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A liposome-based aptasensor integrated with competitive reaction enabling portable and electrochemical detection of Aβ oligomer.

Aggregation of β-amyloid (Aβ) were considered as a typical pathological feature of Alzheimers disease (AD). Extensive studies have verified that soluble Aβ oligomers (AβO) were more toxic to neurons than plaques. Herein, in this work, a glucose entrapped liposome-based portable aptasensor was fabricated for recognizing and interacting with AβO by specific aptamer on liposome (G-Lip-Apt). Then, a single strand DNA, designed to be partially complementary to AβO aptamer, was modified on amino-functionalized Fe

Rates of regional tau accumulation in ageing and across the Alzheimers disease continuum an AIBL

Tau positron emission tomography (PET) imaging enables longitudinal observation of tau accumulation in Alzheimers disease (AD). One hundred and eighty-four participants 89 cognitively unimpaired (CU) beta-amyloid negative (Aβ-), 44 CU Aβ, 51 cognitively impaired Aβ (26 with mild cognitive impairment MCI and 25 with dementia) had follow-up CU Aβ- participants had very low rates of tau accumulation in the mesial temporal lobe (MTL). In CU Aβ, significantly higher rate of accumulation was seen in the MTL (particularly the amygdala), extending into the inferior temporal lobes. In MCI Aβ, the rate of accumulation was greatest in the lateral temporal, parietal and lateral occipital cortex, and plateaued in the MTL. Accumulation was global in AD Aβ, except for a plateau in the MTL. The eroded subcortical white matter reference region showed no significant advantage over the cerebellar cortex and appeared prone to spill-over in AD participants. Data fitting suggested approximately 15-20 years to accumulate tau to typical AD levels. Tau accumulation occurs slowly. Rates vary according to brain region, disease stage and tend to plateau at high levels. Rates of tau accumulation are best measured in the MTL and inferior temporal cortex in preclinical AD and in large neocortical areas, in MCI and AD. NHMRC Cerveau Technologies.

BACE1 influences clinical manifestations and central inflammation in relapsing remitting multiple sclerosis.

Neurodegenerative and inflammatory processes influence the clinical course of multiple sclerosis (MS). The β-site amyloid precursor protein cleaving enzyme 1 (BACE1) has been associated with cognitive dysfunction, amyloid deposition and neuroinflammation in Alzheimers disease. We explored in a group of 50 patients with relapsing-remitting MS the association between the cerebrospinal fluid (CSF) levels of BACE1, clinical characteristics at the time of diagnosis and prospective disability after three-years follow-up. In addition, we assessed the correlations between the CSF levels of BACE 1, amyloid β (Aβ) 1-40 and 1-42, phosphorylated tau (pTau), lactate, and a set of inflammatory and anti-inflammatory molecules. BACE1 CSF levels were correlated positively with depression as measured with Beck Depression Inventory-Second Edition scale, and negatively with visuospatial memory performance evaluated by the Brief Visuospatial Memory Test-Revised. In addition, BACE CSF levels were positively correlated with Bayesian Risk Estimate for MS at onset, and with Expanded Disability Status Scale score assessed three years after diagnosis. Furthermore, a positive correlation was found between BACE1, amyloid β 4240 ratio (Spearmans r 0.334, p 0.018, n 50), pTau (Spearmans r 0.304, p 0.032, n 50) and lactate concentrations (Spearmans r 0.361, p 0.01, n 50). Finally, an association emerged between BACE1 CSF levels and a group of pro and anti-inflammatory molecules, including interleukin (IL)-4, IL-17, IL-13, IL-9 and interferon-γ. BACE1 may have a role in different key mechanisms such as neurodegeneration, oxidative stress and inflammation, influencing mood, cognitive disorders and disability progression in MS.

In vitro characterization on the role of APOE polymorphism in human hippocampal neurogenesis.

Hippocampal neurogenesis (HN) is considered an important mechanism underlying lifelong brain plasticity, and alterations in this process have been implicated in early Alzheimers disease progression. APOE polymorphism is the most common genetic risk factor for late-onset Alzheimers disease where the ε4 genotype is associated with a significantly earlier disease onset compared to the neutral ε3 allele. Recently, APOE has been shown to play an important role in the regulation of HN. However, the time-dependent impact of its polymorphism in humans remains elusive, partially due to the difficulties of studying human HN in vivo. To bridge this gap of knowledge, we used an in vitro cellular model of human HN and performed a time course characterization on isogenic induced pluripotent stem cells with different genotypes of APOE. We found that APOE itself was more highly expressed in ε4 at the stem cell stage, while the divergence of differential gene expression phenotype between ε4 and ε3 became prominent at the neuronal stage of differentiation. This divergence was not associated with the differential capacity to generate dentate gyrus granule cell-like neurons, as its level was comparable between ε4 and ε3. Transcriptomic profiling across different stages of neurogenesis indicated a clear maturation of functional neurons phenotype in ε3 neural progenitors and neurons, while genes differentially expressed only in ε4 neurons suggested potential alterations in metabolism and mitochondrial function. Taken together, our in vitro investigation suggests that APOE ε4 allele can exert a transcriptome-wide effect at the later stages of HN, without altering the overall level of neurogenesis per se.

Exploring genes for immunoglobulin A nephropathy a summary data-based mendelian randomization and FUMA analysis.

Immunoglobulin A nephropathy (IgAN) is a complex autoimmune disease, and the exact pathogenesis remains to be elucidated. This study aimed to explore genes underlying the pathogenesis of IgAN. We conducted the summary data-based Mendelian randomization (SMR) analysis and performed functional mapping and annotation using FUMA to explore genetic loci that are potentially involved in the pathogenies of IgAN. Both analyses used summarized data of a recent genome-wide association study (GWAS) on IgANs, which included 477,784 Europeans (15,587 cases and 462,197 controls) and 175,359 East Asians (71 cases and 175,288 controls). We performed SMR analysis using Consortium for the Architecture of Gene Expression (CAGE) expression quantitative trait loci (eQTL) data and replicated the analysis using Genotype-Tissue Expression (GTEx) eQTL data. Using the CAGE eQTL data, our SMR analysis identified 32 probes tagging 25 unique genes whose expression were pleiotropically associated with IgAN, with the top three probes being ILMN2150787 (tagging HLA-C, P We identified many genetic variantsloci that are potentially involved in the pathogenesis of IgAN. More studies are needed to elucidate the exact mechanisms of the identified genetic variantsloci in the etiology of IgAN.

Identifying clinically useful biomarkers in neurodegenerative disease through a collaborative approach the NeuroToolKit.

Alzheimers disease (AD) is a complex and heterogeneous disease, which requires reliable biomarkers for diagnosis and monitoring disease activity. Preanalytical protocol and technical variability associated with biomarker immunoassays makes comparability of biomarker data across multiple cohorts difficult. This study aimed to compare cerebrospinal fluid (CSF) biomarker results across independent cohorts, including participants spanning the AD continuum. Measured on the NeuroToolKit (NTK) prototype panel of immunoassays, 12 CSF biomarkers were evaluated from three cohorts (ALFA, Wisconsin, and AbbyBlaze). A correction factor was applied to biomarkers found to be affected by preanalytical procedures (amyloid-β Biomarker distributions were comparable across cohorts following correction. Correlations of biomarker values were consistent across cohorts, regardless of disease stage. Disease stage differentiation was highest for neurofilament light (NfL), phosphorylated tau, and total tau, regardless of the cohort. Correlation between biomarker concentration and cognitive scores was comparable across cohorts, and strongest for NfL, chitinase-3-like protein-1 (YKL40), and glial fibrillary acidic protein. The precision of the NTK enables merging of biomarker datasets, after correction for preanalytical confounders. Assessment of multiple cohorts is crucial to increase power in future studies into AD pathogenesis.

Efficacy and safety of the novel GlyT1 inhibitor BI 425809 in Alzheimers dementia a randomized controlled trial.

This phase II proof-of-concept study assessed the efficacy and safety of BI 425809, a novel selective glycine transporter-1 inhibitor, for the treatment of cognitive impairment associated with probable Alzheimers disease dementia. This 12-week, multicenter, double-blind, placebo-controlled, parallel-group study randomized (11111) patients with mild-to-moderate probable Alzheimers disease dementia to BI 425809 2, 5, 10, and 25 mg or placebo once daily. The primary efficacy endpoint was the change from baseline in Alzheimers Disease Assessment Scale-Cognitive Subscale 11-item total score after 12 weeks of treatment. Safety was also assessed. Six hundred and ten male and female patients were randomized to BI 425809 2 mg (n 123), 5 mg (n 122), 10 mg (n 122), and 25 mg (n 123) or placebo (n 120). Approximately 47% (n 286) were male the mean (standard deviation) age was 72.9 (7.7) years. Treatment compliance was above 97% for all dose groups. The Mini-Mental State Examination category on the median score was < 22 in 47% (n 287) of patients and ≥ 22 in 53% (n 322) of patients. No significant, non-flat dose-response relationship was detected for the primary endpoint (adjusted p-value > 0.76 for all models). BI 425809 was generally well-tolerated. Overall, 47.9% (n 292) of patients reported at least one adverse event during the trial the frequency of patients with investigator-defined drug-related adverse events was similar in all treatment groups, ranging from 15.4 to 19.5% across the BI 425809 treatment groups and 15.8% for placebo. No clinically meaningful changes from baseline were observed following treatment with BI 425809 in patients with mild-to-moderate probable Alzheimers disease dementia. ClinicalTrials.gov NCT02788513 (1346-0023). Registered on June 2, 2016. EU Clinical Trials Register 2015-005438-24. Registered on May 6, 2016.

Glutathione depletion results in S-nitrosylation of protein disulfide isomerase in neuroblastoma cells.

Protein disulfide isomerase (PDI) is an essential enzyme involved in oxidative protein folding. PDI is S-nitrosylated in the brains of Alzheimers disease patients, and S-nitrosylated PDI is considered one of main causes of Alzheimers disease. However, the mechanisms underlying PDI S-nitrosylation have not yet been elucidated. Because glutathione (GSH) depletion is a pathological feature of Alzheimers disease, we investigated the effect of GSH depletion on the S-nitrosylation level of PDI. SH-SY5Y cells, which is a human derived neuroblastoma cells, were used in this study. Glutamate and buthionine sulfoximine (BSO) were used as GSH depletors. S-nitrosylated PDI was detected by biotin-switch assay. GSH depletion by glutamate, a cystineglutamate antiporter xCT inhibitor, increased S-nitrosylated PDI at C343 in SH-SY5Y cells, and induced IRE1α phosphorylation. BSO, a γ-glutamylcysteine synthetase inhibitor, also increased S-nitrosylated PDI and phosphorylated IRE1α upon GSH depletion. Because S-nitrosylated PDI at C343 is stable in neuro cells, S-nitrosylated PDI by GSH depletion progresses to neurodegeneration by the induction of endoplasmic reticulum stress via phosphorylated IRE1α signaling from the early to late stage. Furthermore, treatment with neohesperidin, but not N-acetylcysteine (NAC), improved PDI S-nitrosylation level in GSH-depleted SH-SY5Y cells because nitrosylated compound of NAC induces PDI S-nitrosylation. The results of our study provide a new insight into the mechanisms of neurodegeneration, and may be useful for the development of drugs for Alzheimers diseases.

Alpha lipoic acid treatment in late middle age improves cognitive function Proteomic analysis of the protective mechanisms in the hippocampus.

Alpha lipoic acid (ALA), a powerful antioxidant, has the potential to relieve age-related cognitive impairment and neurodegenerative disease. Clinical randomized controlled studies have demonstrated the cognitive improvement effects of lipoic acid in Alzheimers disease (AD). In the present study, we examined the effects of ALA on cognitive function in ageing mice and its protective mechanisms. Eighteen-month-old male C57BL6J mice received ALA or normal saline for 2 months. The Morris water maze test revealed improved cognitive function in animals that received ALA. Furthermore, tandem Mass Tags (TMT) based liquid chromotography with mass spectrometrymass spectrometry (LC-MSMS) was established to identify the target proteins. The results showed that 10 proteins were changed significantly. Gene Ontology (GO) analysis indicated that the upregulated proteins were enriched in terminal bouton, synaptic transmission and lipid transporter activity while the down-regulated proteins were involved in nuclear transcription factor-κB binding, apoptosis and mitogen-activated protein kinase binding. Based on the GO results, two upregulated proteins oxysterol-binding protein-related protein 10 (OSBPL10) and oligophrenin 1 (OPHN1), and one downregulated protein, CDK5 regulatory subunit-associated protein 3 (CDK5rap3), were validated through Western blotting. The results were consistent with the proteomic results. Modulation of synaptic transmission, lipid transporter activity and neuroinflammation appears to be the mechanisms of ALA in the aged brain.

Moschus exerted protective activity against H

The pivotal characteristics of Alzheimers disease (AD) are irreversible memory loss and progressive cognitive decline, eventually causing death from brain failure. In the various proposed hypotheses of AD, oxidative stress is also regarded as a symbolic pathophysiologic cascade contributing to brain diseases. Using Chinese herbal medicine may be beneficial for treating and preventing AD. As a rare and valuable animal medicine, Moschus possesses antioxidant and antiapoptotic efficacy and is extensively applied for treating unconsciousness, stroke, coma, and cerebrovascular diseases. We aim to evaluate whether Moschus protects PC12 cells from hydrogen peroxide (H

Genome-wide identification of murine interferon genes in microglial-mediated neuroinflammation in Alzheimers disease.

Interferons play a major role in microglial-mediated neuroinflammation in Alzheimers disease (AD). We investigated the interferon transcriptome (AD versus non-AD) using N9 and murine microglia. We identified 64 interferon-related differentially expressed genes (DEG) in LPS-stimulated N9 microglia versus control cells, 26 DEG in microglia from 5XFAD versus wild-type mice, with 13 DEG common to both datasets. Network analyses identified potential key mediators (Cxcl10, Ifit3) of the interferon response in AD. Gene-drug interaction analysis identified therapeutics targeting interferon-related genes. These data characterize the microglial interferon response in AD, providing new targets and therapeutics directed towards interferon-related neuroinflammation in AD.

Incorporation of concussion history as part of the LIfestyle for BRAin Health (LIBRA) modifiable factors risk score and associations with cognition in older former National Football League players.

Investigate associations between the LIfestyle for BRAin Health (LIBRA) risk score with odds of mild cognitive impairment (MCI) diagnosis and cognitive function, incorporating concussion history. Former National Football League (NFL) players (N 1050 mean age 64.8 ± 9.0-years) completed initial testing for integration of concussion history into LIBRA scores (i.e., modified-LIBRA) and completed the Brief Test of Adult Cognition by Telephone (BTACT). Modified-LIBRA score (including concussion history) associations with odds of MCI and cognitive dysfunction were assessed via logistic and linear regression. The highest quartile LIBRA scores were six times more likely to have a diagnosis of MCI compared to the lowest quartile (OR 6.273.61, 10.91, p < 0.001). Modified-LIBRA scores significantly improved model fit for odds of MCI above original LIBRA scores (χ Modified-LIBRA score, incorporating concussion history, may help monitoring risk status in former contact sport athletes, by targeting modifiable, lifestyle-related risk factors.

Type-2 Diabetes, Pancreatic Amylin, and Neuronal Metabolic Remodeling in Alzheimers Disease.

Type-2 diabetes raises the risk for Alzheimers disease (AD)-type dementia and the conversion from mild cognitive impairment to dementia, yet mechanisms connecting type-2 diabetes to AD remain largely unknown. Amylin, a pancreatic β-cell hormone co-secreted with insulin, participates in the central regulation of satiation, but also forms pancreatic amyloid in persons with type-2 diabetes and synergistically interacts with brain amyloid β (Aβ) pathology, in both sporadic and familial Alzheimers disease (AD). Growing evidence from studies of tumor growth, together with early observations in skeletal muscle, indicates amylin as a potential trigger of cellular metabolic reprogramming. Because the blood, cerebrospinal fluid, and brain parenchyma in humans with AD have increased concentrations of amylin, amylin-mediated pathological processes in the brain may involve neuronal metabolic remodeling. This review summarizes recent progress in understanding the link between prediabetic hypersecretion of amylin and risk of neuronal metabolic remodeling and AD and suggests nutritional and medical effects of food constituents that might prevent andor ameliorate amylin-mediated neuronal metabolic remodeling.

N-methyl-D-aspartic acid receptor 2A functionalized stationary phase A reliable method for pursuing potential ligands against Alzheimers disease from natural products.

N-methyl-D-aspartic acid (NMDA) receptors play subunit-specific role in central neuronal development. However, insights into the pharmacological modulation of NMDA receptors were mainly lack of subunit and synaptic selectivity. The purpose of the present study was to develop a novel strategy to rapidly recognize NMDA subunit 2A (NMDA-2A) ligands from natural products and provide subunit-selective drug candidates for Alzheimers disease (AD). The recombinant NMDA-2A containing a tag of epidermal growth factor receptor (EGFR) was expressed in Escherichia coli cells and immobilized on ibrutinib-modified microspheres based on the specific reaction between EGFR and its inhibitor ibrutinib. A novel affinity stationary phase was synthesized to screen NMDA-2A ligands from Gardenia jasminoides Ellis. The immobilized receptor column exhibited excellent receptor selectivity and ligand-binding activity. Crocetin was screened by using this method. In a cellular model of AD, the protein level of NMDA-2A was significantly decreased compared with the control group, while treatment with crocetin significantly increased NMDA-2A level in a concentration-dependent manner, confirming that crocetin could bind to NMDA-2A in vitro. In the present study, we developed a reliable method for the rapid identification of NMDA-2A ligands from natural products, which may be used as a platform for new drug discovery to generate high-quality drug candidates.

Apicidin attenuates memory deficits by reducing the Aβ load in APPPS1 mice.

Amyloid beta (Aβ) is an important pathological feature of Alzheimers disease (AD). A disintegrin and metalloproteinase 10 (ADAM10) can reduce the production of toxic Aβ by activating the nonamyloidogenic pathway of amyloid precursor protein (APP). We previously found that apicidin, which is a histone deacetylase (HDAC) inhibitor, can promote the expression of ADAM10 and reduce the production of Aβ in vitro. This study was designed to determine the potential of apicidin treatment to reverse learning and memory impairments in an AD mouse model and the possible correlation of these effects with ADAM10. Nine-month-old APPPS1 mice and C57 mice received intraperitoneal injections of apicidin or vehicle for 2 months. At 11 months of age, we evaluated the memory performance of mice with Morris water maze (MWM) and context fear conditioning tests. The Aβ levels were assessed in mouse brain using the immunohistochemical method and ELISA. The expression of corresponding protein involved in proteolytic processing of APP and the phosphorylation of tau were assessed by Western blotting. Apicidin reversed the deficits of spatial reference memory and contextual fear memory, attenuated the formation of Aβ-enriched plaques, and decreased the levels of soluble and insoluble Aβ4042 in APPPS1 mice. Moreover, apicidin significantly increased the expression of ADAM10, improved the level of sAPPα, and reduced the production of sAPPβ, but did not affect the levels of phosphorylated tau in APPPS1 mice. Apicidin significantly improves the AD symptoms of APPPS1 mice by regulating the expression of ADAM10, which may contribute to decreasing the levels of Aβ rather than decreasing the phosphorylation of tau.

Anti-malaria drug artesunate prevents development of amyloid-β pathology in mice by upregulating PICALM at the blood-brain barrier.

PICALM is one of the most significant susceptibility factors for Alzheimers disease (AD). In humans and mice, PICALM is highly expressed in brain endothelium. PICALM endothelial levels are reduced in AD brains. PICALM controls several steps in Aβ transcytosis across the blood-brain barrier (BBB). Its loss from brain endothelium in mice diminishes Aβ clearance at the BBB, which worsens Aβ pathology, but is reversible by endothelial PICALM re-expression. Thus, increasing PICALM at the BBB holds potential to slow down development of Aβ pathology. To identify a drug that could increase PICALM expression, we screened a library of 2007 FDA-approved drugs in HEK293t cells expressing luciferase driven by a human PICALM promoter, followed by a secondary mRNA screen in human Eahy926 endothelial cell line. In vivo studies with the lead hit were carried out in Picalm-deficient (Picalm Our screen identified anti-malaria drug artesunate as the lead hit. Artesunate elevated PICALM mRNA and protein levels in Eahy926 endothelial cells and in vivo in brain capillaries of Picalm Artesunate increases PICALM levels and Aβ clearance at the BBB which prevents development of Aβ pathology and functional deficits in mice and holds potential for translation to human AD.

Altered dynamics of glymphatic flow in a mature-onset Tet-off APP mouse model of amyloidosis.

Alzheimers disease (AD) is an incurable neurodegenerative disorder characterised by the progressive buildup of toxic amyloid-beta (Aβ) and tau protein aggregates eventually leading to cognitive decline. Recent lines of evidence suggest that an impairment of the glymphatic system (GS), a brain waste clearance pathway, plays a key role in the pathology of AD. Moreover, a relationship between GS function and neuronal network integrity has been strongly implicated. Here, we sought to assess the efficacy of the GS in a transgenic Tet-Off APP mouse model of amyloidosis, in which the expression of mutant APP was delayed until maturity, mimicking features of late-onset AD-the most common form of dementia in humans. To evaluate GS function, we used dynamic contrast-enhanced MRI (DCE-MRI) in 14-month-old Tet-Off APP (AD) mice and aged-matched littermate controls. Brain-wide transport of the Gd-DOTA contrast agent was monitored over time after cisterna magna injection. Region-of-interest analysis and computational modelling were used to assess GS dynamics while characterisation of brain tissue abnormalities at the microscale was performed ex vivo by immunohistochemistry. We observed reduced rostral glymphatic flow and higher accumulation of the contrast agent in areas proximal to the injection side in the AD group. Clustering and subsequent computational modelling of voxel time courses revealed significantly lower influx time constants in AD relative to the controls. Ex vivo evaluation showed abundant amyloid plaque burden in the AD group coinciding with extensive astrogliosis and microgliosis. The neuroinflammatory responses were also found in plaque-devoid regions, potentially impacting brain-fluid circulation. In a context resembling late-onset AD in humans, we demonstrate the disruption of glymphatic function and particularly a reduction in brain-fluid influx in the AD group. We conjecture that the hindered circulation of cerebrospinal fluid is potentially caused by wide-spread astrogliosis and amyloid-related obstruction of the normal routes of glymphatic flow resulting in redirection towards caudal regions. In sum, our study highlights the translational potential of alternative approaches, such as targeting brain-fluid circulation as potential therapeutic strategies for AD.

How does apolipoprotein E genotype influence the relationship between physical activity and Alzheimers disease risk A novel integrative model.

Wide evidence suggests that physical activity (PA) confers protection against Alzheimers disease (AD). On the other hand, the apolipoprotein E gene (APOE) ε4 allele represents the greatest genetic risk factor for developing AD. Extensive research has been conducted to determine whether frequent PA can mitigate the increased AD risk associated with APOE ε4. However, thus far, these attempts have produced inconclusive results. In this context, one possible explanation could be that the influence of the combined effect of PA and APOE ε4 carriage might be dependent on the specific outcome measure utilised. In order to bridge these discrepancies, the aim of this theoretical article is to propose a novel model on the interactive effects of PA and APOE ε4 carriage on well-established mechanisms underlying AD. Available literature was searched to investigate how PA and APOE ε4 carriage, independently and in combination, may alter several molecular pathways involved in AD pathogenesis. The reviewed mechanisms include amyloid beta (Aβ) and tau deposition and clearance, neuronal resilience and neurogenesis, lipid function and cerebrovascular alterations, brain immune response and glucose metabolism. Finally, combining all this information, we have built an integrative model, which includes evidence-based and theoretical synergistic interactions across mechanisms. Moreover, we have identified key knowledge gaps in the literature, providing a list of testable hypotheses that future studies need to address. We conclude that PA influences a wide array of molecular targets involved in AD neuropathology. A deeper understanding of where, when and, most importantly, how PA decreases AD risk even in the presence of the APOE ε4 allele will enable the creation of new protocols using exercise along pharmaceuticals in combined therapeutic approaches.

Decreased cerebrospinal fluid Aβ 38, 40, 42, and 43 levels in sporadic and hereditary cerebral amyloid angiopathy.

Vascular Aβ accumulation is the hallmark of cerebral amyloid angiopathy (CAA). The composition of cerebrospinal fluid (CSF) of CAA patients may serve as diagnostic biomarker of CAA. We studied the diagnostic potential of the peptides Aβ38, Aβ40, Aβ42, and Aβ43 in patients with sporadic CAA (sCAA), hereditary Dutch-type CAA (D-CAA), and Alzheimers disease (AD). Aβ peptides were quantified by immunoassays in a discovery group (26 patients with sCAA and 40 controls), a validation group (40 patients with sCAA, 40 patients with AD and 37 controls) and a group of 22 patients with D-CAA and 54 controls. To determine the diagnostic accuracy, the area-under-the-curve (AUC) was calculated using a receiver operating characteristic curve with 95% confidence interval (CI) RESULTS We found decreased levels of all Aβ peptides in sCAA patients and D-CAA patients compared to controls. The difference was most prominent for Aβ42 (AUC of sCAA versus controls for discovery 0.90 (95% CI 0.82-0.99) for validation 0.94 (95% CI 0.89-0.99) and Aβ43 (AUC of sCAA versus controls for discovery 0.95 (95% CI 0.88-1.00) for validation 0.91 (95% CI 0.83-1.0). All Aβ peptides, except Aβ43, were also decreased in sCAA compared to AD (CSF Aβ38 AUC of 0.82 (95% CI 0.71-0.93), CSF Aβ40 AUC of 0.88 (95% CI 0.80-0.96), CSF Aβ42 AUC of 0.79 (95% CI 0.66-0.92). A combined biomarker panel of CSF Aβ38, Aβ40, Aβ42, and Aβ43 has potential to differentiate sCAA from AD and controls, and D-CAA from controls. This article is protected by copyright. All rights reserved.

Effects of TND1128 (a 5-deazaflavin derivative), with self-redox ability, as a mitochondria activator on the mouse brain slice and its comparison with β-NMN.

We have no definitive treatment for dementia characterized by prolonged neuronal death due to the enormous accumulation of foreign matter, such as β-amyloid. Since Alzheimers type dementia develops slowly, we may be able to delay the onset and improve neuronal dysfunction by enhancing the energy metabolism of individual neurons. TND1128, a derivative of 5-deazaflavin, is a chemical known to have an efficient self-redox ability. We expected TND1128 as an activator for mitochondrial energy synthesis. We used brain slices prepared from mice 22 ± 2 h pretreated with TND1128 or β-NMN. We measured Ca

Caffeic acid protects against atherosclerotic lesions and cognitive decline in ApoE

Caffeic acid has been indicated to benefit cholesterol balance, but the effect of pure caffeic acid on atherosclerosis in vivo has not been tested. Given that atherosclerosis and Alzheimers disease share common features including distracted lipid balance and chronic inflammation, the concurrent effects of caffeic acid on atherosclerotic lesions and cognitive decline were explored here by using the ApoE

Discovery of multi-target directed 3-OH pyrrolidine derivatives through a semisynthetic approach from alkaloid vasicine for the treatment of Alzheimers disease.

Vasicine is a pyrroloquinazoline alkaloid, which has been isolated from the plant Adhatoda vasica. Naturally inspired semi-synthetic transformations were prepared using vasicine as a synthetic precursor to overcome Alzheimers disease (AD). These semi-synthetic analogs exhibited stable interactions and were well resided at AChE and BChE active sites in in-silico studies. Further, in-vitro experiments were performed to assess the cholinesterase inhibitory activity and reduction of amyloid-beta (Aβ

Design, synthesis, and biological evaluation of novel N-Benzyl piperidine derivatives as potent HDACAChE inhibitors for Alzheimers disease.

The multitarget-directed ligands approach represents a potential strategy to provide effective treatments for Alzheimers disease (AD) given its multifactorial pathology. Herein, a series of N-benzyl piperidine derivatives were designed, synthesized, and biologically characterized for dual inhibitions of histone deacetylase (HDAC) and acetylcholinesterase (AChE). Among the compounds tested, d5 and d10 exhibited dual enzyme inhibitions (d5 HDAC

A near infrared two-channel fluorescent probe for the detection of hydrogen sulfide and viscosity with a negligible crosstalk influence.

Both imbalance of H

Separation of Isomeric Tau Phosphopeptides from Alzheimers Disease Brain by Cyclic Ion Mobility Mass Spectrometry.

Alzheimers disease (AD) is a neurodegenerative disorder of increasing concern. It belongs to diseases termed tauopathies which are characterized by inclusions of abnormally hyperphosphorylated and truncated forms of the protein tau. Studies of tauopathies often focus on detection and characterization of these aberrant tau proteoforms, in particular the phosphorylation sites, which represent a significant analytical challenge for example when several phosphosites can be present on the same peptide. Such isomers can even be difficult to fully separate chromatographically. Since recently introduced cyclic ion mobility-mass spectrometry can offer different selectivity, we have investigated the closely positioned phosphorylation sites S214, T212, and T217 of a tryptic peptide from proline rich region of tau-TPSLPTPPTREPK. The conformational heterogeneity of the isomeric peptides in the gas phase hindered their separation due to their overlapping arrival time distributions. Increasing the resolution of the analysis alone is insufficient to distinguish the peptides in a mixture typical of patient samples. We therefore developed a method based on a combination of collision-induced dissociation, isomeric product ions (

Matrix Development for the Detection of Phosphorylated Amyloid-β Peptides by MALDI-TOF-MS.

Amyloid-β (Aβ) peptides, including post-translationally modified variants thereof, are believed to play a key role in the onset and progression of Alzheimers disease. Suggested modified Aβ species with potential disease relevance include Aβ peptides phosphorylated at serine in position eight (pSer8-Aβ) or 26 (pSer26-Aβ). However, the published studies on those Aβ peptides essentially relied on antibody-based approaches. Thus, complementary analyses by mass spectrometry, as shown for other modified Aβ variants, will be necessary not only to unambiguously verify the existence of phosphorylated Aβ species in brain samples but also to reveal their exact identity as to phosphorylation sites and potential terminal truncations. With the aim of providing a novel tool for addressing this still-unresolved issue, we developed a customized matrix formulation, referred to as TOPAC, that allows for improved detection of synthetic phosphorylated Aβ species by matrix-assisted laser desorptionionization time-of-flight mass spectrometry. When TOPAC was compared with standard matrices, we observed higher signal intensities but minimal methionine oxidation and phosphate loss for intact pSer8-Aβ(1-40) and pSer26-Aβ(1-40). Similarly, TOPAC also improved the mass spectrometric detection and sequencing of the proteolytic cleavage products pSer8-Aβ(1-16) and pSer26-Aβ(17-28). We expect that TOPAC will facilitate future efforts to detect and characterize endogenous phosphorylated Aβ species in biological samples and that it may also find its use in phospho-proteomic approaches apart from applications in the Aβ field.

Mechanistic Insights of TiO

Humans may intendedly or unintendedly be exposed to nanomaterials through food, water, and air. Upon exposure, nanomaterials can pierce the bloodstream and translocate to secondary organs, including the brain, which warrants increased concern for the potential health impacts of nanomaterials. Due to their large surface area and interaction energy, nanomaterials can adsorb surrounding proteins. The misfolding and self-aggregation of amyloid-β (Aβ) have been considered significant factors in the pathogenesis of Alzheimers disease. We thus hypothesize that brain-targeted nanomaterials may modulate Aβ aggregation and cause related neurotoxicity. Here, we showed that TiO

Imaging Amyloid and Tau in the Retina Current Research and Future Directions.

The retina is a key focus in the search for biomarkers of Alzheimers disease (AD) because of its accessibility and shared development with the brain. The pathological hallmarks of AD, amyloid beta (Aβ), and hyperphosphorylated tau (pTau) have been identified in the retina, although histopathologic findings have been mixed. Several imaging-based approaches have been developed to detect retinal AD pathology in vivo. Here, we review the research related to imaging AD-related pathology in the retina and implications for future biomarker research. Electronic searches of published literature were conducted using PubMed and Google Scholar. Curcumin fluorescence and hyperspectral imaging are both promising methods for detecting retinal Aβ, although both require validation in larger cohorts. Challenges remain in distinguishing curcumin-labeled Aβ from background fluorescence and standardization of dosing and quantification methods. Hyperspectral imaging is limited by confounding signals from other retinal features and variability in reflectance spectra between individuals. To date, evidence of tau aggregation in the retina is limited to histopathologic studies. New avenues of research are on the horizon, including near-infrared fluorescence imaging, novel Aβ labeling techniques, and small molecule retinal tau tracers. Artificial intelligence (AI) approaches, including machine learning models and deep learning-based image analysis, are active areas of investigation. Although the histopathological evidence seems promising, methods for imaging retinal Aβ require further validation, and in vivo imaging of retinal tau remains elusive. AI approaches may hold the greatest promise for the discovery of a characteristic retinal imaging profile of AD. Elucidating the role of Aβ and pTau in the retina will provide key insights into the complex processes involved in aging and in neurodegenerative disease.

A Novel Digital Digit-Symbol Substitution Test Measuring Processing Speed in Adults At Risk for Alzheimer Disease Validation Study.

Assessing cognitive constructs affected by Alzheimer disease, such as processing speed (PS), is important to screen for potential disease and allow for early detection. Digital PS assessments have been developed to provide widespread, efficient cognitive testing, but all have been validated only based on the correlation between test scores. Best statistical practices dictate that concurrent validity should be assessed for agreement or equivalence rather than using correlation alone. This study aimed to assess the concurrent validity of a novel digital PS assessment against a gold-standard measure of PS. Adults aged 45-75 years (n191) participated in this study. Participants completed the novel digital digit-symbol substitution test (DDSST) and the Repeatable Battery for the Assessment of Neuropsychological Status coding test (RBANS-C). The correlation between the test scores was determined using a Pearson product-moment correlation, and a difference in mean test scores between tests was checked for using a 2-tailed dependent samples t test. Data were analyzed for agreement between the 2 tests using Bland-Altman limits of agreement and equivalency using a two one-sided t tests (TOST) approach. A significant moderate, positive correlation was found between DDSST and RBANS-C scores (r.577 P<.001), and no difference in mean scores was detected between the tests (P.93). Bias was nearly zero (0.04). Scores between the tests were found to display adequate agreement with 90% of score differences falling between -22.66 and 22.75 (90% limits of agreement-22.91 to 22.99), and the scores were equivalent (P.049). Analyses indicate that the DDSST is a valid digital assessment of PS. The DDSST appears to be a suitable option for widespread, immediate, and efficient PS testing. ClinicalTrials.gov NCT04559789 httpsclinicaltrials.govct2showNCT04559789.

Challenges and Opportunities of Metal Chelation Therapy in Trace Metals Overload-Induced Alzheimers Disease.

Essential trace metals like zinc (Zn), iron (Fe), and copper (Cu) play an important physiological role in the metabolomics and healthy functioning of body organs, including the brain. However, abnormal accumulation of trace metals in the brain and dyshomeostasis in the different regions of the brain have emerged as contributing factors in neuronal degeneration, Aβ aggregation, and Tau formation. The link between these essential trace metal ions and the risk of AD has been widely studied, although the conclusions have been ambiguous. Despite the absence of evidence for any clinical benefit, therapeutic chelation is still hypothesized to be a therapeutic option for AD. Furthermore, the parameters like bioavailability, ability to cross the BBB, and chelation specificity must be taken into consideration while selecting a suitable chelation therapy. The data in this review summarizes that the primary intervention in AD is brain metal homeostasis along with brain metal scavenging. This review evaluates the impact of different trace metals (Cu, Zn, Fe) on normal brain functioning and their association with neurodegeneration in AD. Also, it investigates the therapeutic potential of metal chelators in the management of AD. An extensive literature search was carried out on the Web of Science, PubMed, Science Direct, and Google Scholar to investigate the effect of trace elements in neurological impairment and the role of metal chelators in AD. In addition, the current review highlights the advantages and limitations of chelation therapies and the difficulties involved in developing selective metal chelation therapy in AD patients.

Lower semantic fluency scores and a phonemic-over-semantic advantage predict abnormal CSF P-tau

The present study aimed to determine whether patients with mild cognitive impairment (MCI) and dementia due to Alzheimers disease (AD), semantic verbal fluency (SVF), and the semantic-phonemic discrepancy (SPD) could predict abnormal cerebrospinal fluid (CSF) phosphorylated tau (P-tau Phonemic verbal fluency (PVF) and SVF scores of N 116 Aβ-positive patients with either MCI due to AD (N 39) or probable AD dementia (ADD N 77) were retrospectively collected. The SPD was computed by subtracting PVF scores from SVF ones (positive and negative values corresponding to a semantic and phonemic advantage, respectively). Patients were cognitively phenotyped via a thorough test battery and profiled according to the amyloidosistauopathyneurodegeneration (ATN) framework via CSF analyses. Two separate sets of logistic regressions were run to predict normal vs. abnormal P-tau Lower SVF, but not PVF, scores, as well as a greater phonemic advantage (i.e., negative SPD values), predicted abnormal CSF P-tau SVF and the SPD are able to predict tauopathy across the AD spectrum, thus supporting their status of valid, and sufficiently specific, cognitive markers of AD.

Impact of multidomain preventive strategies on functional brain connectivity in older adults with cognitive complaint Subset from the Montpellier center of the ancillary MAPT-MRI study.

The impact of multi-domain preventive interventions on older adults, in particular on those with higher risk to develop Alzheimers disease (AD), could be beneficial, as it may delay cognitive decline. However, the precise mechanism of such positive impact is not fully understood and may involve brain reserve and adaptability of brain functional connectivity (FC). To determine the effect of multidomain interventions (involving physical activity, cognitive training, nutritional counseling alone or in combination with omega-3 fatty acid supplementation and vs. a placebo) on the brain, longitudinal FC changes were assessed after 36 months of intervention on 100 older adults (above 70 year-old) with subjective cognitive complaints. No global change in FC was detected after uni or multidomain preventive interventions. However, an effect of omega-3 fatty acid supplementation dependent on cognitive decline status was underlined for frontoparietal, salience, visual and sensorimotor networks FC. These findings were independent of the cortical thickness and vascular burden. These results emphasize the importance of patient stratification, based on risk factors, for preventive interventions.

The Accuracy of Speech and Linguistic Analysis in Early Diagnostics of Neurocognitive Disorders in a Memory Clinic Setting.

To investigate whether automatic analysis of the Semantic Verbal Fluency test (SVF) is reliable and can extract additional information that is of value for identifying neurocognitive disorders. In addition, the associations between the automatically derived speech and linguistic features and other cognitive domains were explored. We included 135 participants from the memory clinic of the Maastricht University Medical Center (with Subjective Cognitive Decline SCD N 69 and Mild Cognitive Impairment MCIdementia N 66). The SVF task (one minute, category animals) was recorded and processed via a mobile application, and speech and linguistic features were automatically extracted. The diagnostic performance of the automatically derived features was investigated by training machine learning classifiers to differentiate SCD and MCIdementia participants. The intraclass correlation for interrater reliability between the clinical total score (golden standard) and automatically derived total word count was 0.84. The full model including the total word count and the automatically derived speech and linguistic features had an Area Under the Curve (AUC) of 0.85 for differentiating between people with SCD and MCIdementia. The model with total word count only and the model with total word count corrected for age showed an AUC of 0.75 and 0.81, respectively. Semantic switching correlated moderately with memory as well as executive functioning. The one-minute SVF task with automatically derived speech and linguistic features was as reliable as the manual scoring and differentiated well between SCD and MCIdementia. This can be considered as a valuable addition in the screening of neurocognitive disorders and in clinical practice.

Lipids uniquely alter the secondary structure and toxicity of amyloid beta 1-42 aggregates.

Abrupt aggregation of amyloid β

Pleiotropy analysis between lobar intracerebral hemorrhage and CSF β-amyloid highlights new and established associations.

Combining biologically related traits in genome-wide association studies (GWAS) increases the power for genetic discovery. Given the established relationship between lobar intracerebral hemorrhage (ICH) and cerebral amyloid angiopathy (CAA), and between the latter and levels of cerebrospinal fluid amyloid-β 42 (CSF-Aβ42), we leveraged genetic predisposition for lower CSF-Aβ42 levels as a proxy phenotype for CAA to identify new genes associated with lobar ICH. We used publicly available GWAS data for CSF-Aβ42 levels (n 3146) and for lobar ICH (n 2094). First, we evaluated the association between lobar ICH risk and CSF-Aβ42 in lobar ICH patients using a polygenic risk score (PRS) for CSF-Aβ42. Next, we conducted multi-trait analysis of GWAS (MTAG) for pleiotropy analysis of lobar ICH and CSF-Aβ42. MTAG results were further tested using Expression Quantitative Trait Locus and Differential Gene Expression Analyses. CSF-Aβ42 PRS was associated with lobar ICH risk (p 0.04). MTAG analysis identified a novel association within Our pleiotropy analysis suggested a variant possibly implicated with lobar ICH driven by amyloid-related mechanisms in

Recent research advances in young-onset dementia.

Young-onset dementia (YOD) refers to a dementia for which symptom onset occurs below the age of 65. This review summarizes the recent literature in this area, focusing on updates in epidemiology, diagnosis and service provision. In the last year, internationally, the prevalence of YOD was reported as 119 per 100 000, but this may vary according to population types. Although the commonest causes of YOD are Alzheimers disease (AD) and frontotemporal dementia (FTD), there is increasing recognition that YOD is diagnostically and phenotypically broader than AD and FTD. YOD may be due to many other diseases (e.g. Huntingtons disease, vascular dementia) whereas accumulation of the same protein (e.g. amyloid protein) may lead to different phenotypes of Alzheimers disease (such as posterior cortical atrophy and behavioural-variantfrontal-variant AD). This heterogeneity of phenotypic presentation is also seen in YOD due to known genetic mutations. Biomarkers such as plasma and cerebrospinal fluid proteins, neuroimaging and genetics have shown promise in the early identification of YOD as well as providing further understanding behind the overlap between psychiatric and neurodegenerative conditions occurring in younger people. The management of YOD needs to consider age-specific issues for younger people with dementia and their family networks together with better integration with other health services such as aged, disability and improved access to services and financial assistance. These findings emphasize the need for early identification and appropriate age-specific and person-centred management for people with young-onset dementia.

Exosomes for the diagnosis and treatment of dementia.

Dementia is a syndrome with several possible pathologies. To date, definitive methods for diagnosis and treatment of sub-types of dementia have not been established. Emerging evidence suggests that exosomes can provide important information for the diagnosis and treatment of several subtypes of dementia. This article reviews recent studies on the application of exosomes in dementia. Exosomes are involved in the pathogenesis of Alzheimers disease (AD) and Parkinsons disease (PD) through transporting toxic proteins such as amyloid beta (Aβ), tau, and α-synuclein. Exosomal microRNAs (miR) and proteins reflect the disease state, and therefore, exosomes can be used as diagnostic markers for diseases such as AD, PD, Huntingtons disease (HD), vascular dementia (VaD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). Mesenchymal stem cell (MSC)-derived exosomes have been shown to ameliorate disease pathology, and improve cognitive function in AD, PD, and VAD. Recent studies have shown that exosomes could be novel diagnostic agents for dementia because they contain molecules that could be potential biomarker candidates indicative of the type and stage of dementia. Therapeutic application of exosomes in dementia has revealed that exosomes only, or exosomes loaded with an active pharmaceutical ingredient (API), ameliorate disease phenotype of dementia. Further work is needed to exploit this potential.

Age-dependent NMDA receptor function is regulated by the amyloid precursor protein.

N-methyl-D-aspartate receptors (NMDARs) are critical for the maturation and plasticity of glutamatergic synapses. In the hippocampus, NMDARs mainly contain GluN2A andor GluN2B regulatory subunits. The amyloid precursor protein (APP) has emerged as a putative regulator of NMDARs, but the impact of this interaction to their function is largely unknown. By combining patch-clamp electrophysiology and molecular approaches, we unravel a dual mechanism by which APP controls GluN2B-NMDARs, depending on the life stage. We show that APP is highly abundant specifically at the postnatal postsynapse. It interacts with GluN2B-NMDARs, controlling its synaptic content and mediated currents, both in infant mice and primary neuronal cultures. Upon aging, the APP amyloidogenic-derived C-terminal fragments, rather than APP full-length, contribute to aberrant GluN2B-NMDAR currents. Accordingly, we found that the APP processing is increased upon aging, both in mice and human brain. Interfering with stability or production of the APP intracellular domain normalized the GluN2B-NMDARs currents. While the first mechanism might be essential for synaptic maturation during development, the latter could contribute to age-related synaptic impairments.

Systemic Inflammation Causes Microglial Dysfunction With a Vascular AD phenotype.

Studies in rodents and humans have indicated that inflammation outside CNS (systemic inflammation) affects brain homeostasis contributing to neurodevelopmental disorders. Itis becoming increasingly evident that such early insults may also belinked to neurodegenerative diseases like late-onset Alzheimers disease (AD). Importantly, lifestyle and stress, such as viral or bacterial infection causing chronic inflammation, may contribute to neurodegenerative dementia. Systemic inflammatory response triggers a cascade of neuroinflammatory responses, altering brain transcriptome, cell death characteristic of AD, and vascular dementia. Our study aimed to assess the temporal evolution of the pathological impact of systemic inflammation evoked by prenatal and early postnatal peripheral exposure of viral mimetic Polyinosinicpolycytidylic acid (PolyIC) and compare the hippocampal transcriptomic changes with the profiles of human post-mortem AD and vascular dementia brain specimens. We have engineered the PolyIC sterile infection model in wildtype C57BL6 mice to achieve chronic low-grade systemic inflammation. We have conducted a cross-sectional analysis of aging PolyIC and Saline control mice (3 months, 6 months, 9 months, and 16 months), taking the hippocampus as a reference brain region, and compared the brain aging phenotype to AD progression in humans with mild AD, severe AD, and Controls (CTL), in parallel to Vascular dementia (VaD) patients specimens. We found that PolyIC mice display both peripheral and central inflammation with a peak at 6 months, associated with memory deficits. The hippocampus is characterized by a pronounced and progressive tauopathy. In PolyIC brains, microglia undergo aging-dependent morphological shifts progressively adopting a phagocytic phenotype. Transcriptomic analysis reveals a profound change in gene expression throughout aging, with a peak in differential expression at 9 months. We show that the proinflammatory marker The PolyIC model of sterile infection demonstrates that peripheral chronic inflammation causes progressive tau hyperphosphorylation, changes in microglia morphology, astrogliosis and gene reprogramming reflecting increased neuroinflammation, vascular remodeling, and the loss of neuronal functionality seen to some extent in human AD and Vascular dementia suggesting early immune insults could be crucial in neurodegenerative diseases.

Effect of disturbances in neuronal calcium and IP3 dynamics on β-amyloid production and degradation.

Overproduction and accumulation of β-amyloid and its improper clearance can cause neurotoxicity leading to Alzheimers disease. The production and degradation of β-amyloid depend on the calcium (Ca

The effects of repetitive transcranial magnetic stimulation and aerobic exercise on cognition, balance and functional brain networks in patients with Alzheimers disease.

The purpose of this study was to investigate the effects of high-frequency repetitive Transcranial Magnetic Stimulation (rTMS) and aerobic exercises (AE) in addition to the pharmacological therapy (PT) in Alzheimers Disease (AD). Twenty-seven patients with AD aged ≥ 60 years were included in the study and divided into 3 groups (rTMS, AE and control). All groups received PT. rTMS group (n 10) received 20 Hz rTMS over dorsolateral prefrontal cortex (dlPFC) bilaterally and AE group (n 9) received the structured moderate-intensity AE for 5 consecutive daysweek over 2 weeks. Control group (n 8) only received PT. Cognition, balance, mobility, quality of life (QoL), and resting state functional brain activity were evaluated one week before and one week after the interventions. (ClinicalTrials.gov IDNCT05102045). Significant improvements were found in executive functions, behavior, and QoL in the rTMS group, in balance and mobility in the AE group, and in the visual memory and behavior in the control group (

Microglial autophagy in Alzheimers disease and Parkinsons disease.

Alzheimers disease (AD) and Parkinsons disease (PD) are the most common neurodegenerative diseases, characterized by gradual and selective loss of neurons in the central nervous system. They affect more than 50 million people worldwide, and their incidence increases with age. Although most cases of AD and PD are sporadic, some are caused by genetic mutations that are inherited. Both sporadic and familial cases display complex neuropathology and represent the most perplexing neurological disorders. Because of the undefined pathogenesis and complex clinical manifestations, there is still no effective treatment for both AD and PD. Understanding the pathogenesis of these important neurodegenerative diseases is important for developing successful therapies. Increasing evidence suggests that microglial autophagy is associated with the pathogenesis of AD and PD, and its dysfunction has been implicated in disease progression. In this review, we focus on the autophagy function in microglia and its dysfunction in AD and PD disease models in an attempt to help our understanding of the pathogenesis and identifying new therapeutic targets of AD and PD.

Effect of exercise on cognitive function and synaptic plasticity in Alzheimers disease models A systematic review and meta-analysis.

Cognitive decline is a central manifestation of Alzheimers disease (AD), and its process is inseparable from changes in synaptic plasticity. The aim of this review was to summarize and evaluate the effectiveness of exercise on cognitive function and synaptic plasticity in AD animal models. Eligible studies were searched from PubMed, MEDLINE, EMBASE, Web of Science, and Cochrane Library from April to May 2022. The risk of bias was evaluated by Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE). The Morris water maze (MWM) test and synaptic plasticity were considered outcome measures. Data were analyzed using random-effects meta-analyses using the software Stata. Heterogeneity was examined by using I2 test. Sensitivity analysis and publication bias were also assessed. A total of 20 randomized controlled studies were eligible for study inclusion. Compared with controls, exercise decreased escape latency (SMD -0.86, 95% CI -1.21 to -0.50, Our findings suggested that exercise had a potential effect on improving cognitive function and synaptic plasticity. It can play a better neuroprotective role before AD. PROSPERO, identifier CRD42022328438.

Multi-omics analysis revealed the role of CCT2 in the induction of autophagy in Alzheimers disease.

What is the role of lipids in prion conversion and disease

The molecular cause of transmissible spongiform encephalopathies (TSEs) involves the conversion of the cellular prion protein (PrP

The Relationship of Vascular Aging to Reduced Cognitive Function Pulsatile and Steady State Arterial Hemodynamics.

Aortic stiffness increases with age and is a robust predictor of cerebrovascular events and cognitive decline including Alzheimers disease and other forms of dementia. Recent clinical studies have investigated the association between proximal aortic stiffness and pulsatile energy transmission that has deleterious effects on the cerebrovascular network in order to identify potential therapeutic targets. Aging causes disproportionate stiffening of the aorta compared with the carotid arteries, reducing protective impedance mismatches at their interface, increasing the transmission of destructive pulsatile pressure and energy to the cerebral circulation, and leading to cerebral small vessel disease. Thus, aortic stiffening and high-flow pulsatility are associated with alterations in the microvasculature of the brain, vascular endothelial dysfunction, and white matter damage, which contribute to impaired memory function with advancing age. Previous studies have also shown that silent lacunar infarcts and white matter hyperintensities are strongly associated with arterial stiffness. More and more evidence suggests that vascular etiologies, including aortic stiffness, impedance match, and microvascular damage, are associated with cognitive impairment and the pathogenesis of dementia. The measurement of arterial flow and pressure can help understand pulsatile hemodynamics and its impact on vital organs. Interventions that reduce aortic stiffness, such as improvement of the living environment, management of risk factors, and innovation and development of novel drugs, may reduce the risk for dementia.

Personalized transcranial alternating current stimulation improves sleep quality Initial findings.

Insufficient sleep is a major health issue. Inadequate sleep is associated with an array of poor health outcomes, including cardiovascular disease, diabetes, obesity, certain forms of cancer, Alzheimers disease, depression, anxiety, and suicidality. Given concerns with typical sedative hypnotic drugs for treating sleep difficulties, there is a compelling need for alternative interventions. Here, we report results of a non-invasive electrical brain stimulation approach to optimizing sleep involving transcranial alternating current stimulation (tACS). A total of 25 participants (mean age 46.3, S.D. ± 12.4, 15 females) were recruited for a null-stimulation controlled (Control condition), within subjects, randomized crossed design, that included two variants of an active condition involving 15 min pre-sleep tACS stimulation. To evaluate the impact on sleep quality, the two active tACS stimulation conditions were designed to modulate sleep-dependent neural activity in the thetaalpha frequency bands, with both stimulation types applied to all subjects in separate sessions. The first tACS condition used a fixed stimulation pattern across all participants, a pattern composed of stimulation at 5 and 10 Hz. The second tACS condition used a personalized stimulation approach with the stimulation frequencies determined by each individuals peak EEG frequencies in the 4-6 Hz and 9-11 Hz bands. Personalized tACS stimulation increased sleep quantity (duration) by 22 min compared to a Control condition (

Assessing the role of primary healthy microglia and gap junction blocker in hindering Alzheimers disease neuroinflammatory type Early approaches for therapeutic intervention.

Alzheimers disease (AD) is a predominantly heterogeneous disease with a highly complex pathobiology. The presence of amyloid-beta (Aβ) depositions and the accumulation of hyperphosphorylated tau protein remain the characteristic hallmarks of AD. These hallmarks can be detected throughout the brain and other regions, including cerebrospinal fluid (CSF) and the spinal cord. Microglia cells, the brain-resident macrophage type of the brain, are implicated in maintaining healthy brain homeostasis. The localized administration of primary healthy microglia (PHM) is suggested to play a role in mitigating AD hallmark depositions and associated cognitive dysfunction. Carbenoxolone (CBX) is the most common gap junction blocker. It cannot effectively cross the blood-brain barrier (BBB) under systemic administration. Therefore, localized administration of CBX may be a recommended intervention against AD by acting as an antioxidant and anti-inflammatory agent. This study aims to determine whether the localized intracerebroventricular (ICV) administration of PHM and CBX may act as an effective therapeutic intervention for AD neuroinflammatory type. In addition, this study also aims to reveal whether detecting AD hallmarks in the spinal cord and CSF can be considered functional and effective during AD early diagnosis. Male albino rats were divided into four groups control (group 1), lipopolysaccharide (LPS)-induced AD neuroinflammatory type (group 2), ICV injection of LPS isolated PHM (group 3), and ICV injection of LPS CBX (group 4). Morris water maze (MWM) was conducted to evaluate spatial working memory. The brain and spinal cord were isolated from each rat with the collection of CSF. Our findings demonstrate that the localized administration of PHM and CBX can act as promising therapeutic approaches against AD. Additionally, Aβ and tau toxic aggregates were detected in the spinal cord and the CSF of the induced AD model concomitant with the brain tissues. Overall, it is suggested that the ICV administration of PHM and CBX can restore normal brain functions and alleviate AD hallmark depositions. Detecting these depositions in the spinal cord and CSF may be considered in AD early diagnosis. As such, conducting clinical research is recommended to reveal the benefits of related therapeutic approaches compared with preclinical findings.

Melanocortin receptor agonist NDP-α-MSH improves cognitive deficits and microgliosis but not amyloidosis in advanced stages of AD progression in 5XFAD and 3xTg mice.

Alzheimers disease (AD) is the most frequent cause of dementia and still lacks effective therapy. Clinical signs of AD include low levels of endogenous melanocortins (MCs) and previous studies have shown that treatment with MC analogs induces neuroprotection in the early stages of AD. We investigated the neuroprotective role of MCs in two transgenic mouse models of severe AD using 5 and 7 month-old (mo) 5XFAD mice and 9 and 12 mo 3xTg mice. These mice were subjected to a chronic stimulation of MC receptors (MCRs) with MC analogue Nle4-D-Phe7-α-melanocyte stimulating hormone (NDP-α-MSH, 340 μgkg, i.p.). Mouse behavior and ex-vivo histological and biochemical analyses were performed after 50 days of treatment. Our analysis demonstrated an improvement in cognitive abilities of AD mice at late stage of AD progression. We also showed that these protective effects are associated with decreased levels of hyperphosphorylated Tau but not with Aβ burden, that was unaffected in the hippocampus and in the cortex of AD mice. In addition, an age-dependent NDP effect on glial reactivity was observed only in 3xTg mice whereas a global downregulation of p38 mitogen-activated protein kinase was selectively observed in 7 mo 5XFAD and 14 mo 3xTg mice. Our results suggest that MCR stimulation by NDP-α-MSH could represent a promising therapeutic strategy in managing cognitive decline also at late stage of AD, whereas the effects on neuroinflammation may be restricted to specific stages of AD progression.

Leveraging genetic diversity in mice to inform individual differences in brain microstructure and memory.

In human Alzheimers disease (AD) patients and AD mouse models, both differential pre-disease brain features and differential disease-associated memory decline are observed, suggesting that certain neurological features may protect against AD-related cognitive decline. The combination of these features is known as brain reserve, and understanding the genetic underpinnings of brain reserve may advance AD treatment in genetically diverse human populations. One potential source of brain reserve is brain microstructure, which is genetically influenced and can be measured with diffusion MRI (dMRI). To investigate variation of dMRI metrics in pre-disease-onset, genetically diverse AD mouse models, we utilized a population of genetically distinct AD mice produced by crossing the 5XFAD transgenic mouse model of AD to 3 inbred strains (C57BL6J, DBA2J, FVBNJ) and two wild-derived strains (CASTEiJ, WSBEiJ). At 3 months of age, these mice underwent diffusion magnetic resonance imaging (dMRI) to probe neural microanatomy in 83 regions of interest (ROIs). At 5 months of age, these mice underwent contextual fear conditioning (CFC). Strain had a significant effect on dMRI measures in most ROIs tested, while far fewer effects of sex, sexstrain interactions, or strainsex5XFAD genotype interactions were observed. A main effect of 5XFAD genotype was observed in only 1 ROI, suggesting that the 5XFAD transgene does not strongly disrupt neural development or microstructure of mice in early adulthood. Strain also explained the most variance in mouse baseline motor activity and long-term fear memory. Additionally, significant effects of sex and strainsex interaction were observed on baseline motor activity, and significant strainsex and sex5XFAD genotype interactions were observed on long-term memory. We are the first to study the genetic influences of brain microanatomy in genetically diverse AD mice. Thus, we demonstrated that strain is the primary factor influencing brain microstructure in young adult AD mice and that neural development and early adult microstructure are not strongly altered by the 5XFAD transgene. We also demonstrated that strain, sex, and 5XFAD genotype interact to influence memory in genetically diverse adult mice. Our results support the usefulness of the 5XFAD mouse model and convey strong relationships between natural genetic variation, brain microstructure, and memory.

Fornix degeneration in risk factors of Alzheimers disease, possible trigger of cognitive decline.

Risk factors of late-onset Alzheimers disease (AD) such as aging, type 2 diabetes, obesity, heart failure, and traumatic brain injury can facilitate the appearance of cognitive decline and dementia by triggering cerebrovascular pathology and neuroinflammation. White matter (WM) microstructure and function are especially vulnerable to these conditions. Microstructural WM changes, assessed with diffusion weighted magnetic resonance imaging, can already be detected at preclinical stages of AD, and in the presence of the aforementioned risk factors. Particularly, the limbic system and cortico-cortical association WM tracts, which myelinate late during brain development, degenerate at the earliest stages. The fornix, a C-shaped WM tract that originates from the hippocampus, is one of the limbic tracts that shows early microstructural changes. Fornix integrity is necessary for ensuring an intact executive function and memory performance. Thus, a better understanding of the mechanisms that cause fornix degeneration is critical in the development of therapeutic strategies aiming to prevent cognitive decline in populations at risk. In this literature review, i) we deepen the idea that partial loss of forniceal integrity is an early event in AD, ii) we describe the role that common risk factors of AD can play in the degeneration of the fornix, and iii) we discuss some potential cellular and physiological mechanisms of WM degeneration in the scenario of cerebrovascular disease and inflammation.

Nano-Brake Halts Mitochondrial Dysfunction Cascade to Alleviate Neuropathology and Rescue Alzheimers Cognitive Deficits.

Mitochondrial dysfunction has been recognized as the key pathogenesis of most neurodegenerative diseases including Alzheimers disease (AD). The dysregulation of mitochondrial calcium ion (Ca

Challenges and Discoveries in Polypharmacology of Neurodegenerative Diseases.

Neurological disorders are composed of several diseases that affect the central and peripheral nervous system among these are neurodegenerative diseases, which lead to neuronal death. Many of these diseases have treatment for the disease and symptoms, leading patients to use several drugs that cause side effects. The search for new treatments has led to the investigation of multi-target drugs. This review aimed to investigate in the literature the multi-target effect in neurological disorders through an in silico approach. Studies were reviewed on the diseases such as epilepsy, Alzheimers disease, Amyotrophic Lateral Sclerosis (ALS), Huntingtons disease, cerebral ischemia, and Parkinsons disease. As a result, the study emphasize the relevance of research by computational techniques such as quantitative structure-activity relationship (QSAR) prediction models, pharmacokinetic prediction models, molecular docking, and molecular dynamics, besides presenting possible drug candidates with multi-target activity. It was possible to identify several targets with pharmacological activities. Some of these targets had diseases in common such as carbonic anhydrase, acetylcholinesterase, NMDA, and MAO being relevant for possible multi-target approaches.

Myelination as a modulating factor in memory circuitry.

Myelin has been understood for many years as a static component that regulates the speed of electrical impulse transmission. However, multiple works defend a dynamic role dependent on experience. This has allowed the development of a new concept called myelin plasticity that contributes, together with synaptic plasticity, to the long-term changes that occur in neuronal circuits during learning and memory. Therefore, this review will address the latest published data regarding the role of myelination with memory. Evidence from human neuroimaging studies demonstrates that myelination can change due to activity-dependent modulation, such that learning can modify the axon myelination. Alternatively, it has also been shown that interfering with myelination, using transgenic rodent models, significantly impairs memory processes. This has important implications in alterations as severe as Alzheimers disease, where transcriptional changes and in the phenotype of cells associated with the myelination process begin to be described. The new knowledge supports the concept of myelin plasticity and its implications for memory, which opens a new opportunity for the treatment of deficits that affect this cognitive function. La mielinización como un factor modulador de los circuitos de memoria. Introducción. La mielina se ha conceptualizado durante muchos años como un componente estático que regula la velocidad de transmisión del impulso nervioso. Sin embargo, cada vez son más los trabajos que defienden un papel dinámico y dependiente de la experiencia. Esto ha permitido el desarrollo de un nuevo concepto denominado plasticidad mielínica, que contribuye, junto con la plasticidad sináptica, a los cambios a largo plazo que se dan en los circuitos neuronales durante el aprendizaje y la memoria. Por tanto, en esta revisión se abordarán los últimos datos publicados en relación con el papel de la mielinización con la memoria. Desarrollo. La evidencia a partir de estudios de neuroimagen en humanos demuestra que la mielinización puede cambiar debido a la modulación dependiente de la actividad, de forma que los aprendizajes pueden modificar la mielinización de los axones. Alternativamente, también se ha demostrado que interferir sobre la mielinización, utilizando para ello modelos transgénicos de roedores, deteriora significativamente los procesos de memoria. Esto tiene importantes implicaciones en alteraciones tan graves como la enfermedad de Alzheimer, en la que comienzan a describirse cambios transcripcionales y en el fenotipo de las células asociadas al proceso de mielinización. Conclusiones. Los nuevos descubrimientos apoyan el concepto de plasticidad mielínica y sus implicaciones con la memoria, lo que abre una nueva oportunidad para el tratamiento de los déficits que afectan a esta función cognitiva.

The neuroimmune axis of Alzheimers disease.

Alzheimers disease (AD) is a genetically complex and heterogeneous disorder with multifaceted neuropathological features, including β-amyloid plaques, neurofibrillary tangles, and neuroinflammation. Over the past decade, emerging evidence has implicated both beneficial and pathological roles for innate immune genes and immune cells, including peripheral immune cells such as T cells, which can infiltrate the brain and either ameliorate or exacerbate AD neuropathogenesis. These findings support a neuroimmune axis of AD, in which the interplay of adaptive and innate immune systems inside and outside the brain critically impacts the etiology and pathogenesis of AD. In this review, we discuss the complexities of AD neuropathology at the levels of genetics and cellular physiology, highlighting immune signaling pathways and genes associated with AD risk and interactions among both innate and adaptive immune cells in the AD brain. We emphasize the role of peripheral immune cells in AD and the mechanisms by which immune cells, such as T cells and monocytes, influence AD neuropathology, including microglial clearance of amyloid-β peptide, the key component of β-amyloid plaque cores, pro-inflammatory and cytotoxic activity of microglia, astrogliosis, and their interactions with the brain vasculature. Finally, we review the challenges and outlook for establishing immune-based therapies for treating and preventing AD.

Combined metabolic activators improve cognitive functions in Alzheimers disease patients a randomised, double-blinded, placebo-controlled phase-II trial.

Alzheimers disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. We recently administered combined metabolic activators (CMA) to the AD rat model and observed that CMA improves the AD-associated histological parameters in the animals. CMA promotes mitochondrial fatty acid uptake from the cytosol, facilitates fatty acid oxidation in the mitochondria, and alleviates oxidative stress. Here, we designed a randomised, double-blinded, placebo-controlled phase-II clinical trial and studied the effect of CMA administration on the global metabolism of AD patients. One-dose CMA included 12.35 g L-serine (61.75%), 1 g nicotinamide riboside (5%), 2.55 g N-acetyl-L-cysteine (12.75%), and 3.73 g L-carnitine tartrate (18.65%). AD patients received one dose of CMA or placebo daily during the first 28 days and twice daily between day 28 and day 84. The primary endpoint was the difference in the cognitive function and daily living activity scores between the placebo and the treatment arms. The secondary aim of this study was to evaluate the safety and tolerability of CMA. A comprehensive plasma metabolome and proteome analysis was also performed to evaluate the efficacy of the CMA in AD patients. We showed a significant decrease of AD Assessment Scale-cognitive subscale (ADAS-Cog) score on day 84 vs day 0 (P 0.00001, 29% improvement) in the CMA group. Moreover, there was a significant decline (P 0.0073) in ADAS-Cog scores (improvement of cognitive functions) in the CMA compared to the placebo group in patients with higher ADAS-Cog scores. Improved cognitive functions in AD patients were supported by the relevant alterations in the hippocampal volumes and cortical thickness based on imaging analysis. Moreover, the plasma levels of proteins and metabolites associated with NAD and glutathione metabolism were significantly improved after CMA treatment. Our results indicate that treatment of AD patients with CMA can lead to enhanced cognitive functions and improved clinical parameters associated with phenomics, metabolomics, proteomics and imaging analysis. Trial registration ClinicalTrials.gov NCT04044131 Registered 17 July 2019, httpsclinicaltrials.govct2showNCT04044131.

Predicting progression to Alzheimers disease with human hippocampal progenitors exposed to serum.

Adult hippocampal neurogenesis is important for learning and memory and is altered early in Alzheimers disease. As hippocampal neurogenesis is modulated by the circulatory systemic environment, evaluating a proxy of how hippocampal neurogenesis is affected by the systemic milieu could serve as an early biomarker for Alzheimers disease progression. Here, we used an in vitro assay to model the impact of systemic environment on hippocampal neurogenesis. A human hippocampal progenitor cell line was treated with longitudinal serum samples from individuals with mild cognitive impairment, who either progressed to Alzheimers disease or remained cognitively stable. Mild cognitive impairment to Alzheimers disease progression was characterized most prominently with decreased proliferation, increased cell death and increased neurogenesis. A subset of baseline cellular readouts together with education level were able to predict Alzheimers disease progression. The assay could provide a powerful platform for early prognosis, monitoring disease progression and further mechanistic studies.

Gene regulation in activated microglia by adenosine A

Most neurodegenerative disorders, including the two most common, Alzheimers disease (AD) and Parkinsons disease (AD), course with activation of microglia, the resident innate immune cells of the central nervous system. A

Amyloid Precursor Protein 𝛽CTF accumulates in synapses in sporadic and genetic forms of Alzheimers disease.

Amyloid Precursor Protein (APP) 𝛽-C-terminal fragment (𝛽CTF) may have a neurotoxic role in Alzheimer´s disease (AD). 𝛽CTF accumulates in the brains of patients with sporadic (SAD) and genetic forms of Alzheimers Disease (AD). Synapses degenerate early during the pathogenesis of AD. We studied whether the 𝛽CTF accumulates in synapses in SAD, autosomal dominant AD (ADAD) and Down syndrome (DS). We used Array tomography to determine APP at synapses in human AD tissue. We measured 𝛽CTF, A𝛽40, A𝛽42 and phosphorylated tau181 (p-tau181) concentrations in brain homogenates and synaptosomes of frontal and temporal cortex of SAD, ADAD, DS and controls. APP colocalized with pre- and post-synaptic markers in human AD brains. APP 𝛽CTF was enriched in AD synaptosomes. We demonstrate that 𝛽CTF accumulates in synapses in SAD, ADAD and DS. This finding might suggest a role for 𝛽CTF in synapse degeneration. Therapies aimed at mitigating 𝛽CTF accumulation could be potentially beneficial in AD.

Age-related alterations in protein phosphatase 2A methylation levels in brains of cynomolgus monkeys a pilot study.

The abnormal activity of PP2A, a dominant member of type 2A serinethreonine protein phosphatase, has been implicated in the development of Alzheimers disease (AD) and dementia with Lewy bodies (DLB). PP2A is a holoenzyme, and protein methylation of the catalytic subunit, PP2Ac, alters the complex composition. A decrease in PP2Ac methylation levels has been reported in AD and DLB. Aging is the most common risk factor for AD and DLB, but the relationship between aging and PP2A has not been studied in detail. Cynomolgus monkey show increased phosphorylation levels of tau and α-synuclein with aging. In this study, we investigated the alterations in the PP2A activity regulation with aging in monkey brains from 2 to 43 years of age using fractionated proteins. We found that type 2A protein phosphatase activity decreased with aging in cytoplasmic and nuclear-soluble fractions. PP2Ac methylation level was decreased in cytoplasmic and sarkosyl-insoluble fractions. A principal component analysis using PP2Ac, demethylated PP2Ac, and PP2A methylesterase PME-1 levels in cytoplasmic and nuclear-soluble fractions as attributes showed that aged monkeys were in the same cluster. Our results show that brain aging in cynomolgus monkeys is closely related to changes in PP2A methylation.

The shared molecular mechanisms underlying aging of the brain, major depressive disorder, and Alzheimers disease The role of circadian rhythm disturbances.

An association with circadian clock function and pathophysiology of aging, major depressive disorder (MDD), and Alzheimers disease (AD) is well established and has been proposed as a factor in the development of these diseases. Depression and changes in circadian rhythm have been increasingly suggested as the two primary overlapping and interpenetrating changes that occur with aging. The relationship between AD and depression in late life is not completely understood and probably is complex. Patients with major depression or AD suffer from disturbed sleepwake cycles and altered rhythms in daily activities. Although classical monoaminergic hypotheses are traditionally proposed to explain the pathophysiology of MDD, several clinical and preclinical studies have reported a strong association between circadian rhythm and mood regulation. In addition, a large body of evidence supports an association between disruption of circadian rhythm and AD. Some clock genes are dysregulated in rodent models of depression. If aging, AD, and MDD share a common biological basis in pathophysiology, common therapeutic tools could be investigated for their prevention and treatment. Nitro-oxidative stress (NOS), for example, plays a fundamental role in aging, as well as in the pathogenesis of AD and MDD and is associated with circadian clock disturbances. Thus, development of therapeutic possibilities with these NOS-related conditions is advisable. This review describes recent findings that link disrupted circadian clocks to aging, MDD, and AD and summarizes the experimental evidence that supports connections between the circadian clock and molecular pathologic factors as shared common pathophysiological mechanisms underlying aging, AD, and MDD.

Overexpression of alpha synuclein disrupts APP and Endolysosomal axonal trafficking in a mouse model of synucleinopathy.

Mutations or triplication of the alpha synuclein (ASYN) gene contribute to synucleinopathies including Parkinsons disease (PD), Dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Recent evidence suggests that ASYN also plays an important role in amyloid-induced neurotoxicity, although the mechanism(s) remains unknown. One hypothesis is that accumulation of ASYN alters endolysosomal pathways to impact axonal trafficking and processing of the amyloid precursor protein (APP). To define an axonal function for ASYN, we used a transgenic mouse model of synucleinopathy that expresses a GFP-human ASYN (GFP-hASYN) transgene and an ASYN knockout (ASYN

Liquid-liquid phase separation of protein tau An emerging process in Alzheimers disease pathogenesis.

Metabolic reactions within cells occur in various isolated compartments with or without borders, the latter being known as membrane-less organelles (MLOs). The MLOs show liquid-like properties and are formed by a process known as liquid-liquid phase separation (LLPS). MLOs contribute to different molecules interactions such as protein-protein, protein-RNA, and RNA-RNA driven by various factors, such as multivalency of intrinsic disorders. MLOs are involved in several cell signaling pathways such as transcription, immune response, and cellular organization. However, disruption of these processes has been found in different pathologies. Recently, it has been demonstrated that protein aggregates, a characteristic of some neurodegenerative diseases, undergo similar phase separation. Tau protein is known as a major neurofibrillary tangles component in Alzheimers disease (AD). This protein can undergo phase separation to form a MLO known as tau droplet in vitro and in vivo, and this process can be facilitated by several factors, including crowding agents, RNA, and phosphorylation. Tau droplet has been shown to mature into insoluble aggregates suggesting that this process may precede and induce neurodegeneration in AD. Here we review major factors involved in liquid droplet formation within a cell. Additionally, we highlight recent findings concerning tau aggregation following phase separation in AD, along with the potential therapeutic strategies that could be explored in this process against the progression of this pathology.

Ikzf1 as a novel regulator of microglial homeostasis in inflammation and neurodegeneration.

In the last two decades, microglia have emerged as key contributors to disease progression in many neurological disorders, not only by exerting their classical immunological functions but also as extremely dynamic cells with the ability to modulate synaptic and neural activity. This dynamic behavior, together with their heterogeneous roles and response to diverse perturbations in the brain parenchyma has raised the idea that microglia activation is more diverse than anticipated and that understanding the molecular mechanisms underlying microglial states is essential to unravel their role in health and disease from development to aging. The Ikzf1 (a.k.a. Ikaros) gene plays crucial roles in modulating the function and maturation of circulating monocytes and lymphocytes, but whether it regulates microglial functions and states is unknown. Using genetic tools, here we describe that Ikzf1 is specifically expressed in the adult microglia in brain regions such as cortex and hippocampus. By characterizing the Ikzf1 deficient mice, we observed that these mice displayed spatial learning deficits, impaired hippocampal CA3-CA1 long-term potentiation, and decreased spine density in pyramidal neurons of the CA1, which correlates with an increased expression of synaptic markers within microglia. Additionally, these Ikzf1 deficient microglia exhibited a severe abnormal morphology in the hippocampus, which is accompanied by astrogliosis, an aberrant composition of the inflammasome, and an altered expression of disease-associated microglia molecules. Interestingly, the lack of Ikzf1 induced changes on histone 3 acetylation and methylation levels in the hippocampus. Since the lack of Ikzf1 in mice appears to induce the internalization of synaptic markers within microglia, and severe gliosis we then analyzed hippocampal Ikzf1 levels in several models of neurological disorders. Ikzf1 levels were increased in the hippocampus of these neurological models, as well as in postmortem hippocampal samples from Alzheimers disease patients. Finally, over-expressing Ikzf1 in cultured microglia made these cells hyporeactive upon treatment with lipopolysaccharide, and less phagocytic compared to control microglia. Altogether, these results suggest that altered Ikzf1 levels in the adult hippocampus are sufficient to induce synaptic plasticity and memory deficits via altering microglial state and function.

Applications of generative adversarial networks in neuroimaging and clinical neuroscience.

Generative adversarial networks (GANs) are one powerful type of deep learning models that have been successfully utilized in numerous fields. They belong to the broader family of generative methods, which learn to generate realistic data with a probabilistic model by learning distributions from real samples. In the clinical context, GANs have shown enhanced capabilities in capturing spatially complex, nonlinear, and potentially subtle disease effects compared to traditional generative methods. This review critically appraises the existing literature on the applications of GANs in imaging studies of various neurological conditions, including Alzheimers disease, brain tumors, brain aging, and multiple sclerosis. We provide an intuitive explanation of various GAN methods for each application and further discuss the main challenges, open questions, and promising future directions of leveraging GANs in neuroimaging. We aim to bridge the gap between advanced deep learning methods and neurology research by highlighting how GANs can be leveraged to support clinical decision making and contribute to a better understanding of the structural and functional patterns of brain diseases.

Structural and Molecular Determinants for Isoform Bias at Human Histamine H

The human histamine H

Neurological soft signs are associated with reduced medial-lateral postural control in adolescent athletes.

Neurological soft signs (NSS) are minor deviations from the norm in motor performance that are commonly assessed using neurological examinations. NSS may be of clinical relevance for evaluating the developmental status of adolescents. Here we investigate whether quantitative force plate measures may add relevant information to observer-based neurological examinations. Male adolescent athletes (n 141) aged 13-16 years from three European sites underwent a neurological examination including 28 tests grouped into six functional clusters. The performance of tests and functional clusters was rated as optimalnon-optimal resulting in NSSNSS- groups and a continuous total NSS score. Participants performed a postural control task on a Balance Tracking System measured as path length, root mean square and sway area. ANCOVAs were applied to test for group differences in postural control between the NSS and NSS- group, and between optimalnon-optimal performance on a cluster- and test-level. Moreover, we tested for correlations between the total NSS score and postural control variables. There was no significant overall difference between the NSS and NSS- group in postural control. However, non-optimal performing participants in the diadochokinesis test swayed significantly more in the medial-lateral direction than optimal performing participants. Moreover, a lower total NSS score was associated with reduced postural control in the medial-lateral direction. Our findings demonstrate that NSS are related to postural control in adolescent athletes. Thus, force plate measures may add a quantitative, objective measurement of postural control to observer-based qualitative assessments, and thus, may complement clinical testing.

Effects of traditional Chinese exercise on vascular function in patients with Alzheimers disease A protocol for systematic review and network meta-analysis of randomized controlled trials.

Alzheimers disease (AD) is a progressive neurodegenerative disorder with an insidious onset, usually characterized by memory impairment, visual-spatial skill impairment, executive dysfunction and personality behavioral changes. Studies have confirmed that vascular dysfunction may precede AD pathological changes and can present as vascular malformations, atherosclerosis, and impaired self-regulation, and can affect oxidative stress and amyloidosis. Therefore, it is important to improve or prevent vascular dysfunction in AD patients. Regular exercise can effectively inhibit the production of reactive oxygen species during the occurrence of AD and can improve the reduction of cerebral blood flow due to AD. Previous studies have shown that exercise can achieve superior clinical results in improving vascular function in AD patients. Therefore, we hypothesize that traditional Chinese exercises (TCEs) may have a good clinical effect in improving vascular function in patients with AD. We will search PubMed, the Cochrane Library, Embase, Web of Science, CINAHL, ProQuest Dissertations and Theses, and ProQuest-Health Medical Collection, CNKI, SinoMed, VIP, and Wanfang Data to find randomized controlled trials of the effects of TCEs on AD vascular function from the creation of the database to the present, including at least 1 indicator in carotid intima-media thickness (cIMT), middle cerebral artery mean flow velocity (MFV), blood indicators Heme Oxidase-1 (HO-1), angiopoietin I (Ang I), vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor, matrix metalloproteinase-9 (MMP-9), and arterial stiffness (Ankle Brachial Index (ABI), pulse wave velocity (PWV). For the included literature, Excel 2019 will be used for data extraction and collection. For the indicators that can be netted for network meta-analysis, Surface Under the Cumulative Ranking for each exercise modality will be calculated with the help of Stata 16.0 and rank, where the higher the SUCRA score, the higher the ranking. For the indicators that cannot be netted, Review Manager 5.4 will be used for meta-analysis will be performed to evaluate the improvement effect of TCEs on AD patients. This meta-analysis will further determine the efficacy and safety of TCEs on vascular function in AD patients. In this study, randomized controlled trials of the effects of TCEs on vascular function in AD patients will be selected to provide evidence-based medical evidence for promoting the application of TCEs by observing the order of advantages and disadvantages of various exercise modalities through network meta-analysis.

Treatment for cognitive and neuropsychiatric non-motor symptoms in Parkinsons disease current evidence and future perspectives.

Non-motor symptoms (NMS) affect patients with Parkinsons disease (PD) from the prodromal to the advanced stages. NMS phenotypes greatly vary and have a huge impact on patients and caregivers quality of life (QoL). The management of cognitive and neuropsychiatric NMS remains an unmet need. The authors, herein, review the dopaminergic and non-dopaminergic pathogenesis, clinical features, assessment, and pharmacological and non-pharmacological treatments of cognitive and neuropsychiatric NMS in PD. They discuss the current evidence and report the findings of an overview of ongoing trials on pharmacological and selected non-pharmacological strategies. The treatment of cognitive and neuropsychiatric NMS in PD is poorly explored, and therapeutic options are unsatisfactory. Pharmacological treatment of cognitive NMS is based on symptomatic active principles used in Alzheimers disease. Dopamine agonists, selective serotonin, and serotonin-norepinephrine reuptake inhibitors have some evidence on PD-related depression. Clozapine, quetiapine, and pimavanserin may be considered for psychosis in PD. Evidence on the treatment of other neuropsychiatric NMS is limited or lacking. Addressing pathophysiological and clinical issues, which hamper solid evidence on the treatment of cognitive and neuropsychiatric NMS, may reduce the impact on QoL for PD patients and their caregivers.

Age-related changes in tau and autophagy in human brain in the absence of neurodegeneration.

Tau becomes abnormally hyper-phosphorylated and aggregated in tauopathies like Alzheimers disease (AD). As age is the greatest risk factor for developing AD, it is important to understand how tau protein itself, and the pathways implicated in its turnover, change during aging. We investigated age-related changes in total and phosphorylated tau in brain samples from two cohorts of cognitively normal individuals spanning 19-74 years, without overt neurodegeneration. One cohort utilised resected tissue and the other used post-mortem tissue. Total soluble tau levels declined with age in both cohorts. Phosphorylated tau was undetectable in the post-mortem tissue but was clearly evident in the resected tissue and did not undergo significant age-related change. To ascertain if the decline in soluble tau was correlated with age-related changes in autophagy, three markers of autophagy were tested but only two appeared to increase with age and the third was unchanged. This implies that in individuals who do not develop neurodegeneration, there is an age-related reduction in soluble tau which could potentially be due to age-related changes in autophagy. Thus, to explore how an age-related increase in autophagy might influence tau-mediated dysfunctions in vivo, autophagy was enhanced in a Drosophila model and all age-related tau phenotypes were significantly ameliorated. These data shed light on age-related physiological changes in proteins implicated in AD and highlights the need to study pathways that may be responsible for these changes. It also demonstrates the therapeutic potential of interventions that upregulate turnover of aggregate-prone proteins during aging.

A simple genetic stratification method for lower cost, more expedient clinical trials in early Alzheimers disease A preliminary study of tau PET and cognitive outcomes.

Identifying individuals who are most likely to accumulate tau and exhibit cognitive decline is critical for Alzheimers disease (AD) clinical trials. Participants (N 235) who were cognitively normal or with mild cognitive impairment from the Alzheimers Disease Neuroimaging Initiative were stratified by a cutoff on the polygenic hazard score (PHS) at 65th percentile (above as high-risk group and below as low-risk group). We evaluated the associations between the PHS risk groups and tau positron emission tomography and cognitive decline, respectively. Power analyses estimated the sample size needed for clinical trials to detect differences in tau accumulation or cognitive change. The high-risk group showed faster tau accumulation and cognitive decline. Clinical trials using the high-risk group would require a fraction of the sample size as trials without this inclusion criterion. Incorporating a PHS inclusion criterion represents a low-cost and accessible way to identify potential participants for AD clinical trials.

Association of Aging and Cognition With Complex Speech Understanding in Cochlear-Implanted Adults Use of a Modified National Institutes of Health (NIH) Toolbox Cognitive Assessment.

The association between cognitive function and outcomes in cochlear implant (CI) users is not completely understood, partly because some cognitive tests are confounded by auditory status. It is important to determine appropriate cognitive tests to use in a cohort of CI recipients. To provide proof-of-concept for using an adapted version of the National Institutes of Health (NIH) Toolbox Cognition Battery in a cohort of patients with CIs and to explore how hearing in noise with a CI is affected by cognitive status using the adapted test. In this prognostic study, participants listened to sentences presented in a speech-shaped background noise. Cognitive tests consisted of 7 subtests of the NIH Toolbox Cognition Battery that were adapted for hearing impaired individuals by including written instructions and visual stimuli. Participants were prospectively recruited from and evaluated at a tertiary medical center. All participants had at least 6 months experience with their CI. The main outcomes were performance on the adapted cognitive test and a speech recognition in noise task. Participants were 20 adult perilingually or postlingually deafened CI users (50% male participants median range age, 66 26-80 years old). Performance on a sentence recognition in noise task was negatively associated with the chronological age of the listener (R2 0.29 β 0.16 standard error, SE 0.06 t 2.63 95% confidence interval, 0.03-0.27). Testing using the adapted version of the NIH Toolbox Cognition Battery revealed that a test of processing speed was also associated with performance, using a standardized score that accounted for contributions of other demographic factors (R2 0.28 95% confidence interval, -0.42 to -0.05). In this prognostic study, older CI users showed poorer performance on a sentence-in-noise test compared with younger users. This poorer performance was correlated with a cognitive deficit in processing speed when cognitive function was assessed using a test battery adapted for participants with hearing loss. These results provide initial proof-of-concept results for using a standardized and adapted cognitive test battery in CI recipients.

PSEN2 and ABCA7 variants causing early-onset preclinical pathological changes in Alzheimers disease a case report and literature review.

Alzheimers disease (AD) is a debilitating and highly heritable neurodegenerative disease. Early-onset AD (EOAD) was defined as AD occurring before age 65. Although it has a high genetic risk, EOAD due to PSEN2 variation is very rare. ABCA7 is an important risk gene for AD. Previously reported cases mainly carried variations in a single pathogenic or risk gene. METHODS AND RESULTS In this study, we report a 35-year-old female carrying variants in both the PSEN2 gene (c.640G > T p.V214L) and ABCA7 gene (c.2848G > A p.V950M). Four previously reported cases carried PSEN2 V214L, and no reported cases carried ABCA7 V950M. She had a history of migraine, patent foramen ovale, spontaneous subarachnoid hemorrhage without aneurysm, and multiple cerebral microhemorrhages. Her MMSE score was 2430, and her MoCA score was 2230. The concentration of Aβ42 and the ratio of Aβ42 to Aβ40 in cerebral spinal fluid were obviously decreased. Published variants of PSEN2 and ABCA7 in PubMed were reviewed, and the patients characteristics were summarized and compared to provide information for the clinical diagnosis of AD. It is necessary to conduct genetic screening in cases with atypical manifestations.

Opioid medication use and blood DNA methylation epigenome-wide association meta-analysis.

Antithrombotic treatment after stroke due to intracerebral haemorrhage.

This is an update of the Cochrane Review last published in 2017. Survivors of stroke due to intracerebral haemorrhage (ICH) are at risk of major adverse cardiovascular events (MACE). Antithrombotic (antiplatelet or anticoagulant) treatments may lower the risk of ischaemic MACE after ICH, but they may increase the risk of bleeding. To determine the overall effectiveness and safety of antithrombotic drugs on MACE and its components for people with ICH. We searched the Cochrane Stroke Group Trials Register (5 October 2021). We also searched the Cochrane Central Register of Controlled Trials (CENTRAL the Cochrane Library 2021, Issue 10), MEDLINE Ovid (from 1948 to October 2021) and Embase Ovid (from 1980 to October 2021). The online registries of clinical trials searched were the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (5 October 2021). We screened the reference lists of included randomised controlled trials (RCTs) for additional, potentially relevant RCTs. We selected RCTs in which participants with ICH of any age were allocated to a class of antithrombotic treatment as intervention or comparator. In accordance with standard methodological procedures recommended by Cochrane, two review authors assessed each selected RCT for its risk of bias and extracted data independently. The primary outcome was a composite of MACE, and secondary outcomes included death, individual components of the MACE composite, ICH growth, functional status and cognitive status. We estimated effects using the frequency of outcomes that occurred during the entire duration of follow-up and calculated a risk ratio (RR) for each RCT. We grouped RCTs separately for analysis according to 1) the class(es) of antithrombotic treatment used for the intervention and comparator, and 2) the duration of antithrombotic treatment use (short term versus long term). We pooled the intention-to-treat populations of RCTs using a fixed-effect model for meta-analysis, but used a random-effects model if RCTs differed substantially in their design or there was considerable heterogeneity (I We identified seven new completed RCTs for this update, resulting in the inclusion of a total of nine RCTs based in secondary care, comprising 1491 participants (average age ranged from 61 to 79 years and the proportion of men ranged from 44% to 67%). The proportion of included RCTs at low risk of bias, by category was random sequence generation (67%), allocation concealment (67%), performance (22%), detection (78%), attrition (89%), and reporting (78%). For starting versus avoiding short-term prophylactic dose anticoagulation after ICH, no RCT reported MACE. The evidence is very uncertain about the effect of starting short-term prophylactic dose anticoagulation on death (RR 1.00, 95% CI 0.59 to 1.70, P 1.00 3 RCTs very low-certainty evidence), venous thromboembolism (RR 0.84, 95% CI 0.51 to 1.37, P 0.49 4 RCTs very low-certainty evidence), ICH (RR 0.24, 95% CI 0.04 to 1.38, P 0.11 2 RCTs very low-certainty evidence), and independent functional status (RR 2.03, 95% CI 0.78 to 5.25, P 0.15 1 RCT very low-certainty evidence) over 90 days. For starting versus avoiding long-term therapeutic dose oral anticoagulation for atrial fibrillation after ICH, starting long-term therapeutic dose oral anticoagulation probably reduces MACE (RR 0.61, 95% CI 0.40 to 0.94, P 0.02 3 RCTs moderate-certainty evidence) and probably reduces all major occlusive vascular events (RR 0.27, 95% CI 0.14 to 0.53, P 0.0002 3 RCTs moderate-certainty evidence), but probably results in little to no difference in death (RR 1.05, 95% CI 0.62 to 1.78, P 0.86 3 RCTs moderate-certainty evidence), probably increases intracranial haemorrhage (RR 2.43, 95% CI 0.88 to 6.73, P 0.09 3 RCTs moderate-certainty evidence), and may result in little to no difference in independent functional status (RR 0.98, 95% CI 0.78 to 1.24, P 0.87 2 RCTs low-certainty evidence) over one to three years. For starting versus avoiding long-term antiplatelet therapy after ICH, the evidence is uncertain about the effects of starting long-term antiplatelet therapy on MACE (RR 0.89, 95% CI 0.64 to 1.22, P 0.46 1 RCT moderate-certainty evidence), death (RR 1.08, 95% CI 0.76 to 1.53, P 0.66 1 RCT moderate-certainty evidence), all major occlusive vascular events (RR 1.03, 95% CI 0.68 to 1.55, P 0.90 1 RCT moderate-certainty evidence), ICH (RR 0.52, 95% CI 0.27 to 1.03, P 0.06 1 RCT moderate-certainty evidence) and independent functional status (RR 0.95, 95% CI 0.77 to 1.18, P 0.67 1 RCT moderate-certainty evidence) over a median follow-up of two years. For adults within 180 days of non-cardioembolic ischaemic stroke or transient ischaemic attack and a clinical history of prior ICH, there was no evidence of an effect of long-term cilostazol compared to aspirin on MACE (RR 1.33, 95% CI 0.74 to 2.40, P 0.34 subgroup of 1 RCT low-certainty evidence), death (RR 1.65, 95% CI 0.55 to 4.91, P 0.37 subgroup of 1 RCT low-certainty evidence), or ICH (RR 1.29, 95% CI 0.35 to 4.69, P 0.70 subgroup of 1 RCT low-certainty evidence) over a median follow-up of 1.8 years all major occlusive vascular events and functional status were not reported. We did not identify beneficial or hazardous effects of short-term prophylactic dose parenteral anticoagulation and long-term oral antiplatelet therapy after ICH on important outcomes. Although there was a significant reduction in MACE and all major occlusive vascular events after long-term treatment with therapeutic dose oral anticoagulation for atrial fibrillation after ICH, the pooled estimates were imprecise, the certainty of evidence was only moderate, and effects on other important outcomes were uncertain. Large RCTs with a low risk of bias are required to resolve the ongoing dilemmas about antithrombotic treatment after ICH.

Association of white matter lesions and brain atrophy with the development of dementia in a community the Hisayama Study.

To investigate the association of white matter lesions volume (WMLV) levels with dementia risk and the association between dementia risk and the combined measures of WMLV and either total brain atrophy or dementia-related gray matter atrophy in a general older population. One thousand one hundred fifty-eight Japanese dementia-free community-residents aged ≥65 years who underwent brain magnetic resonance imaging were followed for 5.0 years. WMLV were segmented using the Lesion Segmentation Toolbox. Total brain volume (TBV) and regional gray matter volume were estimated by voxel-based morphometry. The WMLV-to-intracranial brain volume ratio (WMLVICV) was calculated, and its association with dementia risk was estimated using Cox proportional hazard models. Total brain atrophy, defined as the TBV-to-ICV ratio (TBVICV), and dementia-related regional brain atrophy defined based on our previous report were calculated. The association between dementia risk and the combined measures of WMLVICV and either total brain atrophy or the number of atrophied regions was also tested. During the follow-up, 113 participants developed dementia. The risks of dementia increased significantly with higher WMLVICV levels. In addition, dementia risk increased additively both in participants with higher WMLVICV levels and lower TBVICV levels and in those with higher WMLVICV levels and a higher number of dementia-related brain regional atrophy. The risk of dementia increased significantly with higher WMLVICV levels. An additive increment in dementia risk was observed with higher WMLVICV levels and lower TBVICV levels or a higher number of dementia-related brain regional atrophy, suggesting the importance of prevention or control of cardiovascular risk factors.

Errorless learning in cognitive rehabilitation of Alzheimer’s disease and primary progressive aphasia.

Alzheimer’s disease (AD) and primary progressive aphasia (PPA) are age-related neurodegenerative diseases characterized by a slowly progressive cognitive decline that significantly impacts functional autonomy. Cognitive interventions remain one of the most useful management perspectives to help patients compensate for their cognitive and functional deficits in everyday life. Errorless learning represents a set of principles and methods aimed at eliminating or minimizing errors in a learning context, which was initially applied to patients with an amnesic syndrome. In this article, we examine the effectiveness of this learning principle in the context of AD and PPA. Based on current data from the literature, errorless learning appears to be useful in (re)learning new information or procedural skills in AD and APP, such as relearning names or certain independent activities of daily living. In addition, the benefits of errorless learning are maintained at follow-up. There are, however, discrepancies in the results between studies which could reflect differences in the learning methods employed and in the parameters of the interventions. In conclusion, such interventions should primarily target learning that is useful for patients and that allows them to preserve their autonomy longer and improve their quality of life. L’intervention cognitive demeure une des perspectives de prise en charge les plus utiles, dès la phase précoce, pour aider les patients atteints de trouble neurocognitif majeur à compenser leurs déficits cognitifs et maintenir leur indépendance fonctionnelle dans la vie quotidienne. L’apprentissage sans erreur représente un ensemble de principes et de techniques visant à éliminer ou réduire au maximum les erreurs commises dans un contexte d’apprentissage ou de réapprentissage. Dans cet article, nous examinons l’efficacité de ce principe d’apprentissage dans le contexte de la démence de type Alzheimer et de l’aphasie primaire progressive. Sur la base des données actuelles, l’apprentissage sans erreur se révèle être efficace pour (ré)apprendre de nouvelles informations ou habiletés procédurales. Dans certains cas, les gains de l’apprentissage sans erreur perdurent à long terme et ce principe d’apprentissage pourrait permettre d’augmenter la motivation et de réduire la frustration liée à l’échec et aux déficits. Il existe néanmoins des divergences dans les résultats entre les études qui pourraient refléter des différences dans les paramètres des interventions. En conclusion, ces interventions devraient cibler des apprentissages qui ont une utilité pour les patients et qui leur permettent de préserver leur indépendance plus longtemps et ainsi améliorer leur qualité de vie.

Dementia, Substance Misuse, and Social Determinants of Health American Indian and Alaska Native Peoples Prevention, Service, and Care.

American Indian and Alaska Native (AIAN) peoples are disproportionately impacted by substance use disorders (SUDs) and health consequences in contrast to all racialethnic groups in the United States. This is alarming that AIAN peoples experience significant health disparities and disease burden that are exacerbated by settler-colonial traumas expressed through prejudice, stigma, discrimination, and systemic and structural inequities. One such compounding disease for AIAN peoples that is expected to increase but little is known is Alzheimers disease and related dementias (ADRD). AIAN approaches for understanding and treating disease have long been rooted in culture, context, and worldview. Thus, culturally based prevention, service, and caregiving are critical to optimal outcomes, and investigating cultural beliefs regarding ADRD can provide insights into linkages of chronic stressors, disease, prevention and treatment, and the role of substance misuse. To understand the cultural practices and values that compose AIAN Elder beliefs and perceptions of ADRD, a grounded theory, qualitative study was conducted. Twelve semistructured interviews with AIAN Elders (M age 73 female 8, male 4) assessed the etiology, course, treatment, caregiving, and the culturally derived meanings of ADRD, which provides a frame of understanding social determinants of health (SDH eg, healthcare equity, community context) and impacts (eg, historical trauma, substance misuse) across the lifespan. Qualitative analyses specific to disease etiology, barriers to treatment, and SDH revealed 6 interrelated and nested subthemes elucidating both the resilience and the chronic stressors and barriers faced by AIAN peoples that directly impact prevention, disease progression, and related services (1) postcolonial distress (2) substance misuse (3) distrust of Western medicine (4) structural inequities (5) walking in two worlds and (6) decolonizing and indigenizing medicine. Barriers to optimal wellbeing and SDH for AIAN peoples are understood through SUDs, ADRD, and compounding symptoms upheld by colonial traumas and postcolonial distress. En masse historical and contemporary discrimination and stress, particularly within Western medicine, both contextualizes the present and points to the ways in which the strengths, wisdom, and balance inherent in AIAN culture are imperative to the holistic health and healing of AIAN peoples, families, and communities.

Sensory impairment and cognitive decline among older adults An analysis of mediation and moderation effects of loneliness.

Multiple studies have reported that hearing and vision impairment are linked to cognitive decline. Yet little is known about factors that may influence the association between sensory impairment and cognitive decline. This study examined if loneliness mediates or moderates the impact of sensory impairment on cognitive decline as individuals age. This was a longitudinal study using data from the Health and Retirement Study (HRS) and The Aging, Demographics, and Memory Study (ADAMS) ( Loneliness moderated but did not mediate the association between visual impairment and the rate of cognitive decline (standardized β -0.108, Visual impairment combined with an elevated level of loneliness may produce a more synergistic, deleterious impact on older adults cognitive function than visual impairment alone. This study highlights the importance of promoting a healthy social and psychological status for older adults with sensory impairment.

A transfer learning approach for multiclass classification of Alzheimers disease using MRI images.

Alzheimers is an acute degenerative disease affecting the elderly population all over the world. The detection of disease at an early stage in the absence of a large-scale annotated dataset is crucial to the clinical treatment for the prevention and early detection of Alzheimers disease (AD). In this study, we propose a transfer learning base approach to classify various stages of AD. The proposed model can distinguish between normal control (NC), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI), and AD. In this regard, we apply tissue segmentation to extract the gray matter from the MRI scans obtained from the Alzheimers Disease National Initiative (ADNI) database. We utilize this gray matter to tune the pre-trained VGG architecture while freezing the features of the ImageNet database. It is achieved through the addition of a layer with step-wise freezing of the existing blocks in the network. It not only assists transfer learning but also contributes to learning new features efficiently. Extensive experiments are conducted and results demonstrate the superiority of the proposed approach.

Case report Ketogenic diet acutely improves cognitive function in patient with Down syndrome and Alzheimers disease.

Ketogenic diets have a century-long history as a therapeutic tool to treat intractable epilepsy. Recently, a renewed interest in neuroketotherapeutics has arisen, with ketogenic diets being explored for the treatment of neurodegenerative diseases such as Alzheimers disease and Parkinsons disease, as well as mental health conditions. Herein, we present a case report of a 47-year-old woman with Down syndrome diagnosed with Alzheimers disease and absence seizures with accelerated cognitive decline over 6 years. A ketogenic diet restored her cognitive function over 6 weeks, with an increase in Activities of Daily Living Scale score from 34 to 58. A therapeutic ketogenic diet was associated with significant cognitive improvement in this patient with concurrent Down syndrome and dementia.

Regulation of autophagy, lipid metabolism, and neurodegenerative pathology by heparan sulfate proteoglycans.

Heparan sulfate modified proteins or proteoglycans (HSPGs) are an abundant class of cell surface and extracellular matrix molecules. They serve important co-receptor functions in the regulation of signaling as well as membrane trafficking. Many of these activities directly affect processes associated with neurodegeneration including uptake and export of Tau protein, disposition of Amyloid Precursor Protein-derived peptides, and regulation of autophagy. In this review we focus on the impact of HSPGs on autophagy, membrane trafficking, mitochondrial quality control and biogenesis, and lipid metabolism. Disruption of these processes are a hallmark of Alzheimers disease (AD) and there is evidence that altering heparan sulfate structure and function could counter AD-associated pathological processes. Compromising presenilin function in several systems has provided instructive models for understanding the molecular and cellular underpinnings of AD. Disrupting presenilin function produces a constellation of cellular deficits including accumulation of lipid, disruption of autophagosome to lysosome traffic and reduction in mitochondrial size and number. Inhibition of heparan sulfate biosynthesis has opposing effects on all these cellular phenotypes, increasing mitochondrial size, stimulating autophagy flux to lysosomes, and reducing the level of intracellular lipid. These findings suggest a potential mechanism for countering pathology found in AD and related disorders by altering heparan sulfate structure and influencing cellular processes disrupted broadly in neurodegenerative disease. Vertebrate and invertebrate model systems, where the cellular machinery of autophagy and lipid metabolism are conserved, continue to provide important translational guideposts for designing interventions that address the root cause of neurodegenerative pathology.

Rb deficiency, neuronal survival and neurodegeneration In search of the perfect mouse model.

Three decades following the introduction of the first Rb knockout (KO) mouse model, the role of this critical protein in regulating brain development during embryogenesis and beyond remains a major scientific interest. Rb is a tumor suppressor gene known as the master regulator of the G1S checkpoint and control of cell cycle progression in stem and progenitor cells, but also their differentiated progeny. Here, we review the recent literature about the various Rb conditional Knockout (cKO) and inducible Knockout (iKO) models studied thus far, highlighting how findings should always be interpreted in light of the model and context under inquiry especially when studying the role of Rb in neuronal survival. There is indeed evidence of age-specific, cell type-specific and region-specific effects following Rb KO in the embryonic and the adult mouse brain. In terms of modeling neurodegenerative processes in human diseases, we discuss cell cycle re-entry (CCE) as a candidate mechanism underlying the increased vulnerability of Rb-deficient neurons to cell death. Notably, mouse models may limit the extent to which CCE due to Rb inactivation can mimic the pathological course of these disorders, such as Alzheimers disease. These remarks ought to be considered in future research when studying the consequences of Rb inactivation on neuronal generation and survival in rodents and their corresponding clinical significance in humans.

A novel strategy for bioactive natural products targeting NLRP3 inflammasome in Alzheimers disease.

Alzheimers disease (AD), the most common type of dementia, is an ageing-related progressive neurodegenerative brain disorder. Extracellular neuritic plaques composed of misfolded amyloid β (Aβ) proteins and intracellular neurofibrillary tangles formed by hyperphosphorylated tau protein are the two classical characteristics of AD. Aβ and tau pathologies induce neurite atrophy and neuronal apoptosis, leading to cognitive, language, and behavioral deficits. For decades, researchers have made great efforts to explore the pathogens and therapeutics of AD however, its intrinsic mechanism remains unclear and there are still no well-established strategies to restore or even prevent this disease. Therefore, it would be beneficial for the establishment of novel therapeutic strategy to determine the intrinsic molecular mechanism that is interrelated with the initiation and progression of AD. A variety of evidence indicates that neuroinflammation plays a crucial role in the pathogenesis of AD. Nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) is a key inflammasome sensor of cellular stress and infection that is involved in the innate immune system. In response to a wide range of stimuli like Aβ, NLRP3 assembles apoptosis-associated speck-like protein (ASC) and procaspase-1 into an inflammasome complex to induce the caspase-1 mediated secretion of interleukin (IL)-1βIL-18 in M1 polarized microglia, triggering the pathophysiological changes and cognitive decline of AD. Therefore, targeting NLRP3 inflammasome seems an efficient path for AD treatment

The paradigm of amyloid precursor protein in amyotrophic lateral sclerosis The potential role of the

Neurodegenerative diseases are characterized by the progressive decline of neuronal function in several brain areas, and are always associated with cognitive, psychiatric, or motor deficits due to the atrophy of certain neuronal populations. Most neurodegenerative diseases share common pathological mechanisms, such as neurotoxic protein misfolding, oxidative stress, and impairment of autophagy machinery. Amyotrophic lateral sclerosis (ALS) is one of the most common adult-onset motor neuron disorders worldwide. It is clinically characterized by the selective and progressive loss of motor neurons in the motor cortex, brain stem, and spinal cord, ultimately leading to muscle atrophy and rapidly progressive paralysis. Multiple recent studies have indicated that the amyloid precursor protein (APP) and its proteolytic fragments are not only drivers of Alzheimers disease (AD) but also one of the earliest signatures in ALS, preceding or anticipating neuromuscular junction instability and denervation. Indeed, altered levels of APP peptides have been found in the brain, muscles, skin, and cerebrospinal fluid of ALS patients. In this short review, we discuss the nature and extent of research evidence on the role of APP peptides in ALS, focusing on the intracellular C-terminal peptide and its regulatory motif

Novel heterozygous mutation in

Many studies have suggested that the alpha-2-macroglobulin ( The patient in this study had progressive memory loss at the age of 60 years and underwent a series of neuropsychological tests, cranial magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) biomarker analysis, and whole-exome sequencing (WES) to evaluate possible mutations. We used in silico tools and three-dimensional (3D) protein structure prediction to analyze the pathogenicity of the mutation and used a co-immunoprecipitation experiment to study the effect of mutations on amyloid-β (Aβ) binding. Based on neuropsychological tests, cranial MRI, and CSF biomarker analysis, the patient was diagnosed with AD. WES showed that there was a missense mutation in Our results demonstrate that this novel A2M p.N410T mutation may have a pathogenic role in AD, by altering the binding interactions between A2M and Aβ.

CSF biomarkers for early-onset Alzheimers disease in Chinese population from PUMCH dementia cohort.

Alzheimers disease (AD) is one of the highly concerned degenerative disorders in recent decades. Though vast amount of researches has been done in various aspects, early-onset subtype, however, needs more investigation in diagnosis for its atypical manifestations and progression process. Fundamental CSF biomarkers of early-onset AD are explored in PUMCH dementia cohort to depict its laboratory characteristics. A total of 125 individuals (age of onset <65 years old) from PUMCH dementia cohort were recruited consecutively and classified into AD, non-AD dementia, and control groups. Levels of amyloid-β 42 (Aβ42), total tau (t-tau) and phosphorylated tau (p-tau) were measured using ELISA INNOTEST (Fujirebio, Ghent, Belgium). Students The average of all three biomarkers and two calculated ratios (t-tauAβ42, p-tauAβ42) were statistically different in the AD group compared with the other two groups ( Our study supports the diagnostic usefulness of biomarkers and defined cutoff values to diagnose early-onset AD. We showed that the ratios of t-tauAβ42 and p-tauAβ42 are more sensitive than relying on Aβ42 levels alone, and that we can further improve diagnostic accuracy by combining biomarkers.

The expression pattern of GDF15 in human brain changes during aging and in Alzheimers disease.

Growth Differentiation Factor 15 (GDF15) is a mitochondrial-stress-responsive molecule whose expression strongly increases with aging and age-related diseases. However, its role in neurodegenerative diseases, including Alzheimers disease (AD), is still debated. We have characterized the expression of GDF15 in brain samples from AD patients and non-demented subjects (controls) of different ages. Although no difference in CSF levels of GDF15 was found between AD patients and controls, GDF15 was expressed in different brain areas and seems to be predominantly localized in neurons. The ratio between its mature and precursor form was higher in the frontal cortex of AD patients compared to age-matched controls ( Although GDF15 seems not to be a reliable CSF marker for AD, it is highly expressed in aging and AD brains, likely as a part of stress response aimed at counteracting mitochondrial dysfunction and neuroinflammation.

Transcranial alternating current stimulation combined with sound stimulation improves cognitive function in patients with Alzheimers disease Study protocol for a randomized controlled trial.

The number of patients with Alzheimers disease (AD) worldwide is increasing yearly, but the existing treatment methods have poor efficacy. Transcranial alternating current stimulation (tACS) is a new treatment for AD, but the offline effect of tACS is insufficient. To prolong the offline effect, we designed to combine tACS with sound stimulation to maintain the long-term post-effect. To explore the safety and effectiveness of tACS combined with sound stimulation and its impact on the cognition of AD patients. This trial will recruit 87 patients with mild to moderate AD. All patients were randomly divided into three groups. The change in Alzheimers Disease Assessment Scale-Cognitive (ADAS-Cog) scores from the day before treatment to the end of treatment and 3 months after treatment was used as the main evaluation index. We will also explore the changes in the brain structural network, functional network, and metabolic network of AD patients in each group after treatment. We hope to conclude that tACS combined with sound stimulation is safe and tolerable in 87 patients with mild to moderate AD under three standardized treatment regimens. Compared with tACS alone or sound alone, the combination group had a significant long-term effect on cognitive improvement. To screen out a better treatment plan for AD patients. tACS combined with sound stimulation is a previously unexplored, non-invasive joint intervention to improve patients cognitive status. This study may also identify the potential mechanism of tACS combined with sound stimulation in treating mild to moderate AD patients. Clinicaltrials.gov, NCT05251649. Registered on February 22, 2022.

Increased functional connectivity patterns in mild Alzheimers disease A rsfMRI study.

Alzheimers disease (AD) is the most common age-related neurodegenerative disorder. In view of our rapidly aging population, there is an urgent need to identify Alzheimers disease (AD) at an early stage. A potential way to do so is by assessing the functional connectivity (FC), i.e., the statistical dependency between two or more brain regions, through novel analysis techniques. In the present study, we assessed the static and dynamic FC using different approaches. A resting state (rs)fMRI dataset from the Alzheimers disease neuroimaging initiative (ADNI) was used ( Our results showed a longer characteristic path length and a decreased degree of EMCI in comparison to the other groups. Additionally, an increased FC in several regions in LMCI and AD in contrast to HC and EMCI was detected. These results suggest a maladaptive short-term mechanism to maintain cognition. The increased pattern of FC in several regions in LMCI and AD is observable in all the analyses however, the PPA enabled us to reduce the computational demands and offered new specific dynamic FC findings.

Effectiveness of vortioxetine in patients with major depressive disorder and comorbid Alzheimers disease in routine clinical practice An analysis of a post-marketing surveillance study in South Korea.

Vortioxetine has demonstrated procognitive effects in patients with major depressive disorder (MDD). We assessed the effectiveness and safety of vortioxetine in a cohort of patients with MDD and comorbid Alzheimers disease participating in a large post-marketing surveillance study in South Korea. Subgroup analysis of a 6-month, prospective, multicenter, non-interventional cohort study in outpatients with MDD with a pre-baseline diagnosis of Alzheimers disease receiving vortioxetine in routine care settings ( Most patients were receiving a mean daily vortioxetine dose of 5 mgday (174190 patients 91.6%). After 24 weeks of vortioxetine treatment, 71.4% of patients (4056) had experienced overall clinical improvement (i.e., CGI-Improvement score ≤3) and 51.9% (2854) had achieved remission from depressive symptoms (i.e., MADRS total score ≤10 points). Respective mean changes in MADRS, PDQ-K, and DSST total scores from baseline to week 24 were -11.5 ( Patients with MDD and comorbid Alzheimers disease receiving vortioxetine in routine care settings in South Korea demonstrated clinically meaningful improvements in depressive symptoms, cognitive symptoms, and objective cognitive performance over the 6-month treatment period. Treatment with vortioxetine was well tolerated in this patient cohort, with reported adverse events consistent with the established tolerability profile of vortioxetine.

Discovery of an evodiamine derivative for PI3KAKTGSK3β pathway activation and AD pathology improvement in mouse models.

Alzheimers disease (AD) is a neurodegenerative disease characterized by progressive neurodegeneration and cognitive decline. Evodiamine, a main component in Chinese medicine, was found to improve cognitive impairment in AD model mice based on several intensive studies. However, evodiamine has high cytotoxicity and poor bioactivity. In this study, several evodiamine derivatives were synthesized

Functional connectivity and mild behavioral impairment in dementia-free elderly.

Mild behavioral impairment (MBI) is a syndrome that uses later-life emergent and persistent neuropsychiatric symptoms (NPS) to identify a group at high risk for incident dementia. MBI is associated with neurodegenerative disease markers in advance of syndromic dementia. Functional connectivity (FC) correlates of MBI are understudied and could provide further insights into mechanisms early in the disease course. We used resting-state functional magnetic resonance imaging (rs-fMRI) to test the hypothesis that FC within the default mode network (DMN) and salience network (SN) of persons with MBI (MBI) is reduced, relative to those without (MBI-). From two harmonized dementia-free cohort studies, using a score of ≥6 on the MBI Checklist to define MBI status, 32 MBI and 63 MBI- individuals were identified (mean age 71.7 years 54.7% female). Seed-based connectivity analysis was implemented in each MBI group using the CONN fMRI toolbox (v20.b), with the posterior cingulate cortex (PCC) as the seed region within the DMN and anterior cingulate cortex (ACC) as the seed within the SN. The average time series from the PCC and ACC were used to determine FC with other regions within the DMN (medial prefrontal cortex, lateral inferior parietal cortex) and SN (anterior insula, supramarginal gyrus, rostral prefrontal cortex), respectively. Age, sex, years of education, and Montreal Cognitive Assessment scores were included as model covariates. The false discovery rate approach was used to correct for multiple comparisons, with a For the DMN, MBI individuals exhibited reduced FC between the PCC and the medial prefrontal cortex, compared to MBI-. For the SN, MBI individuals exhibited reduced FC between the ACC and left anterior insula. MBI in dementia-free older adults is associated with reduced FC in networks known to be disrupted in dementia. Our results complement the evidence linking MBI with Alzheimers disease biomarkers. Resting-state functional magnetic resonance imaging was completed in 95 dementia-free persons from FAVR and COMPASS-ND studies.Participants were stratified by informant-rated Mild Behavioral Impairment Checklist (MBI-C) score, ≥6 for MBI.MBI participants showed reduced functional connectivity (FC) within the default mode network and salience network.These FC changes are consistent with those seen in early-stage Alzheimers disease.MBI may help identify persons with early-stage neurodegenerative disease.

Neuropharmaceutical Properties of Naringin Against Alzheimers and Parkinsons Diseases Naringin Protection Against AD and PD.

Neurological complications are considered the leading cause of disability and the second cause of death worldwide. Although the most common neurological disorders affecting a large population are Alzheimers (AD) and Parkinsons diseases (PD), no definitive treatment has been propounded in the clinic. As in recent years, special attention has been paid to medicinal herbal products as one of the ways to meet the challenges of treating diseases. This review study aimed to introduce the naringin neuroprotective effects as an abundant flavonoid in grapes and citrus fruits on the most common neurological disorders, including AD and PD. For this purpose, the specified keywords were searched in PubMed, Web of Science, Scopus, Embase, and Google Scholar, and the results were entered into the study after a concise overview. The findings show naringin can confront neurological disorders through several mechanisms such as modulating stress response pathways, preventing apoptosis, oxidative stress, and neuroinflammation, excessive chelating amounts of metal ions, thereby improving cognitive impairment and memory loss induced by neurological disorders. However, further studies, particularly on human, are critical for the final confirmation of obtained findings. GMJ.202211e2337.

Mechanism of action and therapeutic effects of oxidative stress and stem cell-based materials in skin aging Current evidence and future perspectives.

Aging is associated with multiple degenerative diseases, including atherosclerosis, osteoporosis, and Alzheimers disease. As the most intuitive manifestation of aging, skin aging has received the most significant attention. Skin aging results from various intrinsic and extrinsic factors. Aged skin is characterized by wrinkles, laxity, elastosis, telangiectasia, and aberrant pigmentation. The underlying mechanism is complex and may involve cellular senescence, DNA damage, oxidative stress (OS), inflammation, and genetic mutations, among other factors. Among them, OS plays an important role in skin aging, and multiple antioxidants (e.g., vitamin C, glutathione, and melatonin) are considered to promote skin rejuvenation. In addition, stem cells that exhibit self-replication, multi-directional differentiation, and a strong paracrine function can exert anti-aging effects by inhibiting OS. With the further development of stem cell technology, treatments related to OS mitigation and involving stem cell use may have a promising future in anti-skin aging therapy.

The different trends in the burden of neurological and mental disorders following dietary transition in China, the USA, and the world An extension analysis for the Global Burden of Disease Study 2019.

The highly processed western diet is substituting the low-processed traditional diet in the last decades globally. Increasing research found that a diet with poor quality such as western diet disrupts gut microbiota and increases the susceptibility to various neurological and mental disorders, while a balanced diet regulates gut microbiota and prevents and alleviates the neurological and mental disorders. Yet, there is limited research on the association between the disease burden expanding of neurological and mental disorders with a dietary transition. We compared the disability-adjusted life-years (DALYs) trend by age for neurological and mental disorders in China, in the United States of America (USA), and across the world from 1990 to 2019, evaluated the dietary transition in the past 60 years, and analyzed the association between the burden trend of the two disorders with the changes in diet composition and food production. We identified an age-related upward pattern in disease burden in China. Compared with the USA and the world, the Chinese neurological and mental disorders DALY percent was least in the generation over 75 but rapidly increased in younger generations and surpassed the USA andor the world in the last decades. The age-related upward pattern in Chinese disease burdens had not only shown in the presence of cardiovascular diseases, neoplasms, and diabetes mellitus but also appeared in the presence of depressive disorders, Parkinsons disease, Alzheimers disease and other dementias, schizophrenia, headache disorders, anxiety disorders, conduct disorders, autism spectrum disorders, and eating disorders, successively. Additionally, the upward trend was associated with the dramatic dietary transition including a reduction in dietary quality and food production sustainability, during which the younger generation is more affected than the older. Following the increase in total calorie intake, alcohol intake, ratios of animal to vegetal foods, and poultry meat to pulses, the burdens of the above diseases continuously rose. Then, following the rise of the ratios of meat to pulses, eggs to pulses, and pork to pulses, the usage of fertilizers, the farming density of pigs, and the burdens of the above disease except diabetes mellitus were also ever-increasing. Even the usage of pesticides was positively correlated with the burdens of Parkinsons disease, schizophrenia, cardiovascular diseases, and neoplasms. Contrary to China, the corresponding burdens of the USA trended to reduce with the improvements in diet quality and food production sustainability. Our results suggest that improving diet quality and food production sustainability might be a promising way to stop the expanding burdens of neurological and mental disorders.

Neuropathology-Independent Association Between

We previously found that the We analyzed Carrying the In a large national sample selected to represent the normal aging-early AD continuum, the

Extracellular vesicles The next generation in gene therapy delivery.

Extracellular vesicles (EVs) are esteemed as a promising delivery vehicle for various genetic therapeutics. They are relatively inert, non-immunogenic, biodegradable, and biocompatible. At least in rodents, they can even transit challenging bodily hurdles such as the blood-brain barrier. Constitutively shed by all cells and with the potential to interact specifically with neighboring and distant targets, EVs can be engineered to carry and deliver therapeutic molecules such as proteins and RNAs. EVs are thus emerging as an elegant in vivo gene therapy vector. Deeper understanding of basic EV biology-including cellular production, EV loading, systemic distribution, and cell delivery-is still needed for effective harnessing of these endogenous cellular nanoparticles as next-generation nanodelivery tools. However, even a perfect EV product will be challenging to produce at clinical scale. In this regard, we propose that vector transduction technologies can be used to convert cells either ex vivo or directly in vivo into EV factories for stable, safe modulation of gene expression and function. Here, we extrapolate from the current EV state of the art to a bright potential future using EVs to treat genetic diseases that are refractory to current therapeutics.

A Review on the Natural Components Applied as Lead Compounds for Potential Multi-target Anti-AD Theranostic Agents.

Alzheimers disease (AD) is a neurodegenerative disease that seriously affects the health and quality of life of the elderly. Its pathogenesis is very complex and there is still a lack of effective clinical drugs to treat or control the development of AD. Studies have shown that β-amyloid (Aβ) deposition, tau protein hyperphosphorylation, reduced levels of brain cholinergic transmitters, and oxidative stress are the main causes of AD. Furthermore, recent studies showed that metal dyshomeostasis could relate to all the above pathogenesis of AD and was a key factor in the development of AD. Natural compounds and their derivatives have multi-target therapeutic effects on AD, and they also have the advantages of low toxicity, and low cost, which are important directions for anti-AD drugs. Meanwhile, early detection may play an important role in in preventing the development of AD. The concept of 34theranostic agent34 combining molecular imaging probes and therapeutic drugs has emerged in recent years. Fluorescence imaging has been widely studied and applied because of its non-invasive, high resolution, high sensitivity, rapid imaging, and low cost. However, at present, most of the research methods in this field use individual therapeutic or diagnostic reagents, which is not conducive to exploring the optimal treatment time window and drug efficacy. Therefore, this work reviewed the natural compounds and their derivatives which all have been studied for both the in vitro and in vivo therapeutic and diagnostic anti-AD activities. At last, structure and activity relationship (SAR) was discussed and potential AD theranostic natural agents were put forwarded to provide a more detailed theoretical basis for the further development of drugs with diagnostic and therapeutic effects in AD.

The beneficial effect on cognition of noninvasive brain stimulation intervention in patients with dementia a network meta-analysis of randomized controlled trials.

Dementia i.e., Alzheimer disease (AD), the most common neurodegenerative disease, causes profound negative impacts on executive function and quality of life. Available pharmacological treatments often fail to achieve satisfactory outcomes. Noninvasive brain stimulation (NIBS) techniques, which focally modify cortical function and enhance synaptic long-term potentiation, are potentially beneficial for the cognition in patients with AD. The aim of the current network meta-analysis (NMA) was to evaluate the efficacy and safety of different NIBS interventions in patients with AD through NMA. Only randomized controlled trials (RCTs) examining NIBS interventions in patients with AD had been included. All NMA procedures were performed under the frequentist model. The primary and secondary outcomes were changes in cognitive function and quality of life, respectively. Nineteen RCTs (639 participants) were included. The mean treatment and follow-up durations were 5.7 and 10.5 weeks, respectively. The combination of cathodal tDCS of the left dorsolateral prefrontal cortex and anodal tDCS over the right supraorbital region (c-tDCS-F3 a-tDCS-Fp2) was associated with a significant beneficial effect on cognition compared with sham controls (standardized mean difference2.43, 95% confidence interval0.61-4.26, n12 and 11). It was also associated with the greatest beneficial effect on cognition among all the investigated NIBS approaches. All the methods were well tolerated with regard to the safety profile, as reflected in the rates of adverse events or local discomfort, as well as acceptability, as indicated by dropout rate. The present findings provide evidence of the benefits of NIBS, especially tDCS, for beneficial effect on cognition in patients with AD. However, because of few studies included, this effect was not replicated yet in the other studies. Therefore, future larger-scale and longer follow-up duration RCTs should be warranted. PROSPERO CRD42020209516. The current study had been approved by the Institutional Review Board of the Tri-Service General Hospital, National Defense Medical Center (TSGHIRB No. B-109-29).