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Aβ42 treatment of the brain side reduced the level of flotillin from endothelial cells on the blood side via FGF-2 signaling in a blood-brain barrier model.

Our previous study showed that the flotillin level is decreased in the blood of patients with Alzheimers disease (AD) when compared to that of patients with non-AD and vascular dementia however, the molecular mechanism remains to be determined. In this study, to elucidate whether Aβ accumulation in the brain has an effect on the blood flotillin level, we used our previously established blood-brain barrier (BBB) culture model using microvascular endothelial cells obtained from human induced pluripotent stem cells (iBMECs) and astrocytes prepared from rat cortex. In this BBB model with iBMECs plated on the upper compartment (blood side) and astrocytes plated on the lower compartment (brain side), the trans-endothelial electrical resistance values are high (over 1500 Ωm

Studies on the mechanism of Toxoplasma gondii Chinese 1 genotype Wh6 strain causing mice abnormal cognitive behavior.

Alzheimers disease presents an abnormal cognitive behavior. TgCtwh6 is one of the predominant T. gondii strains prevalent in China. Although T. gondii type II strain infection can cause host cognitive behavioral abnormalities, we do not know whether TgCtwh6 could also cause host cognitive behavioral changes. So, in this study, we will focus on the effect of TgCtwh6 on mouse cognitive behavior and try in vivo and in vitro to explore the underlying mechanism by which TgCtwh6 give rise to mice cognitive behavior changes at the cellular and molecular level. C57BL6 mice were infected orally with TgCtwh6 cysts. From day 90 post-infection on, all mice were conducted through the open field test and then Morris water maze test to evaluate cognitive behavior. The morphology and number of cells in hippocampus were examined with hematoxylin-eosin (HE) and Nissl staining moreover, Aβ protein in hippocampus was determined with immunohistochemistry and thioflavin S plaque staining. Synaptotagmin 1, apoptosis-related proteins, BACE1 and APP proteins and genes from hippocampus were assessed by western blotting or qRT-PCR. Hippocampal neuronal cell line or mouse microglial cell line was challenged with TgCtwh6 tachyzoites and then separately cultured in a well or co-cultured in a transwell device. The target proteins and genes were analyzed by immunofluorescence staining, western blotting and qRT-PCR. In addition, mouse microglial cell line polarization state and hippocampal neuronal cell line apoptosis were estimated using flow cytometry assay. The OFT and MWMT indicated that infected mice had cognitive behavioral impairments. The hippocampal tissue assay showed abnormal neuron morphology and a decreased number in infected mice. Moreover, pro-apoptotic proteins, as well as BACE1, APP and Aβ proteins, increased in the infected mouse hippocampus. The experiments in vitro showed that pro-apoptotic proteins and p-NF-κBp65, NF-κBp65, BACE1, APP and Aβ proteins or genes were significantly increased in the infected HT22. In addition, CD80, pro-inflammatory factors, notch, hes1 proteins and genes were enhanced in the infected BV2. Interestingly, not only the APP and pro-apoptotic proteins in HT22, but also the apoptosis rate of HT22 increased after the infected BV2 were co-cultured with the HT22 in a transwell device. Neuron apoptosis, Aβ deposition and neuroinflammatory response involved with microglia polarization are the molecular and cellular mechanisms by which TgCtwh6 causes mouse cognitive behavioral abnormalities.

Sex Differences in Dementia.

BackgroundWomen in many cohorts have a higher risk for Alzheimers disease (AD), the most common form of dementia. Sex is a biological construct whereby differences in disease manifestation and prevalence are rooted in genetic differences between XX and XY combinations of chromosomes. This chapter focuses specifically on sex-driven differences in dementia, as opposed to differences driven by gender - a social construct referring to the societal norms that influence peoples roles, relationships, and positional power throughout their lifetime.MethodsUsing a narrative review, this chapter explored the characteristics and risk factors for the dementias, alongside a discussion of sex differences including loss of sex steroid hormones in middle-aged women, differences in the prevalence of cardiovascular diseases and engagement in lifestyle protective factors for dementia.ResultsThe sex difference in AD prevalence may exist because of systematic and historic differences in risk and protective factors for dementia, including level of education obtained and socioeconomic status differences, which can impact on health and dementia risk.Levels of sex steroids decline significantly after menopause in women, whereas this is more gradual in men with age. Animal and cell culture studies show strong biological plausibility for sex steroids to protect the ageing brain against dementia. Sex steroid hormone replacement therapy has in some observational studies shown to protect against AD, but treatment studies in humans have mainly shown disappointing results. Cardiovascular disease (CVD) shares midlife medical risk (e.g. hypertension, hyperlipidaemia, obesity etc.) factors with AD and other forms of dementia, but also with related lifestyle risk - and protective factors (e.g. exercise, not smoking etc.). Men tend to die earlier of CVD, so fewer survive to develop AD at an older age. Those who do survive may have healthier lifestyles and fewer risk factors for both CVD and AD. An earlier age at menopause also confers great risk for both without hormone treatment.DiscussionIt could be the case that the decline in sex steroids around the menopause make women more susceptible to lifestyle-related risk factors associated with dementia and CVD, but this remains to be further investigated. Combining hormone treatment with lifestyle changes in midlife (e.g. exercise) could be an important preventative treatment for dementia and CVD in later life, but this also requires further research.

Preparation of near-infrared AIEgen-active fluorescent probes for mapping amyloid-β plaques in brain tissues and living mice.

Fibrillar aggregates of the amyloid-β protein (Aβ) are the main component of the senile plaques found in brains of patients with Alzheimers disease (AD). Development of probes allowing the noninvasive and high-fidelity mapping of Aβ plaques in vivo is critical for AD early detection, drug screening and biomedical research. QM-FN-SO

Multivariate effects of pH, salt, and Zn

Amyloid-β (Aβ) peptide aggregation plays a central role in the progress of Alzheimers disease (AD), of which Aβ-deposited extracellular amyloid plaques are a major hallmark. The brain micro-environmental variation in AD patients, like local acidification, increased ionic strength, or changed metal ion levels, cooperatively modulates the aggregation of the Aβ peptides. Here, we investigate the multivariate effects of varied pH, ionic strength and Zn

Cortical-blood vessel assembloids exhibit Alzheimers disease phenotypes by activating glia after SARS-CoV-2 infection.

A correlation between COVID-19 and Alzheimers disease (AD) has been proposed recently. Although the number of case reports on neuroinflammation in COVID-19 patients has increased, studies of SARS-CoV-2 neurotrophic pathology using brain organoids have restricted recapitulation of those phenotypes due to insufficiency of immune cells and absence of vasculature. Cerebral pericytes and endothelial cells, the major components of blood-brain barrier, express viral entry receptors for SARS-CoV-2 and response to systemic inflammation including direct cell death. To overcome the limitations, we developed cortical-blood vessel assembloids by fusing cortical organoid with blood vessel organoid to provide vasculature to brain organoids a nd obtained the characteristics of increased expression of microglia and astrocytes in brain organoids. Furthermore, we observed AD pathologies, including β-amyloid plaques, which were affected by the inflammatory response from SARS-CoV-2 infection. These findings provide an advanced platform to investigate human neurotrophic diseases, including COVID-19, and suggest that neuroinflammation caused by viral infection facilitates AD pathology.

Brain FNDC5Irisin Expression in Patients and Mouse Models of Major Depression.

Major depressive disorder (MDD) is a major cause of disability in adults. MDD is both a comorbidity and a risk factor for Alzheimers disease (AD), and regular physical exercise has been associated with reduced incidence and severity of MDD and AD. Irisin is an exercise-induced myokine derived from proteolytic processing of fibronectin type III domain-containing protein 5 (FNDC5). FNDC5irisin is reduced in the brains of AD patients and mouse models. However, whether brain FNDC5irisin expression is altered in depression remains elusive. Here, we investigate changes in

SorCS1 inhibits amyloid-β binding to neurexin and rescues amyloid-β-induced synaptic pathology.

Amyloid-β oligomers (AβOs), toxic peptide aggregates found in Alzheimers disease, cause synapse pathology. AβOs interact with neurexins (NRXs), key synaptic organizers, and this interaction dampens normal trafficking and function of NRXs. Axonal trafficking of NRX is in part regulated by its interaction with SorCS1, a protein sorting receptor, but the impact of SorCS1 regulation of NRXs in Aβ pathology was previously unstudied. Here, we show competition between the SorCS1 ectodomain and AβOs for β-NRX binding and rescue effects of the SorCS1b isoform on AβO-induced synaptic pathology. Like AβOs, the SorCS1 ectodomain binds to NRX1β through the histidine-rich domain of NRX1β, and the SorCS1 ectodomain and AβOs compete for NRX1β binding. In cultured hippocampal neurons, SorCS1b colocalizes with NRX1β on the axon surface, and axonal expression of SorCS1b rescues AβO-induced impairment of NRX-mediated presynaptic organization and presynaptic vesicle recycling and AβO-induced structural defects in excitatory synapses. Thus, our data suggest a role for SorCS1 in the rescue of AβO-induced NRX dysfunction and synaptic pathology, providing the basis for a novel potential therapeutic strategy for Alzheimers disease.

Estrogen Receptor Genes, Cognitive Decline, and Alzheimer Disease.

Lifetime risk of Alzheimers disease (AD) dementia is two-fold higher in women compared with men, and low estrogen levels in post menopause have been suggested as a possible contributor. We examined 3 Participants were followed for an average 10 years in one of two longitudinal clinical pathological studies of aging. Global cognition was assessed using a composite score derived from 19 neuropsychological tests scores. Postmortem pathological assessment included examination of 3 AD (amyloid-β and tau tangles determined by immunohistochemistry, and a global AD pathology score derived from diffuse and neurotic plaques and neurofibrillary tangles count) and 8 non-AD pathology indices. Mean age of women (N1711) at baseline was 78.0 (SD7.7) years. In women,

Dextran-assisted ultrasonic exfoliation of two-dimensional metal-organic frameworks to evaluate acetylcholinesterase activity and inhibitor screening.

Acetylcholinesterase (AChE) is regarded as a biomarker of Alzheimers disease (AD), and its inhibitors show great potential in AD therapy as AChE can increase the neurotoxicity of the amyloid component that induces AD. Because of this, it is crucial and significant to develop a simple and highly sensitive strategy to monitor AChE levels and screen highly efficient AChE inhibitors. Herein, we synthesize an ultrathin two-dimensional (2D) metal-organic framework (MOF) based on copper-catecholate (Cu-CAT) via dextran assisted ultrasound exfoliation, followed by construction of a sensitive sensor for the monitoring AChE and screening of its inhibitors. By adding AChE, the acetylthiocholine (ATCh) substrate is hydrolyzed to be thiocholine (TCh), which decreases the peroxidase-like activity of Cu-CAT nanosheets (Cu-CAT NSs), impairing the signal reaction of 3,3,5,5-tetramethylbenzidine (TMB) to oxidized-TMB (ox-TMB). In the presence of an AChE inhibitor, the signal can be gradually restored. The newly developed sensor shows high sensitivity and selectivity for AChE and huperzine A (HA, an effective drug for AD, an acetylcholine receptor antagonist), as well as for AD drug discovery from traditional Chinese herbs. The limit of detection of the sensor for AChE is 0.01 mU mL

Early impairments of visually-driven neuronal ensemble dynamics in the rTg4510 tauopathy mouse model.

Tau protein pathology is a hallmark of many neurodegenerative diseases, including Alzheimers Disease or frontotemporal dementia. Synaptic dysfunction and abnormal visual evoked potentials have been reported in murine models of tauopathy, but little is known about the state of the network activity on a single neuronal level prior to brain atrophy. In the present study, oscillatory rhythms and single-cell calcium activity of primary visual cortex pyramidal neuron population were investigated in basal and light evoked states in the rTg4510 tauopathy mouse model prior to neurodegeneration. We found a decrease in their responsivity and overall activity which was insensitive to GABAergic modulation. Despite an enhancement of basal state coactivation of cortical pyramidal neurons, a loss of input-output synchronicity was observed. Dysfunction of cortical pyramidal function was also reflected in a reduction of basal theta oscillations and enhanced susceptibility to a sub-convulsive dose of pentylenetetrazol in rTg4510 mice. Our results unveil impairments in visual cortical pyramidal neuron processing and define aberrant oscillations as biomarker candidates in early stages of neurodegenerative tauopathies.

Discovery of new, highly potent and selective inhibitors of BuChE - design, synthesis, in vitro and in vivo evaluation and crystallography studies.

The symptomatic and disease-modifying effects of butyrylcholinesterase (BuChE) inhibitors provide an encouraging premise for researching effective treatments for Alzheimers disease. Here, we examined a series of compounds with a new chemical scaffold based on 3-(cyclohexylmethyl)amino-2-hydroxypropyl, and we identified a highly selective hBuChE inhibitor (29). Based on extensive in vitro and in vivo evaluations of the compound and its enantiomers, (R)-29 was identified as a promising candidate for further development. Compound (R)-29 is a potent hBuChE inhibitor (IC

Do correlates of white matter features differ between older men and women living with human immunodeficiency virus

Given estrogens role in human immunodeficiency virus (HIV) disease progression and the higher rates of neurocognitive decline in affected women, the purpose of this study was to assess whether the relationship of white matter features and reproductive hormone levels differed between men versus women (sex as a moderator), controlling for selected cardiometabolic risk factors, HIV-related health indicators, and demographics in an aging population of persons living with HIV (PLWH). Older PLWH (50 y and older 44 women and 35 men mean ± SD age, 59.8 ± 0.6 y 55.7% women 72.2% non-Hispanic Black) participated in a cross-sectional study involving a fasting blood draw and a demographic survey (visit 1) and a magnetic resonance imaging scan (visit 2) to determine white matter volume and white matter hyperintensity (WMH) volume. Associations between reproductive hormones (follicle-stimulating hormone FSH, estradiol, testosterone, dehydroepiandrosterone sulfate DHEA-S) and white matter features were assessed in linear regression models. Covariates were age, body mass index, hypertension, diabetes, dyslipidemia, current smoking status, CD4 count, and cranial size. For white matter volume, a sexually dimorphic interaction was seen for DHEA-S (B 21.23 P 0.012) and observed for FSH (B -22.97, P 0.08) with a trend for significance after controlling for risk factors. In women, higher white matter volume was associated with higher DHEA-S (B 13.89, P 0.017) and lower FSH (B 23.58, P 0.01). No hormone associations were shown in men for white matter volume. For WMH volume, no significant interaction effects between sex and reproductive hormones were identified. For WMH, sex did not predict associations with reproductive hormones after controlling for risk factors. Although sexually dimorphic interactions of reproductive hormones and total white matter volume were demonstrated, our study findings do not support a role for sex-based differences in reproductive hormones as predictive correlates of WMH in a small sample of older PLWH.

The fidelity of transcription in human cells.

To determine the error rate of transcription in human cells, we analyzed the transcriptome of H1 human embryonic stem cells with a circle-sequencing approach that allows for high-fidelity sequencing of the transcriptome. These experiments identified approximately 100,000 errors distributed over every major RNA species in human cells. Our results indicate that different RNA species display different error rates, suggesting that human cells prioritize the fidelity of some RNAs over others. Cross-referencing the errors that we detected with various genetic and epigenetic features of the human genome revealed that the in vivo error rate in human cells changes along the length of a transcript and is further modified by genetic context, repetitive elements, epigenetic markers, and the speed of transcription. Our experiments further suggest that BRCA1, a DNA repair protein implicated in breast cancer, has a previously unknown role in the suppression of transcription errors. Finally, we analyzed the distribution of transcription errors in multiple tissues of a new mouse model and found that they occur preferentially in neurons, compared to other cell types. These observations lend additional weight to the idea that transcription errors play a key role in the progression of various neurological disorders, including Alzheimers disease.

Distinct patterns of neurodegeneration after TBI and in Alzheimers disease.

Traumatic brain injury (TBI) is a dementia risk factor, with Alzheimers disease (AD) more common following injury. Patterns of neurodegeneration produced by TBI can be compared to AD and aging using volumetric MRI. A total of 55 patients after moderate to severe TBI (median age 40), 45 with AD (median age 69), and 61 healthy volunteers underwent magnetic resonance imaging over 2 years. Atrophy patterns were compared. AD patients had markedly lower baseline volumes. TBI was associated with increased white matter (WM) atrophy, particularly involving corticospinal tracts and callosum, whereas AD rates were increased across white and gray matter (GM). Subcortical WM loss was shared in ADTBI, but deep WM atrophy was TBI-specific and cortical atrophy AD-specific. Post-TBI atrophy patterns were distinct from aging, which resembled AD. Post-traumatic neurodegeneration 1.9-4.0 years (median) following moderate-severe TBI is distinct from agingAD, predominantly involving central WM. This likely reflects distributions of axonal injury, a neurodegeneration trigger. We compared patterns of brain atrophy longitudinally after moderate to severe TBI in late-onset AD and healthy aging. Patients after TBI had abnormal brain atrophy involving the corpus callosum and other WM tracts, including corticospinal tracts, in a pattern that was specific and distinct from AD and aging. This pattern is reminiscent of axonal injury following TBI, and atrophy rates were predicted by the extent of axonal injury on diffusion tensor imaging, supporting a relationship between early axonal damage and chronic neurodegeneration.

Why Hippocampal Glutamate Levels Are Elevated in Schizophrenia.

This article discusses why glutamate levels are abnormally elevated in the hippocampus of patients with schizophrenia and related disorders.

The medial prefrontal cortex and the cardiac baroreflex activity physiological and pathological implications.

The cardiac baroreflex is an autonomic neural mechanism involved in the modulation of the cardiovascular system. It influences the heart rate and peripheral vascular resistance to preserve arterial blood pressure within a narrow variation range. This mechanism is mainly controlled by medullary nuclei located in the brain stem. However, supramedullary areas, such as the ventral portion of medial prefrontal cortex (vMPFC), are also involved. Particularly, the glutamatergic NMDANO pathway in the vMPFC can facilitate baroreflex bradycardic and tachycardic responses. In addition, cannabinoid receptors in this same area can reduce or increase those cardiac responses, possibly through alteration in glutamate release. This vMPFC network has been associated to cardiovascular responses during stressful situations. Recent results showed an involvement of glutamatergic, nitrergic, and endocannabinoid systems in the blood pressure and heart rate increases in animals after aversive conditioning. Consequently, baroreflex could be modified by the vMPFC neurotransmission during stressful situations, allowing necessary cardiovascular adjustments. Remarkably, some mental, neurological and neurodegenerative disorders can involve damage in the vMPFC, such as posttraumatic stress disorder, major depressive disorder, Alzheimers disease, and neuropathic pain. These pathologies are also associated with alterations in glutamateNO release and endocannabinoid functions along with baroreflex impairment. Thus, the vMPFC seems to play a crucial role on the baroreflex control, either during pathological or physiological stress-related responses. The study of baroreflex mechanism under such pathological view may be helpful to establish causality mechanisms for the autonomic and cardiovascular imbalance found in those conditions. It can explain in the future the reasons of the high cardiovascular risk some neurological and neurodegenerative disease patients undergo. Additionally, the present work offers insights on the possible contributions of vMPFC dysfunction on baroreflex alterations, which, in turn, may raise questions in what extent other brain areas may play a role in autonomic deregulation under such pathological situations.

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Parkin Mediates Cannabidiol Prevention of Amyloid-Beta-Induced Senescence in Human Astrocytes.

Genome-Wide Analysis of Structural Variants in Parkinson Disease.

Identification of genetic risk factors for Parkinson disease (PD) has to date been primarily limited to the study of single nucleotide variants, which only represent a small fraction of the genetic variation in the human genome. Consequently, causal variants for most PD risk are not known. Here we focused on structural variants (SVs), which represent a major source of genetic variation in the human genome. We aimed to discover SVs associated with PD risk by performing the first large-scale characterization of SVs in PD. We leveraged a recently developed computational pipeline to detect and genotype SVs from 7,772 Illumina short-read whole genome sequencing samples. Using this set of SV variants, we performed a genome-wide association study using 2,585 cases and 2,779 controls and identified SVs associated with PD risk. Furthermore, to validate the presence of these variants, we generated a subset of matched whole-genome long-read sequencing data. We genotyped and tested 3,154 common SVs, representing over 412 million nucleotides of previously uncatalogued genetic variation. Using long-read sequencing data, we validated the presence of three novel deletion SVs that are associated with risk of PD from our initial association analysis, including a 2 kb intronic deletion within the gene LRRN4. We identified three SVs associated with genetic risk of PD. This study represents the most comprehensive assessment of the contribution of SVs to the genetic risk of PD to date. ANN NEUROL 2023.

Acute sleep loss decreases CSF-to-blood clearance of Alzheimers disease biomarkers.

Sleep deprivation increases cerebrospinal fluid (CSF) amyloid beta (Aβ) and tau levels however, sleeps effect on Aβ and tau in plasma is unknown. In a cross-over design, CSF Aβ and tau concentrations were measured in five cognitively normal individuals who had blood and CSF collected every 2 hours for 36 hours during sleep-deprived and normal sleep control conditions. Aβ40, Aβ42, unphosphorylated tau threonine181 (T181), unphosphorylated tau threonine-217 (T217), and phosphorylated T181 (pT181) concentrations increased ∼35% to 55% in CSF and decreased ∼5% to 15% in plasma during sleep deprivation. CSFplasma ratios of all Alzheimers disease (AD) biomarkers increased during sleep deprivation while the CSFplasma albumin ratio, a measure of blood-CSF barrier permeability, decreased. CSF and plasma Aβ4240, pT181T181, and pT181Aβ42 ratios were stable longitudinally in both groups. These findings show that sleep loss alters some plasma AD biomarkers by lowering brain clearance mechanisms and needs to be taken into account when interpreting individual plasma AD biomarkers but not ratios.

Amyloid-PET of the white matter Relationship to free water, fiber integrity, and cognition in patients with dementia and small vessel disease.

White matter (WM) injury is frequently observed along with dementia. Positron emission tomography with amyloid-ligands (Aβ-PET) recently gained interest for detecting WM injury. Yet, little is understood about the origin of the altered Aβ-PET signal in WM regions. Here, we investigated the relative contributions of diffusion MRI-based microstructural alterations, including free water and tissue-specific properties, to Aβ-PET in WM and to cognition. We included a unique cohort of 115 participants covering the spectrum of low-to-severe white matter hyperintensity (WMH) burden and cognitively normal to dementia. We applied a bi-tensor diffusion-MRI model that differentiates between (i) the extracellular WM compartment (represented via free water), and (ii) the fiber-specific compartment (via free water-adjusted fractional anisotropy FA). We observed that, in regions of WMH, a decrease in Aβ-PET related most closely to higher free water and higher WMH volume. In contrast, in normal-appearing WM, an increase in Aβ-PET related more closely to higher cortical Aβ (together with lower free water-adjusted FA). In relation to cognitive impairment, we observed a closer relationship with higher free water than with either free water-adjusted FA or WM PET. Our findings support free water and Aβ-PET as markers of WM abnormalities in patients with mixed dementia, and contribute to a better understanding of processes giving rise to the WM PET signal.

Dual-target ligand discovery for Alzheimers disease triphenylphosphoranylidene derivatives as inhibitors of acetylcholinesterase and β-amyloid aggregation.

Alzheimer disease (AD) is one of the major neurodegenerative diseases that could not be prevented or completely cured and may lead to death. Here, we target AChE and β-amyloid proteins. Synthesising new triphenylphosphporanylidene derivatives based on the surveyed literature and testing their biological activity revealed promising results especially for the acetyl triphenylphosphoranylidene derivative

Blood-brain barrier opening of the default mode network in Alzheimers disease with magnetic resonance-guided focused ultrasound.

The blood-brain barrier (BBB) protects the brain but is also an important obstacle for the effective delivery of therapeutics in Alzheimers disease and other neurodegenerative disorders. Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) has been shown to reversibly disrupt the BBB. However, treatment of diffuse regions across the brain along with the effect on Alzheimers disease relevant pathology need to be better characterized. This study is an open-labelled single-arm trial (NCT04118764) to investigate the feasibility of modulating BBB permeability in the default mode network and the impact on cognition, amyloid and tau pathology as well as BBB integrity. Nine participants mean age 70.2 ± 7.2 years, mean Mini-Mental State Examination (MMSE) 21.9 underwent three biweekly procedures with follow-up visits up to 6 months. The BBB permeability of the bilateral hippocampi, anterior cingulate cortex and precuneus was transiently increased without grade 3 or higher adverse events. Participants did not experience worsening trajectory of cognitive decline (ADAS-cog11, MMSE). Whole brain vertex-based analysis of the 18F-florbetaben PET imaging demonstrated clusters of modest SUVR reduction in the right parahippocampal and inferior temporal lobe. However, CSF and blood biomarkers did not demonstrate any amelioration of Alzheimers disease pathology (P-tau181, amyloid-β4240 ratio), nor did it show persistent BBB dysfunction (plasma PDGFRbeta and CSF-to-plasma albumin ratio). This study provides neuroimaging and fluid biomarker data to characterize the safety profile of MRgFUS BBB modulation in neurodegeneration as a potential strategy for enhanced therapeutic delivery.

A Low-Molecular-Weight BDNF Mimetic, Dipeptide GSB-214, Prevents Memory Impairment in Rat Models of Alzheimers Disease.

Brain-derived neurotrophic factor (BDNF) is known to be involved in the pathogenesis of Alzheimers disease (AD). However, the pharmacological use of full-length neurotrophin is limited, because of its macromolecular protein nature. A dimeric dipeptide mimetic of the BDNF loop 1, bis-(N-monosuccinyl-L-methionyl-L-serine) heptamethylene diamide (GSB-214), was designed at the Zakusov Research Institute of Pharmacology. GSB-214 activates TrkB, PI3KAKT, and PLC-γ1 in vitro. GSB-214 exhibited a neuroprotective activity during middle cerebral artery occlusion in rats when administered intraperitoneally (i.p.) at a dose of 0.1 mgkg and improved memory in the novel object recognition test (0.1 and 1.0 mgkg, i.p.). In the present study, we investigated the effects of GSB-214 on memory in the scopolamine- and steptozotocin-induced AD models, with reference to activation of TrkB receptors. AD was modeled in rats using a chronic i.p. scopolamine injection or a single streptozotocin injection into the cerebral ventricles. GSB-214 was administered within 10 days after the exposure to scopolamine at doses of 0.05, 0.1, and 1 mgkg (i.p.) or within 14 days after the exposure to streptozotocin at a dose of 0.1 mgkg (i.p.). The effect of the dipeptide was evaluated in the novel object recognition test K252A, a selective inhibitor of tyrosine kinase receptors, was used to reveal a dependence between the mnemotropic action and Trk receptors. GSB-214 at doses of 0.05 and 0.1 mgkg statistically significantly prevented scopolamine-induced long-term memory impairment, while not affecting short-term memory. In the streptozotocin-induced model, GSB-214 completely eliminated the impairment of short-term memory. No mnemotropic effect of GSB-214 was registered when Trk receptors were inhibited by K252A.

Aldehyde dehydrogenase in solid tumors and other diseases Potential biomarkers and therapeutic targets.

The family of aldehyde dehydrogenases (ALDHs) contains 19 isozymes and is involved in the oxidation of endogenous and exogenous aldehydes to carboxylic acids, which contributes to cellular and tissue homeostasis. ALDHs play essential parts in detoxification, biosynthesis, and antioxidants, which are of important value for cell proliferation, differentiation, and survival in normal body tissues. However, ALDHs are frequently dysregulated and associated with various diseases like Alzheimers disease, Parkinsons disease, and especially solid tumors. Notably, the involvement of the ALDHs in tumor progression is responsible for the maintenance of the stem-cell-like phenotype, triggering rapid and aggressive clinical progressions. ALDHs have captured increasing attention as biomarkers for disease diagnosis and prognosis. Nevertheless, these require further longitudinal clinical studies in large populations for broad application. This review summarizes our current knowledge regarding ALDHs as potential biomarkers in tumors and several non-tumor diseases, as well as recent advances in our understanding of the functions and underlying molecular mechanisms of ALDHs in disease development. Finally, we discuss the therapeutic potential of ALDHs in diseases, especially in tumor therapy with an emphasis on their clinical implications.

The derivatives of cromolyn ameliorate the abnormal misfolding of amyloid proteins and neuroinflammation in the neural cells.

The representative symptom of Alzheimers Disease (AD) has mainly been mentioned to be misfolding of amyloid proteins, such as amyloid-beta (Aβ) and tau protein. In addition, the neurological pathology related to neuroinflammatory signaling has recently been raised as an important feature in AD. Currently, numerous drug candidates continue to be investigated to reduce symptoms of AD, including amyloid proteins misfolding and neuroinflammation. Our research aimed to identify the anti-AD effects of two chemical derivatives modified from cromoglicic acid, CNU 010 and CNU 011. CNU 010 and CNU 011 derived from cromoglicic acid were synthesized. The inhibitory effects of Aβ and tau were identified by thioflavin T assay. Moreover, western blots were conducted with derivates CNU 010 and CNU 011 to confirm the effects on inflammation. CNU 010 and CNU 011 significantly inhibited the aggregation of Aβ and tau proteins. Moreover, they reduced the expression levels of mitogen-activated protein (MAP) kinase and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling proteins, which are representative early inflammatory signaling markers. Also, the inhibitory effects on the lipopolysaccharide (LPS)-induced cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) expression referring to late inflammation were confirmed. Our results showing multiple beneficial effects of cromolyn derivatives against abnormal aggregation of amyloid proteins and neuroinflammatory signaling provide evidence that CNU 010 and CNU 011 could be further developed as potential drug candidates for AD treatment.

Homocysteine thiolactone and H

Of the proteinaceous β-sheet-rich amyloid fibrillar structures, the Aβ

Early visual alterations in individuals at-risk of Alzheimers disease a multidisciplinary approach.

The earliest pathological features of Alzheimers disease (AD) appear decades before the clinical symptoms. The pathology affects the brain and the eye, leading to retinal structural changes and functional visual alterations. Healthy individuals at high risk of developing AD present alterations in these ophthalmological measures, as well as in resting-state electrophysiological activity. However, it is unknown whether the ophthalmological alterations are related to the visual-related electrophysiological activity. Elucidating this relationship is paramount to understand the mechanisms underlying the early deterioration of the system and an important step in assessing the suitability of these measures as early biomarkers of disease. In total, 144 healthy subjects 105 with family history of AD and 39 without, underwent ophthalmologic analysis, magnetoencephalography recording, and genotyping. A subdivision was made to compare groups with less demographic and more risk differences 28 high-risk subjects (relativesAPOEɛ4 ) and 16 low-risk (non-relativesAPOEɛ4 -). Differences in visual acuity, contrast sensitivity, and macular thickness were evaluated. Correlations between each variable and visual-related electrophysiological measures (M100 latency and time-frequency power) were calculated for each group. High-risk groups showed increased visual acuity. Visual acuity was also related to a lower M100 latency and a greater power time-frequency cluster in the high-risk group. Low-risk groups did not show this relationship. High-risk groups presented trends towards a greater contrast sensitivity that did not remain significant after correction for multiple comparisons. The highest-risk group showed trends towards the thinning of the inner plexiform and inner nuclear layers that did not remain significant after correction. The correlation between contrast sensitivity and macular thickness, and the electrophysiological measures were not significant after correction. The difference between the high- and low- risk groups correlations was no significant. To our knowledge, this paper is the first of its kind, assessing the relationship between ophthalmological and electrophysiological measures in healthy subjects at distinct levels of risk of AD. The results are novel and unexpected, showing an increase in visual acuity among high-risk subjects, who also exhibit a relationship between this measure and visual-related electrophysiological activity. These results have not been previously explored and could constitute a useful object of research as biomarkers for early detection and the evaluation of potential interventions effectiveness.

Three-dimensional chromatin architecture datasets for aging and Alzheimers disease.

Recently, increasing studies are indicating a close association between dysregulated enhancers and neurodegenerative diseases, such as Alzheimers disease (AD). However, their contributions were poorly defined for lacking direct links to disease genes. To bridge this gap, we presented the Hi-C datasets of 4 AD patients, 4 dementia-free aged and 3 young subjects, including 30 billion reads. As applications, we utilized them to link the AD risk SNPs and dysregulated epigenetic marks to the target genes. Combining with epigenetic data, we observed more detailed interactions among regulatory regions and found that many known AD risk genes were under long-distance promoter-enhancer interactions. For future AD and aging studies, our datasets provide a reference landscape to better interpret findings of association and epigenetic studies for AD and aging process.

Fc effector of anti-Aβ antibody induces synapse loss and cognitive deficits in Alzheimers disease-like mouse model.

Passive immunotherapy is one of the most promising interventions for Alzheimers disease (AD). However, almost all immune-modulating strategies fail in clinical trials with unclear causes although they attenuate neuropathology and cognitive deficits in AD animal models. Here, we showed that Aβ-targeting antibodies including their lgG1 and lgG4 subtypes induced microglial engulfment of neuronal synapses by activating CR3 or FcγRIIb via the complex of Aβ, antibody, and complement. Notably, anti-Aβ antibodies without Fc fragment, or with blockage of CR3 or FcγRIIb, did not exert these adverse effects. Consistently, Aβ-targeting antibodies, but not their Fab fragments, significantly induced acute microglial synapse removal and rapidly exacerbated cognitive deficits and neuroinflammation in APPPS1 mice post-treatment, whereas the memory impairments in mice were gradually rescued thereafter. Since the recovery rate of synapses in humans is much lower than that in mice, our findings may clarify the variances in the preclinical and clinical studies assessing AD immunotherapies. Therefore, Aβ-targeting antibodies lack of Fc fragment, or with reduced Fc effector function, may not induce microglial synaptic pruning, providing a safer and more efficient therapeutic alternative for passive immunotherapy for AD.

Transcriptomics and Metabolomics for Co-Exposure to a Cocktail of Neonicotinoids and the Synergist Piperonyl Butoxide.

Here, the transcriptomics and metabolomics on a model of exposure to a cocktail of neonicotinoids (Neo) containing seven commercial compounds and a synergist piperonyl butoxide (PBO) were established. The results showed that Neo and PBO disrupted mRNA and metabolite levels in a dose-dependent manner. Neo caused tryptophan pathway-related neurotoxicity, reduced lipolysis, and promoted fat mass accumulation in the liver, while PBO induced an increase in inflammatory factors and damage to intercellular membranes. Co-exposure enhanced Neo-induced liver steatosis, focal necrosis, and oxidative stress by inhibiting oxidative phosphorylation (OXPHOS). Furthermore, diglycerides and metabolic biomarkers demonstrated that the activation of insulin signaling is associated with restricted OXPHOS, which commonly leads to a high risk of non-alcoholic fatty liver disease (NAFLD) and Alzheimers disease (AD) as the result of over-synthesis of lipids, low energy supply, and high thermogenesis. The study demonstrates that chronic disease can be induced by Neo and the synergist PBO at the molecular level.

Defective proteostasis in Alzheimers disease.

The homeostasis of cellular proteins, or proteostasis, is critical for neuronal function and for brain processes, including learning and memory. Increasing evidence indicates that defective proteostasis contributes to the progression of neurodegenerative disorders, including Alzheimers disease (AD), the most prevalent form of dementia in the elderly. Proteostasis comprises a set of cellular mechanisms that control protein synthesis, folding, post-translational modification and degradation, all of which are deregulated in AD. Importantly, deregulation of proteostasis plays a key role in synapse dysfunction and in memory impairment, the major clinical manifestation of AD. Here, we discuss molecular pathways involved in protein synthesis and degradation that are altered in AD, and possible pharmacological approaches to correct these defects.

Potential Protective Function of Aβ

While soluble forms of amyloid-β (Aβ) and Tau work together to drive healthy neurons into a disease state, how their interaction may control the prion-like propagation and neurotoxicity of Tau is not fully understood. The cross-linking via disulfide bond formation is crucial for Tau oligomers to obtain stable conformers and spread between cells. This work thus focuses on how Aβ

State-of-the-art therapy for Down syndrome.

In the last decade, an important effort was made in the field of Down syndrome to find new interventions that improve cognition. These therapies have added to the traditional symptomatic treatments and to the drugs for treating Alzheimer disease in the general population repurposed for Down syndrome. Defining next-generation therapeutics will involve biomarker-based therapeutic decision-making, and preventive and multimodal interventions. However, translation of specific findings into effective therapeutic strategies has been disappointingly slow and has failed in many cases at the clinical level, leading to reduced credibility of mouse studies. This is aggravated by a tendency to favour large-magnitude effects and highly significant findings, leading to high expectations but also to a biased view of the complex pathophysiology of Down syndrome. Here, we review some of the most recent and promising strategies for ameliorating the cognitive state of individuals with Down syndrome. We studied the landscape of preclinical and clinical studies and conducted a thorough literature search on PubMed and ClinicalTrials.gov for articles published between June 2012 and August 2022 on therapies for ameliorating cognitive function in individuals with Down syndrome. We critically assess current therapeutic approaches, why therapies fail in clinical trials in Down syndrome, and what could be the path forward. We discuss some intrinsic difficulties for translational research, and the need for a framework that improves the detection of drug efficacy to avoid discarding compounds too early from the companies pipelines.

Renal function and neurodegenerative diseases a two-sample Mendelian randomization study.

Observational studies showed renal function had associations with Alzheimers disease (AD), Parkinsons disease (PD), Lewy body dementia (LBD) and multiple sclerosis (MS). However, it is unknown whether these associations are causal. We use a two-sample Mendelian randomization (MR) analysis to investigate causal relationships between renal function and 6 neurodegenerative diseases (NDDs) AD (including familial AD), PD, LBD, frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and MS. Blood urea nitrogen (BUN), chronic kidney disease (CKD) and estimated glomerular filtration rate (eGFR) were used to measure renal function. The inverse-variance weighted (IVW) was the predominant estimation method. The results were further validated using sensitivity analysis (i.e. MR Egger regression, Cochran Q statistic of IVW, and leave-one-out method). There was no indication of any causative relationship of BUN, CKD, or eGFR with AD, familial AD, PD, LBD, FTD and ALS (all Our study showed that reduced eGFR was related to MS. The value of this study is that it provides a direction for further research on the relationship between reduced eGFR and MS.

Association of Kidney Function With Development of Alzheimer Disease and Other Dementias and Dementia-Related Blood Biomarkers.

Previous research has suggested an association of kidney function with risk of Alzheimer disease (AD) or other dementias and dementia-related blood biomarkers, but a distinct association remains unclear. To evaluate the association of kidney function with risk of diagnosis of incident AD or dementia within 17 years and with the blood biomarkers neurofilament light (NfL), phosphorylated tau181 (p-tau181), and glial fibrillary acidic protein (GFAP). In this prospective, population-based cohort study and nested case-control study, 9940 participants in Germany were enrolled between 2000 and 2002 by their general practitioners and followed up for up to 17 years. Participants were included if information on dementia status and creatininecystatin C measurements were available. A subsample of participants additionally had measurements of NfL, p-tau181, and GFAP obtained from blood samples. Statistical analysis was performed from January 3 to November 25, 2022. Impaired kidney function, based on estimated glomerular filtration rate less than 60 mLmin1.73 m2 according to the 2021 Chronic Kidney Disease Epidemiology Collaboration creatinine-cystatin C equation. All-cause dementia, AD, and vascular dementia diagnosis, as well as log-transformed levels of NfL, p-tau181, and GFAP in blood. Of 6256 participants (3402 women 54.4% mean SD age at baseline, 61.7 6.6 years), 510 received an all-cause dementia diagnosis within 17 years of baseline. The dementia-related blood biomarker nested case-control sample included 766 participants. After adjusting for age and sex, impaired kidney function at baseline was not associated with a higher risk of all-cause dementia (hazard ratio HR, 0.95 95% CI, 0.69-1.29), AD (HR, 0.94 95% CI, 0.55-1.63), or vascular dementia diagnosis (HR, 1.06 95% CI, 0.65-1.70) within 17 years. In the cross-sectional analysis, after adjusting for age and sex, impaired kidney function was significantly associated with NfL and p-tau181 levels in blood (NfL β 0.47 and P < .001 p-tau181 β 0.21 and P .003). After adjusting for age and sex, significant associations with GFAP levels were evident only among men (men β 0.31 and P .006 women β -0.12 and P .11). In this population-based study of community-dwelling adults, reduced kidney function was associated with increased levels of dementia-related blood biomarkers but not increased dementia risk. Kidney function might influence the accuracy of dementia-related blood biomarkers and should be considered in clinical translation.

The longitudinal relationship between meaning in life, depressive symptoms, life satisfaction, and cognitive functioning for older adults with Alzheimers disease.

Studies show the importance of the personal experience of meaning in life for older adults, but adults with dementia have been largely excluded from this research. The current study examined the longitudinal predictive effect of meaning in life for the psychological and cognitive functioning of older adults with Alzheimers disease and whether cognitive decline predicted presence of meaning in life. On three yearly measurement occasions, presence of meaning in life, depressive symptoms, life satisfaction, and cognitive functioning were assessed in structured interviews with a convenience sample of 140 older adults with Alzheimers disease from nine nursing homes in Belgium. Cross-lagged panel and latent growth curve models were used to analyze the longitudinal relationships between the variables. Over the three measurement waves, participants with higher presence of meaning reported lower depressive symptoms one year later. Presence of meaning and life satisfaction predicted each other over time, but only between the first and second wave. The analyses showed no strong evidence for a longitudinal association between meaning in life and cognitive functioning in either direction. The findings emphasize the importance of the experience of meaning in life for the psychological functioning of older adults with Alzheimers disease. The lack of evidence for associations between meaning and cognitive functioning questions the prevailing view that intact cognitive abilities are a necessity for experiencing meaning. More attention to the potential of meaning interventions for persons with dementia is warranted.

Exploring the Role of Glycolytic Enzymes PFKFB3 and GAPDH in the Modulation of Aβ and Neurodegeneration and Their Potential of Therapeutic Targets in Alzheimers Disease.

Alzheimers disease (AD) is presently the 6th major cause of mortality across the globe. However, it is expected to rise rapidly, following cancer and heart disease, as a leading cause of death among the elderly peoples. AD is largely characterized by metabolic changes linked to glucose metabolism and age-induced mitochondrial failure. Recent research suggests that the glycolytic pathway is required for a range of neuronal functions in the brain including synaptic transmission, energy production, and redox balance however, alteration in glycolytic pathways may play a significant role in the development of AD. Moreover, it is hypothesized that targeting the key enzymes involved in glucose metabolism may help to prevent or reduce the risk of neurodegenerative disorders. One of the major pro-glycolytic enzyme is 6-phosphofructo-2-kinasefructose-2,6-bisphosphatase-3 (PFKFB3) it is normally absent in neurons but abundant in astrocytes. Similarly, another key of glycolysis is glyceraldehyde-3-phosphate dehydrogenase (GAPDH) which catalyzes the conversion of aldolase and glyceraldehyde 3 phosphates to 1,3 bisphosphoglycerate. GAPDH has been reported to interact with various neurodegenerative disease-associated proteins, including the amyloid-β protein precursor (AβPP). These findings indicate PFKFB3 and GAPDH as a promising therapeutic target to AD. Current review highlight the contributions of PFKFB3 and GAPDH in the modulation of Aβand AD pathogenesis and further explore the potential of PFKFB3 and GAPDH as therapeutic targets in AD.

The combination of hyperventilation test and graph theory parameters to characterize EEG changes in mild cognitive impairment (MCI) condition.

Hyperventilation (HV) is a voluntary activity that causes changes in the neuronal firing characteristics noticeable in the electroencephalogram (EEG) signals. HV-related changes have been scribed to modulation of pO2pCO2 blood contents. Therefore, an HV test is routinely used for highlighting brain abnormalities including those depending to neurobiological mechanisms at the basis of neurodegenerative disorders. The main aim of the present paper is to study the effectiveness of HV test in modifying the functional connectivity from the EEG signals that can be typical of a prodromal state of Alzheimers disease (AD), the Mild Cognitive Impairment prodromal to Alzheimer condition. MCI subjects and a group of age-matched healthy elderly (Ctrl) were enrolled and subjected to EEG recording during HV, eyes-closed (EC), and eyes-open (EO) conditions. Since the cognitive decline in MCI seems to be a progressive disconnection syndrome, the approach we used in the present study is the graph theory, which allows to describe brain networks with a series of different parameters. Small world (SW), modularity (M), and global efficiency (GE) indexes were computed among the EC, EO, and HV conditions comparing the MCI group to the Ctrl one. All the three graph parameters, computed in the typical EEG frequency bands, showed significant changes among the three conditions, and more interestingly, a significant difference in the GE values between the MCI group and the Ctrl one was obtained, suggesting that the combination of HV test and graph theory parameters should be a powerful tool for the detection of possible cerebral dysfunction and alteration.

General aspects of dementia disorders.

The prevalence of dementia increases with age. In rare cases, people younger than 65 years old are also affected, with substantial consequences for the professional life. The symptoms depend on the form of dementia and can vary individually. Impairment of short-term memory is not always in the foreground and other neurocognitive domains, such as the disturbance of executive functions can have a significant impact on the ability to cope with everyday life. Pathophysiologically, neurodegenerative dementias with the major forms of Alzheimers dementia, Lewy body dementia, and frontotemporal dementia are distinguished from vascular dementias. Mixed forms are common. There is no curative treatment, but progression can be slowed by nonpharmacological measures and, especially in Alzheimers dementia, by pharmacological treatment. Appropriate measures can promote independence and autonomy for as long as possible however, in the course of the disease restrictions in the extended activities of independent living will initially occur, such as banking transactions, use of means of transport and, in the further course, also in the basic activities of daily living. Legal capacity and the ability to consent to health interventions are restricted sooner or later however, this must always be evaluated for the specific situation and is not generally the case with the diagnosis of dementia. Instruments such as living wills, identification of a health care proxy, and advanced care planning should be used at an early stage. To decrease family caregiver burden with the increased risk of developing depression, supportive, accompanying measures and education are of great importance. Demenzen treten mit zunehmendem Lebensalter vermehrt auf. In seltenen Fällen sind auch jüngere Menschen betroffen, mit erheblichem Einfluss auf die Berufstätigkeit. Die Symptome hängen von der Demenzform ab und können individuell unterschiedlich ausgeprägt sein. Nicht immer steht die Störung des Kurzzeitgedächtnisses im Vordergrund, vielmehr können andere neurokognitive Domänen wie die Störung der Exekutivfunktion sich erheblich auf die Alltagsfähigkeit auswirken. Pathophysiologisch werden die neurodegenerativen Demenzen mit den wichtigsten Formen Alzheimer-Demenz, Lewy-Körperchen-Demenz und frontotemporale Demenz abgegrenzt von den vaskulären Demenzen. Mischformen sind häufig. Eine kurative Therapie besteht nicht, die Progression kann jedoch durch nichtpharmakologische Maßnahmen und, insbesondere bei der Alzheimer-Demenz, auch durch pharmakologische Therapie abgebremst werden. Es gilt, die Selbstständigkeit und Autonomie betroffener Patienten zu fördern. Im Verlauf kommt es jedoch zunächst zu Einschränkungen in den erweiterten Aktivitäten der selbstständigen Lebensführung wie Bankgeschäften, Nutzung von Verkehrsmitteln und im weiteren Verlauf auch den basalen Funktionen der Selbsthilfefähigkeit. Geschäftsfähigkeit und Einwilligungsfähigkeit in Bezug auf gesundheitliche Eingriffe sind früher oder später eingeschränkt. Dies muss jedoch immer wieder für die konkrete Situation evaluiert werden und liegt nicht grundsätzlich mit der Diagnose Demenz vor. Frühzeitig sollten Instrumente wie die Patientenverfügung, Vorsorgevollmacht oder vorausschauende Gesundheitsplanung („advance care planning“) genutzt werden. Pflegende Angehörige sind häufig stark belastet und haben ein erhöhtes Risiko, an einer Depression zu erkranken. Daher sind unterstützende begleitende Maßnahmen von großer Bedeutung.

Use it or lose it.

Blocking the activity of neurons in a region of the brain involved in memory leads to cell death, which could help explain the spatiotemporal disorientation observed in Alzheimers disease.

Interplay between the catecholaminergic enzymatic axis and neurodegenerationneuroinflammation processes in the Alzheimers disease continuum.

The locus coeruleus (LC) provides dopaminenoradrenaline (DANA) innervation throughout the brain and undergoes early degeneration in Alzheimers disease (AD). We evaluated catecholaminergic enzyme levels in the cerebrospinal fluid (CSF) of a group of patients biologically defined as within the AD continuum (ADc) and explored their relationship with AD biomarkers and cytokinegrowth factor levels to investigate their interplay with neurodegenerative and neuroinflammatory processes. The CSF concentration of DA transporter (DAT), tyrosine-hydroxylase (TH), DOPA-decarboxylase (DDC), and dopamine-β-hydroxylase (DβH), as well as cytokinegrowth factor levels, were analyzed in 41 ADc patients stratified according to CSF beta-amyloid (Aβ) The ADc group had lower CSF levels of DAT and TH but increased DβH levels to compensate for NA synthesis. DDC levels were higher in the A T subgroup but comparable with controls in the A T- subgroup, probably because the DA system is resilient to the degeneration of LC neurons in the absence of tau pathology. Adjusting for age, sex, APOE genotype, and cognitive status, a significant association was found between TH and Aβ Taken together, these findings suggest that catecholaminergic enzymes, functional markers of the catecholaminergic system, are closely linked to the neurodegenerative and neuroinflammatory processes in AD pathology.

Preanalytic variable effects on segmentation and quantification machine learning algorithms for amyloid-β analyses on digitized human brain slides.

Computational machine learning (ML)-based frameworks could be advantageous for scalable analyses in neuropathology. A recent deep learning (DL) framework has shown promise in automating the processes of visualizing and quantifying different types of amyloid-β deposits as well as segmenting white matter (WM) from gray matter (GM) on digitized immunohistochemically stained slides. However, this framework has only been trained and evaluated on amyloid-β-stained slides with minimal changes in preanalytic variables. In this study, we evaluated select preanalytical variables including magnification, compression rate, and storage format using three digital slides scanners (Zeiss Axioscan Z1, Leica Aperio AT2, and Leica Aperio GT 450), on over 60 whole slide images, in a cohort of 14 cases having a spectrum of amyloid-β deposits. We conducted statistical comparisons of preanalytic variables with repeated measures analysis of variance evaluating the outputs of two DL frameworks for segmentation and object classification tasks. For both WMGM segmentation and amyloid-β plaque classification tasks, there were statistical differences with respect to scanner types (p < 0.05) and magnifications (p < 0.05). Although small numbers of cases were analyzed, this pilot study highlights the significance of preanalytic variables that may alter the performance of ML algorithms.

The status of digital pathology and associated infrastructure within Alzheimers Disease Centers.

Digital pathology (DP) has transformative potential, especially for Alzheimer disease and related disorders. However, infrastructure barriers may limit adoption. To provide benchmarks and insights into implementation barriers, a survey was conducted in 2019 within National Institutes of Healths Alzheimers Disease Centers (ADCs). Questions covered infrastructure, funding sources, and data management related to digital pathology. Of the 35 ADCs to which the survey was sent, 33 responded. Most respondents (81%) stated that their ADC had digital slide scanner access, with the most frequent brand being AperioLeica (62.9%). Approximately a third of respondents stated there were fees to utilize the scanner. For DP and machine learning (ML) resources, 41% of respondents stated none was supported by their ADC. For scanner purchasing and operations, 50% of respondents stated they received institutional support. Some were unsure of the file size of scanned digital images (37%) and total amount of storage space files occupied (50%). Most (76%) were aware of other departments at their institution working with ML a similar (76%) percentage were unaware of multiuniversity or industry partnerships. These results demonstrate many ADCs have access to a digital slide scanner additional investigations are needed to further understand hurdles to implement DP and ML workflows.

Complement proteins levels in serum astrocyte-derived exosomes are associated with cognitive impairment in obstructive sleep apnea.

An association between neuroinflammation and cognitive decline has been established. The complement system regulates neuroinflammation. Dysregulation, impairment or inadvertent activation of complement components contribute to preclinical Alzheimers disease. The astrocyte-derived exosome (ADE) complement proteins, including C3b and C5b-9, may be predictive biomarkers of mild cognitive impairment conversion to Alzheimers disease dementia. We hypothesized that complement proteins might be involved in cognitive impairment during obstructive sleep apnea (OSA). The aim of our study was to explore the correlation between the complement system and mild cognitive impairment (MCI) in patients with OSA. All participants with subjective snoring complaints from the Sleep Medicine Center underwent polysomnography. OSA was defined as apnea-hypopnea index (AHI) ≥ 5 eventshour. MCI was defined as the MoCA < 26 and met the criteria (1) a subjective cognitive impairment (2) an objective impairment in one or more cognitive domains (3) complex instrumental daily abilities can be slightly impaired but independent daily living abilities are maintained and (4) no dementia. The ADEs were isolated immunochemically for enzyme-linked immunosorbent assay quantification of complement proteins, including C3b, C5b-9, and CD55. The participants who received CPAP were followed up and their complement protein levels were reassessed after 1 year of treatment. A total of 212 participants (66.98% males mean age of 56.71±10.10 years) were divided into the OSAMCI group (n90), OSA-MCI group (n79), and controls (normal cognitive state without OSA) (n43). The ADE levels of C3b and C5b-9 in the OSAMCI group were higher than those in the OSA-MCI and control groups. The C3b and C5b-9 were independently associated with cognitive impairment in patients with OSA. The relationship between AHI and MoCA scores was mediated by C3b and C5b-9. We found no linear correlation between the complement proteins and the severity of OSA. The complement proteins were negatively correlated with global cognitive performance and cognitive subdomains. The complement protein levels significantly decreased after CPAP treatment. Complement proteins were implicated in cognitive impairment in patients with OSA and may be promising biomarkers for predicting cognitive impairment in patients with OSA. Registry Chinese Clinical Trial Registry URL httpwww.chictr.org.cn Identifier ChiCTR1900021544 Name Study on early diagnostic markers in patients with dementia and mild cognitive impairment.

Mediterranean diet is associated with a lower probability of prodromal Parkinsons disease and risk for Parkinsons diseasedementia with Lewy bodies A longitudinal study.

Lifestyle factors have been implicated in the long-lasting neurodegenerative process in prodromal Parkinsons disease (pPD). The aim was to investigate the associations between adherence to a Mediterranean diet (MeDi) and longitudinal changes of pPD probability and the development of Parkinsons disease (PD) or pPD in a Mediterranean older population. Data from the Hellenic Longitudinal Investigation of Aging and Diet cohort (community-dwelling individuals, aged ≥ 65 years) were used. A detailed food frequency questionnaire was used to evaluate dietary intake and calculate MeDi adherence score, ranging from 0 to 55, with higher scores indicating higher adherence. The probability of pPD was calculated according to the updated Movement Disorder Society research criteria. In all, 1047 non-PDdementia with Lewy bodies (DLB) participants were followed for 3 ± 1 years. MeDi adherence was associated with lower increase in pPD probability over time (b -0.003, 95% confidence interval -0.006 to -0.001, p 0.010). Forty-nine participants had incident possibleprobable pPD (i.e., pPD probability ≥ 30%). Compared to the participants in the lowest quartile of MeDi adherence, those in the higher quartiles had an approximately 60%-70% lower risk for possibleprobable pPD (p for trend 0.003). MeDi-pPD associations were driven by both motor and non-motor pPD markers and not from risk markers. Also, 21 participants were diagnosed with PDDLB at follow-up. For each unit increase in the MeDi score, there was a 9%-10% lower risk for PDDLB (hazard ratio 0.906 95% confidence interval 0.823-0.997, p 0.044). Mediterranean diet adherence is associated with lower increase in pPD probability over time and lower possibleprobable pPD and PDDLB incidence in older Mediterranean people. More studies are needed to confirm our results in other populations.

The role of FUT8-catalyzed core fucosylation in Alzheimers amyloid-β oligomer-induced activation of human microglia.

Fucosylation, especially core fucosylation of N-glycans catalyzed by α1-6 fucosyltransferase (fucosyltransferase 8 or FUT8), plays an important role in regulating the peripheral immune system and inflammation. However, its role in microglial activation is poorly understood. Here we used human induced pluripotent stem cells-derived microglia (hiMG) as a model to study the role of FUT8-catalyzed core fucosylation in amyloid-β oligomer (AβO)-induced microglial activation, in view of its significant relevance to the pathogenesis of Alzheimers disease (AD). HiMG responded to AβO and lipopolysaccharides (LPS) with a pattern of pro-inflammatory activation as well as enhanced core fucosylation and FUT8 expression within 24 h. Furthermore, we found increased FUT8 expression in both human AD brains and microglia isolated from 5xFAD mice, a model of AD-like cerebral amyloidosis. Inhibition of fucosylation in AβO-stimulated hiMG reduced the induction of pro-inflammatory cytokines, suppressed the activation of p38MAPK, and rectified phagocytic deficits. Specific inhibition of FUT8 by siRNA-mediated knockdown also reduced AβO-induced pro-inflammatory cytokines. We further showed that p53 binds to the two consensus binding sites in the Fut8 promoter, and that p53 knockdown abolished FUT8 overexpression in AβO-activated hiMG. Taken together, our evidence supports that FUT8-catalyzed core fucosylation is a signaling pathway required for AβO-induced microglia activation and that FUT8 is a component of the p53 signaling cascade regulating microglial behavior. Because microglia are a key driver of AD pathogenesis, our results suggest that microglial FUT8 could be an anti-inflammatory therapeutic target for AD.

Embracing Monogenic Parkinsons Disease The MJFF Global Genetic PD Cohort.

As gene-targeted therapies are increasingly being developed for Parkinsons disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants (2) provide harmonized and quality-controlled clinical characterization data for each included individual and (3) further promote collaboration of researchers in the field of monogenic PD. We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants 1322 individuals in our cohort (34%) were indicated as not previously published. Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants (2) provide harmonized and quality-controlled clinical and genetic data for each included individual (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A novel histological staging of hippocampal sclerosis that is evident in gray matter loss in vivo.

Hippocampal sclerosis of aging (HS) is defined by end-stage histological findings, strongly associated with limbic-predominant age-related TAR DNA-binding protein 43 (TDP-43) encephalopathy (LATE). We aimed to characterize features of early HS to refine the understanding of its role within combined pathology. We studied 159 brain donations from the multimodal Vallecas Alzheimers Center Study. A staging system (0 to IV) was developed to account for HS progression and analyzed in relation to pre-mortem cognitive and magnetic resonance imaging (MRI) data. Our HS staging system displayed a significant correlation with disease duration, cognitive performance, and combined neuropathologies, especially with LATE. Two-level assessment along the hippocampal longitudinal axis revealed an anterior-posterior gradient of HS severity. In vivo MRI showed focally reduced hippocampal gray matter density as a function of HS staging. The association of this staging system with clinical progression and structural differences supports its utility in the characterization and potential in vivo monitoring of HS. The definition of hippocampal sclerosis of aging (HS) is currently limited to an end-stage pathological fingerprint. We characterize early HS histological features to define a complete staging system. The proposed staging displays a parallel but not identical progression to limbic-predominant age-related TAR DNA-binding protein 43 (TDP-43) encephalopathy (LATE). The proposed staging also reflects the expected demographic and cognitive differences associated with HS. In vivo magnetic resonance imaging (MRI) showed focal hippocampal gray matter loss as a function of HS staging.

Detection of β-N-methylamino-l-alanine in postmortem olfactory bulbs of Alzheimers disease patients using UHPLC-MSMS An autopsy case-series study.

Cyanobacterial blooms produce toxins that may become aerosolized, increasing health risks through inhalation exposures. Health related effects on the lower respiratory tract caused by these toxins are becoming better understood. However, nasal exposures to cyanotoxins remain understudied, especially for those with neurotoxic potential. Here, we present a case series study evaluating exposure to β-N-methylamino-l-alanine (BMAA), a cyanobacterial toxin linked to neurodegenerative disease, in postmortem olfactory tissues of individuals with varying stages of Alzheimers disease (AD). Olfactory bulb ( BMAA was detected in the Our study demonstrates that the cyanobacterial toxin BMAA can be detected in the olfactory pathway, a window to the brain, and its presence may increase the occurrence of proinflammatory cytokines, reactive glia, and toxicity to axonal processes. Further studies will be needed to evaluate BMAAs toxicity via this route of exposure and factors that increase susceptibility.

APLP2 is predominantly cleaved by β-secretase and γ-secretase in the human brain.

Amyloid-β peptide is well-known as a pathogen of Alzheimers disease, but its precursor, amyloid-beta precursor protein (APP), remains unexplained 30 years after its discovery. APP has two homologues called amyloid precursor-like protein 1 (APLP1) and amyloid precursor-like protein 2 (APLP2), and shares a similar structural organisation with them and has partially overlapping functions. APP family proteins are essential for survival, shown by the crossbreeding analysis of knockout mice of APP family molecules, including APLP1 and APLP2. APLP2 is known to play the most important role among them, but the molecular metabolism of APLP2 is only partially understood. Here, we analysed ectodomain shedding and γ-secretase cleavage of APLP2 by molecular biological and biochemical techniques. We analysed the culture supernatant of HEK293 cells overexpressing APLP2 and human cerebrospinal fluid. For the analysis of secreted APLP2 fragments, we raised the OA603 antibody that reacts with the juxtamembrane domain of APLP2. Substrate cleavage sites were identified by matrix assisted laser desorptionionisation mass spectrometry. By overexpressing in HEK293 cells, APLP2 undergoes ectodomain shedding at three sites in the extracellular region by α- and β-secretase-like activity and then is intramembranously cleaved at three sites by γ-secretase. In particular, in shedding, α-secretase-like activity was dominant in HEK cells. Surprisingly, in human cerebrospinal fluid, APLP2-derived metabolic fragments were mainly cleaved by β-secretase-like activity, not by α-secretase-like activity. Because APP is also mainly cleaved by beta-site amyloid precursor protein cleaving enzyme 1 in neurons and APLP1 is expressed exclusively in neurons, these findings suggest that APP family proteins may play a common role via β-secretase-like cleavage in the central nerve system. Thus, these findings may contribute to a better understanding of the role of APP family proteins in Alzheimers disease.

Identification of the molecular mechanism of insulin-like growth factor-1 (IGF-1) a promising therapeutic target for neurodegenerative diseases associated with metabolic syndrome.

Neurodegenerative disorders are accompanied by neuronal degeneration and glial dysfunction, resulting in cognitive, psychomotor, and behavioral impairment. Multiple factors including genetic, environmental, metabolic, and oxidant overload contribute to disease progression. Recent evidences suggest that metabolic syndrome is linked to various neurodegenerative diseases. Metabolic syndrome (MetS) is known to be accompanied by symptoms such as hyperglycemia, abdominal obesity, hypertriglyceridemia, and hypertension. Despite advances in knowledge about the pathogenesis of neurodegenerative disorders, effective treatments to combat neurodegenerative disorders caused by MetS have not been developed to date. Insulin growth factor-1 (IGF-1) deficiency has been associated with MetS-related pathologies both in-vivo and in-vitro. IGF-1 is essential for embryonic and adult neurogenesis, neuronal plasticity, neurotropism, angiogenesis, metabolic function, and protein clearance in the brain. Here, we review the evidence for the potential therapeutic effects of IGF-1 in the neurodegeneration related to metabolic syndrome. We elucidate how IGF-1 may be involved in molecular signaling defects that occurs in MetS-related neurodegenerative disorders and highlight the importance of IGF-1 as a potential therapeutic target in MetS-related neurological diseases.

Post-translational modifications of soluble α-synuclein regulate the amplification of pathological α-synuclein.

Cell-to-cell transmission and subsequent amplification of pathological proteins promote neurodegenerative disease progression. Most research on this has focused on pathological protein seeds, but how their normal counterparts, which are converted to pathological forms during transmission, regulate transmission is less understood. Here we show in cultured cells that phosphorylation of soluble, nonpathological α-synuclein (α-Syn) at previously identified sites dramatically affects the amplification of pathological α-Syn, which underlies Parkinsons disease and other α-synucleinopathies, in a conformation- and phosphorylation site-specific manner. We performed LC-MSMS analyses on soluble α-Syn purified from Parkinsons disease and other α-synucleinopathies, identifying many new α-Syn post-translational modifications (PTMs). In addition to phosphorylation, acetylation of soluble α-Syn also modified pathological α-Syn transmission in a site- and conformation-specific manner. Moreover, phosphorylation of soluble α-Syn could modulate the seeding properties of pathological α-Syn. Our study represents the first systematic analysis how of soluble α-Syn PTMs affect the spreading and amplification of pathological α-Syn, which may affect disease progression.

Heart failure decouples the precuneus in interaction with social cognition and executive functions.

Aging increases the risk to develop Alzheimers disease. Cardiovascular diseases might accelerate this process. Our study aimed at investigating the impact of heart failure on brain connectivity using functional magnetic resonance imaging at resting state. Here we show brain connectivity alterations related to heart failure and cognitive performance. Heart failure decreases brain connectivity in the precuneus. Precuneus dysconnectivity was associated with biomarkers of heart failure-left ventricular ejection fraction and N-terminal prohormone of brain natriuretic peptide-and cognitive performance, predominantly executive function. Meta-analytical data-mining approaches-conducted in the BrainMap and Neurosynth databases-revealed that social and executive cognitive functions are mainly associated with those neural networks. Remarkably, the precuneus, as identified in our study in a mid-life cohort, represents one central functional hub affected by Alzheimers disease. A long-term follow-up investigation in our cohort after approximately nine years revealed more severe cognitive impairment in the group with heart failure than controls, where social cognition was the cognitive domain mainly affected, and not memory such as in Alzheimers disease. In sum, our results indicate consistently an association between heart failure and decoupling of the precuneus from other brain regions being associated with social and executive functions. Further longitudinal studies are warranted elucidating etiopathological mechanisms.

Diffusion Kurtosis Imaging in Evaluating the Mild Cognitive Impairment of Occupational Aluminum Workers.

To investigate whether diffusion kurtosis imaging (DKI) can distinguish mild cognitive impairment (MCI) from normal controls (NC) in aluminum (Al)-exposed workers, and to explore the association of DKI with cognitive performance and plasma Al concentration. 28 patients with MCI and 25 NC at Al factory were enrolled in this study. All subjects underwent conventional MRI and DKI scans. The mean kurtosis (MK), axial kurtosis (Ka), radial kurtosis (Kr), mean diffusivity (MD) and fractional anisotropy (FA) parameters of the hippocampus, substantia nigra, red nucleus, thalamus, anterior cingulate gyrus, genu and crus of the corpus callosum, frontal, parietal and temporal lobe were measured. To compare the parameters between the two groups, the Mann-Whitney rank sum test was used. The correlation of parameter values with cognitive performance and plasma Al concentration was analyzed using Spearman correlation analysis. The receiver operating characteristic (ROC) curve and the Z-scores were used to evaluate the diagnostic efficacy of each parameter. Compared with the NC group, the MK, Ka, Kr, and FA values in the MCI group were significantly decreased, and the MD values were significantly increased (p<0.05). For the diagnosis of MCI, MK in the right hippocampus showed the largest AUC (0.924). The MK, Kr, MD and FA values were correlated with the Montreal Cognitive Assessment (MoCA) scores, and MK values in the right hippocampus showed the greatest correlation with MoCA scores (r0.744, p <0.001). Plasma Al in the MCI group was higher than that in the NC group, although there was no significant difference in plasma Al between the two groups (p0.057). There was no correlation between DKI parameters and plasma Al. The DKI method might be a sensitive imaging biomarker to discriminate MCI from NC, and could preliminarily assess the severity of cognitive impairment in Al-exposed workers. MK in the right hippocampus appeared to be the best independent predictor. The mechanism of cognitive decline is an important content of aluminum exposure research. This study indicates that the DKI technique could provide valuable information for the diagnosis of MCI.

Alterations in ether lipid metabolism and the consequences for the mouse lipidome.

Alkylglycerol monooxygenase (AGMO) and plasmanylethanolamine desaturase (PEDS1) are enzymes involved in ether lipid metabolism. While AGMO degrades plasmanyl lipids by oxidative cleavage of the ether bond, PEDS1 exclusively synthesizes a specific subclass of ether lipids, the plasmalogens, by introducing a vinyl ether double bond into plasmanylethanolamine phospholipids. Ether lipids are characterized by an ether linkage at the sn-1 position of the glycerol backbone and they are found in membranes of different cell types. Decreased plasmalogen levels have been associated with neurological diseases like Alzheimers disease. Agmo-deficient mice do not present an obvious phenotype under unchallenged conditions. In contrast, Peds1 knockout mice display a growth phenotype. To investigate the molecular consequences of Agmo and Peds1 deficiency on the mouse lipidome, five tissues from each mouse model were isolated and subjected to high resolution mass spectrometry allowing the characterization of up to 2013 lipid species from 42 lipid subclasses. Agmo knockout mice moderately accumulated plasmanyl and plasmenyl lipid species. Peds1-deficient mice manifested striking changes characterized by a strong reduction of plasmenyl lipids and a concomitant massive accumulation of plasmanyl lipids resulting in increased total ether lipid levels in the analyzed tissues except for the class of phosphatidylethanolamines where total levels remained remarkably constant also in Peds1 knockout mice. The rate-limiting enzyme in ether lipid metabolism, FAR1, was not upregulated in Peds1-deficient mice, indicating that the selective loss of plasmalogens is not sufficient to activate the feedback mechanism observed in total ether lipid deficiency.

Phase Separation in Biology and Disease Current Perspectives and Open Questions.

In the past almost 15 years, we witnessed the birth of a new scientific field focused on the existence, formation, biological functions, and disease associations of membraneless bodies in cells, now referred to as biomolecular condensates. Pioneering studies from several laboratories reviewed in

Neuroprotective potential of Honokiol in ICV-STZ induced neuroinflammation, Aβ

Alzheimers disease (AD) is a most common and prevalent age related insidious neurological condition characterised by formation of Aβ

Robust quantitation of gangliosides and sulfatides in human brain using UHPLC-MRM-MS Method development and application in Alzheimers disease.

Gangliosides (GAs) and sulfatides (STs) are acidic glycosphingolipids that are particularly abundant in the nervous system and are closely related to aging and neurodegenerative disorders. To explore their roles in brain diseases, in-depth molecular profiling, including structural variations of sphingoid backbone, fatty acyl group, and sugar chain of GAs and STs was performed. A total of 210 GAs and 38 STs were characterized in the inferior frontal gyrus (IFG) of human brain, with 90 GAs discovered in brain tissues for the first time. Influential MS parameters for detecting GAs and STs in multiple reaction monitoring (MRM) mode were systematically examined and optimized to minimize in-source fragmentation, resulting in remarkable signal intensity enhancement for GAs and STs, especially for polysialylated species. To eliminate analytical variations, isotopic interference-free internal standards were prepared by simple and fast reduction reaction. The final established method facilitated the simultaneous quantitation of 184 GAs and 30 STs from 25 subtypes, which represents the highest number of GAs quantitated among all quantitation methods recorded in literature so far. The method was further validated and applied to reveal the aberrant change of GAs and STs in the IFG of 12 Alzheimers disease (AD) patients. Four GAs exhibited high classification capacity for AD (AUC ≥0.80) and were thereby considered the most promising signatures for AD. These findings suggested the close correlation between GAs and the pathogenesis of AD, highlighting the achievements of our robust method for investigating the roles of GAs and STs in various physiological states and diseases.

pNaktide mitigates inflammation-induced neuronal damage and behavioral deficits through the oxidative stress pathway.

Neuroinflammation is closely related to the etiology and progression of neurodegenerative diseases such as Parkinson disease and Alzheimer disease. pNaktide, an Src inhibitor, exerts antioxidant effects by mimicking NaK-ATPase. It has been verified that its anti-inflammation and anti-oxidation ability could be embodied in obesity, steatohepatitis, uremic cardiomyopathy, aging, and prostate cancer. This study aimed to investigate the effects and mechanisms of pNaktide in lipopolysaccharide (LPS)-induced behavioral damage, neuroinflammation, and neuronal damage. We found that pNaktide improved anxiety, memory, and motor deficits. pNaktide inhibited MAPK and NF-κB pathways induced by TLR4 activation, inhibited the NLRP3 inflammasome complex, and reduced the expression of inflammatory factors, complement factors, and chemokines. pNaktide inhibited the activation of Nrf2 and HO-1 antioxidant stress pathways by LPS and reduced the level of oxidative stress. Inhibition of autophagy and enhancement of apoptosis induced by LPS were also alleviated by pNaktide, which restored LPS-induced injury to newborn neurons in the hippocampus region. In summary, pNaktide attenuates neuroinflammation, reduces the level of oxidative stress, has neuroprotective effects, and may be used for the treatment of neuroinflammation-related diseases.

Insomnia and risk of dementia in a large population-based study with 11-year follow-up The HUNT study.

Despite evidence suggesting that insomnia is associated with the risk of dementia and cognitive dysfunction, studies have shown mixed results. Dementia has a long prodromal phase, and studies with long follow-up are required to avoid reverse causality. In our 11-year follow-up study, we assessed whether probable insomnia disorder (PID) based on diagnostic criteria, and insomnia symptoms were associated with risk of all-cause dementia, Alzheimers disease (AD) and cognition, measured with the Montreal Cognitive Assessment scale. We also examined if Apolipoprotein E genotype modified any associations with dementia through interaction. We analysed data from 7492 participants in the Norwegian Trøndelag Health Study. PID was not associated with all-cause dementia (odds ratio 1.03, 95% confidence interval 0.74-1.43), AD (odds ratio 1.07, 95% confidence interval 0.71-1.60) or Montreal Cognitive Assessment score (regression coefficient 0.37, 95% confidence interval -0.06 to 0.80). The insomnia symptom difficulties maintaining sleep was associated with a lower risk of all-cause dementia (odds ratio 0.81, 95% confidence interval 0.67-0.98), AD (odds ratio 0.73, 95% confidence interval 0.57-0.93), and better Montreal Cognitive Assessment score, mean 0.40 units (95% confidence interval 0.15-0.64). No interaction with Apolipoprotein E genotype was found. PID and insomnia symptoms did not increase the risk of dementia in our study. More research with longer follow-up is needed, and future studies should explore if the associations to dementia risk vary across insomnia subtypes.

Androgens and Parkinsons disease the role in humans and in experiment.

Parkinsons disease (PD) is the second most common neurodegenerative disease after Alzheimers disease. There is evidence that PD has a wider prevalence among men, which indicates the existing role of sex hormones in the pathogenesis of the disease. The article presents an overview of studies devoted to the study of sex differences in the incidence and symptoms of PD. Drug therapy with androgens, androgen precursors, antiandrogens and drugs that modify androgen metabolism is available for the treatment of various endocrine conditions, having translational significance for PD, but none of these drugs has yet shown sufficient effectiveness. Although PD has now been proven to be more common in men than in women, androgens do not always have any effect on the symptoms or progression of the disease. 5α-reductase inhibitors have shown neuroprotective and anti-dyskinetic activity and need further investigation. Despite the fact that the neuroprotective effect of dutasteride was observed only before damage to DA neurons, the absence of a negative effect makes it an attractive drug for use in patients with PD due to its anti-dyskinetic properties. Болезнь Паркинсона (БП) является вторым по распространенности нейродегенеративным заболеванием после болезни Альцгеймера. Имеются данные, что БП имеет более широкую распространенность среди мужчин, что свидетельствует об имеющейся роли половых гормонов в патогенезе развития заболевания. В статье представлен обзор исследований, посвященных изучению половых различий в заболеваемости и симптомах БП. Медикаментозная терапия андрогенами, предшественниками андрогенов, антиандрогенами и препаратами, модифицирующими метаболизм андрогенов, доступна для лечения различных эндокринных состояний, имея трансляционное значение для БП, но ни один из этих препаратов еще не показал достаточной эффективности. Хотя в настоящее время доказано, что БП более распространена у мужчин, чем у женщин, андрогены не всегда оказывают какое-либо влияние на симптомы или прогрессирование заболевания. Ингибиторы 5α-редуктазы показали нейропротекторную и антидискинетическую активность и нуждаются в дальнейшем исследовании. Несмотря на то что нейропротекторный эффект дутастерида наблюдался только до повреждения дофаминовых нейронов, отсутствие негативного влияния делает его привлекательным препаратом для применения у пациентов с БП благодаря его антидискинетическим свойствам.

Markers of olfactory dysfunction and progression to dementia A 12-year population-based study.

We evaluated markers of olfactory dysfunction (OD) for estimating hazard of dementia in older adults. Mild (hyposmia) and severe (anosmia) OD was classified in a population-based study of dementia-free persons (SNAC-K n 2473 mean age 70 years) using the Sniffin sticks odor identification task. Combined variables were created for objective and subjective OD and for OD and APOE status. Hazard of dementia across 12 years was estimated with Cox regression. OD was associated with increased hazard of dementia (2.01 95% confidence interval CI 1.60-2.52), with the strongest association for anosmia (2.92 95% CI 2.14-3.98). Results remained consistent after adjusting for potential confounders and across age and sex subgroups. APOE ε4 carriers with anosmia had the highest hazard of dementia (ε4 6.95 95% CI 4.16-11.62 ε4ε4 19.84 95% CI 6.17-63.78). OD is associated with increased risk of dementia, especially severe impairment in combination with genetic risk of Alzheimers disease.

Stimulus-induced narrow-band gamma oscillations in humans can be recorded using open-hardware low-cost EEG amplifier.

Stimulus-induced narrow-band gamma oscillations (30-70 Hz) in human electro-encephalograph (EEG) have been linked to attentional and memory mechanisms and are abnormal in mental health conditions such as autism, schizophrenia and Alzheimers Disease. However, since the absolute power in EEG decreases rapidly with increasing frequency following a 1f power law, and the gamma band includes line noise frequency, these oscillations are highly susceptible to instrument noise. Previous studies that recorded stimulus-induced gamma oscillations used expensive research-grade EEG amplifiers to address this issue. While low-cost EEG amplifiers have become popular in Brain Computer Interface applications that mainly rely on low-frequency oscillations (< 30 Hz) or steady-state-visually-evoked-potentials, whether they can also be used to measure stimulus-induced gamma oscillations is unknown. We recorded EEG signals using a low-cost, open-source amplifier (OpenBCI) and a traditional, research-grade amplifier (Brain Products GmbH), both connected to the OpenBCI cap, in male (N 6) and female (N 5) subjects (22-29 years) while they viewed full-screen static gratings that are known to induce two distinct gamma oscillations slow and fast gamma, in a subset of subjects. While the EEG signals from OpenBCI were considerably noisier, we found that out of the seven subjects who showed a gamma response in Brain Products recordings, six showed a gamma response in OpenBCI as well. In spite of the noise in the OpenBCI setup, the spectral and temporal profiles of these responses in alpha (8-13 Hz) and gamma bands were highly correlated between OpenBCI and Brain Products recordings. These results suggest that low-cost amplifiers can potentially be used in stimulus-induced gamma response detection.

The Effect of Holistic Therapy in Alzheimers Disease.

Cognitive, psychological, and behavioral problems that occur in individuals with Alzheimers disease (AD) cause impairments in the daily living functions of patients and affect their quality of life adversely. Non-pharmacological treatments are becoming more and more prominent due to the lack of side effects and the effective results from various studies. This study aims to examine the effectiveness of holistic therapy (reminiscence, music, and reality orientation therapy) on depression levels, quality of life, and cognitive status in individuals with AD. Ten people with AD were included in the holistic therapy program for six weeks and ten were included in the control group. All individuals took the mini-mental state examination (MMSE), geriatric depression scale short form (GDS-SF), Nottingham health profile (NHP), and World Health Organization quality of life instrument, elderly module, Turkish version (WHOQOL-OLD) before and after the therapy. The initial and final assessment results were compared in the therapy group there was a significant increase in the MMSE scores and a significant decrease in the GDS-SF scores (P < .05). According to the NHP and WHOQOL-OLD scales, there was a significant increase in the quality of life of the patients in the therapy group (P < .05). In this study, a significant improvement was observed in the therapy group in the following aspects cognition, depression level, and quality of life-especially in sleep, social isolation, emotional reaction, energy, autonomy, intimacy, fear of death, and emotional ability areas. Therefore, non-pharmacological treatment, such as holistic therapy, can be used together with pharmacological treatment in people with AD.

Do artificial neural networks love sex How the combination of artificial neural networks with evolutionary algorithms may help to identify gender influence in rheumatic diseases.

Although medical research has been performed predominantly on men both in preclinical and clinical studies, continuous efforts have been made to overcome this gender bias. Examining retrospectively 21 data sets containing sex as one of the descriptive variables, it was possible to verify how many times our AI protocol decided to keep gender information in the predictive model. The data sets pertained a vast array of diseases such as dyspeptic syndrome, atrophic gastritis, venous thrombosis, gastroesophageal reflux disease, irritable bowel syndrome, Alzheimer diseases and mild cognitive impairment, myocardial infarction, gastrointestinal bleeding, gastric cancer, hypercortisolism, AIDS, COVID diagnosis, extracorporeal membrane oxygenation in intensive therapy, among others. The sample size of these data sets ranged between 80 and 3147 (average 600). The number of variables ranged from 19 to 101 (average 41). Gender resulted to be part of the heuristic predictive model 19 out of 21 times. This means that also for highly adaptive and potent tools like Artificial Neural Networks, information on sex carries a specific value. In the field of rheumatology, there is a specific example in psoriatic arthritis that shows that the presence of gender information allows a significantly better accuracy of ANNs in predicting diagnosis from clinical data (from 87.7% to 94.47%). The results of this study confirm the importance of gender information in building high performance predictive model in the field of Artificial Intelligence (AI). Therefore, also for AI, sex counts.

APOC-III a Gatekeeper in Controlling Triglyceride Metabolism.

Apolipoprotein C-III (ApoC-III) is a widely known player in triglyceride metabolism, and it has been recently recognized as a polyhedric factor which may regulate several pathways beyond lipid metabolism by influencing cardiovascular, metabolic, and neurological disease risk. This review summarizes the different functions of ApoC-III and underlines the recent findings related to its multifaceted pathophysiological role. The role of ApoC-III has been implicated in HDL metabolism and in the development of atherosclerosis, inflammation, and ER stress in endothelial cells. ApoC-III has been recently considered an important player in insulin resistance mechanisms, lipodystrophy, diabetic dyslipidemia, and postprandial hypertriglyceridemia (PPT). The emerging evidence of the involvement of ApoC-III in the in the pathogenesis of Alzheimers disease open the way to further study if modification of ApoC-III level slows disease progression. Furthermore, ApoC-III is clearly linked to cardiovascular disease (CVD) risk, and progression of coronary artery disease (CAD) as well as the calcification of aortic valve and recent clinical trials has pointed out the inhibition of ApoC-III as a promising approach to manage hypertriglyceridemia and prevent CVD. Several evidences highlight the role of ApoC-III not only in triglyceride metabolism but also in several cardio-metabolic pathways. Results from recent clinical trials underline that the inhibition of ApoC-III is a promising therapeutical strategy for the management of severe hypertriglyceridemia and in CVD prevention.

Deficiency of IKKβ in neurons ameliorates Alzheimers disease pathology in APP- and tau-transgenic mice.

In Alzheimers disease (AD) brain, inflammatory activation regulates protein levels of amyloid-β-peptide (Aβ) and phosphorylated tau (p-tau), as well as neurodegeneration however, the regulatory mechanisms remain unclear. We constructed APP- and tau-transgenic AD mice with deletion of IKKβ specifically in neurons, and observed that IKKβ deficiency reduced cerebral Aβ and p-tau, and modified inflammatory activation in both AD mice. However, neuronal deficiency of IKKβ decreased apoptosis and maintained synaptic proteins (e.g., PSD-95 and Munc18-1) in the brain and improved cognitive function only in APP-transgenic mice, but not in tau-transgenic mice. Additionally, IKKβ deficiency decreased BACE1 protein and activity in APP-transgenic mouse brain and cultured SH-SY5Y cells. IKKβ deficiency increased expression of PP2A catalytic subunit isoform A, an enzyme dephosphorylating cerebral p-tau, in the brain of tau-transgenic mice. Interestingly, deficiency of IKKβ in neurons enhanced autophagy as indicated by the increased ratio of LC3B-III in brains of both APP- and tau-transgenic mice. Thus, IKKβ deficiency in neurons ameliorates AD-associated pathology in APP- and tau-transgenic mice, perhaps by decreasing Aβ production, increasing p-tau dephosphorylation, and promoting autophagy-mediated degradation of BACE1 and p-tau aggregates in the brain. However, IKKβ deficiency differently protects neurons in APP- and tau-transgenic mice. Further studies are needed, particularly in the context of interaction between Aβ and p-tau, before IKKβNF-κB can be targeted for AD therapies.

Reweighting estimators to extend the external validity of clinical trials methodological considerations.

Methods to extend the strong internal validity of randomized controlled trials to reliably estimate treatment effects in target populations are gaining attention. This paper enumerates steps recommended for undertaking such extended inference, discusses currently viable choices for each one, and provides recommendations. We demonstrate a complete extended inference from a clinical trial studying a pharmaceutical treatment for Alzheimers disease (AD) to a realistic target population of European residents diagnosed with AD. This case study highlights approaches to overcoming practical difficulties and demonstrates limitations of reliably extending inference from a trial to a real-world population.

(-)-Epigallocatechin-3-gallate, a Polyphenol from Green Tea, Regulates the Liquid-Liquid Phase Separation of Alzheimers-Related Protein Tau.

The microtubule-associated protein tau is involved in Alzheimers disease and other tauopathies. Recently, tau has been shown to undergo liquid-liquid phase separation (LLPS), which is implicated in the physiological function and pathological aggregation of tau. In this report, we demonstrate that the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) promotes the formation of liquid tau droplets at neutral pH by creating a network of hydrophobic interactions and hydrogen bonds, mainly with the proline-rich domain of tau. We further show that EGCG oxidation, tau phosphorylation, and the chemical structure of the polyphenol influence the efficacy of EGCG in facilitating tau LLPS. Complementary to the inhibitory activity of EGCG in tau fibrillization, our findings provide novel insights into the biological activity of EGCG and offer new clues for future studies on the molecular mechanism by which EGCG alleviates neurodegenerative diseases.

Tau, tau kinases, and tauopathies An updated overview.

Tau is a macrotubule-associated protein primarily involved in the stabilization of the cytoskeleton. Under normal conditions, phosphorylation reduces the affinity of tau for tubulin, allowing the protein to detach from microtubules and ensuring the system dynamics in neuronal cells. However, hyperphosphorylated tau aggregates into paired helical filaments, the main constituents of neurofibrillary tangles found in the brains of patients with Alzheimers disease and other tauopathies. In this review, we provide an overview of the structure of tau and the pathophysiological roles of tau phosphorylation. We also evaluate the major protein kinases involved and discuss the progress made in the development of drug therapies aimed at inhibiting tau kinases.

An NIR-Driven UpconversionC

Redox imbalance and abnormal amyloid protein (Aβ) buildup are key factors in the etiology of Alzheimers disease (AD). As an antioxidant, the hydrogen molecule (H

Design, synthesis and evaluation of quinoline-

A series of novel quinoline-

Interactions between amyloid, amyloid precursor protein, and mitochondria.

Mitochondrial dysfunction and Aβ accumulation are hallmarks of Alzheimers disease (AD). Decades of research describe a relationship between mitochondrial function and Aβ production. Amyloid precursor protein (APP), of which Aβ is generated from, is found within mitochondria. Studies suggest Aβ can be generated in mitochondria and imported into mitochondria. APP and Aβ alter mitochondrial function, while mitochondrial function alters Aβ production from APP. The role these interactions contribute to AD pathology and progression are unknown. Here, we discuss prior research, the rigor of those studies, and the critical knowledge gaps of relationships between APP, Aβ, and mitochondria.

The role of altered protein acetylation in neurodegenerative disease.

Acetylation is a key post-translational modification (PTM) involved in the regulation of both histone and non-histone proteins. It controls cellular processes such as DNA transcription, RNA modifications, proteostasis, aging, autophagy, regulation of cytoskeletal structures, and metabolism. Acetylation is essential to maintain neuronal plasticity and therefore essential for memory and learning. Homeostasis of acetylation is maintained through the activities of histone acetyltransferases (HAT) and histone deacetylase (HDAC) enzymes, with alterations to these tightly regulated processes reported in several neurodegenerative diseases including Alzheimers disease (AD), Parkinsons disease (PD), Huntingtons disease (HD), and amyotrophic lateral sclerosis (ALS). Both hyperacetylation and hypoacetylation can impair neuronal physiological homeostasis and increase the accumulation of pathophysiological proteins such as tau, α-synuclein, and Huntingtin protein implicated in AD, PD, and HD, respectively. Additionally, dysregulation of acetylation is linked to impaired axonal transport, a key pathological mechanism in ALS. This review article will discuss the physiological roles of protein acetylation and examine the current literature that describes altered protein acetylation in neurodegenerative disorders.

Exploring the combined effects of sleep apnea and APOE-e4 on biomarkers of Alzheimers disease.

We determined the interactive associations of apolipoprotein e4 (APOE-e4), and obstructive sleep apnea (OSA) on biomarkers of Alzheimers disease and examined for racialethnic differences of this association. We used data from the National Alzheimers Coordinating Center Uniform Dataset (NACC UDS). All participants undergo annual observations, including demographic survey, battery of neuropsychological tests, blood draw (with genotyping), and a clinical evaluation with medical and cognitivedementia status assessment, while a subset of participants have cerebrospinal fluid (CSF) biomarkers and neuroimaging data. Biomarkers of AD were characterized as the presence of abnormally low amyloid in CSF, Biomarker and clinical marker data were derived from 1,387 participants at baseline (mean age 69.73 ± 8.32 58.6% female 13.7% BlackAfrican American), 18.4% of the sample had sleep apnea, and 37.9% were APOE-e4 carriers. Our results confirmed previous reports that OSA and APOE-e4 were independently associated with AD through abnormal levels of amyloid ( OSA and APOE-e4 are interactively associated with WHM in BlackAfrican Americans. This interaction may partially explicate increased levels of risk in this population.

Evaluating the treatment outcomes of repetitive transcranial magnetic stimulation in patients with moderate-to-severe Alzheimers disease.

The repetitive transcranial magnetic stimulation (rTMS) shows great potential in the treatment of Alzheimers disease (AD). However, its treatment efficacy for AD patients in moderate to severe stage is relatively evaluated. Here, we proposed a randomized, sham-controlled, clinical trial of rTMS among 35 moderate-to-severe AD patients. A high frequency (10 Hz) stimulation of the left dorsal lateral prefrontal cortex (DLPFC), 60-session long treatment lasting for 3 months procedure was adopted in the trial. Each participant completed a battery of neuropsychological tests at baseline and post-treatment for evaluation of the rTMS therapeutic effect. Twelve of them completed baseline resting-state functional magnetic resonance imaging (fMRI) for exploration of the underlying neural contribution to individual difference in treatment outcomes. The result showed that the rTMS treatment significantly improved cognitive performance on the severe impairment battery (SIB), reduced psychiatric symptoms on the neuropsychiatric inventory (NPI), and improved the clinicians global impression of change (CIBIC-Plus). Furthermore, the result preliminarily proposed resting-state multivariate functional connectivity in the (para) hippocampal region as well as two clusters in the frontal and occipital cortices as a pre-treatment neuroimaging marker for predicting individual differences in treatment outcomes. The finding could brought some enlightenment and reference for the rTMS treatment of moderate and severe AD patients.

Health-related heterogeneity in brain aging and associations with longitudinal change in cognitive function.

Neuroimaging-based brain age can identify individuals with advanced or resilient brain aging. Brain-predicted age difference (brain-PAD) is predictive of cognitive and physical health outcomes. However, it is unknown how individual health and lifestyle factors may modify the relationship between brain-PAD and future cognitive or functional performance. We aimed to identify health-related subgroups of older individuals with resilient or advanced brain-PAD, and determine if membership in these subgroups is differentially associated with changes in cognition and frailty over three to five years. Brain-PAD was predicted from T1-weighted images acquired from 326 community-dwelling older adults (73.8 ± 3.6 years, 42.3% female), recruited from the larger ASPREE (ASPirin in Reducing Events in the Elderly) trial. Participants were grouped as having resilient (n159) or advanced (n167) brain-PAD, and latent class analysis (LCA) was performed using a set of cognitive, lifestyle, and health measures. We examined associations of class membership with longitudinal change in cognitive function and frailty deficit accumulation index (FI) using linear mixed models adjusted for age, sex and education. Subgroups of resilient and advanced brain aging were comparable in all characteristics before LCA. Two typically similar latent classes were identified for both subgroups of brain agers class 1 were characterized by low prevalence of obesity and better physical health and class 2 by poor cardiometabolic, physical and cognitive health. Among resilient brain agers, class 1 was associated with a decrease in cognition, and class 2 with an increase over 5 years, though was a small effect that was equivalent to a 0.04 standard deviation difference per year. No significant class distinctions were evident with FI. For advanced brain agers, there was no evidence of an association between class membership and changes in cognition or FI. These results demonstrate that the relationship between brain age and cognitive trajectories may be influenced by other health-related factors. In particular, people with age-resilient brains had different trajectories of cognitive change depending on their cognitive and physical health status at baseline. Future predictive models of aging outcomes will likely be aided by considering the mediating or synergistic influence of multiple lifestyle and health indices alongside brain age.

Mild behavioral impairment linked to progression to Alzheimers disease and cortical thinning in amnestic mild cognitive impairment.

Mild behavioral impairment (MBI) is a neurobehavioral syndrome characterized by later life emergence of sustained neuropsychiatric symptoms, as an at-risk state for dementia. However, the associations between MBI and a risk of progression to Alzheimers disease (AD) and its neuroanatomical correlates in mild cognitive impairment (MCI) are still unclear. A total 1,184 older adults with amnestic MCI was followed for a mean of 3.1 ± 2.0 years. MBI was approximated using a transformation algorithm for the Neuropsychiatric Inventory at baseline. A two-step cluster analysis was used to identify subgroups of individuals with amnestic MCI based on profiles of 5 MBI domain symptoms (decreased motivation, affective dysregulation, impulse dyscontrol, social inappropriateness, abnormal perceptionthought content). A Cox regression analysis was applied to investigate differences in the risk of progression to AD between subgroups. A subset of participants ( The cluster analysis classified the patients into 3 groups (1) patients without any MBI domain symptoms (47.4%, asymptomatic group) (2) those with only affective dysregulation (29.4%, affective dysregulation group) (3) those with multiple MBI domain symptoms, particularly affective dysregulation, decreased motivation and impulse dyscontrol (23.2%, complex group). Compared to the asymptomatic group, the complex group was associated with a higher risk of progression to AD (hazard ratio 2.541 1.904-3.392, The multiple co-occuring MBI domains in individuals with amnestic MCI are associated with a higher risk of progression to AD and cortical thinning in temporal, parietal and frontal areas. These results suggest that evaluation of MBI could be useful for risk stratification for AD and appropriate intervention in MCI individuals.

Knowledge domains and emerging trends of microglia research from 2002 to 2021 A bibliometric analysis and visualization study.

Microglia have been identified for a century. In this period, their ontogeny and functions have come to light thanks to the tireless efforts of scientists. However, numerous documents are being produced, making it challenging for scholars, especially those new to the field, to understand them thoroughly. Therefore, having a reliable method for quickly grasping a field is crucial. We searched and downloaded articles from the Web of Science Core Collection with microglia or microglial in the title from 2002 to 2021. Eventually, 12,813 articles were located and, using CiteSpace and VOSviewer, the fundamental data, knowledge domains, hot spots, and emerging trends, as well as the influential literature in the field of microglia research, were analyzed. Following 2011, microglia publications grew significantly. The two prominent journals are Glia and J Neuroinflamm. The United States and Germany dominated the microglia study. The primary research institutions are Harvard Univ and Univ Freiburg, and the leading authors are Prinz Marco and Kettenmann Helmut. The knowledge domains of microglia include eight directions, namely neuroinflammation, lipopolysaccharide, aging, neuropathic pain, macrophages, Alzheimers disease, retina, and apoptosis. Microglial phenotype is the focus of research while RNA-seq, exosome, and glycolysis are emerging topics, a microglial-specific marker is still a hard stone. We also identified 19 influential articles that contributed to the study of microglial origin (Mildner A 2007 Ginhoux F 2010), identity (Butovsky O 2014), homeostasis (Cardona AE 2006 Elmore MRP 2014) microglial function such as surveillance (Nimmerjahn A 2005), movement (Davalos D 2005 Haynes SE 2006), phagocytosis (Simard AR 2006), and synapse pruning (Wake H 2009 Paolicelli RC 2011 Schafer DP 2012 Parkhurst CN 2013) and microglial statephenotype associated with disease (Keren-Shaul H 2017), as well as 5 review articles represented by Kettenmann H 2011. Using bibliometrics, we have investigated the fundamental data, knowledge structure, and dynamic evolution of microglia research over the previous 20 years. We hope this study can provide some inspiration and a reference for researchers studying microglia in neuroscience.

Age and

With age the apolipoprotein E (

Corrigendum Associations between blood-based biomarkers of Alzheimers disease with cognition in motoric cognitive risk syndrome A pilot study using plasma Aβ42 and total tau.

This corrects the article DOI 10.3389fnagi.2022.981632..

Progressive structural and covariance connectivity abnormalities in patients with Alzheimers disease.

Alzheimers disease (AD) is one of most prevalent neurodegenerative diseases worldwide and characterized by cognitive decline and brain structure atrophy. While studies have reported substantial grey matter atrophy related to progression of AD, it remains unclear about brain regions with progressive grey matter atrophy, covariance connectivity, and the associations with cognitive decline in AD patients. This study aims to investigate the grey matter atrophy, structural covariance connectivity abnormalities, and the correlations between grey matter atrophy and cognitive decline during AD progression. We analyzed neuroimaging data of healthy controls (HC, The results showed clear patterns of grey matter atrophy in inferior frontal gyrus, prefrontal cortex, lateral temporal gyrus, posterior cingulate cortex, insula, hippocampus, caudate, and thalamus in AD patients. There was significant atrophy in bilateral superior temporal gyrus (STG) and left caudate in AD patients over a one-year period, and the grey matter volume decrease in right STG and left caudate was correlated with cognitive decline. Additionally, we found reduced structural covariance connectivity between right STG and left caudate in AD patients. Using AD-related grey matter atrophy as features, there was high discrimination accuracy of AD patients from HC, and AD patients at different time points.

Validation of the cross-cultural dementia screening test in Alzheimers disease and Parkinsons disease.

The Cross-Cultural Dementia (CCD) is a new screening tool to evaluate cognitive impairment based on a cross-cultural perspective to reduce the bias of education, and language and cultural differences. We aimed to evaluate the diagnostic properties of the CCD in Spaniards for the assessment of patients with Alzheimers disease in mild cognitive impairment (AD-MCI) and mild dementia stages (AD-D) and patients with mild cognitive impairment associated with Parkinsons disease (PD-MCI). Sixty participants with AD (50% MCI) and thirty with PD-MCI were enrolled. Each clinical group was compared against a healthy control group (HC) with the same number of participants and no significant differences in age, education, and sex. A comprehensive neuropsychological test battery and CCD were completed. Intergroup comparisons, ROC curves, and cut-off scores were calculated for the study of diagnostic properties. Intergroup differences were found in accordance with the cognitive profile of each clinical condition. Memory measures (Objects test) were especially relevant for the classification between AD and HC. Memory and executive function scores (Sun-Moon and Dots tests) were useful in the case of PD-MCI and HC. Furthermore, CCD described differences in executive functions and speed scores comparing AD-MCI and PD-MCI. Correlations between standardized neuropsychological tests and CCD measures supported the convergent validity of the test. CCD showed good discrimination properties and cut-off scores for dementia and extended its application to a sample of prodromal stages of AD and PD with mild cognitive impairment.

Arterial Spin Labelling-Based Blood-Brain Barrier Assessment and Its Applications.

The brain relies on the blood-brain barrier (BBB) for the selective absorption of nutrients and the exclusion of other big molecules from the circulating blood. Therefore, the integrity of BBB is critical to brain health, and assessing BBB condition is of great clinical importance. BBB is often examined using exogenous tracers that can travel across the BBB, but the tracers might cause severe side effects. To avoid the use of external tracers, researchers have used magnetically labeled arterial blood as the endogenous tracer to assess the water permeability of BBB as a surrogate index of BBB. This paper reviews the three major types of Arterial Spin Labelling (ASL) based BBB water permeability assessment techniques and their applications in brain diseases such as Alzheimers Disease.

The PSEN1 E280G mutation leads to increased amyloid-β43 production in induced pluripotent stem cell neurons and deposition in brain tissue.

Mutations in the presenilin 1 gene,

Brain microdialysate tau dynamics predict functional and neurocognitive recovery after poor-grade subarachnoid haemorrhage.

Subarachnoid haemorrhage is a devastating disease that results in neurocognitive deficits and a poor functional outcome in a considerable proportion of patients. In this study, we investigated the prognostic value of microtubule-associated tau protein measured in the cerebral microdialysate for long-term functional and neuropsychological outcomes in poor-grade subarachnoid haemorrhage patients. We recruited 55 consecutive non-traumatic subarachnoid haemorrhage patients who underwent multimodal neuromonitoring, including cerebral microdialysis. Mitochondrial dysfunction was defined as lactate-to-pyruvate ratio >30 together with pyruvate >70 mmolL and metabolic distress as lactate-to-pyruvate ratio >40. The multidimensional 12-month outcome was assessed by means of the modified Rankin scale (poor outcome modified Rankin scale ≥4) and a standardized neuropsychological test battery. We used multivariable generalized estimating equation models to assess associations between total microdialysate-tau levels of the first 10 days after admission and hospital complications and outcomes. Patients were 56 ± 12 years old and presented with a median Hunt Hess score of 5 (interquartile range 3-5). Overall mean total microdialysate-tau concentrations were highest within the first 24 h (5585 ± 6291 pgmL), decreased to a minimum of 2347 ± 4175 pgmL on Day 4 (

Translational potential of synaptic alterations in Alzheimers disease patients and amyloid precursor protein knock-in mice.

Synaptic dysfunction is an early event in Alzheimers disease. Post-mortem studies suggest that alterations in synaptic proteins are associated with cognitive decline in Alzheimers disease. We measured the concentration of three synaptic proteins, zinc transporter protein 3, dynamin1 and AMPA glutamate receptor 3 in cerebrospinal fluid of subjects with mild cognitive impairment (

Amyloid-β in Alzheimers disease - front and centre after all

The amyloid hypothesis, which proposes that accumulation of the peptide amyloid-β at synapses is the key driver of Alzheimers disease (AD) pathogenesis, has been the dominant idea in the field of Alzheimers research for nearly 30 years. Recently, however, serious doubts about its validity have emerged, largely motivated by disappointing results from anti-amyloid therapeutics in clinical trials. As a result, much of the AD research effort has shifted to understanding the roles of a variety of other entities implicated in pathogenesis, such as microglia, astrocytes, apolipoprotein E and several others. All undoubtedly play an important role, but the nature of this has in many cases remained unclear, partly due to their pleiotropic functions. Here, we propose that all of these AD-related entities share at least one overlapping function, which is the local regulation of amyloid-β levels, and that this may be critical to their role in AD pathogenesis. We also review what is currently known of the actions of amyloid-β at the synapse in health and disease, and consider in particular how it might interact with the key AD-associated protein tau in the disease setting. There is much compelling evidence in support of the amyloid hypothesis rather than detract from this, the implication of many disparate AD-associated cell types, molecules and processes in the regulation of amyloid-β levels may lend further support.

Magnoflorine-Loaded Chitosan Collagen Nanocapsules Ameliorate Cognitive Deficit in Scopolamine-Induced Alzheimers Disease-like Conditions in a Rat Model by Downregulating IL-1β, IL-6, TNF-α, and Oxidative Stress and Upregulating Brain-Derived Neurotrophic Factor and DCX Expressions.

Dementia or the loss of cognitive functioning is one of the major health issues in elderly people. Alzheimers disease (AD) is one of the common forms of dementia. Treatment chiefly involves the use of acetylcholinesterase (AChE) inhibitors in AD. However, oxidative stress has also been found to be involved in the proliferation of the disease. Magnoflorine is one of the active compounds of Coptidis Rhizoma and has high anti-oxidative properties. Active principle-loaded nanoparticles have shown increased efficiency for neurodegenerative diseases due to their ability to cross the blood-brain barrier more easily. An

Evaluation of

Corrigendum Intracerebroventricularly Injected Streptozotocin Exerts Subtle Effects on the Cognitive Performance of Long-Evans Rats.

This corrects the article DOI 10.3389fphar.2021.662173..

An insight into the neuroprotective and anti-neuroinflammatory effects and mechanisms of

Neurodegenerative diseases (NDs) are sporadic maladies that affect patients lives with progressive neurological disabilities and reduced quality of life. Neuroinflammation and oxidative reaction are among the pivotal factors for neurodegenerative conditions, contributing to the progression of NDs, such as Parkinsons disease (PD), Alzheimers disease (AD), multiple sclerosis (MS) and Huntingtons disease (HD). Management of NDs is still less than optimum due to its wide range of causative factors and influences, such as lifestyle, genetic variants, and environmental aspects. The neuroprotective and anti-neuroinflammatory activities of

Amelioration of cognitive impairment using epigallocatechin-3-gallate in ovariectomized mice fed a high-fat diet involves remodeling with

Bibliometric analysis of global research profile on ketogenic diet therapies in neurological diseases Beneficial diet therapies deserve more attention.

The protective effects of Ketogenic Diet Therapies (KDTs) on neurological diseases have been extensively studied over the past two decades. The purpose of this study was to quantitatively and qualitatively analyze the publication of KDTs in the neurological field from 2000 to 2021. A literature search was performed on June 7th, 2022, using the search terms ((ketone OR ketogenic OR hydroxybuty) AND (neuro)) in the WoSCC database. Collected data were further analyzed using VOSviewer, CiteSpace and other online bibliometric websites. The annual publication volume and citation trends were summarized. The collaborations among highly cited countries, institutions, authors and journals were visualized. The co-citation analysis of highly cited references and journals were also visualized. Moreover, the research focuses and fronts were revealed by co-occurrence analysis and burst keywords detection. A total of 2808 publications with 88,119 citations were identified. From 2000-2021, the number of publications and citations presented rising trends. We presented the global trend of KDTs in neurological diseases and provided important information for relevant researchers in a bibliometric way. This bibliometric study revealed that treating epilepsy, neuroprotection and functional effects of KDTs on mitochondria and oxidative stress have been the spotlight from 2000 to 2021. These have emerged as the basis for transformation from basic research to clinical application of KDTs.

High-Depth PRNP Sequencing in Brains With Sporadic Creutzfeldt-Jakob Disease.

Sporadic Creutzfeldt-Jakob disease (sCJD) has established genetic risk factors, but, in contrast to genetic and acquired CJD, the initial trigger for misfolded prion aggregation and spread is not known. In this study, we tested the hypotheses that pathologic somatic variants in the prion gene High-depth amplicon-based short read sequencing of the Two sCJD cases had somatic (variant allele frequency 0.5-1%) Somatic variants in

Identification of oxidative stress-related genes and potential mechanisms in atherosclerosis.

Atherosclerosis (AS) is the main cause of death in individuals with cardiovascular and cerebrovascular diseases. A growing body of evidence suggests that oxidative stress plays an essential role in Atherosclerosis pathology. The aim of this study was to determine genetic mechanisms associated with Atherosclerosis and oxidative stress, as well as to construct a diagnostic model and to investigate its immune microenvironment. Seventeen oxidative stress-related genes were identified. A four-gene diagnostic model was constructed using the least absolute shrinkage and selection operator (LASSO) algorithm based on these 17 genes. The area under the Receiver Operating Characteristic (ROC) curve (AUC) was 0.967. Based on the GO analysis, cell-substrate adherens junction and focal adhesion were the most enriched terms. KEGG analysis revealed that these overlapping genes were enriched in pathways associated with Alzheimers disease and Parkinsons disease, as well as with prion disease pathways and ribosomes. Immune cell infiltration correlation analysis showed that the immune cells with significant differences were CD4 memory activated T cells and follicular helper T cells in the GSE43292 dataset and CD4 naïve T cells and CD4 memory resting T cells in the GSE57691 dataset. We identified 17 hub genes that were closely associated with oxidative stress in AS and constructed a four-gene (aldehyde dehydrogenase six family member A1 (

Potential Alzheimers disease therapeutic nano-platform Discovery of amyloid-beta plaque disaggregating agent and brain-targeted delivery system using porous silicon nanoparticles.

There has been a lot of basic and clinical research on Alzheimers disease (AD) over the last 100 years, but its mechanisms and treatments have not been fully clarified. Despite some controversies, the amyloid-beta hypothesis is one of the most widely accepted causes of AD. In this study, we disclose a new amyloid-beta plaque disaggregating agent and an AD brain-targeted delivery system using porous silicon nanoparticles (pSiNPs) as a therapeutic nano-platform to overcome AD. We hypothesized that the negatively charged sulfonic acid functional group could disaggregate plaques and construct a chemical library. As a result of the in vitro assay of amyloid plaques and library screening, we confirmed that 6-amino-2-naphthalenesulfonic acid (ANA) showed the highest efficacy for plaque disaggregation as a hit compound. To confirm the targeted delivery of ANA to the AD brain, a nano-platform was created using porous silicon nanoparticles (pSiNPs) with ANA loaded into the pore of pSiNPs and biotin-polyethylene glycol (PEG) surface functionalization. The resulting nano-formulation, named Biotin-CaCl2-ANA-pSiNPs (BCAP), delivered a large amount of ANA to the AD brain and ameliorated memory impairment of the AD mouse model through the disaggregation of amyloid plaques in the brain. This study presents a new bioactive small molecule for amyloid plaque disaggregation and its promising therapeutic nano-platform for AD brain-targeted delivery.

Unraveling the links between neurodegeneration and Epstein-Barr virus-mediated cell cycle dysregulation.

The Epstein-Barr virus is a well-known cell cycle modulator. To establish successful infection in the host, EBV alters the cell cycle at multiple steps via antigens such as EBNAs, LMPs, and certain other EBV-encoded transcripts. Interestingly, several recent studies have indicated the possibility of EBVs neurotrophic potential. However, the effects and outcomes of EBV infection in the CNS are under-explored. Additionally, more and more epidemiological evidence implicates the cell-cycle dysregulation in neurodegeneration. Numerous hypotheses which describe the triggers that force post-mitotic neurons to re-enter the cell cycle are prevalent. Apart from the known genetic and epigenetic factors responsible, several reports have shown the association of microbial infections with neurodegenerative pathology. Although, studies implicating the herpesvirus family members in neurodegeneration exist, the involvement of Epstein-Barr virus (EBV), in particular, is under-evaluated. Interestingly, a few clinical studies have reported patients of AD or PD to be seropositive for EBV. Based on the findings mentioned above, in this review, we propose that EBV infection in neurons could drive it towards neurodegeneration through dysregulation of cell-cycle events and induction of apoptosis.