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Neuropathology and emerging biomarkers in corticobasal syndrome.

Corticobasal syndrome (CBS) is a clinical syndrome characterised by progressive asymmetric limb rigidity and apraxia with dystonia, myoclonus, cortical sensory loss and alien limb phenomenon. Corticobasal degeneration (CBD) is one of the most common underlying pathologies of CBS, but other disorders, such as progressive supranuclear palsy (PSP), Alzheimers disease (AD) and frontotemporal lobar degeneration with TDP-43 inclusions, are also associated with this syndrome.In this review, we describe common and rare neuropathological findings in CBS, including tauopathies, synucleinopathies, TDP-43 proteinopathies, fused in sarcoma proteinopathy, prion disease (Creutzfeldt-Jakob disease) and cerebrovascular disease, based on a narrative review of the literature and clinicopathological studies from two brain banks. Genetic mutations associated with CBS, including

Subjective short-term memory difficulties at ages 50-75 predict dementia risk in a community-based cohort followed over 17 years.

Subjective cognitive decline (SCD) is an established precursor of dementia. However, the relationship between SCD and dementia has been mostly studied among people aged 65. We aimed to assess the association between subjective memory difficulties at ages 50-75 with all-cause dementia and dementia-subtypes in a community-based cohort with long-term follow-up. 6,190 individuals (51% female) aged 50-75 years (median age, 62) attending a general health examination (by a total of 684 general practitioners) in Saarland, Germany, in 2000-2002 were recruited for a community-based cohort study. Subjective difficulties regarding short-term and long-term memory were assessed at baseline with two simple yesno questions. Associations with dementia (-subtypes) diagnoses during 17 years of follow-up were estimated by Cox proportional hazards models. 492 participants were diagnosed with dementia during 17 years of follow-up. Participants with short-term memory difficulties were at higher risk to receive incident all-cause dementia and vascular dementia diagnoses both within 0-9 years (age and sex adjusted hazard ratios (aHR), 1.80 and 2.00, respectively) and within 0-17 years (aHR 1.55 and 1.78, respectively) from recruitment (P < 0.05 in all cases). For clinical Alzheimers disease, a significant association was only seen within the initial 6 years. There were no associations of long-term memory difficulties with any type of dementia. Subjective difficulties in short-term memory predict both intermediate and long-term risk of vascular and all-cause dementia even among late middle-age adults. These results underline the importance of cardiovascular disease prevention efforts well before old age for maintaining cognitive health.

Brief, interoceptive exposure focused treatment for anxiety in mild cognitive impairment.

Anxiety is common in older adults with mild cognitive impairment (MCI), and Alzheimers disease and related dementias (ADRD). Anxiety has also been identified as a risk factor for cognitive decline. Brief interventions targeting risk mechanisms of anxiety, such as anxiety sensitivity (AS), have been effective in reducing overall anxiety in a variety of populations. This case series investigated the feasibility and efficacy of a brief AS intervention in anxious older adults with MCI (n 9). Paired samples t-test results indicate that this intervention is capable of significantly reducing AS as measured by the Anxiety Sensitivity Index-3 (Δ 5.11, Hedges g 0.82, P < 0.05). Given these large AS reductions and high acceptability, further investigation of this intervention is warranted in older adults with MCI.

p75NTR Ectodomain Ameliorates Cognitive Deficits and Pathologies in a Rapid Eye Movement Sleep Deprivation Mice Model.

The neurotrophin receptor p75 (p75NTR) is a circadian rhythm regulator and mediates cognitive deficits induced by sleep deprivation (SD). The soluble extracellular domain of p75NTR (p75ECD) has been shown to exert a neuroprotective function in Alzheimers disease (AD) and depression animal models. Nevertheless, the role of p75ECD in SD-induced cognitive dysfunction is unclear. In the present study we administrated p75ECD-Fc (10, 3 mgkg), a recombinant fusion protein of human p75ECD and fragment C of immunoglobulin IgG

Brain-resident regulatory T cells and their role in health and disease.

Regulatory T cells (Tregs) control inflammation and maintain immune homeostasis. The well-characterised circulatory population of CD4

Chronic vitamin D

Oxidative stress plays essential role in the pathogenesis of Alzheimers disease, and vitamin D

Automated quantification of brain connectivity in Alzheimers disease using ClusterMetric.

Diffusion magnetic resonance imaging tractography allows investigating brain structural connections in a noninvasive way and has been widely used for understanding neurological disease. Quantification of brain connectivity along with its length by dividing a fiber bundle into multiple segments (node) is a powerful approach to assess biological properties, which is termed as tractometry. However, current tractometry methods face challenges in node identification along with the length of complex bundles whose morphology is difficult to summarize. In addition, the anatomic measure reflecting the macroscopic fiber cross-section has not been followed in previous tractometry. In this paper, we propose an automated fiber bundle quantification, which we refer to as ClusterMetric. The ClusterMetric uses a data-driven approach to identify fiber clusters corresponding to subdivisions of the white matter anatomy and identify consistent space nodes along the length of clusters across individuals. The proposed method is demonstrated by applicating to our collected dataset including 23 Alzheimers disease (AD) patients and 22 healthy controls (HCs) and a public dataset of ADNI including 53 AD patients and 85 HCs. The altered white matter tracts in AD group are observed using both datasets, which involve several major fiber tracts including the corpus callosum, corona-radiata-frontal, arcuate fasciculus, inferior occipito-frontal fasciculus, uncinate fasciculus, thalamo-frontal, superior longitudinal fasciculus, inferior cerebellar peduncle, cingulum bundle, and extreme capsule. These fiber clusters represent the white matter connections that could be most affected in AD, suggesting the ability of our method in identifying potential abnormalities specific to local regions within a fiber cluster.

Autophagy activation by Terminalia chebula Retz. reduce Aβ generation by shifting APP processing toward non-amyloidogenic pathway in APPswe transgenic SH-SY5Y cells.

Alzheimers disease (AD) is the most common neurodegenerative disease. Deposition of amyloid β plaques (Aβ) is a central hallmark of AD. Accumulating evidence suggest that shifting amyloid precursor protein (APP) metabolism pathway to non-amyloidogenic ways and inducing autophagy play key roles in AD pathology. In published reports, there is no research on the APP metabolic process of Terminalia chebula Retz. (T. Chebula). The study aims to assess the effects of T. Chebula in AD transgenic SH-SY5Y cells to determine its underlying mechanisms on reducing Aβ level by regulating APP metabolic process. The effects of T. Chebula water extract (TWE) on APPswe transgenic SH-SY5Y cells were analyzed by cell viability. ELISA used to quantify extracellular Aβ Treatment with TWE significantly suppressed the Aβ In summary, our finding first time expounded that TWE can inhibit the generation of Aβ

Molecular engineering and activity improvement of acetylcholinesterase inhibitors Insights from 3D-QSAR, docking, and molecular dynamics simulation studies.

The carbamate molecule rivastigmine was found to possess promising anti-acetylcholinesterase activity, enabling to target and occupy choline binding sites, and as a result, widely used to improve the treatment of Alzheimers disease (AD). Higher dose of rivastigmine indicates rapid onset but more adverse effects, such as the large fluctuations in plasma concentration level and frequent incidence of gastrointestinal side effect. To solve the dilemma, we developed a three-dimensional quantitative structure-activity relationship (3D-QSAR), docking and molecular dynamics (MD) simulation strategy to construct a dismountable nanoplatform of inhibitor engineering, verification and application for improving the inhibitory activity per unit concentration. With the aid of 3D-QSAR method, we constructed a model by using 25 molecules reported, and verified well the rationality of these QSAR models by non-cross validation coefficient (r

TDP-43 Pathology Exacerbates Cognitive Decline in Primary Age-Related Tauopathy.

Primary age-related tauopathy (PART) refers to tau neurofibrillary tangles restricted largely to the medial temporal lobe in the absence of significant beta-amyloid plaques. PART has been associated with cognitive impairment, but contributions from concomitant limbic age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) are underappreciated. We compare prevalence of LATE-NC and vascular copathologies in age- and Braak-matched patients with PART (n 45, Braak stage I-IV, Thal phase 0-2) or early stage Alzheimer disease neuropathologic change (ADNC n 51, Braak I-IV, Thal 3-5), and examine their influence on clinical and cognitive decline. Concomitant LATE-NC and vascular pathology were equally common, and cognition was equally impaired, in PART (Mini-Mental State Examination MMSE 24.8 ± 6.9) and ADNC (MMSE 24.2 ± 6.0). Patients with LATE-NC were more impaired than those without LATE-NC on the MMSE (by 5.8 points, 95% confidence interval CI 3.0-8.6), Mattis Dementia Rating Scale (DRS 17.5 points, 95% CI 7.1-27.9), Clinical Dementia Rating, sum of boxes scale (CDR-sob 5.2 points, 95% CI 2.1-8.2), memory composite (0.8 standard deviations SD, 95% CI 0.1-1.6), and language composite (1.1 SD, 95% CI 0.2-2.0), and more likely to receive a dementia diagnosis (odds ratio 4.8, 95% CI 1.5-18.0). Those with vascular pathology performed worse than those without on the DRS (by 10.2 points, 95% CI 0.1-20.3) and executive composite (1.3 SD, 95% CI 0.3-2.3). Cognition declined similarly in PART and ADNC over the 5 years preceding death however, LATE-NC was associated with more rapid decline on the MMSE (β 1.9, 95% CI 0.9-3.0), DRS (β 7.8, 95% CI 3.4-12.7), CDR-sob (β 1.9, 95% CI 0.4-3.7), language composite (β 0.5 SD, 95% CI 0.1-0.8), and vascular pathology with more rapid decline on the DRS (β 5.2, 95% CI 0.6-10.2). LATE-NC, and to a lesser extent vascular copathology, exacerbate cognitive impairment and decline in PART and early stage ADNC. ANN NEUROL 202292425-438.

Childhood socioeconomic status interacts with cognitive function to impact scam susceptibility among community-dwelling older adults.

We examined whether childhood socioeconomic status (SES) is related to scam susceptibility in old age and tested the hypothesis that childhood SES interacts with cognitive function to impact scam susceptibility. This study employed a cross-sectional design. All data were collected in participants community-based residences. Participants were 1071 older adults (mean age 81.05 years, SD 7.53) without dementia (median MMSE score 28.29, IQR 27.86-30.00). Participants completed assessments of childhood SES, cognitive function, and scam susceptibility. We used linear regression models to examine the associations of childhood SES and cognitive function with scam susceptibility. In a regression model adjusted for age, gender, and education, poorer cognitive function was associated with higher scam susceptibility, but childhood SES was not. However, in an additional model that included the interaction of childhood SES and cognitive function, the interaction was significant, such that lower childhood SES was associated with higher scam susceptibility among participants with lower cognitive function. Lower childhood SES is associated with higher scam susceptibility among older adults with lower levels of cognitive function. Thus, older adults who experienced limited resources in childhood and have lower cognitive function may represent a specific group for interventions to increase scam awareness and prevent financial exploitation.

Chrysin-Loaded Chitosan Nanoparticle-Mediated Neuroprotection in Aβ

Amyloid β plaques and neurofibrillary tangles are the characteristic features of Alzheimers disease (AD). Plaques of amyloid β play a pivotal role in affecting cognitive functions and memory. Alzheimers disease is a progressive neurodegenerative disease and is one of the leading causes of dementia worldwide. Several treatment strategies focusing on the amyloid cascade have been implemented to treat AD. The blood-brain barrier (BBB) poses the main obstructive barrier by refraining drugs from penetrating the brain. Nanotechnology is a promising research field for brain drug delivery using nanosized particles. Zebrafish is emerging as a model of interest to elaborate on brain targeting and nanotechnology-based therapeutics for neurodegenerative diseases. In the current study, we have synthesized and characterized chrysin-loaded chitosan nanoparticles (Chr-Chi NPs) and evaluated them for neuroprotection against amyloid-β-induced toxicity. We find that treatment with Chr-Chi NPs helps to retain memory, cognition, and synaptic connections, which are otherwise compromised due to Aβ

Safety and Efficacy of Semorinemab in Individuals With Prodromal to Mild Alzheimer Disease A Randomized Clinical Trial.

Neurofibrillary tangles composed of aggregated tau protein are one of the neuropathological hallmarks of Alzheimer disease (AD) and correlate with clinical disease severity. Monoclonal antibodies targeting tau may have the potential to ameliorate AD progression by slowing or stopping the spread andor accumulation of pathological tau. To evaluate the safety and efficacy of the monoclonal anti-tau antibody semorinemab in prodromal to mild AD. This phase 2 randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted between October 18, 2017, and July 16, 2020, at 97 sites in North America, Europe, and Australia. Individuals aged 50 to 80 years (inclusive) with prodromal to mild AD, Mini-Mental State Examination scores between 20 and 30 (inclusive), and confirmed β-amyloid pathology (by positron emission tomography or cerebrospinal fluid) were included. During the 73-week blinded study period, participants received intravenous infusions of placebo or semorinemab (1500 mg, 4500 mg, or 8100 mg) every 2 weeks for the first 3 infusions and every 4 weeks thereafter. The primary outcomes were change from baseline on the Clinical Dementia Rating-Sum of Boxes score from baseline to week 73 and assessments of the safety and tolerability for semorinemab compared with placebo. In the modified intent-to-treat cohort (n 422 mean SD age, 69.6 7.0 years 235 women 55.7%), similar increases were seen on the Clinical Dementia Rating-Sum of Boxes score in the placebo (n 126 Δ 2.19 95% CI, 1.74-2.63) and semorinemab (1500 mg n 86 Δ 2.36 95% CI, 1.83-2.89 4500 mg n 126 Δ 2.36 95% CI, 1.92-2.79 8100 mg n 84 Δ 2.41 95% CI, 1.88-2.94) arms. In the safety-evaluable cohort (n 441), similar proportions of participants experienced adverse events in the placebo (130 93.1%) and semorinemab (1500 mg 89 88.8% 4500 mg 132 94.7% 8100 mg 90 92.2%) arms. In participants with prodromal to mild AD in this randomized clinical trial, semorinemab did not slow clinical AD progression compared with placebo throughout the 73-week study period but did demonstrate an acceptable and well-tolerated safety profile. Additional studies of anti-tau antibodies may be needed to determine the clinical utility of this therapeutic approach. ClinicalTrials.gov Identifier NCT03289143.

Bioavailability Study of a Transdermal Patch Formulation of Rivastigmine Compared with Exelon in Healthy Subjects.

Rivastigmine is a reversible cholinesterase inhibitor indicated for the treatment of all stages of Alzheimers disease (AD). Transdermal patch formulation allows smooth and continuous drug delivery. Its tolerability, efficacy and convenience of use increase treatment compliance. This study was designed to evaluate the bioavailability and to assess the bioequivalence of two rivastigmine transdermal patches at steady state (RIV-TDS Test Product versus Exelon Marketed Reference Product), with a release rate of 13.3 mg24 h, after multiple patch applications. As secondary objectives, safety, patch adhesion and skin irritation were evaluated. This was an open-label, randomized, balanced, two-period, two-sequence, cross-over study of healthy adults (n 31). The treatment period consisted of two 5-day study periods during which consecutive daily application of the investigational patches with a release rate of 13.3 mg24 h rivastigmine took place. Serial blood samples were collected to measure plasma concentrations. Adhesion and skin irritation assessments were performed after application of patches. Point estimates and 90% confidence intervals of pharmacokinetic parameters at steady state, viz. area under the plasma concentration versus time curve from dosing time to the end of the dosing interval τ (profile day) at steady state AUC For both products, bioequivalence was shown and systemic tolerability was in accordance with the safety profile of the drug substance. The trial is registered in ClinicalTrials.gov NCT03573050 and EudraCT 2018-000968-28.

Evidence of beta amyloid independent small vessel disease in familial Alzheimers disease.

We studied small vessel disease (SVD) pathology in Familial Alzheimers disease (FAD) subjects carrying the presenilin 1 (PSEN1) p.Glu280Ala mutation in comparison to those with sporadic Alzheimers disease (SAD) as a positive control for Alzheimers pathology and Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) bearing different NOTCH3 mutations, as positive controls for SVD pathology. Upon magnetic resonance imaging (MRI) in life, some FAD showed mild white matter hyperintensities and no further radiologic evidence of SVD. In post-mortem studies, total SVD pathology in cortical areas and basal ganglia was similar in PSEN1 FAD and CADASIL subjects, except for the feature of arteriosclerosis which was higher in CADASIL subjects than in PSEN1 FAD subjects. Further only a few SAD subjects showed a similar degree of SVD pathology as observed in CADASIL. Furthermore, we found significantly enlarged perivascular spaces in vessels devoid of cerebral amyloid angiopathy in FAD compared with SAD and CADASIL subjects. As expected, there was greater fibrinogen-positive perivascular reactivity in CADASIL but similar reactivity in PSEN1 FAD and SAD groups. Fibrinogen immunoreactivity correlated with onset age in the PSEN1 FAD cases, suggesting increased vascular permeability may contribute to cognitive decline. Additionally, we found reduced perivascular expression of PDGFRβ AQP4 in microvessels with enlarged PVS in PSEN1 FAD cases. We demonstrate that there is Aβ-independent SVD pathology in PSEN1 FAD, that was marginally lower than that in CADASIL subjects although not evident by MRI. These observations suggest presence of covert SVD even in PSEN1, contributing to disease progression. As is the case in SAD, these consequences may be preventable by early recognition and actively controlling vascular disease risk, even in familial forms of dementia.

Antifungal Azole Derivatives Featuring Naphthalene Prove Potent and Competitive Cholinesterase Inhibitors with Potential CNS Penetration According to the in Vitro and in Silico Studies.

Cholinesterase inhibition is of great importance in the fight against neurodegenerative disorders such as Alzheimers disease. Azole antifungals have come under the spotlight with recent discoveries that underline the efficacy and potential of miconazole and its derivatives against cholinesterase enzymes. In this study, we evaluated a library of azoles against acetylcholinesterase and butyrylcholinesterase using in vitro and in silico methods to identify potent inhibitors. Low micromolar IC

Construction of a short version of the Montreal Cognitive Assessment (MoCA) rating scale for the Thai population using Partial Least Squares analysis.

The Montreal Cognitive Assessment (MoCA) rating scale is frequently used to assess cognitive impairments in amnestic mild cognitive impairment (aMCI) and Alzheimers disease (AD). The aims of this study were to a) evaluate the construct validity of the MoCA and its subdomains or whether the MoCA can be improved by feature reduction, and b) develop a short version of the MoCA (MoCA-Brief) for the Thai population. We recruited 181 participants, namely 60 healthy controls, 61 aMCI, and 60 AD patients. The construct reliability of the original MoCA was not optimal and could be improved by deleting one subdomain (Naming) and five items, namely Clock Circle, Lion, Digit Forward, Repeat 2nd Sentence, and Place, which showed inadequate loadings on their latent vectors. To construct the MoCA-Brief, the reduced model underwent further reduction and feature selection based on model quality data of the outer models. We produced a MoCA-Brief rating scale comprising five items, namely Clock Time, Subtract 7, Fluency, Month, and Year. The first latent vector extracted from these five indicators showed adequate construct validity with an Average Variance Extracted of 0.599, composite reliability of 0.822, Cronbachs alpha of 0.832 and rho A of 0.833. The MoCA-Brief factor score showed a strong correlation with the total MoCA score ( The construct validity of the MoCA may be improved by deleting five items. The new MoCA-Brief rating scale deserves validation in independent samples and especially in other countries.

Effects of social restrictions on people with dementia and carers during the pre-vaccine phase of the COVID-19 pandemic Experiences of IDEAL cohort participants.

This qualitative study was designed to understand the impact of social distancing measures on people with dementia and carers living in the community in England and Wales during a period of social restrictions before the COVID-19 vaccination roll-out. We conducted 12 semi-structured interviews with people with dementia aged 50-88 years, living alone or with a partner, and 10 carers aged 61-78 years, all living with the person with dementia. Three of the interviews were with dyads. Participants were recruited during November and December 2020. We used framework analysis to identify themes and elicit suggestions for potential solutions. We identified three interrelated themes. People with dementia experienced a fear of decline in capabilities or mood and attempted to mitigate this. Carers noticed changes in the person with dementia and increased caring responsibilities, and for some, a change in the relationship. Subsequently, reduced confidence in capabilities to navigate a new and hostile environment created a cyclical dilemma of re-engaging where an inability to access usual activities made things worse. People with dementia and carers experienced neglect and being alone in their struggle, alongside feeling socially excluded during the pandemic, and there was little optimism associated with the upcoming vaccine programme. People found their own solutions to reduce the effects of isolation by keeping busy and being socially active, and practising skills deemed to help reduce the progression of dementia. This and some limited local public initiatives for the general public facilitated feelings of social inclusion. This study adds understanding to existing evidence about the longer-term experience of social isolation several months into the pandemic. It highlights the importance of health and community groups and suggests how services can find ways to support, include, and interact with people with dementia and carers during and after social restrictions.

The potential of lumbrokinase and serratiopeptidase for the degradation of Aβ 1-42 peptide - an

Alzheimers disease (AD) is diagnosed with the deposition of insoluble β-amyloid (Aβ) peptides in the neuropil of the brain leading to dementia. The extracellular deposition of the fibrillar Aβ peptide on the neurons is known as senile plaques. Therefore, Aβ degradation and clearance from the human body is a promising therapeutic approach in the medication of AD. In the current study, the enzyme lumbrokinase (LK) was extracted and purified from earthworm and its activity was utilized toward Aβ 1-42 amyloids degradation The output of this study revealed that preformed Aβ 1-42 amyloids was disintegrated by both LK and SP, as demonstrated from fluorescence assay using Thioflavin T dye. In addition, dynamic light scattering study revealed the lower size of the preformed fibrils Aβ 1-42 at various time intervals after incubation with the enzymes LK and SP. Furthermore, The findings of the present study indicated that LK and SP, not only had Aβ 1-42 amyloid degrading potential, but also could reduce the toxicity which can make them a suitable drug candidate for AD. Furthermore, the

Evaluating the Use of Digital Biomarkers to Test Treatment Effects on Cognition and Movement in Patients with Lewy Body Dementia.

PRESENCE was a Phase 2 trial assessing mevidalen for symptomatic treatment of Lewy body dementia (LBD). Participants received daily doses (10, 30, or 75 mg) of mevidalen (LY3154207) or placebo for 12 weeks. To evaluate if frequent cognitive and motor tests using an iPad app and wrist-worn actigraphy to track activity and sleep could detect mevidalen treatment effects in LBD. Of 340 participants enrolled in PRESENCE, 238 wore actigraphy for three 2-week periods pre-, during, and post-intervention. A subset of participants (n 160) enrolled in a sub-study using an iPad trial app with 3 tests digital symbol substitution (DSST), spatial working memory (SWM), and finger-tapping. Compliance was defined as daily test completion or watch-wearing ≥23 hday. Change from baseline to week 12 (app) or week 8 (actigraphy) was used to assess treatment effects using Mixed Model Repeated Measures analysis. Pearson correlations between sensor-derived features and clinical endpoints were assessed. Actigraphy and trial app compliance was > 90% and > 60%, respectively. At baseline, daytime sleep positively correlated with Epworth Sleepiness Scale score (p < 0.01). Physical activity correlated with improvement on Movement Disorder Society -Unified Parkinson Disease Rating Scale (MDS-UPDRS) part II (p < 0.001). Better scores of DSST and SWM correlated with lower Alzheimer Disease Assessment Scale -Cognitive 13-Item Scale (ADAS-Cog13) (p < 0.001). Mevidalen treatment (30 mg) improved SWM (p < 0.01), while dose-dependent decreases in daytime sleep (10 mg p < 0.01, 30 mg p < 0.05, 75 mg p < 0.001), and an increase in walking minutes (75 mg dose p < 0.001) were observed, returning to baseline post-intervention. Devices used in the LBD population achieved adequate compliance and digital metrics detected statistically significant treatment effects.

Alzheimers Disease with Epileptiform EEG Activity Abnormal Cortical Sources of Resting State Delta Rhythms in Patients with Amnesic Mild Cognitive Impairment.

Patients with amnesic mild cognitive impairment due to Alzheimers disease (ADMCI) typically show a slowing of cortical resting-state eyes-closed electroencephalographic (rsEEG) rhythms. Some of them also show subclinical, non-convulsive, and epileptiform EEG activity (EEA) with an unclear relationship with that slowing. Here we tested the hypothesis that the slowing of rsEEG rhythms is related to EEA in ADMCI patients. Clinical and instrumental datasets in 62 ADMCI patients and 38 normal elderly (Nold) subjects were available in a national archive. No participant had received a clinical diagnosis of epilepsy. The eLORETA freeware estimated rsEEG cortical sources. The area under the receiver operating characteristic curve (AUROCC) indexed the accuracy of eLORETA solutions in the classification between ADMCI-EEA and ADMCI-noEEA individuals. EEA was observed in 15% (N 8) of the ADMCI patients. The ADMCI-EEA group showed 1) more abnormal Aβ42 levels in the cerebrospinal fluid as compared to the ADMCI-noEEA group and 2) higher temporal and occipital delta (<4 Hz) rsEEG source activities as compared to the ADMCI-noEEA and Nold groups. Those source activities showed moderate accuracy (AUROCC 0.70-0.75) in the discrimination between ADMCI-noEEA versus ADMCI-EEA individuals. It can be speculated that in ADMCI-EEA patients, AD-related amyloid neuropathology may be related to an over-excitation in neurophysiological low-frequency (delta) oscillatory mechanisms underpinning cortical arousal and quiet vigilance.

Pattern of Altered Magnetization Transfer Rate in Alzheimers Disease.

Biomarkers for Alzheimers disease (AD) are crucial for early diagnosis and treatment monitoring once disease modifying therapies become available. This study aims to quantify the forward magnetization transfer rate (kfor) map from brain tissue water to macromolecular protons and use it to identify the brain regions with abnormal kfor in AD and AD progression. From the Cardiovascular Health Study (CHS) cognition study, magnetization transfer imaging (MTI) was acquired at baseline from 63 participants, including 20 normal controls (NC), 18 with mild cognitive impairment (MCI), and 25 AD subjects. Of those, 53 participants completed a follow-up MRI scan and were divided into four groups 15 stable NC, 12 NC-to-MCI, 12 stable MCI, and 14 MCIAD-to-AD subjects. kfor maps were compared across NC, MCI, and AD groups at baseline for the cross-sectional study and across four longitudinal groups for the longitudinal study. We found a lower kfor in the frontal gray matter (GM), parietal GM, frontal corona radiata (CR) white matter (WM) tracts, frontal and parietal superior longitudinal fasciculus (SLF) WM tracts in AD relative to both NC and MCI. Further, we observed progressive decreases of kfor in the frontal GM, parietal GM, frontal and parietal CR WM tracts, and parietal SLF WM tracts in stable MCI. In the parietal GM, parietal CR WM tracts, and parietal SLF WM tracts, we found trend differences between MCIAD-to-AD and stable NC. Forward magnetization transfer rate is a promising biomarker for AD diagnosis and progression.

Demonstration of Clinical Meaningfulness of the Integrated Alzheimers Disease Rating Scale (iADRS) Association Between Change in iADRS Scores and Patient and Caregiver Health Outcomes.

The integrated Alzheimers Disease Rating Scale (iADRS) is a validated cognitivefunctional composite that effectively captures cognitive and functional decline over a broad spectrum of disease. The clinical meaningfulness of change on iADRS can be supported by establishing an association with changes on important health outcome measures. To evaluate the relationship between change on the iADRS and changes in health outcomes in individuals with mild cognitive impairment (MCI) due to Alzheimers disease (AD), or mild or moderate AD dementia using placebo data from four AD clinical trials and data from one AD observational study. Analysis of covariate (ANCOVA) models were used to estimate the relationship between 18-month change on the iADRS and changes on health outcome measures (related to cost, quality of life, and caregiver burden). The regression coefficients for the iADRS were used to compute impact of natural disease progression and disease-modifying treatment on health outcomes. Additional ANCOVAs were conducted to understand whether cognition andor function was the underlying explanation of any association between iADRS and health outcome change. Across datasets and disease stages, a worsening on the iADRS was significantly associated with increased societal costs, caregiver burden (time and distress) and worsening in measures of patient quality of life. Decline on the iADRS was associated with worsening in health outcome measures. These findings suggest that the iADRS can be used in clinical trials as a proxy measure of clinically meaningful outcomes of AD progression.

Genome-Wide Association Study of Incident Dementia in a Community-Based Sample of Older Subjects.

Alzheimers disease (AD) is a complex disease influenced by the environment and genetics however, much of the genetic component remains unaccounted for. The purpose of this work was to use genome-wide association analyses to detect genetic associations with incident AD in a sample of older adults aged 75 and above. We performed a genome-wide association study (GWAS) on genome-wide genotyped and imputed data (14,072,053 variants) on the Gingko Evaluation of Memory (GEM) study sample consisting of 424 incident dementia (mean age 84.46±3.91) and 2,206 non-demented (mean age 84.55±3.23) subjects. The established association of APOE4 carriers with AD was confirmed in this community-based sample of older subjects (odds ratio (OR) 2.22 p 9.36E-14) and was stronger in females (OR 2.72 p 1.74E-10) than in males (OR 1.88 p 2.43E-05). We observed a novel genome-wide significant (GWS) locus on chromosome 12 near ncRNA LOC105369711rs148377161 (OR 3.31 p 1.66E-08). In addition, sex-stratified analyses identified two novel associations in males one near ncRNA LOC729987rs140076909 on chromosome 1 (OR 4.51 p 3.72E-08) and the other approaching GWS near ncRNA LOC105375138rs117803234 on chromosome 7 (OR 3.76 p 6.93E-08). The use of community-based samples of older individuals and incident dementia as a phenotype may be a helpful approach for the identification of novel genes for AD, which may not be detected in standard case-control studies. Replication of these signals and further studies of these regions and genes will help to provide a clearer picture for their role in AD.

Blood BMP6 Associated with Cognitive Performance and Alzheimers Disease Diagnosis A Longitudinal Study of Elders.

Bone morphogenetic protein (BMP) plays important roles in the pathology of Alzheimers disease (AD). We sought blood BMP6 involved in the processes underlying cognitive decline and detected them in association with AD. A total of 309 participants in Shanghai Mental Health Center (SMHC) and 547 participants in Alzheimers disease Neuroimaging Initiative (ADNI) cohort were included. Blood BMP6 and cognitive functions were measured in all subjects of both cohorts at baseline, and in 482 subjects of ADNI cohort after one year. A total of 300 subjects in ADNI cohort were detected cerebrospinal fluid (CSF) tau biomarker, and 244 received 1-year follow-up. AD patients had lower levels of blood BMP6 compared to normal controls, and BMP6 was positively associated with cognitive functions. Longitudinal BMP6 combing with APOE genotype could distinguish probable AD from normal controls. The influence of blood BMP6 on cognition was modulated by tau pathology. Blood BMP6 was associated with cognitive performance and identified as a potential predictor for probable AD.

Training with Odors Impacts Hippocampal Thickness in Patients with Mild Cognitive Impairment.

The olfactory system is affected early in Alzheimers disease and olfactory loss can already be observed in patients with mild cognitive impairment (MCI). Olfactory training is effective for improving olfactory and cognitive function by stimulating the olfactory pathway, but its effect on patients with MCI remains unclear. The aim of this randomized, prospective, controlled, blinded study was to assess whether a 4-month period of olfactory training (frequent short-term sniffing various odors) may have an effect on olfactory function, cognitive function, and morphology of medial temporal lobe (MTL) subregions and olfactory bulb in MCI patients. A total of thirty-seven MCI patients were randomly assigned to the training group or a placebo group, which were performed twice a day for 4 months. Olfactory assessments, cognitive tests and magnetic resonance imaging were performed at the baseline and follow-up period. After the training, there was an increase in odor discrimination, and increased cortical thickness of bilateral hippocampus (CA23DG and CA1) and mean MTL. Additionally, the change of olfactory score was positively associated with change of volume of olfactory bulb and hippocampus the change of global cognition was positively associated with change of cortical thickness of hippocampus, entorhinal cortex and mean MTL the change of cortical thickness of entorhinal cortex was positively associated with change of executive function. Olfactory training was associated with an increase in cortical thickness of the hippocampus but not olfactory bulb volume in patients with MCI. Olfactory training may serve as an early intervention of preventing hippocampal atrophy.

Metabolic Reprogramming of Microglia Enhances Proinflammatory Cytokine Release through EphA2p38 MAPK Pathway in Alzheimers Disease.

The activation of microglia and neuroinflammation has been implicated in the pathogenesis of Alzheimers disease (AD), but the exact roles of microglia and the underlying mechanisms remain unclear. To clarify how the metabolic reprogramming of microglia induce by amyloid-β (Aβ)1-42 to affect the release of proinflammatory cytokines in AD. MTS assay was used to detect the viability of BV2 cells treated with different concentrations of Aβ1-42 for different periods of time. The expression levels of proinflammatory cytokines were determined by qRT-PCR and western blot assay in BV2 cells and hippocampus of mice. RNA sequencing was applied to evaluate the gene expression profiles in response to HK2 knockdown in BV2 cells treated with Aβ1-42. Low concentrations of Aβ1-42 increased the viability of BV2 cells and promoted the release of proinflammatory cytokines, and this process is accompanied by increased glycolysis. Inhibition of glycolysis significantly downregulated the release of proinflammatory cytokines in BV2 cells and hippocampus of mice treated with Aβ1-42. The results of RNA sequencing revealed the expression of chemokine ligand 2 (Cxcl2) and ephrin receptor tyrosine kinase A2 (EphA2) were significantly downregulated when knocked down HK2 in BV2 cells. Subsequently, the expression of proinflammatory cytokines was downregulated in BV2 cell after knocking down EphA2. This study demonstrated that EphA2p38 MAPK pathway is involved the release of proinflammatory cytokines in microglia induced by Aβ1-42 in AD, which is accompanied by metabolic reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis.

Olfactory Function and Markers of Brain Pathology in Non-Demented Individuals with Autosomal Dominant Alzheimers Disease.

Olfactory dysfunction is one of the earliest signs of Alzheimers disease (AD), highlighting its potential use as a biomarker for early detection. It has also been linked to progression from mild cognitive impairment (MCI) to dementia. To study olfactory function and its associations with markers of AD brain pathology in non-demented mutation carriers of an autosomal dominant AD (ADAD) mutation and non-carrier family members. We analyzed cross-sectional data from 16 non-demented carriers of the Presenilin1 E280A ADAD mutation (mean age SD 40.1 5.3, and 19 non-carrier family members (mean age SD 36.0 5.5) from Colombia, who completed olfactory and cognitive testing and underwent amyloid and tau positron emission tomography (PET) imaging. Worse olfactory identification performance was associated with greater age in mutation carriers (r -0.52 p 0.037). In carriers, worse olfactory identification performance was related to worse MMSE scores (r 0.55, p 0.024) and CERAD delayed recall (r 0.63, p 0.007) and greater cortical amyloid-β (r -0.53, p 0.042) and tau pathology burden (entorhinal r -0.59, p 0.016 inferior temporal r -0.52, p 0.038). Worse performance on olfactory identification tasks was associated with greater age, a proxy for disease progression in this genetically vulnerable ADAD cohort. In addition, this is the first study to report olfactory dysfunction in ADAD mutation carriers with diagnosis of MCI and its correlation with abnormal accumulation of tau pathology in the entorhinal region. Taken together, our findings suggest that olfactory dysfunction has promise as an early marker of brain pathology and future risk for dementia.

The Impact of Agitation in Dementia on Caregivers A Real-World Survey.

Dementia patients frequently depend on caregivers. Agitation is a common behavioral dementia symptom particularly burdensome to patients and caregivers. To assess the association of agitation severity with non-professional caregiver hours, burden, health status, and productivity. Secondarily, to assess the association of agitation severity with these outcomes for patients receiving remote (not living with the patient) and proximate (living with the patient) caregiving. A retrospective analysis of physician and non-professional caregiver-reported data from a US point-in-time survey. Patients were aged ≥50 years, with early cognitive impairment or dementia. Regression analyses compared outcomes by agitation severity covariates included age, sex, and clinical characteristics. Data were included for 1,349 patients (non-agitated n 656, agitated n 693 no care n 305, remote care n 248, proximate care n 691 unknown care n 105). Greater agitation was significantly associated (p < 0.05) in all caregivers with increasing Zarit Burden Interview (ZBI) Total Caregiver Burden, Personal Strain, Role Strain, and Guilt Work Productivity and Activity Index (WPAI) presenteeism, overall work impairment, and total activity impairment. Higher ZBI Total Caregiver Burden, Personal Strain, and Role Strain were associated with greater agitation in proximate caregivers and higher ZBI Guilt associated with greater agitation in remote caregivers (p < 0.05). Higher WPAI presenteeism and total activity impairment were associated (p < 0.05) with greater agitation in proximate caregivers. Caregiving hours increased with increasing agitation for proximate caregiving (p 0.001). Greater agitation severity was associated with higher caregiver burden and lower productivity, with higher indirect costs a likely outcome of agitation.

Effects of Tianeptine Treatment on Depression and Cognitive Function in Patients with Alzheimers Disease A 12-Month Retrospective Observational Study.

Depression is a common manifestation in Alzheimers disease (AD). In clinical practice, antidepressant medication is often used for depression in AD. We explore the effectiveness of the atypical antidepressant tianeptine compared with other conventional antidepressants in AD patients with depression in a real-life setting. We retrospectively identified 126 AD patients who had received antidepressant treatment for 12 months with tianeptine or other antidepressants. Subjects were divided into two groups according to the treatment they had received tianeptine group (n 38) or other antidepressant group (n 88). Drug effects on depression, cognition, behavior, and functional performance were evaluated at baseline, 6, and 12 months. A Mixed Effects Model Analysis was carried out to evaluate changes in performance scores. Both tianeptine and other antidepressants showed an antidepressant effect after 12 months with significant improvement on the Cornell Scale for Depression in Dementia, the Hamilton Depression Rating Scale, and the Neuropsychiatric Inventory-Depression subscale. A statistically significant improvement at 12 months was shown in the tianeptine group versus the other antidepressants group on most of the cognitive measures such as the Mini-Mental State Examination, the Letter and Category Fluency Test, the Rey Auditory Verbal Learning Test, and the Boston Naming Test. Our results suggest that tianeptine reduces depressive symptoms and improves cognition in AD patients. This could be considered clinically relevant and should inspire the design of future long-term randomized controlled trials that contribute to supporting the use of tianeptine for improving cognitive function in AD patients.

Pelargonidin and Berry Intake Association with Alzheimers Disease Neuropathology A Community-Based Study.

An anthocyanidin, pelargonidin, primarily found in berries, has antioxidant and anti-inflammatory properties, and is associated with better cognition and reduced Alzheimers dementia risk. This study investigated if pelargonidin or berry intake is associated with Alzheimers disease (AD) neuropathology in human brains. The study was conducted among 575 deceased participants (age at death 91.3±6.1 years 70% females) of the Rush Memory and Aging Project, with dietary data (assessed using a food frequency questionnaire) and neuropathological evaluations. Calorie-adjusted pelargonidin intake was modeled in quartiles and berry intake as continuous (servingsweek). Mean amyloid-beta load and phosphorylated tau neuronal neurofibrillary tangle density across multiple cortical regions were assessed using immunohistochemistry. Global AD pathology burden, a quantitative summary score of neurofibrillary tangles, and diffuse and neuritic plaques using Bielschowsky silver stains in multiple brain regions, was also assessed. In a linear regression model adjusted for age at death, sex, education, APOE ɛ4 status, vitamin E, and vitamin C, participants in the highest quartile of pelargonidin intake when compared to those in the lowest quartile, had less amyloid-β load (β (SE) -0.293 (0.14), p 0.038), and fewer phosphorylated tau tangles (β (SE) -0.310, p 0.051). Among APOE ɛ4 non-carriers, higher strawberry (β (SE) -0.227 (0.11), p 0.037) and pelargonidin (Q4 versus Q1 β (SE) -0.401 (0.16), p 0.011 p trend 0.010) intake was associated with less phosphorylated tau tangles, no association was observed in APOE ɛ4 carriers. Berry intake was not associated with AD pathology. However, excluding participants with dementia or mild cognitive impairment at baseline, strawberry (p 0.004) and pelargonidin (ptrend 0.007) intake were associated with fewer phosphorylated tau tangles. Higher intake of pelargonidin, a bioactive present in strawberries, is associated with less AD neuropathology, primarily phosphorylated tau tangles.

SERF, a family of tiny highly conserved, highly charged proteins with enigmatic functions.

Amyloid formation is a misfolding process that has been linked to age-related diseases, including Alzheimers and Huntingtons. Understanding how cellular factors affect this process in vivo is vital in realizing the dream of controlling this insidious process that robs so many people of their humanity. SERF (small EDRK-rich factor) was initially isolated as a factor that accelerated polyglutamine amyloid formation in a C. elegans model. SERF knockouts inhibit amyloid formation of a number of proteins that include huntingtin, α-synuclein and β-amyloid which are associated with Huntingtons, Parkinsons and Alzheimers disease, respectively, and purified SERF protein speeds their amyloid formation in vitro. SERF proteins are highly conserved, highly charged and conformationally dynamic proteins that form a fuzzy complex with amyloid precursors. They appear to act by specifically accelerating the primary step of amyloid nucleation. Brain-specific SERF knockout mice, though viable, appear to be more prone to deposition of amyloids, and show modified fibril morphology. Whole-body knockouts are perinatally lethal due to an apparently unrelated developmental issue. Recently, it was found that SERF binds RNA and is localized to nucleic acid-rich membraneless compartments. SERF-related sequences are commonly found fused to zinc finger sequences. These results point towards a nucleic acid-binding function. How this function relates to their ability to accelerate amyloid formation is currently obscure. In this review, we discuss the possible biological functions of SERF family proteins in the context of their structural fuzziness, modulation of amyloid pathway, nucleic acid binding and their fusion to folded proteins.

Multi-Omics-Based Autophagy-Related Untypical Subtypes in Patients with Cerebral Amyloid Pathology.

Recent multi-omics analyses paved the way for a comprehensive understanding of pathological processes. However, only few studies have explored Alzheimers disease (AD) despite the possibility of biological subtypes within these patients. For this study, unsupervised classification of four datasets (genetics, miRNA transcriptomics, proteomics, and blood-based biomarkers) using Multi-Omics Factor Analysis (MOFA), along with systems-biological approaches following various downstream analyses are performed. New subgroups within 170 patients with cerebral amyloid pathology (Aβ) are revealed and the features of them are identified based on the top-rated targets constructing multi-omics factors of both whole (M-TPAD) and immune-focused models (M-IPAD). The authors explored the characteristics of subtypes and possible key-drivers for AD pathogenesis. Further in-depth studies showed that these subtypes are associated with longitudinal brain changes and autophagy pathways are main contributors. The significance of autophagy or clustering tendency is validated in peripheral blood mononuclear cells (PBMCs n 120 including 30 Aβ- and 90 Aβ), induced pluripotent stem cell-derived human brain organoidsmicroglia (n 12 including 5 Aβ-, 5 Aβ, and CRISPR-Cas9 apolipoprotein isogenic lines), and human brain transcriptome (n 78). Collectively, this study provides a strategy for precision medicine therapy and drug development for AD using integrative multi-omics analysis and network modelling.

Effect of stimuli type on affective memory of patients with different severities of cognitive impairment.

To understand the differences in affective memory performance under different degrees of cognitive impairment, this study recruited older people with different degrees of cognitive impairment, to perform emotion recognition memory tasks. Fifty-four elderly participants aged (65-85 years) were recruited. Of these, 18 had mild cognitive impairment, 18 had a mild form of Alzheimers disease, and the remaining 18 were healthy. Factors such as the different emotional valences (positive, neutral, or negative) and stimulus types (pictures, words, or sounds) were manipulated to explore their influences on the emotion recognition memory of people with different degrees of cognitive impairment. The results showed that peoples performance to positive stimuli worsened as their degree of cognitive impairment increased. All participants had difficulty processing memory of affective sound stimuli compared to the other two stimulus types. The results explain the decline in the cognitive ability process, in affective memory performance, of people with different degrees of cognitive impairment. This abnormal decline on affective memory performance could be an early diagnostic indicator of Alzheimers disease. The results can hopefully be used as a reference for subsequent research on cognition-related diseases and age-related decline, especially regarding affective memory.

Application of curcumin nanoformulations in Alzheimers disease prevention, diagnosis and treatment.

The influence of the macular carotenoids on womens eye and brain health.

Whole-Brain Network Models From Physics to Bedside.

Computational neuroscience has come a long way from its humble origins in the pioneering work of Hodgkin and Huxley. Contemporary computational models of the brain span multiple spatiotemporal scales, from single neuronal compartments to models of social cognition. Each spatial scale comes with its own unique set of promises and challenges. Here, we review models of large-scale neural communication facilitated by white matter tracts, also known as whole-brain models (WBMs). Whole-brain approaches employ inputs from neuroimaging data and insights from graph theory and non-linear systems theory to model brain-wide dynamics. Over the years, WBM models have shown promise in providing predictive insights into various facets of neuropathologies such as Alzheimers disease, Schizophrenia, Epilepsy, Traumatic brain injury, while also offering mechanistic insights into large-scale cortical communication. First, we briefly trace the history of WBMs, leading up to the state-of-the-art. We discuss various methodological considerations for implementing a whole-brain modeling pipeline, such as choice of node dynamics, model fitting and appropriate parcellations. We then demonstrate the applicability of WBMs toward understanding various neuropathologies. We conclude by discussing ways of augmenting the biological and clinical validity of whole-brain models.

Focus on the Role of the NLRP3 Inflammasome in Multiple Sclerosis Pathogenesis, Diagnosis, and Therapeutics.

Neuroinflammation is initiated with an aberrant innate immune response in the central nervous system (CNS) and is involved in many neurological diseases. Inflammasomes are intracellular multiprotein complexes that can be used as platforms to induce the maturation and secretion of proinflammatory cytokines and pyroptosis, thus playing a pivotal role in neuroinflammation. Among the inflammasomes, the nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasome is well-characterized and contributes to many neurological diseases, such as multiple sclerosis (MS), Alzheimers disease (AD), and ischemic stroke. MS is a chronic autoimmune disease of the CNS, and its hallmarks include chronic inflammation, demyelination, and neurodegeneration. Studies have demonstrated a relationship between MS and the NLRP3 inflammasome. To date, the pathogenesis of MS is not fully understood, and clinical studies on novel therapies are still underway. Here, we review the activation mechanism of the NLRP3 inflammasome, its role in MS, and therapies targeting related molecules, which may be beneficial in MS.

Comparative Metabolomics Analysis Reveals Key Metabolic Mechanisms and Protein Biomarkers in Alzheimers Disease.

Alzheimers disease (AD) is one of the most common progressive neurodegenerative diseases, accompanied by global alterations in metabolic profiles. In the past 10 years, over hundreds of metabolomics studies have been conducted to unravel metabolic changes in AD, which provides insight into the identification of potential biomarkers for diagnosis, treatment, and prognostic assessment. However, since different species may lead to systemic abnormalities in metabolomic profiles, it is urgently needed to perform a comparative metabolomics analysis between AD animal models and human patients. In this study, we integrated 78 metabolic profiles from public literatures, including 11 metabolomics studies in different AD mouse models and 67 metabolomics studies from AD patients. Metabolites and enrichment analysis were further conducted to reveal key metabolic pathways and metabolites in AD. We totally identified 14 key metabolites and 16 pathways that are both differentially significant in AD mouse models and patients. Moreover, we built a metabolite-target network to predict potential protein markers in AD. Finally, we validated HER2 and NDF2 as key protein markers in APPPS1 mice. Overall, this study provides a comprehensive strategy for AD metabolomics research, contributing to understanding the pathological mechanism of AD.

The Loss of Perineuronal Nets in Alzheimers Disease Missing or Hiding in Plain Sight

Perineuronal nets (PNNs) are chondroitin-sulfate glycosaminoglycan (CS-GAG) containing extracellular matrix structures that assemble around neurons involved in learning, memory, and cognition. Owing to the unique patterning of negative charges stemming from sulfate modifications to the attached CS-GAGs, these matrices play key roles in mediating glycan-protein binding, signaling interactions, and charged ion buffering of the underlying circuitry. Histochemical loss of PNN matrices has been reported for a range of neurocognitive and neurodegenerative diseases, implying that PNNs might be a key player in the pathogenesis of neurological disorders. In this hypothesis and theory article, we begin by highlighting PNN changes observed in human postmortem brain tissue associated with Alzheimers disease (AD) and corresponding changes reported in rodent models of AD neuropathology. We then discuss the technical limitations surrounding traditional methods for PNN analyses and propose alternative explanations to these historical findings. Lastly, we embark on a global re-evaluation of the interpretations for PNN changes across brain regions, across species, and in relation to other neurocognitive disorders.

Football and Dementia Understanding the Link.

Football, also known as soccer or association football, is popular but has a potential link with dementia developing in retired players. The FA and soccer regulators in the USA have imposed guidelines limiting players exposure to heading, despite controversy whether this dementia is caused by heading the ball, a form of mild repetitive head injury (RHI), over many years. Substantial data exist showing that many ex-North American Football players develop a specific neurodegenerative disease chronic traumatic encephalopathy (CTE), the neuropathological disorder of boxers. In the United Kingdom evidence for the neuropathological basis of footballers dementia has been slow to emerge. A 2017 study revealed that in six ex-soccer players four had CTE with Alzheimers disease (AD) and two had AD. A 2019 study showed that ex-footballers were 3.5 times more likely to die from dementia or other neuro-degenerative diseases than matched controls. We argue that in childhood and adolescence the brain is vulnerable to heading, predicated on its disproportionate size and developmental immaturity. RHI in young individuals is associated with early neuroinflammation, a potential trigger for promoting neurodegeneration in later life. Evidence is available to support the guidelines limiting heading for players of all ages, while professional and non-players should be included in prospective studies to investigate the link between soccer and dementia.

MEEG Dynamics Underlying Reserve, Resilience, and Maintenance in Aging A Review.

Cognitive reserve and resilience refer to the set of processes allowing the preservation of cognitive performance in the presence of structural and functional brain changes. Investigations of these concepts have provided unique insights into the heterogeneity of cognitive and brain changes associated with aging. Previous work mainly relied on methods benefiting from a high spatial precision but a low temporal resolution, and thus the temporal brain dynamics underlying these concepts remains poorly known. Moreover, while spontaneous fluctuations of neural activity have long been considered as noise, recent work highlights its critical contribution to brain functions. In this study, we synthesized the current state of knowledge from magnetoencephalography (MEG) and electroencephalography (EEG) studies that investigated the contribution of maintenance of neural synchrony, and variability of brain dynamics, to cognitive changes associated with healthy aging and the progression of neurodegenerative disease (such as Alzheimers disease). The reviewed findings highlight that compensations could be associated with increased synchrony of higher (>10 Hz) frequency bands. Maintenance of young-like synchrony patterns was also observed in healthy older individuals. Both maintenance and compensation appear to be highly related to preserved structural integrity (brain reserve). However, increased synchrony was also found to be deleterious in some cases and reflects neurodegenerative processes. These results provide major elements on the stability or variability of functional networks as well as maintenance of neural synchrony over time, and their association with individual cognitive changes with aging. These findings could provide new and interesting considerations about cognitive reserve, maintenance, and resilience of brain functions and cognition.

Analysis of Genetic Association Between

The study aimed to clarify the association of the 21 single nucleotide polymorphisms (SNPs) with Alzheimers disease (AD) in the population of southern China. A case-control study was conducted with a total sample size of 490 subjects (246 patients with AD and 244 age- and gender-matched healthy controls) enrolled in this study. Twenty-one selected SNPs were detected using SNaPshot assay and polymerase chain reaction (PCR) technique. Then, we assessed how these SNPs correlated with AD susceptibility. The results showed that rs3764650 of This study demonstrated that the G-allele at rs3764650 and the A-allele at rs4147929 appeared at higher risk for developing AD, particularly in

A Novel Key Features Screening Method Based on Extreme Learning Machine for Alzheimers Disease Study.

The Extreme Learning Machine (ELM) is a simple and efficient Single Hidden Layer Feedforward Neural Network(SLFN) algorithm. In recent years, it has been gradually used in the study of Alzheimers disease (AD). When using ELM to diagnose AD based on high-dimensional features, there are often some features that have no positive impact on the diagnosis, while others have a significant impact on the diagnosis. In this paper, a novel Key Features Screening Method based on Extreme Learning Machine (KFS-ELM) is proposed. It can screen for key features that are relevant to the classification (diagnosis). It can also assign weights to key features based on their importance. We designed an experiment to screen for key features of AD. A total of 920 key functional connections screened from 4005 functional connections. Their weights were also obtained. The results of the experiment showed that (1) Using all (4,005) features to diagnose AD, the accuracy is 95.33%. Using 920 key features to diagnose AD, the accuracy is 99.20%. The 3,085 (4,005 - 920) features that were screened out had a negative effect on the diagnosis of AD. This indicates the KFS-ELM is effective in screening key features. (2) The higher the weight of the key features and the smaller their number, the greater their impact on AD diagnosis. This indicates that the KFS-ELM is rational in assigning weights to the key features for their importance. Therefore, KFS-ELM can be used as a tool for studying features and also for improving classification accuracy.

Functional and Phenotypic Diversity of Microglia Implication for Microglia-Based Therapies for Alzheimers Disease.

Alzheimers disease (AD) is a progressive neurodegenerative disease and is closely associated with the accumulation of β-amyloid (Aβ) and neurofibrillary tangles (NFTs). Apart from Aβ and NFT pathologies, AD patients also exhibit a widespread microglial activation in various brain regions with elevated production of pro-inflammatory cytokines, a phenomenon known as neuroinflammation. In healthy central nervous system, microglia adopt ramified, surveying phenotype with compact cell bodies and elongated processes. In AD, the presence of pathogenic proteins such as extracellular Aβ plaques and hyperphosphorylated tau, induce the transformation of ramified microglia into amoeboid microglia. Ameboid microglia are highly phagocytic immune cells and actively secrete a cascade of pro-inflammatory cytokines and chemokines. However, the phagocytic ability of microglia gradually declines with age, and thus the clearance of pathogenic proteins becomes highly ineffective, leading to the accumulation of Aβ plaques and hyperphosphorylated tau in the aging brain. The accumulation of pathogenic proteins further augments the neuroinflammatory responses and sustains the activation of microglia. The excessive production of pro-inflammatory cytokines induces a massive loss of functional synapses and neurons, further worsening the disease condition of AD. More recently, the identification of a subset of microglia by transcriptomic studies, namely disease-associated microglia (DAM), the progressive transition from homeostatic microglia to DAM is TREM2-dependent and the homeostatic microglia gradually acquire the state of DAM during the disease progression of AD. Recent in-depth transcriptomic analysis identifies ApoE and Trem2 from microglia as the major risk factors for AD pathogenesis. In this review, we summarize current understandings of the functional roles of age-dependent microglial activation and neuroinflammation in the pathogenesis of AD. To this end, the exponential growth in transcriptomic data provides a solid foundation for

Phenotypic Displays of Cholinergic Enzymes Associate With Markers of Inflammation, Neurofibrillary Tangles, and Neurodegeneration in Pre- and Early Symptomatic Dementia Subjects.

Cholinergic drugs are the most commonly used drugs for the treatment of Alzheimers disease (AD). Therefore, a better understanding of the cholinergic system and its relation to both AD-related biomarkers and cognitive functions is of high importance. To evaluate the relationships of cerebrospinal fluid (CSF) cholinergic enzymes with markers of amyloidosis, neurodegeneration, neurofibrillary tangles, inflammation and performance on verbal episodic memory in a memory clinic cohort. In this cross-sectional study, 46 cholinergic drug-free subjects (median age 71, 54% female, median MMSE 28) were recruited from an Icelandic memory clinic cohort targeting early stages of cognitive impairment. Enzyme activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) was measured in CSF as well as levels of amyloid-β No significant relationships were found between CSF Aβ Results indicate a relationship between higher activity of the ACh-degrading cholinergic enzymes with increased neurodegeneration, neurofibrillary tangles and inflammation in the stages of pre- and early symptomatic dementia, independent of CSF Aβ

Large Margin and Local Structure Preservation Sparse Representation Classifier for Alzheimers Magnetic Resonance Imaging Classification.

Alzheimers disease (AD) is a progressive dementia in which the brain shrinks as the disease progresses. The use of machine learning and brain magnetic resonance imaging (MRI) for the early diagnosis of AD has a high probability of clinical value and social significance. Sparse representation classifier (SRC) is widely used in MRI image classification. However, the traditional SRC only considers the reconstruction error and classification error of the dictionary, and does not consider the global and local structural information between images, which results in unsatisfactory classification performance. Therefore, a large margin and local structure preservation sparse representation classifier (LMLS-SRC) is developed in this manuscript. The LMLS-SRC algorithm uses the classification large margin term based on the representation coefficient, which results in compactness between representation coefficients of the same class and a large margin between representation coefficients of different classes. The LMLS-SRC algorithm uses local structure preservation term to inherit the manifold structure of the original data. In addition, the LMLS-SRC algorithm imposes the ℓ

Differential Abnormality in Functional Connectivity Density in Preclinical and Early-Stage Alzheimers Disease.

Both subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) have a high risk of progression to Alzheimers disease (AD). While most of the available evidence described changes in functional connectivity (FC) in SCD and aMCI, there was no confirmation of changes in functional connectivity density (FCD) that have not been confirmed. Therefore, the purpose of this study was to investigate the specific alterations in resting-state FCD in SCD and aMCI and further assess the extent to which these changes can distinguish the preclinical and early-stage AD. A total of 57 patients with SCD, 59 patients with aMCI, and 78 healthy controls (HC) were included. The global FCD, local FCD, and long-range FCD were calculated for each voxel to identify brain regions with significant FCD alterations. The brain regions with abnormal FCD were then used as regions of interest for FC analysis. In addition, we calculated correlations between neuroimaging alterations and cognitive function and performed receiver-operating characteristic analyses to assess the diagnostic effect of the FCD and FC alterations on SCD and aMCI. FCD mapping revealed significantly increased global FCD in the left parahippocampal gyrus (PHG.L) and increased long-range FCD in the left hippocampus for patients with SCD when compared to HCs. However, when compared to SCD, patients with aMCI showed significantly decreased global FCD and long-range FCD in the PHG.L. The follow-up FC analysis further revealed significant variations between the PHG.L and the occipital lobe in patients with SCD and aMCI. In addition, patients with SCD also presented significant changes in FC between the left hippocampus, the left cerebellum anterior lobe, and the inferior temporal gyrus. Moreover, changes in abnormal indicators in the SCD and aMCI groups were significantly associated with cognitive function. Finally, combining FCD and FC abnormalities allowed for a more precise differentiation of the clinical stages. To our knowledge, this study is the first to investigate specific alterations in FCD and FC for both patients with SCD and aMCI and confirms differential abnormalities that can serve as potential imaging markers for preclinical and early-stage Alzheimers disease (AD). Also, it adds a new dimension of understanding to the diagnosis of SCD and aMCI as well as the evaluation of disease progression.

Comparing the Effects of Long-term Exposure to Extremely Low-frequency Electromagnetic Fields With Different Values on Learning, Memory, Anxiety, and β-amyloid Deposition in Adult Rats.

Extremely Low-Frequency Electromagnetic Fields (ELF-EMFs) have gathered significant consideration for their possible pathogenicity. However, their effects on the nervous systems functions were not fully clarified. This study aimed to assay the impact of ELF-EMFs with different intensities on memory, anxiety, antioxidant activity, β-amyloid (Aβ) deposition, and microglia population in rats. Fifty male adult rats were randomly separated into 5 groups 4 were exposed to a flux density of 1, 100, 500, and 2000 microtesla (μT), 50 Hz frequency for one hday for two months, and one group as a control group. The control group was without ELF-EMF stimulation. After 8 weeks, passive avoidance and Elevated Plus Maze (EPM) tests were performed to assess memory formation and anxiety-like behavior, respectively. Total free thiol groups and the index of lipid peroxidation were evaluated. Additionally, for detection of Aβ deposition and stained microglia in the brain, anti-β-amyloid and anti-Iba1 antibodies were used. The step-through latency in the retention test in ELF-EMF exposure groups (100500 2000 μT) was significantly greater than the control group (P<0.05). Furthermore, the frequency of the entries into the open arms in ELF-EMF exposure groups (especially 2000 μT) decreased than the control group (P<0.05). No Aβ depositions were detected in the hippocampus of different groups. An increase in microglia numbers in the 100, 500, and 2000 μT groups was observed compared to the control and one μT group. Exposure to ELF-EMF had an anxiogenic effect on rats, promoted memory, and induced oxidative stress. No Aβ depositions were detected in the brain. Moreover, the positive impact of ELF-EMF was observed on the microglia population in the brain. ELF-EMFs have gathered significant consideration for their possible pathogenicity.ELF-EMFs effects on the nervous systems functions were not clarified yet.Positive impact of ELF-EMF was observed on the microglia population in the brain. ELF-EMFs effects on human health are a considerable concern. Studies revealed the adverse effects of ELF-EMF in neurological disorders such as Alzheimers Disease (AD). Anxiety could be an early manifestation of AD. There is a correlation between occupational exposure to ELF-EMF and AD. Recently the researchers interested in the study of the effects of ELF-EMFs on the human body. Some studies examined the molecular mechanisms and the influence of ELF-EMFs on the biologic mechanisms in the body. Also, Microglia act in the Central Nervous system (CNS) immune responses over-activated microglia can be responsible for devastating and progressive neurotoxic consequences in neurodegenerative disorders. This study aimed to evaluate the memory, anxiety, antioxidant activity, β-amyloid deposition, and frequency of the microglial cells exposed to microtesla (μT) and 2000 (μT) ELF-EMFs.

Modulatory Effects of Memantine on Neuronal Response Properties in Rat Barrel Cortex.

Memantine as N-Methyl-D-Aspartic Acid (NMDA) receptor antagonist is used in some neurological disorders. Moreover, memantine presents modulatory effects on the somatosensory information processing in healthy subjects. This study investigated the effects of memantine on electrophysiological properties of barrel cortex neurons in male rats. Single unit recording was used to evaluate the electrophysiological properties of barrel cortex neurons. The neural responses to the Principal Whisker (PW), Adjacent Whisker (AW), and combined displacement of two whiskers 20 ms Inter-Stimulus Intervals (ISIs) were recorded before and 2 hours after memantine gavage (10 mgkg). A Condition Test Ratio (CTR) was calculated for assessing inhibitory interactions. Two hours after memantine gavage, neuronal ON and OFF responses to PW deflection were decreased. Furthermore, CTR for both ON and OFF responses was decreased following memantine administration. The current study demonstrated that memantine modified neural response properties in the rat barrel cortex. Memantine modulated excitatory receptive fields in the rat somatosensory cortex.Memantine decreased integrative receptive fields in rat somatosensory cortex. As an NMDA receptor antagonist, memantine is used to treat moderate to severe Alzheimers disease. Memantine has beneficial effects on cognition, mood, and perform daily activities. However, the current study results suggested that memantine may affect information processing in the somatosensory system. This should be considered for future research in the clinic.

Microglia in Alzheimers Disease A Favorable Cellular Target to Ameliorate Alzheimers Pathogenesis.

Microglial cells serve as molecular sensors of the brain that play a role in physiological and pathological conditions. Under normal physiology, microglia are primarily responsible for regulating central nervous system homeostasis through the phagocytic clearance of redundant protein aggregates, apoptotic cells, damaged neurons, and synapses. Furthermore, microglial cells can promote and mitigate amyloid

Case Report Presence of Anti-MAG in the CSF Can Be Associated With a Neurodegenerative Process With Frontal Involvement.

Autoimmune encephalitis (AIE) is an increasingly broad nosological framework that may clinically mimic neurodegenerative diseases (NDDs). We describe here the clinical, radiological, electrophysiological, and biological evolution of three patients. Two women aged 73 and 72 years and a 69-year-old man presented with complex cognitive and focal neurological symptoms and each had a predominant frontal dysexecutive involvement and an unexpectedly high titer of anti-MAG antibodies in the serum and cerebrospinal fluid (CSF). The question of an autoimmune cause was raised. After 2 years of follow-up and, for two of them, without improvement despite immunosuppressive treatments, diagnoses of NDD were eventually retained post-radiation encephalopathy, progressive supranuclear palsy (PSP), and Alzheimers disease. The presence of a high titer of anti-MAG antibodies may be found in NDD. It could reflect cerebral tissue damages, particularly in the case of significant frontal involvement. Atypical presentations may lead to a search for a paraneoplastic neurologic syndrome or AIE. However, the indirect immunofluorescence staining positivity on a monkey cerebellum section linked with anti-MAG antibodies should not lead to those diagnoses being retained.

Secreted Amyloid Precursor Protein Alpha, a Neuroprotective Protein in the Brain Has Widespread Effects on the Transcriptome and Proteome of Human Inducible Pluripotent Stem Cell-Derived Glutamatergic Neurons Related to Memory Mechanisms.

Secreted amyloid precursor protein alpha (sAPPα) processed from a parent human brain protein, APP, can modulate learning and memory. It has potential for development as a therapy preventing, delaying, or even reversing Alzheimers disease. In this study a comprehensive analysis to understand how it affects the transcriptome and proteome of the human neuron was undertaken. Human inducible pluripotent stem cell (iPSC)-derived glutamatergic neurons in culture were exposed to 1 nM sAPPα over a time course and changes in the transcriptome and proteome were identified with RNA sequencing and Sequential Window Acquisition of All THeoretical Fragment Ion Spectra-Mass Spectrometry (SWATH-MS), respectively. A large subset (∼30%) of differentially expressed transcripts and proteins were functionally involved with the molecular biology of learning and memory, consistent with reported links of sAPPα to memory enhancement, as well as neurogenic, neurotrophic, and neuroprotective phenotypes in previous studies. Differentially regulated proteins included those encoded in previously identified Alzheimers risk genes, APP processing related proteins, proteins involved in synaptogenesis, neurotransmitters, receptors, synaptic vesicle proteins, cytoskeletal proteins, proteins involved in protein and organelle trafficking, and proteins important for cell signalling, transcriptional splicing, and functions of the proteasome and lysosome. We have identified a complex set of genes affected by sAPPα, which may aid further investigation into the mechanism of how this neuroprotective protein affects memory formation and how it might be used as an Alzheimers disease therapy.

Brain-Derived Neurotrophic Factor A Connecting Link Between Nutrition, Lifestyle, and Alzheimers Disease.

Brain-derived neurotrophic factor (BDNF) involving tropomyosin kinase B and low affinity p75 neurotropin receptors is the most abundant and researched neurotropins in mammals brain. It is one of the potential targets for therapeutics in Alzheimers disease (AD) owing to its key role in synaptic plasticity. Low levels of BDNF are implicated in the pathophysiology of neurological diseases including AD. However, a healthy lifestyle, exercise, and dietary modifications are shown to positively influence insulin regulation in the brain, reduce inflammation, and up-regulate the levels of BDNF, and are thus expected to have roles in AD. In this review, the relationship between BDNF, mental health, and AD is discussed. Insights into the interrelationships between nutrition, lifestyle, and environment with BDNF and possible roles in AD are also provided in the review. The review sheds light on the possible new therapeutic targets in neurodegenerative diseases.

Approaches to Address PK-PD Challenges of Conventional Liposome Formulation with Special Reference to Cancer, Alzheimers, Diabetes, and Glaucoma An Update on Modified Liposomal Drug Delivery System.

Liposomes nowadays have become a preferential drug delivery system since they provide facilitating properties to drugs, such as improved therapeutic index of encapsulated drug, target and controlled drug delivery, and less toxicity. However, conventional liposomes have shown some disadvantages, such as less drug loading capacity, poor retention, clearance by kidney or reticuloendothelial system, and less release of hydrophilic drugs. Thus, to overcome these disadvantages recently, scientists have explored new approaches and methods, viz., ligand conjugation, polymer coating, and liposome hybrids, including surface-modified liposomes, biopolymer-incorporated liposomes, guest-in-cyclodextrin-in-liposome, liposome-in-hydrogel, liposome-in-film, liposome-in-nanofiber, etc. These approaches have been shown to improve the physiochemical and pharmacokinetic properties of encapsulated drugs. Lately, pharmacokinetic-pharmacodynamic (PK-PD) computational modeling has emerged as a beneficial tool for analyzing the impact of formulation and system-specific factors on the target disposition and therapeutic efficacy of liposomal drugs. There has been an increasing number of liposome-based therapeutic drugs, both FDA approved and those undergoing clinical trials, having application in cancer, Alzheimers, diabetes, and glaucoma. To meet the continuous demand of health sectors and to produce the desired product, it is important to perform pharmacokinetic studies. This review focuses on the physical, physicochemical, and chemical factors of drugs that influence the target delivery of drugs. It also explains various physiological barriers, such as systemic clearance and extravasation. A novel approach, liposomal-hybrid complex, an innovative approach as a vesicular drug delivery system to overcome limited membrane permeability and bioavailability, has been discussed in the review. Moreover, this review highlights the pharmacokinetic considerations and challenges of poorly absorbed drugs along with the applications of a liposomal delivery system in improving PKPD in various diseases, such as cancer, Alzheimers, diabetes, and glaucoma.

Ameliorative Effects of Phytomedicines on Alzheimers Patients.

Alzheimers disease (AD) is a progressive, neurodegenerative disease that severely affects individuals cognitive abilities, memory, and quality of life. It affects the elderly population, and there is no permanent prevention or cures available to date, treatments mainly aiming to alleviate the symptoms as and when they appear. Alternate therapeutic approaches are being researched constantly, and there is a growing focus on phytomedicine, herbal medicine, organic compounds, and ayurvedic compounds for the treatment of AD. The current study aims to provide an extensive review of these plants against AD from the currently existing literature. Most relevant keywords like Alzheimers Disease, phytomedicines, ethnic medicines, the role of phytomedicine in neuroprotection, common phytomedicines against AD, etc., were used to select the plants and their metabolites effective in treating AD. The study focuses on six plants Panax ginseng, Ginkgo biloba, Bacopa monnieri, Withania somnifera, Curcuma longa, and Lavandula angustifolia. Their active components have been studied along with neuroprotective properties, and evidence of in-vitro, pre-clinical, and clinical studies conducted to prove their therapeutic potential against the disease have been presented. All plants envisaged in the study show potential for fighting against AD to varying degrees. Their compounds have shown therapeutic effects by reversing the neurological changes such as clearing Aβ plaque and neurofibrillary tangle formation, and ameliorative effects against neurodegeneration through processes including improving concentration, memory, cognition and learning, higher working and cue memory, improved spatial memory, inhibition of NF-κB expression, inhibiting the release of pro-inflammatory cytokines, inhibition of AChE and lipid peroxidase enzymes, and reduction of interleukin levels and tumor necrosis factor-alpha. The present review is a comprehensive and up-to-date analysis supported by the evidentiary proofs from pre-clinical studies, meta-analyses, and review papers related to natural phytochemicals impact on neurodegenerative disorders like AD.

Chimeric cerebral organoids reveal the essentials of neuronal and astrocytic APOE4 for Alzheimers tau pathology.

The apolipoprotein E4 (APOE4) genotype is one of the strongest genetic risk factors for Alzheimers disease (AD), and is generally believed to cause widespread pathological alterations in various types of brain cells. Here, we developed a novel engineering method of creating the chimeric human cerebral organoids (chCOs) to assess the differential roles of APOE4 in neurons and astrocytes. First, the astrogenic factors NFIB and SOX9 were introduced into induced pluripotent stem cells (iPSCs) to accelerate the induction of astrocytes. Then the above induced iPSCs were mixed and cocultured with noninfected iPSCs under the standard culturing condition of cerebral organoids. As anticipated, the functional astrocytes were detected as early as 45 days, and it helped more neurons matured in chCOs in comparation of the control human cerebral organoids (hCOs). More interestingly, this method enabled us to generate chCOs containing neurons and astrocytes with different genotypes, namely APOE3 or APOE4. Then, it was found in chCOs that astrocytic APOE4 already significantly promoted lipid droplet formation and cholesterol accumulation in neurons while both astrocytic and neuronal APOE4 contributed to the maximum effect. Most notably, we observed that the co-occurrence of astrocytic and neuronal APOE4 were required to elevate neuronal phosphorylated tau levels in chCOs while Aβ levels were increased in chCOs with neuronal APOE4. Altogether, our results not only revealed the essence of both neuronal and astrocytic APOE4 for tau pathology, but also suggested chCOs as a valuable pathological model for AD research and drug discovery.

C3-targeted host-modulation approaches to oral inflammatory conditions.

Periodontitis is an inflammatory disease caused by biofilm accumulation and dysbiosis in subgingival areas surrounding the teeth. If not properly treated, this oral disease may result in tooth loss and consequently poor esthetics, deteriorated masticatory function and compromised quality of life. Epidemiological and clinical intervention studies indicate that periodontitis can potentially aggravate systemic diseases, such as, cardiovascular disease, type 2 diabetes mellitus, rheumatoid arthritis, and Alzheimer disease. Therefore, improvements in the treatment of periodontal disease may benefit not only oral health but also systemic health. The complement system is an ancient host defense system that plays pivotal roles in immunosurveillance and tissue homeostasis. However, complement has unwanted consequences if not controlled appropriately or excessively activated. Complement overactivation has been observed in patients with periodontitis and in animal models of periodontitis and drives periodontal inflammation and tissue destruction. This review places emphasis on a promising periodontal host-modulation therapy targeting the complement system, namely the complement C3-targeting drug, AMY-101. AMY-101 has shown safety and efficacy in reducing gingival inflammation in a recent Phase 2a clinical study. We also discuss the potential of AMY-101 to treat peri-implant inflammatory conditions, where complement also seems to be involved and there is an urgent unmet need for effective treatment.

How neurons die in Alzheimers disease Implications for neuroinflammation.

Despite the long-standing observation of vast neuronal loss in Alzheimers disease (AD) our understanding of how and when neurons are eliminated is incomplete. While previous investigation has focused on apoptosis, several novel forms of cell death (i.e. necroptosis, parthanatos, ferroptosis, cuproptosis) have emerged that require further investigation. This review aims to collect evidence for different modes of neuronal cell death in AD and to also discuss how these different forms of cell death may impact the neuroinflammatory environment that prevails in the AD brain. Improved understanding of how neurons die may help to delineate disease pathogenesis, provide insights toward treatment, and aid in the development of improved animal models of AD.

Are there morphological differences between Parkinsons disease-dementia and dementia with Lewy bodies

Parkinsons disease dementia (PDD) and dementia with Lewy bodies (DLB) are two major neurocognitive disorders in the spectrum of Lewy body diseases that overlap in many clinical and neuropathological features, although they show several differences. Clinically distinguished mainly based on the duration of parkinsonism prior to development of dementia, their morphology is characterized by a variable combination of Lewy body (LB) and Alzheimers disease (AD) pathologies, the latter usually being more frequent and severe in DLB. The aims of the study were to investigate essential neuropathological differences between PDD and DLB in a larger cohort of autopsy cases. 110 PDD autopsy cases were compared with 78 DLB cases. The major demographic, clinical (duration of illness, final MMSE) and neuropathological data were assessed retrospectively. Neuropathological studies used standardized methods and immunohistochemistry for phospho-tau, β-amyloid (Aß) and α-synuclein, with semiquantitative assessment of the major histological lesions. PDD patients were significantly older at death than DLB ones (mean 83.9 vs. 79.8 years), with a significantly longer disease duration (mean 9.2 vs. 6.7 years). Braak LB scores and particularly neuritic Braak stages were significantly higher in the DLB group (mean 5.1and 5.1 vs. 4.2 and 4.4, respectively), as were Thal Aβ phases (mean 4.1 vs. 3.0). Diffuse striatal Aβ plaques were considerable in 55% and moderate in 45% of DLB cases, but were extremely rare in PDD. The most significant differences concerned the frequency and degree of cerebral amyloid angiopathy (CAA), being significantly higher in DLB (98.7 vs. 50%, and mean degree of 2.9 vs. 0.72, respectively). Worse prognosis in DLB than in PDD was linked to both increased Braak neuritic stages and more severe CAA. These and other recent studies imply the association of CAA, more severe concomitant AD pathology, and striatal Aβ load with cognitive decline and more rapid disease process that distinguishes DLB from PDD, while the influence of other cerebrovascular diseases or co-pathologies in both disorders was not specifically examined. The importance of both CAA and tau pathology in DLB and much less in PDD supports the concept of a pathogenetic continuum from Parkinsons disease (PD) - > PDD - > DLB - > DLB AD and subtypes of AD with LB pathology within the spectrum of age-related proteinopathies.

Dioscin alleviates Alzheimers disease through regulating RAGENOX4 mediated oxidative stress and inflammation.

Alzheimers disease (AD) is a neurodegenerative disease with amyloid beta (Aβ) deposition and intracellular neurofibrillary tangles (NFTs) as its characteristic pathological changes. Ameliorating oxidative stress and inflammation has become a new trend in the prevention and treatment of AD. Dioscin, a natural steroidal saponin which exists in Dioscoreae nipponicae rhizomes, displays various pharmacological activities, but its role in Alzheimers disease (AD) is still unknown. In the present work, effect of dioscin on AD was evaluated in injured SH-SY5Y cells induced by H

APOE ε4 influences medial temporal atrophy and tau deposition in atypical Alzheimers disease.

Apolipoprotein E (APOE) ε4 is an important genetic risk factor for typical Alzheimers disease (AD), influencing brain volume and tau burden. Little is known about its influence in atypical presentations of AD. An atypical AD cohort of 140 patients diagnosed with either posterior cortical atrophy or logopenic progressive aphasia underwent magnetic resonance imaging and positron emission tomography. Linear mixed effects models were fit to assess the influence of APOE ε4 on cross-sectional and longitudinal regional metrics. At baseline, APOE ε4 carriers had smaller hippocampal and amygdala volumes and greater tau standardized uptake volume ratio in the hippocampus and entorhinal cortex compared to non-carriers while longitudinally, APOE ε4 non-carriers showed faster rates of atrophy and tau accumulation in the entorhinal cortex, with faster tau accumulation in the hippocampus. APOE ε4 influences patterns of neurodegeneration and tau deposition and was associated with more medial temporal involvement, although there is evidence that non-carriers may be catching up over time.

Parkin a potential target to promote healthy ageing.

Parkin is an E3 ubiquitin ligase mostly known for its role in regulating the removal of defective mitochondria via mitophagy. However, increasing experimental evidence that Parkin regulates several other aspects of mitochondrial biology in addition to its role in mitophagy has emerged over the past two decades. Indeed, Parkin has been shown to regulate mitochondrial biogenesis and dynamics and mitochondria-derived vesicle formation, suggesting that Parkin plays key roles in maintaining healthy mitochondria. While Parkin is commonly described as a cytosolic E3 ubiquitin ligase, it was also detected in other cellular compartments, including the nucleus, where it regulates transcription factors and acts as a transcription factor itself. New evidence also suggests that Parkin overexpression can be leveraged to delay ageing. In Drosophila, for example, Parkin overexpression extends lifespan. In mammals, Parkin overexpression delays hallmarks of ageing in several tissues and cell types. Parkin overexpression also confers protection in various models of cellular senescence and neurological disorders closely associated with ageing, such as Alzheimers and Parkinsons diseases. Recently, Parkin overexpression has also been shown to suppress tumour growth. In this review, we discuss newly emerging biological roles of Parkin as a modulator of cellular homeostasis, survival and healthy ageing, and we explore potential mechanisms through which Parkin exerts its beneficial effects on cellular health.

Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia.

Genetic mutations underlying familial Alzheimers disease (AD) were identified decades ago, but the field is still in search of transformative therapies for patients. While mouse models based on overexpression of mutated transgenes have yielded key insights in mechanisms of disease, those models are subject to artifacts, including random genetic integration of the transgene, ectopic expression and non-physiological protein levels. The genetic engineering of novel mouse models using knock-in approaches addresses some of those limitations. With mounting evidence of the role played by microglia in AD, high-dimensional approaches to phenotype microglia in those models are critical to refine our understanding of the immune response in the brain. We engineered a novel App knock-in mouse model (App Leveraging multi-omics approaches, we discovered profound alteration of diverse lipids and metabolites as well as an exacerbated disease-associated transcriptomic response in microglia with high intracellular Aβ content. The App Our findings demonstrate that fibrillar Aβ in microglia is associated with lipid dyshomeostasis consistent with lysosomal dysfunction and foam cell phenotypes as well as profound immuno-metabolic perturbations, opening new avenues to further investigate metabolic pathways at play in microglia responding to AD-relevant pathogenesis. The in-depth characterization of pathological hallmarks of AD in this novel and open-access mouse model should serve as a resource for the scientific community to investigate disease-relevant biology.

Synapse pathology in Alzheimers disease.

Synapse loss and damage are central features of Alzheimers disease (AD) and contribute to the onset and progression of its behavioural and physiological features. Here we review the literature describing synapse pathology in AD, from what we have learned from microscopy in terms of its impacts on synapse architecture, to the mechanistic role of Aβ, tau and glial cells, mitochondrial dysfunction, and the link with AD risk genes. We consider the emerging view that synapse pathology may operate at a further level, that of synapse diversity, and discuss the prospects for leveraging new synaptome mapping methods to comprehensively understand the molecular properties of vulnerable and resilient synapses. Uncovering AD impacts on brain synapse diversity should inform therapeutic approaches targeted at preserving or replenishing lost and damaged synapses and aid the interpretation of clinical imaging approaches that aim to measure synapse damage.

Recent advances in Lewy body dementia A comprehensive review.

Lewy Body Dementia is the second most frequent neurodegenerative illness proven to cause dementia, after Alzheimers disease (AD). It is believed to be vastly underdiagnosed, as there is a significant disparity between the number of cases diagnosed clinically and those diagnosed via neuropathology at the time of postmortem autopsy. Strikingly, many of the pharmacologic treatments used to treat behavioral and cognitive symptoms in other forms of dementia exacerbate the symptoms of DLB. Therefore, it is critical to accurately diagnose DLB as these patients require a specific treatment approach. This article focuses on its pathophysiology, risk factors, differentials, and its diverse treatment modalities. In this study, an English language literature search was conducted on Medline, Cochrane, Embase, and Google Scholar till April 2022. The following search strings and Medical Subject Headings (MeSH) terms were used Lewy Body Dementia, Dementia with Lewy bodies, and Parkinsons Disease Dementia. We explored the literature on Lewy Body Dementia for its epidemiology, pathophysiology, the role of various genes and how they bring about the disease, biomarkers, its differential diagnoses and treatment options.

Abnormal Functional Connectivity of Thalamic Subdivisions in Alzheimers Disease A Functional Magnetic Resonance Imaging Study.

Alzheimers disease (AD) is characterized by global cognitive impairment in multiple cognitive domains. Thalamic dysfunction during AD progression has been reported. However, there are limited studies regarding dysfunction in the functional connectivity (FC) of thalamic subdivisions and the relationship between such dysfunction and clinical assessments. This study examined dysfunction in the FC of thalamic subdivisions and determined the relationship between such dysfunction and clinical assessments. Forty-eight patients with AD and 47 matched healthy controls were recruited and assessed with scales for multiple cognitive domains. Group-wise comparisons of FC with thalamic subdivisions as seed points were conducted to identify abnormal cerebral regions. Moreover, correlation analysis was conducted to evaluate the relationship between abnormal FC and cognitive performance. Decreased FC of the intralaminar and medial nuclei with the left precuneus was observed in patients but not in heathy controls. The abnormal FC of the medial nuclei with the left precuneus was correlated with the Mini Mental State Examination score in the patient group. Using the FC values showing between-group differences, the linear support vector machine classifier achieved quite good in accuracy, sensitivity, specificity and area under the curve. Dysfunction in the FC of the intralaminar and medial thalamus with the precuneus may comprise a potential neural substrate for cognitive impairment during AD progression, which in turn may provide new treatment targets.

Automated quantification of neuronal swellings in a preclinical rodent model of Parkinsons disease detects region-specific changes in pathology.

The development of axonal pathology is a key characteristic of many neurodegenerative disease such as Parkinsons disease and Alzheimers disease. With advanced disease progression, affected axons do display several signs of pathology such as swelling and fragmentation. In the AAV vector-mediated alpha-synuclein overexpression model of Parkinsons disease, large (> 20 µm This report describes a novel, macro-based workflow to quantify axonal pathology in the form of axonal swellings in the AAV vector-based alpha-synuclein overexpression model. Specifically, the approach is using background correction and thresholding before quantification of structures in 3D throughout a tissue stack. The method was used to quantify TH and aSYN axonal swellings in the prefrontal cortex, striatum, and hippocampus. Regional differences in volume and number of axonal swellings were observed for both in TH and aSYN, with the striatum displaying the greatest signs of pathology. Existing methods for the quantification of axonal pathology do either rely on proprietary software or are based on manual quantification. The ImageJ workflow described here provides a method to objectively quantify axonal swellings both in volume and number. The method described can readily assess axonal pathology in preclinical rodent models of Parkinsons disease and can be easily adapted to other model systems andor markers.

Population-Based Prevalence of Infarctions on 3D Fluid-Attenuated Inversion Recovery (FLAIR) Imaging.

To report population-based, age-specific prevalence of infarctions as identified via 3D fluid-attenuated inversion recovery (FLAIR) imaging. Participants without dementia in the Mayo Clinic Study of Aging (MCSA), a population-based study in Olmsted County, MN, age 50-89 who underwent 3D FLAIR imaging between 2017 and 2020 were included. Infarctions per participant were determined via visual interpretation. Inter- and intra-reader reliability were calculated. Infarction prevalence on 3D FLAIR was derived by standardization to the Olmsted County population and was compared to that previously reported on 2D FLAIR imaging. Among 580 participants (mean age 71 years, 46% female) the prevalence (95% confidence interval) of any infarction was 5.0% (0.0%-9.9%) at age 50-59 years and 38.8% (28.6%-49.0%) at 80-89 years. In addition to increasing with age, the prevalence varied by sex and type of infarction. Prevalence estimates of cortical infarcts were 0.9% (0.0%-2.7%) at age 50-59 years and 20.2% (10.7%-29.7%) at 80-89 years and lacunar infarcts 4.1% (0.0%-8.8%) at age 50-59 years and 31.2% (21.5%-41.0%) at 80-89 years. Prevalence estimates of any infarction by sex were men, 8.7% (0.0%-18.7%) at 50-59 years and 54.9% (41.0%-68.8%) at 80-89 years and women, 2.4% (0.0%-7.3%) at age 50-59 years and 27.3% (12.9%-41.7%) at 80-89 years. Intra- and inter- reader reliability were very good (kappa 0.85 and 0.82, respectively). After adjusting for age, sex and education, individuals imaged with 3D FLAIR were 1.5 times (95% CI 1.2-1.8, p<0.001) more likely to be identified as positive for infarction compared to those imaged with 2D FLAIR. Infarction prevalence increases with age and is greater in men than women. Infarction prevalence on 3D FLAIR imaging, which has become more widely implemented as an alternative to 2D FLAIR over the past several years, will be a useful reference in future work.

A human factors and ergonomics approach to conceptualizing care work among caregivers of people with dementia.

Society relies upon informal (family, friend) caregivers to provide much of the care to the estimated 43.8 million individuals living with Alzheimers disease and related dementias globally. Caregivers rarely receive sufficient training, resources, or support to meet the demands associated with dementia care, which is often associated with increased risk of suboptimal outcomes. Human factors and ergonomics (HFE) can address the call for new approaches to better understand caregiving and support caregiver performance through systematic attention to and design of systems that support the work of caregivers- their care work. Thus, our objective was to perform a work system analysis of care work. We conducted a qualitative study using a Critical Incident Technique interviewing approach and Grounded Dimensional Analysis analytic procedures. Our findings introduce a new conceptual framework for understanding the care work system of dementia caregivers and suggest that care work is influenced by interactions among distinct caregiver goals, the task demands of the care needs of the person with dementia, daily life needs of the caregiver and family, and contextual factors that shape caregivers perceptions surrounding care. The initial work system model produced by this study provides a foundation from which future work can further elucidate the care work system, determine how the care work system intersects and coordinates with other work systems such as the patient work system, and design systems that address caregivers individual caregiving context.

Stem cells from human exfoliated deciduous teeth relieves Alzheimers disease symptoms in SAMP8 mice by up-regulating the PPARγ pathway.

The pathology of Alzheimers disease (AD) is complex and heterogeneous, and there are currently no drugs that can stop its progression. The failure of traditional chemical small-molecule drug development showed the weakness of single target and made researchers look to cell therapy with multiple regulatory effects. Stem cells from human exfoliated deciduous teeth (SHED) are a kind of neural crest-derived mesenchymal stem cells which have broad prospects in the treatment of neurodegenerative diseases. In this study, we demonstrated the therapeutic effects of SHED in AD mice, including behavioral improvement, neuronal protection, and alleviation of neuroinflammation. Tracking experiments on SHED showed that some of the transplanted cells could enter the brain. To elucidate the role played by the majority of cells transplanted into veins, blood proteomic assays were performed. Data are available via ProteomeXchange with identifier PXD030313. Among the altered proteins, the PPAR pathway related to energy metabolism was considered to be an important signaling pathway involved in regulation through gene ontology analysis and pathway analysis. Western blot showed that the transplantation of SHED improved the glucose metabolism in AD mice by increasing the PPARγ signaling pathway. These results suggested that SHED have a potential in relieving AD pathological symptoms and improving behavioral cognition. The therapeutic mechanism of SHED is related to up-regulating PPARγ signaling pathway and reducing neuronal damage.

FTY720 decreases ceramides levels in the brain and prevents memory impairments in a mouse model of familial Alzheimers disease expressing APOE4.

The protection mediated by the bioactive sphingolipid sphingosine-1-phosphate (S1P) declines during Alzheimers disease (AD) progression, especially in patients carrying the apolipoprotein E ε4 (APOE4) isoform. The drug FTY720 mimics S1P bioactivity, but its efficacy in treating AD is unclear. Two doses of FTY720 (0.1 mg kg and 0.5 mg kg daily) were given by oral gavage for 15 weeks to transgenic mouse models of familial AD carrying human apolipoprotein E (APOE) APOE3 (E3FAD) or APOE4 (E4FAD). After 12 weeks of treatment, animals were subjected to behavioral tests for memory, locomotion, and anxiety. Blood was withdrawn at different time points and brains were collected for sphingolipids analysis by mass spectrometry, gene expression by RT-PCR and Aβ quantification by ELISA. We discovered that low levels of S1P in the plasma is associated with a higher probability of failing the memory test and that FTY720 prevents memory impairments in E4FAD. The beneficial effect of FTY720 was induced by a shift of the sphingolipid metabolism in the brain towards a lower production of toxic metabolites, like ceramide d181160 and d181220, and reduction of amyloid-β burden and inflammation. In conclusion, we provide further evidence of the druggability of the sphingolipid system in AD.

Discovery of novel 2,3-dihydro-1H-inden-1-ones as dual PDE4AChE inhibitors with more potency against neuroinflammation for the treatment of Alzheimers disease.

Recently, the discovery of multifunctional molecules that target different factors in the treatment of dementia is a significant research area. Both PDE4 and AChE inhibitors display improvement in cognitive and memory function. In this study, twenty-eight novel 2,3-dihydro-1H-inden-1-ones were designed, synthesized, and evaluated as catechol ether-based dual PDE4AChE inhibitors to treat Alzheimers disease (AD). Among these compounds, 12C bearing a 2-(piperidin-1-yl)ethoxy group at the 6-position of indanone ring displayed satisfactory inhibitory activities and selectivity against AChE (IC

Alzheimer Type I Astrocytes Still Mysterious Cells.

Over 100 years ago, von Hösslein and Alzheimer described enlarged and multinucleated astrocytes in the brains of patients with Wilson disease. These odd astrocytes, now well known to neuropathologists, are present in a large variety of neurological disorders, and yet the mechanisms underlying their generation and their functional attributes are still not well understood. They undergo abnormal mitoses and fail to accomplish cytokinesis, resulting in multinucleation. Oxidative stress, hypoxia, and inflammation may be contributing pathologies to generate these astrocytes. The abnormal mitoses occur from changes in cell shape, the accumulation of cytoplasmic proteins, and the mislocalization of many of the important molecules whose coordination is necessary for proper mitotic spindle formation. Modern technologies will be able to characterize their abnormalities and solve century old questions of their form and function.

Association of perturbation of oral bacterial with incident of Alzheimers disease A pilot study.

This case-control study was designed to compare the composition of the predominant oral bacterial microbiome in Alzheimers disease (AD) and control group. A total of 30 adult participants (15 AD and 15 healthy individuals) were entered in this study. The composition of oral bacterial microbiome was examined by quantitative real-time polymerase chain reaction (qPCR) using bacterial 16S rDNA gene. The levels of systemic inflammatory cytokines in both groups were assessed using enzyme-linked immunosorbent assays (ELISA). The loads of Porphyromonas gingivalis, Fusobacterium nucleatum, and Prevotella intermedia were significantly more abundant in the AD compared to the control group (p < 0.05). Although Aggregatibacter actinomycetemcomitans and Streptococcus mutans were relatively frequent in the AD group, no significance difference was observed in their copy number between two groups. Although the concentrations of IL-1, IL-6, and TNF-α were higher in the AD group, there was a significant difference in their levels between the two groups (p < 0.05). Finally, there was a significant relationship between increased number of pathogenic bacteria in oral microbiome and higher concentration of cytokines in patients blood. Our knowledge of oral microbiome and its exact association with AD is rather limited our study showed a significant association between changes in oral microbiome bacteria, increased inflammatory cytokines, and AD.

Low physical activity is the strongest factor associated with frailty phenotype and frailty index data from baseline phase of Birjand Longitudinal Aging Study (BLAS).

Frailty is the most complicated expression of aging that is related to disability or multi-morbidity. The aim of the present study was to estimate the prevalence of frailty and its associated factors among community-dwelling aged population. A total of 1529 eligible community- dwelling older adults (≥ 60 years) were enrolled in the baseline phase of Birjand Longitudinal Aging Study (BLAS) from 2019 to 2020. Their frailty status was assessed using the Frieds frailty phenotype and frailty index. Sociodemographic factors, including sex, age, marital status, and education level, were collected. Health status assessment included the history of hypertension, diabetes mellitus, cardiovascular disease, Alzheimers diseases and dementia, and other health conditions. Furthermore, functional assessment (ADL, IADL) and anthropometric measurements including height, weight, waist, calf, and mid-arm circumference were made and the body mass index was calculated. The nutrition status and polypharmacy (use 3 or more medication) were also evaluated. The prevalence of frailty was 21.69% according to the frailty phenotype and 23.97% according to the frailty index. A multiple logistic regression model showed a strong association between low physical activity and frailty phenotype (OR 36.31, CI 16.99-77.56, P < 0.01), and frailty index (OR 15.46, CI 5.65-42.34, P < 0.01). Other factors like old age (≥80), female sex, malnutrition, polypharmacy, obesity, and arthritis were also associated with frailty. The Kappa coefficient of the agreement between these two instruments was 0.18. It seems that low physical activity is the most important determinant of frailty. Low physical activity and some other factors may be preventable or modifiable and thus serve as clinically relevant targets for intervention.

Deficits in spontaneous and stimulus-dependent retrieval as an early sign of abnormal aging.

Research on early cognitive markers of Alzheimers disease is primarily focused on episodic memory tests that involve deliberate retrieval. Our purpose was to provide clear evidence to support a novel Spontaneous Retrieval Deficit hypothesis, which predicts that people at pre-clinical stages of dementia, including those with amnestic Mild Cognitive Impairment (aMCI), are particularly impaired on tasks based on spontaneous retrieval. We compared 27 aMCI individuals and 27 healthy controls on mind-wandering while performing a task during which there were exposed to either highly meaningful or unmeaningful pictures. The substantial reduction in mind-wandering among individuals with aMCI was found with exposure to highly meaningful stimuli, but not to unmeaningful pictures, and it was most pronounced for past-oriented thoughts, i.e., involuntary autobiographical memories. Those findings provide strong support for this novel hypothesis, and show that it is the spontaneous, but bottom-up and cue-driven processes, for which meaningful environmental stimuli are crucial, that are very promising early markers of the disease.

Cis- and trans-resveratrol have opposite effects on histone serine-ADP-ribosylation and tyrosine induced neurodegeneration.

Serum tyrosine levels increase during aging, neurocognitive, metabolic, and cardiovascular disorders. However, calorie restriction (CR) and sleep lower serum tyrosine levels. We previously showed that tyrosine inhibits tyrosyl-tRNA synthetase (TyrRS)-mediated activation of poly-ADP-ribose polymerase 1 (PARP1). Here, we show that histone serine-ADP-ribosylation is decreased in Alzheimers Disease (AD) brains, and increased tyrosine levels deplete TyrRS and cause neuronal DNA damage. However, dopamine and brain-derived neurotrophic factor (BDNF) increase TyrRS and histone serine-ADP-ribosylation. Furthermore, cis-resveratrol (cis-RSV) that binds to TyrRS mimicking a tyrosine-free conformation increases TyrRS, facilitates histone serine-ADP-ribosylation-dependent DNA repair, and provides neuroprotection in a TyrRS-dependent manner. Conversely, trans-RSV that binds to TyrRS mimicking a tyrosine-like conformation decreases TyrRS, inhibits serine-ADP-ribosylation-dependent DNA repair, and induces neurodegeneration in rat cortical neurons. Our findings suggest that age-associated increase in serum tyrosine levels may effect neurocognitive and metabolic disorders and offer a plausible explanation for divergent results obtained in clinical trials using resveratrol.

Cirsiliol mitigates Aβ fibrillation and underlying membrane-leakage associated neurotoxicity A possible implication in the treatment of neurodegenerative disease.

Protein aggregating is known as a leading pathogenic characteristic of a wide range of neurodegenerative diseases (NDs). Preventing amyloid-β (Aβ) aggregation and uncovering the associated mechanism through the application of small bioactive compounds can be considered as a useful strategy in hampering the onset of ND. In this study, we analyzed the inhibitory effects of cirsiliol, a trihydroxy-dimethoxyflavone, against human Αβ

Phenylpropanoids on the Inhibition of β-Amyloid Aggregation and the Movement of These Molecules through the POPC Lipid Bilayer.

Alzheimers disease (AD), caused by Aβ aggregation, is a major concern in medical research. It is a neurodegenerative disorder, leading to a loss of cognitive abilities, which is still claiming the lives of many people all over the world. This poses a challenge before the scientific community to discover effective drugs which can prevent such toxic aggregation. Recent experimental findings suggest the potency of two naturally-occurring phenylpropanoids, Schizotenuin A (SCH) and Lycopic Acid B (LAB) which can effectively combat the deleterious effects of Aβ aggregation, although nothing is known about their mechanism of inhibition. In this work, we deal with an extensive computational study on the inhibitory effects of these inhibitors by using an all-atom molecular dynamics simulation to interpret the underlying mechanism of their inhibitory processes. A series of investigations is carried out while studying the various structural and conformational changes of the peptide chains in the absence and presence of inhibitors. To investigate the details of the interactions between the peptide residues and inhibitors, nonbonding energy calculations, the radial distribution function, the coordination number of water and inhibitor molecules around the peptide residues, and hydrogen-bonding interactions are calculated. The potential of mean force (PMF) is calculated to estimate aggregate formation from their free-energy profiles. It is seen that the hydrophobic core of the

Excessive local host-graft connectivity in aging and amyloid-loaded brain.

Transplantation is a clinically relevant approach for brain repair, but much remains to be understood about influences of the disease environment on transplant connectivity. To explore the effect of amyloid pathology in Alzheimers disease (AD) and aging, we examined graft connectivity using monosynaptic rabies virus tracing in APPPS1 mice and in 16- to 18-month-old wild-type (WT) mice. Transplanted neurons differentiated within 4 weeks and integrated well into the host visual cortex, receiving input from the appropriate brain regions for this area. Unexpectedly, we found a prominent several-fold increase in local inputs, in both amyloid-loaded and aged environments. State-of-the-art deep proteome analysis using mass spectrometry highlights complement system activation as a common denominator of environments promoting excessive local input connectivity. These data therefore reveal the key role of the host pathology in shaping the input connectome, calling for caution in extrapolating results from one pathological condition to another.

Affecting AMPA Receptor Biophysical Gating Properties with Negative Allosteric Modulators.

Glutamatergic chemical synapses mediate excitatory neurotransmission by the ion flow through α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors in the central nervous system (CNS). AMPA receptor-mediated synaptic transmission abnormalities may play a role in neurologic and neurodegenerative diseases, and compounds that can modulate AMPA receptor (AMPAR) signaling have been studied for decades as possible therapies for Alzheimers disease, Parkinsons disease, depression, and epilepsy. Here, we aimed to determine the modulating effect of allosteric regulators on AMPA receptors by comparing their actions on AMPA-evoked currents, desensitization, and deactivation rate in human embryonic kidney cells (HEK293T) recombinant AMPAR subunits. In this study, patch-clamp electrophysiology was performed to examine how the AMPA subunit responded to benzodioxole (BDZ) derivatives. Our results showed that the BDZ derivatives affected AMPARs as negative modulators, particularly BDZs (8, 9, and 15), where they increased the desensitization rate and delayed the deactivation process. The BDZ compounds were utilized in this study as AMPA modulators to investigate fundamental and clinical AMPA receptor processes. We test BDZs as negative allosteric AMPAR modulators to reestablish glutamatergic synaptic transmission. These efforts have resulted in important molecules with neuroprotective properties on AMPA receptors.

Tracking the binding of multi-functional fluorescent tags for Alzheimers disease using quantitative multiphoton microscopy.

A recent theranostic approach to address Alzheimers disease (AD) utilizes multifunctional targets that both tag and negate the toxicity of AD biomarkers. These compounds, which emit fluorescence with both an activation and a spectral shift in the presence of Aβ, were previously characterized with traditional fluorescence imaging for binary characterization. However, these multifunctional compounds have broad and dynamic emission spectra that are dependent on factors such as the local environment, presence of Aβ deposits, etc. Since quantitative multiphoton microscopy is sensitive to the binding dynamics of molecules, we characterized the performance of two such compounds, LS-4 and ZY-12-OMe, using Simultaneous Label-free Autofluorescence Multi-harmonic (SLAM) microscopy and Fast Optical Coherence, Autofluorescence Lifetime imaging and Second harmonic generation (FOCALS) microscopy. This study shows that the combination of quantitative multiphoton imaging with multifunctional tags for AD offers new insights into the interaction of these tags with AD biomarkers and the theranostic mechanisms.

Rosemary oil low energy nanoemulsion optimization, µrheology,

Acetylcholine imbalance in the human brain causes dementia-related symptoms of Alzheimers disease. Acetylcholinesterase (AChE) inhibitors prevent the lysis of acetylcholine in the brain and prevent dementia. Therefore, the present study aims to investigate the

Camouflaged Fluorescent Silica Nanoparticles Target Aggregates and Condensates of the Amyloidogenic Protein Tau.

Intrinsically disordered proteins (IDPs) are increasingly found to be associated with irreversible neurodegenerative disorders. The protein tau is a prototypical IDP whose abnormal aggregation into insoluble filaments is a major hallmark of Alzheimers disease. The view has emerged that aggregation may proceed via alternative pathways involving oligomeric intermediates or phase-separated liquid droplets. Nanoparticles (NPs) offer significant potential for probing the mechanisms of protein fibrillation and may be capable of redirecting conformational transitions. Here, we camouflaged dye-doped silica NPs through functionalization with tau molecules to impart them the ability to associate with protein assemblies such as aggregates or condensates. The prepared NP-tau conjugates showed little influence on the aggregation kinetics and morphology of filamentous aggregates of tau but were found to associate with the filaments. Moreover, NP-tau conjugates were recruited and concentrated into polyanion-induced condensates of tau, driven by multivalent electrostatic interactions, thereby illuminating liquid droplets and their time-dependent transformation, as observed by fluorescence microscopy. NP-tau conjugates were capable of entering human neuroglioma cells and were not cytotoxic. Hence, we propose that NP-tau conjugates could serve as nanotracers for in vitro and in-cell studies to target and visualize tau assemblies and condensates, contributing to an explanation for the molecular mechanisms of abnormal protein aggregation.

Effect of nutritional supports on malnutrition, cognition, function and biomarkers of Alzheimers disease a systematic review.

To summarize the nutritional supplementation on biochemical parameters, cognition, function, Alzheimers Disease (AD) biomarkers and nutritional status. PubMed, Web of Science, Korean Journal Database, Russian Science Citation Index, SciELO Citation Index, Cochrane Library and Scopus databases were searched until 16 April 2021. 22.193 records in total were reached according to inclusion and exclusion criteria. Included Studies were evaluated through the Modified Jadad Scale and gathered under four subheadings. Forty-eight studies with a total of 7009 AD patients were included. Souvenaid, ONS (368 ± 69 kcal), Vegenat-med, 500 mg Resveratrol, ONS (200 mL) were effective nutritional supplements on promoting weight gain and protecting malnutrition status but showed conflicting results in Body mass index, Mid-Upper-Arm Circumference and Triceps Skin Fold Thickness. ONS and a lyophilized whole supplementation Vegenat-med intake made an increase in MNA scores. While all nutritional supplements showed controversial results in biochemical parameters but caused a decrease in Hcy levels which caused reductions in brain Aβ plaque (increase serum Aβ), p-Tau and cognitive improvement. Folic acid and vitamin D decreased serum APP, BACE1, BACE1mRNA. Resveratrol, Better designed trials with holistic measures are needed to investigate the effect of nutritional support on the AD biomarkers, cognitive status, biochemical parameters and functional states. Also, more beneficial results can be obtained by examining the simultaneous effects of nutritional supplements with larger sample groups.