AD Symptoms Research Articles

Exercise interventions for older adults with Alzheimer\u2019s disease: a systematic review and meta-analysis protocol

BackgroundThe growing societal and economic impact of Alzheimer’s disease (AD) is further compounded by the present lack of disease-modifying interventions. Non-pharmacological intervention approaches, such as exercise, have the potential to be powerful approaches to improve or mitigate the symptoms of AD without added side effects or financial burden associated with drug therapies. Various forms and regiments of exercise (i.e., strength, aerobic, multicomponent) have been reported in the literature; however, conflicting evidence obscures clear interpretation of the value and impact of exercise as an intervention for older adults with AD. The primary objective of this review will be to evaluate the effects of exercise interventions for older adults with AD. In addition, this review will evaluate the evidence quality and synthesize the exercise training prescriptions for proper clinical practice guidelines and recommendations.MethodsThis systematic review and meta-analysis will be carried out by an interdisciplinary collective representing clinical and research stakeholders with diverse expertise related to neurodegenerative diseases and rehabilitation medicine. Literature sources will include the following: Embase, PsychINFO, OVID Medline, and Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily. Inclusion criteria are participants with late onset AD and structured exercise interventions with prescribed duration, frequency, and intensity. The primary outcome of this study will center on improved or sustained cognitive functioning. Secondary outcomes will include institutionalization-related outcomes, ability in activities of daily living, mood and emotional well-being, quality of life, morbidity, and mortality. Analysis procedures to include measurement of bias, data synthesis, sensitivity analysis, and assessment of heterogeneity are described in this protocol.DiscussionThis review is anticipated to yield clinically meaningful insight on the specific value of exercise for older adults with AD. Improved understanding of diverse exercise intervention approaches and their specific impact on various health- and function-related outcomes is expected to guide clinicians to more frequently and accurately prescribe meaningful interventions for those affected by AD.Systematic review registrationPROSPERO CRD42020175016.

Alzheimer's and Consciousness: How Much Subjectivity Is Objective?

Does Alzheimer Disease show a decline in cognitive functions that relate to the awareness of external reality? In this paper, we will propose a perspective that patients with increasing symptoms of AD show a change in the awareness of subjective versus objective representative axis of reality thus consequently move to a more internal like perception of reality. This paradigm shift suggests that new insights into the dynamicity of the conscious representation of reality in the AD brain may give us new clues to the very early signs of memory and self-awareness impairment that originates from, in our view the microtubules. Dialog between Adso and William, in Umberto Eco’s The Name of the Rose, Third Day: Vespers. “But how does it happen,” I said with admiration, “that you were able to solve the mystery of the library looking at it from the outside, and you were unable to solve it when you were inside?” “Thus, God knows the world, because He conceived it in His mind, as if it was from the outside, before it was created, and we do not know its rule, because we live inside it, having found it already made.”

The variability of functional MRI brain signal increases in Alzheimer's disease at cardiorespiratory frequencies

Biomarkers sensitive to prodromal or early pathophysiological changes in Alzheimer’s disease (AD) symptoms could improve disease detection and enable timely interventions. Changes in brain hemodynamics may be associated with the main clinical AD symptoms. To test this possibility, we measured the variability of blood oxygen level-dependent (BOLD) signal in individuals from three independent datasets (totaling 80 AD patients and 90 controls). We detected a replicable increase in brain BOLD signal variability in the AD populations, which constituted a robust biomarker for clearly differentiating AD cases from controls. Fast BOLD scans showed that the elevated BOLD signal variability in AD arises mainly from cardiovascular brain pulsations. Manifesting in abnormal cerebral perfusion and cerebrospinal fluid convection, present observation presents a mechanism explaining earlier observations of impaired glymphatic clearance associated with AD in humans.

The API Generation program: Biomarker phenotyping of cognitively unimpaired participants screened in Generation study 1 and Generation study 2

AbstractBackgroundAPI Generation Program evaluated the effectiveness of the BACE1 inhibitor umibecestat and the active immunotherapy CAD106 in delaying the onset of AD symptoms in APOE4 carriers. Data from imaging (vMRI and PET scans), and fluid biomarkers (blood and CSF) were collected during the 12‐week Screening phase. In this presentation, we will summarize results across the two studies and investigate the relationships between the various biomarkers and key baseline characteristics.MethodAmyloid levels were assessed via CSF and/or Amyloid PET scan in both studies for the APOE4 carriers. Generation Study 2 enrolled heterozygotes based on the following elevated amyloid inclusion criteria: Roche Elecsys® CSF p‐Tau/Abeta42 ratio > 0.024 and/or PET scans with any of the 3 amyloid F18 tracers (florbetapir, flutemetamol or florbetaben). If the centralized visual read of PET scan was negative, the SUVr was calculated (cortical composite in reference to whole cerebellum) for the three tracers in order to assess borderline cases. Thresholds for amyloid positivity equivalent to SUVR of 1.1 with florbetapir were used for the final decision on inclusion.ResultAcross both studies, over 500 lumbar punctures, 2700 amyloid PET scans and about 150 tau PET scans (conducted using flortaucipir) were performed. In Generation Study 1, over 200 FDG PET scans were also performed. Participants underwent amyloid testing during screening, blood sampling (plasma and serum) and underwent MRI scans for safety and to measure brain volumes. All baseline biomarker data will be presented, including available concentrations from CSF Tau/p‐Tau/Aβ42/Aβ40 along with the eligibility ratio for pTau/ab42. In about 150 participants, concordance between elevated/non elevated amyloid status by CSF and PET (using centiloids) will be shown. Baseline brain volume (whole brain and hippocampus) will be summarized for the different co‐variates (age, sex, cognition, genotype and amyloid status). Correlations among the various fluid biomarkers and imaging will be discussed.ConclusionThese data describe the biomarker signature of the world’s largest cohort of cognitively unimpaired APOE4 carriers with and without elevated amyloid. The anonymized study data, biomarker samples as well as images collected will be shared with the scientific community after study completion and reporting. ELECSYS is a registered trademark of Roche.

Temporal Quantitative Profiling of Newly Synthesized Proteins during Aβ Accumulation.

Accumulation of aggregated amyloid beta (Aβ) in the brain is believed to impair multiple cellular pathways and play a central role in Alzheimer's disease pathology. However, how this process is regulated remains unclear. In theory, measuring protein synthesis is the most direct way to evaluate a cell's response to stimuli, but to date, there have been few reliable methods to do this. To identify the protein regulatory network during the development of Aβ deposition in AD, we applied a new proteomic technique to quantitate newly synthesized protein (NSP) changes in the cerebral cortex and hippocampus of 2-, 5-, and 9-month-old APP/PS1 AD transgenic mice. This bio-orthogonal noncanonical amino acid tagging analysis combined PALM (pulse azidohomoalanine labeling in mammals) and HILAQ (heavy isotope labeled AHA quantitation) to reveal a comprehensive dataset of NSPs prior to and post Aβ deposition, including the identification of proteins not previously associated with AD, and demonstrated that the pattern of differentially expressed NSPs is age-dependent. We also found dysregulated vesicle transportation networks including endosomal subunits, coat protein complex I (COPI), and mitochondrial respiratory chain throughout all time points and two brain regions. These results point to a pathological dysregulation of vesicle transportation which occurs prior to Aβ accumulation and the onset of AD symptoms, which may progressively impact the entire protein network and thereby drive neurodegeneration. This study illustrates key pathway regulation responses to the development of AD pathogenesis by directly measuring the changes in protein synthesis and provides unique insights into the mechanisms that underlie AD.

Linguistic markers predict onset of Alzheimer's disease.

BackgroundThe aim of this study is to use classification methods to predict future onset of Alzheimer's disease in cognitively normal subjects through automated linguistic analysis.MethodsTo study linguistic performance as an early biomarker of AD, we performed predictive modeling of future diagnosis of AD from a cognitively normal baseline of Framingham Heart Study participants. The linguistic variables were derived from written responses to the cookie-theft picture-description task. We compared the predictive performance of linguistic variables with clinical and neuropsychological variables. The study included 703 samples from 270 participants out of which a dataset consisting of a single sample from 80 participants was held out for testing. Half of the participants in the test set developed AD symptoms before 85 years old, while the other half did not. All samples in the test set were collected during the cognitively normal period (before MCI). The mean time to diagnosis of mild AD was 7.59 years.FindingsSignificant predictive power was obtained, with AUC of 0.74 and accuracy of 0.70 when using linguistic variables. The linguistic variables most relevant for predicting onset of AD have been identified in the literature as associated with cognitive decline in dementia.InterpretationThe results suggest that language performance in naturalistic probes expose subtle early signs of progression to AD in advance of clinical diagnosis of impairment.FundingPfizer, Inc. provided funding to obtain data from the Framingham Heart Study Consortium, and to support the involvement of IBM Research in the initial phase of the study. The data used in this study was supported by Framingham Heart Study's National Heart, Lung, and Blood Institute contract (N01-HC-25195), and by grants from the National Institute on Aging grants (R01-AG016495, R01-AG008122) and the National Institute of Neurological Disorders and Stroke (R01-NS017950).

Systems pharmacology-based approach to investigate the mechanisms of Danggui-Shaoyao-san prescription for treatment of Alzheimer\u2019s disease

BackgroundAlzheimer’s disease (AD) is the most common cause of dementia in the elderly, characterized by a progressive and irreversible loss of memory and cognitive abilities. Currently, the prevention and treatment of AD still remains a huge challenge. As a traditional Chinese medicine (TCM) prescription, Danggui-Shaoyao-san decoction (DSS) has been demonstrated to be effective for alleviating AD symptoms in animal experiments and clinical applications. However, due to the complex components and biological actions, its underlying molecular mechanism and effective substances are not yet fully elucidated.MethodsIn this study, we firstly systematically reviewed and summarized the molecular effects of DSS against AD based on current literatures of in vivo studies. Furthermore, an integrated systems pharmacology framework was proposed to explore the novel anti-AD mechanisms of DSS and identify the main active components. We further developed a network-based predictive model for identifying the active anti-AD components of DSS by mapping the high-quality AD disease genes into the global drug-target network.ResultsWe constructed a global drug-target network of DSS consisting 937 unique compounds and 490 targets by incorporating experimental and computationally predicted drug–target interactions (DTIs). Multi-level systems pharmacology analyses revealed that DSS may regulate multiple biological pathways related to AD pathogenesis, such as the oxidative stress and inflammatory reaction processes. We further conducted a network-based statistical model, drug-likeness analysis, human intestinal absorption (HIA) and blood-brain barrier (BBB) penetration prediction to uncover the key ani-AD ingredients in DSS. Finally, we highlighted 9 key ingredients and validated their synergistic role against AD through a subnetwork.ConclusionOverall, this study proposed an integrative systems pharmacology approach to disclose the therapeutic mechanisms of DSS against AD, which also provides novel in silico paradigm for investigating the effective substances of complex TCM prescription.

An analytic framework for conceptualisations of disease: nine structuring questions and how some conceptualisations of Alzheimer\u2019s disease can lead to \u2018diseasisation\u2019

According to the US National Institute on Aging and the Alzheimer’s Association (NIA-AA), Alzheimer’s disease (AD) should be understood as a biological construct. It can be diagnosed based on AD-characteristic biomarkers only, even if AD biomarkers can be present many years before a person experiences any symptoms of AD. The NIA-AA’s conceptualisation of AD radically challenges past AD conceptualisations. This article offers an analytic framework for the clarification and analysis of meanings and effects of conceptualisations of diseases such as that of AD. This framework consists of nine questions that allows us to determine how the conceptualisations of diseases, such as that of AD, link or decouple the following terms to/from each other: screening, diagnosis, pathology, disease (along the lines of what have been labelled as “biological-physiological” or “normative” conceptions of disease in philosophy of medicine), symptoms, and illness. It also includes questions regarding how specific decouplings open up for new categories through which people can understand themselves in new ways, and what spaces of possibilities specific conceptualisations (and their decouplings and linkages) open to. The article shows how specific decouplings/linkages can open up not only for the phenomena of pathologisation but also for a distinct, but related phenomenon here termed as diseasisation.

Assessing what matters most to patients with or at risk for Alzheimer\u2019s and care partners: a qualitative study evaluating symptoms, impacts, and outcomes

BackgroundThe What Matters Most (WMM) study was initiated to evaluate symptoms, AD-related impacts, treatment-related needs, preferences, and priorities among individuals with or at risk for Alzheimer’s disease (AD) and their care partners. The objective of this qualitative study phase was to identify a comprehensive set of concepts of interest that are meaningful to individuals across the AD continuum.MethodsInterviews were conducted with 60 clinically referred individuals and care partners across 5 AD stages (n = 12 each): group 1 (non-clinically impaired individuals with AD pathology), group 2 (individuals with mild cognitive impairment and AD pathology), group 3 (individuals with mild AD), group 4 (individuals with moderate AD and their care partners), and group 5 (care partners of individuals with severe AD). Interviews were conducted by experienced interviewers, audio-recorded, and transcribed. Dominant trends were identified in each interview and compared across subsequent interviews to generate themes or patterns in descriptions of AD symptoms, impacts, and desired treatment outcomes.ResultsAll participants endorsed current issues related to memory; nearly all participants (n = 55; 92%) across the five groups endorsed symptoms related to communication and language. Groups 1–3 reported an impact on mood/emotions (n = 23; 64%) and a decrease in social activities or outgoingness (n = 17; 47%). Current and future concerns reported by the overall sample included memory (n = 48; 80%), dependence (n = 40; 67%), and “other” concerns (n = 33; 55.0%) (e.g., uncertainty about the future, burdening others). The most desired AD treatment outcomes were improvement or restoration of memory (n = 40; 67%) and stopping AD progression (n = 35; 58.3%). Group-level differences were observed in the symptoms, impacts, and desired treatment outcomes among patients and care partners across the AD continuum.ConclusionsCognitive functioning issues—particularly in memory and communication—are present even in preclinical and early-stage AD, including among those without a formal AD diagnosis. While the impacts of AD vary across the disease-severity spectrum, improved memory and disease modification were treatment outcomes considered most important to participants across all 5 AD stages. Neuropsychological assessments traditionally used in AD clinical trials may not evaluate the often-subtle concepts that are important to patients and care partners. Results from this study will inform the second phase of the WMM project—a quantitative study to elicit the relative importance of these concepts of interest to people at risk for and living with AD and their care partners.

A Randomized Double-blind Study on the Efficacy of 20% VCO Cream versus a Commercial Emollient for Atopic Dermatitis in Children

Objective. To assess the effects of a formulated 20% VCO cream on symptoms of atopic dermatitis in children relative to a commercial emollient with skin barrier protective property indicated for dry, itchy skin. Methods. In a randomized, double-blind, pilot study, pediatric patients with atopic dermatitis according to the modified Hanifin and Rajka criteria were enrolled and assigned to use either formulated VCO cream or commercial emollient. Treatments were applied twice daily for four (4) weeks. Outcome measures were investigator- and patientassessed clinical efficacy based on Severity Scoring of Atopic Dermatitis (SCORAD) severity index, and incidences of documented adverse events.Results. Twenty-nine patients were recruited in the study and in an intention-to-treat analysis, mean SCORAD indices were reduced by 41.79% and 29.77% in the VCO cream group and commercial emollient group, respectively. Both study groups showed significant reduction in the mean subjective SCORAD index relating to pruritus and sleep loss. Mean objective SCORAD index, based on intensity items and total surface with eczema, was also significantly improved in the VCO cream group after four weeks of product usage. The study products were generally well-tolerated, with minor adverse events reported for the VCO cream group. Conclusion. Results of the study suggest that application of VCO at 20% in a cream formulation is more effective than the tested commercial emollient in alleviating symptoms of AD in children.

An agent-based model to investigate microbial initiation of Alzheimer\u2019s via the olfactory system

BackgroundAlzheimer’s disease (AD) is a degenerative brain disease. A novel agent-based modelling framework was developed in NetLogo 3D to provide fundamental insights into the potential mechanisms by which a microbe (eg. Chlamydia pneumoniae) may play a role in late-onset AD. The objective of our initial model is to simulate one possible spatial and temporal pathway of bacterial propagation via the olfactory system, which may then lead to AD symptoms. The model maps the bacteria infecting cells from the nasal cavity and the olfactory epithelium, through the olfactory bulb and into the olfactory cortex and hippocampus regions of the brain.ResultsBased on the set of biological rules, simulated randomized infection by the microbe led to the formation of beta-amyloid (Aβ) plaque and neurofibrillary (NF) tangles as well as caused immune responses. Our initial simulations demonstrated that breathing in C. pneumoniae can result in infection propagation and significant buildup of Aβ plaque and NF tangles in the olfactory cortex and hippocampus. Our model also indicated how mucosal and neural immunity can play a significant role in the pathway considered. Lower immunities, correlated with elderly individuals, had quicker and more Aβ plaque and NF tangle formation counts. In contrast, higher immunities, correlated with younger individuals, demonstrated little to no such formation.ConclusionThe modelling framework provides an organized visual representation of how AD progression may occur via the olfactory system to better understand disease pathogenesis. The model confirms current conclusions in available research but can be easily adjusted to match future evidence and be used by researchers for their own individual purposes. The goal of our initial model is to ultimately guide further hypothesis refinement and experimental testing to better understand the dynamic system interactions present in the etiology and pathogenesis of AD.

Transgenic Mice Overexpressing Human STIM2 and ORAI1 in Neurons Exhibit Changes in Behavior and Calcium Homeostasis but Show No Signs of Neurodegeneration.

The maintenance of proper cytosolic Ca2+ level is crucial for neuronal survival, and dysregulation of Ca2+ homeostasis is found in a variety of neurological disorders, including Alzheimer’s disease. According to the “Ca2+ hypothesis of aging”, Ca2+ disturbances precede the onset of AD symptoms and lead to neurodegeneration. STIM and ORAI proteins are involved in neuronal physiological and pathological processes as essential components of the store-operated Ca2+ entry. Our previous data suggested that overexpression of STIM2 and ORAI1 might increase basal neuronal cytosolic Ca2+ level. We generated double transgenic mice overexpressing these two genes in neurons, expecting that the increased basal Ca2+ concentration will lead to premature neurodegeneration. We observed changes in Ca2+ homeostasis and electrophysiological properties in acute brain slices of STIM2/ORAI1 neurons. However, we did not observe any augmentation of neurodegenerative processes, as tested by Fluoro-Jade® C staining and assessment of amyloidogenesis. The battery of behavioral tests did not show any signs of accelerated aging. We conclude that changes of calcium homeostasis induced by overexpression of STIM2 and ORAI1 had no substantial adverse effects on neurons and did not lead to early neurodegeneration.

MiR-22-3p Regulates Amyloid β Deposit in Mice Model of Alzheimer's Disease by Targeting Mitogen-activated Protein Kinase 14.

Morris water maze test was performed to test the spatial memory. Quantitative polymerase chain reaction (qPCR) was used to assess the expression level of miR-22-3p. The enzymelinked immunosorbent assay (ELISA) was used to assess the levels of Aβ40 and Aβ42. Immunoblotting analysis was performed to detect the protein expression levels of amyloid precursor protein (APP), mitogen-activated protein kinase 14 (MAPK14) and beta-site Amyloid precursor protein Cleaving Enzyme 1 (BACE1). Luciferase assay was used to identify the interaction between miR- 22-3p and MAPK14. The tetrazolium dye (MTT) colorimetric assay was used to test the influence of miR-22-3p overexpression on cell viability. Flow cytometry analysis was performed to evaluate the effect of miR-22-3p overexpression on cell apoptosis. Morris water maze test showed that mice model of AD had impaired spatial memory, which was able to be ameliorated by miR-22-3p overexpression. Immunoblotting analysis revealed that the protein expression levels of APP, MAPK14 and BACE1 were enhanced in AD model, which could be prevented by miR-22-3p overexpression. ELISA showed that Aβ40 and Aβ42 levels were dramatically increased in AD model, which were inhibited by miR-22-3p overexpression. Luciferase assay and immunoblotting analysis indicated that miR-22-3p targeted and regulated MAPK14 expression. MiR-22-3p overexpression reduced Aβ deposit and alleviated AD symptoms by targeting and regulating MAPK14 expression, which ameliorated AD symptoms.

The Trial-Ready Cohort for Preclinical and Prodromal Alzheimer\u2019s Disease (TRC-PAD): Experience from the First 3 Years

BackgroundThe Trial-Ready Cohort for Preclinical and Prodromal Alzheimer’s disease (TRC-PAD) aims to accelerate enrollment for Alzheimer’s disease (AD) clinical trials by remotely identifying and tracking individuals who are at high risk for developing symptoms of AD, and referring these individuals to in-person cognitive and biomarker evaluation with the purpose of engaging them in clinical trials. A risk algorithm using statistical modeling to predict brain amyloidosis will be refined as TRC-PAD advances with a maturing data set.ObjectivesTo provide a summary of the steps taken to build this Trial-Ready cohort (TRC) and share results of the first 3 years of enrollment into the program.DesignParticipants are remotely enrolled in the Alzheimer Prevention Trials (APT) Webstudy with quarterly assessments, and through an algorithm identified as potentially at high risk, referred to clinical sites for biomarker confirmation, and enrolled into the TRC.SettingBoth an online study and in-clinic non-interventional cohort study.ParticipantsAPT Webstudy participants are aged 50 or older, with an interest in participation in AD therapeutic trials. TRC participants must have a study partner, stable medical condition, and elevated brain amyloid, as measured by amyloid positron emission tomography or cerebrospinal fluid analysis. Additional risk assessments include apolipoprotein E genotyping.MeasurementsIn the APT Webstudy, participants complete the Cognitive Function Index and Cogstate Brief Battery. The TRC includes the Preclinical Alzheimer’s Cognitive Composite, comprised of the Free and Cued Selective Reminding Test, the Delayed Paragraph Recall score on the Logical Memory IIa test from the Wechsler Memory Scale, the Digit-Symbol Substitution test from the Wechsler Adult Intelligence Scale-Revised, and the Mini Mental State Examination total score (1).ResultsDuring the first 3 years of this program, the APT Webstudy has 30,650 consented participants, with 23 sites approved for in person screening, 112 participants have been referred for in-clinic screening visits with eighteen enrolled to the TRC. The majority of participants consented to APT Webstudy have a family history of AD (62%), identify as Caucasian (92.5%), have over twelve years of formal education (85%), and are women (73%). Follow up rates for the first quarterly assessment were 38.2% with 29.5% completing the follow up Cogstate Battery.ConclusionsAfter successfully designing and implementing this program, the study team’s priority is to improve diversity of participants both in the APT Webstudy and TRC, to continue enrollment into the TRC to our target of 2,000, and to improve longitudinal retention, while beginning the process of referring TRC participants into clinical trials.

New Alzheimer\u2019s disease model mouse specialized for analyzing the function and toxicity of intraneuronal Amyloid \u03b2 oligomers

Oligomers of intracellular amyloid β protein (Aβ) are strongly cytotoxic and play crucial roles in synaptic transmission and cognitive function in Alzheimer’s disease (AD). However, there is currently no AD model mouse in which to specifically analyze the function of Aβ oligomers only. We have now developed a novel AD model mouse, an Aβ-GFP transgenic mouse (Aβ-GFP Tg), that expresses the GFP-fused human Aβ1-42 protein, which forms only Aβ oligomers within neurons throughout their life. The fusion proteins are expressed mainly in the hippocampal CA1-CA2 region and cerebral cortex, and are not secreted extracellularly. The Aβ-GFP Tg mice exhibit increased tau phosphorylation, altered spine morphology, decreased expressions of the GluN2B receptor and neuroligin in synaptic regions, attenuated hippocampal long-term potentiation, and impaired object recognition memory compared with non-Tg littermates. Interestingly, these dysfunctions have already appeared in 2–3-months-old animals. The Aβ-GFP fusion protein is bioactive and highly toxic, and induces the similar synaptic dysfunctions as the naturally generated Aβ oligomer derived from postmortem AD patient brains and synthetic Aβ oligomers. Thus, Aβ-GFP Tg mouse is a new tool specialized to analyze the function of Aβ oligomers in vivo and to find subtle changes in synapses in early symptoms of AD.

Familial Alzheimer\u2019s Disease and Recessive Modifiers

Alzheimer’s disease (AD) is progressive brain disorder that affects ~ 50 million people worldwide and has no current effective treatment. AD age of onset (ADAOO) has shown to be critical for the identification of genes that modify the appearance of AD signs and symptoms in a specific population. We clinically characterized and whole-exome genotyped 71 individuals with AD from the Paisa genetic isolate, segregating the (PSEN1) E280A dominant fully penetrant mutation, and analyzed the potential recessive effects of ~ 50,000 common functional genomic variants to the ADAOO. Standard quality control and filtering procedures were applied, and recessive single- and multi-locus linear mixed-effects models were used. We identified genetic variants in the SLC9C1, CSN1S1, and LOXL4 acting recessively to delay ADAOO up to ~ 11, ~ 6, and ~ 9 years on average, respectively. In contrast, the CC recessive genotype in marker DHRS4L2-rs2273946 accelerates ADAOO by ~ 8 years. This study, reports new recessive variants modifying ADAOO in PSEN1 E280A mutation carriers. This set of genes are implicated in important biological processes and molecular functions commonly affected by genes associated with the etiology of AD such as APP, APOE, and CLU. Future functional studies using modern techniques such as induced pluripotent stem cells will allow a better understanding of the over expression and down regulation of these recessive modifier variants and hence the pathogenesis of AD. These results are important for prediction of AD and ultimately, substantial to develop new therapeutic strategies for individuals at risk or affected by AD.

Structure-based screening and molecular dynamics simulation studies for the identification of potential acetylcholinesterase inhibitors

ABSTRACTAlzheimer’s disease (AD) is an irreversible, progressive neurodegenerative disease characterised by the appearance of amyloid β plaques and neurofibrillary tangles in the brain. The loss of cholinergic neurons is considered to be one of the contributing factors for cognitive and memory deficits in the disease. Donepezil, the most successful and prescribed drug to treat the symptoms of AD, is acetylcholinesterase (AChE) inhibitor that improves the memory and brain’s cognitive functions. In this study, the pharmacophoric features of donepezil were mapped from its cocrystal with AChE and were used to screen the Zinc15 database. The obtained hits were subjected to molecular properties and PAINS filter. The homology modelling and molecular dynamics (MD) were performed to prepare selected AChE protein model (PDB id 4EY7) for advanced studies. The virtual screening and precision docking led to the identification of five compounds. The ADMET property prediction and free energy calculations were carried out to obtain three final compounds. The Alanine scanning and MD study of the compounds viz. ZINC000013719534, ZINC000035551243 and ZINC000035596918 produced stable complexes of the ligands. The identified virtual leads have the potential for better AChE inhibition.HighlightsPharmacophore mapping of donepezil was developed from PDB id 4EY7.Pharmacophore-based screening yielded 601 compounds with RMSD < 0.5 Å.PAINS and Drug likeliness filtration resulted in 199 compounds for further virtual screening and precision docking studies.Free binding energy and ADMET studies provided three active compounds.The molecular dynamics study indicated that the compounds ZINC000013719534, ZINC000035551243 and ZINC000035596918 formed stable interactions with the protein.

Exploring content and psychometric validity of newly developed assessment tools for itch and skin pain in atopic dermatitis

BackgroundAtopic dermatitis (AD) is a common skin disorder characterized by chronic inflammation, altered skin barrier function, and inflammatory cell skin infiltration that decreases health-related quality of life (HRQoL). The study objective was to understand the patient perspective of AD burden and determine suitable patient-reported outcome (PRO) measures.MethodsThis mixed methods study involved the collection of qualitative and quantitative information from adults (≥ 18 years old) and adolescents (12 – 17 years old) with clinician-confirmed AD regarding their experiences of AD symptoms and its impact on HRQoL. The first part of the study included three stages: in-person concept elicitation (CE) interviews, a 2-week daily electronic diary (eDiary) study, and in-person cognitive debriefing (CD) interviews. An Itch numeric rating scale (NRS) (v1.0) and a Skin Pain NRS (v1.0) evaluation during CD interviews required participants to think about their ‘worst’ itch and ‘worst’ skin pain in the past 24 h. Other PRO measures allowed for psychometric testing. The second part of the study involved telephone-depth interviews (TDIs) and qualitative feedback from participants who had not participated in the CD interviews. Qualitative data were thematically analyzed. Psychometric evaluation of NRS measures was performed using eDiary data.ResultsIn the CE interviews, itch and/or itching and skin pain were the most prevalent symptoms consistently discussed by participants. Both NRS measures demonstrated strong psychometric reliability and were applicable across ages with suitable concurrent validity. During the CD interviews, some participants focused their answers on their ‘average’ itch/itching in the past 24 h, rather than their ‘worst’ itch. Some participants answered the Skin Pain NRS thinking about general pain or other types of pain, rather than skin pain specifically. Consequently, modifications to both measures addressed these issues and re-tested as paper-and-pen versions in subsequent TDIs. Itch NRS (v2.0) modifications helped participants focus on their worst itching. Most participants preferred Skin Pain NRS v2.0b, which included skin pain descriptors.ConclusionsItching and skin pain are the most important and relevant AD symptoms. The Itch NRS (v2.0) and Skin Pain NRS (v2.0b) appear to be appropriate endpoints for the assessment of itching and skin pain severity for clinical trials with adults and adolescents with AD.

Bee Venom Alleviates Atopic Dermatitis Symptoms through the Upregulation of Decay-Accelerating Factor (DAF/CD55).

Bee venom (BV)—a complex mixture of peptides and toxic proteins including phospholipase A2 and melittin—promotes blood clotting. In this study, we investigated the anti-atopic properties of BV and the mechanism associated with its regulation of the complement system. BV treatment upregulated the mRNA and protein levels of CD55 in THP-1 cells. Further experiments revealed that the phosphorylation of ERK was associated with upregulation of CD55. A complement-dependent cytotoxicity assay and a bacteria-killing assay showed that BV inactivated the complement system through the induction of CD55. The serum levels of C3 convertase (C3C) and Membrane attack complex (MAC) increased, while CD55 decreased in mice with AD-like lesions from DNCB treatment. However, the levels were inverted when the AD-like mice were treated with BV using subcutaneous injection, and we observed that the AD symptoms were alleviated. BV is often used to treat AD but its mechanism has not been elucidated. Here, we suggest that BV alleviates AD through the inactivation of the complement system, especially by the induction of CD55.

Reduced Baroreflex Function in the STZ‐Induced Rat Model of Alzheimer's Disease

BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder causing multiple autonomic conditions including cardiovascular impairments. The inability to maintain blood pressure via baroreflex regulation is up to 5.6 times more prevalent in AD and patients present most commonly with orthostatic hypotension. This study aimed to assess the influence of AD on autonomic regulation of blood pressure using the streptozotocin (STZ)‐induced AD rat model, which mimics many hallmark symptoms of sporadic AD in humans.MethodsMale Sprague‐Dawley rats (345 ± 18 g) were randomly divided into two groups and subjected to intracerebroventricular injection of either vehicle (citrate buffer, CTL) or 2 mg/kg STZ in citrate buffer. After two weeks, memory performance (Morris water maze, MWM), baroreflex function (via femoral cannulation), and heart rate variability (HRV) were evaluated.ResultsMWM verified memory impairment in STZ‐treated rats when compared to CTL (p≤0.01). Analysis of baroreflex function in anesthetized rats revealed a significant impairment in the STZ group when compared to CTL. Particularly, STZ‐treated rats were unable to increase compensatory HR at lower blood pressures (at 50 mmHg: CTL, n=5, 369 ± 13 bpm vs. STZ, n=7, 315 ± 14 bpm; p≤0.05). STZ rats also had a lower baroreflex gain indicating reduced sensitivity to blood pressure fluctuations (p≤0.001). Additionally, recordings of splanchnic sympathetic nerve activity (SSNA) in a subset of rats identified reduced nerve activity during low blood pressure in the STZ group (∫SSNA at 50 mmHg: CTL, n=3, 0.3 ± 0.03 mV.s vs. STZ, n=3, 0.17 ± 0.02 mV.s; p≤0.05). There was no difference between groups at higher blood pressures (150 mmHg). Within the STZ group, HRV was significantly increased only during PE infusion (SDNN, p≤0.05; SD1, p≤0.05; SD2, p≤0.05). Interestingly, the change in HR following blockage of sympathetic or parasympathetic input was not different between groups. Also intrinsic HR and the blood pressure change to ganglionic blockage were similar between STZ and CTL rats.ConclusionsOur study provides the first insight into the pathological influence of AD on baroreflex function. We showed that STZ rats exhibit lower HR and reduced sympathetic output in response to low blood pressure. These results provide the basis for identifying the mechanism behind orthostatic hypotension in AD patients.Support or Funding InformationATSU biomedical grant (JCE) and seed money (TDO)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.