the observed global FCD differences were the additive effects of altered FC between the superior frontal gyrus and the posterior default model network.

DISCUSSION: These results depicted the global information communication capability impairment in AD and MCI providing a new insight into the progressive brain changes from MCI to AD.}, } @article {pmid36590604, year = {2022}, author = {Guo, L and Zhang, Y and Liu, Q and Guo, K and Wang, Z}, title = {Multi-band network fusion for Alzheimer's disease identification with functional MRI.}, journal = {Frontiers in psychiatry}, volume = {13}, number = {}, pages = {1070198}, pmid = {36590604}, issn = {1664-0640}, abstract = {INTRODUCTION: The analysis of functional brain networks (FBNs) has become a promising and powerful tool for auxiliary diagnosis of brain diseases, such as Alzheimer's disease (AD) and its prodromal stage. Previous studies usually estimate FBNs using full band Blood Oxygen Level Dependent (BOLD) signal. However, a single band is not sufficient to capture the diagnostic and prognostic information contained in multiple frequency bands.

METHOD: To address this issue, we propose a novel multi-band network fusion framework (MBNF) to combine the various information (e.g., the diversification of structural features) of multi-band FBNs. We first decompose the BOLD signal adaptively into two frequency bands named high-frequency band and low-frequency band by the ensemble empirical mode decomposition (EEMD). Then the similarity network fusion (SNF) is performed to blend two networks constructed by two frequency bands together into a multi-band fusion network. In addition, we extract the features of the fused network towards a better classification performance.

RESULT: To verify the validity of the scheme, we conduct our MBNF method on the public ADNI database for identifying subjects with AD/MCI from normal controls.

DISCUSSION: Experimental results demonstrate that the proposed scheme extracts rich multi-band network features and biomarker information, and also achieves better classification accuracy.}, } @article {pmid36590531, year = {2022}, author = {Chauvière, L}, title = {Early cognitive comorbidities before disease onset: A common symptom towards prevention of related brain diseases?.}, journal = {Heliyon}, volume = {8}, number = {12}, pages = {e12259}, pmid = {36590531}, issn = {2405-8440}, abstract = {Brain diseases are very heterogeneous; however they also display multiple common risk factors and comorbidities. With a paucity of disease-modifying therapies, prevention became a health priority. Towards prevention, one strategy is to focus on similar symptoms of brain diseases occurring before disease onset. Cognitive deficits are a promising candidate as they occur across brain diseases before disease onset. Based on recent research, this review highlights the similarity of brain diseases and discusses how early cognitive deficits can be exploited to tackle disease prevention. After briefly introducing common risk factors, I review common comorbidities across brain diseases, with a focus on cognitive deficits before disease onset, reporting both experimental and clinical findings. Next, I describe network abnormalities associated with early cognitive deficits and discuss how these abnormalities can be targeted to prevent disease onset. A scenario on brain disease etiology with the idea that early cognitive deficits may constitute a common symptom of brain diseases is proposed.}, } @article {pmid36590474, year = {2022}, author = {Liu, S and Li, S and Xia, Y and Zhang, H and Tian, J and Shan, C and Pang, F and Wang, Y and Shang, Y and Chen, N}, title = {Effects of multi-mode physical stimulation on APP/PS1 Alzheimer's disease model mice.}, journal = {Heliyon}, volume = {8}, number = {12}, pages = {e12366}, pmid = {36590474}, issn = {2405-8440}, abstract = {Some researchers and clinics have reported that non-drug treatments for Alzheimer disease (AD) such as electrical stimulation, light stimulation, music stimulation, laser stimulation, and transcranial magnetic stimulation may have beneficial treatment effects. Following these findings, in this study, we performed multimodel physical stimulation on APP/PS1 mice using visible light, music with a γ rhythm, and an infrared laser. And the effects of physical stimulation on APP/PS1 mice were evaluated by behavioral analysis, the content of amyloid (Aβ40 and Aβ42), and NISSL staining of hippocampal tissue slices. The results of subsequent behavioral and tissue analyses showed that the multi-model physical stimulations could relieve APP/PS1 mice's dementia symptoms, such as the behavior ability, the content of Aβ40 and Aβ42 in the hippocampal tissue suspension, and Nissl staining for hippocampal tissue analyses.}, } @article {pmid36590421, year = {2022}, author = {Huang, Z and Liu, K and Ma, W and Li, D and Mo, T and Liu, Q}, title = {The gut microbiome in human health and disease-Where are we and where are we going? A bibliometric analysis.}, journal = {Frontiers in microbiology}, volume = {13}, number = {}, pages = {1018594}, pmid = {36590421}, issn = {1664-302X}, abstract = {BACKGROUND: There are trillions of microbiota in our intestinal tract, and they play a significant role in health and disease via interacting with the host in metabolic, immune, neural, and endocrine pathways. Over the past decades, numerous studies have been published in the field of gut microbiome and disease. Although there are narrative reviews of gut microbiome and certain diseases, the whole field is lack of systematic and quantitative analysis. Therefore, we outline research status of the gut microbiome and disease, and present insights into developments and characteristics of this field to provide a holistic grasp and future research directions.

METHODS: An advanced search was carried out in the Web of Science Core Collection (WoSCC), basing on the term "gut microbiome" and its synonyms. The current status and developing trends of this scientific domain were evaluated by bibliometric methodology. CiteSpace was used to perform collaboration network analysis, co-citation analysis and citation burst detection.

RESULTS: A total of 29,870 articles and 13,311 reviews were retrieved from the database, which involve 42,900 keywords, 176 countries/regions, 19,065 institutions, 147,225 authors and 4,251 journals. The gut microbiome and disease research is active and has received increasing attention. Co-cited reference analysis revealed the landmark articles in the field. The United States had the largest number of publications and close cooperation with other countries. The current research mainly focuses on gastrointestinal diseases, such as inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease (CD), while extra-intestinal diseases are also rising, such as obesity, diabetes, cardiovascular disease, Alzheimer's disease, Parkinson's disease. Omics technologies, fecal microbiota transplantation (FMT) and metabolites linked to mechanism would be more concerned in the future.

CONCLUSION: The gut microbiome and disease has been a booming field of research, and the trend is expected to continue. Overall, this research field shows a multitude of challenges and great opportunities.}, } @article {pmid36590326, year = {2023}, author = {Leanza, G and Zorec, R}, title = {Towards Astroglia-based Noradrenergic Hypothesis of Alzheimer's Disease.}, journal = {Function (Oxford, England)}, volume = {4}, number = {1}, pages = {zqac060}, pmid = {36590326}, issn = {2633-8823}, mesh = {Humans ; *Alzheimer Disease ; Astrocytes ; Norepinephrine ; Locus Coeruleus ; }, } @article {pmid36590248, year = {2023}, author = {Rasmi, Y and Shokati, A and Hassan, A and Aziz, SG and Bastani, S and Jalali, L and Moradi, F and Alipour, S}, title = {The role of DNA methylation in progression of neurological disorders and neurodegenerative diseases as well as the prospect of using DNA methylation inhibitors as therapeutic agents for such disorders.}, journal = {IBRO neuroscience reports}, volume = {14}, number = {}, pages = {28-37}, pmid = {36590248}, issn = {2667-2421}, abstract = {UNLABELLED: Genome-wide studies related to neurological disorders and neurodegenerative diseases have pointed to the role of epigenetic changes such as DNA methylation, histone modification, and noncoding RNAs. DNA methylation machinery controls the dynamic regulation of methylation patterns in discrete brain regions.

OBJECTIVE: This review aims to describe the role of DNA methylation in inhibiting and progressing neurological and neurodegenerative disorders and therapeutic approaches.

METHODS: A Systematic search of PubMed, Web of Science, and Cochrane Library was conducted for all qualified studies from 2000 to 2022.

RESULTS: For the current need of time, we have focused on the DNA methylation role in neurological and neurodegenerative diseases and the expression of genes involved in neurodegeneration such as Alzheimer's, Depression, and Rett Syndrome. Finally, it appears that the various epigenetic changes do not occur separately and that DNA methylation and histone modification changes occur side by side and affect each other. We focused on the role of modification of DNA methylation in several genes associated with depression (NR3C1, NR3C2, CRHR1, SLC6A4, BDNF, and FKBP5), Rett syndrome (MECP2), Alzheimer's, depression (APP, BACE1, BIN1 or ANK1) and Parkinson's disease (SNCA), as well as the co-occurring modifications to histones and expression of non-coding RNAs. Understanding these epigenetic changes and their interactions will lead to better treatment strategies.

CONCLUSION: This review captures the state of understanding of the epigenetics of neurological and neurodegenerative diseases. With new epigenetic mechanisms and targets undoubtedly on the horizon, pharmacological modulation and regulation of epigenetic processes in the brain holds great promise for therapy.}, } @article {pmid36590218, year = {2022}, author = {Ikeuchi, T and Kanda, M and Kitamura, H and Morikawa, F and Toru, S and Nishimura, C and Kasuga, K and Tokutake, T and Takahashi, T and Kuroha, Y and Miyazawa, N and Tanaka, S and Utsumi, K and Ono, K and Yano, S and Hamano, T and Naruse, S and Yajima, R and Kawashima, N and Kaneko, C and Tachibana, H and Yano, Y and Kato, Y and Toue, S and Jinzu, H and Kitamura, A and Yokoyama, Y and Kaneko, E and Yamakado, M and Nagao, K}, title = {Decreased circulating branched-chain amino acids are associated with development of Alzheimer's disease in elderly individuals with mild cognitive impairment.}, journal = {Frontiers in nutrition}, volume = {9}, number = {}, pages = {1040476}, pmid = {36590218}, issn = {2296-861X}, abstract = {BACKGROUND: Nutritional epidemiology has shown that inadequate dietary protein intake is associated with poor brain function in the elderly population. The plasma free amino acid (PFAA) profile reflects nutritional status and may have the potential to predict future changes in cognitive function. Here, we report the results of a 2-year interim analysis of a 3-year longitudinal study following mild cognitive impairment (MCI) participants.

METHOD: In a multicenter prospective cohort design, MCI participants were recruited, and fasting plasma samples were collected. Based on clinical assessment of cognitive function up to 2 years after blood collection, MCI participants were divided into two groups: remained with MCI or reverted to cognitively normal ("MCI-stable," N = 87) and converted to Alzheimer's disease (AD) ("AD-convert," N = 68). The baseline PFAA profile was compared between the two groups. Stratified analysis based on apolipoprotein E ε4 (APOE ε4) allele possession was also conducted.

RESULTS: Plasma concentrations of all nine essential amino acids (EAAs) were lower in the AD-convert group. Among EAAs, three branched-chain amino acids (BCAAs), valine, leucine and isoleucine, and histidine (His) exhibited significant differences even in the logistic regression model adjusted for potential confounding factors such as age, sex, body mass index (BMI), and APOE ε4 possession (p < 0.05). In the stratified analysis, differences in plasma concentrations of these four EAAs were more pronounced in the APOE ε4-negative group.

CONCLUSION: The PFAA profile, especially decreases in BCAAs and His, is associated with development of AD in MCI participants, and the difference was larger in the APOE ε4-negative population, suggesting that the PFAA profile is an independent risk indicator for AD development. Measuring the PFAA profile may have importance in assessing the risk of AD conversion in the MCI population, possibly reflecting nutritional status.

CLINICAL TRIAL REGISTRATION: [https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000025322], identifier [UMIN000021965].}, } @article {pmid36590098, year = {2022}, author = {Nguyen, D and Nguyen, H and Ong, H and Le, H and Ha, H and Duc, NT and Ngo, HT}, title = {Ensemble learning using traditional machine learning and deep neural network for diagnosis of Alzheimer's disease.}, journal = {IBRO neuroscience reports}, volume = {13}, number = {}, pages = {255-263}, pmid = {36590098}, issn = {2667-2421}, abstract = {In recent years, Alzheimer's disease (AD) diagnosis using neuroimaging and deep learning has drawn great research attention. However, due to the scarcity of training neuroimaging data, many deep learning models have suffered from severe overfitting. In this study, we propose an ensemble learning framework that combines deep learning and machine learning. The deep learning model was based on a 3D-ResNet to exploit 3D structural features of neuroimaging data. Meanwhile, Extreme Gradient Boosting (XGBoost) machine learning was applied on a voxel-wise basis to draw the most significant voxel groups out of the image. The 3D-ResNet and XGBoost predictions were combined with patient demographics and cognitive test scores (Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR)) to give a final diagnosis prediction. Our proposed method was trained and validated on brain MRI brain images of the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. During the training phase, multiple data augmentation methods were employed to tackle overfitting. Our test set contained only baseline scans, i.e., the first visit scans since we aimed to investigate the ability of our approach in detecting AD during the first visit of AD patients. Our 5-fold cross-validation implementation achieved an average AUC of 100% during training and 96% during testing. Using the same computer, our method was much faster in scoring a prediction, approximately 10 min, than feature extraction-based machine learning methods, which often take many hours to score a prediction. To make the prediction explainable, we visualized the brain MRI image regions that primarily affected the 3D-ResNet model's prediction via heatmap. Lastly, we observed that proper generation of test sets was critical to avoiding the data leakage issue and ensuring the validity of results.}, } @article {pmid36590097, year = {2022}, author = {Komal, P and Manjari, SKV and Nashmi, R}, title = {An opinion on the debatable function of brain resident immune protein, T-cell receptor beta subunit in the central nervous system.}, journal = {IBRO neuroscience reports}, volume = {13}, number = {}, pages = {235-242}, pmid = {36590097}, issn = {2667-2421}, abstract = {In recent years scientific research has established that the nervous and immune systems have shared molecular signaling components. Proteins native to immune cells, which are also found in the brain, have neuronal functions in the nervous system where they affect synaptic plasticity, axonal regeneration, neurogenesis, and neurotransmission. Certain native immune molecules like major histocompatibility complex I (MHC-I), paired immunoglobulin receptor B (PirB), toll-like receptor (TLR), cluster of differentiation-3 zeta (CD3ζ), CD4 co-receptor, and T-cell receptor beta (TCR-β) expression in neurons have been extensively documented. In this review, we provide our opinion and discussed the possible roles of T-cell receptor beta subunits in modulating the function of neurons in the central nervous system. Based on the previous findings of Syken and Shatz., 2003; Nishiyori et al., 2004; Rodriguez et., 1993 and Komal et., 2014; we discuss whether restrictive expression of TCR-β subunits in selected brain regions could be involved in the pathology of neurological disorders and whether their aberrant enhancement in expression may be considered as a suitable biomarker for aging or neurodegenerative diseases like Huntington's disease (HD).}, } @article {pmid36590090, year = {2022}, author = {Yeung, JHY and Palpagama, TH and Turner, C and Waldvogel, HJ and Faull, RLM and Kwakowsky, A}, title = {mGluR1α expression in the hippocampus, subiculum, entorhinal cortex and superior temporal gyrus in Alzheimer's disease.}, journal = {IBRO neuroscience reports}, volume = {13}, number = {}, pages = {78-86}, pmid = {36590090}, issn = {2667-2421}, abstract = {Glutamate is the main excitatory neurotransmitter in the central nervous system, responsible for a plethora of cellular processes including memory formation and higher cerebral function and has been implicated in various neurological disease states. Alzheimer's disease (AD) is the leading neurodegenerative disorder worldwide and is characterized by significant cell loss and glutamatergic dysfunction. While there has been a focus on ionotropic glutamatergic receptors few studies have attempted to elucidate the pathological changes of metabotropic glutamate receptors (mGluRs) in AD. mGluRs are G-protein coupled receptors which have a wide-ranging functionality, including the regulation of neuronal injury and survival. In particular, the group I mGluRs (mGluR1 and mGluR5) are associated with ionotropic receptor activation and upregulation with resultant glutamate release in normal neuronal functioning. The mGluR subtype 1 splice variant a (mGluR1α) is the longest variant of the mGluR1 receptor, is localized to dendritic processes and is mainly plasma membrane-bound. Activation of mGluR1a has been shown to result in increased constitutive activity of ionotropic receptors, although its role in neurodegenerative and other neurological diseases is controversial, with some animal studies demonstrating potential neuroprotective properties in excito- and neurotoxic environments. In this study, the expression of mGluR1a within normal and AD human hippocampal tissue was quantified using immunohistochemistry. We found a significantly reduced expression of mGluR1α within the stratum pyramidale and radiatum of the CA1subregion, subiculum, and entorhinal cortex. This downregulation could result in potential dysregulation of the glutamatergic system with consequences on AD progression by promoting excitotoxicity, but alternatively may also be a neuroprotective mechanism to prevent mGluR1α associated excitotoxic effects. In summary, more research is required to understand the role and possible consequences of mGluR1α downregulation in the human AD hippocampus, subiculum and entorhinal cortex and its potential as a therapeutic target.}, } @article {pmid36590062, year = {2022}, author = {Huang, J and Jung, JY and Nam, CS}, title = {Estimating effective connectivity in Alzheimer's disease progression: A dynamic causal modeling study.}, journal = {Frontiers in human neuroscience}, volume = {16}, number = {}, pages = {1060936}, pmid = {36590062}, issn = {1662-5161}, abstract = {INTRODUCTION: Alzheimer's disease (AD) affects the whole brain from the cellular level to the entire brain network structure. The causal relationship among brain regions concerning the different AD stages is not yet investigated. This study used Dynamic Causal Modeling (DCM) method to assess effective connectivity (EC) and investigate the changes that accompany AD progression.

METHODS: We included the resting-state fMRI data of 34 AD patients, 31 late mild cognitive impairment (LMCI) patients, 34 early MCI (EMCI) patients, and 31 cognitive normal (CN) subjects selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The parametric Empirical Bayes (PEB) method was used to infer the effective connectivities and the corresponding probabilities. A linear regression analysis was carried out to test if the connection strengths could predict subjects' cognitive scores.

RESULTS: The results showed that the connections reduced from full connection in the CN group to no connection in the AD group. Statistical analysis showed the connectivity strengths were lower for later-stage patients. Linear regression analysis showed that the connection strengths were partially predictive of the cognitive scores.

DISCUSSION: Our results demonstrated the dwindling connectivity accompanying AD progression on causal relationships among brain regions and indicated the potential of EC as a loyal biomarker in AD progression.}, } @article {pmid36589809, year = {2022}, author = {Lin, Y and Wang, Y and Li, PF}, title = {PPARα: An emerging target of metabolic syndrome, neurodegenerative and cardiovascular diseases.}, journal = {Frontiers in endocrinology}, volume = {13}, number = {}, pages = {1074911}, pmid = {36589809}, issn = {1664-2392}, mesh = {Humans ; *Cardiovascular Diseases/drug therapy/genetics/metabolism ; Fenofibrate/pharmacology/therapeutic use ; *Metabolic Syndrome/drug therapy/genetics/metabolism ; *Neurodegenerative Diseases/drug therapy/genetics/metabolism ; *PPAR alpha/genetics/agonists/metabolism ; }, abstract = {Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that is involved in lipid metabolism of various tissues. Different metabolites of fatty acids and agonists like fibrates activate PPARα for its transactivative or repressive function. PPARα is known to affect diverse human diseases, and we focus on advanced studies of its transcriptional regulation in these diseases. In MAFLD, PPARα shows a protective function with its upregulation of lipid oxidation and mitochondrial biogenesis and transcriptional repression of inflammatory genes, which is similar in Alzheimer's disease and cardiovascular disease. Activation of PPARα also prevents the progress of diabetes complications; however, its role in diabetes and cancers remains uncertain. Some PPARα-specific agonists, such as Wy14643 and fenofibrate, have been applied in metabolic syndrome treatment, which might own potential in wider application. Future studies may further explore the functions and interventions of PPARα in cancer, diabetes, immunological diseases, and neurodegenerative disease.}, } @article {pmid36589695, year = {2022}, author = {Chan, AWS and Cho, IK and Li, CX and Zhang, X and Patel, S and Rusnak, R and Raper, J and Bachevalier, J and Moran, SP and Chi, T and Cannon, KH and Hunter, CE and Martin, RC and Xiao, H and Yang, SH and Gumber, S and Herndon, JG and Rosen, RF and Hu, WT and Lah, JJ and Levey, AI and Smith, Y and Walker, LC}, title = {Cerebral Aβ deposition in an Aβ-precursor protein-transgenic rhesus monkey.}, journal = {Aging brain}, volume = {2}, number = {}, pages = {}, pmid = {36589695}, issn = {2589-9589}, support = {P50 AG025688/AG/NIA NIH HHS/United States ; P51 OD011132/OD/NIH HHS/United States ; R24 OD010930/OD/NIH HHS/United States ; }, abstract = {With the ultimate goal of developing a more representative animal model of Alzheimer's disease (AD), two female amyloid-β-(Aβ) precursor protein-transgenic (APPtg) rhesus monkeys were generated by lentiviral transduction of the APP gene into rhesus oocytes, followed by in vitro fertilization and embryo transfer. The APP-transgene included the AD-associated Swedish K670N/M671L and Indiana V717F mutations (APPSWE/IND) regulated by the human polyubiquitin-C promoter. Overexpression of APP was confirmed in lymphocytes and brain tissue. Upon sacrifice at 10 years of age, one of the monkeys had developed Aβ plaques and cerebral Aβ-amyloid angiopathy in the occipital, parietal, and caudal temporal neocortices. The induction of Aβ deposition more than a decade prior to its usual emergence in the rhesus monkey supports the feasibility of creating a transgenic nonhuman primate model for mechanistic analyses and preclinical testing of treatments for Alzheimer's disease and cerebrovascular amyloidosis.}, } @article {pmid36589552, year = {2022}, author = {Galvez, EJ and Sharma, B and Williams, FK and You, CJ and Khajavi, B and Castrillon, J and Shi, L and Mamani, S and Sordillo, LA and Zhang, L and Alfano, RR}, title = {Decoherence of photon entanglement by transmission through brain tissue with Alzheimer's disease.}, journal = {Biomedical optics express}, volume = {13}, number = {12}, pages = {6621-6630}, pmid = {36589552}, issn = {2156-7085}, abstract = {The generation, manipulation and quantification of non-classical light, such as quantum-entangled photon pairs, differs significantly from methods with classical light. Thus, quantum measures could be harnessed to give new information about the interaction of light with matter. In this study we investigate if quantum entanglement can be used to diagnose disease. In particular, we test whether brain tissue from subjects suffering from Alzheimer's disease can be distinguished from healthy tissue. We find that this is indeed the case. Polarization-entangled photons traveling through brain tissue lose their entanglement via a decohering scattering interaction that gradually renders the light in a maximally mixed state. We found that in thin tissue samples (between 120 and 600 micrometers) photons decohere to a distinguishable lesser degree in samples with Alzheimer's disease than in healthy-control ones. Thus, it seems feasible that quantum measures of entangled photons could be used as a means to identify brain samples with the neurodegenerative disease.}, } @article {pmid36589543, year = {2022}, author = {Ma, N and Liang, Y and Yue, L and Liu, P and Xu, Y and Zhu, C}, title = {The identities of insulin signaling pathway are affected by overexpression of Tau and its phosphorylation form.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1057281}, pmid = {36589543}, issn = {1663-4365}, abstract = {INTRODUCTION: Hyperphosphorylated Tau formed neurofibrillary tangles was one of the major neuropathological hallmarks of Alzheimer's disease (AD). Dysfunctional insulin signaling in brain is involved in AD. However, the effect of Tau pathology on brain insulin resistance remains unclear. This study explored the effects of overexpressing wild-type Tau (WTau) or Tau with pseudo-phosphorylation at AT8 residues (PTau) on the insulin signaling pathway (ISP).

METHODS: 293T cells or SY5Y cells overexpressing WTau or PTau were treated with or without insulin. The elements in ISP or the regulators of IPS were analyzed by immunoblotting, immunofluorescent staining and co-immunoprecipitation. Akt inhibitor MK2206 was used for evaluating the insulin signaling to downstream of mTOR in Tau overexpressing cells. The effects of anti-aging drug lonafarnib on ISP in WTau or PTau cells were also analyzed with immunoblotting. Considering lonafarnib is an inhibitor of FTase, the states of Rhes, one of FTase substrate in WTau or PTau cells were analyzed by drug affinity responsive target stability (DARTS) assay and the cellular thermal shift assay (CETSA).

RESULTS: WTau or PTau overexpression in cells upregulated basal activity of elements in ISP in general. However, overexpression of WTau or PTau suppressed the ISP signaling transmission responses induced by insulin simulation, appearing relative higher response of IRS-1 phosphorylation at tyrosine 612 (IRS-1 p612) in upstream IPS, but a lower phosphorylation response of downstream IPS including mTOR, and its targets 4EPB1 and S6. This dysregulation of insulin evoked signaling transmission was more obvious in PTau cells. Suppressing Akt with MK2206 could compromise the levels of p-S6 and p-mTOR in WTau or PTau cells. Moreover, the changes of phosphatases detected in WTau and PTau cells may be related to ISP dysfunction. In addition, the effects of lonafarnib on the ISP in SY5Y cells with WTau and PTau overexpression were tested, which showed that lonafarnib treatment resulted in reducing the active levels of ISP elements in PTau cells but not in WTau cells. The differential effects are probably due to Tau phosphorylation modulating lonafarnib-induced alterations in Rhes, as revealed by DARTS assay.

CONCLUSION AND DISCUSSION: Overexpression of Tau or Tau with pseudo-phosphorylation at AT8 residues could cause an upregulation of the basal/tonic ISP, but a suppression of insulin induced the phasic activation of ISP. This dysfunction of ISP was more obvious in cells overexpressing pseudo-phosphorylated Tau. These results implied that the dysfunction of ISP caused by Tau overexpression might impair the physiological fluctuation of neuronal functions in AD. The different effects of lonafarnib on ISP between WTau and PTau cells, indicating that Tau phosphorylation mediates an additional effect on ISP. This study provided a potential linkage of abnormal expression and phosphorylation of Tau to the ISP dysfunction in AD.}, } @article {pmid36589542, year = {2022}, author = {Ali, N and Liu, J and Tian, H and Pan, W and Tang, Y and Zhong, Q and Gao, Y and Xiao, M and Wu, H and Sun, C and Wu, T and Yang, X and Wang, T and Zhu, Y}, title = {A novel dual-task paradigm with story recall shows significant differences in the gait kinematics in older adults with cognitive impairment: A cross-sectional study.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {992873}, pmid = {36589542}, issn = {1663-4365}, abstract = {OBJECTIVE: Cognitive and motor dysfunctions in older people become more evident while dual-tasking. Several dual-task paradigms have been used to identify older individuals at the risk of developing Alzheimer's disease and dementia. This study evaluated gait kinematic parameters for dual-task (DT) conditions in older adults with mild cognitive impairment (MCI), subjective cognitive decline (SCD), and normal cognition (NC).

METHOD: This is a cross-sectional, clinical-based study carried out at the Zhongshan Rehabilitation Branch of First Affiliated Hospital of Nanjing Medical University, China.

PARTICIPANTS: We recruited 83 community-dwelling participants and sorted them into MCI (n = 24), SCD (n = 33), and NC (n = 26) groups based on neuropsychological tests. Their mean age was 72.0 (5.55) years, and male-female ratio was 42/41 (p = 0.112). Each participant performed one single-task walk and four DT walks: DT calculation with subtracting serial sevens; DT naming animals; DT story recall; and DT words recall.

OUTCOME AND MEASURES: Kinematic gait parameters of speed, knee peak extension angle, and dual-task cost (DTC) were obtained using the Vicon Nexus motion capture system and calculated by Visual 3D software. A mixed-effect linear regression model was used to analyze the data.

RESULTS: The difference in gait speed under DT story recall and DT calculation was -0.099 m/s and - 0.119 m/s (p = 0.04, p = 0.013) between MCI and SCD, respectively. Knee peak extension angle under DT story recall, words recall, and single task was bigger in the MCI group compared to the NC group, respectively (p = 0.001, p = 0.001, p = 0.004). DTC was higher in the DT story recall test than all other DT conditions (p < 0.001).

CONCLUSION: Kinematic gait parameters of knee peak extension angle for the DT story recall were found to be sensitive enough to discriminate MCI individuals from NC group. DTC under DT story recall was higher than the other DT conditions.}, } @article {pmid36589536, year = {2022}, author = {Manippa, V and Palmisano, A and Filardi, M and Vilella, D and Nitsche, MA and Rivolta, D and Logroscino, G}, title = {An update on the use of gamma (multi)sensory stimulation for Alzheimer's disease treatment.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1095081}, pmid = {36589536}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) is characterized by reduced fast brain oscillations in the gamma band (γ, > 30 Hz). Several animal studies show that inducing gamma oscillations through (multi)sensory stimulation at 40 Hz has the potential to impact AD-related cognitive decline and neuropathological processes, including amyloid plaques deposition, neurofibrillary tangles formation, and neuronal and synaptic loss. Therefore Gamma Entrainment Using Sensory stimulation (GENUS) is among the most promising approaches for AD patients' treatment. This review summarizes the evidence on GENUS effectiveness, from animal models to AD patients. Despite the application on human is in its infancy, the available findings suggest its feasibility for the treatment of AD. We discuss such results in light of parameter improvement and possible underlying mechanisms. We finally emphasize the need for further research for its development as a disease-modifying non-pharmacological intervention.}, } @article {pmid36589440, year = {2022}, author = {Kopp, W}, title = {Pathogenesis of (smoking-related) non-communicable diseases-Evidence for a common underlying pathophysiological pattern.}, journal = {Frontiers in physiology}, volume = {13}, number = {}, pages = {1037750}, pmid = {36589440}, issn = {1664-042X}, abstract = {Non-communicable diseases, like diabetes, cardiovascular diseases, cancer, stroke, chronic obstructive pulmonary disease, osteoporosis, arthritis, Alzheimer's disease and other more are a leading cause of death in almost all countries. Lifestyle factors, especially poor diet and tobacco consumption, are considered to be the most important influencing factors in the development of these diseases. The Western diet has been shown to cause a significant distortion of normal physiology, characterized by dysregulation of the sympathetic nervous system, renin-angiotensin aldosterone system, and immune system, as well as disruption of physiological insulin and oxidant/antioxidant homeostasis, all of which play critical roles in the development of these diseases. This paper addresses the question of whether the development of smoking-related non-communicable diseases follows the same pathophysiological pattern. The evidence presented shows that exposure to cigarette smoke and/or nicotine causes the same complex dysregulation of physiology as described above, it further shows that the factors involved are strongly interrelated, and that all of these factors play a key role in the development of a broad spectrum of smoking-related diseases. Since not all smokers develop one or more of these diseases, it is proposed that this disruption of normal physiological balance represents a kind of pathogenetic "basic toolkit" for the potential development of a range of non-communicable diseases, and that the decision of whether and what disease will develop in an individual is determined by other, individual factors ("determinants"), such as the genome, epigenome, exposome, microbiome, and others. The common pathophysiological pattern underlying these diseases may provide an explanation for the often poorly understood links between non-communicable diseases and disease comorbidities. The proposed pathophysiological process offers new insights into the development of non-communicable diseases and may influence the direction of future research in both prevention and therapy.}, } @article {pmid36589242, year = {2022}, author = {Faris, S and Jin, W and Gibson, J and Murray, A and Smith, N and He, P and Zhang, F and Linhardt, R and Wang, C}, title = {Small-molecule compound from AlphaScreen disrupts tau-glycan interface.}, journal = {Frontiers in molecular biosciences}, volume = {9}, number = {}, pages = {1083225}, pmid = {36589242}, issn = {2296-889X}, support = {RF1 AG069039/AG/NIA NIH HHS/United States ; T32 AG057464/AG/NIA NIH HHS/United States ; }, abstract = {Tauopathies are neurodegenerative diseases characterized by intracellular abnormal tau deposits in the brain. Tau aggregates can propagate from one neuron to another in a prion-like manner, mediated by the interaction between tau and cell surface heparan sulfate proteoglycans. We developed an AlphaScreen assay, with His-tagged tau and biotinylated heparin, to represent the tau-HS interface to target the tau-glycan interface. Using our AlphaScreen assay, with a Z-factor of 0.65, we screened ∼300 compounds and discovered a small-molecule compound (herein referred to as A9), which can disrupt the tau-heparin interaction with micromolar efficacy. A9 also effectively inhibited heparin-induced tau aggregation in Thioflavin T fluorescence assays and attenuated tau internalization by H4 neuroglioma cells. These results strongly suggest that A9 can disrupt the tau-glycan interface in both in vitro molecular and cellular environments. We further determined that A9 interacts with heparin rather than tau and does so with micromolar binding affinity as shown by nuclear magnetic resonance and surface plasmon resonance experiments. A9 binds to heparin in a manner that blocks the sites where tau binds to heparin on the cell surface. These results demonstrate our AlphaScreen method as an effective method for targeting the tau-glycan interface in drug discovery and A9 as a promising lead compound for tauopathies, including Alzheimer's disease.}, } @article {pmid36589231, year = {2022}, author = {Kasimir, F and Toomey, D and Liu, Z and Kaiping, AC and Ariza, ME and Prusty, BK}, title = {Tissue specific signature of HHV-6 infection in ME/CFS.}, journal = {Frontiers in molecular biosciences}, volume = {9}, number = {}, pages = {1044964}, pmid = {36589231}, issn = {2296-889X}, abstract = {First exposure to various human herpesviruses (HHVs) including HHV-6, HCMV and EBV does not cause a life-threatening disease. In fact, most individuals are frequently unaware of their first exposure to such pathogens. These herpesviruses acquire lifelong latency in the human body where they show minimal genomic activity required for their survival. We hypothesized that it is not the latency itself but a timely, regionally restricted viral reactivation in a sub-set of host cells that plays a key role in disease development. HHV-6 (HHV-6A and HHV-6B) and HHV-7 are unique HHVs that acquire latency by integration of the viral genome into sub-telomeric region of human chromosomes. HHV-6 reactivation has been linked to Alzheimer's Disease, Chronic Fatigue Syndrome, and many other diseases. However, lack of viral activity in commonly tested biological materials including blood or serum strongly suggests tissue specific localization of active HHV-6 genome. Here in this paper, we attempted to analyze active HHV-6 transcripts in postmortem tissue biopsies from a small cohort of ME/CFS patients and matched controls by fluorescence in situ hybridization using a probe against HHV-6 microRNA (miRNA), miR-aU14. Our results show abundant viral miRNA in various regions of the human brain and associated neuronal tissues including the spinal cord that is only detected in ME/CFS patients and not in controls. Our findings provide evidence of tissue-specific active HHV-6 and EBV infection in ME/CFS, which along with recent work demonstrating a possible relationship between herpesvirus infection and ME/CFS, provide grounds for renewed discussion on the role of herpesviruses in ME/CFS.}, } @article {pmid36589021, year = {2022}, author = {Shirdel, S and Esmaeeli, S and Alavi, K and Ghaemmaghami, P and Shariat, SV}, title = {Verbal Fluency Performance in Normal Adult Population in Iran: Norms and Effects of Age, Education, and Gender.}, journal = {Basic and clinical neuroscience}, volume = {13}, number = {1}, pages = {129-138}, pmid = {36589021}, issn = {2008-126X}, abstract = {INTRODUCTION: Verbal fluency is a cognitive function that can be easily assessed at the bedside and provide valuable data for clinical assessment of various cognitive functions. We decided to provide a standardized test to assess verbal fluency in the Persian language, including both phonemic and semantic fluency subtests.

METHODS: First, three phonemes (/p/, /d/, and /ʃ/) and three categories (animals, fruits, and kitchen appliances) were selected based on a pilot study and a panel of specialists. Then, we selected 500 Persian-speaking participants (47.8% male) aged 18 to 65 years via a convenient sampling method from the general population. Participants were grouped according to age, gender, and education. They performed the verbal fluency test.

RESULTS: The Mean±SD number of generated words in letter fluency and semantic fluency was 8.3±4.1 and 18.0±5.5, respectively. Age, educational level, and mother tongue were associated with letter fluency. Semantic fluency was associated with age, gender, education level, and mother tongue.

CONCLUSION: For a more reliable clinical assessment, we suggest using all three letters (phonemes) and three semantic categories for each subject, calculating the mean of the produced words, and comparing them with the suggested cut-off points provided for each subcategory. Age was negatively correlated with the number of generated words in letter fluency (r=-0.33; P<0.001) and semantic fluency tasks (r=-0.26; P<0.001). In the letter fluency task, there was no statistically significant difference between males and females according to the number of generated words (P=0.057). However, in semantic fluency, female participants generated more words (P=0.005). Mother tongue (Farsi) showed a significant effect both on letter fluency (t=5.55, P<0.001) and semantic fluency (t=9.41, P<0.001). Level of education had a significant association with both letter fluency (F=117.23, P<0.001) and semantic fluency (F=64.48, P<0.001).

HIGHLIGHTS: The study subjects generated 8.3±4.1 words in one minute in the letter fluency test.Letter fluency was associated with educational level and mother tongue.The Mean±SD number of generated words in semantic fluency (18±5.5) was higher than letter fluency.Semantic fluency was associated with age, gender, education level, and mother tongue.

PLAIN LANGUAGE SUMMARY: Practitioners use neuropsychological tests to diagnose mental problems. Verbal fluency is a test in which participants have to generate as many words as possible from a specified category in a given time. This category can be phonemic (letter), which means words beginning with a specified letter or semantic, including objects such as animals or fruits. The number of words produced by participants is essential, and if it is fewer than normal, it shows psychological or neurological conditions such as Alzheimer disease. The norms are variable in different languages, cultures, and educational levels. We found that the Mean±SD numbers of generated words in letter fluency and semantic fluency were 8.3±4.1 and 18.0±5.5, respectively. These values can be used for neuropsychological testing in the Iranian population.}, } @article {pmid36589020, year = {2022}, author = {Sahraei, R and Aminyavari, S and Hosseini, M and Hassanzadeh-Taheri, M and Foadoddini, M and Saebipour, MR}, title = {The Ameliorative Impact of Centella asiatica on the Working Memory Deficit in Streptozotocin-induced Rat Model of Alzheimer Disease.}, journal = {Basic and clinical neuroscience}, volume = {13}, number = {1}, pages = {25-34}, pmid = {36589020}, issn = {2008-126X}, abstract = {INTRODUCTION: Alzheimer disease (AD) is a complex neurodegenerative disorder with a progressive nature leading to neural damage and cognitive and memory deficit. The present study investigated the neuroprotective effects of Centella asiatica (CA) in Streptozotocin (STZ)-induced rat model of memory impairment and neuronal damage.

METHODS: The intracerebroventricular infusion of STZ (3 mg/rat) or saline (as the vehicle) was performed on days 1 and 3. CA (150 and 300 mg/kg/d) was administered through oral gavage for 21 days after model induction. We used the Y-maze test to assess the working memory-related performances of animals. Rats were then sacrificed, and their hippocampi were harvested for evaluation of neuronal density in the cornu ammonis (CA1, CA2, CA3) and Dentate Gyrus (DG) regions using stereology technique.

RESULTS: The intracerebroventricular infusion of STZ caused significant working memory impairment demonstrated in the Y-maze apparatus, with a significant decrease in alternative behavior compared to control animals (40.67±2.04 vs 73.00±1.88, P<0.0001). Oral administration of CA (150 and 300 mg/kg each day) for 21 days significantly improved STZ-induced working memory deficit (55.33±3.34 and 57.17±3.81 vs 40.67±2.04, P<0.013, P<0.004, respectively). Furthermore, 21 days of consecutive administration of CA significantly ameliorated STZ-induced neuronal loss in the CA1, CA2, and DG subfields of the hippocampus.

CONCLUSION: Overall, these data demonstrate that CA increases neuronal density and improves cognitive impairment in the STZ-induced rat model of AD, thereby having promising therapeutic potential for neurodegenerative disorders. Accordingly, further studies are needed to determine the exact molecular mechanism of CA protective effects in brain disorders, particularly AD.

HIGHLIGHTS: Centella asiatica (CA) improved the STZ-induced working memory deficit.CA could prevent hippocampal neural cell loss dose-dependent manner.CA improved memory through mitigating neuronal loss in hippocampus.

PLAIN LANGUAGE SUMMARY: Memory loss is the first signs of dementia. It is well known that a healthy diet might be as good for your brain as it is for your heart. Numerous traditionally used medicinal herbs could significantly affect key events culminating in dementia and Alzheimer's disease. Centella asiatica, commonly known as Gotu Kola or Indian Pennywort, is a tropical, medicinal plant native to Southeast Asian countries. It is one of the becoming popular medicinal plants in the world. Centella asiatica (CA) is widely used in different traditional medicine systems for various purposes, such as reducing blood pressure, memory enhancement, and promoting longevity. In the present study, we tested the possible impact of CA leaf and stem extract in an animal model of memory damage. Memory impairment was induced in adult rats by intracerebral infusion of a neurotoxin chemical. Then, the memory-impaired animals were orally treated with 150-300 mg/kg of CA extract for 21 days. Finally, we tested their working memory by placing them in a Y-maze apparatus. Furthermore, their most involved brain part (hippocampus) was dissected, and its cell density was evaluated. Our findings exhibited that CA treatment considerably improved rats' memory performance, indicating by enhancing working memory score in the Y-maze task. In addition, CA treatment significantly prevented neuronal cell loss in the hippocampus of memory-impaired rats. This study shows that CA has beneficial effects on memory and cognitive function.}, } @article {pmid36588906, year = {2022}, author = {Lv, YN and Cui, Y and Zhang, B and Huang, SM}, title = {Sleep deficiency promotes Alzheimer's disease development and progression.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {1053942}, pmid = {36588906}, issn = {1664-2295}, abstract = {Sleep disorders are a common health problem in modern society. Long-term sleep deficiency increases the risk for Alzheimer's disease. However, the exact mechanisms by which sleep deficiency affects Alzheimer's disease remain unclear. Therefore, we reviewed the relevant studies and investigated the role of sleep deprivation in Alzheimer's disease pathogenesis. Sleep deficiency was found to be associated with oxidative stress, β-amyloid protein deposition, tau hyperphosphorylation, and neuroinflammation, which are known to increase the risk for Alzheimer's disease. In addition, insufficient sleep also increases glucocorticoid levels, decreases brain-derived neurotrophic factor levels, and reduces the number of synapses in the central nervous system. These factors also promote Alzheimer's disease development and progression. The present study showed that a growing body of evidence supports an association between sleep disturbances and Alzheimer's disease. It discusses the role of sleep insufficiency in Alzheimer's disease pathogenesis, which may provide a theoretical basis for effective treatment and prevention strategies.}, } @article {pmid36588745, year = {2023}, author = {Barnes-Vélez, JA and Aksoy Yasar, FB and Hu, J}, title = {Myelin lipid metabolism and its role in myelination and myelin maintenance.}, journal = {Innovation (Cambridge (Mass.))}, volume = {4}, number = {1}, pages = {100360}, pmid = {36588745}, issn = {2666-6758}, abstract = {Myelin is a specialized cell membrane indispensable for rapid nerve conduction. The high abundance of membrane lipids is one of myelin's salient features that contribute to its unique role as an insulator that electrically isolates nerve fibers across their myelinated surface. The most abundant lipids in myelin include cholesterol, glycosphingolipids, and plasmalogens, each playing critical roles in myelin development as well as function. This review serves to summarize the role of lipid metabolism in myelination and myelin maintenance, as well as the molecular determinants of myelin lipid homeostasis, with an emphasis on findings from genetic models. In addition, the implications of myelin lipid dysmetabolism in human diseases are highlighted in the context of hereditary leukodystrophies and neuropathies as well as acquired disorders such as Alzheimer's disease.}, } @article {pmid36588726, year = {2022}, author = {Naz, S and Imran, I and Farooq, MA and Shah, SAH and Ajmal, I and Zahra, Z and Aslam, A and Sarwar, MI and Shah, J and Aleem, A}, title = {Hyperglycemia-associated Alzheimer's-like symptoms and other behavioral effects attenuated by Plumeria obtusa L. Extract in alloxan-induced diabetic rats.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1077570}, pmid = {36588726}, issn = {1663-9812}, abstract = {Diabetes mellitus is a chronic metabolic complaint with numerous short- and long-term complications that harm a person's physical and psychological health. Plumeria obtusa L. is a traditional medicine used in the treatment of diabetes to reduce complications related to behavior. Plumeria is a genus with antipsychotic activities. The objective of this study was to examine the effects of a methanolic extract of Plumeria obtusa L. in the attenuation of diabetes, on symptoms of Alzheimer disease, and on other associated behavioral aspects. A single dose of alloxan was administered to an experimental group of rats to induce development of diabetes (150 mg/kg, intraperitoneal) and the rats were then administered selected doses of methanolic extract of Plumeria obtusa L. (Po.Cr) or glibenclamide (0.6 mg/kg) for 45 consecutive days. Behavioral effects were evaluated using three validated assays of anxiety-related behavior: the open field test, the light and dark test, and the elevated plus maze. Anti-depressant effects of Plumeria obtusa L. were evaluated using the forced swim test (FST) and memory and learning were assessed using the Morris water maze (MWM) task. Po.Cr was also evaluated for phytochemicals using total phenolic content (TPC), total flavonoid content (TFC), and high-performance liquid chromatography assays, and antioxidant capability was assessed through assays of DPPH radical scavenging, total oxidation capacity, and total reducing capacity. In the alloxan-induced model of diabetes, the administration of Po.Cr and glibenclamide for 45 days produced a marked decrease (p < 0.001) in hyperglycemia compared to control animals. Po.Cr treatment also resulted in improvement in indicators, such as body weight and lipid profile (p < 0.05), as well as restoration of normal levels of alanine transaminase (ALT) (p < 0.001), a biomarker of liver function. Diabetic rats presented more Alzheimer-like symptoms, with greater impairment of memory and learning, and increased anxiety and depression compared to non-diabetic normal rats, whereas treated diabetic rats showed significant improvements in memory and behavioral outcomes. These results demonstrate that Po.Cr reversed alloxan-induced hyperglycemia and ameliorated Alzheimer-related behavioral changes, which supports additional study and assessment of conventional use of the plant to treat diabetes and associated behavioral complications.}, } @article {pmid36588719, year = {2022}, author = {Keimasi, M and Salehifard, K and Shahidi, M and Esmaeili, F and Mirshah Jafar Esfahani, N and Beheshti, S and Amirsadri, M and Naseri, F and Keimasi, M and Ghorbani, N and Mofid, MR and Moradmand, M}, title = {Ameliorative effects of omega-lycotoxin-Gsp2671e purified from the spider venom of Lycosa praegrandis on memory deficits of glutamate-induced excitotoxicity rat model.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1048563}, pmid = {36588719}, issn = {1663-9812}, abstract = {Memory impairment is one of the main complications of Alzheimer's disease (AD). This condition can be induced by hyper-stimulation of N-Methyl-D-aspartate receptors (NMDARs) of glutamate in the hippocampus, which ends up to pyramidal neurons determination. The release of neurotransmitters relies on voltage-gated calcium channels (VGCCs) such as P/Q-types. Omega-lycotoxin-Gsp2671e (OLG1e) is a P/Q-type VGCC modulator with high affinity and selectivity. This bio-active small protein was purified and identified from the Lycosa praegrandis venom. The effect of this state-dependent low molecular weight P/Q-type calcium modulator on rats was investigated via glutamate-induced excitotoxicity by N-Methyl-D-aspartate. Also, Electrophysiological amplitude of field excitatory postsynaptic potentials (fEPSPs) in the input-output and Long-term potentiation (LTP) curves were recorded in mossy fiber and the amount of synaptophysin (SYN), synaptosomal-associated protein, 25 kDa (SNAP-25), and synaptotagmin 1(SYT1) genes expression were measured using Real-time PCR technique for synaptic quantification. The outcomes of the current study suggest that OLG1e as a P/Q-type VGCC modulator has an ameliorative effect on excitotoxicity-induced memory defects and prevents the impairment of pyramidal neurons in the rat hippocampus.}, } @article {pmid36588689, year = {2022}, author = {Mi, L and Fan, M and Liu, T and Wu, D and Wang, Y and Li, F and Cai, Y and Qiu, Z and Liu, D and Cao, L}, title = {Ginsenoside Rd protects transgenic Caenorhabditis elegans from β-amyloid toxicity by activating oxidative resistant.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1074397}, pmid = {36588689}, issn = {1663-9812}, abstract = {Alzheimer's disease (AD) is a serious public health issue but few drugs are currently available for the disease, and these only target the symptoms. It is well established that oxidative stress plays a crucial role in AD, and there is compelling evidence linking oxidative stress to β-amyloid (Aβ). An exciting source of potential new AD therapeutic medication possibilities is medicinal plants. Ginsenoside Rd (GS-Rd) is one of the main bioactive substances in ginseng extracts. In our study, we used a network pharmacology analysis to identify overlapping GS-Rd (therapeutic) and AD (disease)-relevant protein targets, gene ontology (GO) and bio-process annotation, and the KEGG pathway analysis data predicted that GS-Rd impacts multiple targets and pathways, such as the MAPK signal pathway and the JAT-STAT3 signaling pathway. We then assessed the role of GS-Rd in C. elegans and found that GS-Rd prolongs lifespan, improves resistance to heat stress, delays physical paralysis and increases oxidative stress responses. Overall, these results suggest that GS-Rd protects against the toxicity of Aβ. The RNA-seq analysis revealed that GS-Rd achieves its effects by regulating gene expressions like daf-16 and skn-1, as well as by participating in many AD-related pathways like the MAPK signaling pathway. In addition, in CL4176 worms, GS-Rd decreased reactive oxygen species (ROS) levels and increased SOD activity. Additional research with transgenic worms showed that GS-Rd aided in the movement of DAF-16 from the cytoplasm to the nucleus. Taken together, the results indicate that GS-Rd significantly reduces Aβ aggregation by targeting the MAPK signal pathway, induces nuclear translocation of DAF-16 to activate downstream signaling pathways and increases resistance to oxidative stress in C. elegans to protect against Aβ-induced toxicity.}, } @article {pmid36588673, year = {2022}, author = {Lapresa, R and Agulla, J and Bolaños, JP and Almeida, A}, title = {APC/C-Cdh1-targeted substrates as potential therapies for Alzheimer's disease.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1086540}, pmid = {36588673}, issn = {1663-9812}, abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the main cause of dementia in the elderly. The disease has a high impact on individuals and their families and represents a growing public health and socio-economic burden. Despite this, there is no effective treatment options to cure or modify the disease progression, highlighting the need to identify new therapeutic targets. Synapse dysfunction and loss are early pathological features of Alzheimer's disease, correlate with cognitive decline and proceed with neuronal death. In the last years, the E3 ubiquitin ligase anaphase promoting complex/cyclosome (APC/C) has emerged as a key regulator of synaptic plasticity and neuronal survival. To this end, the ligase binds Cdh1, its main activator in the brain. However, inactivation of the anaphase promoting complex/cyclosome-Cdh1 complex triggers dendrite disruption, synapse loss and neurodegeneration, leading to memory and learning impairment. Interestingly, oligomerized amyloid-β (Aβ) peptide, which is involved in Alzheimer's disease onset and progression, induces Cdh1 phosphorylation leading to anaphase promoting complex/cyclosome-Cdh1 complex disassembly and inactivation. This causes the aberrant accumulation of several anaphase promoting complex/cyclosome-Cdh1 targets in the damaged areas of Alzheimer's disease brains, including Rock2 and Cyclin B1. Here we review the function of anaphase promoting complex/cyclosome-Cdh1 dysregulation in the pathogenesis of Alzheimer's disease, paying particular attention in the neurotoxicity induced by its molecular targets. Understanding the role of anaphase promoting complex/cyclosome-Cdh1-targeted substrates in Alzheimer's disease may be useful in the development of new effective disease-modifying treatments for this neurological disorder.}, } @article {pmid36588423, year = {2022}, author = {Grashow, R and Shaffer-Pancyzk, TV and Dairi, I and Lee, H and Marengi, D and Baker, J and Weisskopf, MG and Speizer, FE and Whittington, AJ and Taylor, HA and Keating, D and Tenforde, A and Guseh, JS and Wasfy, MM and Zafonte, R and Baggish, A}, title = {Healthspan and chronic disease burden among young adult and middle-aged male former American-style professional football players.}, journal = {British journal of sports medicine}, volume = {57}, number = {3}, pages = {166-171}, pmid = {36588423}, issn = {1473-0480}, abstract = {OBJECTIVE: To examine the relationships between age, healthspan and chronic illness among former professional American-style football (ASF) players.

METHODS: We compared age-specific race-standardised and body mass index-standardised prevalence ratios of arthritis, dementia/Alzheimer's disease, hypertension and diabetes among early adult and middle-aged (range 25-59 years) male former professional ASF players (n=2864) with a comparator cohort from the National Health and Nutrition Examination Survey and National Health Interview Survey, two representative samples of the US general population. Age was stratified into 25-29, 30-39, 40-49 and 50-59 years.

RESULTS: Arthritis and dementia/Alzheimer's disease were more prevalent among ASF players across all study age ranges (all p<0.001). In contrast, hypertension and diabetes were more prevalent among ASF players in the youngest age stratum only (p<0.001 and p<0.01, respectively). ASF players were less likely to demonstrate intact healthspan (ie, absence of chronic disease) than the general population across all age ranges.

CONCLUSION: These data suggest the emergence of a maladaptive early ageing phenotype among former professional ASF players characterised by premature burden of chronic disease and reduced healthspan. Additional study is needed to investigate these findings and their impact on morbidity and mortality in former ASF players and other athlete groups.}, } @article {pmid36588335, year = {2022}, author = {Bernaards, CA and Fischer, KI and Rylands, A and Gater, A and Tolley, C and Zarit, SH and Lansdall, CJ}, title = {Development and Psychometric Validation of the 27 Item Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD-27).}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/1567205020666221230103505}, pmid = {36588335}, issn = {1875-5828}, abstract = {Caring for an individual with Alzheimer's disease (AD) is an all-encompassing challenge that affects daily life. Assessment of the care partner experience is needed to support the development and evaluation of successful interventions for people with AD and their care partners. We developed the 27-item Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD-27) to assess the impact of informal caregiving in the context of AD.

Objective: We assessed the psychometric validity of the ZCI-AD-27 in a population of care partners for individuals with moderate AD, and established thresholds for meaningful score change.

Methods: Secondary data were obtained from informal care partners of participants in a clinical trial (NCT01677754). Psychometric analyses were conducted to assess validity, reliability, and responsiveness of the ZCI-AD-27. Anchor-based and distribution-based methods were performed to determine clinically meaningful score change.

Results: The ZCI-AD-27 had a 12-domain factor structure, including a second-order domain termed Humanistic impact that included four key domains (Physical, Emotional, Social, and Daily life) as confirmed by confirmatory factor analysis with the adequate fit. Internal consistency (Cronbach's alpha ranging from 0.66 to 0.93 for domains), convergent validity, and discriminant validity indicated the good performance of the ZCI-AD-27. Known-groups validity analyses showed a greater impact on care partners with increasing disease severity. Responsiveness results demonstrated that the ZCI-AD-27 is sensitive to change over time and meaningful change analyses indicated a range of meaningful score changes in this population.

Conclusion: The ZCI-AD-27 is a comprehensive, psychometrically valid measure to assess the impact of caring for individuals with moderate AD.}, } @article {pmid36588011, year = {2022}, author = {Evering, TH and Marston, JL and Gan, L and Nixon, DF}, title = {Transposable elements and Alzheimer's disease pathogenesis.}, journal = {Trends in neurosciences}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tins.2022.12.003}, pmid = {36588011}, issn = {1878-108X}, support = {R21 AG071433/AG/NIA NIH HHS/United States ; R21 NS126094/NS/NINDS NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) is characterized by the pathological accumulation of amyloid β (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau. Microglia and astrocytes respond to the abnormal presence of tau protein with induced transposable element (TE) transcription. In this Forum, we discuss new data that link dysregulated TE expression to AD pathogenesis.}, } @article {pmid36587998, year = {2022}, author = {Peng, J and Wang, W and Song, Q and Hou, J and Jin, H and Qin, X and Yuan, Z and Wei, Y and Shu, Z}, title = {[18]F-FDG-PET Radiomics Based on White Matter Predicts The Progression of Mild Cognitive Impairment to Alzheimer Disease: A Machine Learning Study.}, journal = {Academic radiology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.acra.2022.12.033}, pmid = {36587998}, issn = {1878-4046}, abstract = {RATIONALE AND OBJECTIVES: To build a model using white-matter radiomics features on positron-emission tomography (PET) and machine learning methods to predict progression from mild cognitive impairment (MCI) to Alzheimer disease (AD).

MATERIALS AND METHODS: We analyzed the data of 341 MCI patients from the Alzheimer's Disease Neuroimaging Initiative, of whom 102 progressed to AD during an 8-year follow-up. The patients were divided into the training (238 patients) and test groups (103 patients). PET-based radiomics features were extracted from the white matter in the training group, and dimensionally reduced to construct a psychoradiomics signature (PS), which was combined with multimodal data using machine learning methods to construct an integrated model. Model performance was evaluated using receiver operating characteristic curves in the test group.

RESULTS: Clinical Dementia Rating (CDR) scores, Alzheimer's Disease Assessment Scale (ADAS) scores, and PS independently predicted MCI progression to AD on multivariate logistic regression. The areas under the curve (AUCs) of the CDR, ADAS and PS in the training and test groups were 0.683, 0.755, 0.747 and 0.737, 0.743, 0.719 respectively, and were combined using a support vector machine to construct an integrated model. The AUC of the integrated model in the training and test groups was 0.868 and 0.865, respectively (sensitivity, 0.873 and 0.839, respectively; specificity, 0.784 and 0.806, respectively). The AUCs of the integrated model significantly differed from those of other predictors in both groups (p < 0.05, Delong test).

CONCLUSION: Our psych radiomics signature based on white-matter PET data predicted MCI progression to AD. The integrated model built using multimodal data and machine learning identified MCI patients at a high risk of progression to AD.}, } @article {pmid36587923, year = {2023}, author = {Tang, Z and Cao, J and Yao, J and Fan, X and Zhao, J and Zhao, M and Duan, Q and Han, B and Duan, S}, title = {KDM1A-mediated upregulation of METTL3 ameliorates Alzheimer's disease via enhancing autophagic clearance of p-Tau through m6A-dependent regulation of STUB1.}, journal = {Free radical biology & medicine}, volume = {195}, number = {}, pages = {343-358}, doi = {10.1016/j.freeradbiomed.2022.12.099}, pmid = {36587923}, issn = {1873-4596}, mesh = {Humans ; Mice ; Animals ; *Alzheimer Disease/metabolism ; Amyloid beta-Peptides/genetics/metabolism ; Up-Regulation ; *Neuroblastoma ; Mice, Transgenic ; Autophagy/genetics ; Ubiquitin-Protein Ligases/genetics ; Methyltransferases/genetics/metabolism/therapeutic use ; Histone Demethylases/genetics ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a severe neurodegenerative disorder that progressively destroys cognitive skills. Exploring the mechanism underlying autophagic clearance of phosphorylated tau (p-Tau) contributes to developing novel therapeutic strategies for AD.

METHODS: SH-SY5Y and HT22 cells were treated with Aβ1-42 to establish an in vitro model of AD. Cell viability was examined using CCK-8. TUNEL staining was applied to evaluate cell apoptosis. LC3 puncta was examined by IF staining. m6A modification level was evaluated through MeRIP. RNA pull-down and RIP assays were used for analyzing the interaction between IGF2BP1 and STUB1 transcripts. The binding of KDM1A to the promoter of METTL3 was confirmed by ChIP assays. APP/PS1 transgenic mice were used as an in vivo model of AD. Cognitive skills of mice were evaluated with the Morris water maze. Hippocampal damage and Aβ deposition were detected through H&E and IHC staining.

RESULTS: Dysregulated levels of autophagy, p-Tau and m6A was observed in an in vitro model of AD. Overexpression of METTL3 or STUB1 enhanced autophagy but reduced p-Tau level in Aβ1-42-treated cells. METTL3 stabilized STUB1 mRNA through the m6A-IGF2BP1-dependent mechanism and naturally promoted STUB1 expression, thereby enhancing autophagic p-Tau clearance in Aβ1-42-treated cells. Overexpression of KDM1A enhanced autophagy, m6A modification and autophagic p-Tau clearance in Aβ1-42-treated cells. KDM1A-mediated upregulation of METTL3 promoted autophagic p-Tau clearance and ameliorated Alzheimer's disease both in vitro and in vivo.

CONCLUSION: KDM1A-mediated upregulation of METTL3 enhances autophagic clearance of p-Tau through m6A-dependent regulation of STUB1, thus ameliorating Alzheimer's disease. Our study provides novel mechanistic insights into AD pathogenesis and potential drug targets for AD.}, } @article {pmid36587866, year = {2023}, author = {Blackwell, AA and Jodelka, FM and Lake, RI and Hastings, ML and Wallace, DG}, title = {Spatial Disorientation Under Dark Conditions Across Development in an Alzheimer's Disease Mouse Model.}, journal = {Neuroscience}, volume = {511}, number = {}, pages = {53-69}, doi = {10.1016/j.neuroscience.2022.12.012}, pmid = {36587866}, issn = {1873-7544}, abstract = {Alzheimer's disease (AD) is associated with hippocampal neuropathology and cognitive impairments, including wandering behavior or becoming lost in a familiar environment. Wandering behavior is severe and manifests early in life for people with specific genetic mutations. Genetic mouse models of AD have been developed to characterize the onset and progression of behavioral deficits that represent human behaviors, such as wandering, to test the efficacy of therapeutics. It is not clear if current assessments of mouse models capture the onset of AD or a snapshot of its progression. Sequential analysis of open field behavior provides a robust, quick test to dissociate navigation cues that contribute to spatial disorientation, a feature of wandering. Despite potential utility in evaluating this feature of AD, little work has been reported using animal models of dementia in this task. Thus, we examined the use of different sources of information to maintain spatial orientation at two prodromal ages in female transgenic CRND8 AD (n = 17) and Control mice (n = 16). These mice exhibit amyloid plaques, a hallmark neuropathological feature of AD, that are associated with cognitive dysfunction at ∼three months of age. Spatial disorientation was observed at two months and more severely at four months under dark conditions, but performance was spared when visual environmental cues were available. This study provides documentation of impaired self-movement cue processing in AD mice, establishing the dark open field as a behavioral tool to characterize spatial disorientation associated with AD. These findings may accelerate future assessments of novel therapeutic interventions for neurological disorders.}, } @article {pmid36587558, year = {2023}, author = {She, L and Xiong, L and Li, L and Zhang, J and Sun, J and Wu, H and Ren, J and Wang, W and Zhao, X and Liang, G}, title = {Ginsenoside Rk3 ameliorates Aβ-induced neurotoxicity in APP/PS1 model mice via AMPK signaling pathway.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {158}, number = {}, pages = {114192}, doi = {10.1016/j.biopha.2022.114192}, pmid = {36587558}, issn = {1950-6007}, mesh = {Animals ; Mice ; *Alzheimer Disease/metabolism ; *AMP-Activated Protein Kinases/metabolism ; Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; Mice, Transgenic ; Presenilin-1/genetics ; Signal Transduction ; }, abstract = {Alzheimer's disease (AD) has become a major public health problem affecting the elderly population, and there is currently no effective treatment. Although the pathogenesis of AD is unclear, neurotoxicity induced by oxidative stress plays an important role in the progression of AD. Ginseng, the root and rhizome of Panax ginseng C. A. Meyer, is used not only as an herbal medicine but also as a functional food to support bodily functions. Ginsenoside Rk3 (Rk3), the main bioactive component in ginseng, has a strong antioxidant effect and has not been reported in AD. In this study, we showed that Rk3 improved neuronal apoptosis, decreased intracellular reactive oxygen species (ROS) production and restored mitochondrial membrane potential in PC12 and primary neuronal cells. In vivo, we found that Rk3 improved spatial learning and memory deficit in precursor protein (APP)/presenilin 1 (PS1) double transgenic mouse model of AD. Additionally, Rk3 increases glutathione reductase (GSH) and superoxide dismutase (SOD) levels while inhibits malondialdehyde (MDA) production, apoptosis and activation of glial cells in APP/PS1 mice. Mechanistically, we found that the protective effect of Rk3 is in correlation with the activation of AMPK/Nrf2 signaling pathway. In conclusion, the findings of this study provide support for Rk3 as a new strategy for the treatment of AD.}, } @article {pmid36587227, year = {2022}, author = {Fernandez-Alvarez, M and Atienza, M and Cantero, JL}, title = {Effects of non-modifiable risk factors of Alzheimer's disease on intracortical myelin content.}, journal = {Alzheimer's research & therapy}, volume = {14}, number = {1}, pages = {202}, pmid = {36587227}, issn = {1758-9193}, mesh = {Humans ; Aged ; *Alzheimer Disease/diagnostic imaging/genetics ; Apolipoprotein E4/genetics ; Myelin Sheath ; Magnetic Resonance Imaging ; Brain ; Risk Factors ; }, abstract = {BACKGROUND: Non-modifiable risk factors of Alzheimer's disease (AD) have lifelong effects on cortical integrity that could be mitigated if identified at early stages. However, it remains unknown whether cortical microstructure is affected in older individuals with non-modifiable AD risk factors and whether altered cortical tissue integrity produces abnormalities in brain functional networks in this AD-risk population.

METHODS: Using relative T1w/T2w (rT1w/T2w) ratio maps, we have compared tissue integrity of normal-appearing cortical GM between controls and cognitively normal older adults with either APOE4 (N = 50), with a first-degree family history (FH) of AD (N = 52), or with the co-occurrence of both AD risk factors (APOE4+FH) (N = 35). Additionally, individuals with only one risk factor (APOE4 or FH) were combined into one group (N = 102) and compared with controls. The same number of controls matched in age, sex, and years of education was employed for each of these comparisons. Group differences in resting state functional connectivity (rs-FC) patterns were also investigated, using as FC seeds those cortical regions showing significant changes in rT1w/T2w ratios.

RESULTS: Overall, individuals with non-modifiable AD risk factors exhibited significant variations in rT1w/T2w ratios compared to controls, being APOE4 and APOE4+FH at opposite ends of a continuum. The co-occurrence of APOE4 and FH was further accompanied by altered patterns of rs-FC.

CONCLUSIONS: These findings may have practical implications for early detection of cortical abnormalities in older populations with APOE4 and/or FH of AD and open new avenues to monitor changes in cortical tissue integrity associated with non-modifiable AD risk factors.}, } @article {pmid36587215, year = {2022}, author = {Shim, KH and Kang, MJ and Youn, YC and An, SSA and Kim, S}, title = {Alpha-synuclein: a pathological factor with Aβ and tau and biomarker in Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {14}, number = {1}, pages = {201}, pmid = {36587215}, issn = {1758-9193}, mesh = {Humans ; *Alzheimer Disease/diagnosis/pathology ; alpha-Synuclein/metabolism ; tau Proteins/metabolism ; Amyloid beta-Peptides ; Biomarkers ; }, abstract = {BACKGROUND: Alpha-synuclein (α-syn) is considered the main pathophysiological protein component of Lewy bodies in synucleinopathies. α-Syn is an intrinsically disordered protein (IDP), and several types of structural conformations have been reported, depending on environmental factors. Since IDPs may have distinctive functions depending on their structures, α-syn can play different roles and interact with several proteins, including amyloid-beta (Aβ) and tau, in Alzheimer's disease (AD) and other neurodegenerative disorders.

MAIN BODY: In previous studies, α-syn aggregates in AD brains suggested a close relationship between AD and α-syn. In addition, α-syn directly interacts with Aβ and tau, promoting mutual aggregation and exacerbating the cognitive decline. The interaction of α-syn with Aβ and tau presented different consequences depending on the structural forms of the proteins. In AD, α-syn and tau levels in CSF were both elevated and revealed a high positive correlation. Especially, the CSF α-syn concentration was significantly elevated in the early stages of AD. Therefore, it could be a diagnostic marker of AD and help distinguish AD from other neurodegenerative disorders by incorporating other biomarkers.

CONCLUSION: The overall physiological and pathophysiological functions, structures, and genetics of α-syn in AD are reviewed and summarized. The numerous associations of α-syn with Aβ and tau suggested the significance of α-syn, as a partner of the pathophysiological roles in AD. Understanding the involvements of α-syn in the pathology of Aβ and tau could help address the unresolved issues of AD. In particular, the current status of the CSF α-syn in AD recommends it as an additional biomarker in the panel for AD diagnosis.}, } @article {pmid36586663, year = {2023}, author = {Yu, J and Wu, D and Zhao, Y and Guo, L and Liu, P}, title = {Study on multi-target effects of PIMPC on Aβ/Cu[2+]-induced Alzheimer's disease model of rats.}, journal = {Brain research}, volume = {1802}, number = {}, pages = {148226}, doi = {10.1016/j.brainres.2022.148226}, pmid = {36586663}, issn = {1872-6240}, mesh = {Animals ; Rats ; *Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Brain/metabolism ; Glycogen Synthase Kinase 3/metabolism ; Glycogen Synthase Kinase 3 beta/metabolism ; Phosphorylation ; tau Proteins/metabolism ; Copper/pharmacology ; }, abstract = {Glycogen synthase kinase-3 (GSK-3), a key role in the pathogenesis of Alzheimer's disease (AD), has been linked with the formation of β-amyloid (Aβ), tubulin-associated unit (tau) protein phosphorylation and apoptosis. Moreover, the excessive presence of elements such as copper (Cu) can promote Aβ aggregation and increase the risk of AD. Combined with the role of GSK-3 and metal elements in AD, a metal-chelating imine GSK-3 inhibitor N-(4-{[(2-amino-5-phenylpyridin-3-ylidene)imino]methyl} pyridin-2-yl)cyclopropanecarboxamide (PIMPC) was designed and synthesized. In our study, Aβ/Cu[2+]-induced AD rat model was established and treated with PIMPC. The results indicated that PIMPC can not only down-regulate the high expression levels of Aβ, tau and p-tau proteins of the AD rats, but also chelate Cu and aluminum (Al) elements in the brain. In addition, PIMPC may play an anti-apoptotic effect by down-regulating the high expression of cleaved Caspase-3 protein, and it can modulate ATPase and nitric oxide synthase (NOS) levels, oxidative stress and neurotransmitter disturbance. In summary, PIMPC acts on multiple targets to relieve the learning and memory impairment of AD rats induced by Aβ/Cu[2+].}, } @article {pmid36586653, year = {2022}, author = {Eze, FN and Eze, RC and Ovatlarnporn, C}, title = {Insights into the remarkable attenuation of hen egg white lysozyme amyloid fibril formation mediated by biogenic gold nanoparticles stabilized by quercetin-functionalized tara gum.}, journal = {International journal of biological macromolecules}, volume = {232}, number = {}, pages = {123044}, doi = {10.1016/j.ijbiomac.2022.12.263}, pmid = {36586653}, issn = {1879-0003}, abstract = {Aberrant protein misfolding and/or aggregation and fibrillation has been linked to the pathogenesis of several debilitating chronic diseases including Alzheimer's and Parkinson's disease. Inhibiting protein amyloidogenesis has been proposed as a viable strategy to prevent or ameliorate associated disorders. Herein, we investigated the anti-amyloidogenic properties of biogenic gold nanoparticles (QTG-GNP) prepared via a simple green chemistry route and stabilized by quercetin-functionalized tara gum (QTG). The synthesized QTG-GNP was extensively characterized for its physicochemical attributes via UV-visible spectroscopy, TEM, FESEM, EDX, DLS/Zeta potential, FTIR, RAMAN, XRD, XPS, and TGA analyses, as well as for its biological properties. The results revealed that small-sized (5.01 ± 1.17 nm), well-dispersed, highly stable and round-shaped biogenic gold nanoparticles were successfully synthesized at room temperature with QTG as the sole reductant /stabilizer. Importantly, QTG-GNP demonstrated potent anti-aggregation and fibrillation inhibitory effects against amyloidogenic hen egg white lysozyme (HEWL). Also, QTG-GNP was able to dissociate pre-formed HEWL amyloid fibrils. Furthermore, the constructed nanoparticles exhibited potent anti-radical activities against DPPH and ABTS[+] and were cytocompatible with mouse L929 fibroblast cells. On the basis of these findings, it was established that QTG-GNP holds strong prospects for further development as an agent for countering protein aggregation and associated disease conditions.}, } @article {pmid36586644, year = {2023}, author = {Imbimbo, BP and Ippati, S and Watling, M and Imbimbo, C}, title = {Role of monomeric amyloid-β in cognitive performance in Alzheimer's disease: Insights from clinical trials with secretase inhibitors and monoclonal antibodies.}, journal = {Pharmacological research}, volume = {187}, number = {}, pages = {106631}, doi = {10.1016/j.phrs.2022.106631}, pmid = {36586644}, issn = {1096-1186}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Amyloid Precursor Protein Secretases ; Antibodies, Monoclonal/pharmacology/therapeutic use ; Amyloid beta-Peptides ; Cognition ; }, abstract = {According to the β-amyloid (Aβ) hypothesis of Alzheimer's disease (AD), brain Aβ accumulation is the primary cascade event leading to cognitive deficit and dementia. Numerous anti-Aβ drugs either inhibiting production or aggregation of Aβ or stimulating its clearance have failed to show clinical benefit in large scale AD trials, with β- and γ-secretase inhibitors consistently worsening cognitive and clinical decline. In June 2021, the FDA approved aducanumab, an anti-Aβ monoclonal antibody for early AD based on its ability to reduce brain amyloid plaques, while two other amyloid-clearing antibodies (lecanemab and donanemab) have recently produced encouraging cognitive and clinical results. We reviewed AD trials using PubMed, meeting abstracts and ClinicalTrials.gov and evaluated the effects of such drugs on cerebrospinal fluid (CSF) Aβ levels, correlating them with cognitive effects. We found that β-secretase and γ-secretase inhibitors produce detrimental cognitive effects by significantly reducing CSF Aβ levels. We speculate that monoclonal antibodies targeting Aβ protofibrils, fibrils or plaques may improve cognitive performance in early AD by increasing soluble Aβ levels through Aβ aggregate disassembly and/or stabilization of existing Aβ monomers.These findings suggest that the real culprit in AD may be decreased levels of soluble monomeric Aβ due to sequestration into brain Aβ aggregates and plaques.}, } @article {pmid36586468, year = {2023}, author = {Ren, P and Ding, W and Li, S and Liu, G and Luo, M and Zhou, W and Cheng, R and Li, Y and Wang, P and Li, Z and Yao, L and Jiang, Q and Liang, X and , }, title = {Regional transcriptional vulnerability to basal forebrain functional dysconnectivity in mild cognitive impairment patients.}, journal = {Neurobiology of disease}, volume = {177}, number = {}, pages = {105983}, doi = {10.1016/j.nbd.2022.105983}, pmid = {36586468}, issn = {1095-953X}, support = {U01 AG016976/AG/NIA NIH HHS/United States ; U24 AG072122/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/genetics/metabolism ; *Basal Forebrain/pathology ; Basal Nucleus of Meynert/metabolism ; *Cognitive Dysfunction/diagnostic imaging/genetics/metabolism ; Amyloid beta-Peptides/metabolism ; }, abstract = {Nucleus basalis of Meynert (NbM), one of the earliest targets of Alzheimer's disease (AD), may act as a seed for pathological spreading to its connected regions. However, the underlying basis of regional vulnerability to NbM dysconnectivity remains unclear. NbM functional dysconnectivity was assessed using resting-state fMRI data of health controls and mild cognitive impairment (MCI) patients from the Alzheimer's disease Neuroimaging Initiative (ADNI2/GO phase). Transcriptional correlates of NbM dysconnectivity was explored by leveraging public intrinsic and differential post-mortem brain-wide gene expression datasets from Allen Human Brain Atlas (AHBA) and Mount Sinai Brain Bank (MSBB). By constructing an individual-level tissue-specific gene set risk score (TGRS), we evaluated the contribution of NbM dysconnectivity-correlated gene sets to change rate of cerebral spinal fluid (CSF) biomarkers during preclinical stage of AD, as well as to MCI onset age. An independent cohort of health controls and MCI patients from ADNI3 was used to validate our main findings. Between-group comparison revealed significant connectivity reduction between the right NbM and right middle temporal gyrus in MCI. This regional vulnerability to NbM dysconnectivity correlated with intrinsic expression of genes enriched in protein and immune functions, as well as with differential expression of genes enriched in cholinergic receptors, immune, vascular and energy metabolism functions. TGRS of these NbM dysconnectivity-correlated gene sets are associated with longitudinal amyloid-beta change at preclinical stages of AD, and contributed to MCI onset age independent of traditional AD risks. Our findings revealed the transcriptional vulnerability to NbM dysconnectivity and their crucial role in explaining preclinical amyloid-beta change and MCI onset age, which offer new insights into the early AD pathology and encourage more investigation and clinical trials targeting NbM.}, } @article {pmid36586382, year = {2023}, author = {Gumus, E and Bingol, H and Zor, E}, title = {Lateral flow assays for detection of disease biomarkers.}, journal = {Journal of pharmaceutical and biomedical analysis}, volume = {225}, number = {}, pages = {115206}, doi = {10.1016/j.jpba.2022.115206}, pmid = {36586382}, issn = {1873-264X}, mesh = {*Point-of-Care Testing ; *Biological Assay ; Biomarkers ; }, abstract = {Early diagnosis saves lives in many diseases. In this sense, monitoring of biomarkers is crucial for the diagnosis of diseases. Lateral flow assays (LFAs) have attracted great attention among paper-based point-of-care testing (POCT) due to their low cost, user-friendliness, and time-saving advantages. Developments in the field of health have led to an increase of interest in these rapid tests. LFAs are used in the diagnosis and monitoring of many diseases, thanks to biomarkers that can be observed in body fluids. This review covers the recent advances dealing with the design and strategies for the development of LFA for the detection of biomarkers used in clinical applications in the last 5 years. We focus on various strategies such as choosing the nanoparticle type, single or multiple test approaches, and equipment for signal transducing for the detection of the most common biomarkers in different diseases such as cancer, cardiovascular, infectious, and others including Parkinson's and Alzheimer's diseases. We expect that this study will contribute to the different approaches in LFA and pave the way for other clinical applications.}, } @article {pmid36586361, year = {2022}, author = {Putcha, D and Katsumi, Y and Brickhouse, M and Flaherty, R and Salat, DH and Touroutoglou, A and Dickerson, BC}, title = {Gray to white matter signal ratio as a novel biomarker of neurodegeneration in Alzheimer's disease.}, journal = {NeuroImage. Clinical}, volume = {37}, number = {}, pages = {103303}, pmid = {36586361}, issn = {2213-1582}, abstract = {Alzheimer's disease (AD) is characterized neuropathologically by β-amyloid (Aβ) plaques, hyperphosphorylated tau neurofibrillary tangles, and neurodegeneration, which lead to a phenotypically heterogeneous cognitive-behavioral dementia syndrome. Our understanding of how these neuropathological and neurodegeneration biomarkers relate to each other is still evolving. A relatively new approach to measuring structural brain change, gray matter to white matter signal intensity ratio (GWR), quantifies the signal contrast between these tissue compartments, and has emerged as a promising marker of AD-related neurodegeneration. We sought to validate GWR as a novel MRI biomarker of neurodegeneration in 29 biomarker positive individuals across the atypical syndromic spectrum of AD. Bivariate correlation analyses revealed that GWR was associated with cortical thickness, tau PET, and amyloid PET, with GWR showing a larger magnitude of abnormality than cortical thickness. We also found that combining GWR, cortical thickness, and amyloid PET better explained observed tau PET signal than using these modalities alone, suggesting that the three imaging biomarkers contribute independently and synergistically to explaining the variance in the distribution of tau pathology. We conclude that GWR is a uniquely sensitive in vivo marker of neurodegenerative change that reflects pathological mechanisms which may occur prior to cortical atrophy. By using all of these imaging biomarkers of AD together, we may be better able to capture, and possibly predict, AD neuropathologic changes in vivo. We hope that such an approach will ultimately contribute to better endpoints to evaluate the efficacy of therapeutic interventions as we move toward an era of disease-modifying treatments for this devastating disease.}, } @article {pmid36586358, year = {2022}, author = {Rizvi, B and Sathishkumar, M and Kim, S and Márquez, F and Granger, SJ and Larson, MS and Miranda, BA and Hollearn, MK and McMillan, L and Nan, B and Tustison, NJ and Lao, PJ and Brickman, AM and Greenia, D and Corrada, MM and Kawas, CH and Yassa, MA}, title = {Posterior white matter hyperintensities are associated with reduced medial temporal lobe subregional integrity and long-term memory in older adults.}, journal = {NeuroImage. Clinical}, volume = {37}, number = {}, pages = {103308}, pmid = {36586358}, issn = {2213-1582}, abstract = {White matter hyperintensities are a marker of small vessel cerebrovascular disease that are strongly related to cognition in older adults. Similarly, medial temporal lobe atrophy is well-documented in aging and Alzheimer's disease and is associated with memory decline. Here, we assessed the relationship between lobar white matter hyperintensities, medial temporal lobe subregional volumes, and hippocampal memory in older adults. We collected MRI scans in a sample of 139 older adults without dementia (88 females, mean age (SD) = 76.95 (10.61)). Participants were administered the Rey Auditory Verbal Learning Test (RAVLT). Regression analyses tested for associations among medial temporal lobe subregional volumes, regional white matter hyperintensities and memory, while adjusting for age, sex, and education and correcting for multiple comparisons. Increased occipital white matter hyperintensities were related to worse RAVLT delayed recall performance, and to reduced CA1, dentate gyrus, perirhinal cortex (Brodmann area 36), and parahippocampal cortex volumes. These medial temporal lobe subregional volumes were related to delayed recall performance. The association of occipital white matter hyperintensities with delayed recall performance was fully mediated statistically only by perirhinal cortex volume. These results suggest that white matter hyperintensities may be associated with memory decline through their impact on medial temporal lobe atrophy. These findings provide new insights into the role of vascular pathologies in memory loss in older adults and suggest that future studies should further examine the neural mechanisms of these relationships in longitudinal samples.}, } @article {pmid36585999, year = {2022}, author = {Sharma, S and Shukla, MK and Sharma, KC and Tirath, and Kumar, L and Anal, JMH and Upadhyay, SK and Bhattacharyya, S and Kumar, D}, title = {Revisiting the therapeutic potential of gingerols against different pharmacological activities.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {1-15}, pmid = {36585999}, issn = {1432-1912}, abstract = {The rhizomes of ginger have been in use in many forms of traditional and alternative medicines. Besides being employed as condiment and flavoring agent, it is used in the treatment of nausea, osteoarthritis, muscle pain, menstrual pain, chronic indigestion, Alzheimer's disease, and cancer. Ginger rhizome contains volatile oils, phenolic compounds and resins, and characterization studies showed that [6]-gingerol, [6]-shogaol, and [6]-paradol are reported to be the pharmacologically active components. Gingerol is a major chemical constituent found as volatile oil in the rhizomes of ginger. It has several medicinal benefits and used for the treatment of rheumatoid arthritis, nausea, cancer, and diabetes. Many studies have been carried out in various parts of the world to isolate and standardize gingerol for their use as a complementary medicine. The present review summarizes wide range of research studies on gingerol and its pharmacological roles in various metabolic diseases.}, } @article {pmid36585910, year = {2022}, author = {Geethadevi, GM and Peel, R and Bell, JS and Cross, AJ and Hancock, S and Ilomaki, J and Tang, T and Attia, J and George, J}, title = {Validity of three risk prediction models for dementia or cognitive impairment in Australia.}, journal = {Age and ageing}, volume = {51}, number = {12}, pages = {}, pmid = {36585910}, issn = {1468-2834}, mesh = {Humans ; *Dementia/diagnosis/epidemiology ; Australia/epidemiology ; *Cognitive Dysfunction/diagnosis/epidemiology ; Brain ; Life Style ; }, abstract = {BACKGROUND: no studies have compared the predictive validity of different dementia risk prediction models in Australia.

OBJECTIVES: (i) to investigate the predictive validity of the Australian National University-Alzheimer's Disease Risk Index (ANU-ADRI), LIfestyle for BRAin Health (LIBRA) Index and cardiovascular risk factors, ageing and dementia study (CAIDE) models for predicting probable dementia/cognitive impairment in an Australian cohort. (ii) To develop and assess the predictive validity of a new hybrid model combining variables from the three models.

METHODS: the Hunter Community Study (HCS) included 3,306 adults aged 55-85 years with a median follow-up of 7.1 years. Probable dementia/cognitive impairment was defined using Admitted Patient Data Collection, dispensing of cholinesterase inhibitors or memantine, or a cognitive test. Model validity was assessed by calibration and discrimination. A hybrid model was developed using deep neural network analysis, a machine learning method.

RESULTS: 120 (3.6%) participants developed probable dementia/cognitive impairment. Mean calibration by ANU-ADRI, LIBRA, CAIDE and the hybrid model was 19, 0.5, 4.7 and 3.4%, respectively. The discrimination of the models was 0.65 (95% CI 0.60-0.70), 0.65 (95% CI 0.60-0.71), 0.54 (95% CI 0.49-0.58) and 0.80 (95% CI 0.78-0.83), respectively.

CONCLUSION: ANU-ADRI and LIBRA were better dementia prediction tools than CAIDE for identification of high-risk individuals in this cohort. ANU-ADRI overestimated and LIBRA underestimated the risk. The new hybrid model had a higher predictive performance than the other models but it needs to be validated independently in longitudinal studies.}, } @article {pmid36585893, year = {2022}, author = {Potter, AJ and Wright, B and Akiyama, J and Stehlin, GG and Trivedi, AN and Wolinsky, FD}, title = {Primary care patterns among dual eligibles with Alzheimer's disease and related dementias.}, journal = {Journal of the American Geriatrics Society}, volume = {}, number = {}, pages = {}, doi = {10.1111/jgs.18166}, pmid = {36585893}, issn = {1532-5415}, support = {R01MD011513/MD/NIMHD NIH HHS/United States ; }, abstract = {BACKGROUND: Primary care is essential for persons with Alzheimer's disease and related dementias (ADRD). Prior research suggests that the propensity to provide high-quality, continuous primary care varies by provider setting, but the settings used by Medicare-Medicaid dual-eligibles with ADRD have not been described at the population level.

METHODS: Using 2012-2018 Medicare data, we identified dual-eligibles with ADRD. For each person-year, we identified primary care visits occurring in six settings. We calculated descriptive statistics for beneficiaries with a majority of visits in each setting, and conducted a k-means cluster analysis to determine utilization patterns, using the standardized count of primary care visits in each setting.

RESULTS: Each year from 2012 to 2018, at least 45.6% of dual-eligibles with ADRD received a majority of their primary care in nursing facilities, while at least 25.2% did so in physician offices. Over time, the share relying on nursing facilities for primary care decreased by 5.2 percentage points, offset by growth in Federally Qualified Health Centers (FQHCs) and miscellaneous settings (2.3 percentage points each). Dual-eligibles relying on nursing facilities had more annual primary care visits (16.1) than those relying on other settings (range: 6.8-10.7 visits). Interpersonal care continuity was also higher in nursing facilities (97.0%) and physician offices (87.9%) than in FQHCs (54.2%), rural health clinics (RHCs, 46.6%), or hospital-based clinics (56.8%). Among dual-eligibles without care continuity, 82.7% were assigned to a cluster with few primary care visits.

CONCLUSIONS: A trend toward care in different settings likely reflects improved access to patient-centered primary care. Low rates of interpersonal care continuity in FQHCs, RHCs, and physician offices may warrant concern, unless providers in these settings function as a care team. Nonetheless, every healthcare system encounter presents an opportunity to designate a primary care provider for dual-eligibles with ADRD who use little or no primary care.}, } @article {pmid36585610, year = {2022}, author = {Wang, K and Cao, X and Li, Z and Liu, S and Zhou, Y and Guo, L and Li, P}, title = {Anesthesia and surgery-induced elevation of CSF sTREM2 is associated with early cognitive dysfunction after thoracoabdominal aortic dissection surgery.}, journal = {BMC anesthesiology}, volume = {22}, number = {1}, pages = {413}, pmid = {36585610}, issn = {1471-2253}, mesh = {Humans ; Amyloid beta-Peptides/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; *Dissection, Abdominal Aorta ; Biomarkers/cerebrospinal fluid ; *Cognitive Dysfunction/etiology ; *Anesthesia ; }, abstract = {PURPOSE: Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) concentration is increased in cerebrospinal fluid (CSF) in early symptomatic phase of Alzheimer's disease (AD). This study investigated whether CSF sTREM2 has a relationship with early cognitive dysfunction following surgery in cardiac surgery patients.

METHODS: A total of 82 patients undergoing thoracoabdominal aortic replacement were recruited in this study. Neuropsychological testing battery was conducted before and after surgery. Postoperative cognitive dysfunction (POCD) was defined as a Z-score > 1.96 on at least 2 different tests or Telephone Interviews for Cognitive Status-Modified (TICS-M) score < 27. The CSF and serum sTREM2, Aβ42, T-tau and P-tau were collected and measured by ELISA on day before surgery and postoperative day 3.

RESULTS: Patients were classified into POCD (n = 34) and non-POCD (n = 48) groups according to Z-score. Compared to non-POCD group, the levels of CSF sTREM2 (p < 0.001) and serum sTREM2 (p = 0.001) were significantly higher in POCD group on postoperative day 3. The levels of Aβ42 (p = 0.005) and Aβ42/T-tau ratio (p = 0.036) were significantly lower in POCD group on postoperative day 3. Multivariate logistic regression analysis revealed that higher value of postoperative CSF sTREM2 (odds ratio: 1.06, 95% confidence interval: 1.02-1.11, p = 0.009), age (OR: 1.15, 95%CI: 1.03-1.28, p = 0.014) and POD duration (OR: 2.47, 95%CI: 1.15-5.29, p = 0.02) were the risk factors of POCD.

CONCLUSION: This study indicates that anesthesia and surgery-induced elevation of CSF sTREM2 is associated with an increased risk of early cognitive dysfunction following surgery.}, } @article {pmid36585141, year = {2022}, author = {Fauria, K and Minguillon, C and Knezevic, I and Tort-Colet, N and Stankeviciute, L and Hernández, L and Rădoi, A and Deulofeu, C and Fuentes-Julián, S and Turull, I and Fusté, D and Sánchez-Benavides, G and Arenaza-Urquijo, EM and Suárez-Calvet, M and Holst, SC and Garcés, P and Mueggler, T and Zetterberg, H and Blennow, K and Arqueros, A and Iranzo, Á and Domingo Gispert, J and Molinuevo, JL and Grau-Rivera, O}, title = {Exploring cognitive and biological correlates of sleep quality and their potential links with Alzheimer's disease (ALFASleep project): protocol for an observational study.}, journal = {BMJ open}, volume = {12}, number = {12}, pages = {e067159}, pmid = {36585141}, issn = {2044-6055}, mesh = {Humans ; Middle Aged ; *Alzheimer Disease/diagnosis ; Biomarkers ; Cognition/physiology ; *Cognitive Dysfunction/diagnosis ; Observational Studies as Topic ; Orexins/cerebrospinal fluid ; Sleep Quality ; }, abstract = {INTRODUCTION: The growing worldwide prevalence of Alzheimer's disease (AD) and the lack of effective treatments pose a dire medical challenge. Sleep disruption is also prevalent in the ageing population and is increasingly recognised as a risk factor and an early sign of AD. The ALFASleep project aims to characterise sleep with subjective and objective measurements in cognitively unimpaired middle/late middle-aged adults at increased risk of AD who are phenotyped with fluid and neuroimaging AD biomarkers. This will contribute to a better understanding of the pathophysiological mechanisms linking sleep with AD, thereby paving the way for the development of non-invasive biomarkers and preventive strategies targeting sleep.

METHODS AND ANALYSIS: We will invite 200 participants enrolled in the ALFA+ (for ALzheimer and FAmilies) prospective observational study to join the ALFASleep study. ALFA+ participants are cognitively unimpaired middle-aged/late middle-aged adults who are followed up every 3 years with a comprehensive set of evaluations including neuropsychological tests, blood and cerebrospinal fluid (CSF) sampling, and MRI and positron emission tomography acquisition. ALFASleep participants will be additionally characterised with actigraphy and CSF-orexin-A measurements, and a subset (n=90) will undergo overnight polysomnography. We will test associations of sleep measurements and CSF-orexin-A with fluid biomarkers of AD and glial activation, neuroimaging outcomes and cognitive performance. In case we found any associations, we will test whether changes in AD and/or glial activation markers mediate the association between sleep and neuroimaging or cognitive outcomes and whether sleep mediates associations between CSF-orexin-A and AD biomarkers.

ETHICS AND DISSEMINATION: The ALFASleep study protocol has been approved by the independent Ethics Committee Parc de Salut Mar, Barcelona (2018/8207/I). All participants have signed a written informed consent before their inclusion (approved by the same ethics committee). Study findings will be presented at national and international conferences and submitted for publication in peer-reviewed journals.

TRIAL REGISTRATION NUMBER: NCT04932473.}, } @article {pmid36584844, year = {2023}, author = {Zhang, Y and Ebelt, ST and Shi, L and Scovronick, NC and D'Souza, RR and Steenland, K and Chang, HH}, title = {Short-term associations between warm-season ambient temperature and emergency department visits for Alzheimer's disease and related dementia in five US states.}, journal = {Environmental research}, volume = {220}, number = {}, pages = {115176}, pmid = {36584844}, issn = {1096-0953}, support = {R01 ES027892/ES/NIEHS NIH HHS/United States ; R21 ES032606/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; Aged ; Seasons ; Temperature ; *Alzheimer Disease/epidemiology ; Emergency Service, Hospital ; Hot Temperature ; }, abstract = {BACKGROUND: Ambient temperatures are projected to increase in the future due to climate change. Alzheimer's disease (AD) and Alzheimer's disease-related dementia (ADRD) affect millions of individuals and represent substantial health burdens in the US. High temperature may be a risk factor for AD/ADRD outcomes with several recent studies reporting associations between temperature and AD mortality. However, the link between heat and AD morbidity is poorly understood.

METHODS: We examined short-term associations between warm-season daily ambient temperature and AD/ADRD emergency department (ED) visits for individuals aged 45 years or above during the warm season (May to October) for up to 14 years (2005-2018) in five US states: California, Missouri, North Carolina, New Jersey, and New York. Daily ZIP code-level maximum, average and minimum temperature exposures were derived from 1 km gridded Daymet products. Associations are assessed using a time-stratified case-crossover design using conditional logistic regression.

RESULTS: We found consistent positive short-term effects of ambient temperature among 3.4 million AD/ADRD ED visits across five states. An increase of the 3-day cumulative temperature exposure of daily average temperature from the 50th to the 95th percentile was associated with a pooled odds ratio of 1.042 (95% CI: 1.034, 1.051) for AD/ADRD ED visits. We observed evidence of the association being stronger for patients 65-74 years of age and for ED visits that led to hospital admissions. Temperature associations were also stronger among AD/ADRD ED visits compared to ED visits for other reasons, particularly among patients aged 65-74 years.

CONCLUSION: People with AD/ADRD may represent a vulnerable population affected by short-term exposure to high temperature. Our results support the development of targeted strategies to reduce heat-related AD/ADRD morbidity in the context of global warming.}, } @article {pmid36583718, year = {2023}, author = {Roy, R and Khan, J and Pradhan, K and Nayak, P and Sarkar, A and Nandi, S and Ghosh, S and Ram, H and Ghosh, S}, title = {Short Peptoid Evolved from the Key Hydrophobic Stretch of Amyloid-β42 Peptide Serves as a Potent Therapeutic Lead of Alzheimer's Disease.}, journal = {ACS chemical neuroscience}, volume = {14}, number = {2}, pages = {246-260}, doi = {10.1021/acschemneuro.2c00549}, pmid = {36583718}, issn = {1948-7193}, mesh = {Rats ; Animals ; *Alzheimer Disease/metabolism ; Reactive Oxygen Species ; *Peptoids/pharmacology/metabolism ; Amyloid beta-Peptides/metabolism ; Peptide Fragments/metabolism ; Hydrophobic and Hydrophilic Interactions ; }, abstract = {Amyloid-β 42(Aβ42), an enzymatically cleaved (1-42 amino acid long) toxic peptide remnant, has long been reported to play the key role in Alzheimer's disease (AD). Aβ42 also plays the key role in the onset of other AD-related factors including hyperphosphorylation of tau protein that forms intracellular neurofibrillary tangles, imbalances in the function of the neurotransmitter acetylcholine, and even generation of reactive oxygen species (ROS), disrupting the cytoskeleton and homeostasis of the cell. To address these issues, researchers have tried to construct several strategies to target multiple aspects of the disease but failed to produce any clinically successful therapeutic molecules. In this article, we report a new peptoid called RA-1 that was designed and constructed from the hydrophobic stretch of the Aβ42 peptide, [16]KLVFFA[21]. This hydrophobic stretch is primarily responsible for the Aβ42 peptide aggregation. Experimental study showed that the RA-1 peptoid is stable under proteolytic conditions, can stabilize the microtubule, and can inhibit the formation of toxic Aβ42 aggregates by attenuating hydrophobic interactions between Aβ42 monomers. Furthermore, results from various intracellular assays showed that RA-1 inhibits Aβ42 fibril formation caused by the imbalance in AchE activity, reduces the production of cytotoxic reactive oxygen species (ROS), and promotes neurite outgrowth even in the toxic environment. Remarkably, we have also demonstrated that our peptoid has significant ability to improve the cognitive ability and memory impairment in in vivo rats exposed to AlCl3 and d-galactose (d-gal) dementia model. These findings are also validated with histological studies. Overall, our newly developed peptoid emerges as a multimodal potent therapeutic lead molecule against AD.}, } @article {pmid36583625, year = {2022}, author = {Rus, T and Mlakar, J and Ležaić, L and Vo, A and Nguyen, N and Tang, C and Fiorini, M and Prieto, E and Marti-Andres, G and Arbizu, J and Eidelberg, D and Trošt, M}, title = {Sporadic Creutzfeldt-Jakob disease is associated with reorganization of metabolic connectivity in a pathological brain network.}, journal = {European journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1111/ene.15669}, pmid = {36583625}, issn = {1468-1331}, abstract = {BACKGROUND AND PURPOSE: Although sporadic Creutzfeldt-Jakob disease (sCJD) is a rare cause of dementia, it is critical to understand its functional networks as the prion protein spread throughout the brain may share similar mechanisms with other more common neurodegenerative disorders. In this study, the metabolic brain network associated with sCJD was investigated and its internal network organization was explored.

METHODS: We explored 2-[[18] F]fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) brain scans of 29 sCJD patients, 56 normal controls (NCs) and 46 other dementia patients from two independent centers. sCJD-related pattern (CJDRP) was identified in a cohort of 16 pathologically proven sCJD patients and 16 age-matched NCs using scaled subprofile modeling/principal component analysis and was prospectively validated in an independent cohort of 13 sCJD patients and 20 NCs. The pattern's specificity was tested on other dementia patients and its clinical relevance by clinical correlations. The pattern's internal organization was further studied using graph theory methods.

RESULTS: The CJDRP was characterized by relative hypometabolism in the bilateral caudate, thalami, middle and superior frontal gyri, parietal lobe and posterior cingulum in association with relative hypermetabolism in the hippocampi, parahippocampal gyri and cerebellum. The pattern's expression significantly discriminated sCJD from NCs and other dementia patients (p < 0.005; receiver operating characteristic analysis CJD vs. NCs area under the curve [AUC] 0.90-0.96, sCJD vs. Alzheimer's disease AUC 0.78, sCJD vs. behavioral variant of frontotemporal dementia AUC 0.84). The pattern's expression significantly correlated with cognitive, functional decline and disease duration. The metabolic connectivity analysis revealed inefficient information transfer with specific network reorganization.

CONCLUSIONS: The CJDRP is a robust metabolic biomarker of sCJD. Due to its excellent clinical correlations it has the potential to monitor disease in emerging disease-modifying trials.}, } @article {pmid36583624, year = {2022}, author = {Dauar, MT and Labonté, A and Picard, C and Miron, J and Rosa-Neto, P and Zetterberg, H and Blennow, K and Villeneuve, S and Poirier, J}, title = {Characterization of the contactin 5 protein and its risk-associated polymorphic variant throughout the Alzheimer's disease spectrum.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {}, number = {}, pages = {}, doi = {10.1002/alz.12868}, pmid = {36583624}, issn = {1552-5279}, abstract = {INTRODUCTION: We investigate the CNTN5 rs1461684 G variant and the contactin 5 protein in sporadic Alzheimer's disease (sAD).

METHODS: Contactin 5, sAD biomarkers, and synaptic markers were measured in the cerebrospinal fluid (CSF). Amyloid and tau deposition were assessed using positron emission tomography. Contactin 5 protein and mRNA levels were measured in brain tissue.

RESULTS: CSF contactin 5 increases progressively in cognitively unimpaired individuals and is decreased in mild cognitive impairment and sAD. CSF contactin 5 correlates with sAD biomarkers and with synaptic markers. The rs1461684 G variant associates with faster disease progression in cognitively unimpaired subjects. Cortical full-length and isoform 3 CNTN5 mRNAs are decreased in the presence of the G allele and as a function of Consortium to Establish a Registry for Alzheimer's Disease stages.

DISCUSSION: The newly identified rs1461684 G variant associates with sAD risk, rate of disease progression, and gene expression. Contactin 5 protein and mRNA are affected particularly in the early stages of the disease.}, } @article {pmid36583547, year = {2022}, author = {Zhang, M and Ganz, AB and Rohde, S and Rozemuller, AJM and Bank, NB and Reinders, MJT and Scheltens, P and Hulsman, M and Hoozemans, JJM and Holstege, H}, title = {Resilience and resistance to the accumulation of amyloid plaques and neurofibrillary tangles in centenarians: An age-continuous perspective.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {}, number = {}, pages = {}, doi = {10.1002/alz.12899}, pmid = {36583547}, issn = {1552-5279}, abstract = {INTRODUCTION: With increasing age, neuropathological substrates associated with Alzheimer's disease (AD) accumulate in brains of cognitively healthy individuals-are they resilient, or resistant to AD-associated neuropathologies?

METHODS: In 85 centenarian brains, we correlated NIA (amyloid) stages, Braak (neurofibrillary tangle) stages, and CERAD (neuritic plaque) scores with cognitive performance close to death as determined by Mini-Mental State Examination (MMSE) scores. We assessed centenarian brains against 2131 brains from AD patients, non-AD demented, and non-demented individuals in an age continuum ranging from 16 to 100+ years.

RESULTS: With age, brains from non-demented individuals reached the NIA and Braak stages observed in AD patients, while CERAD scores remained lower. In centenarians, NIA stages varied (22.4% were the highest stage 3), Braak stages rarely exceeded stage IV (5.9% were V), and CERAD scores rarely exceeded 2 (4.7% were 3); within these distributions, we observed no correlation with the MMSE (NIA: P = 0.60; Braak: P = 0.08; CERAD: P = 0.16).

DISCUSSION: Cognitive health can be maintained despite the accumulation of high levels of AD-related neuropathological substrates.

HIGHLIGHTS: Cognitively healthy elderly have AD neuropathology levels similar to AD patients. AD neuropathology loads do not correlate with cognitive performance in centenarians. Some centenarians are resilient to the highest levels of AD neuropathology.}, } @article {pmid36583449, year = {2022}, author = {Kisby, GE and Oakes, H and Beckett, D and Spencer, PS}, title = {MGMT, a risk factor for both genetic and environmental forms of dementia.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {}, number = {}, pages = {}, doi = {10.1002/alz.12900}, pmid = {36583449}, issn = {1552-5279}, abstract = {MGMT, the gene coding for the DNA-repair protein O[6] -methylguanine methyltransferase, which has been recently shown to be a risk factor for inherited forms of Alzheimer's disease (AD), notably among women, might also be linked to Western Pacific amyotrophic lateral sclerosis and Parkinsonism-dementia complex (ALS/PDC), one phenotype of which is an AD-like dementia. Guam ALS/PDC is strongly considered to be an environmental disorder caused by oral exposure to natural toxins (i.e., genotoxic/epigenotoxic chemicals), notably methylazoxymethanol (MAM) that alkylates guanine to form O[6] -methylguanine, found in the seed of cycad plants traditionally used for food. Thus, the DNA-repair protein MGMT might participate in both AD and in the AD-related disorder ALS/PDC.}, } @article {pmid36583371, year = {2022}, author = {Furtado, A and Esgalhado, AJ and Duarte, AC and Costa, AR and Costa-Brito, AR and Carro, E and Ishikawa, H and Schroten, H and Schwerk, C and Gonçalves, I and Arosa, FA and Santos, CRA and Quintela, T}, title = {Circadian rhythmicity of amyloid-beta-related molecules is disrupted in the choroid plexus of a female Alzheimer's disease mouse model.}, journal = {Journal of neuroscience research}, volume = {}, number = {}, pages = {}, doi = {10.1002/jnr.25164}, pmid = {36583371}, issn = {1097-4547}, abstract = {The choroid plexus (CP) is part of the blood-cerebrospinal fluid barrier (BCSFB) and was recently described as an important component of the circadian clock system. It is the principal source of cerebrospinal fluid (CSF) and responsible for the synthesis and secretion of various neuroprotective peptides including those involved in amyloid-β (Aβ) transport/degradation, contributing to Aβ homeostasis. Inadequate Aβ metabolic clearance and transport across the BCSFB have been associated with circadian dysfunctions in Alzheimer's disease (AD) patients. To investigate whether AD pathology influences Aβ scavengers circadian expression, we collected CP at different time points from an AD mouse model (APP/PS1) (female and male animals, aged 6- and 12-months-old) and analyzed their mRNA expression by Real-time RT-PCR. Only angiotensin-converting enzyme (Ace) expression in 6-month-old female wild-type mice and transthyretin (Ttr) expression in 12-month-old female wild-type mice presented significant rhythmicity. The circadian rhythmicity of Ace and Ttr, prompt us to analyze the involvement of circadian rhythm in Aβ uptake. A human CP papilloma (HIBCPP) cell line was incubated with Aβ-488 and uptake was evaluated at different time points using flow cytometry. Aβ uptake displayed circadian rhythmicity. Our results suggest that AD might affect Aβ scavengers rhythmicity and that Aβ clearance is a rhythmic process possibly regulated by the rhythmic expression of Aβ scavengers.}, } @article {pmid36583247, year = {2022}, author = {De Wit, L and Goldstein, FC and Loring, DW}, title = {Clinical value of the Montreal Cognitive Assessment free recall condition alone versus cued recall and recognition conditions to detect true memory impairment.}, journal = {Applied neuropsychology. Adult}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/23279095.2022.2161050}, pmid = {36583247}, issn = {2327-9109}, abstract = {The Montreal Cognitive Assessment (MoCA) is widely used as a screener to characterize cognition. Although only the delayed free recall condition is required for administration, performance on the optional cued recall and multiple-choice recognition conditions may improve diagnostic accuracy over free recall alone. Data on 719 individuals with MCI and 601 controls were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The Rey Auditory Verbal Learning Test (AVLT) delayed free recall condition was used as the gold standard of memory status. Participants with T-scores ≤30 (≤2 SDs below the mean) were classified as memory "impaired." Binary logistic regressions assessed if combined MoCA cued recall/recognition predicted impaired delayed recall on the AVLT beyond the contribution of MoCA free recall. Results showed that MoCA free recall predicted AVLT delayed recall, and that the addition of combined MoCA cued recall/recognition improved the ability to detect impaired AVLT recall, with a better overall model fit. The combined MoCA cued recall/recognition score also had higher specificity and likelihood ratios in detecting memory impairment than MoCA free recall, while higher sensitivity values were present for free recall. Thus, the additional administration of the MoCA cued recall and recognition is recommended.}, } @article {pmid36583189, year = {2022}, author = {Chen, F and Wang, N and Tian, X and Qin, Y and Su, J and He, R and He, X}, title = {The potential diagnostic accuracy of urine formaldehyde levels in Alzheimer's disease: A systematic review and meta-analysis.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1057059}, pmid = {36583189}, issn = {1663-4365}, abstract = {BACKGROUND: Formaldehyde (FA), a toxic aldehyde, has been shown to be associated with a variety of cognitive disorders, including Alzheimer's disease (AD). There is increasing evidence that FA levels are significantly increased in AD patients and may be involved in the pathological process of AD. The aim of this study was to assess the potential diagnostic value of urine FA levels in AD using meta-analysis techniques.

METHODS: Original reports of morning urine FA levels in AD patients and healthy controls (HCs) were included in the meta-analysis. Standardized mean differences (SMD) were calculated using a random-effects model, heterogeneity was explored using methodological, age, sex difference and sensitivity analyses, and receiver operating characteristic (ROC) curves were constructed to assess the diagnostic value of urine FA levels in AD.

RESULTS: A total of 12 studies were included, and the urine FA levels of 874 AD patients and 577 HCs were reviewed. Compared with those in HCs, the FA levels were significantly increased in AD patients. The heterogeneity of the results did not affect their robustness, and results of the area under the curve (AUC) suggested that urine FA levels had good potential diagnostic value.

CONCLUSION: Urine FA levels are involved in AD disease progression and are likely to be useful as a potential biomarker for clinical auxiliary diagnosis. However, further studies are needed to validate the results of this study.}, } @article {pmid36583187, year = {2022}, author = {El Gaamouch, F and Chen, F and Ho, L and Lin, HY and Yuan, C and Wong, J and Wang, J}, title = {Benefits of dietary polyphenols in Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1019942}, pmid = {36583187}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) is an irreversible progressive neurodegenerative disease affecting approximately 50 million people worldwide. It is estimated to reach 152 million by the year 2050. AD is the fifth leading cause of death among Americans age 65 and older. In spite of the significant burden the disease imposes upon patients, their families, our society, and our healthcare system, there is currently no cure for AD. The existing approved therapies only temporarily alleviate some of the disease's symptoms, but are unable to modulate the onset and/or progression of the disease. Our failure in developing a cure for AD is attributable, in part, to the multifactorial complexity underlying AD pathophysiology. Nonetheless, the lack of successful pharmacological approaches has led to the consideration of alternative strategies that may help delay the onset and progression of AD. There is increasing recognition that certain dietary and nutrition factors may play important roles in protecting against select key AD pathologies. Consistent with this, select nutraceuticals and phytochemical compounds have demonstrated anti-amyloidogenic, antioxidative, anti-inflammatory, and neurotrophic properties and as such, could serve as lead candidates for further novel AD therapeutic developments. Here we summarize some of the more promising dietary phytochemicals, particularly polyphenols that have been shown to positively modulate some of the important AD pathogenesis aspects, such as reducing β-amyloid plaques and neurofibrillary tangles formation, AD-induced oxidative stress, neuroinflammation, and synapse loss. We also discuss the recent development of potential contribution of gut microbiome in dietary polyphenol function.}, } @article {pmid36583186, year = {2022}, author = {Wu, YQ and Wang, YN and Zhang, LJ and Liu, LQ and Pan, YC and Su, T and Liao, XL and Shu, HY and Kang, M and Ying, P and Xu, SH and Shao, Y}, title = {Corrigendum: Regional homogeneity in patients with mild cognitive impairment: A resting-state functional magnetic resonance imaging study.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1098983}, pmid = {36583186}, issn = {1663-4365}, abstract = {[This corrects the article DOI: 10.3389/fnagi.2022.877281.].}, } @article {pmid36583148, year = {2022}, author = {Han, SS and White, K and Cisek, E}, title = {A Feasibility Study of Individuals Living at Home with Alzheimer's Disease and Related Dementias: Utilization of Visual Mapping Assistive Technology to Enhance Quality of Life and Reduce Caregiver Burden.}, journal = {Clinical interventions in aging}, volume = {17}, number = {}, pages = {1885-1892}, pmid = {36583148}, issn = {1178-1998}, mesh = {Humans ; *Alzheimer Disease/therapy ; Quality of Life ; *Dementia/psychology ; Activities of Daily Living ; Caregiver Burden ; Feasibility Studies ; Caregivers/psychology ; *Self-Help Devices ; }, abstract = {Efficacy of assistive technology continues to evolve as a means of helping individuals with cognitive and intellectual disabilities, asserting the importance of its research. We report outcomes of a six-week randomized control feasibility study in a small cohort of 16 family caregivers of individuals living with Alzheimer's disease and related dementias. An experimental group of seven family caregivers used visual mapping software on smart devices (step-by-step pictures, audio, and videos instructing how to complete a task) to support carrying out activities of daily living with their care recipients. In comparison, control group of nine family caregivers used smart devices to access and view educational videos focused on dementia care. After a six-week study, compared to caregivers using educational videos, caregivers using visual maps assistive technology reported higher satisfaction of use and stronger recommendation of use to others. Caregivers using visual maps technology also exhibited more improved quality of life scores and improved completion of activities of daily living for their dementia care recipients, as well as reduced caregiver burden scores compared to the caregivers in the control group. These promising findings show that the use of assistive technology is feasible in the home setting and suggest time is ripe for undertaking systematic studies of assistive technology's potential to advance effective behavioral interventions in dementia home and family settings.}, } @article {pmid36583137, year = {2023}, author = {Maito, MA and Santamaría-García, H and Moguilner, S and Possin, KL and Godoy, ME and Avila-Funes, JA and Behrens, MI and Brusco, IL and Bruno, MA and Cardona, JF and Custodio, N and García, AM and Javandel, S and Lopera, F and Matallana, DL and Miller, B and de Oliveira, MO and Pina-Escudero, SD and Slachevsky, A and Ortiz, ALS and Takada, LT and Tagliazuchi, E and Valcour, V and Yokoyama, JS and Ibañez, A}, title = {Classification of Alzheimer's disease and frontotemporal dementia using routine clinical and cognitive measures across multicentric underrepresented samples: A cross sectional observational study.}, journal = {Lancet regional health. Americas}, volume = {17}, number = {}, pages = {}, pmid = {36583137}, issn = {2667-193X}, support = {R01 AG057234/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Global brain health initiatives call for improving methods for the diagnosis of Alzheimer's disease (AD) and frontotemporal dementia (FTD) in underrepresented populations. However, diagnostic procedures in upper-middle-income countries (UMICs) and lower-middle income countries (LMICs), such as Latin American countries (LAC), face multiple challenges. These include the heterogeneity in diagnostic methods, lack of clinical harmonisation, and limited access to biomarkers.

METHODS: This cross-sectional observational study aimed to identify the best combination of predictors to discriminate between AD and FTD using demographic, clinical and cognitive data among 1794 participants [904 diagnosed with AD, 282 diagnosed with FTD, and 606 healthy controls (HCs)] collected in 11 clinical centres across five LAC (ReDLat cohort).

FINDINGS: A fully automated computational approach included classical statistical methods, support vector machine procedures, and machine learning techniques (random forest and sequential feature selection procedures). Results demonstrated an accurate classification of patients with AD and FTD and HCs. A machine learning model produced the best values to differentiate AD from FTD patients with an accuracy = 0.91. The top features included social cognition, neuropsychiatric symptoms, executive functioning performance, and cognitive screening; with secondary contributions from age, educational attainment, and sex.

INTERPRETATION: Results demonstrate that data-driven techniques applied in archival clinical datasets could enhance diagnostic procedures in regions with limited resources. These results also suggest specific fine-grained cognitive and behavioural measures may aid in the diagnosis of AD and FTD in LAC. Moreover, our results highlight an opportunity for harmonisation of clinical tools for dementia diagnosis in the region.

FUNDING: This work was supported by the Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat), funded by NIA/NIH (R01AG057234), Alzheimer's Association (SG-20-725707-ReDLat), Rainwater Foundation, Takeda (CW2680521), Global Brain Health Institute; as well as CONICET; FONCYT-PICT (2017-1818, 2017-1820); PIIECC, Facultad de Humanidades, Usach; Sistema General de Regalías de Colombia (BPIN2018000100059), Universidad del Valle (CI 5316); ANID/FONDECYT Regular (1210195, 1210176, 1210176); ANID/FONDAP (15150012); ANID/PIA/ANILLOS ACT210096; and Alzheimer's Association GBHI ALZ UK-22-865742.}, } @article {pmid36583084, year = {2022}, author = {Cohen, LD and Ziv, T and Ziv, NE}, title = {Synapse integrity and function: Dependence on protein synthesis and identification of potential failure points.}, journal = {Frontiers in molecular neuroscience}, volume = {15}, number = {}, pages = {1038614}, pmid = {36583084}, issn = {1662-5099}, abstract = {Synaptic integrity and function depend on myriad proteins - labile molecules with finite lifetimes that need to be continually replaced with freshly synthesized copies. Here we describe experiments designed to expose synaptic (and neuronal) properties and functions that are particularly sensitive to disruptions in protein supply, identify proteins lost early upon such disruptions, and uncover potential, yet currently underappreciated failure points. We report here that acute suppressions of protein synthesis are followed within hours by reductions in spontaneous network activity levels, impaired oxidative phosphorylation and mitochondrial function, and, importantly, destabilization and loss of both excitatory and inhibitory postsynaptic specializations. Conversely, gross impairments in presynaptic vesicle recycling occur over longer time scales (days), as does overt cell death. Proteomic analysis identified groups of potentially essential 'early-lost' proteins including regulators of synapse stability, proteins related to bioenergetics, fatty acid and lipid metabolism, and, unexpectedly, numerous proteins involved in Alzheimer's disease pathology and amyloid beta processing. Collectively, these findings point to neuronal excitability, energy supply and synaptic stability as early-occurring failure points under conditions of compromised supply of newly synthesized protein copies.}, } @article {pmid36582800, year = {2022}, author = {Khalilian, S and Abedinlou, H and Hussen, BM and Imani, SZH and Ghafouri-Fard, S}, title = {The emerging role of miR-20b in human cancer and other disorders: Pathophysiology and therapeutic implications.}, journal = {Frontiers in oncology}, volume = {12}, number = {}, pages = {985457}, pmid = {36582800}, issn = {2234-943X}, abstract = {miR-20b is a microRNA with diverse and somehow contradictory roles in the pathogenesis of human disorders, especially cancers. It has been known to be a tumor suppressor in colon cancer, renal cell carcinoma, prostate cancer, osteosarcoma and papillary thyroid cancer. In lung cancer and breast cancers, both tumor suppressor and oncogenic effects have been identified for this miRNA. Finally, in T cell leukemia, hepatocellular carcinoma, esophageal squamous cell carcinoma and cervical and gastric cancers, miR-20b is regarded as an oncogenic miRNA. In several types of cancer, dysregulation of miR-20b has been recognized as a predictive marker for patients' survival. Dysregulation of miR-20b has also been recognized in Alzheimer's disease, diabetic retinopathy, myocardial ischemia/infarction, chronic hepatitis B and multiple sclerosis. In the current review, we have summarized the miR-20b targets and related cellular processes. We have also provided a review of participation of this miRNA in different human disorders.}, } @article {pmid36582660, year = {2022}, author = {Estupiñán Artiles, C and Regan, J and Donnellan, C}, title = {Physiological Mechanisms and Associated Pathophysiology of Dysphagia in Older Adults.}, journal = {Gerontology & geriatric medicine}, volume = {8}, number = {}, pages = {23337214221142949}, pmid = {36582660}, issn = {2333-7214}, abstract = {Dysphagia can be a common secondary sequela of neurological and neurodegenerative disorders in older adults. Early screening, identification, and management of dysphagia is essential to avoid serious complications, including malnutrition, dehydration, aspiration pneumonia; and promote quality of life. Although individuals of all ages may experience swallowing difficulties, dysphagia and its complications are more common in older adults. This literature review aims to provide an overview of the physiological mechanisms of normal swallowing in healthy individuals and age-related changes to swallowing function, the pathophysiology of dysphagia associated with three common neurological disorders affecting older adults (stroke, Parkinson's disease, and dementia), and implications for interdisciplinary clinical practice. Increased awareness of these issues may contribute to a more timely and efficient identification of older adults with dysphagia and to improve overall dysphagia management.}, } @article {pmid36582609, year = {2022}, author = {Li, J and Wang, Z and Nan, X and Yin, M and Fang, H}, title = {Hotspots and frontier trends of diabetic associated cognitive decline research based on rat and mouse models from 2012 to 2021: A bibliometric study.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {1073224}, pmid = {36582609}, issn = {1664-2295}, abstract = {BACKGROUND: The establishment of rodent models, such as rat and mouse models, plays a critical role in the study of diabetic associated cognitive decline. With the continuous growth of relevant literature information, it is difficult for researchers to accurately and timely capture the topics in this field. Therefore, this study aims to explore the current status and frontier trends of diabetic associated cognitive decline research based on rat and mouse models through a bibliometric analysis.

METHODS: We collected 701 original articles on this subject from the Science Citation Index Expanded of the Web of Science Core Collection from 2012 to 2021. Then we utilized CiteSpace and VOSviewer for plotting knowledge maps and evaluating hotpots and trends.

RESULTS: During this decade, except for a slight decline in 2020, the number of annual outputs on diabetes associated cognitive decline research using rat and mouse models increased every year. China (country), China Pharmaceutical University (institution), Gao, Hongchang (the author from the School of Pharmacy of Wenzhou Medical University, China), and Metabolic Brain Disease (journal) published the most papers in this research field. The analysis results of co-cited references and co-occurrence keywords indicated that "mechanisms and prevention and treatment methods", especially "oxidative stress", "potential association with Alzheimer's disease" and "spatial memory" are research focuses in this subject area. The bursts detection of references and keywords implied that "cognitive impairment of type 1 diabetes" and "autophagy and diabetes associated cognitive decline" will be potential directions for future research in this subject area.

CONCLUSION: This study systematically assessed general information, current status and emerging trends of diabetic associated cognitive decline research using rat and mouse models in the past decade based on a bibliometric analysis. The number of publications was annually increasing although a slight decline was observed in 2020. Contributions from different countries/regions, institutions, authors, co-cited authors, journals and co-cited journals were evaluated, which may also be used to guide future research. Through the analysis of references and keywords, we predicted the future research hotspots and trends in this field.}, } @article {pmid36582459, year = {2022}, author = {Guo, F and Li, Q and Zhang, X and Liu, Y and Jiang, J and Cheng, S and Yu, S and Zhang, X and Liu, F and Li, Y and Rose, G and Zhang, H}, title = {Applications of Carbon Dots for the Treatment of Alzheimer's Disease.}, journal = {International journal of nanomedicine}, volume = {17}, number = {}, pages = {6621-6638}, pmid = {36582459}, issn = {1178-2013}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Carbon/pharmacology ; Quality of Life ; Blood-Brain Barrier ; Brain ; Pharmaceutical Preparations ; }, abstract = {There are currently approximately 50 million victims of Alzheimer's disease (AD) worldwide. The exact cause of the disease is unknown at this time, but amyloid plaques and neurofibrillary tangles in the brain are hallmarks of the disease. Current drug treatments for AD may slow the progression of the disease and improve the quality of life of patients, but they are often only minimally effective and are not cures. A major obstacle to developing and delivering more effective drug therapies is the presence of the blood-brain barrier (BBB), which prevents many compounds with therapeutic potential from reaching the central nervous system. Nanotechnology may provide a solution to this problem. Among the medical nanomaterials currently being studied, carbon dots (CDs) have attracted widespread attention because of their ability to cross the BBB, non-toxicity, and potential for drug/gene delivery.}, } @article {pmid36582176, year = {2022}, author = {Sun, Y and Islam, S and Gao, Y and Nakamura, T and Zou, K and Michikawa, M}, title = {Apolipoprotein E4 inhibits γ-secretase activity via binding to the γ-secretase complex.}, journal = {Journal of neurochemistry}, volume = {}, number = {}, pages = {}, doi = {10.1111/jnc.15750}, pmid = {36582176}, issn = {1471-4159}, abstract = {The mechanisms of amyloid accumulation in familial Alzheimer's disease (FAD) and sporadic AD (SAD) are controversial. In FAD, mutations in presenilin (PSEN) impair γ-secretase activity and lead to abnormal amyloid β-protein (Aβ) production, thereby increasing the Aβ42/40 ratio. SAD is postulated to be caused by decreased Aβ clearance of apolipoprotein E4 (APOE4), the strongest risk factor for SAD. However, whether intracellular APOE4 affects Aβ production is unclear. Using APOE3 and APOE4 knock-in (KI) mouse brain and primary cultured fibroblasts from these mice, in this study, we demonstrated that APOE3 and APOE4 bind to the γ-secretase complex and isoform-dependently regulate its activity and Aβ production. We found that Aβ40 levels and γ-secretase activity were higher in APOE knockout mouse brain than in wild-type mouse brain. APOE4-KI fibroblasts had significant lower Aβ levels and γ-secretase activity but higher Aβ42/40 ratio compared with APOE3-KI cells, indicating that APOE4-KI reduces Aβ production by inhibiting γ-secretase activity. Interestingly, the levels of γ-secretase complex bound to APOE4 are higher than those bound to APOE3, and the levels of γ-secretase complex in the brain and fibroblasts of APOE4-KI mice were higher than those of APOE3-KI mice. Taken together, our findings demonstrate that intracellular APOE4 inhibits Aβ production, more preferentially inhibits Aβ40 production, and thereby induces an increase in the Aβ42/40 ratio via binding to the γ-secretase complex. These results suggest a novel mechanism in which intracellular APOE4 contributes to the pathogenesis of SAD by inhibiting γ-secretase activity.}, } @article {pmid36581949, year = {2022}, author = {Oliver, MD and Morrison, C and Kamal, F and Graham, J and Dadar, M}, title = {Subjective cognitive decline is a better marker for future cognitive decline in females than in males.}, journal = {Alzheimer's research & therapy}, volume = {14}, number = {1}, pages = {197}, pmid = {36581949}, issn = {1758-9193}, support = {MFE-176608//CIHR/Canada ; }, mesh = {Humans ; Male ; Female ; Aged ; *Alzheimer Disease/psychology ; Neuropsychological Tests ; *Cognitive Dysfunction/diagnosis ; Cognition/physiology ; Biomarkers ; }, abstract = {BACKGROUND: The identification of biomarkers for early detection of Alzheimer's disease (AD) is critical to the development of therapies and interventions targeted at symptom management and tracking the pathophysiology of disease. The endorsement of subjective cognitive decline (SCD) has emerged as a potential indicator of early change in cognitive status that may be predictive of future impairment at a time when measurable declines in neuropsychological performance cannot be detected. While there are numerous findings revealing sex differences in the prevalence of AD, there is a paucity of research examining sex differences in SCD. Therefore, the goal of this project was to determine if the relationship between the endorsement of SCD and future cognitive changes differ as a function of biological sex.

METHODS: A sample of 3019 male and female healthy older adults (2188 without SCD, 831 with SCD), with a mean follow-up time of 5.7 years, were included from the Rush Alzheimer's Disease Center Research Sharing Hub. Linear regressions were performed to determine group differences in baseline cognitive scores, while linear mixed-effects models were completed to determine group differences in the rate of cognitive change over time.

RESULTS: Individuals endorsing SCD had significantly lower baseline cognitive scores and increased rates of decline in all cognitive domains compared to those without SCD. Males exhibited significantly lower scores in baseline performance in global cognition, episodic memory, and perceptual speed regardless of SCD classification. Females with SCD were found to decline at significantly faster rates than both males with SCD and males and females without SCD in all cognitive domains over a maximum 15-year follow-up period.

CONCLUSIONS: SCD is related to lower baseline cognitive performance and faster cognitive decline compared to those who do not endorse SCD. Females with SCD have the fastest rate of decline suggesting that SCD may be more predictive of future decline in females than in males. Targeted assessments of SCD may allow for the identification of individuals for inclusion in intervention trials, and other research studies, aiming to attenuate casual disease processes, which may ultimately aid in the mitigation of sex disparities in AD.}, } @article {pmid36581943, year = {2022}, author = {Pini, L and de Lange, SC and Pizzini, FB and Boscolo Galazzo, I and Manenti, R and Cotelli, M and Galluzzi, S and Cotelli, MS and Corbetta, M and van den Heuvel, MP and Pievani, M}, title = {A low-dimensional cognitive-network space in Alzheimer's disease and frontotemporal dementia.}, journal = {Alzheimer's research & therapy}, volume = {14}, number = {1}, pages = {199}, pmid = {36581943}, issn = {1758-9193}, mesh = {Humans ; Middle Aged ; Aged ; Aged, 80 and over ; *Alzheimer Disease/complications/diagnostic imaging ; *Frontotemporal Dementia/complications/diagnostic imaging/pathology ; Magnetic Resonance Imaging/methods ; Brain/pathology ; Brain Mapping ; Cognition ; *Connectome ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) and frontotemporal dementia (FTD) show network dysfunctions linked with cognitive deficits. Within this framework, network abnormalities between AD and FTD show both convergent and divergent patterns. However, these functional patterns are far from being established and their relevance to cognitive processes remains to be elucidated.

METHODS: We investigated the relationship between cognition and functional connectivity of major cognitive networks in these diseases. Twenty-three bvFTD (age: 71±10), 22 AD (age: 72±6), and 20 controls (age: 72±6) underwent cognitive evaluation and resting-state functional MRI. Principal component analysis was used to describe cognitive variance across participants. Brain network connectivity was estimated with connectome analysis. Connectivity matrices were created assessing correlations between parcels within each functional network. The following cognitive networks were considered: default mode (DMN), dorsal attention (DAN), ventral attention (VAN), and frontoparietal (FPN) networks. The relationship between cognition and connectivity was assessed using a bootstrapping correlation and interaction analyses.

RESULTS: Three principal cognitive components explained more than 80% of the cognitive variance: the first component (cogPC1) loaded on memory, the second component (cogPC2) loaded on emotion and language, and the third component (cogPC3) loaded on the visuo-spatial and attentional domains. Compared to HC, AD and bvFTD showed impairment in all cogPCs (p<0.002), and bvFTD scored worse than AD in cogPC2 (p=0.031). At the network level, the DMN showed a significant association in the whole group with cogPC1 and cogPC2 and the VAN with cogPC2. By contrast, DAN and FPN showed a divergent pattern between diagnosis and connectivity for cogPC2. We confirmed these results by means of a multivariate analysis (canonical correlation).

CONCLUSIONS: A low-dimensional representation can account for a large variance in cognitive scores in the continuum from normal to pathological aging. Moreover, cognitive components showed both convergent and divergent patterns with connectivity across AD and bvFTD. The convergent pattern was observed across the networks primarily involved in these diseases (i.e., the DMN and VAN), while a divergent FC-cognitive pattern was mainly observed between attention/executive networks and the language/emotion cognitive component, suggesting the co-existence of compensatory and detrimental mechanisms underlying these components.}, } @article {pmid36581903, year = {2022}, author = {Tang, L and Wang, ZB and Ma, LZ and Cao, XP and Tan, L and Tan, MS}, title = {Dynamic changes of CSF clusterin levels across the Alzheimer's disease continuum.}, journal = {BMC neurology}, volume = {22}, number = {1}, pages = {508}, pmid = {36581903}, issn = {1471-2377}, mesh = {Humans ; *Alzheimer Disease/pathology ; Amyloid beta-Peptides/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; Clusterin ; Peptide Fragments ; Disease Progression ; Biomarkers/cerebrospinal fluid ; }, abstract = {BACKGROUND: Clusterin is a multifunctional protein, which is associated with the pathogenesis and the development of Alzheimer's disease (AD). Compared with normal controls, inconsistent results have yielded in previous studies for concentration of cerebrospinal fluid (CSF) clusterin in AD patients. We explored CSF clusterin levels in different pathological processes of AD.

METHODS: Following the National Institute on Aging-Alzheimer's Association (NIA-AA) criteria, we employed on the levels of CSF Aβ42(A), phosphorylated-Tau (T), and total-tau (N). Based on previously published cutoffs and the close correlation between CSF p-tau and t-tau, 276 participants from the publicly available ADNI database with CSF biomarkers were divided into four groups: A-(TN)- (normal Aβ42 and normal p-tau and t-tau; n = 50), A+(TN)- (abnormal Aβ42 and normal p-tau and t-tau; n = 39), A+(TN) + (abnormal Aβ42 and abnormal p-tau or t-tau; n = 147), A-(TN) + (normal Aβ42 and abnormal p-tau or t-tau; n = 40). To assess CSF clusterin levels in AD continuum, intergroup differences in four groups were compared. Pairwise comparisons were conducted as appropriate followed by Bonferroni post hoc analyses. To further study the relationships between CSF clusterin levels and AD core pathological biomarkers, we employed multiple linear regression method in subgroups.

RESULTS: Compared with the A-(TN)- group, CSF clusterin levels were decreased in A+ (TN)- group (P = 0.002 after Bonferroni correction), but increased in the A+(TN) + group and the A-(TN) + group (both P <  0.001 after Bonferroni correction). Moreover, we found CSF clusterin levels are positively associated with CSF Aβ42 (β = 0.040, P <  0. 001), CSF p-tau (β = 0.325, P <  0.001) and CSF t-tau (β = 0.346, P <  0.001).

CONCLUSIONS: Our results indicated that there are differences levels of CSF clusterin in different stages of AD pathology. The CSF clusterin level decreased at the early stage are related to abnormal Aβ pathology; and the increased levels are associated with tau pathology and neurodegeneration.}, } @article {pmid36581878, year = {2022}, author = {Lerner, AJ and Arnold, SE and Maxfield, E and Koenig, A and Toth, ME and Fortin, B and Mast, N and Trombetta, BA and Denker, J and Pieper, AA and Tatsuoka, C and Raghupathy, S and Pikuleva, IA}, title = {CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {14}, number = {1}, pages = {198}, pmid = {36581878}, issn = {1758-9193}, support = {P30 AG062428/AG/NIA NIH HHS/United States ; P30 EY011373/EY/NEI NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/metabolism ; Brain/metabolism ; Cholesterol ; Cholesterol 24-Hydroxylase/metabolism/therapeutic use ; Pilot Projects ; }, abstract = {BACKGROUND: Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer's disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Here, we sought to determine whether CYP46A1 could be similarly activated by a low-dose efavirenz in human subjects. METHODS: This pilot study enrolled 5 subjects with early AD. Participants were randomized to placebo (n = 1) or two daily efavirenz doses (50 mg and 200 mg, n = 2 for each) for 20 weeks and evaluated for safety and CYP46A1 target engagement (plasma 24HC levels). A longitudinal mixed model was used to ascertain the statistical significance of target engagement. We also measured 24HC in CSF and conducted a unique stable isotope labeling kinetics (SILK) study with deuterated water to directly measure CYP46A1 activity changes in the brain.

RESULTS: In subjects receiving efavirenz, there was a statistically significant within-group increase (P ≤ 0.001) in the levels of plasma 24HC from baseline. The levels of 24HC in the CSF of subjects on the 200-mg dose of efavirenz were also increased. Target engagement was further supported by the labeling kinetics of 24HC by deuterated water in the SILK study. There were no serious adverse effects in any subjects.

CONCLUSIONS: Our findings suggest efavirenz target engagement in human subjects with early AD. This supports the pursuit of a larger trial for further determination and confirmation of the efavirenz dose that exerts maximal enzyme activation, as well as evaluation of this drug's effects on AD biomarkers and clinical symptomatology.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT03706885.}, } @article {pmid36581785, year = {2022}, author = {Kim, J and Kelley, J and Kleinschmit, K and Richards, N and Adams, T}, title = {Development of dementia in patients who underwent bariatric surgery.}, journal = {Surgical endoscopy}, volume = {}, number = {}, pages = {}, pmid = {36581785}, issn = {1432-2218}, abstract = {BACKGROUND: Dementia, including Alzheimer's disease, interfere with daily function and are one of the major causes of disability, institutionalization, and death. Obesity is associated with an increased risk of dementia. However, the effect of significant and sustained weight loss following bariatric surgery on dementia is not known. The purpose of this study was to assess the long-term risk of dementia following bariatric surgery.

METHODS: A surgical cohort was identified from the Utah Bariatric Surgery Registry and was linked to the Utah Population Database that includes electronic medical records, death records, and State Facility data. Adult subjects (≥ 18 years old) at time of surgery (1996-2016) were matched with non-surgical subjects. The final sample included 51,078 subjects (1:2 matching); surgery group n = 17,026; non-surgery subjects n = 34,052). Dementia were identified by ICD-9/10 diagnosis codes following surgery year or matched baseline year. Cox proportional hazard model was used to calculate the hazard ratio in the outcome between the groups.

RESULTS: Average (SD) age of the subjects was 42 (12) years old at surgery or matched baseline year, 78% were female and mean follow-up time was 10.5 years. 1.4% of the surgery group and 0.5% of the control group had an incidence of dementia. Controlling the covariates in the Cox regression, the surgery group had a higher risk for dementia incidence than the matched non-surgery subjects (HR = 1.33, p = 0.02).

CONCLUSIONS: The study showed an increased hazard for dementia in individuals who underwent bariatric surgery compared to matched non-surgical subjects. Additional long-term data is needed to verify this association.}, } @article {pmid36581749, year = {2022}, author = {Arnold, C and Webster, P}, title = {11 clinical trials that will shape medicine in 2023.}, journal = {Nature medicine}, volume = {28}, number = {12}, pages = {2444-2448}, doi = {10.1038/s41591-022-02132-3}, pmid = {36581749}, issn = {1546-170X}, mesh = {*Medicine ; Research Design ; }, abstract = {Nature Medicine asks leading researchers to name their top clinical trial for 2023, from cervical and prostate cancer screening to new drugs for Parkinson’s disease and Alzheimer’s disease.}, } @article {pmid36581576, year = {2022}, author = {He, Y and Wang, Z}, title = {The roles of HSP40/DNAJ protein family in neurodegenerative diseases.}, journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences}, volume = {51}, number = {5}, pages = {640-646}, doi = {10.3724/zdxbyxb-2021-0406}, pmid = {36581576}, issn = {1008-9292}, mesh = {Humans ; HSP40 Heat-Shock Proteins/genetics ; alpha-Synuclein/metabolism ; *Neurodegenerative Diseases ; *Essential Tremor ; Protein Folding ; Nerve Tissue Proteins ; Molecular Chaperones/metabolism ; }, abstract = {Molecular chaperones and co-chaperones facilitate the assembly of newly synthesized polypeptides and refolding of unfolded or misfolded proteins, thereby maintaining protein homeostasis in cells. As co-chaperones of the master chaperone heat shock protein (HSP) 70, the HSP40 (DNAJ) proteins are largest chaperone family in eukaryotic cells. They contain a characteristic J-domain which mediates interaction with HSP70, thereby helping protein folding. It is well perceived that protein homeostasis is vital for neuronal health. DNAJ family proteins have been linked to the occurrence and progression of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, spinocerebellar ataxia, Charcot-Marie-Tooth disease, spinal muscular atrophy, distal hereditary motor neuropathy, limb-girdle type muscular dystrophy, neuronal ceroid lipofuscinosis and essential tremor in recent studies. DNAJA1 effectively degrades huntington aggregates; DNAJB1 can degrade protein aggregates ataxin-3; DNAJB2 can inhibit the formation of huntington aggregates; DNAJB6 can inhibit the aggregation of Aβ 42 and α-synuclein; DNAJC5 can promote the release of TDP-43, τ protein, and α-synuclein into the extracellular space. Mutations in the essential tremor-associated DNAJC13 gene can prevent endosome protein trafficking. This article reviews the mechanism of DNAJ protein family in neurodegenerative diseases.}, } @article {pmid36581185, year = {2023}, author = {Zhang, F and Rakhimbekova, A and Lashley, T and Madl, T}, title = {Brain regions show different metabolic and protein arginine methylation phenotypes in frontotemporal dementias and Alzheimer's disease.}, journal = {Progress in neurobiology}, volume = {221}, number = {}, pages = {102400}, doi = {10.1016/j.pneurobio.2022.102400}, pmid = {36581185}, issn = {1873-5118}, mesh = {Humans ; *Alzheimer Disease/diagnosis/pathology ; *Frontotemporal Dementia/diagnosis ; Methylation ; *Neurodegenerative Diseases/pathology ; Brain/pathology ; Biomarkers ; Phenotype ; }, abstract = {Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disease with multiple histopathological subtypes. FTD patients share similar symptoms with Alzheimer's disease (AD). Hence, FTD patients are commonly misdiagnosed as AD, despite the consensus clinical diagnostic criteria. It is therefore of great clinical need to identify a biomarker that can distinguish FTD from AD and control individuals, and potentially further differentiate between FTD pathological subtypes. We conducted a metabolomic analysis on post-mortem human brain tissue from three regions: cerebellum, frontal cortex and occipital cortex from control, FTLD-TDP type A, type A-C9, type C and AD. Our results indicate that the brain subdivisions responsible for different functions show different metabolic patterns. We further explored the region-specific metabolic characteristics of different FTD subtypes and AD patients. Different FTD subtypes and AD share similar metabolic phenotypes in the cerebellum, but AD exhibited distinct metabolic patterns in the frontal and occipital regions compared to FTD. The identified brain region-specific metabolite biomarkers could provide a tool for distinguishing different FTD subtypes and AD and provide the first insights into the metabolic changes of FTLD-TDP type A, type A-C9, type C and AD in different regions of the brain. The importance of protein arginine methylation in neurodegenerative disease has come to light, so we investigated whether the arginine methylation level contributes to disease pathogenesis. Our findings provide new insights into the relationship between arginine methylation and metabolic changes in FTD subtypes and AD that could be further explored, to study the molecular mechanism of pathogenesis.}, } @article {pmid36581132, year = {2023}, author = {Li, Y and Fan, H and Han, X and Sun, J and Ni, M and Zhang, L and Fang, F and Zhang, W and Ma, P}, title = {PR-957 Suppresses Th1 and Th17 Cell Differentiation via Inactivating PI3K/AKT Pathway in Alzheimer's Disease.}, journal = {Neuroscience}, volume = {510}, number = {}, pages = {82-94}, doi = {10.1016/j.neuroscience.2022.10.021}, pmid = {36581132}, issn = {1873-7544}, mesh = {Animals ; Mice ; *Th17 Cells/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; *Alzheimer Disease/metabolism ; Leukocytes, Mononuclear ; Cell Differentiation ; }, abstract = {PR-957 [low molecular mass polypeptide (LMP)-7 selective inhibitor] regulates T helper (Th) cell differentiation and inflammatory response in multiple neurological diseases. Hence, this study aimed to explore the effect of PR-957 on Th1/Th2/Th17 cell differentiation, therapeutic efficacy and its potential mechanisms in Alzheimer's disease (AD). The LMP7 expressions in peripheral blood mononuclear cells from 30 AD patients and 30 healthy controls (HC) were detected. PR-957 was added for the incubation of naive cluster of differentiation (CD)4[+] T cells from AD patients, then SC79 [phosphorylated protein kinase B (pAKT) agonist] was added. LMP7, Th1 cells, and Th17 cells were upregulated, while Th2 cells were downregulated in AD patients compared to HC. Also, LMP7 was positively related to Th1 cells and Th17 cells, but it did not correlate with Th2 cells in AD patients. PR-957 treatment downregulated Th1 cells, Th17 cells, and their secreted cytokines as well as phosphorylated phosphoinositide 3-kinase (pPI3K)/PI3K and pAKT/AKT expressions in AD CD4[+] T cells. SC79 addition upregulated pAKT/AKT expression, Th1 cells, and Th17 cells, while downregulated Th2 cells; also SC79 could alleviate the effect of PR-957 on regulating PI3K/AKT pathway and Th1, Th2, and Th17 cell differentiation in AD CD4[+] T cells. Furthermore, PR-957 attenuated cognitive impairment and neurofibrillary tangle; also it inhibited Th17 cell differentiation and PI3K/AKT pathway in the brain and spleen of AD mice. In conclusion, PR-957 suppresses Th1 and Th17 cell differentiation, attenuates neural injury and improves cognitive function via inactivating PI3K/AKT pathway in AD.}, } @article {pmid36581096, year = {2023}, author = {Turkez, H and Altay, O and Yildirim, S and Li, X and Yang, H and Bayram, C and Bolat, I and Oner, S and Tozlu, OO and Arslan, ME and Arif, M and Yulug, B and Hanoglu, L and Cankaya, S and Lam, S and Velioglu, HA and Coskun, E and Idil, E and Nogaylar, R and Ozsimsek, A and Hacimuftuoglu, A and Shoaie, S and Zhang, C and Nielsen, J and Borén, J and Uhlén, M and Mardinoglu, A}, title = {Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases.}, journal = {Life sciences}, volume = {314}, number = {}, pages = {121325}, doi = {10.1016/j.lfs.2022.121325}, pmid = {36581096}, issn = {1879-0631}, mesh = {Humans ; Animals ; Rats ; *Neurodegenerative Diseases/metabolism ; *Parkinson Disease/metabolism ; *Alzheimer Disease/metabolism ; Mitochondria/metabolism ; Models, Animal ; Disease Models, Animal ; }, abstract = {BACKGROUND: Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), are associated with metabolic abnormalities. Integrative analysis of human clinical data and animal studies have contributed to a better understanding of the molecular and cellular pathways involved in the progression of NDDs. Previously, we have reported that the combined metabolic activators (CMA), which include the precursors of nicotinamide adenine dinucleotide and glutathione can be utilized to alleviate metabolic disorders by activating mitochondrial metabolism.

METHODS: We first analysed the brain transcriptomics data from AD patients and controls using a brain-specific genome-scale metabolic model (GEM). Then, we investigated the effect of CMA administration in animal models of AD and PD. We evaluated pathological and immunohistochemical findings of brain and liver tissues. Moreover, PD rats were tested for locomotor activity and apomorphine-induced rotation.

FINDINGS: Analysis of transcriptomics data with GEM revealed that mitochondrial dysfunction is involved in the underlying molecular pathways of AD. In animal models of AD and PD, we showed significant damage in the high-fat diet groups' brain and liver tissues compared to the chow diet. The histological analyses revealed that hyperemia, degeneration and necrosis in neurons were improved by CMA administration in both AD and PD animal models. These findings were supported by immunohistochemical evidence of decreased immunoreactivity in neurons. In parallel to the improvement in the brain, we also observed dramatic metabolic improvement in the liver tissue. CMA administration also showed a beneficial effect on behavioural functions in PD rats.

INTERPRETATION: Overall, we showed that CMA administration significantly improved behavioural scores in parallel with the neurohistological outcomes in the AD and PD animal models and is a promising treatment for improving the metabolic parameters and brain functions in NDDs.}, } @article {pmid36580744, year = {2023}, author = {Liu, P and Cheng, M and Guo, J and Cao, D and Luo, J and Wan, Y and Fang, Y and Jin, Y and Xie, SS and Liu, J}, title = {Dual functional antioxidant and butyrylcholinesterase inhibitors for the treatment of Alzheimer's disease: Design, synthesis and evaluation of novel melatonin-alkylbenzylamine hybrids.}, journal = {Bioorganic & medicinal chemistry}, volume = {78}, number = {}, pages = {117146}, doi = {10.1016/j.bmc.2022.117146}, pmid = {36580744}, issn = {1464-3391}, mesh = {Mice ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; Antioxidants/pharmacology/therapeutic use ; Butyrylcholinesterase/metabolism ; *Melatonin/pharmacology/therapeutic use ; Cholinesterase Inhibitors ; Acetylcholinesterase/metabolism ; Structure-Activity Relationship ; Amyloid beta-Peptides/metabolism ; Drug Design ; *Neuroprotective Agents/pharmacology ; }, abstract = {Here, we have designed and synthesized a series of melatonin-alkylbenzylamine hybrids as multitarget agents for the treatment of Alzheimer's disease (AD). Most of them exhibited a potent multifunctional profile involving cholinesterase inhibition and antioxidant effects. Among these compounds, compound 5 was most the potent antioxidant (ORAC = 5.13) and also an excellent selective inhibitor of BuChE (huBuChE IC50 = 1.20 μM, huAChE IC50 = 177.49 μM, SI = 147.91). Moreover, kinetic study indicated compound 5 was a mixed-type inhibitor for huBuChE. Furthermore, it could induce expression of the Nrf2 as well as its downstream markers at the protein level in cells. More importantly, compound 5 display no acute toxicity in mice at doses up to 2500 mg/kg. And we found compound 5 could improve memory function of scopolamine-induced amnesia mice. These results highlighted compound 5 as a possible hit molecule for further investigation of new anti-AD drugs.}, } @article {pmid36580473, year = {2022}, author = {Cardoen, B and Wong, T and Alan, P and Lee, S and Matsubara, JA and Nabi, IR and Hamarneh, G}, title = {SPECHT: Self-tuning Plausibility based object detection Enables quantification of Conflict in Heterogeneous multi-scale microscopy.}, journal = {PloS one}, volume = {17}, number = {12}, pages = {e0276726}, pmid = {36580473}, issn = {1932-6203}, support = {PJT-159845//CIHR/Canada ; PJT-156424//CIHR/Canada ; PJT-175112//CIHR/Canada ; R01 AG061138/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Microscopy, Fluorescence/methods ; Microscopy, Confocal/methods ; *Algorithms ; *Alzheimer Disease/diagnostic imaging ; Amyloid beta-Peptides ; }, abstract = {Identification of small objects in fluorescence microscopy is a non-trivial task burdened by parameter-sensitive algorithms, for which there is a clear need for an approach that adapts dynamically to changing imaging conditions. Here, we introduce an adaptive object detection method that, given a microscopy image and an image level label, uses kurtosis-based matching of the distribution of the image differential to express operator intent in terms of recall or precision. We show how a theoretical upper bound of the statistical distance in feature space enables application of belief theory to obtain statistical support for each detected object, capturing those aspects of the image that support the label, and to what extent. We validate our method on 2 datasets: distinguishing sub-diffraction limit caveolae and scaffold by stimulated emission depletion (STED) super-resolution microscopy; and detecting amyloid-β deposits in confocal microscopy retinal cross-sections of neuropathologically confirmed Alzheimer's disease donor tissue. Our results are consistent with biological ground truth and with previous subcellular object classification results, and add insight into more nuanced class transition dynamics. We illustrate the novel application of belief theory to object detection in heterogeneous microscopy datasets and the quantification of conflict of evidence in a joint belief function. By applying our method successfully to diffraction-limited confocal imaging of tissue sections and super-resolution microscopy of subcellular structures, we demonstrate multi-scale applicability.}, } @article {pmid36580407, year = {2022}, author = {Bouguerra, K and Tazir, M and Melouli, H and Khelil, M}, title = {The methylenetetrahydrofolate reductase C677T and A1298C genetic polymorphisms and plasma homocysteine in Alzheimer's disease in an Algerian population.}, journal = {The International journal of neuroscience}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/00207454.2022.2158825}, pmid = {36580407}, issn = {1563-5279}, abstract = {BACKGROUND: The etiology of Alzheimer's disease (AD) is multifactorial. The most important challenge of research is the identification of potential biomarkers associated with AD pathogenesis that may significantly contribute to early diagnosis of the disease. We aim to explore an eventual association of the C677T and A1298C genetic polymorphisms in the MTHFR gene with AD risk in an Algerian population.

METHODS: This case-control study involved comparing a group of 106 patients that had developed AD to another group of 104 non-demented individuals. The MTHFR genotypes were determined using PCR-RFLP method. Additionally, the homocysteine level was evaluated.

RESULTS: Genotypes analysis did not show an association for both MTHFR677CT and 677TT variants with AD risk (OR = 1.12; p = 0.66; OR = 1.76; p = 0.09) respectively. As expected, the 677CC wild type genotype showed a protective role against AD (OR = 0.52; p = 0.03). For 1298AC MTHFR variant, the distribution of different genotypes did not show a statistical significant difference between the two cohorts. However the silmutaneous carrier, CT/AC presented association with AD (OR = 5.96; p = 0.05). On the other hand, carrier-state of MTHFR T allele showed a relationship with AD (OR = 1.98; p = 0.02). Additionally, hyperhomocysteinemia seems to be a risk factor for AD (OR = 1.08; p = 0.02).

CONCLUSION: Our exploration reveals that the silmutaneous carrier, CT/AC, carrier-state of MTHFR T allele, and hyperhomocysteinemia seem to be risk factors for AD.}, } @article {pmid36580191, year = {2022}, author = {Gao, H and Zhou, Y and Jin, PS and Wu, DG and Wang, YN and Zhao, X and Zhao, B}, title = {Molecular alteration of the proteasome contributes to AD-like pathology in the brain of HFD-STZ diabetic rats.}, journal = {Metabolic brain disease}, volume = {}, number = {}, pages = {}, pmid = {36580191}, issn = {1573-7365}, abstract = {Diabetes-related cognitive impairment has been shown in diverse epidemiological investigations and lab-based studies, although the underlying pathological mechanisms remain unclear. Unbalanced protein homeostasis may contribute to cognitive decline by inducing abnormal protein aggregation in the diabetic brain. This study aimed to determine possible changes in the proteasome, which is an important pathway involved in abnormal protein degradation. To this end, we examined potential alterations of proteasomal subunits and hydrolytic activity in the brain of diabetic rats fed with high-fat diet combined with small doses of streptozotocin (STZ). Furthermore, lactacystin were used to inhibit proteasomal activity in vivo and typical Alzheimer's disease (AD)-like pathologies were detected, including amyloid-beta, tau phosphorylation, and oxidative protein changes. Our results showed that proteasomal activity increased in the brains of diabetic rats compared to age-matched control rats. After proteasome inhibition, the levels of tau phosphorylation and protein oxidative modification significantly increased; however, no changes were detected in the pathway involved in amyloid production. These results indicated that changes in protein homeostasis balance in diabetes play a role in some typical AD-like changes, especially in oxidative protein degradation, providing evidence that prevention of diabetes-induced protein imbalance may be a potential therapeutic target.}, } @article {pmid36579934, year = {2022}, author = {Vontell, RT and de Rivero Vaccari, JP and Sun, X and Gultekin, SH and Bramlett, HM and Dietrich, WD and Keane, RW}, title = {Identification of inflammasome signaling proteins in neurons and microglia in early and intermediate stages of Alzheimer's disease.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {}, number = {}, pages = {e13142}, doi = {10.1111/bpa.13142}, pmid = {36579934}, issn = {1750-3639}, support = {1RF1NS12557801/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease that destroys memory and cognitive function. Inflammasome activation has been suggested to play a critical role in the neuroinflammatory response in AD progression, but the cell-type expression of inflammasome proteins in the brain has not been fully characterized. In this study, we used samples from the hippocampus formation, the subiculum, and the entorhinal cortex brain from 17 donors with low-level AD pathology and 17 intermediate AD donors to assess the expression of inflammasome proteins. We performed analysis of hippocampal thickness, β-amyloid plaques, and hyperphosphorylated tau to ascertain the cellular pathological changes that occur between low and intermediate AD pathology. Next, we determined changes in the cells that express the inflammasome sensor proteins NOD-like receptor proteins (NLRP) 1 and 3, and caspase-1. In addition, we stained section with IC100, a humanized monoclonal antibody directed against the inflammasome adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and a commercially available anti-ASC antibody. Our results indicate that hippocampal cortical thickness did not significantly change between low and intermediate AD pathology, but there was an increase in pTau and β-amyloid clusters in intermediate AD cases. NLRP3 was identified mainly in microglial populations, whereas NLRP1 was seen in neuronal cytoplasmic regions. There was a significant increase of ASC in neurons labeled by IC100, whereas microglia in the hippocampus and subiculum were labeled with the commercial anti-ASC antibody. Caspase-1 was present in the parenchyma in the CA regions where amyloid and pTau were identified. Together, our results indicate increased inflammasome protein expression in the early pathological stages of AD, that IC100 identifies neurons in early stages of AD and that ASC expression correlates with Aβ and pTau in postmortem AD brains.}, } @article {pmid36579663, year = {2022}, author = {Momota, Y and Liang, KC and Horigome, T and Kitazawa, M and Eguchi, Y and Takamiya, A and Goto, A and Mimura, M and Kishimoto, T}, title = {Language Patterns in Japanese Patients with Alzheimer Disease: A Machine Learning Approach.}, journal = {Psychiatry and clinical neurosciences}, volume = {}, number = {}, pages = {}, doi = {10.1111/pcn.13526}, pmid = {36579663}, issn = {1440-1819}, abstract = {AIM: We applied natural language processing and machine learning to explore the disease-related language patterns which deserve objective measures for assessing language ability in Japanese patients with Alzheimer disease, while most previous studies have used large publicly available datasets in Euro-American languages.

METHODS: We obtained 276 speech-samples from 42 patients with Alzheimer disease and 52 healthy controls, aged 50 years or over. We used a natural language processing library for Python called spaCy with an add-on library called GiNZA, which is a Japanese parser based on Universal Dependencies designed to facilitate multilingual parser development. We used eXtreme Gradient Boosting for our classification algorithm. Each unit of part-of-speech and dependency was tagged and counted to create features such as tag-frequency and tag-to-tag transition-frequency. Each feature's importance was computed during the 100-fold repeated random sub-sampling validation and averaged.

RESULTS: The model resulted in an accuracy of 0.84 (SD = 0.06), and an Area Under the Curve of 0.90 (SD = 0.03). Among the features that were important for such predictions, 7 of the top 10 features were related to part-of-speech, while the remaining 3 were related to dependency. A box-plot analysis demonstrated that the appearance rates of content word-related features were lower among the patients, whereas those with stagnation-related features were higher.

CONCLUSION: This study demonstrated a promising level of accuracy for predicting Alzheimer disease and found the language patterns corresponding to the type of lexical-semantic decline known as "empty speech," which is regarded as a characteristic of Alzheimer disease. This article is protected by copyright. All rights reserved.}, } @article {pmid36579548, year = {2022}, author = {Bowirrat, A}, title = {Immunosenescence and Aging: Neuroinflammation Is a Prominent Feature of Alzheimer's Disease and Is a Likely Contributor to Neurodegenerative Disease Pathogenesis.}, journal = {Journal of personalized medicine}, volume = {12}, number = {11}, pages = {}, pmid = {36579548}, issn = {2075-4426}, abstract = {Alzheimer's disease (AD) is a chronic multifactorial and complex neuro-degenerative disorder characterized by memory impairment and the loss of cognitive ability, which is a problem affecting the elderly. The pathological intracellular accumulation of abnormally phosphorylated Tau proteins, forming neurofibrillary tangles, and extracellular amyloid-beta (Aβ) deposition, forming senile plaques, as well as neural disconnection, neural death and synaptic dysfunction in the brain, are hallmark pathologies that characterize AD. The prevalence of the disease continues to increase globally due to the increase in longevity, quality of life, and medical treatment for chronic diseases that decreases the mortality and enhance the survival of elderly. Medical awareness and the accurate diagnosis of the disease also contribute to the high prevalence observed globally. Unfortunately, no definitive treatment exists that can be used to modify the course of AD, and no available treatment is capable of mitigating the cognitive decline or reversing the pathology of the disease as of yet. A plethora of hypotheses, ranging from the cholinergic theory and dominant Aβ cascade hypothesis to the abnormally excessive phosphorylated Tau protein hypothesis, have been reported. Various explanations for the pathogenesis of AD, such as the abnormal excitation of the glutamate system and mitochondrial dysfunction, have also been suggested. Despite the continuous efforts to deliver significant benefits and an effective treatment for this distressing, globally attested aging illness, multipronged approaches and strategies for ameliorating the disease course based on knowledge of the underpinnings of the pathogenesis of AD are urgently needed. Immunosenescence is an immune deficit process that appears with age (inflammaging process) and encompasses the remodeling of the lymphoid organs, leading to alterations in the immune function and neuroinflammation during advanced aging, which is closely linked to the outgrowth of infections, autoimmune diseases, and malignant cancers. It is well known that long-standing inflammation negatively influences the brain over the course of a lifetime due to the senescence of the immune system. Herein, we aim to trace the role of the immune system in the pathogenesis of AD. Thus, we explore alternative avenues, such as neuroimmune involvement in the pathogenesis of AD. We determine the initial triggers of neuroinflammation, which is an early episode in the pre-symptomatic stages of AD and contributes to the advancement of the disease, and the underlying key mechanisms of brain damage that might aid in the development of therapeutic strategies that can be used to combat this devastating disease. In addition, we aim to outline the ways in which different aspects of the immune system, both in the brain and peripherally, behave and thus to contribute to AD.}, } @article {pmid36579430, year = {2022}, author = {Halder, D and Das, S and R S, J and Joseph, A}, title = {Role of multi-targeted bioactive natural molecules and their derivatives in the treatment of Alzheimer's disease: an insight into structure-activity relationship.}, journal = {Journal of biomolecular structure & dynamics}, volume = {}, number = {}, pages = {1-38}, doi = {10.1080/07391102.2022.2158136}, pmid = {36579430}, issn = {1538-0254}, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder involving cognitive dysfunction like short-term memory and behavioral changes as the disease progresses due to other unaltered physiological factors. The solution for this problem is Multi-targeted Drugs (MTDs), which can affect multiple determinants to realize the multifunctional effects. Acetylcholinesterase (AChE) inhibitors donepezil, rivastigmine, galantamine, and N-methyl-D-aspartate (NMDA) receptor antagonist memantine are FDA-approved drugs used to treat AD symptomatically. The key objective of this review is to understand multitargeted bioactive natural molecules that could be considered as leads for further development as effective drugs for treating AD, along with understanding its pharmacology and structure-activity relationship (SAR). Understanding the molecular mechanism of the AD pathophysiology, the role of existing drugs, treatment of AD via amyloid beta (Aβ) plaque, and neurofibrillary tangle (NFT) inhibition by natural bioactive molecules were also discussed in the review. The current quest and recent advancements with natural bioactive compounds like physostigmine, resveratrol, curcumin, and catechins, along with the study of in silico SAR, were reported in the present study. This review summarises the structural properties required for bioactive natural molecules to show anti-Alzheimer's activity by emphasizing on SAR of several bioactive natural molecules targeting various AD pathologies, their key molecular interactions that are critical for target specificity, their role as multitargeted ligands, used with adjunctive therapy for AD followed by related US patents granted recently. This article highlights the significance of the structural features of natural bioactive molecules in the treatment of AD and establishes a connection between them.Communicated by Ramaswamy H. Sarma.}, } @article {pmid36579387, year = {2022}, author = {Mehendale-Munj, S and Patil, PB}, title = {Drug Discovery To Drug Development Of Bace1 Inhibitor As Anti-Alzheimers's: A Review.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/1568026623666221228140450}, pmid = {36579387}, issn = {1873-4294}, abstract = {Alzheimer's Disease (AD) is a complex and progressive neurodegenerative disease, and the most common cause of dementia usually occurs due to old age. Production and accumulation of amyloid-β peptide (Aβ) represent the major pathological event of the disease. The formation of amyloid-β results due to proteolytic cleavage of amyloid precursor protein (APP) by beta-site amyloid precursor protein cleaving enzyme (BACE1) shown as the amyloid hypothesis, a prevalent theory for AD pathogenesis. Thus, BACE1 represents a novel target to decrease cerebral Aβ concentration and slow down the disease's progression. The structure-based drug design approach led to a wide variety of small molecules with the mechanism of action centered around inhibition of β-secretase protease (BACE1), which are shown to have drug-like properties and reduce brain Aβ levels. Based on transition state isosteres, BACE1 inhibitors can largely be classified as peptidomimetics and non-peptidomimetics. The subclasses of the two categories have been covered with different scaffolds like statin, norstatin, carbinamine, hydroxyethylene, hydroxyethylamine, acyl guanidine, 2-aminopyridine, aminoimidazole, aminohydantoin, aminothiazoline, aminooxazoline, aminoquinoline, piperazine-based. Among these small molecules, those who fulfilled general requirements for a drug aimed at the central nervous system (CNS) and selectivity over other aspartyl proteases reached the final pipeline of clinical trials. Here, in this review, we summarize the journey of BACE1 inhibitors through different practices of drug design development, Structural Activity Relationship (SAR), and other inhibitor candidates that are currently in clinical trials as BACE1 inhibitors.}, } @article {pmid36579344, year = {2022}, author = {Wang, X and Li, Z and Sun, R and Li, X and Guo, R and Cui, X and Liu, B and Li, W and Yang, Y and Huang, X and Qu, H and Liu, C and Wang, Z and Lü, Y and Yue, C}, title = {Zunyimycin C enhances immunity and improves cognitive impairment and its mechanism.}, journal = {Frontiers in cellular and infection microbiology}, volume = {12}, number = {}, pages = {1081243}, pmid = {36579344}, issn = {2235-2988}, mesh = {Mice ; Animals ; Neuroinflammatory Diseases ; Phosphatidylinositol 3-Kinases/metabolism ; *Cognitive Dysfunction/drug therapy/metabolism/prevention & control ; *Alzheimer Disease/drug therapy ; Brain/metabolism ; Disease Models, Animal ; }, abstract = {This study aimed to explore the efficacy of zunyimycin C in the immunological enhancement of hypoimmune mice and improvement of cognitive impairment in a mice model of Alzheimer's disease (AD). Zunyimycin C was administered intranasally to interfere with AD mouse models or gavage to hypoimmune animals. Results of the Morris water maze (MWM) showed that zunyimycin may improve the learning and memory abilities of the AD mice model. The results of differential expression analysis of mRNA levels of inflammatory factors and pathways in brain tissues of the AD mouse model suggested that differential expression was more obvious under Zun-Int L. Western blot revealed that the relative expression of glial fibrillary acidic protein in the brain tissue of the AD mouse model in the Zun-Pre group was significantly higher than that in the other groups, and the difference was statistically significant. The relative expression of interleukin (IL)-6 protein in the brain tissue of mice in the low-dose intervention group was significantly lower than that in the other groups, and the difference was statistically significant. As for hypoimmune animals, short chain fatty acids (SCFAs) assay and intestinal flora assay results showed that zunyimycin C may change intestinal flora diversity and SCFA biosynthesis. The prophylactic administration of zunyimycin C could not inhibit acute neuroinflammation in AD mice. Zunyimycin C may participate in the immune response by activating the Ras-Raf-MEK-ERK signaling pathway to stimulate microglia to produce more inflammatory factors. Zunyimycin C may inhibit autophagy by activating the PI3K-AKT-mTOR signaling pathway, promote cell survival, mediate neuroprotective effects of reactive microglia and reactive astrocytes, and reduce IL-1β in brain tissue and IL-6 secretion, thereby attenuating neuroinflammation in AD mice and achieving the effect of improving learning and memory impairment. Zunyimycin C may play a role in immunological enhancement by changing intestinal flora diversity and SCFAs.}, } @article {pmid36579132, year = {2022}, author = {Mank, A and van Maurik, IS and van Harten, AC and Rhodius-Meester, HFM and Teunissen, CE and van Berckel, BNM and Berkhof, J and van der Flier, WM and Rijnhart, JJM}, title = {Life satisfaction across the entire trajectory of Alzheimer's disease: A mediation analysis.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {14}, number = {1}, pages = {e12389}, pmid = {36579132}, issn = {2352-8729}, abstract = {INTRODUCTION: We studied life satisfaction across Alzheimer's disease (AD) stages and studied mobility and meaningful activities as mediators of the associations between these AD stages and life satisfaction.

METHODS: In this cross-sectional study, we included n = 269 amyloid-positive patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD dementia from the Amsterdam Dementia Cohort. Life satisfaction was measured with the satisfaction with life scale. The mediating role of transportation, work, sports, and hobbies on life satisfaction was examined in single and multiple mediator models.

RESULTS: Patients with dementia are less satisfied with life compared to SCD and MCI. These differences in life satisfaction are explained by reduced participation in meaningful activities, which in turn, was largely attributable to decreased transportation use.

DISCUSSION: Our findings suggest that improving access to transportation, therewith allowing participation in meaningful activities help to maintain life satisfaction and may be an important target for intervention.}, } @article {pmid36579131, year = {2022}, author = {Parra, MA and Granada, J and Fernández, G}, title = {Memory-driven eye movements prospectively predict dementia in people at risk of Alzheimer's disease.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {14}, number = {1}, pages = {e12386}, pmid = {36579131}, issn = {2352-8729}, abstract = {INTRODUCTION: Oculomotor behaviors linked to cognitive performance revealed neurocognitive features of Alzheimer's disease (AD) that can enhance the accuracy of its assessment and diagnosis.

METHODS: A sample of 107 participants (i.e., 65 mild cognitive impairment [MCI] and 42 controls) were recruited and followed up for 40 months. At baseline, they underwent assessment with the ViewMind digital biomarker, which draws cognitive-related patterns of eye movement while people perform the visual short-term memory binding task.

RESULTS: Baseline data predicted that 36 patients with MCI would progress to the AD clinical syndrome (ADS Progressing). The remaining 29 MCI patients were predicted to remain as MCI or progress to other forms of dementia. After 40 months of follow-up, 94% of ADS Progressing patients had received a diagnosis of dementia, whereas none of the non-ADS Progressing had.

DISCUSSION: The analysis of eye movement behavior combined with cognitive markers for AD can effectively predict progression to ADS among patients with MCI.}, } @article {pmid36579025, year = {2022}, author = {Testo, A and McBride, C and Bernstein, IM and Dumas, J}, title = {Corrigendum: Preeclampsia and its relationship to pathological brain aging.}, journal = {Frontiers in physiology}, volume = {13}, number = {}, pages = {1096042}, doi = {10.3389/fphys.2022.1096042}, pmid = {36579025}, issn = {1664-042X}, abstract = {[This corrects the article DOI: 10.3389/fphys.2022.979547.].}, } @article {pmid36578987, year = {2022}, author = {Yener, G and Öz, D}, title = {Innovations in Neurophysiology and Their Use in Neuropsychiatry.}, journal = {Noro psikiyatri arsivi}, volume = {59}, number = {Suppl 1}, pages = {S67-S74}, pmid = {36578987}, issn = {1300-0667}, abstract = {Many structural and functional tests are used to explore the nature of neurodevelopmental and neurodegenerative diseases. Cognitive involvement has become more and more remarkable in many neurological and psychiatric diseases. This condition evoked a paradigm shift, and today disorders are addressed from a neuroscientific perspective, including silent symptoms. The spatial resolution of structural studies is lacking and is combined with the unique temporal resolution of EEG methods. In our current clinical practice, EEG does not have definitive diagnostic value in psychiatric disorders, but it helps to make a correct diagnosis by excluding other neurological diseases. However, the use of EEG for research purposes is promising in both groups. In this review; there is up-to-date information on the use of electrophysiological examinations in neurological diseases, especially Alzheimer's disease, Parkinson's disease, Frontotemporal dementia, and psychiatric disorders such as schizophrenia, mood disorders, attention deficit and hyperactivity disorder, and obsessive-compulsive disorder, to define the point we have reached in our journey to understand these disorders.}, } @article {pmid36578986, year = {2022}, author = {Öz, D and Yıldırım, Z and Kıyı, İ and Özbek, Y and Kulaç, İ and Erkol, G and Tihan, T and Gürvit, İH and Yener, G}, title = {Senior Moments Are Never-ending Times When You Are Old (Are They?): First Step of Turquoise Project.}, journal = {Noro psikiyatri arsivi}, volume = {59}, number = {Suppl 1}, pages = {S10-S16}, pmid = {36578986}, issn = {1300-0667}, abstract = {INTRODUCTION: The number of dementia patients in Turkey is increasing, as well as all over the world. However, we do not know how much society knows about dementia. The aim of this study is to evaluate people's concept of dementia, their awareness of dementia research and treatment, whether dementia and forgetfulness are considered normal in old age, and whether having dementia is associated with a lack of mental abilities.

METHODS: A Dementia Awareness Questionnaire was created in the form of a self-report questionnaire, consisting of 20 questions and using a five-point Likert-type answering method in order to question participants' information about dementia. In addition, we asked for demographic information such as age, gender, occupation, education level of the participants, as well as whether they have had relatives diagnosed with a neurodegenerative disease. The surveys were administered online.

RESULTS: A total of 1551 participants from 53 cities were included in the study. Approximately half of the participants did not know the definition of dementia, 20.9% thought that dementia and Alzheimer's disease were the same; 50.4% considered forgetfulness, and 55.2% considered dementia as a natural consequence of aging. While 34.5% of the participants thought that dementia patients could be dangerous, 10.3% thought they could not continue living as a part of society. While 38.5% of healthcare professionals do not know the definition of dementia, 18.5% of them say that dementia and Alzheimer's disease are the same, 58.5% think that dementia patients are not fit to make their own decisions, 40.6% believe that dementia patients have criminal liability. 15.8% of healthcare professionals thought that dementia is only seen in elderly people; 21.4% thought that dementia, and 49.2% thought that forgetfulness was a result of normal aging.

CONCLUSION: Our study confirms that dementia is still an unknown concept in society and among healthcare professionals. It is widely believed that forgetfulness and dementia are part of normal aging, and there is no cure for dementia. This study, which we have done in order to understand the level of dementia awareness in Turkish society, reveals the necessity for research on dementia and studies on how to increase dementia awareness.}, } @article {pmid36578980, year = {2022}, author = {Topçuoğlu, ES and Akdemir, ÜÖ and Atay, LÖ}, title = {What is New in Nuclear Medicine Imaging for Dementia.}, journal = {Noro psikiyatri arsivi}, volume = {59}, number = {Suppl 1}, pages = {S17-S23}, pmid = {36578980}, issn = {1300-0667}, abstract = {Advances in the molecular biology, pathology and genetics of Alzheimer's disease (AD) and other degenerative dementias have led to the development of biomarkers specific to these diseases and radiotracers that are used in nuclear medicine. Imaging and non-imaging markers have enabled very early recognition of these diseases and have caused significant changes in their definitions. Amyloid positron emission tomography (PET) and tau PET, which are molecular imaging methods, [F18]fluorodeoxyglucose (FDG) PET showing the glucose metabolism pattern in the brain, dopamine transporter single photon emission computerized tomography (SPECT) that marks dopaminergic terminals are valuable tools for early recognition and differentiation of AD and its atypical variants, frontotemporal dementias and dementia with Lewy bodies. These imaging methods, which have different advantages over each other, have different indications for use and sometimes provide complementary information. In addition, research on radiotracers targeting neuroinflammation, astrocytes, synaptic density, and cholinergic terminals is ongoing. In this review, routinely used and newly developed nuclear imaging methods in AD and other neurodegenerative dementias, the agents used and their diagnostic features will be presented together with case examples.}, } @article {pmid36578541, year = {2022}, author = {Bhat, JA and Akther, T and Najar, RA and Rasool, F and Hamid, A}, title = {Withania somnifera (L.) Dunal (Ashwagandha); current understanding and future prospect as a potential drug candidate.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1029123}, pmid = {36578541}, issn = {1663-9812}, abstract = {Cancer and Neurodegenerative diseases are one of the most dreadful diseases to cure and chemotherapy has found a prime place in cancerous treatments while as different strategies have been tested in neurodegenerative diseases as well. However, due to adverse shortcomings like the resistance of cancerous cells and inefficiency in neurodegenerative disease, plant sources have always found a prime importance in medicinal use for decades, Withania somnifera (L.) Dunal (W. somnifera) is a well-known plant with medicinal use reported for centuries. It is commonly known as winter cherry or ashwagandha and is a prime source of pharmaceutically active compounds withanolides. In recent years research is being carried in understanding the extensive role of W. somnifera in cancer and neurological disorders. W. somnifera has been reported to be beneficial in DNA repair mechanisms; it is known for its cellular repairing properties and helps to prevent the apoptosis of normal cells. This review summarizes the potential properties and medicinal benefits of W. somnifera especially in cancer and neurodegenerative diseases. Available data suggest that W. somnifera is effective in controlling disease progressions and could be a potential therapeutic target benefiting human health status. The current review also discusses the traditional medicinal applications of W. somnifera, the experimental evidence supporting its therapeutical potential as well as obstacles that necessitate being overcome for W. somnifera to be evaluated as a curative agent in humans.}, } @article {pmid36578263, year = {2022}, author = {Bou Zerdan, M and Hebbo, E and Hijazi, A and El Gemayel, M and Nasr, J and Nasr, D and Yaghi, M and Bouferraa, Y and Nagarajan, A}, title = {The Gut Microbiome and Alzheimer's Disease: A Growing Relationship.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/1567205020666221227090125}, pmid = {36578263}, issn = {1875-5828}, abstract = {Evidence that the gut microbiota plays a key role in the pathogenesis of Alzheimer's disease is already un-ravelling. The microbiota-gut-brain axis is a bidirectional communication system that is not fully understood but includes neural, immune, endocrine, and metabolic pathways. The progression of Alzheimer's disease is supported by mechanisms related to the imbalance in the gut microbiota and the development of amyloid plaques in the brain, which are at the origin of Alzheimer's disease. Alterations in the composition of the gut microbiome led to dysregulation in the pathways governing this system. This leads to neurodegeneration through neuroinflammation and neurotransmitter dysregulation. Neurodegeneration and disruption of the blood-brain barrier are frontiers at the origin of Alzheimer's disease. Furthermore, bacteria populating the gut microbiota can secrete large amounts of amyloid proteins and lipopolysaccharides, which modulate signaling pathways and alter the production of proinflammatory cytokines associated with the pathogenesis of Alz-heimer's disease. Importantly, through molecular mimicry, bacterial amyloids may elicit cross-seeding of misfolding and induce microglial priming at different levels of the brain-gut-microbiota axis. The potential mechanisms of amyloid spreading include neuron-to-neuron or distal neuron spreading, direct blood-brain barrier crossing, or via other cells such as astrocytes, fibroblasts, microglia, and immune system cells. Gut microbiota metabolites, including short-chain fatty acids, pro-inflammatory factors, and neurotransmitters may also affect AD pathogenesis and associated cognitive decline. The purpose of this review is to summarize and discuss the current findings that may elucidate the role of gut microbiota in the development of Alzheimer's disease. Understanding the underlying mechanisms may provide new insights into novel therapeutic strategies for Alzheimer's disease, such as probiotics and targeted oligosaccharides.}, } @article {pmid36578233, year = {2023}, author = {Bourbon-Teles, J and Jorge, L and Canário, N and Martins, R and Santana, I and Castelo-Branco, M}, title = {Associations between cortical β-amyloid burden, fornix microstructure and cognitive processing of faces, places, bodies and other visual objects in early Alzheimer's disease.}, journal = {Hippocampus}, volume = {33}, number = {2}, pages = {112-124}, doi = {10.1002/hipo.23493}, pmid = {36578233}, issn = {1098-1063}, mesh = {Humans ; Amyloid beta-Peptides ; *Alzheimer Disease/diagnostic imaging/psychology ; Diffusion Tensor Imaging/methods ; Prospective Studies ; Cognition ; *Cognitive Dysfunction ; Positron-Emission Tomography/methods ; }, abstract = {Using two imaging modalities, that is, Pittsburgh compound B (PiB) positron emission tomography (PET) and diffusion tensor imaging (DTI) the present study tested associations between cortical amyloid-beta (Aβ) burden and fornix microstructural changes with cognitive deficits in early Alzheimer's disease (AD), namely deficits in working memory (1-back) processing of visual object categories (faces, places, objects, bodies and verbal material). Second, we examined cortical Aβ associations with fornix microstructure. Seventeen early AD patients and 17 healthy-matched controls were included. Constrained spherical deconvolution-based tractography was used to segment the fornix and a control tract the central branch of the superior longitudinal fasciculus (CB-SLF) previously implicated in working memory processes. Standard uptake value ratios (SUVR) of Aβ were extracted from 45 cortical/subcortical regions from the AAL atlas and subject to principal component analysis for data reduction. Patients exhibited (i) impairments in cognitive performance (ii) reductions in fornix fractional anisotropy (FA) and (iii) increases in a component that loaded highly on cortical Aβ. There were no group differences in CB-SLF FA and in a component loading highly on subcortical Aβ. Partial correlation analysis in the patient group showed (i) positive associations between fornix FA and performance for all the visual object categories and (ii) a negative association between the cortical Aβ component and performance for the object categories but not for the remaining classes of visual stimuli. A subsequent analysis showed a positive association between overall cognition (performance across distinct 1-back task conditions) with fornix FA but no association with cortical Aβ burden, in keeping with influential accounts on early onset AD. This indicates that the fornix degenerates early in AD and contributes to deficits in working memory processing of visual object categories; though it is also important to acknowledge the importance of prospective longitudinal studies with larger samples. Overall, the effect sizes of fornical degeneration on visual working memory appeared stronger than the ones related to amyloid burden.}, } @article {pmid36578089, year = {2022}, author = {Sandberg, A and Berenjeno-Correa, E and Rodriguez, RC and Axenhus, M and Weiss, SS and Batenburg, K and Hoozemans, JJM and Tjernberg, LO and Scheper, W}, title = {Aβ42 oligomer-specific antibody ALZ-201 reduces the neurotoxicity of Alzheimer's disease brain extracts.}, journal = {Alzheimer's research & therapy}, volume = {14}, number = {1}, pages = {196}, pmid = {36578089}, issn = {1758-9193}, mesh = {Mice ; Animals ; *Alzheimer Disease/genetics ; Amyloid beta-Peptides ; Peptide Fragments/metabolism ; Brain/metabolism ; Antibodies, Monoclonal/therapeutic use ; }, abstract = {BACKGROUND: In Alzheimer's disease (AD), amyloid-β 1-42 (Aβ42) neurotoxicity stems mostly from its soluble oligomeric aggregates. Studies of such aggregates have been hampered by the lack of oligomer-specific research tools and their intrinsic instability and heterogeneity. Here, we developed a monoclonal antibody with a unique oligomer-specific binding profile (ALZ-201) using oligomer-stabilising technology. Subsequently, we assessed the etiological relevance of the Aβ targeted by ALZ-201 on physiologically derived, toxic Aβ using extracts from post-mortem brains of AD patients and controls in primary mouse neuron cultures.

METHODS: Mice were immunised with stable oligomers derived from the Aβ42 peptide with A21C/A30C mutations (AβCC), and ALZ-201 was developed using hybridoma technology. Specificity for the oligomeric form of the Aβ42CC antigen and Aβ42 was confirmed using ELISA, and non-reactivity against plaques by immunohistochemistry (IHC). The antibody's potential for cross-protective activity against pathological Aβ was evaluated in brain tissue samples from 10 individuals confirmed as AD (n=7) and non-AD (n=3) with IHC staining for Aβ and phosphorylated tau (p-Tau) aggregates. Brain extracts were prepared and immunodepleted using the positive control 4G8 antibody, ALZ-201 or an isotype control to ALZ-201. Fractions were biochemically characterised, and toxicity assays were performed in primary mouse neuronal cultures using automated high-content microscopy.

RESULTS: AD brain extracts proved to be more toxic than controls as demonstrated by neuronal loss and morphological determinants (e.g. synapse density and measures of neurite complexity). Immunodepletion using 4G8 reduced Aβ levels in both AD and control samples compared to ALZ-201 or the isotype control, which showed no significant difference. Importantly, despite the differential effect on the total Aβ content, the neuroprotective effects of 4G8 and ALZ-201 immunodepletion were similar, whereas the isotype control showed no effect.

CONCLUSIONS: ALZ-201 depletes a toxic species in post-mortem AD brain extracts causing a positive physiological and protective impact on the integrity and morphology of mouse neurons. Its unique specificity indicates that a low-abundant, soluble Aβ42 oligomer may account for much of the neurotoxicity in AD. This critical attribute identifies the potential of ALZ-201 as a novel drug candidate for achieving a true, clinical therapeutic effect in AD.}, } @article {pmid36578067, year = {2022}, author = {Wang, ZB and Ma, YH and Sun, Y and Tan, L and Wang, HF and Yu, JT and , }, title = {Interleukin-3 is associated with sTREM2 and mediates the correlation between amyloid-β and tau pathology in Alzheimer's disease.}, journal = {Journal of neuroinflammation}, volume = {19}, number = {1}, pages = {316}, pmid = {36578067}, issn = {1742-2094}, mesh = {Humans ; Animals ; Mice ; *Alzheimer Disease/pathology ; Interleukin-3 ; Longitudinal Studies ; tau Proteins/cerebrospinal fluid ; Membrane Glycoproteins/cerebrospinal fluid ; Receptors, Immunologic ; Amyloid beta-Peptides/cerebrospinal fluid ; *Cognitive Dysfunction/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; }, abstract = {BACKGROUND: Dysfunction of glial cell communication is involved in Alzheimer's disease (AD) pathogenesis, and the recent study reported that astrocytic secreted interleukin-3 (IL-3) participated in astrocyte-microglia crosstalk and restricted AD pathology in mice, but the effect of IL-3 on the pathological progression of AD in human is still unclear.

METHODS: A total of 311 participants with cerebrospinal fluid (CSF) IL-3, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and AD biomarkers were included from the Alzheimer's disease Neuroimaging Initiative (ADNI). We assessed the associations of IL-3 with sTREM2 and AD biomarkers at baseline, and with cognitive change in longitudinal study. The mediation models were used to explore the potential mechanism of how IL-3 affects AD pathology.

RESULTS: We found that CSF IL-3 was significantly associated with CSF sTREM2 and CSF AD core biomarkers (Aβ42, p-tau, and t-tau) at baseline, and was also markedly related to cognitive decline in longitudinal analysis. Moreover, mediation analysis revealed that CSF IL-3 modulated the level of CSF sTREM2 and contributed to tau pathology (as measured by CSF p-tau/t-tau) and subsequent cognitive decline. In addition, Aβ pathology (as measured by CSF Aβ42) affected the development of tau pathology partly by modifying the levels of CSF IL-3 and CSF sTREM2. Furthermore, the effect of Aβ pathology on cognitive decline was partially mediated by the pathway from CSF IL-3 and CSF sTREM2 to tau pathology.

CONCLUSIONS: Our findings provide evidence to suggest that IL-3 is linked to sTREM2 and mediates the correlation between Aβ pathology to tau pathology. It indicates that IL-3 may be a major factor in the spreading from Aβ pathology to tau pathology to cognitive impairment.}, } @article {pmid36578035, year = {2022}, author = {Mol, MO and Miedema, SSM and Melhem, S and Li, KW and Koopmans, F and Seelaar, H and Gottmann, K and Lessmann, V and Bank, NB and Smit, AB and van Swieten, JC and van Rooij, JGJ}, title = {Proteomics of the dentate gyrus reveals semantic dementia specific molecular pathology.}, journal = {Acta neuropathologica communications}, volume = {10}, number = {1}, pages = {190}, pmid = {36578035}, issn = {2051-5960}, mesh = {Humans ; *Frontotemporal Dementia/pathology ; Pathology, Molecular ; Proteomics ; *Frontotemporal Lobar Degeneration/pathology ; *Alzheimer Disease/pathology ; Dentate Gyrus/metabolism ; Cadherins/metabolism ; Catenins/metabolism ; }, abstract = {Semantic dementia (SD) is a clinical subtype of frontotemporal dementia consistent with the neuropathological diagnosis frontotemporal lobar degeneration (FTLD) TDP type C, with characteristic round TDP-43 protein inclusions in the dentate gyrus. Despite this striking clinicopathological concordance, the pathogenic mechanisms are largely unexplained forestalling the development of targeted therapeutics. To address this, we carried out laser capture microdissection of the dentate gyrus of 15 SD patients and 17 non-demented controls, and assessed relative protein abundance changes by label-free quantitative mass spectrometry. To identify SD specific proteins, we compared our results to eight other FTLD and Alzheimer's disease (AD) proteomic datasets of cortical brain tissue, parallel with functional enrichment analyses and protein-protein interactions (PPI). Of the total 5,354 quantified proteins, 151 showed differential abundance in SD patients (adjusted P-value < 0.01). Seventy-nine proteins were considered potentially SD specific as these were not detected, or demonstrated insignificant or opposite change in FTLD/AD. Functional enrichment indicated an overrepresentation of pathways related to the immune response, metabolic processes, and cell-junction assembly. PPI analysis highlighted a cluster of interacting proteins associated with adherens junction and cadherin binding, the cadherin-catenin complex. Multiple proteins in this complex showed significant upregulation in SD, including β-catenin (CTNNB1), γ-catenin (JUP), and N-cadherin (CDH2), which were not observed in other neurodegenerative proteomic studies, and hence may resemble SD specific involvement. A trend of upregulation of all three proteins was observed by immunoblotting of whole hippocampus tissue, albeit only significant for N-cadherin. In summary, we discovered a specific increase of cell adhesion proteins in SD constituting the cadherin-catenin complex at the synaptic membrane, essential for synaptic signaling. Although further investigation and validation are warranted, we anticipate that these findings will help unravel the disease processes underlying SD.}, } @article {pmid36578022, year = {2022}, author = {Verma, A and Shteinfer-Kuzmine, A and Kamenetsky, N and Pittala, S and Paul, A and Nahon Crystal, E and Ouro, A and Chalifa-Caspi, V and Pandey, SK and Monsonego, A and Vardi, N and Knafo, S and Shoshan-Barmatz, V}, title = {Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer's disease protects against mitochondrial dysfunction and mitigates brain pathology.}, journal = {Translational neurodegeneration}, volume = {11}, number = {1}, pages = {58}, pmid = {36578022}, issn = {2047-9158}, mesh = {Mice ; Animals ; *Alzheimer Disease/drug therapy/genetics/metabolism ; Mitochondrial Proteins ; Amyloid beta-Peptides/metabolism ; Brain/metabolism ; Mitochondria/metabolism ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) exhibits mitochondrial dysfunctions associated with dysregulated metabolism, brain inflammation, synaptic loss, and neuronal cell death. As a key protein serving as the mitochondrial gatekeeper, the voltage-dependent anion channel-1 (VDAC1) that controls metabolism and Ca[2+] homeostasis is positioned at a convergence point for various cell survival and death signals. Here, we targeted VDAC1 with VBIT-4, a newly developed inhibitor of VDAC1 that prevents its pro-apoptotic activity, and mitochondria dysfunction.

METHODS: To address the multiple pathways involved in AD, neuronal cultures and a 5 × FAD mouse model of AD were treated with VBIT-4. We addressed multiple topics related to the disease and its molecular mechanisms using immunoblotting, immunofluorescence, q-RT-PCR, 3-D structural analysis and several behavioral tests.

RESULTS: In neuronal cultures, amyloid-beta (Aβ)-induced VDAC1 and p53 overexpression and apoptotic cell death were prevented by VBIT-4. Using an AD-like 5 × FAD mouse model, we showed that VDAC1 was overexpressed in neurons surrounding Aβ plaques, but not in astrocytes and microglia, and this was associated with neuronal cell death. VBIT-4 prevented the associated pathophysiological changes including neuronal cell death, neuroinflammation, and neuro-metabolic dysfunctions. VBIT-4 also switched astrocytes and microglia from being pro-inflammatory/neurotoxic to neuroprotective phenotype. Moreover, VBIT-4 prevented cognitive decline in the 5 × FAD mice as evaluated using several behavioral assessments of cognitive function. Interestingly, VBIT-4 protected against AD pathology, with no significant change in phosphorylated Tau and only a slight decrease in Aβ-plaque load.

CONCLUSIONS: The study suggests that mitochondrial dysfunction with its gatekeeper VDAC1 is a promising target for AD therapeutic intervention, and VBIT-4 is a promising drug candidate for AD treatment.}, } @article {pmid36577843, year = {2022}, author = {Varma, VR and Desai, RJ and Navakkode, S and Wong, LW and Anerillas, C and Loeffler, T and Schilcher, I and Mahesri, M and Chin, K and Horton, DB and Kim, SC and Gerhard, T and Segal, JB and Schneeweiss, S and Gorospe, M and Sajikumar, S and Thambisetty, M}, title = {Hydroxychloroquine lowers Alzheimer's disease and related dementias risk and rescues molecular phenotypes related to Alzheimer's disease.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, pmid = {36577843}, issn = {1476-5578}, abstract = {We recently nominated cytokine signaling through the Janus-kinase-signal transducer and activator of transcription (JAK/STAT) pathway as a potential AD drug target. As hydroxychloroquine (HCQ) has recently been shown to inactivate STAT3, we hypothesized that it may impact AD pathogenesis and risk. Among 109,124 rheumatoid arthritis patients from routine clinical care, HCQ initiation was associated with a lower risk of incident AD compared to methotrexate initiation across 4 alternative analyses schemes addressing specific types of biases including informative censoring, reverse causality, and outcome misclassification (hazard ratio [95% confidence interval] of 0.92 [0.83-1.00], 0.87 [0.81-0.93], 0.84 [0.76-0.93], and 0.87 [0.75-1.01]). We additionally show that HCQ exerts dose-dependent effects on late long-term potentiation (LTP) and rescues impaired hippocampal synaptic plasticity prior to significant accumulation of amyloid plaques and neurodegeneration in APP/PS1 mice. Additionally, HCQ treatment enhances microglial clearance of Aβ1-42, lowers neuroinflammation, and reduces tau phosphorylation in cell culture-based phenotypic assays. Finally, we show that HCQ inactivates STAT3 in microglia, neurons, and astrocytes suggesting a plausible mechanism associated with its observed effects on AD pathogenesis. HCQ, a relatively safe and inexpensive drug in current use may be a promising disease-modifying AD treatment. This hypothesis merits testing through adequately powered clinical trials in at-risk individuals during preclinical stages of disease progression.}, } @article {pmid36577842, year = {2022}, author = {Crawford, K and Leonenko, G and Baker, E and Grozeva, D and Lan-Leung, B and Holmans, P and Williams, J and O'Donovan, MC and Escott-Price, V and Ivanov, DK}, title = {Golgi apparatus, endoplasmic reticulum and mitochondrial function implicated in Alzheimer's disease through polygenic risk and RNA sequencing.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, pmid = {36577842}, issn = {1476-5578}, abstract = {Polygenic risk scores (PRS) have been widely adopted as a tool for measuring common variant liability and they have been shown to predict lifetime risk of Alzheimer's disease (AD) development. However, the relationship between PRS and AD pathogenesis is largely unknown. To this end, we performed a differential gene-expression and associated disrupted biological pathway analyses of AD PRS vs. case/controls in human brain-derived cohort sample (cerebellum/temporal cortex; MayoRNAseq). The results highlighted already implicated mechanisms: immune and stress response, lipids, fatty acids and cholesterol metabolisms, endosome and cellular/neuronal death, being disrupted biological pathways in both case/controls and PRS, as well as previously less well characterised processes such as cellular structures, mitochondrial respiration and secretion. Despite heterogeneity in terms of differentially expressed genes in case/controls vs. PRS, there was a consensus of commonly disrupted biological mechanisms. Glia and microglia-related terms were also significantly disrupted, albeit not being the top disrupted Gene Ontology terms. GWAS implicated genes were significantly and in their majority, up-regulated in response to different PRS among the temporal cortex samples, suggesting potential common regulatory mechanisms. Tissue specificity in terms of disrupted biological pathways in temporal cortex vs. cerebellum was observed in relation to PRS, but limited tissue specificity when the datasets were analysed as case/controls. The largely common biological mechanisms between a case/control classification and in association with PRS suggests that PRS stratification can be used for studies where suitable case/control samples are not available or the selection of individuals with high and low PRS in clinical trials.}, } @article {pmid36577819, year = {2022}, author = {Taylor, NL and Shine, JM}, title = {A whole new world: embracing the systems-level to understand the indirect impact of pathology in neurodegenerative disorders.}, journal = {Journal of neurology}, volume = {}, number = {}, pages = {}, pmid = {36577819}, issn = {1432-1459}, abstract = {The direct link between neuropathology and the symptoms that emerge from damage to the brain is often difficult to discern. In this perspective, we argue that a satisfying account of neurodegenerative symptoms most naturally emerges from the consideration of the brain from the systems-level. Specifically, we will highlight the role of the neuromodulatory arousal system, which is uniquely positioned to coordinate the brain's ability to flexibly integrate the otherwise segregated structures required to support higher cognitive functions. Importantly, the neuromodulatory arousal system is highly heterogeneous, encompassing structures that are common sites of neurodegeneration across Alzheimer's and Parkinson's disease. We will review studies that implicate the dysfunctional interactions amongst distributed brain regions as a side-effect of pathological involvement of the neuromodulatory arousal system in these neurodegenerative disorders. From this perspective, we will argue that future work in clinical neuroscience should attempt to consider the inherent complexity in the brain and employ analytic techniques that do not solely focus on regional functional impairments, but rather captures the brain as an inherently dynamic, distributed, multi-scale system. Through this lens, we hope that we will devise new and improved diagnostic markers and interventional approaches to aid in the treatment of neurodegenerative disorders.}, } @article {pmid36577740, year = {2022}, author = {Dove, A and Guo, J and Marseglia, A and Fastbom, J and Vetrano, DL and Fratiglioni, L and Pedersen, NL and Xu, W}, title = {Cardiometabolic multimorbidity and incident dementia: the Swedish twin registry.}, journal = {European heart journal}, volume = {}, number = {}, pages = {}, doi = {10.1093/eurheartj/ehac744}, pmid = {36577740}, issn = {1522-9645}, abstract = {AIMS: Cardiometabolic diseases (CMDs), including diabetes, heart disease, and stroke, are established risk factors for dementia, but their combined impact has been investigated only recently. This study aimed to examine the association between mid- and late-life cardiometabolic multimorbidity and dementia and explore the role of genetic background in this association.

METHODS AND RESULTS: Within the Swedish Twin Registry, 17 913 dementia-free individuals aged ≥60 were followed for 18 years. CMDs [including age of onset in mid (60) or late (≥60) life] and dementia were ascertained from medical records. Cardiometabolic multimorbidity was defined as having ≥2 CMDs. Cox regression was used to estimate the CMD-dementia association in (i) a classical cohort study design and (ii) a co-twin study design involving 356 monozygotic and dizygotic pairs. By comparing the strength of the association in the two designs, the contribution of genetic background was estimated. At baseline, 3,312 (18.5%) participants had 1 CMD and 839 (4.7%) had ≥2 CMDs. Over the follow-up period, 3,020 participants developed dementia. In the classic cohort design, the hazard ratio (95% confidence interval) of dementia was 1.42 (1.27-1.58) for 1 CMD and 2.10 (1.73-2.57) for ≥2 CMDs. Dementia risk was stronger with mid-life as opposed to late-life CMDs. In the co-twin design, the CMD-dementia association was attenuated among monozygotic [0.99 (0.50-1.98)] but not dizygotic [1.55 (1.15-2.09)] twins, suggesting that the association was in part due to genetic factors common to both CMDs and dementia.

CONCLUSION: Cardiometabolic multimorbidity, particularly in mid-life, is associated with an increased risk of dementia. Genetic background may underpin this association.}, } @article {pmid36577381, year = {2022}, author = {Morgan, CE and Zhang, Z and Miyagi, M and Golczak, M and Yu, EW}, title = {Toward structural-omics of the bovine retinal pigment epithelium.}, journal = {Cell reports}, volume = {41}, number = {13}, pages = {111876}, pmid = {36577381}, issn = {2211-1247}, support = {R01 AI145069/AI/NIAID NIH HHS/United States ; R01 EY023948/EY/NEI NIH HHS/United States ; S10 RR031537/RR/NCRR NIH HHS/United States ; }, mesh = {Animals ; Cattle ; *Retinal Pigment Epithelium/metabolism ; Cryoelectron Microscopy ; Proteins/metabolism ; *Parkinson Disease/metabolism ; Glycolysis ; }, abstract = {The use of an integrated systems biology approach to investigate tissues and organs has been thought to be impracticable in the field of structural biology, where the techniques mainly focus on determining the structure of a particular biomacromolecule of interest. Here, we report the use of cryoelectron microscopy (cryo-EM) to define the composition of a raw bovine retinal pigment epithelium (RPE) lysate. From this sample, we simultaneously identify and solve cryo-EM structures of seven different RPE enzymes whose functions affect neurotransmitter recycling, iron metabolism, gluconeogenesis, glycolysis, axonal development, and energy homeostasis. Interestingly, dysfunction of these important proteins has been directly linked to several neurodegenerative disorders, including Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, and schizophrenia. Our work underscores the importance of cryo-EM in facilitating tissue and organ proteomics at the atomic level.}, } @article {pmid36577365, year = {2022}, author = {Araya, P and Kinning, KT and Coughlan, C and Smith, KP and Granrath, RE and Enriquez-Estrada, BA and Worek, K and Sullivan, KD and Rachubinski, AL and Wolter-Warmerdam, K and Hickey, F and Galbraith, MD and Potter, H and Espinosa, JM}, title = {IGF1 deficiency integrates stunted growth and neurodegeneration in Down syndrome.}, journal = {Cell reports}, volume = {41}, number = {13}, pages = {111883}, pmid = {36577365}, issn = {2211-1247}, support = {R01 AI150305/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Biomarkers/metabolism ; *Down Syndrome/genetics ; Growth Disorders/genetics ; Insulin-Like Growth Factor I/genetics ; }, abstract = {Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), is characterized by stunted growth, cognitive impairment, and increased risk of diverse neurological conditions. Although signs of lifelong neurodegeneration are well documented in DS, the mechanisms underlying this phenotype await elucidation. Here we report a multi-omics analysis of neurodegeneration and neuroinflammation biomarkers, plasma proteomics, and immune profiling in a diverse cohort of more than 400 research participants. We identified depletion of insulin growth factor 1 (IGF1), a master regulator of growth and brain development, as the top biosignature associated with neurodegeneration in DS. Individuals with T21 display chronic IGF1 deficiency downstream of growth hormone production, associated with a specific inflammatory profile involving elevated tumor necrosis factor alpha (TNF-α). Shorter children with DS show stronger IGF1 deficiency, elevated biomarkers of neurodegeneration, and increased prevalence of autism and other conditions. These results point to disruption of IGF1 signaling as a potential contributor to stunted growth and neurodegeneration in DS.}, } @article {pmid36577280, year = {2023}, author = {Yang, D and Masurkar, AV and Khasiyev, F and Rundek, T and Wright, CB and Elkind, MSV and Sacco, RL and Gutierrez, J}, title = {Intracranial artery stenosis is associated with cortical thinning in stroke-free individuals of two longitudinal cohorts.}, journal = {Journal of the neurological sciences}, volume = {444}, number = {}, pages = {120533}, pmid = {36577280}, issn = {1878-5883}, support = {R56 NS029993/NS/NINDS NIH HHS/United States ; R37 NS029993/NS/NINDS NIH HHS/United States ; R01 AG057709/AG/NIA NIH HHS/United States ; R01 NS029993/NS/NINDS NIH HHS/United States ; R01 AG066162/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Constriction, Pathologic/diagnostic imaging ; Cross-Sectional Studies ; Cerebral Cortical Thinning ; *Noma ; *Stroke/diagnostic imaging ; Magnetic Resonance Imaging ; Arteries/pathology ; *Atherosclerosis ; *Intracranial Arteriosclerosis/complications/diagnostic imaging ; *Carotid Stenosis ; }, abstract = {BACKGROUND: We examined the association between asymptomatic intracranial artery stenosis (aICAS) and cortical thickness using brain magnetic resonance morphometry in two cohorts.

METHODS: This cross-sectional study included stroke-free participants from the Northern Manhattan Study (NOMAS) and the National Alzheimer's Coordinating Center (NACC). We represented the predictor aICAS in NOMAS as a continuous global stenosis score reflecting an overall burden of stenosis (possible range 0-44) assessed by magnetic resonance angiography and in NACC as a dichotomous autopsy-determined Circle of Willis (CoW) atherosclerosis (none-mild vs moderate-severe). The primary outcome of interest was total cortical thickness. We analyzed each dataset separately using multivariable linear regression.

RESULTS: The analysis included 1209 NOMAS (46% had any stenosis, 5% had ≥70% stenosis of at least one vessel; stenosis score range 0-11) and 392 NACC (36% moderate-severe CoW atherosclerosis) participants. We found an inverse relationship between stenosis score and total cortical thickness (β-estimate [95% confidence interval (CI)]: -2.98 [-5.85, -0.11]) in adjusted models. We replicated these results in NACC (β-estimate [95% CI]: -0.06 [-0.11, -0.003]). Post-hoc, we segregated stenosis scores by location and only posterior circulation stenosis score was associated with total cortical thickness (anterior β-estimate [95% CI]: -0.90 [-5.16, 3.36], posterior β-estimate [95% CI]: -7.25 [-14.30, -0.20]).

CONCLUSION: We found both radiographically and neuropathologically determined aICAS to be associated with global cortical thinning. Interestingly, posterior circulation stenoses appeared to drive this association with global cortical thinning, raising the possibility of pathophysiologic mechanisms for cortical thinning other than impaired hemodynamics.}, } @article {pmid36577203, year = {2023}, author = {Chen, Z and Zhang, H and Yang, X and Wu, S and He, X and Xu, J and Guo, J and Prosperi, M and Wang, F and Xu, H and Chen, Y and Hu, H and DeKosky, ST and Farrer, M and Guo, Y and Wu, Y and Bian, J}, title = {Assess the documentation of cognitive tests and biomarkers in electronic health records via natural language processing for Alzheimer's disease and related dementias.}, journal = {International journal of medical informatics}, volume = {170}, number = {}, pages = {104973}, doi = {10.1016/j.ijmedinf.2022.104973}, pmid = {36577203}, issn = {1872-8243}, support = {R01 AG076234/AG/NIA NIH HHS/United States ; R56 AG069880/AG/NIA NIH HHS/United States ; R21 AG068717/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/diagnosis ; Natural Language Processing ; Electronic Health Records ; Biomarkers ; Documentation ; }, abstract = {BACKGROUND: Cognitive tests and biomarkers are the key information to assess the severity and track the progression of Alzheimer's' disease (AD) and AD-related dementias (AD/ADRD), yet, both are often only documented in clinical narratives of patients' electronic health records (EHRs). In this work, we aim to (1) assess the documentation of cognitive tests and biomarkers in EHRs that can be used as real-world endpoints, and (2) identify, extract, and harmonize the different commonly used cognitive tests from clinical narratives using natural language processing (NLP) methods into categorical AD/ADRD severity.

METHODS: We developed a rule-based NLP pipeline to extract the cognitive tests and biomarkers from clinical narratives in AD/ADRD patients' EHRs. We aggregated the extracted results to the patient level and harmonized the cognitive test scores into severity categories using cutoffs determined based on both relevant literature and domain knowledge of AD/ADRD clinicians.

RESULTS: We identified an AD/ADRD cohort of 48,912 patients from the University of Florida (UF) Health system and identified 7 measurements (6 cognitive tests and 1 biomarker) that are frequently documented in our data. Our NLP pipeline achieved an overall F1-score of 0.9059 across the 7 measurements. Among the 6 cognitive tests, we were able to harmonize 4 cognitive test scores into severity categories, and the population characteristics of patients with different severity were described. We also identified several factors related to the availability of their documentation in EHRs.

CONCLUSION: This study demonstrates that our NLP pipelines can extract cognitive tests and biomarkers of AD/ADRD accurately for downstream studies. Although, the documentation of cognitive tests and biomarkers in EHRs appears to be low, RWD is still an important resource for AD/ADRD research. Nevertheless, providing standardized approach to document cognitive tests and biomarkers in EHRS are also warranted.}, } @article {pmid36577190, year = {2023}, author = {Wang, Z and Li, T and Du, M and Zhang, L and Xu, L and Song, H and Zhang, J}, title = {β-hydroxybutyrate improves cognitive impairment caused by chronic cerebral hypoperfusion via amelioration of neuroinflammation and blood-brain barrier damage.}, journal = {Brain research bulletin}, volume = {193}, number = {}, pages = {117-130}, doi = {10.1016/j.brainresbull.2022.12.011}, pmid = {36577190}, issn = {1873-2747}, mesh = {Rats ; Animals ; Blood-Brain Barrier/metabolism ; 3-Hydroxybutyric Acid/pharmacology ; Neuroinflammatory Diseases ; Maze Learning ; *Cognitive Dysfunction/drug therapy/etiology/metabolism ; *Brain Ischemia/complications/drug therapy ; Disease Models, Animal ; }, abstract = {BACKGROUND: Vascular cognitive impairment (VCI) is the second most common type of dementia after Alzheimer's disease (AD) in elderly people. Chronic cerebral hypoperfusion (CCH) is the early pathophysiological basis of VCI. β-Hydroxybutyrate (BHB) is one of the important components of ketone bodies, an intermediate product of endogenous energy metabolism, which can mitigate neuroinflammation in stroke and neurodegenerative diseases. The present study aimed to investigate whether BHB can improve cognitive impairment caused by CCH and the underlying mechanism.

METHODS: The CCH model was established by permanent bilateral common carotid artery occlusion (2VO). CCH rats were intraperitoneally injected with BHB (1.5 mmol/kg/d) every day for 8 consecutive weeks from 2 weeks before surgery. The hippocampal blood flow of rats was measured by using a laser Doppler velocimetry. Used the Morris water maze test (MWM) to assess spatial learning and memory of rats, and harvested brain tissues for molecular, biochemical, and pathological tests.

RESULTS: We found that BHB intervention for 8 weeks could effectively restore hippocampal blood flow and improve spatial learning and memory in CCH rats. BHB can protect the blood-brain barrier (BBB), as manifested by reducing the ultrastructural damage and leakage of the BBB, restoring the expression of tight junction-related proteins and reducing the expression of Matrix Metalloproteinases-9 (MMP-9). Additionally, after BHB intervention, microglia activation was reduced, oligodendrocyte motility was active, and the expression levels of pro-inflammatory factors such as tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), nuclear factor-κB (NF-κB) and advanced glycation end-products (RAGE) were lower, which also indicated that BHB had a beneficial effect in mitigating neuroinflammation.

CONCLUSION: BHB can improve the cognitive impairment caused by CCH. The potential mechanisms of BHB may be through reducing neuroinflammation and protecting BBB.}, } @article {pmid36577130, year = {2023}, author = {Tang, Y and Zhang, D and Chang, Y and Zheng, J}, title = {Atrial Natriuretic Peptide Associated with Cardiovascular Diseases Inhibits Amyloid-β Aggregation via Cross-Seeding.}, journal = {ACS chemical neuroscience}, volume = {14}, number = {2}, pages = {312-322}, doi = {10.1021/acschemneuro.2c00712}, pmid = {36577130}, issn = {1948-7193}, mesh = {Animals ; Humans ; Atrial Natriuretic Factor ; *Cardiovascular Diseases ; Caenorhabditis elegans ; Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/metabolism ; Peptide Fragments ; }, abstract = {Both cardiovascular diseases (CVDs) and Alzheimer's disease (AD) share some common risk factors (e.g., age, obesity, oxidative stress, inflammation, hypertension) that contribute to their overlapping pathogenesis, indicating a "head-to-heart" pathological connection between CVDs and AD. To explore this potential connection at the protein level, we study the potential cross-seeding (heterotypic interactions) between CVD-associated atrial natriuretic peptide (ANP) and AD-associated β-amyloid (Aβ). Collective aggregation and cell assays demonstrate the cross-seeding of ANP with different Aβ species including monomers, oligomers, and fibrils with high binding affinity (KD = 1.234-1.797 μM) in a dose-dependent manner. Such ANP-induced cross-seeding also modifies the Aβ aggregation pathway, fibril morphology, and cell deposition pattern by inhibiting Aβ fibrillization from small aggregates, disassembling preformed Aβ fibrils, and alleviating Aβ-associated cytotoxicity. Finally, using transgenic C. elegans worms that express the human muscle-specific Aβ1-42, ANP can also effectively delay Aβ-induced worm paralysis, decrease Aβ plaques in worm brains, and reduce reactive oxygen species (ROS) production, confirming its in vivo inhibition ability to prevent neurodevelopmental toxicity in worms. This work discovers not only a new cross-seeding system between the two disease-related proteins but also a new finding that ANP possesses a new biological function as an Aβ inhibitor in the nonaggregated state.}, } @article {pmid36576960, year = {2022}, author = {Gómez-Tortosa, E and Baradaran-Heravi, Y and Dillen, L and Choudhury, NR and Agüero Rabes, P and Pérez-Pérez, J and Kocoglu, C and Sainz, MJ and Ruiz González, A and Téllez, R and Cremades-Jimeno, L and Cárdaba, B and , and Van Broeckhoven, C and Michlewski, G and van der Zee, J}, title = {TRIM25 mutation (p.C168*), coding for an E3 ubiquitin ligase, is a cause of early-onset autosomal dominant dementia with amyloid load and parkinsonism.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {}, number = {}, pages = {}, doi = {10.1002/alz.12913}, pmid = {36576960}, issn = {1552-5279}, abstract = {INTRODUCTION: Patients with familial early-onset dementia (EOD) pose a unique opportunity for gene identification studies.

METHODS: We present the phenotype and whole-exome sequencing (WES) study of an autosomal dominant EOD family. Candidate genes were examined in a set of dementia cases and controls (n = 3712). Western blotting was conducted of the wild-type and mutant protein of the final candidate.

RESULTS: Age at disease onset was 60 years (range 56 to 63). The phenotype comprised mixed amnestic and behavioral features, and parkinsonism. Cerebrospinal fluid and plasma biomarkers, and a positron emission tomography amyloid study suggested Alzheimer's disease. WES and the segregation pattern pointed to a nonsense mutation in the TRIM25 gene (p.C168*), coding for an E3 ubiquitin ligase, which was absent in the cohorts studied. Protein studies supported a loss-of-function mechanism.

DISCUSSION: This study supports a new physiopathological mechanism for brain amyloidosis. Furthermore, it extends the role of E3 ubiquitin ligases dysfunction in the development of neurodegenerative diseases.

HIGHLIGHTS: A TRIM25 nonsense mutation (p.C168*) is associated with autosomal dominant early-onset dementia and parkinsonism with biomarkers suggestive of Alzheimer's disease. TRIM25 protein studies support that the mutation exerts its effect through loss of function. TRIM25, an E3 ubiquitin ligase, is known for its role in the innate immune response but this is the first report of association with neurodegeneration. The role of TRIM25 dysfunction in development of amyloidosis and neurodegeneration merits a new line of research.}, } @article {pmid36576708, year = {2022}, author = {Brandimarti, R and Irollo, E and Meucci, O}, title = {The US9-Derived Protein gPTB9TM Modulates APP Processing Without Targeting Secretase Activities.}, journal = {Molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {36576708}, issn = {1559-1182}, support = {DA032444/RG/CSR NIH HHS/United States ; DA040519/RG/CSR NIH HHS/United States ; DA015014/RG/CSR NIH HHS/United States ; }, abstract = {Alteration of neuronal protein processing is often associated with neurological disorders and is highly dependent on cellular protein trafficking. A prime example is the amyloidogenic processing of amyloid precursor protein (APP) in intracellular vesicles, which plays a key role in age-related cognitive impairment. Most approaches to correct this altered processing aim to limit enzymatic activities that lead to toxic products, such as protein cleavage by β-secretase and the resulting amyloid β production. A viable alternative is to direct APP to cellular compartments where non-amyloidogenic mechanisms are favored. To this end, we exploited the molecular properties of the herpes simplex virus 1 (HSV-1) transport protein US9 to guide APP interaction with preferred endogenous targets. Specifically, we generated a US9 chimeric construct that facilitates APP processing through the non-amyloidogenic pathway and tested it in primary cortical neurons. In addition to reducing amyloid β production, our approach controls other APP-dependent biochemical steps that lead to neuronal deficits, including phosphorylation of APP and tau proteins. Notably, it also promotes the release of neuroprotective soluble αAPP. In contrast to other neuroprotective strategies, these US9-driven effects rely on the activity of endogenous neuronal proteins, which lends itself well to the study of fundamental mechanisms of APP processing/trafficking. Overall, this work introduces a new method to limit APP misprocessing and its cellular consequences without directly targeting secretase activity, offering a novel tool to reduce cognitive decline in pathologies such as Alzheimer's disease and HIV-associated neurocognitive disorders.}, } @article {pmid36576695, year = {2022}, author = {Rahmani, A and Najand, B and Sonnega, A and Akhlaghipour, G and Mendez, MF and Assari, S and , }, title = {Intersectional Effects of Race and Educational Attainment on Memory Function of Middle-Aged and Older Adults With Alzheimer's Disease.}, journal = {Journal of racial and ethnic health disparities}, volume = {}, number = {}, pages = {}, pmid = {36576695}, issn = {2196-8837}, abstract = {BACKGROUND: High educational attainment may protect individuals, particularly middle-aged and older adults, against a wide range of health risks, including memory decline with age; however, this protection is less clear in patients with Alzheimer's disease (AD). In addition, this effect may differ across racial groups. According to the Marginalized-Related Diminished Return (MDR) theory, for example, the protective effect of high educational attainment on mental and physical health shows a weaker protective effect for racial minority groups, particularly Black people compared to White individuals.

OBJECTIVES: This longitudinal study used data of middle-aged and older adults with AD with two aims: first, to test the association between educational attainment and memory, and second, to explore racial differences in this association in the USA.

METHODS: Data came from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. The total sample was 1673 American middle-aged and older adults. The independent variable was educational attainment measured as years of education. The main outcome was memory operationalized as Rey Auditory Verbal Learning Test (RAVLT) Verbal Forgetting percentage (VF%). Age, gender, and follow-up duration were covariates. Race was the effect modifier. Linear regression model was utilized to analyze the data.

RESULTS: Of all participants, 68 (4.1%) were Black, and the remaining were White, with a mean age of 75 years old. In the pooled sample, educational attainment did not show a significant association with memory, independent of confounders. Educational attainment showed a significant interaction with race on memory, with higher educational attainment having a different effect on memory in White patients compared to Black patients.

CONCLUSION: The effect of higher educational attainment on memory differs for Black patients with AD compared to White patients. To prevent cognitive disparities by race, we need to go beyond racial inequality in access to resources (e.g., education) and minimize diminished returns of educational attainment for racial minorities. To tackle health inequalities, social policies should not be limited to equalizing socioeconomic status but also help minority groups leverage their available resources, such as educational attainment, and secure tangible outcomes.}, } @article {pmid36576665, year = {2022}, author = {Kuang, F and Xiang, T}, title = {Molecular mechanism of Acanthopanax senticosus in the treatment of Alzheimer's disease based on network pharmacology and molecular docking.}, journal = {Molecular diversity}, volume = {}, number = {}, pages = {}, pmid = {36576665}, issn = {1573-501X}, abstract = {Alzheimer's disease is the most common neurodegenerative disease. Acanthopanax senticosus, also known as Ciwujia or Siberian ginseng in Chinese, has a wide range of antioxidant and anti-inflammatory activities. The study aims to explore the action mechanism of A. senticosus against Alzheimer's disease using network pharmacology and molecular docking. The active ingredients and targets of A. senticosus were searched through the ETCM database, and Alzheimer's disease-related targets were obtained through the OMIM and GeneCards databases. The Cytoscape 3.7.2 software was used to construct a "drug-component-target" relationship network, and the target genes of A. senticosus against Alzheimer's disease were imported into the String database to establish a protein interaction (PPI) network. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes gene enrichment analyses were performed through the Metascape database to obtain potential pathways of action of A. senticosus for the treatment of Alzheimer's disease, and the ability of these active ingredients to bind to core targets was then verified by molecular docking. 51 active ingredients were screened from A. senticosus, and 88 effective targets for Alzheimer's disease were screened. Topological and pathway-enrichment analyses revealed that A. senticosus could play a beneficial role in the treatment of Alzheimer's disease by regulating apoptosis and inflammation. Molecular docking results showed that Ciwujianoside B, Chiisanoside, and Ciwujianoside D1 had strong binding abilities to key target proteins (TNFα, IL1β, and CASP3). Collectively, A. senticosus is feasible in the treatment of Alzheimer's disease.}, } @article {pmid36576642, year = {2023}, author = {Ballesteros-Álvarez, J and Nguyen, W and Sivapatham, R and Rane, A and Andersen, JK}, title = {Urolithin A reduces amyloid-beta load and improves cognitive deficits uncorrelated with plaque burden in a mouse model of Alzheimer's disease.}, journal = {GeroScience}, volume = {45}, number = {2}, pages = {1095-1113}, pmid = {36576642}, issn = {2509-2723}, support = {RF1 AG062280/AG/NIA NIH HHS/United States ; RF1 AG062280/AG/NIA NIH HHS/United States ; }, mesh = {Mice ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; Mice, Transgenic ; Maze Learning ; Amyloid beta-Peptides/metabolism ; *Cognitive Dysfunction/drug therapy ; Cognition ; }, abstract = {In the present study, we investigated the effects of urolithin A (UA), a metabolite generated from ellagic acid via its metabolism by gut bacteria, as an autophagy activator with potential neuroprotective activity. WT and 3xTg-AD mice were administered long-term intermittent dietary supplementation with UA. UA was found to prevent deficits in spatial memory, cued fear response, and exploratory behavior in this model. It also decreased the Aβ plaque burden in areas of the hippocampus where these protein deposits are prominent in the model. Interestingly, correlation analyses demonstrate that Aβ plaque burden positively correlates with enhanced spatial memory in 3xTg-AD mice on a control diet but not in those supplemented with UA. In contrast, Aβ42 abundance in cortical and hippocampal homogenates negatively correlate with spatial memory in UA-fed mice. Our data suggest that plaque formation may be a protective mechanism against neurodegeneration and cognitive decline and that targeting the generation of proteotoxic Aβ species might be a more successful approach in halting disease progression. UA was also found to extend lifespan in normal aging mice. Mechanistically, we demonstrate that UA is able to induce autophagy and to increase Aβ clearance in neuronal cell lines. In summary, our studies reveal UA, likely via its actions as a autophagy inducer, is capable of removing Aβ from neurons and its dietary administration prevents the onset of cognitive deficits associated with pathological Aβ deposition in the 3xTg-AD mouse model as well as extending lifespan in normal aging mice.}, } @article {pmid36576369, year = {2022}, author = {Anderson, A and Malone, M}, title = {The Differential Diagnosis and Treatment of Mild Cognitive Impairment and Alzheimer Disease.}, journal = {The Journal of clinical psychiatry}, volume = {84}, number = {1}, pages = {}, doi = {10.4088/JCP.BG21120COM4}, pmid = {36576369}, issn = {1555-2101}, mesh = {Humans ; *Alzheimer Disease/diagnosis/drug therapy ; Diagnosis, Differential ; *Cognitive Dysfunction/diagnosis/therapy/chemically induced ; Cholinesterase Inhibitors/therapeutic use ; Memantine/therapeutic use ; Disease Progression ; }, abstract = {Identifying patients at risk for developing mild cognitive impairment (MCI) and Alzheimer disease (AD) remains challenging in clinical practice, even as scientific understanding of dementia advances generally. That said, successfully navigating the associated differential diagnosis in AD is essential, as various causes of cognitive impairment require different treatment strategies. In recent years, the armamentarium in AD has expanded with regulatory approval of a disease-modifying therapy-aducanumab-and may be shifting away from symptomatic treatments such as cholinesterase inhibitors and memantine. Concurrently, the role of biomarkers in AD is increasing, and these entities may soon play a greater role in determining patient eligibility for prophylactic interventions and the likelihood of disease progression. As the standard of care progresses, clinicians should educate patients and their care providers on the implications of these advances and reinforce lifestyle changes that can delay or prevent the onset of disease in those at risk of AD. In doing so, care providers can deliver the best care possible.}, } @article {pmid36576368, year = {2022}, author = {Anderson, A and Malone, M}, title = {Recent Advances in Screening for Mild Cognitive Impairment and Alzheimer Disease.}, journal = {The Journal of clinical psychiatry}, volume = {84}, number = {1}, pages = {}, doi = {10.4088/JCP.BG21120COM3}, pmid = {36576368}, issn = {1555-2101}, mesh = {Humans ; *Alzheimer Disease/diagnosis/psychology ; *Cognitive Dysfunction/diagnosis/psychology ; Cognition ; Biomarkers ; Mental Status and Dementia Tests ; Amyloid beta-Peptides ; }, abstract = {In recent years, scientific understanding of the pathophysiology underlying Alzheimer disease (AD) has advanced substantially. Among the most transformative of discoveries is the existence of biomarkers, such as Aβ42, which can manifest in the central nervous system decades before the onset of disease-associated dementia. By detecting these biological entities early, clinicians can close diagnostic delays and substantially improve outcomes for patients with AD. With prompt news of a diagnosis, patients can initiate long-term planning and devise goals for treatment while their cognition is relatively intact. To differentiate among different forms of dementia, neurologists and supporting clinicians should additionally capitalize on the availability of validated screening tools. Increasingly adopted, tests such as the Montreal Cognitive Assessment yield highly sensitive, specific findings that can improve the standard of care. These results, when paired with insights gleaned from patient histories and clinical examinations, can further inform treatment-decision making and help ensure that patients receive care tailored to their unique circumstances and needs.}, } @article {pmid36576325, year = {2022}, author = {Alan, E and Kerry, Z and Sevin, G}, title = {Molecular mechanisms of Alzheimer's disease: From therapeutic targets to promising drugs.}, journal = {Fundamental & clinical pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1111/fcp.12861}, pmid = {36576325}, issn = {1472-8206}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment so widespread that it interferes with a person's ability to complete daily activities. AD is becoming increasingly common, and it is estimated that the number of patients will reach 152 million by 2050. Current treatment options for AD are symptomatic and have modest benefits. Therefore, considering the human, social, and economic burden of the disease, the development of drugs with the potential to alter disease progression has become a global priority. In this review, the molecular mechanisms involved in the pathology of AD were evaluated as therapeutic targets. The main aim of the review is to focus on new knowledge about mitochondrial dysfunction, oxidative stress, and neuronal transmission in AD, as well as a range of cellular signaling mechanisms and associated treatments. Important molecular interactions leading to AD were described in amyloid cascade and in tau protein function, oxidative stress, mitochondrial dysfunction, cholinergic and glutamatergic neurotransmission, cAMP-regulatory element-binding protein (CREB), the silent mating type information regulation 2 homolog 1 (SIRT-1), neuroinflammation (glial cells), and synaptic alterations. This review summarizes recent experimental and clinical research in AD pathology and analyzes the potential of therapeutic applications based on molecular disease mechanisms.}, } @article {pmid36576270, year = {2022}, author = {Zahraee, H and Arab, SS and Khoshbin, Z and Bozorgmehr, MR}, title = {A comprehensive computer simulation insight into inhibitory mechanisms of EGCG and NQTrp ligands on amyloid-beta assemblies as the Alzheimer's disease insignia.}, journal = {Journal of biomolecular structure & dynamics}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/07391102.2022.2158939}, pmid = {36576270}, issn = {1538-0254}, abstract = {Amyloid-β peptide with predominant presence in the senile plaques is the most common agent for Alzheimer's disease (AD) incidence. Assembly of the amyloid-β(1-42) (Aβ1-42) isoform is known as the main reason for the AD appearance. Epigallocatechin gallate (EGCG) and 1,4-naphthoquinone-2-yl-L-tryptophan (NQTrp) are two small molecules that inhibit the formation of the Aβ1-42 fibrils. The present study provides molecular insight to clarify the inhibitory mechanisms of the EGCG and NQTrp ligands on the Aβ1-42 assemblies by using molecular dynamics (MD) simulation. Hence, nine different Aβ1-42-containing systems including the monomer, dimer, and hexamer of Aβ1-42 considering each of them in a media with no ligands, in the presence of one EGCG ligand, and in the presence of one EGCG ligand were studied with a simulation time of 1 µs for each system. The precise investigation of the peptide-ligand distance, conformational factor (Pi), solvent accessible surface area (SASA), dictionary of secondary structure (DSSP), and Lys28-Ala42 salt bridge analyses confirmed that the hydroxyl-rich structure of the EGCG ligand applied its inhibitory effect on the aggregation of the peptides indirectly by involving water molecules. While the hydroxyl-free structure of the NQTrp ligand exposed its inhibitory effect through a direct interaction with the Aβ1-42 peptides. Besides, reduced density gradient (RDG) analysis clarified the hydrogen bonding interactions as the dominant ones for the peptide-EGCG systems, and also, steric and van der Waals interactions for the peptide-NQTrp systems.Communicated by Ramaswamy H. Sarma.}, } @article {pmid36576199, year = {2022}, author = {Ghosh, P and Singh, R and Ganeshpurkar, A and Swetha, R and Kumar, D and Singh, SK and Kumar, A}, title = {Identification of potential death-associated protein kinase-1 (DAPK1) inhibitors by an integrated ligand-based and structure-based computational drug design approach.}, journal = {Journal of biomolecular structure & dynamics}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/07391102.2022.2158935}, pmid = {36576199}, issn = {1538-0254}, abstract = {Death-associated protein kinase 1 (DAPK1) is a calcium/calmodulin (Ca[2+]/CaM)-dependent serine/threonine kinase that is abundantly expressed in the memory- and cognition-related brain areas. DAPK1 is associated with several pathological hallmarks of Alzheimer's disease (AD); it is an attractive target for designing a novel DAPK1 inhibitor as an effective therapeutic treatment for AD. In the present study, we have used an integrated ligand-based and structure-based drug design method to identify DAPK1 inhibitors. The pharmacophoric features of compound 38 G (PDB ID 4TXC) were mapped, and the models were evaluated using enrichment factor (EF) and goodness of hit (GH) score. The selected models were used to screen Zinc 15 compounds library. The identified hits were passed through drug-likeliness and PAINS filtering. The docking study was performed in three steps to yield molecules with good binding energy and ligand-target interactions. Finally, three hits were obtained, that is, ZINC000020648330, ZINC000006755051 and ZINC000020650468, which were subjected to rigorous molecular dynamics simulation. All three hits exhibited optimal stability under simulated conditions and low predicted toxicity.Communicated by Ramaswamy H. Sarma.}, } @article {pmid36576157, year = {2022}, author = {Velioglu, HA and Ayyildiz, B and Ayyildiz, S and Sutcubasi, B and Hanoglu, L and Bayraktaroglu, Z and Yulug, B}, title = {A structural and resting-state functional connectivity investigation of the pulvinar in elderly individuals and Alzheimer's disease patients.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {}, number = {}, pages = {}, doi = {10.1002/alz.12850}, pmid = {36576157}, issn = {1552-5279}, abstract = {In Alzheimer's disease (AD), structural and functional changes in the brain may give rise to disruption of specific cognitive functions. The aim of this study is to investigate the functional connectivity alterations in the pulvinar's subdivisions and total pulvinar voxel-based morphometry (VBM) changes in individuals with AD and healthy controls. A seed-based functional connectivity analysis was applied to the anterior, inferior, lateral, and medial pulvinar in each hemisphere. Furthermore, VBM analysis was carried out to compare gray matter (GM) volume differences in the pulvinar and thalamus between the two groups. Connectivity analysis revealed that the pulvinar subdivisions had decreased connectivity in individuals with AD. In addition, the pulvinar and thalamus in each hemisphere were significantly smaller in the AD group. The pulvinar may have a role in AD-related cognitive impairments and the intrinsic connectivity network changes and GM loss in pulvinar subdivisions suggest the cognitive deterioration occurring in those with AD. HIGHLIGHTS: The pulvinar may play a role in pathophysiology of cognitive impairments in those with Alzheimer's disease (AD). Decreased structural volume and functional connectivity were found in patients with AD. The inferior pulvinar is functionally the most affected subdivision by AD compared to the others.}, } @article {pmid36576155, year = {2022}, author = {Chatterjee, P and Vermunt, L and Gordon, BA and Pedrini, S and Boonkamp, L and Armstrong, NJ and Xiong, C and Singh, AK and Li, Y and Sohrabi, HR and Taddei, K and Molloy, M and Benzinger, TLS and Morris, JC and Karch, C and Berman, S and Chhatwal, J and Cruchaga, C and Graff-Radford, NR and Day, GS and Farlow, M and Fox, N and Goate, A and Hassenstab, J and Lee, JH and Levin, J and McDade, E and Mori, H and Perrin, R and Sanchez-Valle, R and Schofield, PR and Levey, A and Jucker, M and Masters, CL and Fagan, AM and Bateman, RJ and Martins, RN and Teunissen, C and , }, title = {Plasma glial fibrillary acidic protein in autosomal dominant Alzheimer's disease: Associations with Aβ-PET, neurodegeneration, and cognition.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {}, number = {}, pages = {}, doi = {10.1002/alz.12879}, pmid = {36576155}, issn = {1552-5279}, support = {U19 AG032438/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Glial fibrillary acidic protein (GFAP) is a promising candidate blood-based biomarker for Alzheimer's disease (AD) diagnosis and prognostication. The timing of its disease-associated changes, its clinical correlates, and biofluid-type dependency will influence its clinical utility.

METHODS: We evaluated plasma, serum, and cerebrospinal fluid (CSF) GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease.

RESULTS: Plasma GFAP elevations appear a decade before expected symptom onset, after amyloid beta (Aβ) accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished Aβ-positive from Aβ-negative ADAD participants and showed a stronger relationship with Aβ load in asymptomatic than symptomatic ADAD. Higher plasma GFAP was associated with the degree and rate of neurodegeneration and cognitive impairment. Serum GFAP showed similar relationships, but these were less pronounced for CSF GFAP.

CONCLUSION: Our findings support a role for plasma GFAP as a clinical biomarker of Aβ-related astrocyte reactivity that is associated with cognitive decline and neurodegeneration.

HIGHLIGHTS: Plasma glial fibrillary acidic protein (GFAP) elevations appear a decade before expected symptom onset in autosomal dominant Alzheimer's disease (ADAD). Plasma GFAP was associated to amyloid positivity in asymptomatic ADAD. Plasma GFAP increased with clinical severity and predicted disease progression. Plasma and serum GFAP carried similar information in ADAD, while cerebrospinal fluid GFAP did not.}, } @article {pmid36575854, year = {2022}, author = {Moon, SW and Zhao, L and Matloff, W and Hobel, S and Berger, R and Kwon, D and Kim, J and Toga, AW and Dinov, ID and , }, title = {Brain structure and allelic associations in Alzheimer's disease.}, journal = {CNS neuroscience & therapeutics}, volume = {}, number = {}, pages = {}, doi = {10.1111/cns.14073}, pmid = {36575854}, issn = {1755-5949}, support = {R01 CA233487/CA/NCI NIH HHS/United States ; R01 MH121079/MH/NIMH NIH HHS/United States ; R01 MH126137/MH/NIMH NIH HHS/United States ; T32 GM141746/GM/NIGMS NIH HHS/United States ; UL1 TR002240/TR/NCATS NIH HHS/United States ; }, abstract = {BACKGROUND: Alzheimer's disease (AD), the most prevalent form of dementia, affects 6.5 million Americans and over 50 million people globally. Clinical, genetic, and phenotypic studies of dementia provide some insights of the observed progressive neurodegenerative processes, however, the mechanisms underlying AD onset remain enigmatic.

AIMS: This paper examines late-onset dementia-related cognitive impairment utilizing neuroimaging-genetics biomarker associations.

MATERIALS AND METHODS: The participants, ages 65-85, included 266 healthy controls (HC), 572 volunteers with mild cognitive impairment (MCI), and 188 Alzheimer's disease (AD) patients. Genotype dosage data for AD-associated single nucleotide polymorphisms (SNPs) were extracted from the imputed ADNI genetics archive using sample-major additive coding. Such 29 SNPs were selected, representing a subset of independent SNPs reported to be highly associated with AD in a recent AD meta-GWAS study by Jansen and colleagues.

RESULTS: We identified the significant correlations between the 29 genomic markers (GMs) and the 200 neuroimaging markers (NIMs). The odds ratios and relative risks for AD and MCI (relative to HC) were predicted using multinomial linear models.

DISCUSSION: In the HC and MCI cohorts, mainly cortical thickness measures were associated with GMs, whereas the AD cohort exhibited different GM-NIM relations. Network patterns within the HC and AD groups were distinct in cortical thickness, volume, and proportion of White to Gray Matter (pct), but not in the MCI cohort. Multinomial linear models of clinical diagnosis showed precisely the specific NIMs and GMs that were most impactful in discriminating between AD and HC, and between MCI and HC.

CONCLUSION: This study suggests that advanced analytics provide mechanisms for exploring the interrelations between morphometric indicators and GMs. The findings may facilitate further clinical investigations of phenotypic associations that support deep systematic understanding of AD pathogenesis.}, } @article {pmid36575843, year = {2022}, author = {Melrose, J and Smith, MM}, title = {Natural and Semi-Synthetic Flavonoid Anti-SARS-CoV-2 Agents for the Treatment of Long COVID-19 Disease and Neurodegenerative Disorders of Cognitive Decline.}, journal = {Frontiers in bioscience (Elite edition)}, volume = {14}, number = {4}, pages = {27}, doi = {10.31083/j.fbe1404027}, pmid = {36575843}, issn = {1945-0508}, mesh = {Humans ; SARS-CoV-2 ; *COVID-19 ; Flavonoids/therapeutic use/pharmacology ; Post-Acute COVID-19 Syndrome ; Molecular Docking Simulation ; Antiviral Agents/therapeutic use/pharmacology ; Anti-Inflammatory Agents/therapeutic use ; *Neurodegenerative Diseases/drug therapy ; *Cognitive Dysfunction/drug therapy ; }, abstract = {The aim of this review is to highlight the beneficial attributes of flavonoids, a diverse family of widely-distributed polyphenolic phytochemicals that have beneficial cell and tissue protective properties. Phytochemicals are widely distributed in plants, herbs and shrubs used in traditional complimentary medical formulations for centuries. The bioactive components that convey beneficial medicinal effects in these complex herbal preparations are now being identified using network pharmacology and molecular docking procedures that identify their molecular targets. Flavonoids have anti-oxidant, anti-inflammatory, antiviral, antibacterial and anti-cancer properties that have inspired the development of potent multifunctional derivatised flavonoids of improved efficacy. The antiviral properties of flavonoids and the emergence of the severe acute respiratory syndrome (SARS-CoV-2) pandemic has resulted in a resurgence of interest in phytochemicals in the search for efficacious compounds that can prevent viral infection or replication, with many promising plant compounds identified. Promising semi-synthetic flavonoid derivatives have also been developed that inhibit multiple pathological neurodegenerative processes; these offer considerable promise in the treatment of diseases of cognitive decline. Clinical trials are currently being undertaken to evaluate the efficacy of dietary supplements rich in flavonoids for the treatment of virally-mediated diseases. Such trials are expected to identify flavonoids with cell and tissue protective properties that can be harnessed in biomedical applications that may serve as supportive adjunctive procedures to conventional anti-viral drug therapies against diseases such as COVID-19.}, } @article {pmid36575534, year = {2022}, author = {Kong, C and Yang, EJ and Shin, J and Park, J and Kim, SH and Park, SW and Chang, WS and Lee, CH and Kim, H and Kim, HS and Chang, JW}, title = {Enhanced delivery of a low dose of aducanumab via FUS in 5×FAD mice, an AD model.}, journal = {Translational neurodegeneration}, volume = {11}, number = {1}, pages = {57}, pmid = {36575534}, issn = {2047-9158}, mesh = {Animals ; Humans ; Mice ; *Alzheimer Disease/drug therapy/genetics/metabolism ; Brain/metabolism ; Mice, Transgenic ; Plaque, Amyloid/drug therapy ; Ultrasonography ; }, abstract = {BACKGROUND: Aducanumab (Adu), which is a human IgG1 monoclonal antibody that targets oligomer and fibril forms of beta-amyloid, has been reported to reduce amyloid pathology and improve impaired cognition after administration of a high dose (10 mg/kg) of the drug in Alzheimer's disease (AD) clinical trials. The purpose of this study was to investigate the effects of a lower dose of Adu (3 mg/kg) with enhanced delivery via focused ultrasound (FUS) in an AD mouse model.

METHODS: The FUS with microbubbles opened the blood-brain barrier (BBB) of the hippocampus for the delivery of Adu. The combined therapy of FUS and Adu was performed three times in total and each treatment was performed biweekly. Y-maze test, Brdu labeling, and immunohistochemical experimental methods were employed in this study. In addition, RNA sequencing and ingenuity pathway analysis were employed to investigate gene expression profiles in the hippocampi of experimental animals.

RESULTS: The FUS-mediated BBB opening markedly increased the delivery of Adu into the brain by approximately 8.1 times in the brains. The combined treatment induced significantly less cognitive decline and decreased the level of amyloid plaques in the hippocampi of the 5×FAD mice compared with Adu or FUS alone. Combined treatment with FUS and Adu activated phagocytic microglia and increased the number of astrocytes associated with amyloid plaques in the hippocampi of 5×FAD mice. Furthermore, RNA sequencing identified that 4 enriched canonical pathways including phagosome formation, neuroinflammation signaling, CREB signaling and reelin signaling were altered in the hippocami of 5×FAD mice receiving the combined treatment.

CONCLUSION: In conclusion, the enhanced delivery of a low dose of Adu (3 mg/kg) via FUS decreases amyloid deposits and attenuates cognitive function deficits. FUS-mediated BBB opening increases adult hippocampal neurogenesis as well as drug delivery. We present an AD treatment strategy through the synergistic effect of the combined therapy of FUS and Adu.}, } @article {pmid36575455, year = {2022}, author = {Murray, ME and Moloney, CM and Kouri, N and Syrjanen, JA and Matchett, BJ and Rothberg, DM and Tranovich, JF and Sirmans, TNH and Wiste, HJ and Boon, BDC and Nguyen, AT and Reichard, RR and Dickson, DW and Lowe, VJ and Dage, JL and Petersen, RC and Jack, CR and Knopman, DS and Vemuri, P and Graff-Radford, J and Mielke, MM}, title = {Global neuropathologic severity of Alzheimer's disease and locus coeruleus vulnerability influences plasma phosphorylated tau levels.}, journal = {Molecular neurodegeneration}, volume = {17}, number = {1}, pages = {85}, pmid = {36575455}, issn = {1750-1326}, support = {RF1 AG069052/AG/NIA NIH HHS/United States ; R01 AG034676/AG/NIA NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; U01 AG057195/AG/NIA NIH HHS/United States ; R33 AG058738/AG/NIA NIH HHS/United States ; R01 AG073282/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; R37 AG011378/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; R01 AG054449/AG/NIA NIH HHS/United States ; R01 AG075802/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/pathology ; Locus Coeruleus/metabolism/pathology ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Brain/metabolism ; *Cognitive Dysfunction/pathology ; Biomarkers ; }, abstract = {BACKGROUND: Advances in ultrasensitive detection of phosphorylated tau (p-tau) in plasma has enabled the use of blood tests to measure Alzheimer's disease (AD) biomarker changes. Examination of postmortem brains of participants with antemortem plasma p-tau levels remains critical to understanding comorbid and AD-specific contribution to these biomarker changes.

METHODS: We analyzed 35 population-based Mayo Clinic Study of Aging participants with plasma p-tau at threonine 181 and threonine 217 (p-tau181, p-tau217) available within 3 years of death. Autopsied participants included cognitively unimpaired, mild cognitive impairment, AD dementia, and non-AD neurodegenerative disorders. Global neuropathologic scales of tau, amyloid-β, TDP-43, and cerebrovascular disease were examined. Regional digital pathology measures of tau (phosphorylated threonine 181 and 217 [pT181, pT217]) and amyloid-β (6F/3D) were quantified in hippocampus and parietal cortex. Neurotransmitter hubs reported to influence development of tangles (nucleus basalis of Meynert) and amyloid-β plaques (locus coeruleus) were evaluated.

RESULTS: The strongest regional associations were with parietal cortex for tau burden (p-tau181 R = 0.55, p = 0.003; p-tau217 R = 0.66, p < 0.001) and amyloid-β burden (p-tau181 R = 0.59, p < 0.001; p-tau217 R = 0.71, p < 0.001). Linear regression analysis of global neuropathologic scales explained 31% of variability in plasma p-tau181 (Adj. R[2] = 0.31) and 59% in plasma p-tau217 (Adj. R[2] = 0.59). Neither TDP-43 nor cerebrovascular disease global scales independently contributed to variability. Global scales of tau pathology (β-coefficient = 0.060, p = 0.016) and amyloid-β pathology (β-coefficient = 0.080, p < 0.001) independently predicted plasma p-tau217 when modeled together with co-pathologies, but only amyloid-β (β-coefficient = 0.33, p = 0.021) significantly predicted plasma p-tau181. While nucleus basalis of Meynert neuron count/mm[2] was not associated with plasma p-tau levels, a lower locus coeruleus neuron count/mm[2] was associated with higher plasma p-tau181 (R = -0.50, p = 0.007) and higher plasma p-tau217 (R = -0.55, p = 0.002). Cognitive scores (Adj. R[2] = 0.25-0.32) were predicted by the global tau scale, but not by the global amyloid-β scale or plasma p-tau when modeled simultaneously.

CONCLUSIONS: Higher soluble plasma p-tau levels may be the result of an intersection between insoluble deposits of amyloid-β and tau accumulation in brain, and may be associated with locus coeruleus degeneration.}, } @article {pmid36575454, year = {2022}, author = {Brand, AL and Lawler, PE and Bollinger, JG and Li, Y and Schindler, SE and Li, M and Lopez, S and Ovod, V and Nakamura, A and Shaw, LM and Zetterberg, H and Hansson, O and Bateman, RJ}, title = {The performance of plasma amyloid beta measurements in identifying amyloid plaques in Alzheimer's disease: a literature review.}, journal = {Alzheimer's research & therapy}, volume = {14}, number = {1}, pages = {195}, pmid = {36575454}, issn = {1758-9193}, support = {U19 AG024904/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; R01 MH117114/MH/NIMH NIH HHS/United States ; R01 AG070941/AG/NIA NIH HHS/United States ; RF1 AG061900/AG/NIA NIH HHS/United States ; R01 NS095773/NS/NINDS NIH HHS/United States ; R21 AG067559/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; Amyloid beta-Peptides/cerebrospinal fluid ; Plaque, Amyloid/diagnostic imaging ; Peptide Fragments/cerebrospinal fluid ; Brain/diagnostic imaging/metabolism ; Amyloid ; Amyloidogenic Proteins ; Biomarkers/cerebrospinal fluid ; Positron-Emission Tomography/methods ; }, abstract = {The extracellular buildup of amyloid beta (Aβ) plaques in the brain is a hallmark of Alzheimer's disease (AD). Detection of Aβ pathology is essential for AD diagnosis and for identifying and recruiting research participants for clinical trials evaluating disease-modifying therapies. Currently, AD diagnoses are usually made by clinical assessments, although detection of AD pathology with positron emission tomography (PET) scans or cerebrospinal fluid (CSF) analysis can be used by specialty clinics. These measures of Aβ aggregation, e.g. plaques, protofibrils, and oligomers, are medically invasive and often only available at specialized medical centers or not covered by medical insurance, and PET scans are costly. Therefore, a major goal in recent years has been to identify blood-based biomarkers that can accurately detect AD pathology with cost-effective, minimally invasive procedures.To assess the performance of plasma Aβ assays in predicting amyloid burden in the central nervous system (CNS), this review compares twenty-one different manuscripts that used measurements of 42 and 40 amino acid-long Aβ (Aβ42 and Aβ40) in plasma to predict CNS amyloid status. Methodologies that quantitate Aβ42 and 40 peptides in blood via immunoassay or immunoprecipitation-mass spectrometry (IP-MS) were considered, and their ability to distinguish participants with amyloidosis compared to amyloid PET and CSF Aβ measures as reference standards was evaluated. Recent studies indicate that some IP-MS assays perform well in accurately and precisely measuring Aβ and detecting brain amyloid aggregates.}, } @article {pmid36575201, year = {2022}, author = {Cheon, DY and Han, KD and Oh, MS and Yu, KH and Lee, BC and Kim, CH and Kim, Y and Lee, SH and Kim, C and Lim, JS and Lee, M}, title = {Risk of dementia according to the smoking habit change after ischemic stroke: a nationwide population-based cohort study.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {22422}, pmid = {36575201}, issn = {2045-2322}, mesh = {Adult ; Aged ; Humans ; Middle Aged ; *Alzheimer Disease/epidemiology/etiology ; Cohort Studies ; *Dementia, Vascular/etiology/complications ; Incidence ; *Ischemic Stroke/complications ; Proportional Hazards Models ; Risk Factors ; *Smoking/adverse effects ; *Stroke/etiology/complications ; }, abstract = {There is a paucity of research regarding the association between the risk of incident dementia and changes in smoking habits in the acute ischemic stroke population. We aimed to investigate the effects of smoking habit change on the risk of incident dementia in an ischemic stroke population using data from the Korean National Health Insurance Services Database. This nationwide population-based cohort study included 197,853 patients with ischemic stroke. The patients were divided into never smokers, former smokers, smoking quitters, sustained smokers, and new smokers, based on the 2-year change in smoking status between the two consecutive health examinations before and after the index stroke. The patients were followed up from the index date to 2018 to assess the development of dementia. Dementia was further categorized into Alzheimer's, vascular, and other types of dementia according to the International Classification of Diseases, Tenth Revision diagnosis. Multivariable Cox proportional hazards models were used to assess the association between changes in smoking habits and the risk of dementia. After a median of 4.04 years of follow-up, 19,595 (9.9%) dementia cases were observed. Among them, 15,189 (7.7%) were diagnosed with Alzheimer's disease dementia and 2719 (1.4%) were diagnosed with vascular dementia. After adjusting for covariates, including age, sex, alcohol intake habits, cigarette pack-year, regular physical activity, income, history of hypertension, diabetes mellitus, dyslipidemia, and chronic kidney disease, new smokers, sustained smokers, and smoking quitters were significantly associated with a higher risk of all-cause dementia than never smokers (adjusted hazard ratio [aHR] 1.395, 95% confidence interval [CI] 1.254-1.552; aHR 1.324, 95% CI 1.236-1.418; and aHR 1.170, 95% CI 1.074-1.275, respectively). Similar trends were observed for both Alzheimer's dementia and vascular dementia, but the association between new smokers and vascular dementia was not significant. The impact of smoking habit change was more prominent in the 40-65-year-old group. New and sustained smokers had a substantially higher risk of incident dementia after ischemic stroke than never smokers. Smoking quitters also had an elevated risk of incident dementia, but the detrimental effects were lower than those in new and sustained smokers.}, } @article {pmid36575159, year = {2022}, author = {Pan, D and Zeng, A and Yang, B and Lai, G and Hu, B and Song, X and Jiang, T and , }, title = {Deep Learning for Brain MRI Confirms Patterned Pathological Progression in Alzheimer's Disease.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e2204717}, doi = {10.1002/advs.202204717}, pmid = {36575159}, issn = {2198-3844}, abstract = {Deep learning (DL) on brain magnetic resonance imaging (MRI) data has shown excellent performance in differentiating individuals with Alzheimer's disease (AD). However, the value of DL in detecting progressive structural MRI (sMRI) abnormalities linked to AD pathology has yet to be established. In this study, an interpretable DL algorithm named the Ensemble of 3-dimensional convolutional neural network (Ensemble 3DCNN) with enhanced parsing techniques is proposed to investigate the longitudinal trajectories of whole-brain sMRI changes denoting AD onset and progression. A set of 2369 T1-weighted images from the multi-centre Alzheimer's Disease Neuroimaging Initiative and Open Access Series of Imaging Studies cohorts are applied to model derivation, validation, testing, and pattern analysis. An Ensemble-3DCNN-based P-score is generated, based on which multiple brain regions, including amygdala, insular, parahippocampal, and temporal gyrus, exhibit early and connected progressive neurodegeneration. Complex individual variability in the sMRI is also observed. This study combining non-invasive sMRI and interpretable DL in detecting patterned sMRI changes confirmed AD pathological progression, shedding new light on predicting AD progression using whole-brain sMRI.}, } @article {pmid36575093, year = {2022}, author = {Liu, Y and Li, Z and Wei, Z and Xu, Y and Xie, P and Wang, Y and Liu, Q and Li, X}, title = {[The current applicating state of neural network-based electroencephalogram diagnosis of Alzheimer's disease].}, journal = {Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering = Shengwu yixue gongchengxue zazhi}, volume = {39}, number = {6}, pages = {1233-1239}, doi = {10.7507/1001-5515.202201001}, pmid = {36575093}, issn = {1001-5515}, mesh = {Humans ; *Alzheimer Disease/diagnosis ; Neural Networks, Computer ; Machine Learning ; Brain ; Electroencephalography ; }, abstract = {The electroencephalogram (EEG) signal is a general reflection of the neurophysiological activity of the brain, which has the advantages of being safe, efficient, real-time and dynamic. With the development and advancement of machine learning research, automatic diagnosis of Alzheimer's diseases based on deep learning is becoming a research hotspot. Started from feedforward neural networks, this paper compared and analysed the structural properties of neural network models such as recurrent neural networks, convolutional neural networks and deep belief networks and their performance in the diagnosis of Alzheimer's disease. It also discussed the possible challenges and research trends of this research in the future, expecting to provide a valuable reference for the clinical application of neural networks in the EEG diagnosis of Alzheimer's disease.}, } @article {pmid36575072, year = {2022}, author = {Wohlfahrt, P}, title = {Cognitive impairment and the threat of dementia pandemic or the journey of hypertensive patients to self-care deficit.}, journal = {Vnitrni lekarstvi}, volume = {68}, number = {8}, pages = {532-536}, doi = {10.36290/vnl.2022.112}, pmid = {36575072}, issn = {0042-773X}, mesh = {Middle Aged ; Humans ; Adolescent ; *Cognition Disorders/etiology ; Antihypertensive Agents/therapeutic use ; Pandemics ; Self Care/adverse effects ; *Hypertension/complications ; *Cognitive Dysfunction/etiology/complications ; *Dementia/epidemiology/complications/drug therapy ; }, abstract = {In the Czech Republic, due to the population aging, the prevalence of cognitive dysfunction is increasing. Researchers estimate that by 2050 the number of patients with dementia in the Czech Republic will more than double. Since dementia cannot be cured, it is important to prevent the cognitive dysfunction development by influencing modifiable risk factors. Arterial hypertension (AH) is one of the main risk factors for the development of cognitive dysfunction and dementia. Elevated blood pressure values in youth are associated with a higher risk of cognitive decline in middle age and with the development of dementia in old age. Blood pressure control in low-risk patients with stage I hypertension reduces the risk of dementia development, including Alzheimers disease. Therefore, improving the AH control in the population since younghood will be needed to influence the emerging cognitive dysfunction pandemic.}, } @article {pmid36574855, year = {2023}, author = {Verma, AK and Singh, S and Rizvi, SI}, title = {Aging, circadian disruption and neurodegeneration: Interesting interplay.}, journal = {Experimental gerontology}, volume = {172}, number = {}, pages = {112076}, doi = {10.1016/j.exger.2022.112076}, pmid = {36574855}, issn = {1873-6815}, mesh = {Humans ; Circadian Rhythm/physiology ; Aging/physiology ; *Circadian Clocks/genetics ; *Alzheimer Disease/etiology ; }, abstract = {The circadian system is an intricate molecular network of coordinating circadian clocks that organize the internal synchrony of the organism in response to the environment. These rhythms are maintained by genetically programmed positive and negative auto-regulated transcriptional and translational feedback loops that sustain 24-hour oscillations in mRNA and protein components of the endogenous circadian clock. Since inter and intracellular activity of the central pacemaker appears to reduce with aging, the interaction between the circadian clock and aging continues to elude our understanding. In this review article, we discuss circadian clock components at the molecular level and how aging adversely affects circadian clock functioning in rodents and humans. The natural decline in melatonin levels with aging strongly contributes to circadian dysregulation resulting in the development of neurological anomalies. Additionally, inappropriate environmental conditions such as Artificial Light at Night (ALAN) can cause circadian disruption or chronodisruption (CD) which can result in a variety of pathological diseases, including premature aging. Furthermore, we summarize recent evidence suggesting that CD may also be a predisposing factor for the development of age-related neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), although more investigation is required to prove this link. Finally, certain chrono-enhancement approaches have been offered as intervention strategies to prevent, alleviate, or mitigate the impacts of CD. This review thus aims to bring together recent advancements in the chronobiology of the aging process, as well as its role in NDDs.}, } @article {pmid36574761, year = {2022}, author = {Ota, M and Nemoto, K and Nemoto, M and Numata, Y and Kitabatake, A and Yamada, Y and Shinkawa, K and Kobayashi, M and Arai, T}, title = {Structural Cerebral Network Differences in Prodromal Alzheimer's Disease and Prodromal Dementia with Lewy Bodies.}, journal = {Dementia and geriatric cognitive disorders}, volume = {51}, number = {5}, pages = {421-427}, doi = {10.1159/000527443}, pmid = {36574761}, issn = {1421-9824}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; *Lewy Body Disease/diagnostic imaging ; Brain/diagnostic imaging ; *Cognitive Dysfunction/diagnostic imaging ; Gray Matter ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) have long prodromal phases without dementia. However, the patterns of cerebral network alteration in this early stage of the disease remain to be clarified.

METHOD: Participants were 48 patients with mild cognitive impairment (MCI) due to AD (MCI-AD), 18 patients with MCI with DLB (MCI with Lewy bodies: MCI-LB), and 23 healthy controls who underwent a 1.5-Tesla magnetic resonance imaging scan. Cerebral networks were extracted from individual T1-weighted images based on the intracortical similarity, and we estimated the differences of network metrics among the three diagnostic groups.

RESULTS: Whole-brain analyses for degree, betweenness centrality, and clustering coefficient images were performed using SPM8 software. The patients with MCI-LB showed significant reduction of degree in right putamen, compared with healthy subjects. The MCI-AD patients showed significant lower degree in left insula and bilateral posterior cingulate cortices compared with healthy subjects. There were no significant differences in small-world properties and in regional gray matter volume among the three groups.

CONCLUSIONS: We found the change of degree in the patients with MCI-AD and with MCI-LB, compared with healthy controls. These findings were consistent with the past single-photon emission computed tomography studies focusing on AD and DLB. The disease-related difference in the cerebral neural network might provide an adjunct biomarker for the early detection of AD and DLB.}, } @article {pmid36574656, year = {2023}, author = {Eck, RJ and Kow, RL and Black, AH and Liachko, NF and Kraemer, BC}, title = {SPOP loss of function protects against tauopathy.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {120}, number = {1}, pages = {e2207250120}, doi = {10.1073/pnas.2207250120}, pmid = {36574656}, issn = {1091-6490}, support = {AG066729/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Caenorhabditis elegans/genetics/metabolism ; *Tauopathies/metabolism ; tau Proteins/genetics/metabolism ; Nuclear Proteins/genetics/metabolism ; Animals, Genetically Modified ; *Alzheimer Disease/metabolism ; Disease Models, Animal ; Mammals/metabolism ; *Caenorhabditis elegans Proteins/genetics/metabolism ; Poly(A)-Binding Proteins/metabolism ; }, abstract = {The pathological accumulation of the microtubule binding protein tau drives age-related neurodegeneration in a variety of disorders, collectively called tauopathies. In the most common tauopathy, Alzheimer's disease (AD), the accumulation of pathological tau strongly correlates with cognitive decline. The underlying molecular mechanisms that drive neurodegeneration in tauopathies remain incompletely understood and no effective disease modifying pharmacological interventions currently exist. Here, we show that tau toxicity depends on the highly conserved nuclear E3 ubiquitin ligase adaptor protein SPOP in a Caenorhabditis elegans model of tauopathy. Loss of function mutations in the C. elegans spop-1 gene significantly improves behavioral deficits in tau transgenic animals, while neuronal overexpression of SPOP-1 protein significantly worsens behavioral deficits. In addition, loss of spop-1 rescues a variety of tau-related phenotypes including the accumulation of total and phosphorylated tau protein, neurodegeneration, and shortened lifespan. Knockdown of SPOP-1's E3 ubiquitin ligase cul-3/Cullin3 does not improve tauopathy suggesting a non-degradative mechanism of action for SPOP-1. Suppression of disease-related phenotypes occurs independently of the nuclear speckle resident poly(A)-binding protein SUT-2/MSUT2. MSUT2 modifies tauopathy in mammalian neurons and in AD. Our work identifies SPOP as a novel modifier of tauopathy and a conceptual pathway for therapeutic intervention.}, } @article {pmid36574646, year = {2023}, author = {Shi, L and Zhu, Q and Wang, Y and Hao, H and Zhang, H and Schwartz, J and Amini, H and van Donkelaar, A and Martin, RV and Steenland, K and Sarnat, JA and Caudle, WM and Ma, T and Li, H and Chang, HH and Liu, JZ and Wingo, T and Mao, X and Russell, AG and Weber, RJ and Liu, P}, title = {Incident dementia and long-term exposure to constituents of fine particle air pollution: A national cohort study in the United States.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {120}, number = {1}, pages = {e2211282119}, doi = {10.1073/pnas.2211282119}, pmid = {36574646}, issn = {1091-6490}, support = {R01 AG074357/AG/NIA NIH HHS/United States ; P30 ES000002/ES/NIEHS NIH HHS/United States ; R21 ES032606/ES/NIEHS NIH HHS/United States ; P50 AG025688/AG/NIA NIH HHS/United States ; P30 ES019776/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; Aged ; United States/epidemiology ; *Air Pollutants/adverse effects/analysis ; Cohort Studies ; Medicare ; *Air Pollution/adverse effects/analysis ; Particulate Matter/adverse effects/analysis ; Dust ; *Dementia/chemically induced/epidemiology ; Environmental Exposure/adverse effects ; China ; }, abstract = {Growing evidence suggests that fine particulate matter (PM2.5) likely increases the risks of dementia, yet little is known about the relative contributions of different constituents. Here, we conducted a nationwide population-based cohort study (2000 to 2017) by integrating the Medicare Chronic Conditions Warehouse database and two independently sourced datasets of high-resolution PM2.5 major chemical composition, including black carbon (BC), organic matter (OM), nitrate (NO3[-]), sulfate (SO4[2-]), ammonium (NH4[+]), and soil dust (DUST). To investigate the impact of long-term exposure to PM2.5 constituents on incident all-cause dementia and Alzheimer's disease (AD), hazard ratios for dementia and AD were estimated using Cox proportional hazards models, and penalized splines were used to evaluate potential nonlinear concentration-response (C-R) relationships. Results using two exposure datasets consistently indicated higher rates of incident dementia and AD for an increased exposure to PM2.5 and its major constituents. An interquartile range increase in PM2.5 mass was associated with a 6 to 7% increase in dementia incidence and a 9% increase in AD incidence. For different PM2.5 constituents, associations remained significant for BC, OM, SO4[2-], and NH4[+] for both end points (even after adjustments of other constituents), among which BC and SO4[2-] showed the strongest associations. All constituents had largely linear C-R relationships in the low exposure range, but most tailed off at higher exposure concentrations. Our findings suggest that long-term exposure to PM2.5 is significantly associated with higher rates of incident dementia and AD and that SO4[2-], BC, and OM related to traffic and fossil fuel combustion might drive the observed associations.}, } @article {pmid36574616, year = {2022}, author = {Borges-Machado, F and Teixeira, L and Carvalho, J and Ribeiro, O}, title = {Does Multicomponent Physical Exercise Training Work for Dementia? Exploring the Effects on Cognition, Neuropsychiatric Symptoms, and Quality of Life.}, journal = {Journal of geriatric psychiatry and neurology}, volume = {}, number = {}, pages = {8919887221149152}, doi = {10.1177/08919887221149152}, pmid = {36574616}, issn = {0891-9887}, abstract = {OBJECTIVE: To explore the effects of a multicomponent training (MT) physical exercise intervention in the cognitive function, neuropsychiatric symptoms, and quality of life of older adults with major neurocognitive disorder (NCD).

METHODS: Quasi-experimental controlled trial. Thirty-six individuals (25 female) were equally distributed to an exercise group (aged 74.33 ± 5.87 years) or a control group (aged 81.83 ± 6.18 years). The Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog), the Neuropsychiatric Inventory (NPI) and the Quality of Life - Alzheimer's Disease (QoL-AD) tests were performed before and after the intervention.

RESULTS: There was no clear interaction effect factor of intervention on ADAS-Cog (B = 1.33, 95% CI: -2.61 - 5.28, P = .513), NPI (B = -8.35, 95% CI: -18.48 - 1.72, P = .115), and QoL-AD (B = 2.87, 95% CI: .01 - 5.73, P = .058).

CONCLUSIONS: The 6-month MT physical exercise intervention did not present evidence of slowing down cognitive decline neither improving neuropsychiatric symptomatology, and quality of life of older adults with major NCD. Future studies with larger samples are needed to better understand the impact of physical exercise interventions using MT methodology on specific cognitive abilities, neuropsychiatric symptoms, and quality of life domains.}, } @article {pmid36574591, year = {2022}, author = {Chatterjee, P and Pedrini, S and Doecke, JD and Thota, R and Villemagne, VL and Doré, V and Singh, AK and Wang, P and Rainey-Smith, S and Fowler, C and Taddei, K and Sohrabi, HR and Molloy, MP and Ames, D and Maruff, P and Rowe, CC and Masters, CL and Martins, RN and , }, title = {Plasma Aβ42/40 ratio, p-tau181, GFAP, and NfL across the Alzheimer's disease continuum: A cross-sectional and longitudinal study in the AIBL cohort.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {}, number = {}, pages = {}, doi = {10.1002/alz.12724}, pmid = {36574591}, issn = {1552-5279}, abstract = {INTRODUCTION: Plasma amyloid beta (Aβ)1-42/Aβ1-40 ratio, phosphorylated-tau181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) are putative blood biomarkers for Alzheimer's disease (AD). However, head-to-head cross-sectional and longitudinal comparisons of the aforementioned biomarkers across the AD continuum are lacking.

METHODS: Plasma Aβ1-42, Aβ1-40, p-tau181, GFAP, and NfL were measured utilizing the Single Molecule Array (Simoa) platform and compared cross-sectionally across the AD continuum, wherein Aβ-PET (positron emission tomography)-negative cognitively unimpaired (CU Aβ-, n = 81) and mild cognitive impairment (MCI Aβ-, n = 26) participants were compared with Aβ-PET-positive participants across the AD continuum (CU Aβ+, n = 39; MCI Aβ+, n = 33; AD Aβ+, n = 46) from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) cohort. Longitudinal plasma biomarker changes were also assessed in MCI (n = 27) and AD (n = 29) participants compared with CU (n = 120) participants. In addition, associations between baseline plasma biomarker levels and prospective cognitive decline and Aβ-PET load were assessed over a 7 to 10-year duration.

RESULTS: Lower plasma Aβ1-42/Aβ1-40 ratio and elevated p-tau181 and GFAP were observed in CU Aβ+, MCI Aβ+, and AD Aβ+, whereas elevated plasma NfL was observed in MCI Aβ+ and AD Aβ+, compared with CU Aβ- and MCI Aβ-. Among the aforementioned plasma biomarkers, for models with and without AD risk factors (age, sex, and apolipoprotein E (APOE) ε4 carrier status), p-tau181 performed equivalent to or better than other biomarkers in predicting a brain Aβ-/+ status across the AD continuum. However, for models with and without the AD risk factors, a biomarker panel of Aβ1-42/Aβ1-40, p-tau181, and GFAP performed equivalent to or better than any of the biomarkers alone in predicting brain Aβ-/+ status across the AD continuum. Longitudinally, plasma Aβ1-42/Aβ1-40, p-tau181, and GFAP were altered in MCI compared with CU, and plasma GFAP and NfL were altered in AD compared with CU. In addition, lower plasma Aβ1-42/Aβ1-40 and higher p-tau181, GFAP, and NfL were associated with prospective cognitive decline and lower plasma Aβ1-42/Aβ1-40, and higher p-tau181 and GFAP were associated with increased Aβ-PET load prospectively.

DISCUSSION: These findings suggest that plasma biomarkers are altered cross-sectionally and longitudinally, along the AD continuum, and are prospectively associated with cognitive decline and brain Aβ-PET load. In addition, although p-tau181 performed equivalent to or better than other biomarkers in predicting an Aβ-/+ status across the AD continuum, a panel of biomarkers may have superior Aβ-/+ status predictive capability across the AD continuum.

HIGHLIGHTS:  Area under the curve (AUC) of p-tau181 ≥ AUC of Aβ42/40, GFAP, NfL in predicting PET Aβ-/+ status (Aβ-/+).  AUC of Aβ42/40+p-tau181+GFAP panel ≥ AUC of Aβ42/40/p-tau181/GFAP/NfL for Aβ-/+.  Longitudinally, Aβ42/40, p-tau181, and GFAP were altered in MCI versus CU.  Longitudinally, GFAP and NfL were altered in AD versus CU.  Aβ42/40, p-tau181, GFAP, and NfL are associated with prospective cognitive decline.  Aβ42/40, p-tau181, and GFAP are associated with increased PET Aβ load prospectively.}, } @article {pmid36574473, year = {2023}, author = {Baumann, KN and Šneiderienė, G and Sanguanini, M and Schneider, M and Rimon, O and González Díaz, A and Greer, H and Thacker, D and Linse, S and Knowles, TPJ and Vendruscolo, M}, title = {A Kinetic Map of the Influence of Biomimetic Lipid Model Membranes on Aβ42 Aggregation.}, journal = {ACS chemical neuroscience}, volume = {14}, number = {2}, pages = {323-329}, pmid = {36574473}, issn = {1948-7193}, mesh = {Humans ; *Amyloid beta-Peptides/metabolism ; Kinetics ; Biomimetics ; *Alzheimer Disease/metabolism ; Lipid Bilayers/chemistry ; Peptide Fragments/metabolism ; }, abstract = {The aggregation of the amyloid β (Aβ) peptide is one of the molecular hallmarks of Alzheimer's disease (AD). Although Aβ deposits have mostly been observed extracellularly, various studies have also reported the presence of intracellular Aβ assemblies. Because these intracellular Aβ aggregates might play a role in the onset and progression of AD, it is important to investigate their possible origins at different locations of the cell along the secretory pathway of the amyloid precursor protein, from which Aβ is derived by proteolytic cleavage. Senile plaques found in AD are largely composed of the 42-residue form of Aβ (Aβ42). Intracellularly, Aβ42 is produced in the endoplasmatic reticulum (ER) and Golgi apparatus. Since lipid bilayers have been shown to promote the aggregation of Aβ, in this study, we measure the effects of the lipid membrane composition on the in vitro aggregation kinetics of Aβ42. By using large unilamellar vesicles to model cellular membranes at different locations, including the inner and outer leaflets of the plasma membrane, late endosomes, the ER, and the Golgi apparatus, we show that Aβ42 aggregation is inhibited by the ER and Golgi model membranes. These results provide a preliminary map of the possible effects of the membrane composition in different cellular locations on Aβ aggregation and suggest the presence of an evolutionary optimization of the lipid composition to prevent the intracellular aggregation of Aβ.}, } @article {pmid36574317, year = {2023}, author = {Høilund-Carlsen, PF and Alavi, A and Perry, G and Barrio, JR}, title = {MRI Monitoring of Anti-Alzheimer Therapy Amyloid-Related Imaging Abnormalities: Due Diligence or Overkill?.}, journal = {AJNR. American journal of neuroradiology}, volume = {44}, number = {1}, pages = {E4-E5}, pmid = {36574317}, issn = {1936-959X}, mesh = {Humans ; *Magnetic Resonance Imaging/methods ; Amyloid ; *Alzheimer Disease/diagnostic imaging/drug therapy ; Amyloid beta-Peptides ; }, } @article {pmid36574096, year = {2022}, author = {Kaur, K and Singh, L and Kaur, A and Bhatti, R}, title = {Exploring the possible mechanism involved in the anti-nociceptive effect of β-sitosterol: modulation of oxidative stress, nitric oxide and IL-6.}, journal = {Inflammopharmacology}, volume = {}, number = {}, pages = {}, pmid = {36574096}, issn = {1568-5608}, abstract = {Β-sitosterol is a phytosterol, documented to possess various activities including protection against inflammation, diabetes and Alzheimer's disease. The current investigation was designed to explore the analgesic potential of β-sitosterol and the possible molecular mechanism involved in the observed effect. β-sitosterol was administered at varying doses of 10, 20, and 40 mg/kg before subjecting the mice to acetic acid and formalin challenges. The number of writhings in acetic acid and the number of flinchings and foot tappings were quantified in the formalin test. For mechanistic studies, substance P (cyclooxygenase-2 (COX-2) stimulator) and L-Nitro arginine methyl ester (L-NAME) (nitric oxide synthetases (NOS) inhibitor) and L-arginine (nitric oxide precursor) were administered before β-sitosterol treatment. β-sitosterol (10, 20, 40 mg/kg) treatment significantly reduced acetic acid-induced writhings and ameliorated the formalin-induced inflammatory phase dose-dependently. Whereas, 40 mg/kg dose of β-sitosterol abrogated the formalin-induced neurogenic phase. Substance-P abrogated the effect of β-sitosterol in both neurogenic and inflammatory phases. Whereas, L-arginine only abrogated the inflammatory phase. In biochemical analysis, β-sitosterol treatment reduced the level of interleukin-6 (IL-6), thiobarbituric acid reactive substances (TBARS) and increased the level of reduced glutathione (GSH). Furthermore, L-arginine and substance-P abrogated the GSH increasing and TBARS lowering effect of β-sitosterol (40 mg/kg). Overall, the current study delineated that β-sitosterol may induce an anti-nociceptive effect via inhibiting the IL-6, oxidative stress, cyclo-oxygenase and nitric oxide.}, } @article {pmid36573329, year = {2023}, author = {Ruan, D and Sun, L}, title = {Amyloid-β PET in Alzheimer's disease: A systematic review and Bayesian meta-analysis.}, journal = {Brain and behavior}, volume = {13}, number = {1}, pages = {e2850}, pmid = {36573329}, issn = {2162-3279}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; Bayes Theorem ; Amyloid beta-Peptides ; *Cognitive Dysfunction/diagnostic imaging ; Sensitivity and Specificity ; Positron-Emission Tomography ; }, abstract = {BACKGROUND: In recent years, longitudinal studies of Alzheimer's disease (AD) have been successively concluded. Our aim is to determine the efficacy of amyloid-β (Aβ) PET in diagnosing AD and early prediction of mild cognitive impairment (MCI) converting to AD. By pooling studies from different centers to explore in-depth whether diagnostic performance varies by population type, radiotracer type, and diagnostic approach, thus providing a more comprehensive theoretical basis for the subsequent widespread application of Aβ PET in the clinical setting.

METHODS: Relevant studies were searched through PubMed. The pooled sensitivities, specificities, DOR, and the summary ROC curve were obtained based on a Bayesian random-effects model.

RESULTS: Forty-eight studies, including 5967 patients, were included. Overall, the pooled sensitivity, specificity, DOR, and AUC of Aβ PET for diagnosing AD were 0.90, 0.80, 35.68, and 0.91, respectively. Subgroup analysis showed that Aβ PET had high sensitivity (0.91) and specificity (0.81) for differentiating AD from normal controls but very poor specificity (0.49) for determining AD from MCI. The pooled sensitivity and specificity were 0.84 and 0.62, respectively, for predicting the conversion of MCI to AD. The differences in diagnostic efficacy between visual assessment and quantitative analysis and between [11] C-PIB PET and [18] F-florbetapir PET were insignificant.

CONCLUSIONS: The overall performance of Aβ PET in diagnosing AD is favorable, but the differentiation between MCI and AD patients should consider that some MCI may be at risk of conversion to AD and may be misdiagnosed. A multimodal diagnostic approach and machine learning analysis may be effective in improving diagnostic accuracy.}, } @article {pmid36573138, year = {2022}, author = {Zheng, L and Wang, Z and Liu, Y and Zhao, J and Huang, S}, title = {Activation of the RMTg Nucleus by Chemogenetic Techniques Alleviates the Learning and Memory Impairment in APP/PS1 Mice.}, journal = {Neuropsychiatric disease and treatment}, volume = {18}, number = {}, pages = {2957-2965}, pmid = {36573138}, issn = {1176-6328}, abstract = {OBJECTIVE: There is a relationship between non-rapid eye movement (NREM) sleep and Alzheimer's disease (AD). The rostromedial tegmental nucleus (RMTg) is activated can enhance NREM. Therefore, our experiment was designed to investigate the effects of activation of RMTg by chemical genetic techniques on APP/PS1 mice learning and memory.

MATERIALS AND METHODS: After the AAV-hSyn-hM3Dq-mCherry virus was injected into the RMTg nucleus, CNO solution was intraperitoneally injected to activate RMTg. The new object test and Morris water maze were used to determine the learning and memory level; T2-weighted imaging (T2WI) scanning was performed to analyze the volume of hippocampus and entorhinal cortex of each group; The virus transfection status was determined by laser confocal microscope and use immunohistochemical detection to observe the deposition of Beta Amyloid 1-42 (Aβ42).

RESULTS: Activation of RMTg by chemical genetic techniques can reduce the escape latency and increase discrimination index (RI) and the number of crossing platform; Activation of RMTg by chemical genetic techniques reduced the atrophy of the entorhinal cortex. Aβ42 deposition in the brain was decreased after activation of RMTg.

CONCLUSION: Activation of the RMTg nucleus by chemogenetic techniques can improve the learning and memory impairment in APP/PS1 mice.}, } @article {pmid36573058, year = {2022}, author = {Kunnath Ramachandran, A and Das, S and Shenoy, GG and Mudgal, J and Joseph, A}, title = {Relation between apolipoprotein e in alzheimer's disease and sars-cov-2 and their treatment strategy: A review.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/1871527322666221226145141}, pmid = {36573058}, issn = {1996-3181}, abstract = {COVID-19, which primarily affects the pulmonary system, turned out to be a global pandemic, whereas the effects on other systems are still unknown. SARS-CoV-2, binds to angiotensin-converting enzyme 2 (ACE2) receptors in the lungs, causing pneumonia-like symptoms. The same ACE receptors are also present in organs other than the lungs. Therefore, there is a need to study the impact of coronavirus on other human body organs. Recently, UK Biobank reports on the genetic risk factor of the virus attack. A double mutation in the apolipoprotein E (APOE4) allele has shown a significant role in COVID-19. The same APOE4 mutation has already been proven to hold a key role in developing early-onset Alzheimer's disease (EOAD). Despite this data, Alzheimer's disease is believed to be a comorbidity of COVID-19. Previous virus attacks on the same viral family, Coronaviridae, produced neurological effects like neurodegeneration, neuronal inflammation, and other central nervous system-related dysfunctions. Since the long-term implications of COVID-19 are unknown, more research into the impact of the virus on the central nervous system is needed. Both COVID-19 and AD share a common genetic factor, so that AD patients may have a greater risk of SARS-CoV-2. Here, in this review, we have briefly discussed the role of APOE4 in the pathogenesis of AD and SARS-CoV-2, along with their treatment strategy, current scenario, and possible future directions.}, } @article {pmid36573053, year = {2022}, author = {Gulmammadli, N and Konukoğlu, D and Merve Kurtuluş, E and Tezen, D and Ibrahim Erbay, M and Bozluolçay, M}, title = {Serum Sirtuin-1, HMGB1-TLR4, NF-KB and IL-6 levels in Alzheimer's: The Relation Between Neuroinflammatory Pathway and Severity of Dementia.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/1567205020666221226140721}, pmid = {36573053}, issn = {1875-5828}, abstract = {UNLABELLED: Alzheimer's disease (AD), which affects the world's aging population, is a progressive neurodegenerative disease requiring markers or tools to accurately and easily diagnose and monitor the process accurately and easily.

OBJECTIVE: In this study, serum Sirtuin-1(SIRT-1), High Mobility Group Box 1 (HMGB1), Toll-Like Receptor-4 (TLR4), Nuclear Factor Kappa B (NF-kB), Interleukine-6 (IL-6), Amyloid βeta-42 (Aβ-42), and p-tau181 levels in patients diagnosed with AD according to NINCS-ADRA criteria were studied. We investigated the inflammatory pathways that lead to progressive neuronal loss and highlight their possible relationship with dementia severity in the systemic circulation.

METHODS: Patients over 60 years of age were grouped according to their Standard Mini Mental Test results, MRI, and/or Fludeoxyglucose positron emission tomography or according to their CT findings as Control n:20; AD n:32; Vascular Dementia (VD) n:17; AD + VD; n=21. Complete blood count, Glucose, Vitamin B12, Folic Acid, Enzymes, Urea, Creatinine, Electrolytes, Bilirubin, and Thyroid Function tests were evaluated. ELISA was used for the analysis of serum SIRT1, HMGB1, TLR4, NF-kB, IL-6, Aβ-42, and p-tau181 levels.

RESULTS: Levels of serum Aβ-42, SIRT1, HMGB1, and IL-6 were significantly higher (p˂0.001, p<0.01, p<0.001, and p<0.001, respectively), and TLR4 levels were significantly lower (p˂0.001) in the dementia group than in the control group. No significant difference was observed between dementia and control groups for serum NF-kB and p-tau181 levels.

CONCLUSION: Our results show that the levels of the Aβ42, SIRT 1, HMGB1, and TLR4 pathways are altered in AD and VD. SIRT 1 activity plays an important role in the inflammatory pathway of dementia development, particularly in AD.}, } @article {pmid36573011, year = {2022}, author = {Karlsson, IK and Ploner, A and Wang, Y and Gatz, M and Pedersen, NL and Hägg, S}, title = {Leukocyte DNA methylation in Alzheimer´s disease associated genes: replication of findings from neuronal cells.}, journal = {Epigenetics}, volume = {}, number = {}, pages = {1-5}, doi = {10.1080/15592294.2022.2158285}, pmid = {36573011}, issn = {1559-2308}, abstract = {Differences in gene-wide DNA methylation of the Alzheimer's disease (AD)-associated genes BIN1, HLA-DRB5, SORL1, SLC24A4, and ABCA7 are reported to be associated with AD in post-mortem brain samples. We investigated whether the same associations could be found in leukocytes collected pre-mortem. Using cohort data of 544 Swedish twins (204 dementia diagnoses), we replicated the findings in HLA-DRB5 and SLC24A4 at P < 0.05. However, co-twin control analyses indicated that the associations were partly explained by familial confounding. Thus, DNA methylation differences in HLA-DRB5 and SLC24A4 are present in both neuronal cells and leukocytes, and not fully explained familial factors.}, } @article {pmid36572964, year = {2022}, author = {Hua, CL and Cornell, PY and White, EM and Thomas, KS}, title = {Injury-related emergency department use among assisted living residents with Alzheimer's disease and related dementias.}, journal = {Journal of the American Geriatrics Society}, volume = {}, number = {}, pages = {}, doi = {10.1111/jgs.18207}, pmid = {36572964}, issn = {1532-5415}, support = {1R03AG073805/AG/NIA NIH HHS/United States ; R01AG057746/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Injuries are a leading cause of emergency department (ED) visits among older adults, and individuals with Alzheimer's disease and related dementias (ADRD) may be at particular risk. We compared injury-related ED use among assisted living (AL) residents with and without ADRD and assessed differences in the risk of injury-related ED visits among individuals with ADRD residing in ALs with memory care designation versus general AL.

METHODS: Using Medicare claims, we identified a cohort of fee-for-service beneficiaries who lived in AL in 2018 and resided in one of 20 states with site-specific information on memory care designation (n = 116,754). Outcomes included all injury-related ED visits and injury-related ED visits resulting in hospitalization in the calendar year 2018. We fit multilevel models of the association between ADRD and outcomes, adjusting for resident demographic characteristics and chronic conditions, license type characteristics, and AL characteristics, with random intercepts at the AL and license type levels. Among residents with ADRD, we examined whether memory care licensure was associated with injury-related ED visits.

RESULTS: The adjusted risk of injury-related ED use during the year was 20.1% (95% CI: 19.6%, 20.6%) for residents with ADRD compared to 16.1% for residents without ADRD (95% CI: 15.7%, 16.5%; p < 0.001). The adjusted risk of injury-related ED use ending in hospitalization was 4.9% (95% CI: 4.6%, 5.1%) for AL residents with ADRD and 3.9% for residents without ADRD (95% CI: 3.8%, 4.1%; p < 0.001). There were no significant differences in injury-related ED visits between residents with ADRD in ALs with memory care designation and residents in general AL.

CONCLUSIONS: Injury-related ED visits are common among AL residents with ADRD and residents in memory care, but residents in memory care AL experienced similar risks of injury as those in general AL. Further research should identify modifiable factors that can prevent injury among AL residents with ADRD.}, } @article {pmid36572909, year = {2022}, author = {Ko, YA and Billheimer, JT and Lyssenko, NN and Kueider-Paisley, A and Wolk, DA and Arnold, SE and Leung, YY and Shaw, LM and Trojanowski, JQ and Kaddurah-Daouk, RF and Kling, MA and Rader, DJ}, title = {ApoJ/Clusterin concentrations are determinants of cerebrospinal fluid cholesterol efflux capacity and reduced levels are associated with Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {14}, number = {1}, pages = {194}, pmid = {36572909}, issn = {1758-9193}, support = {RF1 AG059093/AG/NIA NIH HHS/United States ; U01 AG061359/AG/NIA NIH HHS/United States ; RF1 AG057452/AG/NIA NIH HHS/United States ; RF1 AG051550/AG/NIA NIH HHS/United States ; R01 AG046171/AG/NIA NIH HHS/United States ; P30 AG010124/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Mice ; Animals ; Clusterin ; *Alzheimer Disease/cerebrospinal fluid ; Apolipoprotein A-I ; *Neurodegenerative Diseases ; *Neuroblastoma ; Apolipoproteins E/cerebrospinal fluid ; Cholesterol ; *Cardiovascular Diseases ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) shares risk factors with cardiovascular disease (CVD) and dysregulated cholesterol metabolism is a mechanism common to both diseases. Cholesterol efflux capacity (CEC) is an ex vivo metric of plasma high-density lipoprotein (HDL) function and inversely predicts incident CVD independently of other risk factors. Cholesterol pools in the central nervous system (CNS) are largely separate from those in blood, and CNS cholesterol excess may promote neurodegeneration. CEC of cerebrospinal fluid (CSF) may be a useful measure of CNS cholesterol trafficking. We hypothesized that subjects with AD and mild cognitive impairment (MCI) would have reduced CSF CEC compared with Cognitively Normal (CN) and that CSF apolipoproteins apoA-I, apoJ, and apoE might have associations with CSF CEC.

METHODS: We retrieved CSF and same-day ethylenediaminetetraacetic acid (EDTA) plasma from 108 subjects (40 AD; 18 MCI; and 50 CN) from the Center for Neurodegenerative Disease Research biobank at the Perelman School of Medicine, University of Pennsylvania. For CSF CEC assays, we used N9 mouse microglial cells and SH-SY5Y human neuroblastoma cells, and the corresponding plasma assay used J774 cells. Cells were labeled with [[3]H]-cholesterol for 24 h, had ABCA1 expression upregulated for 6 h, were exposed to 33 μl of CSF, and then were incubated for 2.5 h. CEC was quantified as percent [[3]H]-cholesterol counts in medium of total counts medium+cells, normalized to a pool sample. ApoA-I, ApoJ, ApoE, and cholesterol were also measured in CSF.

RESULTS: We found that CSF CEC was significantly lower in MCI compared with controls and was poorly correlated with plasma CEC. CSF levels of ApoJ/Clusterin were also significantly lower in MCI and were significantly associated with CSF CEC. While CSF ApoA-I was also associated with CSF CEC, CSF ApoE had no association with CSF CEC. CSF CEC is significantly and positively associated with CSF Aβ. Taken together, ApoJ/Clusterin may be an important determinant of CSF CEC, which in turn could mitigate risk of MCI and AD risk by promoting cellular efflux of cholesterol or other lipids. In contrast, CSF ApoE does not appear to play a role in determining CSF CEC.}, } @article {pmid36572791, year = {2022}, author = {Elgammal, YM and Zahran, MA and Abdelsalam, MM}, title = {A new strategy for the early detection of alzheimer disease stages using multifractal geometry analysis based on K-Nearest Neighbor algorithm.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {22381}, pmid = {36572791}, issn = {2045-2322}, mesh = {Humans ; Aged ; *Alzheimer Disease/diagnosis ; Magnetic Resonance Imaging/methods ; *Neurodegenerative Diseases ; Algorithms ; Brain ; *Cognitive Dysfunction/diagnosis ; }, abstract = {Alzheimer's Disease (AD) is considered one of the most diseases that much prevalent among elderly people all over the world. AD is an incurable neurodegenerative disease affecting cognitive functions and were characterized by progressive and collective functions deteriorating. Remarkably, early detection of AD is essential for the development of new and invented treatment strategies. As Dementia causes irreversible damage to the brain neurons and leads to changes in its structure that can be described adequately within the framework of multifractals. Hence, the present work focus on developing a promising and efficient computing technique to pre-process and classify the AD disease especially in the early stages using multifractal geometry to extract the most changeable features due to AD. Then, A machine learning classification algorithm (K-Nearest Neighbor) has been implemented in order to classify and detect the main four early stages of AD. Two datasets have been used to ensure the validation of the proposed methodology. The proposed technique has achieved 99.4% accuracy and 100% sensitivity. The comparative results show that the proposed classification technique outperforms is recent techniques in terms of performance measures.}, } @article {pmid36572752, year = {2022}, author = {Banco, E and Veronelli, L and Briguglio, M and Luzzatti, C and Vallar, G}, title = {The Semantic Association Test (SAT): normative data from healthy Italian participants and a validation study in aphasic patients.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {}, number = {}, pages = {}, pmid = {36572752}, issn = {1590-3478}, abstract = {The Semantic Association Test assesses several aspects of Semantic Memory (Categorical, Encyclopedic, Functional, and Visual Encyclopedic associations: CAs, EAs, FAs and VEAs), using a picture-to-picture matching paradigm. Normative data were collected from a group of 329 healthy participants (178 females) with mean 51.1 (range 20-90) years of age and mean 11.89 (range 5-19) years of education. Raw scores of healthy participants, pre-calculated correction factors for age and educational level, and Equivalent Scores are provided. The SAT was validated in a sample of 139 left brain-damaged persons with aphasia (PWA). Both groups (healthy participants and PWA) scored worse in the CA and EA conditions. The performance of the PWA group was overall defective, and global aphasics scored worse than persons with other types of aphasia. However, several PWA did not show impairments in the SAT. Dissociations were also found, with individual PWA showing defective performance confined to a single category. These results present the SAT as a tool that is useful to detect impairments of visual Semantic Memory, providing normative data from healthy participants and a validation study in PWA.}, } @article {pmid36572740, year = {2022}, author = {Völter, F and Beyer, L and Eckenweber, F and Scheifele, M and Bui, N and Patt, M and Barthel, H and Katzdobler, S and Palleis, C and Franzmeier, N and Levin, J and Perneczky, R and Rauchmann, BS and Sabri, O and Hong, J and Cumming, P and Rominger, A and Shi, K and Bartenstein, P and Brendel, M}, title = {Assessment of perfusion deficit with early phases of [[18]F]PI-2620 tau-PET versus [[18]F]flutemetamol-amyloid-PET recordings.}, journal = {European journal of nuclear medicine and molecular imaging}, volume = {}, number = {}, pages = {}, pmid = {36572740}, issn = {1619-7089}, abstract = {PURPOSE: Characteristic features of amyloid-PET (A), tau-PET (T), and FDG-PET (N) can serve for the A/T/N classification of neurodegenerative diseases. Recent studies showed that the early, perfusion-weighted phases of amyloid- or tau-PET recordings serve to detect cerebrometabolic deficits equally to FDG-PET, therefore providing a surrogate of neuronal injury. As such, two channels of diagnostic information can be obtained in the setting of a single PET scan. However, there has hitherto been no comparison of early-phase amyloid- and tau-PET as surrogates for deficits in perfusion/metabolism. Therefore, we undertook to compare [[18]F]flutemetamol-amyloid-PET and [[18]F]PI-2620 tau-PET as "one-stop shop" dual purpose tracers for the detection of neurodegenerative disease.

METHODS: We obtained early-phase PET recordings with [[18]F]PI-2620 (0.5-2.5 min p.i.) and [[18]F]flutemetamol (0-10 min p.i.) in 64 patients with suspected neurodegenerative disease. We contrasted global mean normalized images (SUVr) in the patients with a normal cohort of 15 volunteers without evidence of increased pathology to β-amyloid- and tau-PET examinations. Regional group differences of tracer uptake (z-scores) of 246 Brainnetome volumes of interest were calculated for both tracers, and the correlations of the z-scores were evaluated using Pearson's correlation coefficient. Lobar compartments, regions with significant neuronal injury (z-scores <  - 3), and patients with different neurodegenerative disease entities (e.g., Alzheimer's disease or 4R-tauopathies) served for subgroup analysis. Additionally, we used partial regression to correlate regional perfusion alterations with clinical scores in cognition tests.

RESULTS: The z-scores of perfusion-weighted images of both tracers showed high correlations across the brain, especially in the frontal and parietal lobes, which were the brain regions with pronounced perfusion deficit in the patient group (R = 0.83 ± 0.08; range, 0.61-0.95). Z-scores of individual patients correlated well by region (R = 0.57 ± 0.15; range, 0.16-0.90), notably when significant perfusion deficits were present (R = 0.66 ± 0.15; range, 0.28-0.90).

CONCLUSION: The early perfusion phases of [[18]F]PI-2620 tau- and [[18]F]flutemetamol-amyloid-PET are roughly equivalent indices of perfusion defect indicative of regional and lobar neuronal injury in patients with various neurodegenerative diseases. As such, either tracer may serve for two diagnostic channels by assessment of amyloid/tau status and neuronal activity.}, } @article {pmid36572715, year = {2022}, author = {Liampas, I and Siokas, V and Lyketsos, CG and Dardiotis, E}, title = {Associations between neuropsychiatric symptoms and incident Alzheimer's dementia in men versus women.}, journal = {Journal of neurology}, volume = {}, number = {}, pages = {}, pmid = {36572715}, issn = {1432-1459}, abstract = {OBJECTIVE: To examine whether associations between individual neuropsychiatric symptoms (NPS) and incident Alzheimer's dementia (AD) differ in men versus women.

METHODS: Data were acquired from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set. Two sets of older (≥ 60 years) participants were formed: one of cognitively unimpaired (CU) individuals, and one of participants with mild cognitive impairment (MCI). NPS were assessed using the Neuropsychiatric Inventory Questionnaire. Cox proportional hazards models examined associations between individual NPS and AD incidence separately for each participant set. These models featured individual NPS, sex, NPS by sex interactions as well as a number of covariates.

RESULTS: The analysis involved 9,854 CU individuals followed for 5.5 ± 3.8 years and 6,369 participants with MCI followed for 3.8 ± 3.0 years. NPS were comparably associated with future AD in men and women with MCI. Regarding CU participants, the following significant sex by NPS interactions were noted: female sex moderated the risk conferred by moderate/severe apathy (HR = 7.36, 3.25-16.64) by 74%, mitigated the risk conferred by moderate/severe depression (HR = 3.61, 2.08-6.28) by 52%, and augmented the risks conferred by mild depression (HR = 1.00, 0.60-1.68) and agitation (HR = 0.81, 0.40-1.64) by 83% and 243%, respectively.

CONCLUSIONS: Apathy, depression and agitation were differentially associated with incident AD in CU men and women. No individual NPS was associated with different risks of future AD in men versus women with MCI.}, } @article {pmid36572594, year = {2023}, author = {Fleeman, RM and Snyder, AM and Kuhn, MK and Chan, DC and Smith, GC and Crowley, NA and Arnold, AC and Proctor, EA}, title = {Predictive link between systemic metabolism and cytokine signatures in the brain of apolipoprotein E ε4 mice.}, journal = {Neurobiology of aging}, volume = {123}, number = {}, pages = {154-169}, pmid = {36572594}, issn = {1558-1497}, support = {R01 AA029403/AA/NIAAA NIH HHS/United States ; T32 NS115667/NS/NINDS NIH HHS/United States ; R01 AG072513/AG/NIA NIH HHS/United States ; F31 AG071131/AG/NIA NIH HHS/United States ; S10 OD026980/OD/NIH HHS/United States ; }, mesh = {Mice ; Male ; Female ; Animals ; *Apolipoprotein E4/genetics/metabolism ; Cytokines/metabolism ; Apolipoproteins E/genetics ; Brain/metabolism ; Genotype ; *Alzheimer Disease/metabolism ; Apolipoprotein E3/genetics ; Apolipoprotein E2/genetics ; }, abstract = {The ε4 variant of apolipoprotein E (APOE) is the strongest and most common genetic risk factor for Alzheimer's disease (AD). While the mechanism of conveyed risk is incompletely understood, promotion of inflammation, dysregulated metabolism, and protein misfolding and aggregation are contributors to accelerating disease. Here we determined the concurrent effects of systemic metabolic changes and brain inflammation in young (3-month-old) and aged (18-month-old) male and female mice carrying the APOE4 gene. Using functional metabolic assays alongside multivariate modeling of hippocampal cytokine levels, we found that brain cytokine signatures are predictive of systemic metabolic outcomes, independent of AD proteinopathies. Male and female mice each produce different cytokine signatures as they age and as their systemic metabolic phenotype declines, and these signatures are APOE genotype dependent. Ours is the first study to identify a quantitative and predictive link between systemic metabolism and specific pathological cytokine signatures in the brain. Our results highlight the effects of APOE4 beyond the brain and suggest the potential for bi-directional influence of risk factors in the brain and periphery.}, } @article {pmid36572177, year = {2023}, author = {Launay, A and Nebie, O and Vijaya Shankara, J and Lebouvier, T and Buée, L and Faivre, E and Blum, D}, title = {The role of adenosine A2A receptors in Alzheimer's disease and tauopathies.}, journal = {Neuropharmacology}, volume = {226}, number = {}, pages = {109379}, doi = {10.1016/j.neuropharm.2022.109379}, pmid = {36572177}, issn = {1873-7064}, mesh = {Humans ; *Alzheimer Disease/metabolism ; Adenosine ; *Tauopathies/drug therapy ; tau Proteins ; Amyloid beta-Peptides/metabolism ; Receptor, Adenosine A2A/metabolism ; }, abstract = {Adenosine signals through four distinct G protein-coupled receptors that are located at various synapses, cell types and brain areas. Through them, adenosine regulates neuromodulation, neuronal signaling, learning and cognition as well as the sleep-wake cycle, all strongly impacted in neurogenerative disorders, among which Alzheimer's Disease (AD). AD is a complex form of cognitive deficits characterized by two pathological hallmarks: extracellular deposits of aggregated β-amyloid peptides and intraneuronal fibrillar aggregates of hyper- and abnormally phosphorylated Tau proteins. Both lesions contribute to the early dysfunction and loss of synapses which are strongly associated to the development of cognitive decline in AD patients. The present review focuses on the pathophysiological impact of the A2ARs dysregulation observed in cognitive area from AD patients. We are reviewing not only evidence of the cellular changes in A2AR levels in pathological conditions but also describe what is currently known about their consequences in term of synaptic plasticity, neuro-glial miscommunication and memory abilities. We finally summarize the proof-of-concept studies that support A2AR as credible targets and the clinical interest to repurpose adenosine drugs for the treatment of AD and related disorders. This article is part of the Special Issue on "Purinergic Signaling: 50 years".}, } @article {pmid36572143, year = {2023}, author = {Ramírez-Hernández, E and Sánchez-Maldonado, C and Patricio-Martínez, A and Limón, ID}, title = {Amyloid-β (25-35) induces the morphological alteration of dendritic spines and decreases NR2B and PSD-95 expression in the hippocampus.}, journal = {Neuroscience letters}, volume = {795}, number = {}, pages = {137030}, doi = {10.1016/j.neulet.2022.137030}, pmid = {36572143}, issn = {1872-7972}, mesh = {Animals ; Rats ; *Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; *Dendritic Spines/metabolism ; Disks Large Homolog 4 Protein/metabolism ; Hippocampus/metabolism ; Maze Learning ; Memory Disorders/metabolism ; Peptide Fragments/pharmacology/metabolism ; Spatial Memory ; }, abstract = {Research on the memory impairment caused by the Amyloid-β 25-35 (Aβ25-35) peptide in animal models has provided an understanding of the causes that occurs in Alzheimer's disease. However, it is uncertain whether this cognitive impairment occurs due to disruption of information encoding and consolidation or impaired retrieval of stored memory. The aim of this study was to determine the effect of the Aβ25-35 peptide on the morphology of dendritic spines and the changes in the expression of NR2B and PSD-95 in the hippocampus associated with learning and memory deficit. Vehicle or Aβ25-35 peptide (0.1 µg/µL) was bilaterally administered into the CA1 subfield of the rat hippocampus, then tested for spatial learning and memory in the Morris Water Maze. On Day 39, the morphological changes in the CA1 of the hippocampus and dentate gyrus were examined via Golgi-Cox stain. It was observed that the Aβ25-35 peptide administered in the CA1 region of the rat hippocampus induced changes to the morphology of dendritic spines and the expression of the NR2B subunit of the NMDA receptor co-localized with both the spatial memory and PSD-95 protein in the hippocampus of learning rats. We conclude that, in soluble form, the Aβ25-35 peptide perturbs synaptic plasticity, specifically in the formation of new synapses, thus promoting the progression of memory impairment.}, } @article {pmid36572135, year = {2023}, author = {Abildgaard, A and Parkner, T and Knudsen, CS and Gottrup, H and Klit, H}, title = {Diagnostic Cut-offs for CSF β-amyloid and tau proteins in a Danish dementia clinic.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {539}, number = {}, pages = {244-249}, doi = {10.1016/j.cca.2022.12.023}, pmid = {36572135}, issn = {1873-3492}, mesh = {Humans ; *Amyloid beta-Peptides/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; Retrospective Studies ; *Alzheimer Disease/diagnosis/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Denmark ; Peptide Fragments/cerebrospinal fluid ; }, abstract = {BACKGROUND: Analysis of beta-amyloid 1-42 (Aβ42), total tau (t-tau) and phosphorylated-tau 181 (p-tau) in the cerebrospinal fluid (CSF) is often performed as a part of the diagnostic work-up in case of suspected Alzheimer's dementia (AD). Unfortunately, studies on optimal CSF biomarker cut-offs in a real-world clinical setting are scarce.

METHODS: We retrospectively evaluated the biomarker levels of 264 consecutive patients referred to our dementia clinic. The biomarkers were analysed with the Elecsys(R) assays. Diagnoses were based on all available clinical information, including FDG-PET scans.

RESULTS: In total, we identified 233 patients diagnosed with dementia. The median MMSE score was 22 (IQR 18-25). AD pathophysiology was suspected in 156 patients, and the corresponding cut-offs based on the Youden index were: Aβ42: 903 ng/L (ROC-AUC 0.78); t-tau: 272 ng/L (ROC-AUC 0.78); p-tau: 24 ng/L (ROC-AUC 0.85); t-tau/Aβ42 ratio: 0.34 (ROC-AUC 0.91); p-tau/Aβ42 ratio: 0.029 (ROC-AUC 0.92).

CONCLUSIONS: We found the tau/Aβ42 ratios to possess the best diagnostic performance, but our estimated cut-off values for the ratios were somewhat higher than previously reported. Consequently, if the CSF analyses are used to support a diagnosis of AD in a heterogeneous high-prevalence cohort, adjustment of the cut-offs may be warranted.}, } @article {pmid36572122, year = {2022}, author = {Gonzalez-Ortiz, F and Turton, M and Kac, PR and Smirnov, D and Premi, E and Ghidoni, R and Benussi, L and Cantoni, V and Saraceno, C and Rivolta, J and Ashton, NJ and Borroni, B and Galasko, D and Harrison, P and Zetterberg, H and Blennow, K and Karikari, TK}, title = {Brain-derived tau: a novel blood-based biomarker for Alzheimer's disease-type neurodegeneration.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awac407}, pmid = {36572122}, issn = {1460-2156}, support = {#681712/ERC_/European Research Council/International ; #AARF-21-850325/ALZ/Alzheimer's Association/United States ; }, abstract = {Blood-based biomarkers for amyloid beta and phosphorylated tau show good diagnostic accuracies and agreements with their corresponding CSF and neuroimaging biomarkers in the amyloid/tau/neurodegeneration [A/T/(N)] framework for Alzheimer's disease. However, the blood-based neurodegeneration marker neurofilament light is not specific to Alzheimer's disease while total-tau shows lack of correlation with CSF total-tau. Recent studies suggest that blood total-tau originates principally from peripheral, non-brain sources. We sought to address this challenge by generating an anti-tau antibody that selectively binds brain-derived tau and avoids the peripherally expressed 'big tau' isoform. We applied this antibody to develop an ultrasensitive blood-based assay for brain-derived tau, and validated it in five independent cohorts (n = 609) including a blood-to-autopsy cohort, CSF biomarker-classified cohorts and memory clinic cohorts. In paired samples, serum and CSF brain-derived tau were significantly correlated (rho = 0.85, P < 0.0001), while serum and CSF total-tau were not (rho = 0.23, P = 0.3364). Blood-based brain-derived tau showed equivalent diagnostic performance as CSF total-tau and CSF brain-derived tau to separate biomarker-positive Alzheimer's disease participants from biomarker-negative controls. Furthermore, plasma brain-derived tau accurately distinguished autopsy-confirmed Alzheimer's disease from other neurodegenerative diseases (area under the curve = 86.4%) while neurofilament light did not (area under the curve = 54.3%). These performances were independent of the presence of concomitant pathologies. Plasma brain-derived tau (rho = 0.52-0.67, P = 0.003), but not neurofilament light (rho = -0.14-0.17, P = 0.501), was associated with global and regional amyloid plaque and neurofibrillary tangle counts. These results were further verified in two memory clinic cohorts where serum brain-derived tau differentiated Alzheimer's disease from a range of other neurodegenerative disorders, including frontotemporal lobar degeneration and atypical parkinsonian disorders (area under the curve up to 99.6%). Notably, plasma/serum brain-derived tau correlated with neurofilament light only in Alzheimer's disease but not in the other neurodegenerative diseases. Across cohorts, plasma/serum brain-derived tau was associated with CSF and plasma AT(N) biomarkers and cognitive function. Brain-derived tau is a new blood-based biomarker that outperforms plasma total-tau and, unlike neurofilament light, shows specificity to Alzheimer's disease-type neurodegeneration. Thus, brain-derived tau demonstrates potential to complete the AT(N) scheme in blood, and will be useful to evaluate Alzheimer's disease-dependent neurodegenerative processes for clinical and research purposes.}, } @article {pmid36572121, year = {2022}, author = {Corsi, GI and Gadekar, VP and Haukedal, H and Doncheva, NT and Anthon, C and Ambardar, S and Palakodeti, D and Hyttel, P and Freude, K and Seemann, SE and Gorodkin, J}, title = {The transcriptomic landscape of neurons carrying PSEN1 mutations reveals changes in extracellular matrix components and non-coding gene expression.}, journal = {Neurobiology of disease}, volume = {178}, number = {}, pages = {105980}, doi = {10.1016/j.nbd.2022.105980}, pmid = {36572121}, issn = {1095-953X}, abstract = {Alzheimer's disease (AD) is a progressive and irreversible brain disorder, which can occur either sporadically, due to a complex combination of environmental, genetic, and epigenetic factors, or because of rare genetic variants in specific genes (familial AD, or fAD). A key hallmark of AD is the accumulation of amyloid beta (Aβ) and Tau hyperphosphorylated tangles in the brain, but the underlying pathomechanisms and interdependencies remain poorly understood. Here, we identify and characterise gene expression changes related to two fAD mutations (A79V and L150P) in the Presenilin-1 (PSEN1) gene. We do this by comparing the transcriptomes of glutamatergic forebrain neurons derived from fAD-mutant human induced pluripotent stem cells (hiPSCs) and their individual isogenic controls generated via precision CRISPR/Cas9 genome editing. Our analysis of Poly(A) RNA-seq data detects 1111 differentially expressed coding and non-coding genes significantly altered in fAD. Functional characterisation and pathway analysis of these genes reveal profound expression changes in constituents of the extracellular matrix, important to maintain the morphology, structural integrity, and plasticity of neurons, and in genes involved in calcium homeostasis and mitochondrial oxidative stress. Furthermore, by analysing total RNA-seq data we reveal that 30 out of 31 differentially expressed circular RNA genes are significantly upregulated in the fAD lines, and that these may contribute to the observed protein-coding gene expression changes. The results presented in this study contribute to a better understanding of the cellular mechanisms impacted in AD neurons, ultimately leading to neuronal damage and death.}, } @article {pmid36571832, year = {2022}, author = {Anderson, G}, title = {Why Do Anti-Amyloid Beta Antibodies not work? Time to reconceptualize Dementia Pathophysiology by incorporating astrocyte melatonergic pathway desynchronization from amyloid-beta production.}, journal = {Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999)}, volume = {}, number = {}, pages = {}, doi = {10.47626/1516-4446-2022-2949}, pmid = {36571832}, issn = {1809-452X}, abstract = {Recent work has challenged the classical, long-standing conceptualization of Alzheimer's disease pathophysiology as driven by amyloid-β plaques and hyperphosphorylated tau tangles, including the treatments thereby derived. This article highlights the importance of the lost synchronization of Nuclear factor kappa B (NF-κB) and yin yang 1 (YY1) induction of β-site amyloid precursor proteincleaving enzyme (BACE)1 induction and amyloid-β production with the melatonergic pathway. Emphasis is placed on the importance of released glia melatonin and autocrine effects in limiting the duration of amyloid-β production and paracrine melatonin's anti-inflammatory effects in neurons, including the suppression of hyperphosphorylated tau. Many of the broader bodies of data on dementia pathophysiology, including the role of the gut microbiome, gut permeability and inflammation, are intimately linked to the regulation of tryptophan's conversion to melatonin and the factors regulating this, including 14-3-3 isoforms, tryptophan hydroxylase (TPH)2, acetyl-CoA, sirtuin-3 and circadian, pineal melatonin. The glia melatonergic pathway is intimately linked to mitochondrial function, from where most melatonin is derived, and provides an important hub to better link wider dementia pathophysiology as well as providing novel treatment targets, challenging the treatment limitations imposed by anti-amyloid antibody treatments. This also has relevance for wider neurodegenerative and neuro-psychiatric conditions.}, } @article {pmid36571821, year = {2022}, author = {Aguillon, D and Langella, S and Chen, Y and Sanchez, JS and Su, Y and Vila-Castelar, C and Vasquez, D and Zetterberg, H and Hansson, O and Dage, JL and Janelidze, S and Chen, K and Fox-Fuller, JT and Aduen, P and Martinez, JE and Garcia, G and Baena, A and Guzman, C and Johnson, KA and Sperling, RA and Blennow, K and Reiman, EM and Lopera, F and Quiroz, YT}, title = {Plasma p-tau217 predicts in vivo brain pathology and cognition in autosomal dominant Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {}, number = {}, pages = {}, doi = {10.1002/alz.12906}, pmid = {36571821}, issn = {1552-5279}, support = {RF1 AG077627/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Plasma-measured tau phosphorylated at threonine 217 (p-tau217) is a potential non-invasive biomarker of Alzheimer's disease (AD). We investigated whether plasma p-tau217 predicts subsequent cognition and positron emission tomography (PET) markers of pathology in autosomal dominant AD.

METHODS: We analyzed baseline levels of plasma p-tau217 and its associations with amyloid PET, tau PET, and word list delayed recall measured 7.61 years later in non-demented age- and education-matched presenilin-1 E280A carriers (n = 24) and non-carrier (n = 20) family members.

RESULTS: Carriers had higher plasma p-tau217 levels than non-carriers. Baseline plasma p-tau217 was associated with subsequent amyloid and tau PET pathology levels and cognitive function.

DISCUSSION: Our findings suggest that plasma p-tau217 predicts subsequent brain pathological burden and memory performance in presenilin-1 E280A carriers. These results provide support for plasma p-tau217 as a minimally invasive diagnostic and prognostic biomarker for AD, with potential utility in clinical practice and trials.

HIGHLIGHTS: Non-demented presenilin-1 E280A carriers have higher plasma tau phosphorylated at threonine 217 (p-tau217) than do age-matched non-carriers. Higher baseline p-tau217 is associated with greater future amyloid positron emission tomography (PET) pathology burden. Higher baseline p-tau217 is associated with greater future tau PET pathology burden. Higher baseline p-tau217 is associated with worse future memory performance.}, } @article {pmid36571791, year = {2022}, author = {Wang, S and Wang, J and Dove, A and Guo, J and Yang, W and Qi, X and Bennett, DA and Xu, W}, title = {Association of impaired kidney function with dementia and brain pathologies: A community-based cohort study.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {}, number = {}, pages = {}, doi = {10.1002/alz.12910}, pmid = {36571791}, issn = {1552-5279}, abstract = {INTRODUCTION: The relationship between impaired kidney function (KF), dementia, and brain pathologies remains unclear.

METHODS: A total of 1354 dementia- and kidney disease-free participants including 895 with normal and 459 with impaired KF were followed from 2002 until 2020 (median [interquartile range]: 5 [2-9]) to detect incident dementia. KF was assessed at baseline and categorized as normal or impaired. Over the follow-up, 453 participants died and underwent autopsies for neuropathological assessment.

RESULTS: Compared to those with normal KF, the hazard ratios (95% confidence intervals [CIs]) of those with impaired KF was 1.48 (1.15, 1.90)/1.44 (1.10, 1.88) for dementia/Alzheimer's dementia. Furthermore, impaired KF was related to a significantly higher burden of cerebral amyloid angiopathy (CAA; odds ratio = 1.96, 95% CI: 1.17, 3.30), but not to other brain pathologies.

DISCUSSION: Impaired KF is associated with an increased risk of dementia and Alzheimer's dementia. CAA may underlie, in part, this association.

HIGHLIGHTS: Impaired kidney function (KF) was associated with higher dementia and Alzheimer's dementia risk. Impaired KF anticipated dementia and Alzheimer's dementia onset by more than 1.5 years. Impaired KF was significantly related to a higher burden of cerebral amyloid angiopathy (CAA) but not to other brain pathologies.}, } @article {pmid36571781, year = {2022}, author = {Li, S and Han, L and Shi, H and Chong, MKC and Zhao, S and Ran, J}, title = {Excess deaths from Alzheimer's disease and Parkinson's disease during the COVID-19 pandemic in the USA.}, journal = {Age and ageing}, volume = {51}, number = {12}, pages = {}, doi = {10.1093/ageing/afac277}, pmid = {36571781}, issn = {1468-2834}, mesh = {Male ; Female ; Humans ; United States/epidemiology ; *COVID-19/epidemiology ; *Alzheimer Disease ; Pandemics ; *Parkinson Disease/diagnosis/epidemiology ; Ethnicity ; }, abstract = {BACKGROUND: COVID-19 pandemic has indirect impacts on patients with chronic medical conditions, which may increase mortality risks for various non-COVID-19 causes. This study updates excess death statistics for Alzheimer's disease (AD) and Parkinson's disease (PD) up to 2022 and evaluates their demographic and spatial disparities in the USA.

METHODS: This is an ecological time-series analysis of AD and PD mortality in the USA from January 2018 to March 2022. Poisson log-linear regressions were utilised to fit the weekly death data. Excess deaths were calculated with the difference between the observed and expected deaths under a counterfactual scenario of pandemic absence.

RESULTS: From March 2020 to March 2022, we observed 41,115 and 10,328 excess deaths for AD and PD, respectively. The largest percentage increases in excess AD and PD deaths were found in the initial pandemic wave. For people aged ≥85 years, excess mortalities of AD and PD (per million persons) were 3946.0 (95% confidence interval [CI]: 2954.3, 4892.3) and 624.3 (95% CI: 369.4, 862.5), which were about 23 and 9 times higher than those aged 55-84 years, respectively. Females had a three-time higher excess mortality of AD than males (182.6 vs. 67.7 per million persons). The non-Hispanic Black people experienced larger increases in AD or PD deaths (excess percentage: 31.8% for AD and 34.6% for PD) than the non-Hispanic White population (17.1% for AD and 14.7% for PD).

CONCLUSION: Under the continuing threats of COVID-19, efforts should be made to optimise health care capacity for patients with AD and PD.}, } @article {pmid36571634, year = {2022}, author = {Agrawal, RR and Larrea, D and Xu, Y and Shi, L and Zirpoli, H and Cummins, LG and Emmanuele, V and Song, D and Yun, TD and Macaluso, FP and Min, W and Kernie, SG and Deckelbaum, RJ and Area-Gomez, E}, title = {Alzheimer's-Associated Upregulation of Mitochondria-Associated ER Membranes After Traumatic Brain Injury.}, journal = {Cellular and molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {36571634}, issn = {1573-6830}, support = {T32-DK007647/DK/NIDDK NIH HHS/United States ; R01-AG056387/AG/NIA NIH HHS/United States ; R01-NS088197/NS/NINDS NIH HHS/United States ; R01-NS095803/NS/NINDS NIH HHS/United States ; R01-EB029523/EB/NIBIB NIH HHS/United States ; P30-CA013330/CA/NCI NIH HHS/United States ; }, abstract = {Traumatic brain injury (TBI) can lead to neurodegenerative diseases such as Alzheimer's disease (AD) through mechanisms that remain incompletely characterized. Similar to AD, TBI models present with cellular metabolic alterations and modulated cleavage of amyloid precursor protein (APP). Specifically, AD and TBI tissues display increases in amyloid-β as well as its precursor, the APP C-terminal fragment of 99 a.a. (C99). Our recent data in cell models of AD indicate that C99, due to its affinity for cholesterol, induces the formation of transient lipid raft domains in the ER known as mitochondria-associated endoplasmic reticulum (ER) membranes ("MAM" domains). The formation of these domains recruits and activates specific lipid metabolic enzymes that regulate cellular cholesterol trafficking and sphingolipid turnover. Increased C99 levels in AD cell models promote MAM formation and significantly modulate cellular lipid homeostasis. Here, these phenotypes were recapitulated in the controlled cortical impact (CCI) model of TBI in adult mice. Specifically, the injured cortex and hippocampus displayed significant increases in C99 and MAM activity, as measured by phospholipid synthesis, sphingomyelinase activity and cholesterol turnover. In addition, our cell type-specific lipidomics analyses revealed significant changes in microglial lipid composition that are consistent with the observed alterations in MAM-resident enzymes. Altogether, we propose that alterations in the regulation of MAM and relevant lipid metabolic pathways could contribute to the epidemiological connection between TBI and AD.}, } @article {pmid36571564, year = {2022}, author = {Rubinski, A and Frerich, S and Malik, R and Franzmeier, N and Ramirez, A and Dichgans, M and Ewers, M and , }, title = {Polygenic Effect on Tau Pathology Progression in Alzheimer's Disease.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.26588}, pmid = {36571564}, issn = {1531-8249}, abstract = {OBJECTIVE: Polygenic variation accounts for a substantial portion of the risk of Alzheimer's disease (AD), but its effect on the rate of fibrillar-tau accumulation as a key driver of dementia symptoms is unclear.

METHODS: We combined the to-date largest number of genetic risk variants of AD (n = 85 lead single-nucleotide polymorphisms [SNPs]) from recent genome-wide association studies (GWAS) to generate a polygenic score (PGS). We assessed longitudinal tau-positron emission tomography (PET), amyloid-PET, and cognition in 231 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Using the PGS, together with global amyloid-PET, we predicted the rate of tau-PET increases in Braak-stage regions-of-interest and cognitive decline. We also assessed PGS-risk enrichment effects on the required sample size in clinical trials targeting tau pathology.

RESULTS: We found that a higher PGS was associated with higher rates of tau-PET accumulation, in particular at elevated amyloid-PET levels. The tau-PET increases mediated the association between PGS and faster cognitive decline. Risk enrichment through high PGS afforded sample size savings by 34%.

INTERPRETATION: Our results demonstrate that the PGS predicts faster tau progression and thus cognitive decline, showing utility to enhance statistical power in clinical trials. ANN NEUROL 2023.}, } @article {pmid36571504, year = {2022}, author = {Mroz, EL and Piechota, A and Ali, T and Matta-Singh, TD and Abboud, A and Sharma, S and White, MA and Fried, TR and Monin, JK}, title = {"Been there, done that:" A grounded theory of future caregiver preparedness in former caregivers of parents living with dementia.}, journal = {Journal of the American Geriatrics Society}, volume = {}, number = {}, pages = {}, doi = {10.1111/jgs.18209}, pmid = {36571504}, issn = {1532-5415}, support = {P30AG21342/AG/NIA NIH HHS/United States ; T32AG019134/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Family caregivers offer essential support to persons living with dementia (PLWD). Providing care for more than one family member or close other across adulthood is becoming increasingly common, yet little is known about the ways that caregiving experiences shape caregiver preparedness. The current study presents a grounded theory of future caregiver preparedness in former caregivers of PLWD.

METHOD: A coding team (five coders and two auditors) used Consensual Qualitative Research and grounded theory techniques to analyze transcripts from 32 semi-structured interviews with midlife former caregivers of parents who died following advanced Alzheimer's disease and related dementias.

RESULTS: Qualitative analysis revealed two dimensions of future caregiver preparedness: caregiving confidence and caregiving insights. Narratives from caregiving experiences informed participants' descriptions of their future caregiver preparedness. Though some former caregivers described a positive (i.e., boosted or sustained) sense of caregiving confidence following care for their parents, others described a diminished (i.e., restricted or impeded) sense of confidence. Regardless of their confidence, all caregivers described specific caregiving insights related to one or more categories (i.e., caregiving self-conduct, care systems and resources, and relating with a care partner).

CONCLUSIONS: Preparedness for future caregiving following recent care for a PLWD varies: For some, past experiences appear to offer cumulative advantages in anticipating future care roles, whereas for others, past experiences may contribute to apprehension towards, or rejection of, future care roles. Entering new caregiving roles with diminished confidence may have negative consequences for caregivers' and care partners' wellbeing. Multidimensional assessment of future caregiver preparedness in former caregivers of PLWD may support development of resources for former caregivers entering new caregiving roles.}, } @article {pmid36571386, year = {2022}, author = {Beason-Held, LL and Kerley, CI and Chaganti, S and Moghekar, A and Thambisetty, M and Ferrucci, L and Resnick, SM and Landman, BA}, title = {Health Conditions Associated with Alzheimer's Disease and Vascular Dementia.}, journal = {Annals of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ana.26584}, pmid = {36571386}, issn = {1531-8249}, abstract = {OBJECTIVE: We examined medical records to determine health conditions associated with dementia at varied intervals prior to dementia diagnosis in participants from the Baltimore Longitudinal Study of Aging (BLSA).

METHODS: Data were available for 347 Alzheimer's disease (AD), 76 vascular dementia (VaD), and 811 control participants without dementia. Logistic regressions were performed associating International Classification of Diseases, 9th Revision (ICD-9) health codes with dementia status across all time points, at 5 and 1 year(s) prior to dementia diagnosis, and at the year of diagnosis, controlling for age, sex, and follow-up length of the medical record.

RESULTS: In AD, the earliest and most consistent associations across all time points included depression, erectile dysfunction, gait abnormalities, hearing loss, and nervous and musculoskeletal symptoms. Cardiomegaly, urinary incontinence, non-epithelial skin cancer, and pneumonia were not significant until 1 year before dementia diagnosis. In VaD, the earliest and most consistent associations across all time points included abnormal electrocardiogram (EKG), cardiac dysrhythmias, cerebrovascular disease, non-epithelial skin cancer, depression, and hearing loss. Atrial fibrillation, occlusion of cerebral arteries, essential tremor, and abnormal reflexes were not significant until 1 year before dementia diagnosis.

INTERPRETATION: These findings suggest that some health conditions are associated with future dementia beginning at least 5 years before dementia diagnosis and are consistently seen over time, while others only reach significance closer to the date of diagnosis. These results also show that there are both shared and distinctive health conditions associated with AD and VaD. These results reinforce the need for medical intervention and treatment to lessen the impact of health comorbidities in the aging population. ANN NEUROL 2023.}, } @article {pmid36571249, year = {2022}, author = {Takaya, K and Asou, T and Kishi, K}, title = {Identification of Apolipoprotein D as a dermal fibroblast marker of human aging for development of skin rejuvenation therapy.}, journal = {Rejuvenation research}, volume = {}, number = {}, pages = {}, doi = {10.1089/rej.2022.0056}, pmid = {36571249}, issn = {1557-8577}, abstract = {The current understanding of skin aging is that senescent fibroblasts accumulate within the dermis and subcutaneous fat to cause abnormal tissue remodeling and extracellular matrix dysfunction, triggering a senescence-associated secretory phenotype (SASP). A novel therapeutic approach to prevent skin aging is to specifically eliminate senescent dermal fibroblasts; this requires the identification of specific protein markers for senescent cells. Apolipoprotein D (ApoD) is involved in lipid metabolism and antioxidant responses and is abundantly expressed in tissues affected by age-related diseases such as Alzheimer's disease and atherosclerosis. However, its behavior and role in skin aging remain unclear. In this study, we examined whether ApoD functions as a marker of aging using human dermal fibroblast aging models. In cellular senescence models induced via replicative aging and ionizing radiation exposure, ApoD expression was upregulated at the gene and protein levels and correlated with senescence-associated β-galactosidase activity and the decreased uptake of the proliferation marker BrdU, which was concomitant with the upregulation of SASP genes. Furthermore, ApoD-positive cells were found to be more abundant in the aging human dermis using fluorescence flow cytometry. These results suggest that ApoD is a potential clinical marker for identifying aging dermal fibroblasts.}, } @article {pmid36571230, year = {2022}, author = {Xu, H and Han, YJ and Gao, YH and Liu, WN and Gao, Q}, title = {[Bibliometric analysis on the literature characteristics of animal experiment research with acupuncture and moxibustion].}, journal = {Zhen ci yan jiu = Acupuncture research}, volume = {47}, number = {12}, pages = {1123-1129}, doi = {10.13702/j.1000-0607.20220766}, pmid = {36571230}, issn = {1000-0607}, mesh = {Animals ; United States ; *Moxibustion ; *Animal Experimentation ; *Acupuncture Therapy ; *Acupuncture ; Bibliometrics ; China ; }, abstract = {OBJECTIVE: To compare the diversities in the literature characteristics of animal experiments with acupuncture and moxibustion (acu-moxibustion) published in both Chinese and English, so as to summarize the similarities and differences in the reporting content for the animal experiment research with acu-moxibustion in the journals at home and abroad.

METHODS: The articles of animal experiments with acu-moxibustion published from 2016 to 2018 were searched from CNKI, Wanfang, SinoMed, PubMed and Web of Science databases. The articles were screened according to the inclusion and exclusion criteria, and the database was established by importing the essential information, e.g. title, author, journal, impact factor, country, year of publication, citation frequency, funding, disease type, as well as the number of observation indicators and charts. The diversity was initially summarized among this type of articles between China and foreign countries.

RESULTS: A total of 7 515 articles of animal experiments with acu-moxibustion were retrieved and 2 458 articles were eligible in compliance with the inclusion and exclusion criteria. Of them, there were 1 827 articles in Chinese and 631 in English. (1) Among those of Chinese-version, 169 articles (9.25%) were published in Acupuncture Research, listed the first of the article publications. Regarding the impact factor of published journal, Acupuncture Research was ranked the highest (3.187). For those published in English, 78 articles (12.36%) were published in Evidence-based Complementary and Alternative Medicine, listed the top of the article publications. Gastroenterology occupied the highest in terms of the impact factor (17.373) of published journal. (2) The first authors of Chinese-version articles were all from China, distributing in 461 institutions; of which, Beijing University of Chinese Medicine occupied the top for article publications (142 articles, 7.77%). For the English articles, 16 countries were involved regarding the first authors, and the most of them were from China (523 articles, 82.88%), followed by South Korea, Brazil, the United States and Japan. (3) The frequency of citations of Chinese articles was 7.50, which was significantly higher than that of English ones (4.61). (4) The funding supported Chinese and English articles were 1 680 (91.95%) and 569 (90.17%) respectively. (5) In the aspects of disease name and animal model, 135 and 220 diseases were included in Chinese and English articles respectively. The common top 10 diseases referred to 8 categories, i.e. stroke-related diseases, arthritis, Alzheimer's disease, depression, diabetes, spinal cord injury, hypertension and obesity. (6) In terms of the number of indicators, the maximum number was 6 for Chinese-version articles, averagely 2.46, while, it was 12 for English-version ones, 4.02 in average. (7) Among the articles of Chinese-version, the maximum number of charts was 17, and 1 028 articles had 2 to 4 charts, accounting the largest proportion (56.27%). Among those of English-version, the top number of charts was 27, and 347 articles had 4 to 6 charts, occupying the largest proportion (54.99%).

CONCLUSION: The number of Chinese-version articles for acu-moxibustion experiment research is much higher than that of the English ones, the authorship is led by Chinese and most of the researches are supported by funds. There is less difference in the disease types between Chinese and English articles, but the frequency citation of Chinese articles is obviously higher than that of English ones; while, the numbers of observation indicators and charts in English articles are much more than those of Chinese ones. It is suggested that the great attention has been drawn on the acu-moxibustion experiment researches published in Chinese journals, and the reports of the researches are more complete in English journals.}, } @article {pmid36571218, year = {2022}, author = {Tan, YX and Zhang, Y and Gao, YS and Pei, YN and Yang, XK and Li, CL and Xue, WG}, title = {[Effects of electroacupuncture on the expression of β-amyloid and autophagy-related proteins in hippocampal cells of mice with Alzheimer's disease].}, journal = {Zhen ci yan jiu = Acupuncture research}, volume = {47}, number = {12}, pages = {1048-1053}, doi = {10.13702/j.1000-0607.20211232}, pmid = {36571218}, issn = {1000-0607}, mesh = {Mice ; Male ; Animals ; *Alzheimer Disease/genetics/therapy ; Amyloid beta-Peptides/genetics/metabolism ; *Electroacupuncture ; Autophagy-Related Proteins/metabolism ; Mice, Inbred C57BL ; Hippocampus/metabolism ; Mice, Transgenic ; Spatial Learning ; }, abstract = {OBJECTIVE: To investigate the effect of electroacupuncture (EA) on the expression of β-amyloid (Aβ) and autophagy-related proteins in hippocampal cells of Alzheimer's disease (AD) model mice, so as to explore its underlying mechanisms.

METHODS: Eighteen male APP/PS1 transgenic mice (6 months old) were randomly divided into model and EA groups, with 9 mice in each group. Nine male C57BL/6 wild-type mice of the same age were chosen as the normal group. Mice in the EA group were treated with acupuncture on "Baihui" (GV20) and EA (1 Hz/50 Hz, 1 mA) on bilateral "Yongquan" (KI1), once every other day, 20 min each time for a total of 21 times. After the interventions, the spatial learning and memory ability were observed by Morris water maze test. The autophagy-related pathological changes in hippocampus were observed by transmission electron microscopy. The expressions of microtublue associated protein 1 light chain 3 (LC3) and Aβ in hippocampus were observed by immunofluorescence and the expression levels of LC3 and p62 proteins were detected by Western blot.

RESULTS: Compared with the normal group, the escape latency was prolonged (P<0.01), the residence time in the original quadrant platform was shor-tened (P<0.05), the positive expressions of LC3 and Aβ, the expression levels of LC3Ⅱ and p62 proteins, and the ratio of LC3Ⅱ/LC3Ⅰ proteins in hippocampus were increased (P<0.01, P<0.05) in the model group. Compared with the model group, the escape latency was shortened (P<0.05), the residence time in the original quadrant platform was prolonged (P<0.05), the positive expressions of LC3 and Aβ, the expression levels of LC3Ⅱ and p62 proteins, and the ratio of LC3Ⅱ/LC3Ⅰ proteins in hippocampus were decreased (P<0.05) in the EA group. The transmission electron microscopy showed that the structure of neurons was normal in the normal group, a large number of autolysosomes and autophagosomes existed in hip-pocampal nerve cells in the model group, and only a small number of autophagosomes were observed in the EA group.

CONCLUSION: EA can reduce the expression levels of autophagy-related proteins LC3 and p62 in APP/PS1 transgenic mice, improve the hip-pocampal autophagy state, reduce intracellular Aβ aggregation, and thus improve the learning and memory ability.}, } @article {pmid36571008, year = {2022}, author = {Kleineidam, L and Wolfsgruber, S and Weyrauch, AS and Zulka, LE and Forstmeier, S and Roeske, S and van den Bussche, H and Kaduszkiewicz, H and Wiese, B and Weyerer, S and Werle, J and Fuchs, A and Pentzek, M and Brettschneider, C and König, HH and Weeg, D and Bickel, H and Luppa, M and Rodriguez, FS and Freiesleben, SD and Erdogan, S and Unterfeld, C and Peters, O and Spruth, EJ and Altenstein, S and Lohse, A and Priller, J and Fliessbach, K and Kobeleva, X and Schneider, A and Bartels, C and Schott, BH and Wiltfang, J and Maier, F and Glanz, W and Incesoy, EI and Butryn, M and Düzel, E and Buerger, K and Janowitz, D and Ewers, M and Rauchmann, BS and Perneczky, R and Kilimann, I and Görß, D and Teipel, S and Laske, C and Munk, MHJ and Spottke, A and Roy, N and Brosseron, F and Heneka, MT and Ramirez, A and Yakupov, R and Scherer, M and Maier, W and Jessen, F and Riedel-Heller, SG and Wagner, M}, title = {Midlife occupational cognitive requirements protect cognitive function in old age by increasing cognitive reserve.}, journal = {Frontiers in psychology}, volume = {13}, number = {}, pages = {957308}, pmid = {36571008}, issn = {1664-1078}, abstract = {INTRODUCTION: Several lifestyle factors promote protection against Alzheimer's disease (AD) throughout a person's lifespan. Although such protective effects have been described for occupational cognitive requirements (OCR) in midlife, it is currently unknown whether they are conveyed by brain maintenance (BM), brain reserve (BR), or cognitive reserve (CR) or a combination of them.

METHODS: We systematically derived hypotheses for these resilience concepts and tested them in the population-based AgeCoDe cohort and memory clinic-based AD high-risk DELCODE study. The OCR score (OCRS) was measured using job activities based on the O*NET occupational classification system. Four sets of analyses were conducted: (1) the interaction of OCR and APOE-ε4 with regard to cognitive decline (N = 2,369, AgeCoDe), (2) association with differentially shaped retrospective trajectories before the onset of dementia of the Alzheimer's type (DAT; N = 474, AgeCoDe), (3) cross-sectional interaction of the OCR and cerebrospinal fluid (CSF) AD biomarkers and brain structural measures regarding memory function (N = 873, DELCODE), and (4) cross-sectional and longitudinal association of OCR with CSF AD biomarkers and brain structural measures (N = 873, DELCODE).

RESULTS: Regarding (1), higher OCRS was associated with a reduced association of APOE-ε4 with cognitive decline (mean follow-up = 6.03 years), consistent with CR and BR. Regarding (2), high OCRS was associated with a later onset but subsequently stronger cognitive decline in individuals converting to DAT, consistent with CR. Regarding (3), higher OCRS was associated with a weaker association of the CSF Aβ42/40 ratio and hippocampal volume with memory function, consistent with CR. Regarding (4), OCR was not associated with the levels or changes in CSF AD biomarkers (mean follow-up = 2.61 years). We found a cross-sectional, age-independent association of OCRS with some MRI markers, but no association with 1-year-change. OCR was not associated with the intracranial volume. These results are not completely consistent with those of BR or BM.

DISCUSSION: Our results support the link between OCR and CR. Promoting and seeking complex and stimulating work conditions in midlife could therefore contribute to increased resistance to pathologies in old age and might complement prevention measures aimed at reducing pathology.}, } @article {pmid36570840, year = {2022}, author = {Chen, L and Jiao, J and Zhang, Y}, title = {Therapeutic approaches for improving cognitive function in the aging brain.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {1060556}, pmid = {36570840}, issn = {1662-4548}, abstract = {The rapid aging of populations around the world has become an unprecedented challenge. Aging is associated with cognitive impairment, including dementia and mild cognitive impairment. Successful drug development for improving or maintaining cognition in the elderly is critically important. Although 4 drugs for improving cognition in Alzheimer's disease have been approved, a variety of potential drugs targeting age-related cognitive impairment are still in development. In addition, non-pharmacological interventions, including cognition-oriented treatments, non-invasive brain stimulation physical exercise, and lifestyle-related interventions, have also been suggested as cognitive enhancers in the last decade. In this paper, we reviewed the recent evidence of pharmacological and non-pharmacological interventions aimed at improving or maintaining cognition in the elderly.}, } @article {pmid36570831, year = {2022}, author = {Al-Hilaly, YK and Hurt, C and Rickard, JE and Harrington, CR and Storey, JMD and Wischik, CM and Serpell, LC and Siemer, AB}, title = {Solid-state NMR of paired helical filaments formed by the core tau fragment tau(297-391).}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {988074}, pmid = {36570831}, issn = {1662-4548}, abstract = {Aggregation of the tau protein into fibrillar cross-β aggregates is a hallmark of Alzheimer's diseases (AD) and many other neurodegenerative tauopathies. Recently, several core structures of patient-derived tau paired helical filaments (PHFs) have been solved revealing a structural variability that often correlates with a specific tauopathy. To further characterize the dynamics of these fibril cores, to screen for strain-specific small molecules as potential biomarkers and therapeutics, and to develop strain-specific antibodies, recombinant in-vitro models of tau filaments are needed. We recently showed that a 95-residue fragment of tau (from residue 297 to 391), termed dGAE, forms filaments in vitro in the absence of polyanionic co-factors often used for in vitro aggregation of full-length tau. Tau(297-391) was identified as the proteolytic resistant core of tau PHFs and overlaps with the structures characterized by cryo-electron microscopy in ex vivo PHFs, making it a promising model for the study of AD tau filaments in vitro. In the present study, we used solid-state NMR to characterize tau(297-391) filaments and show that such filaments assembled under non-reducing conditions are more dynamic and less ordered than those made in the presence of the reducing agent DTT. We further report the resonance assignment of tau(297-391)+DTT filaments and compare it to existing core structures of tau.}, } @article {pmid36570653, year = {2022}, author = {Nepal, P and Al Bashit, A and Yang, L and Makowski, L}, title = {Small-angle X-ray microdiffraction from fibrils embedded in tissue thin sections.}, journal = {Journal of applied crystallography}, volume = {55}, number = {Pt 6}, pages = {1562-1571}, pmid = {36570653}, issn = {0021-8898}, abstract = {Small-angle X-ray scattering (SAXS) from fibrils embedded in a fixed, thin section of tissue includes contributions from the fibrils, the polymeric matrix surrounding the fibrils, other constituents of the tissue, and cross-terms due to the spatial correlation between fibrils and neighboring molecules. This complex mixture severely limits the amount of information that can be extracted from scattering studies. However, availability of micro- and nano-beams has made the measurement of scattering from very small volumes possible, which, in some cases, may be dominated by a single fibrillar constituent. In such cases, information about the predominant species may be accessible. Nevertheless, even in these cases, the correlations between the positions of fibrils and other constituents have a significant impact on the observed scattering. Here, strategies are proposed to extract partial information about fibril structure and tissue organization on the basis of SAXS from samples of this type. It is shown that the spatial correlation function of the fibril in the direction perpendicular to the fibril axis can be computed and contains information about the predominant fibril structure and the organization of the surrounding tissue matrix. This has significant advantages over approaches based on techniques developed for X-ray solution scattering. Examples of correlation calculations in different types of samples are given to demonstrate the information that can be obtained from these measurements.}, } @article {pmid36570623, year = {2022}, author = {Lin, JB and Murakami, Y and Miller, JW and Vavvas, DG}, title = {Neuroprotection for Age-Related Macular Degeneration.}, journal = {Ophthalmology science}, volume = {2}, number = {4}, pages = {100192}, pmid = {36570623}, issn = {2666-9145}, abstract = {Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. Early to intermediate AMD is characterized by the accumulation of lipid- and protein-rich drusen. Late stages of the disease are characterized by the development of choroidal neovascularization, termed "exudative" or "neovascular AMD," or retinal pigment epithelium (RPE) cell and photoreceptor death, termed "geographic atrophy" (GA) in advanced nonexudative AMD. Although we have effective treatments for exudative AMD in the form of anti-VEGF agents, they have no role for patients with GA. Neuroprotection strategies have emerged as a possible way to slow photoreceptor degeneration and vision loss in patients with GA. These approaches include reduction of oxidative stress, modulation of the visual cycle, reduction of toxic molecules, inhibition of pathologic protein activity, prevention of cellular apoptosis or programmed necrosis (necroptosis), inhibition of inflammation, direct activation of neurotrophic factors, delivery of umbilical tissue-derived cells, and RPE replacement. Despite active investigation in this area and significant promise based on preclinical studies, many clinical studies have not yielded successful results. We discuss selected past and current neuroprotection trials for AMD, highlight the lessons learned from these past studies, and discuss our perspective regarding remaining questions that must be answered before neuroprotection can be successfully applied in the field of AMD research.}, } @article {pmid36570602, year = {2023}, author = {Halili, A}, title = {Temporal model for central sensitization: A hypothesis for mechanism and treatment using systemic manual therapy, a focused review.}, journal = {MethodsX}, volume = {10}, number = {}, pages = {101942}, pmid = {36570602}, issn = {2215-0161}, abstract = {The purpose of this focused review is to develop a consolidated hypothesis as to the causes and mechanisms of central sensitization and a related model for a treatment approach using Systemic Manual Therapy (SMT). The key to understanding central sensitization is a firm grasp on structure and function of the Locus-coeruleus noradrenaline system (LC-NA). This system uses an elaborate switching mechanism to control the level and rate of activation of multiple systems. This review evaluates the mechanisms and temporal relationships behind four components: salient stimuli, threat coding, aberrant afferent input, and oxidative stress. The five-stage temporal model for central sensitization includes phasic activation of the LC-NA system, salient stimuli, threat coding of salient stimuli, central sensitization, and neural degeneration. The three components of treatment include temporarily reducing afferent visceral input, shifting humoral inflammatory activity away from the brain and outside the body, and reducing oxidative stress by making oxygenated blood more available around the LC and other stressed areas in the brain. The SMT protocols that could help in reduction of visceral afferent input are GUOU, Barral and LAUG. Protocols that should shift humoral inflammatory activity away from the brain or completely out of the body include UD and DCS. One protocol that can potentially reduce oxidative stress by making oxygenated blood more available around the LC is CCCV. Future research and hypothesis-testing strategies as well as limitations are further discussed.}, } @article {pmid36570538, year = {2022}, author = {Yuan, Q and Liang, X and Xue, C and Qi, W and Chen, S and Song, Y and Wu, H and Zhang, X and Xiao, C and Chen, J}, title = {Altered anterior cingulate cortex subregional connectivity associated with cognitions for distinguishing the spectrum of pre-clinical Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1035746}, pmid = {36570538}, issn = {1663-4365}, abstract = {BACKGROUND: Subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) are considered part of the early progression continuum of Alzheimer's disease (AD). The anterior cingulate cortex (ACC), a hub of information processing and regulation in the brain, plays an essential role in AD pathophysiology. In the present study, we aimed to systematically identify changes in the functional connectivity (FC) of ACC subregions in patients with SCD and aMCI and evaluate the association of these changes with cognition.

MATERIALS AND METHODS: Functional connectivity (FC) analysis of ACC sub-regions was performed among 66 patients with SCD, 71 patients with aMCI, and 78 healthy controls (HCs). Correlation analyses were performed to examine the relationship between FC of altered ACC subnetworks and cognition.

RESULTS: Compared to HCs, SCD patients showed increased FC of the bilateral precuneus (PCUN) and caudal ACC, left superior frontal gyrus (SFG) and subgenual ACC, left inferior parietal lobule (IPL) and dorsal ACC, left middle occipital gyrus (MOG) and dorsal ACC, and left middle temporal gyrus (MTG) and subgenual ACC, while aMCI patients showed increased FC of the left inferior frontal gyrus (IFG) and dorsal ACC and left medial frontal gyrus (MFG) and subgenual ACC. Compared to patients with SCD, patients with aMCI showed increased FC of the right MFG and dorsal ACC and left ACC and subgenual ACC, while the left posterior cingulate cortex (PCC) showed decreased FC with the caudal ACC. Moreover, some FC values among the altered ACC subnetworks were significantly correlated with episodic memory and executive function.

CONCLUSION: SCD and aMCI, part of the spectrum of pre-clinical AD, share some convergent and divergent altered intrinsic connectivity of ACC subregions. These results may serve as neuroimaging biomarkers of the preclinical phase of AD and provide new insights into the design of preclinical interventions.}, } @article {pmid36570537, year = {2022}, author = {Clark, C and Rabl, M and Dayon, L and Popp, J}, title = {The promise of multi-omics approaches to discover biological alterations with clinical relevance in Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1065904}, pmid = {36570537}, issn = {1663-4365}, abstract = {Beyond the core features of Alzheimer's disease (AD) pathology, i.e. amyloid pathology, tau-related neurodegeneration and microglia response, multiple other molecular alterations and pathway dysregulations have been observed in AD. Their inter-individual variations, complex interactions and relevance for clinical manifestation and disease progression remain poorly understood, however. Heterogeneity at both pathophysiological and clinical levels complicates diagnosis, prognosis, treatment and drug design and testing. High-throughput "omics" comprise unbiased and untargeted data-driven methods which allow the exploration of a wide spectrum of disease-related changes at different endophenotype levels without focussing a priori on specific molecular pathways or molecules. Crucially, new methodological and statistical advances now allow for the integrative analysis of data resulting from multiple and different omics methods. These multi-omics approaches offer the unique advantage of providing a more comprehensive characterisation of the AD endophenotype and to capture molecular signatures and interactions spanning various biological levels. These new insights can then help decipher disease mechanisms more deeply. In this review, we describe the different multi-omics tools and approaches currently available and how they have been applied in AD research so far. We discuss how multi-omics can be used to explore molecular alterations related to core features of the AD pathologies and how they interact with comorbid pathological alterations. We further discuss whether the identified pathophysiological changes are relevant for the clinical manifestation of AD, in terms of both cognitive impairment and neuropsychiatric symptoms, and for clinical disease progression over time. Finally, we address the opportunities for multi-omics approaches to help discover novel biomarkers for diagnosis and monitoring of relevant pathophysiological processes, along with personalised intervention strategies in AD.}, } @article {pmid36570536, year = {2022}, author = {Kurano, M and Saito, Y and Uranbileg, B and Saigusa, D and Kano, K and Aoki, J and Yatomi, Y}, title = {Modulations of bioactive lipids and their receptors in postmortem Alzheimer's disease brains.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1066578}, pmid = {36570536}, issn = {1663-4365}, abstract = {BACKGROUND: Analyses of brain samples from Alzheimer's disease (AD) patients may be expected to help us improve our understanding of the pathogenesis of AD. Bioactive lipids, including sphingolipids, glycerophospholipids, and eicosanoids/related mediators have been demonstrated to exert potent physiological actions and to be involved in the pathogenesis of various human diseases. In this cross-sectional study, we attempted to elucidate the associations of these bioactive lipids with the pathogenesis/pathology of AD through postmortem studies of human brains.

METHODS: We measured the levels of glycerophospholipids, sphingolipids, and eicosanoids/related mediators in the brains of patients with AD (AD brains), patients with Cerad score B (Cerad-b brains), and control subjects (control brains), using a liquid chromatography-mass spectrometry method; we also measured the mRNA levels of specific receptors for these bioactive lipids in the same brain specimens.

RESULTS: The levels of several species of sphingomyelins and ceramides were higher in the Cerad-b and AD brains. Levels of several species of lysophosphatidic acids (LPAs), lysophosphatidylcholine, lysophosphatidylserine, lysophosphatidylethanolamine (LPE), lysophosphatidylinositol, phosphatidylcholine, phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylinositol, and phosphatidylglycerol were especially high in the Cerad-b brains, while those of lysophosphatidylglycerol (LPG) were especially high in the AD brains. Several eicosanoids, including metabolites of prostaglandin E2, oxylipins, metabolites of epoxide, and metabolites of DHA and EPA, such as resolvins, were also modulated in the AD brains. Among the lipid mediators, the levels of S1P2, S1P5, LPA1, LPA2, LPA6, P2Y10, GPR174, EP1, DP1, DP2, IP, FP, and TXA2r were lower in the AD and/or Cerad-b brains. The brain levels of ceramides, LPC, LPI, PE, and PS showed strong positive correlations with the Aβ contents, while those of LPG showed rather strong positive correlations with the presence of senile plaques and neurofibrillary tangles. A discriminant analysis revealed that LPG is especially important for AD and the LPE/PE axis is important for Cerad-b.

CONCLUSIONS: Comprehensive lipidomics, together with the measurement of lipid receptor expression levels provided novel evidence for the associations of bioactive lipids with AD, which is expected to facilitate future translational research and reverse translational research.}, } @article {pmid36570535, year = {2022}, author = {Geng, R and Zhang, Y and Liu, M and Deng, S and Ding, J and Zhong, H and Tu, Q}, title = {Elevated serum uric acid is associated with cognitive improvement in older American adults: A large, population-based-analysis of the NHANES database.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1024415}, pmid = {36570535}, issn = {1663-4365}, abstract = {BACKGROUND: The many studies revealing a connection between serum uric acid (SUA) and dementia have reported conflicting results. This study sought to investigate the relations between SUA and cognitive function in older adults.

MATERIALS AND METHODS: The sample was 2,767 American adults aged ≥60 years from the National Health and Nutrition Examination Survey 2011-2014. Cognitive performance was evaluated by the Consortium to Establish a Registry for Alzheimer's Disease test, animal fluency test, digit symbol substitution test, and composite z-score. Multivariate linear regression analyses were conducted to estimate the association