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Near-infrared fluorescence lifetime imaging of amyloid-β aggregates and tau fibrils through the intact skull of mice.

Non-invasive methods for the in vivo detection of hallmarks of Alzheimers disease can facilitate the study of the progression of the disease in mouse models and may enable its earlier diagnosis in humans. Here we show that the zwitterionic heptamethine fluorophore ZW800-1C, which has peak excitation and emission wavelengths in the near-infrared optical window, binds in vivo and at high contrast to amyloid-β deposits and to neurofibrillary tangles, and allows for the microscopic imaging of amyloid-β and tau aggregates through the intact skull of mice. In transgenic mouse models of Alzheimers disease, we compare the performance of ZW800-1C with that of the two spectrally similar heptamethine fluorophores ZW800-1A and indocyanine green, and show that ZW800-1C undergoes a longer fluorescence-lifetime shift when bound to amyloid-β and tau aggregates than when circulating in blood vessels. ZW800-1C may prove advantageous for tracking the proteinic aggregates in rodent models of amyloid-β and tau pathologies.

Osteocalcin ameliorates cognitive dysfunctions in a mouse model of Alzheimers Disease by reducing amyloid β burden and upregulating glycolysis in neuroglia.

Alzheimers disease (AD) is the most common neurodegenerative disease characterized by the accumulation of amyloid β peptides (Aβ) and impaired glucose metabolism in the brain. Osteocalcin (OCN), an osteoblast-derived protein, has been shown to modulate brain functions but whether it has any effect on AD is undetermined. In this study, daily intraperitoneal injection of OCN for 4 weeks ameliorated the anxiety-like behaviors and cognitive dysfunctions in the APPPS1 transgenic AD mice model, as shown in the increased entries into the central area in open field test, the increased time and entries into open arms in elevated plus maze test, the increased time spent in the light chamber in light-dark transition test, as well as the reduced escape latency and the increased preference for target quadrant in Morris water maze test. Aβ burden in the hippocampus and cortex of AD mice was ameliorated by OCN. Besides, OCN improved the neural network function of the brain, mainly in the enhanced power of high gamma band in the medial prefrontal cortex of AD mice. The proliferation of astrocytes in the hippocampus in AD mice was also inhibited by OCN as demonstrated by immunofluorescence. Furthermore, OCN enhanced glycolysis in astrocytes and microglia, as evidenced by elevated glucose consumption, lactate production, and increased extracellular acidification rate. Such an effect was abolished when the receptor of OCN - Gpr158 was knockdown in astrocytes. Our study revealed OCN as a novel therapeutic factor for AD potentially through reducing Aβ burden and upregulation of glycolysis in neuroglia.

Inflammasome-independent NLRP3 function enforces ATM activity in response to genotoxic stress.

NLRP3 is a pattern recognition receptor with a well-documented role in inducing inflammasome assembly in response to cellular stress. Deregulation of its activity leads to many inflammatory disorders including gouty arthritis, Alzheimer disease, and cancer. Whereas its role in the context of cancer has been mostly explored in the immune compartment, whether NLRP3 exerts functions unrelated to immunity in cancer development remains unexplored. Here, we demonstrate that NLRP3 interacts with the ATM kinase to control the activation of the DNA damage response, independently of its inflammasome activity. NLRP3 down-regulation in both broncho- and mammary human epithelial cells significantly impairs ATM pathway activation, leading to lower p53 activation, and provides cells with the ability to resist apoptosis induced by acute genotoxic stress. Interestingly, NLRP3 expression is down-regulated in non-small cell lung cancers and breast cancers, and its expression positively correlates with patient overall survival. Our findings identify a novel non-immune function for NLRP3 in maintaining genome integrity and strengthen the concept of a functional link between innate immunity and DNA damage sensing pathways to maintain cell integrity.

DOPA pheomelanin is increased in nigral neuromelanin of Parkinsons disease.

Neuromelanin (NM) in dopaminergic neurons of human substantia nigra (SN) has a melanic component that consists of pheomelanin and eumelanin moieties and has been proposed as a key factor contributing to dopaminergic neuron vulnerability in Parkinsons disease (PD). While eumelanin is considered as an antioxidant, pheomelanin and related oxidative stress are associated with compromised drug and metal ion binding and melanoma risk. Using postmortem SN from patients with PD or Alzheimers disease (AD) and unaffected controls, we identified increased L-3,4-dihydroxyphenylalanine (DOPA) pheomelanin and increased ratios of dopamine (DA) pheomelanin markers to DA in PD SN compared to controls. Eumelanins derived from both DOPA and DA were reduced in PD group. In addition, we report an increase in DOPA pheomelanin relative to DA pheomelanin in PD SN. In AD SN, we observed unaltered melanin markers despite reduced DOPA compared to controls. Furthermore, synthetic DOPA pheomelanin induced neuronal cell death in vitro while synthetic DOPA eumelanin showed no significant effect on cell viability. Our findings provide insights into the different roles of pheomelanin and eumelanin in PD pathophysiology. We anticipate our study will lead to further investigations on pheomelanin and eumelanin individually as biomarkers and possibly therapeutic targets for PD.

Blood Biomarkers of NeuronalAxonal and Glial Injury in Human Immunodeficiency Virus-Associated Neurocognitive Disorders.

Approximately half of the people living with HIV (PLWH) experience HIV-associated neurocognitive disorders (HANDs). However, the neuropathogenesis of HAND is complex, and identifying reliable biomarkers has been challenging. This study included 132 participants aged 50 and older from greater San Diego County. The participants were divided into three groups PLWH with HAND (n 29), PLWH without HAND (n 73), and seronegatives without cognitive impairment (n 30). Peripheral blood was collected at the clinical assessment, and plasma levels of neurofilament light chain (NfL), phosphorylated Tau 181 (pTau181), and glial fibrillary acidic protein (GFAP) were measured by enzyme-linked immunosorbent assay (ELISA). Plasma levels of NfL (but not pTau181 and GFAP) were significantly associated with HAND at a medium effect size (p 0.039, Cohens d 0.45 for HAND vs. HAND-). Notably, higher levels of NfL were significantly associated with HAND diagnosis even after adjusting for sex. Our data suggest that neuronal degeneration (as evidenced by increased levels of NfL), but not tau pathology or glial degeneration, is related to cognitive status in PLWH. Our results corroborate the view that blood NfL is a promising biomarker of cognitive impairment in PLWH.

Transcriptional activation of CSTB gene expression by transcription factor Sp3.

CSTB has been reported to be associated with the pathogenesis of many malignant tumors, especially hepatocellular carcinoma (HCC). However, how the expression of this gene is regulated is largely unknown. We initially cloned and analyzed the promoter region of the CSTB gene by luciferase assay and the Sp3 binding site (CCCCGCCCCGCG) was found in it. The results of electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) experiments verified that the transcription factor, Sp3 could bind to the CCCCGCCCCGCG ″ site of the CSTB gene promoter. We showed that the overexpression of Sp3 significantly increased the endogenous mRNA and protein expression levels of CSTB, whereas knockdown of Sp3 decreased the mRNA and protein expression levels according to quantitative real-time PCR (qRT‒PCR) and western blotting. In conclusion, CSTB gene expression is closely regulated by transcription factor Sp3, which may be a potential mechanism for the dysregulation of CSTB expression in HCC.

An attention-based deep learning approach for the classification of subjective cognitive decline and mild cognitive impairment using resting-state EEG.

Structural Proteomic Profiling of Cerebrospinal Fluids to Reveal Novel Conformational Biomarkers for Alzheimers Disease.

Alzheimers disease (AD) is the most common representation of dementia, with brain pathological hallmarks of protein abnormal aggregation, such as with amyloid beta and tau protein. It is well established that posttranslational modifications on tau protein, particularly phosphorylation, increase the likelihood of its aggregation and subsequent formation of neurofibrillary tangles, another hallmark of AD. As additional misfolded proteins presumably exist distinctly in AD disease states, which would serve as potential source of AD biomarkers, we used limited proteolysis-coupled with mass spectrometry (LiP-MS) to probe protein structural changes. After optimizing the LiP-MS conditions, we further applied this method to human cerebrospinal fluid specimens collected from healthy control, mild cognitive impairment (MCI), and AD subject groups to characterize proteome-wide misfolding tendencies as a result of disease progression. The fully tryptic peptides embedding LiP sites were compared with the half-tryptic peptides generated from internal cleavage of the same region to determine any structural unfolding or misfolding. We discovered hundreds of significantly up- and down-regulated peptides associated with MCI and AD indicating their potential structural changes in AD progression. Moreover, we detected 53 structurally changed regions in 12 proteins with high confidence between the healthy control and disease groups, illustrating the functional relevance of these proteins with AD progression. These newly discovered conformational biomarker candidates establish valuable future directions for exploring the molecular mechanism of designing therapeutic targets for AD.

Brain aerobic glycolysis and resilience in Alzheimer disease.

The distribution of brain aerobic glycolysis (AG) in normal young adults correlates spatially with amyloid-beta (Aβ) deposition in individuals with symptomatic and preclinical Alzheimer disease (AD). Brain AG decreases with age, but the functional significance of this decrease with regard to the development of AD symptomatology is poorly understood. Using PET measurements of regional blood flow, oxygen consumption, and glucose utilization-from which we derive AG-we find that cognitive impairment is strongly associated with loss of the typical youthful pattern of AG. In contrast, amyloid positivity without cognitive impairment was associated with preservation of youthful brain AG, which was even higher than that seen in cognitively unimpaired, amyloid negative adults. Similar findings were not seen for blood flow nor oxygen consumption. Finally, in cognitively unimpaired adults, white matter hyperintensity burden was found to be specifically associated with decreased youthful brain AG. Our results suggest that AG may have a role in the resilience andor response to early stages of amyloid pathology and that age-related white matter disease may impair this process.

Investigation of the gait parameters after donepezil treatment in patients with alzheimer s disease.

Clinical studies remark that gait disturbance is common in patients with Alzheimers disease (AD). However, the treatment response of gait disturbance in those patients may constitute a more interesting issue that is rarely addressed. In this prospective, interventional study, we included 14 consecutive patients with a new diagnosis of AD. Basal gait analysis was performed using a Gait Analyzer program that was uploaded to a mobile phone. The gait parameters including Step time (ST), step length (SL), step number (SN), gait velocity (GV), and cadence were measured. Afterward, donepezil 5 mg daily was initiated, and the re-assessments were re-performed 8 weeks after the treatment. The mean age was 71.78 ± 5.02 (FM 86). The evaluations after the donepezil treatment showed that there was a significant improvement in the SN (p 0.021) and SL (p 0.001) in comparison to the basal evaluations. The repeated analysis in the subgroup of early-stage AD subjects (n 10) yielded that there were significant improvements in SN (p 0.003), SL (p 0.005), and cadence (p 0.026) after treatment. Our results support the efficiency of cholinergic treatment in gait functions in AD subjects.

Changes in Alcohol Consumption and Risk of Dementia in a Nationwide Cohort in South Korea.

The impact of serial changes in alcohol consumption on dementia risk has rarely been investigated to date. To investigate the association of comprehensive patterns of changes in alcohol consumption with the incidence of all-cause dementia, Alzheimer disease (AD), and vascular dementia (VaD). This is a retrospective cohort study. Data were obtained from the Korean National Health Insurance Service database. Adults aged 40 years and older underwent 2 health examinations in 2009 and 2011. The cohort was assessed until December 31, 2018, and statistical analysis was performed in December 2021. Alcohol consumption level was categorized into none (0 g per day), mild (<15 g per day), moderate (15-29.9 g per day), and heavy (≥30 g per day) drinking. On the basis of changes in alcohol consumption level from 2009 to 2011, participants were categorized into the following groups nondrinker, quitter, reducer, sustainer, and increaser. The primary outcome was newly diagnosed AD, VaD, or other dementia. Among 3 933 382 participants (mean SD age, 55.0 9.6 years 2 037 948 men 51.8%), during a mean (SD) follow-up of 6.3 (0.7) years, there were 100 282 cases of all-cause dementia, 79 982 cases of AD, and 11 085 cases of VaD. Compared with sustained nondrinking, sustained mild (adjusted hazard ratio aHR, 0.79 95% CI, 0.77-0.81) and moderate (aHR, 0.83 95% CI, 0.79-0.88) drinking were associated with a decreased risk of all-cause dementia, whereas sustained heavy drinking was associated with an increased risk of all-cause dementia (aHR, 1.08 95% CI, 1.03-1.12). Compared with sustained levels of drinking, reducing alcohol consumption from a heavy to a moderate level (aHR, 0.92 95% CI, 0.86-0.99) and the initiation of mild alcohol consumption (aHR, 0.93 95% CI, 0.90-0.96) were associated with a decreased risk of all-cause dementia. Increasers and quitters exhibited an increased risk of all-cause dementia compared with sustainers. The trends in AD and VaD remained consistent. In this cohort study of a Korean population, decreased risk of dementia was associated with maintaining mild to moderate alcohol consumption, reducing alcohol consumption from a heavy to a moderate level, and the initiation of mild alcohol consumption, suggesting that the threshold of alcohol consumption for dementia risk reduction is low.

Prediction of Longitudinal Cognitive Decline in Preclinical Alzheimer Disease Using Plasma Biomarkers.

Alzheimer disease (AD) pathology starts with a prolonged phase of β-amyloid (Aβ) accumulation without symptoms. The duration of this phase differs greatly among individuals. While this disease phase has high relevance for clinical trial designs, it is currently unclear how to best predict the onset of clinical progression. To evaluate combinations of different plasma biomarkers for predicting cognitive decline in Aβ-positive cognitively unimpaired (CU) individuals. This prospective population-based prognostic study evaluated data from 2 prospective longitudinal cohort studies (the Swedish BioFINDER-1 and the Wisconsin Registry for Alzheimer Prevention WRAP), with data collected from February 8, 2010, to October 21, 2020, for the BioFINDER-1 cohort and from August 11, 2011, to June 27, 2021, for the WRAP cohort. Participants were CU individuals recruited from memory clinics who had brain Aβ pathology defined by cerebrospinal fluid (CSF) Aβ4240 in the BioFINDER-1 study and by Pittsburgh Compound B (PiB) positron emission tomography (PET) in the WRAP study. A total of 564 eligible Aβ-positive and Aβ-negative CU participants with available relevant data from the BioFINDER-1 and WRAP cohorts were included in the study of those, 171 Aβ-positive participants were included in the main analyses. Baseline P-tau181, P-tau217, P-tau231, glial fibrillary filament protein, and neurofilament light measured in plasma CSF biomarkers in the BioFINDER-1 cohort, and PiB PET uptake in the WRAP cohort. The primary outcome was longitudinal measures of cognition (using the Mini-Mental State Examination MMSE and the modified Preclinical Alzheimer Cognitive Composite mPACC) over a median of 6 years (range, 2-10 years). The secondary outcome was conversion to AD dementia. Baseline biomarkers were used in linear regression models to predict rates of longitudinal cognitive change (calculated separately). Models were adjusted for age, sex, years of education, apolipoprotein E ε4 allele status, and baseline cognition. Multivariable models were compared based on model R2 coefficients and corrected Akaike information criterion. Among 171 Aβ-positive CU participants included in the main analyses, 119 (mean SD age, 73.0 5.4 years 60.5% female) were from the BioFINDER-1 study, and 52 (mean SD age, 64.4 4.6 years 65.4% female) were from the WRAP study. In the BioFINDER-1 cohort, plasma P-tau217 was the best marker to predict cognitive decline in the mPACC (model R2 0.41) and the MMSE (model R2 0.34) and was superior to the covariates-only models (mPACC R2 0.23 MMSE R2 0.04 P < .001 for both comparisons). Results were validated in the WRAP cohort for example, plasma P-tau217 was associated with mPACC slopes (R2 0.13 vs 0.01 in the covariates-only model P .01) and MMSE slopes (R2 0.29 vs 0.24 in the covariates-only model P .046). Sparse models were identified with plasma P-tau217 as a predictor of cognitive decline. Power calculations for enrichment in hypothetical clinical trials revealed large relative reductions in sample sizes when using plasma P-tau217 to enrich for CU individuals likely to experience cognitive decline over time. In this study, plasma P-tau217 predicted cognitive decline in patients with preclinical AD. These findings suggest that plasma P-tau217 may be used as a complement to CSF or PET for participant selection in clinical trials of novel disease-modifying treatments.

Establishing the Validity and Reliability of an Online Motor Learning Game Applications for Alzheimers Disease Research Within MindCrowd.

Integrated use of ligand and structure-based virtual screening, molecular dynamics, free energy calculation and ADME prediction for the identification of potential PTP1B inhibitors.

Protein tyrosine phosphatases (PTPs) are the group of enzymes that control both cellular activity and the dephosphorylation of tyrosine (Tyr)-phosphorylated proteins. Dysregulation of PTP1B has contributed to numerous diseases including Diabetes Mellitus, Alzheimers disease, and obesity rendering PTP1B as a legitimate target for therapeutic applications. It is highly challenging to target this enzyme because of its highly conserved and positively charged active-site pocket motivating researchers to find novel lead compounds against it. The present work makes use of an integrated approach combining ligand-based and structure-based virtual screening to find hit compounds targeting PTP1B. Initially, pharmacophore modeling was performed to find common features like two hydrogen bond acceptors, an aromatic ring and one hydrogen bond donor from the potent PTP1B inhibitors. The dataset of compounds matching with the common pharmacophoric features was filtered to remove Pan-Assay Interference substructure and to match the Lipinski criteria. Then, compounds were further prioritized using molecular docking and top fifty compounds with good binding affinity were selected for absorption, distribution, metabolism, and excretion (ADME) predictions. The top five compounds with high solubility, absorption and permeability holding score of - 10 to - 9.3 kcalmol along with Ertiprotafib were submitted to all-atom molecular dynamic (MD) studies. The MD studies and binding free energy calculations showed that compound M4, M5 and M8 were having better binding affinity for PTP1B enzyme with ∆G

Traversing through the cell signaling pathways of neuroprotection by betanin therapeutic relevance to Alzheimers Disease and Parkinsons Disease.

Modulation of cell signaling pathways is the key area of research towards the treatment of neurodegenerative disorders. Altered Nrf2-Keap1-ARE (Nuclear factor erythroid-2-related factor 2-Kelch-like ECH-associated protein 1-Antioxidant responsive element) and SIRT1 (Sirtuin 1) cell signaling pathways are considered to play major role in the etiology and pathogenesis of Alzheimers disease (AD) and Parkinsons disease (PD). Strikingly, betanin, a betanidin 5-O-β-D-glucoside compound is reported to show commendable anti-oxidative, anti-inflammatory and anti-apoptotic effects in several disease studies including AD and PD. The present review discusses the pre-clinical studies demonstrating the neuroprotective effects of betanin by virtue of its potential to ameliorate oxidative stress, neuroinflammation, abnormal protein aggregation and cell death. It highlights the direct linkage between the neuroprotective abilities of betanin and upregulation of the Nrf2-Keap1-ARE and SIRT1 signaling pathways. The review further hypothesizes the involvement of the betanin-Nrf2-ARE route in the inhibition of beta-amyloid aggregation through beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), one of the pivotal hallmarks of AD. The present review hereby for the first time elaborately discusses the reported neuroprotective abilities of betanin and decodes the Nrf2 and SIRT1 modulating potential of betanin as a primary mechanism of action behind, hence highlighting it as a novel drug candidate for the treatment of neurodegenerative diseases in the near future.

How does neurokinin 3 receptor agonism affect pathological and cognitive impairments in an Alzheimers disease-like rat model

Alzheimers disease (AD) is accepted as a form of progressive dementia. Cholinergic systems are commonly affected in AD. Neurokinin 3 receptor (NK3R) is involved in learning memory-related processes. It is known that the activation of NK3R affects the release of many neurotransmitters. The aim of this project was to investigate the effects of NK3R agonist senktide administration on neurobehavioral mechanisms in the experimental AD-like rat model. 50 male Wistar albino rats were divided into Control (C), AD, Control NK3R agonist (CS), AD NK3R agonist (ADS), AD NK3Ragonist antagonist groups (ADSO). We designed AD-like model by intrahippocampal administration of Aβ1-42. After NK3R agonist antagonist injections, open field (OF), Morris water maze (MWM) tests were applied. Cholinergic mechanism analysis from hippocampus-cortex tissues was performed by ELISA and catecholamine analysis from brain stem tissue were performed by HPLC method. The transitions from edge to center, rearing, grooming parameters were found to be reduced in final values of OF. While the group-time interaction was significant in the OF test findings, there was no significant difference between the groups. In MWM test, ADS group showed a learning level close to control group and animals in AD and ADSO groups could not learn target quadrant in MWM test. The brain stem NA and DA concentrations were not statistically significant. Hippocampal AChE-ChAT levels were supported by positive effects of senktide on learning via the cholinergic mechanisms. As a result, NK3R agonists were found to be effective in improving cognitive functions in rats with AD pathology. In the experimental AD model, positive effects of NK3R on learning memory may be mediated by cholinergic mechanisms.

Focused ultrasound Innovation in use for neurologic conditions.

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 Alzheimers 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.

Digital Intervention For The Management Of Alzheimers Disease.

Alzheimers disease (AD) is a progressive, multifactorial, chronic, neurodegenerative disease with high prevalence and limited therapeutic options, making it a global health crisis. Being the most common cause of dementia, AD erodes the cognitive, functional, and social abilities of the individual and causes escalating medical and psychosocial needs. As yet, this disorder has no cure and current treatment options are palliative in nature. There is an urgent need for novel therapy to address this pressing challenge. Digital therapeutics (Dtx) is one such novel therapy that is gaining popularity globally. Dtx provides evidence based therapeutic interventions driven by internet and software, employing tools such as mobile devices, computers, videogames, apps, sensors, virtual reality aiding in the prevention, management, and treatment of ailments like neurological abnormalities and chronic diseases. Dtx acts as a supportive tool for the optimization of patient care, individualized treatment and improved health outcomes. Dtx uses visual, sound and other non-invasive approaches for instance-consistent therapy, reminiscence therapy, computerised cognitive training, semantic and phonological assistance devices, wearables and computer-assisted rehabilitation environment to find applications in Alzheimers disease for improving memory, cognition, functional abilities and managing motor symptom. A few of the Dtx-based tools employed in AD include Memory Matters, AlzSense, Alzheimer Assistant, smart robotic dog, Immersive virtual reality (iVR) and the most current gamma stimulation. The purpose of this review is to summarize the current trends in digital health in AD and explore the benefits, challenges, and impediments of using Dtx as an adjunctive therapy for the management of AD.

Pesticide exposure and Alzheimers disease A case-control study.

This study aimed to investigate the levels of organochlorine pesticides (OCPs) in the serum of Alzheimers disease (AD) patients. 63 AD patients and 50 healthy individuals participated, and the levels of some OCPs derivatives (including α-HCH, β-HCH, γ-HCH, 2,4-DDT, 4,4-DDT, 2,4-DDE, and 4,4-DDE), total antioxidant capacity (TAC), protein carbonyl (PC), malondialdehyde (MDA), Nitric oxide (NO) along with the activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), paraoxonase 1(PON1), and acetylcholinesterase (AChE) were measured. The mean OCP level of OCPs in AD patients was significantly higher than in the control group. However, the patients mean levels of TAC, PC, MDA and activity of SOD, GPx, PON1 and AChE were significantly lower than controls. A significant positive correlation was also observed between 2,4-DDE and MDA and between γ-HCH and PC in AD patients. These findings showed that pesticide exposure is associated with an increased risk of AD. Furthermore, the mean levels of oxidative stress markers, which may result from pesticide exposure, were significantly lower in AD patients compared to healthy individuals. Therefore, it may conclude that pesticides, at least in part, contribute to AD development through several mechanisms, including the induction of oxidative stress.

Sense of Purpose in Life and Beliefs and Knowledge of Alzheimers Disease.

A sense of purpose in life is associated with healthier cognitive outcomes, including lower risk of Alzheimers Disease (ad). The present research examines whether purpose is also associated with beliefs and knowledge of ad. A random subsample (N 1,187) of community-dwelling participants from the Health and Retirement Study completed a module on self-reported beliefs and knowledge of ad. Purpose in life was associated with lower perceived threat of ad and greater belief that modifiable factors (e.g., physical activity) decrease risk. Associations were not moderated by experience with ad or depressive symptoms. Purpose was unrelated to beliefs that genetics or stress increase risk or knowledge of ad. Individuals with a sense of purpose are less concerned about risk of developing ad and believe modifiable factors reduce risk. These beliefs may support engagement in behaviors that reduce risk and be one psychological pathway through which purpose protects against ad.

Association of Influenza Vaccination and Dementia Risk A Meta-Analysis of Cohort Studies.

Dementia is a critical global public health problem. Previous cohort studies have found that influenza vaccination can decrease the risk of dementia. This meta-analysis aimed to systematically examine the relationship between influenza vaccination and dementia risk. We searched PubMed, Embase, Web of Science, ScienceDirect, medRxiv, and bioRxiv for studies investigating dementia risk based on influenza vaccination status, up to September 14, 2022. Relative risks (RRs) and 95% confidence intervals (95% CIs) were pooled in the meta-analysis. Subgroup analyses and sensitivity analyses were conducted as well. Of the 4,087 articles initially reviewed, 6 cohort studies were included in the final meta-analysis, and all eligible studies were at low risk of bias. There were 2,087,195 participants without dementia at baseline (mean age 61.8-75.5 years, 57.05% males), and 149,804 (7.18%) cases of dementia occurred during 4.00-13.00 years of follow-up. Pooled analysis of adjusted RRs found that influenza vaccination could reduce dementia risk by 31% (RR 0.69, 95% CI 0.57-0.83). Subgroup analyses showed that in the study with a mean age of 75-80 years or 75%-100% males, the association was generally weakened compared with studies with a mean age of 60-75 years or 25%-50% males. The results were stable in the sensitivity analyses, and no publication bias was observed. Influenza vaccination in older adults was markedly associated with a decreased risk of dementia. More mechanistic studies and epidemiological studies are needed to clarify the association between influenza vaccination and decreased dementia risk.

PSA-NCAM Regulatory Gene Expression Changes in the Alzheimers Disease Entorhinal Cortex Revealed with Multiplexed in situ Hybridization.

Alzheimers disease (AD) is the most common form of dementia and is characterized by a substantial reduction of neuroplasticity. Our previous work demonstrated that neurons involved in memory function may lose plasticity because of decreased protein levels of polysialylated neural cell adhesion molecule (PSA-NCAM) in the entorhinal cortex (EC) of the human AD brain, but the cause of this decrease is unclear. To investigate genes involved in PSA-NCAM regulation which may underlie its decrease in the AD EC. We subjected neurologically normal and AD human EC sections to multiplexed fluorescent in situ hybridization and immunohistochemistry to investigate genes involved in PSA-NCAM regulation. Gene expression changes were sought to be validated in both human tissue and a mouse model of AD. In the AD EC, a cell population expressing a high level of CALB2 mRNA and a cell population expressing a high level of PST mRNA were both decreased. CALB2 mRNA and protein were not decreased globally, indicating that the decrease in CALB2 was specific to a sub-population of cells. A significant decrease in PST mRNA expression was observed with single-plex in situ hybridization in middle temporal gyrus tissue microarray cores from AD patients, which negatively correlated with tau pathology, hinting at global loss in PST expression across the AD brain. No significant differences in PSA-NCAM or PST protein expression were observed in the MAPT P301S mouse brain at 9 months of age. We conclude that PSA-NCAM dysregulation may cause subsequent loss of structural plasticity in AD, and this may result from a loss of PST mRNA expression. Due PSTs involvement in structural plasticity, intervention for AD may be possible by targeting this disrupted plasticity pathway.

Effect of Metabolic Syndrome Risk Factors on Processing Speed and Executive Function in Three Racialized Groups.

Metabolic syndrome (MetS) has been associated with increased risk for Alzheimers disease and related dementias (ADRD). Understanding the association of MetS risk factors to processing speed and executive function in the pre-clinical stages of ADRD in under-represented groups would offer insight on potential mechanisms through which MetS associates with ADRD risk. Examine association of MetS features and processing speed and executive function across three racial groups. Cognitively unimpaired adults from the Wisconsin Alzheimers Disease Research Center and the Wisconsin Registry for Alzheimers Disease Prevention completed blood-draws and neuropsychological testing. Six cognitive outcomes were assessed in association to MetS risk factors Trailmaking Tests A and B, Animal Fluency, Digit Symbol, and composite scores for Processing Speed and Executive Function. Linear mixed effect models were used to assess the relationship between MetS risk factor count and longitudinal cognitive performance across three racialized groups. Participant sample sizes varied by outcome analyzed (N 714-1,088). African American and Native American groups exhibited higher rates of MetS than non-Hispanic Whites. MetS was associated with processing speed and executive function across all racialized groups. Three-way interaction by racialized group was limited to one cognitive outcome Trailmaking Test A. Metabolic dysfunction incrementally affects cognitive trajectory, with generally similar associations across racial groups. Since racialized groups exhibit higher levels of both MetS and ADRD, MetS may represent a driving factor for increased ADRD risk experience by racialized group and an important and modifiable target through which to reduce risk of ADRD.

Urinary Amino Acid-Conjugated Acrolein and Taurine as New Biomarkers for Detection of Dementia.

Dementia, including Alzheimers disease (AD), is one of the serious diseases at advanced age, and its early detection is important for maintaining quality of life (QOL). In this study, we sought novel biomarkers for dementia in urine. Samples of urine were collected from 57 control subjects without dementia, 62 mild cognitive impairment (MCI) patients, and 42 AD patients. Mini-Mental State Examination (MMSE) was evaluated when subjects were examined by medical doctors. Urinary amino acid (lysine)-conjugated acrolein (AC-Acro) was measured using N ɛ -(3-formyl-3, 4-dehydropiperidine) lysine (FDP-Lys) ELISA kit, and taurine content was measured using a taurine assay kit. Values were normalized by creatinine content which was measured with the colorimetric assay kit. We found that urinary amino acid (lysine)-conjugated acrolein (AC-Acro) and taurine negatively correlated with MMSE score and are significantly lower in dementia patients compared to the normal subjects. When AC-Acro and taurine were evaluated together with age using an artificial neural network model, median relative risk values for subjects with AD, subjects with mild cognitive impairment, and control subjects were 0.96, 0.53, and 0.06, respectively. Since urine is relatively easy to collect, our findings provide a novel biomarker for dementia without invasiveness.

Impaired Early Insulin Response to Glucose Load Predicts Episodic Memory Decline A 10-Year Population-Based Cohort Follow-Up of 45-74-Year-Old Men and Women.

Diabetes increases the risk for cognitive decline, but the mechanisms behind this association remain unknown. Impaired early insulin secretion in elderly men and insulin resistance, both of which are pathophysiological features of type 2 diabetes, have previously been linked to Alzheimers disease. To examine if the early insulin response to oral glucose load predicts cognitive performance after 10 years in men and women aged 45-74 years. This study was based on a subpopulation of the Health 2000 Survey, a Finnish nationwide, population-based health examination study, and its follow-up, the Health 2011 Study. In total, 961 45-74-year-old individuals (mean age at baseline 55.6 years, 55.8% women) were examined. An oral glucose tolerance test was performed in 2001-2002, and early insulin response was defined as the ratio of the 30-min increment in insulin concentration to that of glucose concentration. Cognitive function was evaluated at baseline and follow-up with categorical verbal fluency, word-list learning, and word-list delayed recall. Statistical analyses were performed using multivariable linear models adjusted for age, sex, education, APOEz.epsi4 genotype, vascular risk factors including diabetes, and depressive symptoms. A lower early insulin response to glucose load predicted lower performance (β 0.21, p 0.03) and greater decline (β 0.19, p 0.03) in the word-list delayed recall test. Baseline early insulin response did not predict verbal fluency or word-list learning (all p-values≥0.13). Our results suggest that decreased early insulin secretion predicts episodic memory decline in middle-aged to elderly men and women.

Regional White Matter Hyperintensities and Alzheimers Disease Biomarkers Among Older Adults with Normal Cognition and Mild Cognitive Impairment.

Alzheimers disease (AD) frequently co-occurs with other brain pathologies. Recent studies suggest there may be a mechanistic link between AD and small vessel cerebrovascular disease (CVD), as opposed to simply the overlap of two disorders. We investigated the cross-sectional relationship between white matter hyperintensity (WMH) volumes (markers of CVD) and cerebrospinal fluid (CSF) biomarkers of AD. WMH volumes were assessed globally and regionally (i.e., frontal, parietal, temporal, occipital, and limbic). CSF AD biomarkers (i.e., Aβ 40, Aβ 42, Aβ 42Aβ 40 ratio, phosphorylated tau-181 p-tau181, and total tau t-tau) were measured among 152 non-demented individuals (134 cognitively unimpaired and 18 with mild cognitive impairment (MCI)). Linear regression models showed that among all subjects, higher temporal WHM volumes were associated with AD biomarkers (higher levels of p-tau181, t-tau, and Aβ 40), particularly among APOE ɛ 4 carriers (independent of Aβ 42 levels). Higher vascular risk scores were associated with greater parietal and frontal WMH volumes (independent of CSF AD biomarker levels). Among subjects with MCI only, parietal WMH volumes were associated with a lower level of Aβ 42Aβ 40. In addition, there was an association between higher global WMH volumes and higher CSF t-tau levels among younger participants versus older ones (∼<65 versus 65 years), independent of Aβ 42Aβ 40 and p-tau181. These findings suggest that although WMH are primarily related to systemic vascular risk and neurodegeneration (i.e., t-tau), AD-specific pathways may contribute to the formation of WMH in a regionally-specific manner, with neurofibrillary tangles (i.e., p-tau) playing a role in temporal WMHs and amyloid (i.e., Aβ 42Aβ 40) in parietal WMHs.

Progression from Prodromal Alzheimers Disease to Mild Alzheimers Disease Dementia in the Verubecestat APECS Study Adjudicating Diagnostic Transitions.

Delay of progression from prodromal Alzheimers disease (AD) to dementia is an important outcome in AD trials. Centralized adjudication is intended to improve the consistency of dementia diagnosis but has not been scrutinized. To evaluate centralized adjudication for determining progression to dementia compared with Site Investigator opinion or change in Clinical Dementia Rating (CDR). We used data from the 2-year APECS trial of verubecestat versus placebo in 1,451 prodromal AD participants. Cases were triggered for central adjudication if 1) the Site Investigator judged the participant had progressed to dementia, or 2) the participants CDR sum-of-boxes score increased ≥2 points from baseline. Post-hoc analyses were performed on pooled treatment-group data to compare methods of assessing progression. 5811,451 (40% ) participants had changes triggering adjudication and most (83% ) were confirmed as progression to dementia. Only 66% of those who met CDR criteria (regardless of whether they also met Site Investigator criteria) were adjudicated to have progressed to dementia and just 15% of those who met only CDR criteria were adjudicated to have progressed, representing 5% of progressors. In contrast, 99% of those who met Site Investigator criteria (regardless of whether they also met CDR criteria) were adjudicated to have progressed, and the same was true for those who met only Site Investigator criteria. A positive Site Investigator opinion is an excellent predictor for a positive adjudication decision regarding onset of dementia. Conversely, sole use of CDR sum-of-boxes change ≥2 is inadequate. The benefit of centralized adjudication appears doubtful.

Soluble TREM2, Alzheimers Disease Pathology, and Risk for Progression of Cerebral Small Vessel Disease A Longitudinal Study.

BackgroundUntil recently, studies on associations between neuroinflammation in vivo and cerebral small vessel disease (CSVD) are scarce. Cerebrospinal fluid (CSF) levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a candidate biomarker of microglial activation and neuroinflammation, were found elevated in Alzheimers disease (AD), but they have not been fully explored in CSVD.ObjectiveTo determine whether CSF sTREM2 levels are associated with the increased risk of CSVD progression.MethodsA total of 426 individuals from the Alzheimers Disease Neuroimaging Initiative (ADNI) database were included in this study. All participants underwent measurements of CSF sTREM2 and AD pathology (Aβ 1 - 42, P-tau181P). The progression of CSVD burden and imaging markers, including cerebral microbleeds (CMBs), white matter hyperintensities and lacunes, were estimated based on neuroimaging changes. Logistic regression and moderation effect models were applied to explore associations of sTREM2 with CSVD progression and AD pathology.Results Higher CSF sTREM2 levels at baseline were associated with increased CSVD burden (OR 1.28 95% CI, 1.01-1.62) and CMBs counts (OR 1.32 95% CI, 1.03-1.68). Similarly, increased change rates of CSF sTREM2 might predict elevated CMBs counts (OR 1.44 95% CI, 1.05-1.98). Participants with AD pathology (Aβ 1 - 42 and P-tau181P) showed a stronger association between CSF sTREM2 and CSVD progression.ConclusionThis longitudinal study found a positive association between CSF sTREM2 and CSVD progression, suggesting that neuroinflammation might promote CSVD. Furthermore, neuroinflammation could be a shared pathogenesis of CSVD and AD at the early stage. Targeting neuroinflammation to intervene the progression of CSVD and AD warrants further investigation.

Uncovering the Oxidative Stress Mechanisms and Targets in Alzheimers Disease by Integrating Phenotypic Screening Data and Polypharmacology Networks.

The oxidative stress hypothesis is challenging the dominant position of amyloid-β (Aβ) in the field of understanding the mechanisms of Alzheimers disease (AD), a complicated and untreatable neurodegenerative disease. The goal of the present study was to uncover the oxidative stress mechanisms causing AD, as well as the potential therapeutic targets and neuroprotective drugs against oxidative stress mechanisms. In this study, a systematic workflow combining pharmacological experiments and computational prediction were proposed. 222 drugs and natural products were collected first and then tested on SH-SY5Y cells to obtain phenotypic screening data on neuroprotection. The preliminary screening data were integrated with drug-target interactions (DTIs) and multi-scale biomedical data, which were analyzed with statistical tests and gene set enrichment analysis. A polypharmacology network was further constructed for investigation. 340 DTIs were matched in multiple databases, and 222 cell viability ratios were calculated for experimental compounds. We identified significant potential therapeutic targets based on oxidative stress mechanisms for AD, including NR3C1, SHBG, ESR1, PGR, and AVPR1A, which might be closely related to neuroprotective effects and pathogenesis. 50% of the top 14 enriched pathways were found to correlate with AD, such as arachidonic acid metabolism and neuroactive ligand-receptor interaction. Several approved drugs in this research were also found to exert neuroprotective effects against oxidative stress mechanisms, including beclometasone, methylprednisolone, and conivaptan. Our results indicated that NR3C1, SHBG, ESR1, PGR, and AVPR1A were promising therapeutic targets and several drugs may be repurposed from the perspective of oxidative stress and AD.

Liver-Specific Polygenic Risk Score Is Associated with Alzheimers Disease Diagnosis.

Our understanding of the pathophysiology underlying Alzheimers disease (AD) has benefited from genomic analyses, including those that leverage polygenic risk score (PRS) models of disease. The use of functional annotation has been able to improve the power of genomic models. We sought to leverage genomic functional annotations to build tissue-specific AD PRS models and study their relationship with AD and its biomarkers. We built 13 tissue-specific AD PRS and studied the scores relationships with AD diagnosis, cerebrospinal fluid (CSF) amyloid, CSF tau, and other CSF biomarkers in two longitudinal cohort studies of AD. The AD PRS model that was most predictive of AD diagnosis (even without APOE) was the liver AD PRS n 1,115 odds ratio 2.15 (1.67-2.78), p 3.62×10-9. The liver AD PRS was also statistically significantly associated with cerebrospinal fluid biomarker evidence of amyloid-β (Aβ 42Aβ 40 ratio, p 3.53×10-6) and the phosphorylated tauamyloid-β ratio (p 1.45×10-5). These findings provide further evidence of the role of the liver-functional genome in AD and the benefits of incorporating functional annotation into genomic research.

Type 2 Diabetes Mellitus and its comorbidity, Alzheimers disease Identifying critical microRNA using machine learning.

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

Recent Treatment Strategies in Alzheimers Disease and Chronic Traumatic Encephalopathy.

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 Alzheimers 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.

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.

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 Alzheimers disease and related dementias. This mixed methods study identifies and compares areas of guilt most frequently experienced by spouse and adult child caregivers (N83) 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.

Isoniazid improves cognitive performance, clears Aβ plaques, and protects dendritic synapses in APPPS1 transgenic mice.

Alzheimers disease (AD) is characterized by amyloid β (Aβ) aggregation and neuroinflammation. This study aimed to investigate the therapeutic effect of isoniazid (INH) against AD. The APPPS1 transgenic mouse model of AD was adopted. The APPPS1 mice received oral INH (45 mgkgd) for 14 days. The cognitive capability was assessed by the Morris Water Maze test. Amyloid plaques and Aβ levels were determined by immunohistochemistry and ELISA assay. The dendritic spines were analyzed by DiOlistic labeling. Immunofluorescence staining was used to observe the microglia and astrocytes. The Morris Water Maze test suggested that INH administration can effectively attenuate the reference memory deficit and improve the working memory of the APPPS1 mice compared to the untreated mice (all Isoniazid administration effectively improved cognitive performance, cleared Aβ plaques, protected dendritic synapses, and reduced innate immune cells around the Aβ plaques, suggesting that INH could be a potential drug for AD treatment.

Genetic Risk for Alzheimer Disease and Plasma Tau Are Associated With Accelerated Parietal Cortex Thickness Change in Middle-Aged Adults.

Neuroimaging and biomarker studies in Alzheimer disease (AD) have shown well-characterized patterns of cortical thinning and altered biomarker concentrations of tau and β-amyloid (Aβ). However, earlier identification of AD has great potential to advance clinical care and determine candidates for drug trials. The extent to which AD risk markers relate to cortical thinning patterns in midlife is unknown. The first objective of this study was to examine cortical thickness change associated with genetic risk for AD among middle-aged military veterans. The second objective was to determine the relationship between plasma tau and Aβ and change in brain cortical thickness among veterans stratified by genetic risk for AD. Participants consisted of post-911 veterans (N 155) who were consecutively enrolled in the Translational Research Center for TBI and Stress Disorders prospective longitudinal cohort and were assessed for mild traumatic brain injury (TBI) and posttraumatic disorder (PTSD). Genome-wide polygenic risk scores (PRSs) for AD were calculated using summary results from the International Genomics of Alzheimers Disease Project. T-tau and Aβ40 and Aβ42 plasma assays were run using Simoa technology. Whole-brain MRI cortical thickness change estimates were obtained using the longitudinal stream of FreeSurfer. Follow-up moderation analyses examined the AD PRS × plasma interaction on change in cortical thickness in AD-vulnerable regions. Higher AD PRS, signifying greater genetic risk for AD, was associated with accelerated cortical thickness change in a right hemisphere inferior parietal cortex cluster that included the supramarginal gyrus, angular gyrus, and intraparietal sulcus. Higher tau, but not Aβ4240 ratio, was associated with greater cortical thickness change among those with higher AD PRS. Mild TBI and PTSD were not associated with cortical thickness change. Plasma tau, particularly when combined with genetic stratification for AD risk, can be a useful indicator of brain change in midlife. Accelerated inferior parietal cortex changes in midlife may be an important factor to consider as a marker of AD-related brain alterations.

High levels of kappa free light chain synthesis predict cognitive decline in relapsing-remitting multiple sclerosis.

Evolving evidence suggests that measurement of cerebrospinal fluid (CSF) kappa free light chain (KFLC) synthesis has high diagnostic sensitivity and specificity for multiple sclerosis (MS), but its prognostic ability is less investigated. The usefulness of KFLC in predicting cognitive impairment (CI) is still unknown. In a monocentric longitudinal retrospecitve cohort study, KFLC-index (CSF KFLCserum KFLCCSF albuminserum albumin) measured by latex-enhanced immunonephelometry was prospectively determined as part of the diagnostic workup in patients with early relapsing-remitting MS (RRMS, n77). The ability of KFLC-index to predict information processing speed (IPS) worsening as assessed with the symbol digit modalities test (SDMT) was investigated in univariable and multivariable models. In patients with KFLC-index>100 (n31), 11 subjects (35.5%) showed reduced SDMT scores by ≥8 points at follow-up (mean follow-up time 7.3 ± 2.6 years), compared with their baseline scores (p0.01). Baseline KFLC-index>100 was strongly associated with a higher hazard of SDMT score reduction at follow-up (adjusted hazard ratio 10.5, 95% confidence interval 2.2-50.8, p0.003 median time to SDMT reduction 7 years). Intrathecal KFLC synthesis has become an attractive diagnostic tool for MS. We show for the first time that in a real-world setting of early RRMS, KFLC-index predicted cognitive decline. Whether this predictive ability of KFLC-index also concerns other cognitive domains than IPS, warrants further investigations.

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Dendritic spinule-mediated structural synaptic plasticity Implications for development, aging, and psychiatric disease.

Dendritic spines are highly dynamic and changes in their density, size, and shape underlie structural synaptic plasticity in cognition and memory. Fine membranous protrusions of spines, termed dendritic spinules, can contact neighboring neurons or glial cells and are positively regulated by neuronal activity. Spinules are thinner than filopodia, variable in length, and often emerge from large mushroom spines. Due to their nanoscale, spinules have frequently been overlooked in diffraction-limited microscopy datasets. Until recently, our knowledge of spinules has been interpreted largely from single snapshots in time captured by electron microscopy. We summarize herein the current knowledge about the molecular mechanisms of spinule formation. Additionally, we discuss possible spinule functions in structural synaptic plasticity in the context of development, adulthood, aging, and psychiatric disorders. The literature collectively implicates spinules as a mode of structural synaptic plasticity and suggests the existence of morphologically and functionally distinct spinule subsets. A recent time-lapse, enhanced resolution imaging study demonstrated that the majority of spinules are small, short-lived, and dynamic, potentially exploring their environment or mediating retrograde signaling and membrane remodeling

Disruption of DYRK1A-induced hyperphosphorylation of amyloid-beta and tau protein in Alzheimers disease An integrative molecular modeling approach.

Alzheimers 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 kcalmol

Retracted Effect of Resveratrol Combined with Donepezil Hydrochloride on Inflammatory Factor Level and Cognitive Function Level of Patients with Alzheimers Disease.

This retracts the article DOI 10.115520229148650..

Longitudinal association between changes in resting-state network connectivity and cognition trajectories The moderation role of a healthy diet.

Healthy diet has been shown to alter brain structure and function and improve cognitive performance, and prior work from our group showed that Mediterranean diet (MeDi) moderates the effect of between-network resting-state functional connectivity (rsFC) on cognitive function in a cross-sectional sample of healthy adults. The current study aimed to expand on this previous work by testing whether MeDi moderates the effects of changes in between- and within-network rsFC on changes in cognitive performance over an average of 5 years. At baseline and 5-year follow up, 124 adults aged 20-80 years underwent resting state fMRI to measure connectivity within and between 10 pre-defined networks, and completed six cognitive tasks to measure each of four cognitive reference abilities (RAs) fluid reasoning (FLUID), episodic memory, processing speed and attention, and vocabulary. Participants were categorized into low, moderate, and high MeDi groups based on food frequency questionnaires (FFQs). Multivariable linear regressions were used to test relationships between MeDi, change in within- and between-network rsFC, and change in cognitive function. Results showed that MeDi group significantly moderated the effects of change in overall between-network and within-network rsFC on change in memory performance. Exploratory analyses on individual networks revealed that interactions between MeDi and between-network rsFC were significant for nearly all individual networks, whereas the moderating effect of MeDi on the relationship between within-network rsFC change and memory change was limited to a subset of specific functional networks. These findings suggest healthy diet may protect cognitive function by attenuating the negative effects of changes in connectivity over time. Further research is warranted to understand the mechanisms by which MeDi exerts its neuroprotective effects over the lifespan.

Limited Proteolysis-Mass Spectrometry Reveals Aging-Associated Changes in Cerebrospinal Fluid Protein Abundances and Structures.

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-PLA

Nanotechnology-based drug delivery for the treatment of CNS disorders.

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 Alzheimers disease, multiple sclerosis, epilepsy, and Parkinsons 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.

The pathogenesis of Alzheimers 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

Free complement and complement containing extracellular vesicles as potential biomarkers for neuroinflammatory and neurodegenerative disorders.

The complement system is implicated in a broad range of neuroinflammatory disorders such as Alzheimers 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.

The impact of a high-sodium diet regimen on cerebrovascular morphology and cerebral perfusion in Alzheimers disease.

Various lifestyle factors such as chronic hypertension and a high-sodium diet regimen are shown to impact cerebrovascular morphology and structure. Unusual cerebrovascular morphological and structural changes may contribute to cerebral hypoperfusion in Alzheimers disease (AD). The objective of this study was to examine whether a high-sodium diet mediates cerebrovascular morphology and cerebral perfusion alterations in AD. Double transgenic mice harboring Aβ precursor protein (APPswe) and presenilin-1 (PSEN1) along with wild-type controls were divided into four groups. Group A (APPPS1) and B (controls) were both fed a high-sodium (4.00%), while group C (APPPS1) and D (controls) were both fed a low-sodium (0.08% a regular chow diet) for three months. Then, changes in regional cerebral perfusion and diffusion, cerebrovascular morphology, and structure were quantified. A 3-month high-sodium diet causes pyknosis and deep staining in hippocampal neurons and reduced vascular density in both hippocampal and cortical areas ( A high-sodium diet regimen causes cerebrovascular morphology alteration in APPPS1 mouse model of AD.

Toward attention-based learning to predict the risk of brain degeneration with multimodal medical data.

Brain degeneration is commonly caused by some chronic diseases, such as Alzheimers 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). 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. 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. The prediction performance is significantly better than the benchmarks, including MRI-only, EHR-only, and state-of-the-art multimodal fusion methods.

Weakly supervised learning analysis of Aβ plaque distribution in the whole rat brain.

Alzheimers 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.

Glucagon-Like Peptide 1 Therapy From Discovery to Type 2 Diabetes and Beyond.

The therapeutic benefits of the incretin hormone, glucagon-like peptide 1 (GLP1), for people with type 2 diabetes andor obesity, are now firmly established. The evidence-base arising from head-to-head comparative effectiveness studies in people with type 2 diabetes, as well as the recommendations by professional guidelines suggest that GLP1 receptor agonists should replace more traditional treatment options such as sulfonylureas and dipeptidyl-peptidase 4 (DPP4) inhibitors. Furthermore, their benefits in reducing cardiovascular events in people with type 2 diabetes beyond improvements in glycaemic control has led to numerous clinical trials seeking to translate this benefit beyond type 2 diabetes. Following early trial results their therapeutic benefit is currently being tested in other conditions including fatty liver disease, kidney disease, and Alzheimers disease.

New Perspectives of Taxifolin in neurodegenerative diseases.

Neurodegenerative diseases, such as Alzheimers disease (AD), Parkinsons disease (PD), Cerebral amyloid angiopathy (CAA) and Huntingtons disease (HD), are characterized by cognitive and motor dysfunctions and neurodegeneration. These diseases become more severe over time and cannot be cured currently. Until now, most treatments for these diseases are only used to relieve the symptoms. Taxifolin (TAX), 3, 5, 7, 3, 4-pentahydroxy flavanone, also named dihydroquercetin, is a compound derived primarily from Douglas fir and Larix gemelini. TAX has been confirmed to present various pharmacological activities, including anti-inflammation, anti-cancer, anti-virus and regulation of oxidative stress effects. In central nervous system, TAX is demonstrated to inhibit Aβ fibril formation, protect neurons and improve cerebral blood flow, cognitive ability and dyskinesia. At present, TAX is only applied as a health additive in clinical practice. This review aimed to summarize the application of TAX in neurodegenerative diseases and the underlying neuroprotective mechanisms, such as suppressing inflammation, attenuating oxidative stress, preventing Aβ protein formation, maintaining dopamine levels and thus reducing neuronal loss.

Roles of Microglia in AD Pathology.

Amyloid plaques and neurofibrillary tangles are two main characteristics of Alzheimers disease (AD). As cerebral resident phagocytes, microglia have different roles in Aβ pathology and tau pathology. In this review, we discuss microglial functions in the formation, clearance, and spread of Aβ and tau. Many receptors and enzymes, which are related to microglia, participate in AD pathologies and thus are thought to be potential targets of AD. So, making use of microglia can be beneficial to confine AD pathologies. To sum up, we review the roles of microglia in AD pathology and possible corresponding treatments.

Stroke and Vascular Cognitive Impairment The Role of Intestinal Microbiota Metabolite TMAO.

The gut microbiome interacts with the brain bidirectionally through the microbiome-gut-brain axis, which plays a key role in regulating various nervous system pathophysiological processes. Trimethylamine N-oxide (TMAO) is produced by choline metabolism through intestinal microorganisms, which can cross the blood-brain barrier to act on the central nervous system. Previous studies have shown that elevated plasma TMAO concentrations increase the risk of major adverse cardiovascular events, but there are few studies on TMAO in cerebrovascular disease and vascular cognitive impairment. This review summarized a decade of research on the impact of TMAO on stroke and related cognitive impairment, with particular attention to the effects on vascular cognitive disorders. We demonstrated that TMAO has a marked impact on the occurrence, development, and prognosis of stroke by regulating cholesterol metabolism, foam cell formation, platelet hyperresponsiveness and thrombosis, and promoting inflammation and oxidative stress. TMAO can also influence the cognitive impairment caused by Alzheimers disease and Parkinsons disease via inducing abnormal aggregation of key proteins, affecting inflammation and thrombosis. However, although clinical studies have confirmed the association between the microbiome-gut-brain axis and vascular cognitive impairment (cerebral small vessel disease and post-stroke cognitive impairment), the molecular mechanism of TMAO has not been clarified, and TMAO precursors seem to play the opposite role in the process of post-stroke cognitive impairment. In addition, several studies have also reported the possible neuroprotective effects of TMAO. Existing therapies for these diseases targeted to regulate intestinal flora and its metabolites have shown good efficacy. TMAO is probably a new target for early prediction and treatment of stroke and vascular cognitive impairment.

Acridine A Scaffold for the development of drugs for Alzheimers disease.

Alzheimers disease (AD) is drawing scientists consideration, being one of the gravest diseases mankind will have to battle against in the near future. The number of people with AD is expected to triple in the next 40 years. It is a most common age-related multifactorial neurodegenerative disease and characterized by two histopathological hallmarks the formation of senile plaques composed of the amyloid-β (Aβ) peptide and neurofibrillary tangles composed of hyperphosphorylated tau protein. Discovery and development of rationally designed multi-targeted ligands for the management of AD could be more beneficial than classical single targeted molecules. Acridine, a heterocyclic nucleus is a sole moiety in various existing drug molecules such as quinacrine (antimalarial), acriflavine and proflavine (antiseptics), ethacridine (abortifacient), amsacrine and nitracine (anticancer) and tacrine (anti-Alzheimer). It is proposed that acridine may combat the AD by acting on several targets like acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), dual specificity tyrosine kinase 1A (Dyrk 1A), amyloid and prion protein (PrPC) etc. involved in its pathogenesis. The main aim of this compilation is to review the most promising therapeutic developments within the vast research area dealing with acridine derivatives. Further research is required to evaluate the effectiveness of the acridine derivatives with various substitutions in the treatment of AD. In conclusion, our review will suggest the potentiality of the versatile acridine framework for drug designing and developing novel multi-target inhibitors for the Alzheimers disease.

Targeting galectin-3 to counteract spike-phase uncoupling of fast-spiking interneurons to gamma oscillations in Alzheimers disease.

Alzheimers disease (AD) is a progressive multifaceted neurodegenerative disorder for which no disease-modifying treatment exists. Neuroinflammation is central to the pathology progression, with evidence suggesting that microglia-released galectin-3 (gal3) plays a pivotal role by amplifying neuroinflammation in AD. However, the possible involvement of gal3 in the disruption of neuronal network oscillations typical of AD remains unknown. Here, we investigated the functional implications of gal3 signaling on experimentally induced gamma oscillations ex vivo (20-80 Hz) by performing electrophysiological recordings in the hippocampal CA3 area of wild-type (WT) mice and of the 5×FAD mouse model of AD. In addition, the recorded slices from WT mice under acute gal3 application were analyzed with RT-qPCR to detect expression of some neuroinflammation-related genes, and amyloid-β (Aβ) plaque load was quantified by immunostaining in the CA3 area of 6-month-old 5×FAD mice with or without Gal3 knockout (KO). Gal3 application decreased gamma oscillation power and rhythmicity in an activity-dependent manner, which was accompanied by impairment of cellular dynamics in fast-spiking interneurons (FSNs) and pyramidal cells. We found that the gal3-induced disruption was mediated by the gal3 carbohydrate-recognition domain and prevented by the gal3 inhibitor TD139, which also prevented Aβ42-induced degradation of gamma oscillations. Furthermore, the 5×FAD mice lacking gal3 (5×FAD-Gal3KO) exhibited WT-like gamma network dynamics and decreased Aβ plaque load. We report for the first time that gal3 impairs neuronal network dynamics by spike-phase uncoupling of FSNs, inducing a network performance collapse. Moreover, our findings suggest gal3 inhibition as a potential therapeutic strategy to counteract the neuronal network instability typical of AD and other neurological disorders encompassing neuroinflammation and cognitive decline.

Genetic correlation and gene-based pleiotropy analysis for four major neurodegenerative diseases with summary statistics.

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 Alzheimers disease (AD), Parkinsons 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.

Influence of cognitive reserve on cognitive and motor function in α-synucleinopathies A systematic review protocol.

Cognitive reserve has been used to justify neuropathologically unexplainable mismatches in Alzheimers disease outcomes. Recent evidence has suggested this effect may be replicable across other conditions. However, it is still unclear whether cognitive reserve applies to α-synucleinopathies or to motor outcomes, or if medication confounds effects. This review protocol follows PRISMA-P guidelines and aims to investigate whether cognitive reserve can predict both cognitive and motor outcomes for α-synucleinopathy patients. MEDLINE (via PubMed), Scopus, psycINFO (via Ovid), CINAHL (via EBSCO), and Web of Science have been searched. Cross-sectional, cohort, case-control, and longitudinal studies investigating the association between cognitive reserve and cognitive andor motor outcomes for Parkinsons disease, dementia with Lewy bodies, or multiple system atrophy will be included. Reviewers will independently perform screening, while also extracting data, assessing the risk of bias (using a version of the Quality in Prognostic Studies tool), and rating evidence quality (using GRADE). If possible, random-effects meta-analyses will be conducted for each unique outcome variable and α-synucleinopathy otherwise, a narrative synthesis will be performed. Depending on the number of studies, exploratory analyses may involve meta-regression to assess potential confounding effects. Understanding the broader protective effect of cognitive reserve has significant implications for preventive interventions in the wider population.

Deep neural network heatmaps capture Alzheimers disease patterns reported in a large meta-analysis of neuroimaging studies.

Deep neural networks currently provide the most advanced and accurate machine learning models to distinguish between structural MRI scans of subjects with Alzheimers disease and healthy controls. Unfortunately, the subtle brain alterations captured by these models are difficult to interpret because of the complexity of these multi-layer and non-linear models. Several heatmap methods have been proposed to address this issue and analyze the imaging patterns extracted from the deep neural networks, but no quantitative comparison between these methods has been carried out so far. In this work, we explore these questions by deriving heatmaps from Convolutional Neural Networks (CNN) trained using T1 MRI scans of the ADNI data set and by comparing these heatmaps with brain maps corresponding to Support Vector Machine (SVM) activation patterns. Three prominent heatmap methods are studied Layer-wise Relevance Propagation (LRP), Integrated Gradients (IG), and Guided Grad-CAM (GGC). Contrary to prior studies where the quality of heatmaps was visually or qualitatively assessed, we obtained precise quantitative measures by computing overlap with a ground-truth map from a large meta-analysis that combined 77 voxel-based morphometry (VBM) studies independently from ADNI. Our results indicate that all three heatmap methods were able to capture brain regions covering the meta-analysis map and achieved better results than SVM activation patterns. Among them, IG produced the heatmaps with the best overlap with the independent meta-analysis.

L-type calcium channel antagonist isradipine age-dependently decreases plaque associated dystrophic neurites in 5XFAD mouse model.

Epidemiological studies suggest that L-type calcium channel (LTCC) antagonists may reduce the incidence of age-associated neurodegenerative diseases including Alzheimers disease (AD). However, the neuroprotective mechanism of LTCC antagonists is unknown. Amyloid-β (Aβ) pathology disrupts intracellular calcium signaling, which regulates lysosomes and microglial responses. Neurons near Aβ plaques develop dystrophic neurites, which are abnormal swellings that accumulate lysosomes. Further, microglia accumulate around Aβ plaques and secrete inflammatory cytokines. We hypothesized that antagonism of LTCCs with isradipine would reduce Aβ plaque-associated dystrophic neurites and inflammatory microglia in the 5XFAD mouse model by restoring normal intracellular calcium regulation. To test this hypothesis, we treated 6- and 9-month-old 5XFAD mice with isradipine and tested behavior, examined Aβ plaques, microglia, and dystrophic neurites. We found that isradipine treatment age-dependently reduces dystrophic neurites and leads to trending decreases in Aβ but does not modulate plaque associated microglia regardless of age. Our findings provide insight into how antagonizing LTCCs alters specific cell types in the Aβ plaque environment, providing valuable information for potential treatment targets in future AD studies.

Erythropoietin ameliorates cognitive deficits by improving hippocampal and synaptic damage in streptozotocin-induced diabetic mice.

Recent studies have shown that erythropoietin (EPO) is an effective neuroprotective and neurotrophic agent for neurological disorders, such as traumatic brain injury and Alzheimers disease. However, the effectiveness of EPO administration against diabetic cognitive impairments has rarely been examined. In this study, we investigated the effects of EPO on streptozotocin (STZ)-induced male C57BL6 J mice. Then, we sought to clarify the mechanisms of EPO-mediated neuroprotection in high-glucose (HG)-stimulated HT22 cells. In vivo, we found that STZ-induced diabetic mice showed impaired spatial learning and memory, which was alleviated by EPO treatment. EPO also significantly lowered elevated fasting blood glucose levels, improved pancreatic and hippocampal damage, and restored oxidative stress in the STZ-induced diabetic mice. In vitro, EPO markedly increased cell viability, restrained the expression of pro-apoptotic Bax, enhanced the expression of pro-caspase 3, anti-apoptotic Bcl-2, brain-derived neurotrophic factor (BDNF) and postsynaptic density 95 (PSD-95), and attenuated the upregulation of N-methyl-d-aspartic acid (NMDA) receptor subunits NR1, NR2A and NR2B in HG-induced HT22 cells. The protective effects of EPO was obviously abolished by treatment with an NMDA receptor agonist. Our findings revealed that EPO impedes hippocampal and synaptic damage and neuronal apoptosis by regulating BDNF and PSD-95 expression through NMDA receptors, thereby ameliorating cognitive impairments in mice with T1DM.

Prototype-guided multi-scale domain adaptation for Alzheimers disease detection.

Alzheimers disease (AD) is the most common form of dementia and there is no effective treatment currently. Using artificial intelligence technology to assist the diagnosis and intervention as early as possible is of great significance to delay the development of AD. Structural Magnetic Resonance Imaging (sMRI) has shown great practical values on computer-aided AD diagnosis. Affected by data from different sources or acquisition domains in realistic scenarios, MRI data often suffer from domain shift problem. In this paper, we propose a deep Prototype-Guided Multi-Scale Domain Adaptation (PMDA) framework to handle MRI data with domain shift problem, and realize automatic auxiliary diagnosis of AD, Mild Cognitive Impairment (MCI) and Cognitively Normal (CN). PMDA is composed of three modules (1) MRI multi-scale feature extraction module combines the advantages of 3D convolution and self-attention to effectively extract multi-scale features in high-dimensional space, (2) Prototype Maximum Density Divergence (Pro-MDD) module adopts prototype learning to constrain the feature outlier samples in a mini-batch when MDD is used to align source domain and target domain, and (3) Adversarial Domain Adaptation module is applied to achieve global feature alignment of the source domain and target domain and co-training two distinctive discriminators to mitigate the over-fitting issue. Experiments have been performed on 3T and 1.5T sMRI with domain shift in ADNI dataset. The experimental results demonstrated that the proposed framework PMDA outperforms supervised learning methods and several state-of-the-art domain adaptation methods and achieves a superior accuracy of 92.11%, 76.01% and 82.37% on AD vs. CN, AD vs. MCI, and MCI vs. CN tasks, respectively.

Enzyme colorimetric cellulose membrane bioactivity strips based on acetylcholinesterase immobilization for inhibitors preliminary screening.

To quickly screen the active pharmaceutical ingredient that can be used as acetylcholinesterase inhibitors (AChEIs) to treat Alzheimers disease, an enzyme colorimetric cellulose membrane bioactivity strip (CBS) was developed for simple and rapid screening of AChEIs. The amino group of acetylcholinesterase (AChE) undergoes Schiff base reaction with the aldehyde group on the oxidized cellulose membranes, then the AChE was covalently cross-linking on the surface of cellulose membranes, enabling the screening based on Ellmans enzyme colorimetric method. When the enzyme activity of AChE was inhibited after incubation with inhibitors, the hydrolysis of S-Acetylthiocholine iodide decreased, consequently, the 5-thio-2-nitrobenzoic acid generated by the reaction with 5,5-dithiobis (2-nitrobenzoic acid) also decreased, leading to a decreased color intensity. In addition, CBSs had fast chromogenic time, excellent specificity, and extraordinary storage stability. Tacrine and Donepezil were used as representative inhibitors during the detection, while their IC

The sleep and wake electroencephalogram over the lifespan.

Both sleep and wake encephalograms (EEG) change over the lifespan. While prior studies have characterized age-related changes in the EEG, the datasets span a particular age group, or focused on sleep and wake macrostructure rather than the microstructure. Here, we present sex-stratified data from 3372 community-based or clinic-based otherwise neurologically and psychiatrically healthy participants ranging from 11 days to 80 years of age. We estimate age norms for key sleep and wake EEG parameters including absolute and relative powers in delta, theta, alpha, and sigma bands, as well as sleep spindle density, amplitude, duration, and frequency. To illustrate the potential use of the reference measures developed herein, we compare them to sleep EEG recordings from age-matched participants with Alzheimers disease, severe sleep apnea, depression, osteoarthritis, and osteoporosis. Although the partially clinical nature of the datasets may bias the findings towards less normal and hence may underestimate pathology in practice, age-based EEG reference values enable objective screening of deviations from healthy aging among individuals with a variety of disorders that affect brain health.

Neural atrophy produced by AAV tau injections into hippocampus and anterior cortex of middle-aged mice.

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

Distinguishing apathy from depression A review differentiating the behavioral, neuroanatomic, and treatment-related aspects of apathy from depression in neurocognitive disorders.

This narrative review describes the clinical features of apathy and depression in individuals with neurocognitive disorders (NCDs), with the goal of differentiating the two syndromes on the basis of clinical presentation, diagnostic criteria, neuropathological features, and contrasting responses to treatments. Literature was identified using PubMed, with search terms to capture medical conditions of interest additional references were also included based on our collective experience and knowledge of the literature. Evidence from current literature supports the distinction between the two disorders apathy and depression occur with varying prevalence in individuals with NCDs, pose different risks of progression to dementia, and have distinct, if overlapping, neurobiological underpinnings. Although apathy is a distinct neuropsychiatric syndrome, distinguishing apathy from depression can be challenging, as both conditions may occur concurrently and share several overlapping features. Apathy is associated with unfavorable outcomes, especially those with neurodegenerative etiologies (e.g., Alzheimers disease) and is associated with an increased burden for both patients and caregivers. Diagnosing apathy is important not only to serve as the basis for appropriate treatment, but also for the development of novel targeted interventions for this condition. Although there are currently no approved pharmacologic treatments for apathy, the research described in this review supports apathy as a distinct neuropsychiatric condition that warrants specific treatments aimed at alleviating patient disability. Despite differences between these disorders, both apathy and depression pose significant challenges to patients, their families, and caregivers better diagnostics are needed to develop more tailored treatment and support.

Chemical shift assignments of calmodulin bound to the GluN1 C0 domain (residues 841-865) of the NMDA receptor.

Neuroplasticity and synaptic transmission in the brain are regulated by N-methyl-D-aspartate receptors (NMDARs) that consist of hetero-tetrameric combinations of the glycine-binding GluN1 and glutamate-binding GluN2 subunits. Calmodulin (CaM) binds to the cytosolic C0 domain of GluN1 (residues 841-865) that may play a role in the Ca

Designing an interprofessional dementia specialty clinic Conceptualization and evaluation of a patient-centered model.

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.

The EtOH extracts of the leaves of two new cultivars (Uysal-SFU and Turgut-SFT) of Salvia fruticosa Mill. was tested against acetylcholinesterase (IC50 30.62 ± 3.27 and 32.97 ± 2.33 µgmL for SFU and SFT, respectively) and butyrylcholinesterase (IC50 69.91 ± 1.08 µgmL and 86.55 ± 1.26 µgmL), respectively, relevant to Alzheimers disease. The essential oils showed a stumpy inhibition against AChE and no inhibition against BChE. DPPH radical scavenging activity of the extracts (86.70 ± 0.17% and 86.14 ± 1.13% for SFU and SFT, respectively) was stronger than that of quercetin (85.51 ± 0.17%) Their (1.24 ± 0.05 and 1.04 ± 0.16 for SFU and SFT, respectively) ferric-reducing antioxidant power were close to that of the reference (e.g. quercetin, 1.42 ± 0.14). Molecular docking simulations were performed on their major monoterpenes. Our findings revealed that the leaf EtOH extracts of two cultivars are promising inhibitors of both AChE and BChE.

Outcome of epidural blood patch for imaging-negative spontaneous intracranial hypotension.

Spontaneous intracranial hypotension is diagnosed by an abnormal finding in brain MRI, spinal imaging, or lumbar puncture. However, the sensitivity of each test is low. We investigated whether patients with suspected spontaneous intracranial hypotension and negative imaging findings would respond to epidural blood patch. We prospectively recruited patients with new-onset orthostatic headache admitted at the Samsung Medical Center from January 2017 to July 2021. In patients without abnormal imaging findings and no history of prior epidural blood patch, treatment outcome-defined as both 50% response in maximal headache intensity and improvement of orthostatic component-was collected at discharge and three months after epidural blood patch. We included 21 treatment-naïve patients with orthostatic headache and negative brain and spinal imaging results who received epidural blood patch. After epidural blood patch (mean 1.3 times, range 1-3), 14 (66.7%) and 19 (90.5%) patients achieved both 50% response and improvement of orthostatic component at discharge and three months post-treatment, respectively. Additionally, complete remission was reported in 11 (52.4%) patients at three-month follow-up, while most of the remaining patients had only mild headaches. Among nine (42.9%) patients who underwent lumbar puncture, none had an abnormally low opening pressure (median 13.8 cm H Given the high responder rates of epidural blood patch in our study, empirical epidural blood patch should be considered to treat new-onset orthostatic headache, even when brain and spinal imaging are negative. The necessity of lumbar puncture is questionable considering the high response rate of epidural blood patch and low rate of low pressure.

Noncanonical regulation of imprinted gene Igf2 by amyloid-beta 1-42 in Alzheimers disease.

Reduced insulin-like growth factor 2 (IGF2) levels in Alzheimers disease (AD) may be the mechanism relating age-related metabolic disorders to dementia. Since Igf2 is an imprinted gene, we examined age and sex differences in the relationship between amyloid-beta 1-42 (Aβ

New balance capability index as a screening tool for mild cognitive impairment.

Mild cognitive impairment (MCI) is not just a prodrome to dementia, but a very important intervention point to prevent dementia caused by Alzheimers disease (AD). It has long been known that people with AD have a higher frequency of falls with some gait instability. Recent evidence suggests that vestibular impairment is disproportionately prevalent among individuals with MCI and dementia due to AD. Therefore, we hypothesized that the measurement of balance capability is helpful to identify individuals with MCI. First, we developed a useful method to evaluate balance capability as well as vestibular function using Nintendo Wii balance board as a stabilometer and foam rubber on it. Then, 49 healthy volunteers aged from 56 to 75 with no clinically apparent cognitive impairment were recruited and the association between their balance capability and cognitive function was examined. Cognitive functions were assessed by MoCA, MMSE, CDR, and TMT-A and -B tests. The new balance capability indicator, termed visual dependency index of postural stability (VPS), was highly associated with cognitive impairment assessed by MoCA, and the area under the receiver operating characteristic (ROC) curve was more than 0.8, demonstrating high sensitivity and specificity (app. 80% and 60%, respectively). Early evidence suggests that VPS measured using Nintendo Wii balance board as a stabilometer helps identify individuals with MCI at an early and preclinical stage with high sensitivity, establishing a useful method to screen MCI.

Functional genomics identify causal variant underlying the protective CTSH locus for Alzheimers disease.

Alzheimers disease (AD) is the most prevalent age-related neurodegenerative disease, which has a high heritability of up to 79%. Exploring the genetic basis is essential for understanding the pathogenic mechanisms underlying AD development. Recent genome-wide association studies (GWASs) reported an AD-associated signal in the Cathepsin H (CTSH) gene in European populations. However, the exact functionalcausal variant(s), and the genetic regulating mechanism of CTSH in AD remain to be determined. In this study, we carried out a comprehensive study to characterize the role of CTSH variants in the pathogenesis of AD. We identified rs2289702 in CTSH as the most significant functional variant that is associated with a protective effect against AD. The genetic association between rs2289702 and AD was validated in independent cohorts of the Han Chinese population. The CTSH mRNA expression level was significantly increased in AD patients and AD animal models, and the protective allele T of rs2289702 was associated with a decreased expression level of CTSH through the disruption of the binding affinity of transcription factors. Human microglia cells with CTSH knockout showed a significantly increased phagocytosis of Aβ peptides. Our study identified CTSH as being involved in AD genetic susceptibility and uncovered the genetic regulating mechanism of CTSH in pathogenesis of AD.

Brain-neuron targeted nanoparticles for peptide synergy therapy at dual-target of Alzheimers disease.

Since the complex interactions of multiple mechanisms involved in Alzheimers disease (AD) preclude the monotherapeutic approaches from clinical application, combination therapy has become an attractive strategy for AD treatment. However, to be emphasized, the realization of the edges of combination therapy greatly depends on the reasonable choice of targets and the rational design of combination scheme. Acknowledgedly, amyloid plaques and hyperphosphorylated tau (p-tau) are two main hallmarks in AD with close pathological correlations, implying the hopeful prospect of combined intervention in them for AD treatment. Herein, we developed the nano-combination system, neuron-targeting PEG-PLA nanoparticles (CT-NP) loading two peptide drugs H102, a β-sheet breaker acting on Aβ, and NAP, a microtubule stabilizer acting on p-tau. Compared with free peptide combination, nano-combination system partly aligned the in vivo behaviors of combined peptides and enhanced peptide accumulation in lesion neurons by the guidance of targeting peptide CGN and Tet1, facilitating the therapeutic performance of peptide combination. Further, to maximize the therapeutic potential of nano-combination system, the combination ratio and mode were screened by the quantitative evaluation with combination index and U test, respectively, in vitro and in vivo. The results showed that the separated-loading CT-NP at the combination molar ratio of 21 (H102NAP), CT-NPH102 CT-NPNAP(21), generated the strongest synergistic therapeutic effects on Aβ, p-tau and their linkage, and effectually prevented neuroinflammation, reversed the neuronal damage and restored cognitive performance in 3 × Tg-AD transgenic mice. Our studies provide critical data on the effectiveness of nano-combination therapy simultaneously intervening in Aβ and p-tau, confirming the promising application of nano-combination strategy in AD treatment.

lncRNA NEAT1 Key player in neurodegenerative diseases.

Neurodegenerative diseases are the most common causes of disability worldwide. Given their high prevalence, devastating symptoms, and lack of definitive diagnostic tests, there is an urgent need to identify potential biomarkers and new therapeutic targets. Long non-coding RNAs (lncRNAs) have recently emerged as powerful regulatory molecules in neurodegenerative diseases. Among them, lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) has been reported to be upregulated in Alzheimers disease (AD), Parkinsons disease (PD), Huntingtons disease (HD), and amyotrophic lateral sclerosis (ALS). However, whether this is part of a protective or harmful mechanism is still unclear. This review summarizes our current knowledge of the role of NEAT1 in neurodegenerative diseases and its association with the characteristic aggregation of misfolded proteins amyloid-β and tau in AD, α-synuclein in PD, mutant huntingtin in HD, and TAR DNA-binding protein-43 fused in sarcomatranslocated in liposarcoma in ALS. The aim of this review is to stimulate further research on more precise and effective treatments for neurodegenerative diseases.

An insight into the TAM system in Alzheimers disease.

The TAM receptors may help delay the progression of Alzheimers disease (AD). AD is the most common neurodegenerative disease associated with human aging. The TAM receptors, derived from the first letter of its three constituents -Tyro3, Axl, and Mertk, are associated with immune responses, cellular differentiation and migration, and clearance of apoptotic cells and debris, with the two canonical ligands, Growth Arrest Specific 6 (Gas6) and ProS1. Several kinds of research have indicated the participation of the TAM system in AD pathology. Also, the TAMs regulate multiple features of microglia, the significant sensors of disorder in the central nervous system (CNS). In this review, we describe the biology of the TAM receptors and ligands in the CNS. Then, we discuss the relationship between the TAM system and AD, specially focusing on its functional expression in the microglia. Finally, we also summarize some agents that could interfere with the TAM signaling pathways and discuss potential difficulties and strategies for drug development.

Life-space mobility in older adults with Alzheimers-type dementia.

Mobility is an important component of functioning. Motor and cognitive impairment in older people with Alzheimers disease can exert a negative impact on life-space mobility. To compare life-space mobility in older adults with mild and moderate Alzheimer-type dementia and those without dementia and determine associations with health factors. Life-space mobility was assessed using the Life Space Assessment (LSA) in 33 older adults with Alzheimer-type dementia (AD group) and 24 older adults without dementia (WD group). The World Health Organization Disability Assessment Schedule (WHODAS 2.0), Addenbrookes Cognitive Examination (ACE-R), Geriatric Depression Scale (GDS), Modified Baecke Questionnaire for Older Adults (MBQOA), and Short Physical Performance Battery (SPPB) were completed. Statistical analysis was performed with unpaired t-test or Mann-Whitney tests for comparisons between groups and Spearmans correlation test. The AD group had a lower total LSA score compared to the WD group (44 vs 65, mean difference -20.7 95% CI -28.6, -12.9), 21% of the AD group were restricted to their homes when no assistance was available. In both groups, moderate correlations were found between LSA and both functioning and physical activity level. Symptoms of depression presented moderate correlation only in the WD group. Older adults with AD have lower life-space mobility and require assistance to achieve higher levels of mobility. LSA can help assess life-space mobility. Encouraging and enabling assistance is fundamental to a greater life-space for older adults with dementia.

Translationally controlled tumor protein restores impaired memory and altered synaptic protein expression in animal models of dementia.

This study describes the effects of translationally controlled tumor protein (TCTP) on mice with memory impairment caused by scopolamine (SCO) administration. Specifically, memory functions and expression levels of hippocampal synaptic proteins in 7- to 12-month-old SCO-treated wild-type (WT-SCO) mice were compared to those of TCTP-overexpressing (TG) and TCTP knocked-down (KD) mice similarly treated with SCO. Passive-avoidance tasks were performed with WT, TG, and KD mice for four weeks after intraperitoneal injection of SCO or saline followed by an acquisition test. After completing behavioral studies, hippocampi of all mice groups were collected and their synaptic protein contents were subjected to Western blotting or immunohistochemical analyses, and compared with those of 5x familial Alzheimers disease (5xFAD) mice and postmortem AD patients. Results of passive avoidance tests revealed that SCO-induced memory impairment was repaired in TCTP-TG mice, but not in TCTP-KD mice. Hippocampal expression levels of synaptophysin, synapsin-1, and PSD-95 were increased in TCTP-TG mice treated with SCO (TG-SCO) but decreased in TCTP-KD mice treated with SCO (KD-SCO). Decreased levels of TCTP, synaptophysin, and PSD-95 were also found in hippocampi of 5xFAD mice and AD patients. Expression levels of p-CREBCREB and brain-derived neurotrophic factor (BDNF) in TCTP-TG and TG-SCO mice were similar to or increased compared to those in WT mice, but decreased in TCTP-KD and KD-SCO mice. BDNF immunoreactivity was restored in CA1 regions of hippocampi of TG-SCO mice, but not in KD-SCO mice. These results suggest that TCTP can restore damaged memory in mice possibly through restored synaptic protein expression.

Efficacy of Artemisia annua Linné in improving cognitive impairment in a chronic cerebral hypoperfusion-induced vascular dementia animal model.

Vascular dementia (VaD) is the second most common type of dementia after Alzheimers disease. Currently, no FDA-approved drugs are available for the treatment of VaD. Artemisia annua Linné (AA) is known to have antioxidant properties, but its effects and mechanisms of action on cognitive impairment are still unknown. In this study, the improvement in cognitive impairment by AA in terms of protection against oxidative stress, neuroinflammation, and preservation of the integrity of the neurovascular unit (NVU) was assessed in an animal model of VaD with bilateral common carotid artery occlusion (BCCAO). Eight-week-old male Wistar rats were allowed to adapt for four weeks, and BCCAO was induced at 12 weeks of age. The rats were randomly assigned into four groups, with seven rats in each group sham group without BCCAO, VaD group that received oral administration of distilled water after BCCAO surgery, and two AA groups that received oral administration of 150 mgkg or 750 mgkg AA after BCCAO surgery for 8 weeks. Nine weeks after BCCAO surgery, the cognitive function of the rats was evaluated and accumulated oxidative stress was assessed by immunohistochemistry, immunofluorescence, and western blotting. Damage to the components of the NVU was evaluated, and sirtuin (Sirt) 1 and 2 expression and nuclear factor-erythrocyte 2-associated factor 2 (Nrf2)Kelch-like ECH-associated protein1 (Keap1) activation were investigated to assess the reduction in cell signaling and antioxidant pathways. BCCAO-induced cerebral perfusion decreased memory function and induced neuroinflammation and oxidative stress. But AA treatment mitigated cognitive impairment and reduced neuroinflammation and oxidative stress caused by chronic cerebral hypoperfusion. AA extracts activated the Nrf2Keap1activating antioxidant response elements pathway and maintained Sirt 1 and 2, subsequently leading to the maintenance of neurons, improved construct of microvessels, increased platelet-derived growth factor receptor beta, and platelet-endothelial cell adhesion molecule-1 associated with the blood-brain barrier integrity. AA is effective in alleviating BCCAO-induced cognitive decline and its administration may be a useful therapeutic approach for VaD.

The relationship between hippocampal amyloid beta burden and spatial distribution of neurofibrillary degeneration.

Neurofibrillary degeneration in Alzheimers disease (AD) typically involves the entorhinal cortex and CA1 subregion of the hippocampus early in the disease process, whereas in primary age-related tauopathy (PART), there is an early selective vulnerability of the CA2 subregion. Image analysis-based quantitative pixel assessments were used to objectively evaluate amyloid beta (Aβ) burden in the medial temporal lobe in relation to the distribution of hyperphosphorylated-tau (p-tau) in 142 cases of PART and AD. Entorhinal, CA1, CA3, and CA4 p-tau deposition levels are significantly correlated with Aβ burden, while CA2 p-tau is not. Furthermore, the CA2CA1 p-tau ratio is inversely correlated with Aβ burden and distribution. In addition, cognitive impairment is correlated with overall p-tau burden. These data indicate that the presence and extent of medial temporal lobe Aβ may determine the distribution and spread of neurofibrillary degeneration. The resulting p-tau distribution patterns may discriminate between PART and AD. Subregional hyperphosphorylated-tau (p-tau) distribution is influenced by hippocampal amyloid beta burden. Higher CA2CA1 p-tau ratio is predictive of primary age-related tauopathy-like neuropathology. Cognitive function is correlated with the overall hippocampal p-tau burden.

Identification of novel genes for age-at-onset of Alzheimers disease by combining quantitative and survival trait analyses.

Our understanding of the genetic predisposition for age-at-onset (AAO) of Alzheimers disease (AD) is limited. Here, we sought to identify genes modifying AAO and examined whether any have sex-specific effects. Genome-wide association analysis were performed on imputed genetic data of 9219 AD cases and 10,345 controls from 20 cohorts of the Alzheimers Disease Genetics Consortium. AAO was modeled from cases directly and as a survival outcome. We identified 11 genome-wide significant loci (P < 5 × 10 Genes that influence AAO of AD are excellent therapeutic targets for delaying onset of AD. Several loci identified include genes with promising functional implications for AD.

Living Arrangements and Education Duration Associated With Memory Clinic Attendance in Alzheimers Disease.

Some new outpatients with mild cognitive impairment (MCI) or Alzheimers disease (AD) do not regularly attend treatment appointments at memory clinics. To explore factors related to non-regular attendance, we divided new outpatients according to regular or non-regular attendance during the first 6 months of treatment and analyzed the relationship between individual patient factors and attendance. Approximately half of patients living alone did not regularly attend appointments. Living with family and longer duration of school education were significantly associated with regular attendance. Patients with mild or moderate AD attended appointments more regularly than patients with MCI or moderate-to-severe AD. Patients in Kyoto City had significantly better cognitive function than patients in satellite cities, and there were a significantly higher proportion of patients with MCI or AD at first visit in Kyoto City. Living arrangements and duration of education are important patient factors to consider to promote regular attendance at treatment appointments.

Preventive effect of Indian gooseberry (Phyllanthus emblica L.) fruit extract on cognitive decline in high-fat diet (HFD)-fed rats.

Methylglyoxal (MG)-derived advanced glycation end products (AGEs) directly bind to the receptor for advanced glycation end products (RAGE), subsequently exacerbating obesity and obesity-induced cognitive decline. Indian gooseberry (Phyllanthus emblica L.) fruit has antiobesity properties. However, the underlying mechanism by which Indian gooseberry fruit prevents obesity-induced cognitive decline remains unclear. This study aimed to investigate the preventive effect of a water extract of Indian gooseberry fruit (WEIG) and its bioactive compound gallic acid (GA) on the obesity-induced cognitive decline through MG suppression and gut microbiota modulation in high-fat diet (HFD)-fed rats. Trapping MG, WEIG, and GA significantly ameliorated fat accumulation in adipose tissue and learning and memory deficits. Mechanistically, WEIG and GA administration effectively reduced brain MG and AGE levels and subsequently reduced insulin resistance, inflammatory cytokines, MDA production, and Alzheimers disease-related proteins, but increased both antioxidant enzyme activities and anti-inflammatory cytokine with inhibiting RAGE, MAPK, and NF-κB levels in HFD-fed rats. Additionally, WEIG and GA supplementation increased the relative abundances of Bacteroidetes, Gammaproteobacteria, and Parasutterella, which negatively correlate with MG, inflammatory cytokine, and Alzheimers disease-related protein expressions. This novel finding provides a possible mechanism by which WEIG prevents obesity-induced cognitive decline through the gut-brain axis. This article is protected by copyright. All rights reserved.

The impact of depression on language function in individuals with Alzheimers disease a prepost-treatment design.

It is uncertain whether depression might affect cognitive function in Alzheimers disease (AD). Most of studies on the effect of depression treatment on cognitive function in AD were briefly evaluated by Mini-Mental State Examination (MMSE). MMSE is poor sensitive to detect cognitive change. This study examined the cognitive response to depression treatment in AD via multi-domain assessment. In addition, we explored whether effect of depression treatment in AD is different those of late-life depression (LLD). This study include AD patients with depression (AD D) and without depression (AD - D), LLD patients (LLD), and healthy controls (HC). The patients were treated according to their diagnosis for 16 weeks acetylcholinesterase inhibitors (AChEIs) and selective serotonin reuptake inhibitors (SSRIs) for AD D, AChEIs for AD - D, and SSRIs for LLD. The cognitive changes from pre- to post-treatment were compared between AD D and AD - D or LLD and HC. An independent sample t test was performed to compare the degree of change between the groups. Paired t tests were used to determine cognitive function changes in each depression treatment responder group. At baseline, AD D had more impairment in language function compared to AD - D, and LLD had greater deficit in executive function than HC. After depression treatment, more impaired cognitive domains at baseline were improved in AD D and LLD, respectively. Moreover, AD D showed an improvement in the global cognitive function (MMSE). Results indicated that language function was influenced by depression in AD, which is first evidence for specific cognitive domain related to depression in AD. Our finding indicates that depression could negatively impact cognitive function, and depression treatment may have beneficial cognitive effect in both AD and LLD. This study suggests the importance of early detection and treatment of depression in AD and LLD. Trial registration Clinical Research Information Service, CRIS, ID KCT0004041, Registered 5 June 2019, retrospectively registered after first patient enrollment date (4 March 2014) httpscris.nih.go.krcrissearchdetailSearch.doseq14140status5seqgroup14140searchpageM .

Plasma proteins related to inflammatory diet predict future cognitive impairment.

Dysregulation of the immune system and dietary patterns that increase inflammation can increase the risk for cognitive decline, but the mechanisms by which inflammatory nutritional habits may affect the development of cognitive impairment in aging are not well understood. To determine whether plasma proteins linked to inflammatory diet predict future cognitive impairment, we applied high-throughput proteomic assays to plasma samples from a subset (n 1528) of Womens Health Initiative Memory Study (WHIMS) participants (mean SD baseline age, 71.3 SD 3.8 years). Results provide insights into how inflammatory nutritional patterns are associated with an immune-related proteome and identify a group of proteins (CXCL10, CCL3, HGF, OPG, CDCP1, NFATC3, ITGA11) related to future cognitive impairment over a 14-year follow-up period. Several of these inflammatory diet proteins were also associated with dementia risk across two external cohorts (ARIC, ESTHER), correlated with plasma biomarkers of Alzheimers disease (AD) pathology (Aβ

Three-dimensional mapping in multi-samples with large-scale imaging and multiplexed post staining.

Dissection of the anatomical information at the single-cell level is crucial for understanding the organization rule and pathological mechanism of biological tissues. Mapping the whole organ in numerous groups with multiple conditions brings the challenges in imaging and analysis. Here, we describe an approach, named array fluorescent micro-optical sectioning tomography (array-fMOST), to identify the three-dimensional information at single-cell resolution from multi-samples. The pipeline contains array embedding, large-scale imaging, post-imaging staining and data analysis, which could image over 24 mouse brains simultaneously and collect the slices for further analysis. With transgenic mice, we acquired the distribution information of neuropeptide somatostatin neurons during natural aging and compared the changes in the microenvironments by multi-component labeling of serial sections with precise co-registration of serial datasets quantitatively. With viral labeling, we also analyzed the input circuits of the medial prefrontal cortex in the whole brain of Alzheimers disease and autism model mice. This pipeline is highly scalable to be applied to anatomical alterations screening and identification. It provides new opportunities for combining multi-sample whole-organ imaging and molecular phenotypes identification analysis together. Such integrated high-dimensional information acquisition method may accelerate our understanding of pathogenesis and progression of disease in situ at multiple levels.

Detection of β-amyloid peptide aggregates by quartz crystal microbalance based on dual-aptamer assisted signal amplification.

β-amyloid peptide (Aβ) aggregates are regarded as a typical neuropathology hallmark for the diagnosis of Alzheimers disease (AD). Aβ

Nicotines effect on cognition, a friend or foe

Tobacco smoking is a preventable cause of morbidity and mortality throughout the world. Smoking comes in form of absorption of many compounds, among which nicotine is the main psychoactive component of tobacco and its positive and negative reinforcement effects are proposed to be the key mechanism for the initiation and maintenance of smoking. Growing evidence suggests that the cognitive enhancement effects of nicotine may also contribute to the difficulty of quitting smoking, especially in individuals with psychiatric disorders. In this review, we first introduce the beneficial effect of nicotine on cognition including attention, short-term memory and long-term memory. We next summarize the beneficial effect of nicotine on cognition under pathological conditions, including Alzheimers disease, Parkinsons disease, Schizophrenia, Stress-induced Anxiety, Depression, and drug-induced memory impairment. The possible mechanism underlying nicotines effect is also explored. Finally, nicotines detrimental effect on cognition is discussed, including in the prenatal and adolescent periods, and high-dose nicotine- and withdrawal-induced memory impairment is emphasized. Therefore, nicotine serves as both a friend and foe. Nicotine-derived compounds could be a promising strategy to alleviate neurological disease-associated cognitive deficit, however, due to nicotines detrimental effect, continued educational programs and public awareness campaigns are needed to reduce tobacco use among pregnant women and smoking should be quitted even if it is e-cigarette, especially for the adolescents.

Gut-brain axis through the lens of gut microbiota and their relationships with Alzheimers disease pathology Review and recommendations.

Alzheimers disease (AD) is a neurodegenerative disorder that affects millions of people worldwide. Growing evidence suggests that the gut microbiome (GM) plays a pivotal role in the pathogenesis of AD through the microbiota-gut-brain axis (MGB). Alterations in GM composition and diversity have been observed in both animal models and in human patients with AD. GM dysbiosis has been implicated in increased intestinal permeability, blood-brain barrier (BBB) impairment, neuroinflammation and the development of hallmarks of AD. Further elucidation of the role of GM in AD could pave way for the development of holistic predictive methods for determining AD risk and progression of disease. Furthermore, accumulating evidence suggests that GM modulation could alleviate adverse symptoms of AD or serve as a preventive measure. In addition, increasing evidence shows that Type 2 Diabetes Mellitus (T2DM) is often comorbid with AD, with common GM alterations and inflammatory response, which could chart the development of GM-related treatment interventions for both diseases. We conclude by exploring the therapeutic potential of GM in alleviating symptoms of AD and in reducing risk. Furthermore, we also propose future directions in AD research, namely fecal microbiota transplantation (FMT) and precision medicine.

PARP in the neuropathogenesis of cytomegalovirus infection - Possible role and therapeutic perspective.

Cytomegalovirus infects the majority of the population globally. Congenital CMV infection acquired through primary maternal infection in pregnancy is the most common intrauterine infection with a high mortality rate due to severe long-term neurodevelopmental sequelae. The demyelination and neuroinflammation during CMV infection have been attributed to altered immune response and ROS-mediated apoptosis. PARP-1 protein is linked to apoptotic neuronal loss with subsequent neurotoxicity and CNS injury as a result of PARP hyperactivation. PARP-1 play a critical role in the establishment of latency including EBV, HHV-8 and HIV. Research on PARP inhibitors recently shows significant progress against neurodegenerative diseases such as Alzheimers disease and cancer therapy including malignant lymphoma and hepatitis B virus-induced hepatocellular carcinoma. The role of PARP1 in the neuropathogenesis of CMV and the potential of PARP inhibitors in the prevention of neurological sequelae is still elusive. Further studies on the role of PARP on the neuropathogenesis of CMV infection can help thwart neurodegeneration through the potential development of PARP inhibitors such as small molecule inhibitors.

Brain region-specific myelinogenesis is not directly linked to amyloid-β in APPPS1 transgenic mice.

Alzheimers disease (AD) is characterized by aggregating amyloid beta-protein (Aβ). Recent evidence has shown that insufficient myelinogenesis contributes to AD-related functional deficits. However, it remains unclear whether Aβ, in either plaque or soluble form, could alter myelinogenesis in AD brains. By cell-lineage tracing and labeling, we found both myelinogenesis and Aβ deposits displayed a region-specific pattern in the 13-month-old APPPS1 transgenic mouse brains. Aβ plaques cause focal demyelination, but only about 15% Aβ plaques are closely associated with newly formed myelin in the APPPS1 brains. Further, the Aβ plaque total area and the amount of new myelin are not linearly correlated across different cortical regions, suggesting that Aβ plaques induce demyelination but may not exclusively trigger remyelination. To understand the role of soluble Aβ in regulating myelinogenesis, we chose to observe the visual system, wherein soluble Aβ is detectable but without the presence of Aβ plaques in the APPPS1 retina, optic nerve, and optic tract. Interestingly, newly-formed myelin density was not significantly altered in the APPPS1 optic nerves and optic tracts as compared to the wildtype controls, suggesting soluble Aβ probably does not change myelinogenesis. Further, treatment of purified oligodendrocyte precursor cells (OPCs) with soluble Aβ (oligomers) for 48 h did not change the cell densities of MBP positive cells and PDGFRα positive OPCs in vitro. Consistently, injection of soluble Aβ into the lateral ventricles did not alter myelinogenesis in the corpus callosum of NG2-CreErt Tau-mGFP mice significantly. Together, these findings indicate that the region-dependent myelinogenesis in AD brains is not directly linked to Aβ, but rather probably a synergic result in adapting to AD pathology.

Relationship of Apolipoprotein E with Alzheimers Disease and Other Neurological Disorders An Updated Review.

Alzheimers disease (AD) and other neurodegenerative diseases, for which there is no effective cure, cause great social burden. Apolipoprotein E (APOE) is an important lipid transporter, which has been shown to have a close relationship with AD and other neurological disorders in an increasing number of studies, suggesting its potential as a therapeutic target. In this review, we summarize the recent advances in clinical and basic research on the role of APOE in the pathogenesis of multiple neurological diseases, with an emphasis on the new associations between APOE and AD, and between APOE and depression. The progress of APOE research in Parkinsons disease (PD) and some other neurological diseases is briefly discussed.

Comparison of Machine Learning-based Approaches to Predict the Conversion to Alzheimers Disease from Mild Cognitive Impairment.

In Mild Cognitive Impairment (MCI), identifying a high risk of conversion to Alzheimers Disease Dementia (AD) is a primary goal for patient management. Machine Learning (ML) algorithms are widely employed to pursue data-driven diagnostic and prognostic goals. An agreement on the stability of these algorithms -when applied to different biomarkers and other conditions- is far from being reached. In this study, we compared the different prognostic performances of three supervised ML algorithms fed with multimodal biomarkers of MCI subjects obtained from the Alzheimers Disease Neuroimaging Initiative (ADNI) database. Random Forest, Gradient Boosting, and eXtreme Gradient Boosting algorithms predict MCI conversion to AD. They can also be simultaneously employed -with the voting procedure- to improve predictivity. AD prediction accuracy is influenced by the nature of the data (i.e., neuropsychological test scores, cerebrospinal fluid AD-related proteins and APOE ε4, cerebral structural MRI (sMRI) data). In our study, independent of the applied ML algorithms, sMRI data showed the lowest accuracy (0.79) compared to other classes. Multimodal data were helpful in the algorithms performances by combining clinical and biological measures. Accordingly, using the three ML algorithms, the highest accuracy (0.90) was reached by employing neuropsychological and AD-related biomarkers. Finally, the feature selection procedure indicated that the most critical variables in the respective classes were the ADAS-Cog-13 scale, the medial temporal lobe and hippocampus atrophy, and the ratio between phosphorylated Tau and Aβ42 proteins. In conclusion, our data support the notion that using multiple ML algorithms and multimodal biomarkers helps make more accurate and solid predictions.

High-carbohydrate and fat diet consumption causes metabolic deterioration, neuronal damage, and loss of recognition memory in rats.

The number of people diagnosed with metabolic syndrome (MetS) has increased dramatically to reach alarming proportions worldwide. The origin of MetS derives from bad eating habits and sedentary lifestyle. Most people consume foods high in carbohydrates and saturated fat. In recent years, it has been reported that alterations in insulin at the brain level could have an impact on the appearance of neurodegenerative diseases such as Alzheimers disease, Parkinsons disease, dementia, depression, and other types of disorders that compromise brain function. These alterations have been associated with damage to the structure and function of neurons located in the reptilian and limbic systems, a decrease in dendritic arborization and an exacerbated inflammatory state that impaired learning and memory and increased in the state of stress and anxiety. Although the molecular mechanisms induced by MetS to cause neurodegeneration are not fully understood. The aim of this study is to know the effect of the intake of hypercaloric diets on the structure and function of neurons located in the frontal cortex, hypothalamus and hippocampus and its impact on behavior in rats with metabolic syndrome. In conclusion, the present study illustrated that chronic exposure to hypercaloric diets, with a high content of sugars and saturated fatty acids, induces a proinflammatory state and exacerbates oxidative stress in brain regions such as the hypothalamus, hippocampus, and frontal cortex, leading to dysfunction. metabolism, neuronal damage, and recognition memory loss.

A novel regulator in Alzheimers disease progression The astrocyte-derived extracellular vesicles.

Alzheimers disease (AD) is known as an age-related irreversible neurodegenerative disease. AD seriously endangers the health of the elderly, but there is still no effective treatment. In the past several decades, the significant role of astrocytes in the process of AD has been universally acknowledged. In addition, extracellular vesicles (EVs) have been recognized as an essential mediator in intercellular communication and participate in various pathophysiological processes by carrying and transporting diverse cargoes. Moreover, specific conditions and stimuli can modulate the amount and properties of astrocyte-derived EVs (ADEVs) to affect AD progression. Thus, recent studies focused on the involvement of ADEVs in the pathogenesis of AD and the potential application of ADEVs in the diagnosis and treatment of AD, which provides a new direction and possibility for revealing the mystery of AD. Interestingly, it can be concluded that ADEVs have both pathogenic and protective effects in the process of AD through a comprehensive generalization. In this review, we aim to summarize the multi-faces of ADEVs effects on AD development, which can provide a novel strategy to investigate the underlying mechanism in AD. We also summarize the current ADEVs clinically relevant studies to raise the potential use of ADEVs in the discovery of novel biomarkers for diagnosis and therapeutic targets for AD.

Adult hippocampal neurogenesis in Alzheimers disease A roadmap to clinical relevance.

Adult hippocampal neurogenesis (AHN) drops sharply during early stages of Alzheimers disease (AD), via unknown mechanisms, and correlates with cognitive status in AD patients. Understanding AHN regulation in AD could provide a framework for innovative pharmacological interventions. We here combine molecular, behavioral, and clinical data and critically discuss the multicellular complexity of the AHN niche in relation to AD pathophysiology. We further present a roadmap toward a better understanding of the role of AHN in AD by probing the promises and caveats of the latest technological advancements in the field and addressing the conceptual and methodological challenges ahead.

Cognitive rehabilitation and mindfulness reduce cognitive complaints in multiple sclerosis (REMIND-MS) A randomized controlled trial.

Cognitive problems, both complaints and objective impairments, are frequent and disabling in patients with multiple sclerosis (MS) and profoundly affect daily living. However, intervention studies that focus on cognitive problems that patients experience in their daily lives are limited. This study therefore aimed to investigate the effectiveness of cognitive rehabilitation therapy (CRT) and mindfulness-based cognitive therapy (MBCT) on patient-reported cognitive complaints in MS. In this randomized-controlled trial, MS patients with cognitive complaints completed questionnaires and underwent neuropsychological assessments at baseline, post-treatment and 6-month follow-up. Patient-reported cognitive complaints were primarily investigated. Secondary outcomes included personalized cognitive goals and objective cognitive function. CRT and MBCT were compared to enhanced treatment as usual (ETAU) using linear mixed models. Patients were randomized into CRT (n 37), MBCT (n 36) or ETAU (n 37), of whom 100 completed the study. Both CRT and MBCT positively affected patient-reported cognitive complaints compared to ETAU at post-treatment (p<.05), but not 6 months later. At 6-month follow-up, CRT had a positive effect on personalized cognitive goals (p.028) and MBCT on processing speed (p.027). Patients with less cognitive complaints at baseline benefited more from CRT on the Cognitive Failures Questionnaire (i.e. primary outcome measuring cognitive complaints) at post-treatment (p.012-.040), and those with better processing speed at baseline benefited more from MBCT (p.016). Both CRT and MBCT alleviated cognitive complaints in MS patients immediately after treatment completion, but these benefits did not persist. In the long term, CRT showed benefits on personalized cognitive goals and MBCT on processing speed. These results thereby provide insight in the specific contributions of available cognitive treatments for MS patients.

Novel N

A series of new α-carboline analogues modified at N

How Can Static and Oscillating Electric Fields Serve in Decomposing Alzheimers and Other Senile Plaques

Alzheimers disease is one of the most common neurodegenerative conditions, which are ascribed to extracellular accumulation of β-amyloid peptides into plaques. This phenomenon seems to typify other related neurodegenerative diseases. The present study uses classical molecular-dynamics simulations to decipher the aggregation-disintegration behavior of β-amyloid peptide plaques in the presence of static and oscillating oriented external electric fields (OEEFs). A long-term disintegration of such plaques is highly desirable since this may improve the prospects of therapeutic treatments of Alzheimers disease and of other neurodegenerative diseases typified by senile plaques. Our study illustrates the spontaneous aggregation of the β-amyloid, its prevention and breakdown when OEEF is applied, and the fate of the broken aggregate when the OEEF is removed. Notably, we demonstrate that the usage of an oscillating OEEF on β-amyloid aggregates appears to lead to an irreversible disintegration. Insight is provided into the root causes of the various modes of aggregation, as well as into the different fates of OEEF-induced disintegration in oscillating vs static fields. Finally, our simulation results are compared to the well-established TTFields and the Deep Brain Stimulation (DBS) therapies, which are currently used options for treatments of Alzheimers disease and other related neurodegenerative diseases.

Construction of a DNA Nanoassembly Based on Spatially Ordered Recognition Elements for Inhibiting β-Amyloid Aggregation.

A β-amyloid (Aβ) aggregation process is a spontaneous process where the original random coil or helical structure changes into a regularly arranged β-sheet structure. The development of inhibitors with the features of low cost, high efficiency, and biosafety by targeting Aβ self-aggregation is significant for Alzheimers disease treatment. However, the issues of low inhibition efficiency under low concentrations of inhibitors and biological toxicity are currently to be addressed. To resolve the above problems, a DNA nanoassembly (HCR-Apt) based on spatially ordered recognition elements was constructed by targeted disruption of Aβ ordered arrangement. It was discovered that HCR-Apt could inhibit effectively the fibrillation of Aβ

Photocatalysis and Kinetic Resolution by Lithiation to Give Enantioenriched 2-Arylpiperazines.

Piperazines are important heterocycles in drug compounds. We report the asymmetric synthesis of arylpiperazines by photocatalytic decarboxylative arylation (metallaphotoredox catalysis) then kinetic resolution using

Betaine-The dark knight of the brain.

The role of betaine in the liver and kidney has been well documented, even from the cellular and molecular point of view. Despite literature reporting positive effects of betaine supplementation in Alzheimers, Parkinsons and schizophrenia, the role and function of betaine in the brain are little studied and reviewed. Beneficial effects of betaine in neurodegeneration, excitatory and inhibitory imbalance and against oxidative stress in the central nervous system (CNS) have been collected and analysed to understand the main role of betaine in the brain. There are many dark aspects needed to complete the picture. The understanding of how this osmolyte is transported across neuron and glial cells is also controversial, as the expression levels and functioning of the known protein capable to transport betaine expressed in the brain, betaine-GABA transporter 1 (BGT-1), is itself not well clarified. The reported actions of betaine beyond BGT-1 related to neuronal degeneration and memory impairment are the focus of this work. With this review, we underline the scarcity of detailed molecular and cellular information about betaine action. Consequently, the requirement of detailed focus on and study of the interaction of this molecule with CNS components to sustain the therapeutic use of betaine.