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27 Sep 2020 at 01:30
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Bibliography on: Alzheimer Disease — Current Literature


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RJR: Recommended Bibliography 27 Sep 2020 at 01:30 Created: 

Alzheimer Disease — Current Literature

Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills, and eventually the ability to carry out the simplest tasks. In most people with Alzheimer's, symptoms first appear in their mid-60s. Alzheimer's is the most common cause of dementia among older adults. Dementia is the loss of cognitive functioning — thinking, remembering, and reasoning — and behavioral abilities to such an extent that it interferes with a person's daily life and activities. Dementia ranges in severity from the mildest stage, when it is just beginning to affect a person's functioning, to the most severe stage, when the person must depend completely on others for basic activities of daily living. Scientists don't yet fully understand what causes Alzheimer's disease in most people. There is a genetic component to some cases of early-onset Alzheimer's disease. Late-onset Alzheimer's arises from a complex series of brain changes that occur over decades. The causes probably include a combination of genetic, environmental, and lifestyle factors. The importance of any one of these factors in increasing or decreasing the risk of developing Alzheimer's may differ from person to person. This bibliography runs a generic query on "Alzheimer" and then restricts the results to papers published in or after 2017.

Created with PubMed® Query: alzheimer[TIAB] and (2017[PDAT] OR [2018[PDAT] OR 2019[PDAT] OR 2020[PDAT]) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)


RevDate: 2020-09-25

Abdel-Haq H (2020)

The Potential of Liquid Biopsy of the Brain Using Blood Extracellular Vesicles: The First Step Toward Effective Neuroprotection Against Neurodegenerative Diseases.

Molecular diagnosis & therapy pii:10.1007/s40291-020-00493-4 [Epub ahead of print].

Early diagnosis and biomarker-based ante-mortem tests are essential in efforts against the development of neurodegenerative diseases and can be considered primary neuroprotective measures. Blood is the ideal biofluid for a routine ante-mortem screening test. However, biomarker discovery in the blood is particularly difficult because of interference from factors both intrinsic and extrinsic to blood with the detection of hallmark neurodegenerative biomarkers, such as the pathological prion protein, amyloid-β, and others. Blood extracellular vesicles (EVs), such as exosomes, are cell-derived vesicles released into the blood from all parts of the body (including the brain and spinal cord). They are an enriched source of neural-derived EVs containing neurodegenerative biomarkers that mirror (in the blood) the condition present in the brain. The feasibility of using, and the reliability of, neural-derived blood EVs (NDBEVs) as a method of diagnosing Alzheimer disease and other neurodegenerative diseases has been assessed in strong proof-of-concept studies. Results from these studies strongly suggest that NDBEVs might represent the right strategy for specific, reliable, and early diagnosis of neurodegenerative diseases. Based on these results, NDBEVs might enable the creation of an ante-mortem blood test (liquid biopsy of the brain) for neurodegenerative diseases. This would enormously accelerate the therapy of neurodegenerative diseases. This review highlights the powerful potential of liquid biopsy of the brain using NDBEVs for early diagnosis and treatment of neurodegenerative diseases, and the challenges and limitations related to the identification of clinically applicable EV (exosomal) biomarkers using blood are discussed.

RevDate: 2020-09-25

Stefano GB, Esch T, Ptacek R, et al (2020)

Dysregulation of Nitric Oxide Signaling in Microglia: Multiple Points of Functional Convergence in the Complex Pathophysiology of Alzheimer Disease.

Medical science monitor : international medical journal of experimental and clinical research, 26:e927739 pii:927739.

Current critical thinking has displaced the elaborated beta amyloid theory as the underlying unitary mechanism of Alzheimer disease (AD) in favor of concerted, long-term disruption or dysregulation of broad-based physiological processes. We present a critical discussion in which a chronic state of systemic proinflammation sustained over the course of several decades and engendered by ongoing metabolic or autoimmune disease is predicted to promote severe disruptions of central neurological processes. Specifically, long-term functional rundown of microglial-mediated phagocytic activity in concert with aberrant expression and cellular deposition of beta amyloid and tau protein facilitates formation of senile plaques and neurofibrillary tangles. Within this functional context, we hypothesize that early initiation events in the pathophysiology of AD may operationally involve a convergence of dysregulated peripheral and central constitutive nitric oxide signaling pathways resulting from a chronic state of systemic proinflammation and leading to severely dysfunctional "hyperactivated" microglia.

RevDate: 2020-09-25

Parfenov VA, Zakharov VV, Kabaeva AR, et al (2020)

Subjective cognitive decline as a predictor of future cognitive decline: a systematic review.

Dementia & neuropsychologia, 14(3):248-257.

Over 44 million people suffer from dementia around the world. Researchers estimated that there will be 48.1 million people with dementia by 2020 and 90.3 million by 2040. In addition to dementia, mild cognitive impairment (MCI) and subjective cognitive decline (SCD) relate to cognitive impairment. It has been established that MCI precedes dementia, however the significance of SCD is still unclear. Recent studies suggest that SCD could be a risk factor for objective cognitive impairment. SCD is defined as а self-estimated decline in cognitive capacity in comparison to an individual's previous level of functioning, which cannot be determined by neuropsychological tests.

Objectives: To perform a systematic review of prospective longitudinal cohort studies that assessed the risk of MCI and dementia among people with SCD.

Methods: A search was carried out for all available peer-reviewed articles in English related to SCD in PubMed and PsychINFO databases from database initiation through January 2020. The keywords used for the search were 'subjective cognitive (or memory) impairment (or decline or complaints)'. Three authors separately determined the inclusion or exclusion of all articles retrieved for full-text evaluation.

Results: The chance of progression to dementia in the SCD group was 2.17 (95% confidence interval [95%CI] 1.53‒3.07; p<0.05) compared to normal aging. Furthermore, the SCD group was 2.15 times more likely to progress to MCI than the group without SCD (95%CI 1.39‒3.30; p=0.005).

Conclusions: SCD might precede cognitive impairment, however, more detailed longitudinal studies should be conducted.

RevDate: 2020-09-25

Allegri RF (2020)

Moving from neurodegenerative dementias, to cognitive proteinopathies, replacing "where" by "what"….

Dementia & neuropsychologia, 14(3):237-242.

Neurodegenerative dementias have been described based on their phenotype, in relation to selective degeneration occurring in a particular neuroanatomical system. More recently however, the term proteinopathy has been introduced to describe diseases in which one or more altered proteins can be detected. Neurodegenerative diseases can be produced by more than one abnormal protein and each proteinopathy can determine different clinical phenotypes. Specific biomarkers have now been linked to certain molecular pathologies in live patients. In 2016, a new biomarker-based classification, currently only approved for research in Alzheimer's disease, was introduced. It is based on the evaluation three biomarkers: amyloid (A) detected on amyloid-PET or amyloid- beta 42 assay in CSF; tau (T) measured in CSF as phosphorylated tau or on tau PET imaging; and neuronal injury/neurodegeneration (N), detected by total T-tau in CSF, FDG PET hypometabolism and on MRI brain scan. Results of clinical research using the ATN biomarkers at FLENI, a Neurological Institute in Buenos Aires, Argentina have, since 2011, contributed to ongoing efforts to move away from the concept of neurodegenerative dementias and more towards one of cognitive proteinopathies. Today, clinical diagnosis in dementia can only tell us "where" abnormal tissue is found but not "what" molecular mechanisms are involved.

RevDate: 2020-09-25

Agrawal I, S Jha (2020)

Mitochondrial Dysfunction and Alzheimer's Disease: Role of Microglia.

Frontiers in aging neuroscience, 12:252.

In 1907, Alois Alzheimer observed, as he quoted, development of "numerous fibers" and "adipose saccules" in the brain of his diseased patient Auguste Deter. The neurodegenerative disease became known as Alzheimer's disease (AD) and is the most common cause of dementia worldwide. AD normally develops with aging and is mostly initiated because of the imbalance between the formation and clearance of amyloid-β (Aβ). Formation of neurofibrillary tangles (NFTs) of hyperphosphorylated tau is another hallmark of AD. Neuroinflammation plays a significant role in the development and pathology of AD. This chapter explores the role of mitochondrial dysfunction in microglia in case of AD. Mitochondrial oxidative stress in microglia has been linked to the development of AD. Elevated generation of reactive oxygen species (ROS) and loss of mitochondrial membrane potential through various mechanisms have been observed in AD. Aβ interacts with microglial receptors, such as triggering receptor expressed in myeloid cells 2 (TREM2), activating downstream pathways causing mitochondrial damage and aggravating inflammation and cytotoxicity. Fibrillar Aβ activates nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in microglia leading to elevated induction of mitochondrial ROS which further causes neurotoxicity. Elevated ROS in microglia causes activation of inflammatory and cell death pathways. Production of ATP, regulation of mitochondrial health, autophagy, and mitophagy in microglia play significant roles in the AD pathology. Understanding microglial physiology and mitochondrial dysfunction will enable better therapeutic interventions.

RevDate: 2020-09-25

Rong X, Xiang L, Li Y, et al (2020)

Chronic Periodontitis and Alzheimer Disease: A Putative Link of Serum Proteins Identification by 2D-DIGE Proteomics.

Frontiers in aging neuroscience, 12:248.

Increasing evidence indicates Chronic Periodontitis (CP) is a comorbidity of Alzheimer's disease (AD), which is the most common form of age-related dementia, and for the latter, effective diagnostic and treatment strategies are lacking. Although inflammation is present in both diseases, the exact mechanisms and cross-links between CP and AD are poorly understood; and a direct association between the two has not been reported. This study aimed to identify a direct serum proteins link between AD and CP. Two-dimensional differential in-gel electrophoresis was employed to analyze serum samples from 12 CP patients and 12 age-matched controls. Furthermore, to determine the molecular link between CP and AD, neuroblastoma SK-N-SH APPwt cells were treated with 1 μg/ml of lipopolysaccharide from Porphyromonas gingivalis (P.g-LPS). Ten differentially expressed proteins were identified in CP patients. Among them, nine proteins were up-regulated, and one protein was down-regulated. Of the 10 differentially expressed proteins, five proteins were reportedly involved in the pathology of AD: Cofilin-2, Cathepsin B, Clusterin, Triosephosphate isomerase, and inter-alpha-trypsin inhibitor heavy chain H4 (ITI-H4). Western blotting indicated significantly higher expression of Cofilin-2, Cathepsin B, and Clusterin and lower expression of ITI-H4 in the CP group than in the Control group. The serum concentration of Cathepsin B has a good correlation with MMSE scores. Moreover, the protein level of Cathepsin B (but not that of ADAM10 and BACE1) increased significantly along with a prominent increase in Aβ1-40 and Aβ1-42 in the cell lysates of P.g-LPS-treated SK-N-SH APPwt cells. Cathepsin B inhibition resulted in a sharp decrease in Aβ1-40 and Aβ1-42 in the cell lysates. Furthermore, TNF-α was one of the most important inflammatory cytokines for the P.g-LPS-induced Cathepsin B upregulation in SK-N-SH APPwt cells. These results show that CP and AD share an association, while Cathepsin B could be a key link between the two diseases. The discovery of the identical serum proteins provides a potential mechanism underlying the increased risk of AD in CP patients, which could be critical for elucidating the pathophysiology of AD.

RevDate: 2020-09-25

Hanes J, Kovac A, Kvartsberg H, et al (2020)

Evaluation of a novel immunoassay to detect p-Tau Thr127 in the CSF to distinguish Alzheimer disease from other dementias.

Neurology pii:WNL.0000000000010814 [Epub ahead of print].

OBJECTIVE: To investigate whether p-tau T217 assay in cerebrospinal fluid (CSF) can distinguish Alzheimer's disease from other dementias and healthy controls.

METHODS: We developed and validated a novel Simoa immunoassay to detect p-tau T217 in CSF. There was a total of 190 participants from three cohorts with AD (n = 77) and other neurodegenerative diseases (n = 69) as well as healthy subjects (n = 44).

RESULTS: The p-tau T217 assay (cut-off 242 pg/ml) identified AD subjects with accuracy of 90%, with 78% positive predictive value (PPV), 97% negative predictive value (NPV), 93% sensitivity, 88% specificity compared favorably with p-tau T181 ELISA (52 pg/ml) showing 78% accuracy, 58% PPV, 98% NPV, 71% specificity, 97% sensitivity. The assay distinguished AD patients from age-matched healthy subjects (cut-off 163 pg/ml, sensitivity 98%, specificity 93%) similarly to p-tau T181 ELISA (cut-off 60 pg/ml, 96% sensitivity and 86% specificity). In AD patients, we found a strong correlation between p-tau T217-tau and p-tau T181, t-tau and Aβ40 but not with Aβ42.

CONCLUSIONS: This study demonstrates that p-tau T217 displayed better diagnostic accuracy than p-tau T181. The data suggests that the new p-tau T217 assay has a potential as an AD diagnostic test in the clinical evaluation.

CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a CSF immunoassay for p-tau T217 distinguishes AD from other dementias and healthy controls.

RevDate: 2020-09-25

Siddiqui A, Akhtar MS, Shah Z, et al (2020)

Inflammation Drives Alzheimer's Disease: Emphasis on 5-lipoxygenase pathways.

Current neuropharmacology pii:CN-EPUB-110201 [Epub ahead of print].

It is a known fact that inflammation affects several physiological processes, including the functioning of the central nervous system. Additionally, impairment of lipid mechanisms/pathways have been associated with a number of neurodegenerative disorders and Alzheimer's Disease (AD) is one of them. However, much attention has been given to the link between tau and beta-amyloid hypothesis in AD pathogenesis/prognosis. Increasing evidences suggest that biologically active lipid molecules could influence the pathophysiology of AD via different mechanism of inflammation. In this review, we intend to highlight the role of inflammatory responses in the context of AD with the emphasis on biochemical pathways of lipid metabolism enzyme, 5-lipoxygenase (5-LO).

RevDate: 2020-09-25

Sato N (2020)

The Emerging Role of the Apolipoproteins APOE and APOJ in the Interaction Between Diabetes and Alzheimer Disease.

The Journal of clinical endocrinology and metabolism, 105(11):.

RevDate: 2020-09-24

Atsmon R, I Slutsky (2020)

The Sound of Silence: Hidden Responses of Neural Circuits to Alzheimer-Linked Mutations.

Neuron, 107(6):990-991.

Dysfunctions of cortico-hippocampal circuits represent a hallmark of Alzheimer's disease. In this issue of Neuron, Jun et al. illuminate the spatial coding failures by familial Alzheimer's disease mutations that may underlie the progressive decline in spatial mnemonic processing.

RevDate: 2020-09-24

Anstey KJ, Cherbuin N, Kim S, et al (2020)

An Internet-Based Intervention Augmented With a Diet and Physical Activity Consultation to Decrease the Risk of Dementia in At-Risk Adults in a Primary Care Setting: Pragmatic Randomized Controlled Trial.

Journal of medical Internet research, 22(9):e19431 pii:v22i9e19431.

BACKGROUND: There is a need to develop interventions to reduce the risk of dementia in the community by addressing lifestyle factors and chronic diseases over the adult life course.

OBJECTIVE: This study aims to evaluate a multidomain dementia risk reduction intervention, Body Brain Life in General Practice (BBL-GP), targeting at-risk adults in primary care.

METHODS: A pragmatic, parallel, three-arm randomized trial involving 125 adults aged 18 years or older (86/125, 68.8% female) with a BMI of ≥25 kg/m2 or a chronic health condition recruited from general practices was conducted. The arms included (1) BBL-GP, a web-based intervention augmented with an in-person diet and physical activity consultation; (2) a single clinician-led group, Lifestyle Modification Program (LMP); and (3) a web-based control. The primary outcome was the Australian National University Alzheimer Disease Risk Index Short Form (ANU-ADRI-SF).

RESULTS: Baseline assessments were conducted on 128 participants. A total of 125 participants were randomized to 3 groups (BBL-GP=42, LMP=41, and control=42). At immediate, week 18, week 36, and week 62 follow-ups, the completion rates were 43% (18/42), 57% (24/42), 48% (20/42), and 48% (20/42), respectively, for the BBL-GP group; 71% (29/41), 68% (28/41), 68% (28/41), and 51% (21/41), respectively, for the LMP group; and 62% (26/42), 69% (29/42), 60% (25/42), and 60% (25/42), respectively, for the control group. The primary outcome of the ANU-ADRI-SF score was lower for the BBL-GP group than the control group at all follow-ups. These comparisons were all significant at the 5% level for estimates adjusted for baseline differences (immediate: difference in means -3.86, 95% CI -6.81 to -0.90, P=.01; week 18: difference in means -4.05, 95% CI -6.81 to -1.28, P<.001; week 36: difference in means -4.99, 95% CI -8.04 to -1.94, P<.001; and week 62: difference in means -4.62, 95% CI -7.62 to -1.62, P<.001).

CONCLUSIONS: A web-based multidomain dementia risk reduction program augmented with allied health consultations administered within the general practice context can reduce dementia risk exposure for at least 15 months. This study was limited by a small sample size, and replication on a larger sample with longer follow-up will strengthen the results.

TRIAL REGISTRATION: Australian clinical trials registration number (ACTRN): 12616000868482; https://anzctr.org.au/ACTRN12616000868482.aspx.

RevDate: 2020-09-24

Ortega LV, Aprahamian I, Martinelli JE, et al (2020)

Diagnostic Accuracy of Usual Cognitive Screening Tests Versus Appropriate Tests for Lower Education to Identify Alzheimer Disease.

Journal of geriatric psychiatry and neurology [Epub ahead of print].

INTRODUCTION: The accuracy of commonly used screening tests for Alzheimer's disease (AD) has not been directly compared to those that could be more appropriate for lower schooling.

OBJECTIVE: To compare the diagnostic accuracy of usual screening tests for AD with instruments that might be more appropriate for lower schooling among older adults with low or no literacy.

METHODS: The study included a clinical sample of 117 elderly outpatients from a Geriatric Clinic classified as literate controls (n = 39), illiterate controls (n = 30), literate AD (n = 30) and illiterate AD (n = 18). The tests were compared as follows: Black and White versus Colored Figure Memory Test; Clock Drawing Test versus Clock Reading Test; Verbal Fluency (VF) animal versus grocery category; CERAD Constructional Praxis versus Stick Design Test.

RESULTS: The means of literate and illiterate controls did not differ in the Black and White Figure Memory Test (immediate recall), Colored Figure Memory Test (delayed recall), Clock Reading Test and VF animals and grocery categories. The means of the clinical groups (controls versus AD), in the 2 schooling levels, differed significantly in most of the tests, except for the CERAD Constructive Praxis and the Stick Design Test. Diagnostic accuracy was not significantly different between the compared tests.

CONCLUSION: Commonly used screening tests for AD were as accurate as those expected to overcome the education bias in a sample of older adults with lower or no education.

RevDate: 2020-09-24

Iwaloye O, Elekofehinti OO, Oluwarotimi EA, et al (2020)

Insight into glycogen synthase kinase-3β inhibitory activity of phyto-constituents from Melissa officinalis: in silico studies.

In silico pharmacology, 8(1):2 pii:54.

Over activity of Glycogen synthase kinase-3β (GSK-3β), a serine/threonine-protein kinase has been implicated in a number of diseases including stroke, type II diabetes and Alzheimer disease (AD). This study aimed to find novel inhibitors of GSK-3β from phyto-constituents of Melissa officinalis with the aid of computational analysis. Molecular docking, induced-fit docking (IFD), calculation of binding free energy via the MM-GBSA approach and Lipinski's rule of five (RO5) were employed to filter the compounds and determine their druggability. Most importantly, the compounds pIC50 were predicted by machine learning-based model generated by AutoQSAR algorithm. The generated model was validated to affirm its predictive model. The best model obtained was Model kpls_desc_38 (R2 = 0.8467 and Q2 = 0.8069), and this external validated model was utilized to predict the bioactivities of the lead compounds. While a number of characterized compounds from Melissa officinalis showed better docking score, binding free energy alongside adherence to RO5 than co-cystallized ligand, only three compounds (salvianolic acid C, ellagic acid and naringenin) showed more satisfactory pIC50. The results obtained in this study can be useful to design potent inhibitors of GSK-3β.

RevDate: 2020-09-24

Jia F, Li Y, Li M, et al (2020)

Subjective Cognitive Decline, Cognitive Reserve Indicators, and the Incidence of Dementia.

Journal of the American Medical Directors Association pii:S1525-8610(20)30695-2 [Epub ahead of print].

OBJECTIVE: Both cognitive reserve and subjective cognitive decline are closely related to the risk of dementia. We investigated whether cognitive reserve can modify the risk of dementia developing from subjective cognitive decline.

DESIGN: Longitudinal population-based study.

SETTING AND PARTICIPANTS: The prospective study analyzed data from 2099 participants aged 65 or over from the Cognitive Function and Ageing Study-Wales (CFAS-Wales).

METHODS: Dementia was ascertained through the comprehensive judgment symptoms of geriatric mental state automated geriatric examination for computer assisted taxonomy (GMS-AGECAT). Subjective cognitive decline was evaluated by 2 questions in the baseline interview. Cognitive reserve indicators were derived from 3 previously identified factors: early life education, mid-life occupational complexity, and late-life cognitive activities. We used logistic regression models to estimate dementia risk in relation to subjective cognitive decline and indicators of cognitive reserve. The interaction between subjective cognitive decline and cognitive reserve were evaluated by additive and multiplicative scales.

RESULTS: Baseline subjective cognitive decline and low cognitive reserve significantly increased the risk of dementia, after 2 years of follow-up. There was an additive interaction between subjective cognitive decline and cognitive reserve [the relative excess risk due to interaction = -0.63, 95% confidence interval (CI) = -0.89 to -0.36, P for additive interaction <0.001]. There was no multiplicative interaction between subjective cognitive decline and cognitive reserve indicator (P = .138). Statistically significant association between subjective cognitive decline and dementia was found only in the low-level and medium-level cognitive reserve group (OR = 3.78, 95% CI = 1.50-9.55 and OR = 3.64, 95% CI = 1.09-12.2, respectively), but not in the high-level groups.

CONCLUSION AND IMPLICATIONS: Cognitive reserve attenuated subjective cognitive decline associated risk of developing dementia. This finding suggests the need for greater emphasis on detecting prodromal dementia when older patients having lower cognitive reserve present with subjective cognitive decline.

RevDate: 2020-09-24

Sun K, Jing X, Guo J, et al (2020)

Mitophagy in degenerative joint diseases.

Autophagy [Epub ahead of print].

Mitochondrial dysfunction is involved in aging and multiple degenerative diseases, including intervertebral disc degeneration (IVDD) and osteoarthritis (OA). Thus, the maintenance of mitochondria homeostasis and function is important. Mitophagy, a process that selectively clears damaged or dysfunctional mitochondria through autophagic machinery, functions to maintain mitochondrial quality control and homeostasis. IVDD and OA are similar joint diseases involving the degradation of cartilaginous tissues that are mainly caused by oxidative stress, cell apoptosis and extracellular matrix (ECM) degradation. Over the past decade, accumulating evidence indicates the essential role of mitophagy in the pathogenesis of IVDD and OA. Importantly, strategies by the regulation of mitophagy exert beneficial effects in the pre-clinical experiments. Given the importance and novelty of mitophagy, we provide an overview of mitophagy pathways and discuss the roles of mitophagy in IVDD and OA. We also highlight the potential of targeting mitophagy for the treatment of degenerative joint diseases. Abbreviations: AD: Alzheimer disease; AF: annulus fibrosus; ADORA2A/A2AR: adenosine A2a receptor; AMBRA1: autophagy and beclin 1 regulator 1; BMSCs: bone marrow mesenchymal stem cells; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2/adenovirus E1B interacting protein 3-like; CDH6: cadherin 6; CEP: cartilaginous endplates; circRNA: circular RNA; DNM1L/DRP1: dynamin 1-like; ECM: extracellular matrix; HIF1A: hypoxia inducible factor 1: alpha subunit; IL1B: interleukin 1 beta; IMM: inner mitochondrial membranes; IVDD: intervertebral disc degeneration; MAPK8/JNK: mitogen-activated protein kinase 8; MFN1: mitofusin 1; MFN2: mitofusin 2; MIA: monosodium iodoacetate; RHOT/MIRO: ras homolog family member T; MMP: mitochondrial transmembrane potential; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; NFE2L2: nuclear factor: erythroid 2 like 2; NP: nucleus pulposus; OA: osteoarthritis; OPA1: OPA1: mitochondrial dynamin like GTPase; OPTN: optineurin; PRKN: parkin RBR E3 ubiquitin protein ligase; PD: Parkinson disease; PGAM5: PGAM family member 5; PPARGC1A/PGC-1A: peroxisome proliferator activated receptor: gamma: coactivator 1 alpha; PHF23: PHD finger protein 23; PINK1: PTEN induced putative kinase 1; ROS: reactive oxygen species; SfMSCs: synovial fluid MSCs; SIRT1: sirtuin 1; SIRT2: sirtuin 2; SIRT3: sirtuin 3; SQSTM1/p62: sequestosome 1; TNF: tumor necrosis factor; Ub: ubiquitin; UBL: ubiquitin-like; VDAC: voltage-dependent anion channel.

RevDate: 2020-09-23

Sedighi M, Baluchnejadmojarad T, Fallah S, et al (2020)

The Association Between Circulating Klotho and Dipeptidyl Peptidase-4 Activity and Inflammatory Cytokines in Elderly Patients With Alzheimer Disease.

Basic and clinical neuroscience, 11(3):349-357.

Introduction: Klotho and Dipeptidyl Peptidase-4 (DPP4) are two proteins that modulate inflammatory pathways. We investigated the association between circulating klotho and DPP4 activity and their relationship with inflammatory cytokines, miR-29a, and miR-195 in Alzheimer Disease (AD).

Methods: This study was conducted on 16 AD patients and 16 healthy age-matched controls. Plasma levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β, interleukin-6 (IL-6), klotho, and DPP4 were measured by enzyme-linked immunosorbent assay. Plasma expression of miR-29a and miR-195 were also measured and compared by a real-time polymerase chain reaction.

Results: There was a significant increase in TNF-α (p=0.006), IL-1β (p=0.012), and IL-6 (p=0.012) levels in the AD subjects compared with controls. Also, we found a decrease in plasma levels of klotho and an increase in plasma levels of DPP4 in the AD group that was not significant compared with the controls. Lower expression of miR-29a (P=0.009) and higher expression of miR-195 (P=0.003) were observed in the AD group that was significant than controls. Further analysis showed a negative correlation between klotho and plasma levels of IL-6 (r=-0.58, p=0.01). Also, there was a positive correlation between plasma DPP4 activity and TNF-α levels (r=0.50, P=0.04) and IL-1β (r=0.62, P=0.01). Likewise, plasma klotho concentration showed a negative correlation with the age of AD subjects (r=-0.56, P=0.02).

Conclusion: TNF-α, IL-1β, and IL-6 are involved in AD pathophysiology, and dysregulation of DPP4 and klotho may be associated with the inflammatory response of AD. Down-regulation of miR-29a and up-regulation of miR-195 indicated the role of miRNAs in the AD process.

RevDate: 2020-09-23

Rafii MS, PS Aisen (2020)

The search for Alzheimer disease therapeutics - same targets, better trials?.

Nature reviews. Neurology pii:10.1038/s41582-020-00414-3 [Epub ahead of print].

RevDate: 2020-09-23

Sarrias-Arrabal E, Izquierdo-Ayuso G, M Vázquez-Marrufo (2020)

Attentional networks in neurodegenerative diseases: anatomical and functional evidence from the Attention Network Test.

Neurologia (Barcelona, Spain) pii:S0213-4853(20)30218-8 [Epub ahead of print].

INTRODUCTION: Understanding alterations to brain anatomy and cognitive function associated with neurodegenerative diseases remains a challenge for neuroscience today. In experimental neuroscience, several computerised tests have been developed to contribute to our understanding of neural networks involved in cognition. The Attention Network Test (ANT) enables us to measure the activity of 3 attentional networks (alertness, orienting, and executive function).

OBJECTIVES: The main aim of this review is to describe all the anatomical and functional alterations found in diverse neurological diseases using the ANT.

MATERIAL AND METHODS: We collected studies published since 2010 in the PubMed database that employed the ANT in different neurological diseases. Thirty-two articles were obtained, addressing multiple sclerosis, epilepsy, and Parkinson's disease, among other disorders.

CONCLUSIONS: Some of the anatomical structures proposed in the 3 attentional networks model were confirmed. The most relevant structures in the alertness network are the prefrontal cortex, parietal region, thalamus, and cerebellum. The thalamus is also relevant in the orienting network, together with posterior parietal regions. The executive network does not depend exclusively on the prefrontal cortex and anterior cingulate cortex, but also involves such subcortical structures as the basal ganglia and cerebellum and their projections towards the entire cortex.

RevDate: 2020-09-22

Luningham JM, Chen J, Tang S, et al (2020)

Bayesian Genome-wide TWAS Method to Leverage both cis- and trans-eQTL Information through Summary Statistics.

American journal of human genetics pii:S0002-9297(20)30291-3 [Epub ahead of print].

Transcriptome-wide association studies (TWASs) have been widely used to integrate gene expression and genetic data for studying complex traits. Due to the computational burden, existing TWAS methods do not assess distant trans-expression quantitative trait loci (eQTL) that are known to explain important expression variation for most genes. We propose a Bayesian genome-wide TWAS (BGW-TWAS) method that leverages both cis- and trans-eQTL information for a TWAS. Our BGW-TWAS method is based on Bayesian variable selection regression, which not only accounts for cis- and trans-eQTL of the target gene but also enables efficient computation by using summary statistics from standard eQTL analyses. Our simulation studies illustrated that BGW-TWASs achieved higher power compared to existing TWAS methods that do not assess trans-eQTL information. We further applied BWG-TWAS to individual-level GWAS data (N = ∼3.3K), which identified significant associations between the genetically regulated gene expression (GReX) of ZC3H12B and Alzheimer dementia (AD) (p value = 5.42 × 10-13), neurofibrillary tangle density (p value = 1.89 × 10-6), and global measure of AD pathology (p value = 9.59 × 10-7). These associations for ZC3H12B were completely driven by trans-eQTL. Additionally, the GReX of KCTD12 was found to be significantly associated with β-amyloid (p value = 3.44 × 10-8) which was driven by both cis- and trans-eQTL. Four of the top driven trans-eQTL of ZC3H12B are located within APOC1, a known major risk gene of AD and blood lipids. Additionally, by applying BGW-TWAS with summary-level GWAS data of AD (N = ∼54K), we identified 13 significant genes including known GWAS risk genes HLA-DRB1 and APOC1, as well as ZC3H12B.

RevDate: 2020-09-22

Bi HR, Zhou CH, Zhang YZ, et al (2020)

Neuron-specific deletion of presenilin enhancer2 causes progressive astrogliosis and age-related neurodegeneration in the cortex independent of the Notch signaling.

CNS neuroscience & therapeutics [Epub ahead of print].

INTRODUCTION: Presenilin enhancer2 (Pen-2) is an essential subunit of γ-secretase, which is a key protease responsible for the cleavage of amyloid precursor protein (APP) and Notch. Mutations on Pen-2 cause familial Alzheimer disease (AD). However, it remains unknown whether Pen-2 regulates neuronal survival and neuroinflammation in the adult brain.

METHODS: Forebrain neuron-specific Pen-2 conditional knockout (Pen-2 cKO) mice were generated for this study. Pen-2 cKO mice expressing Notch1 intracellular domain (NICD) conditionally in cortical neurons were also generated.

RESULTS: Loss of Pen-2 causes astrogliosis followed by age-dependent cortical atrophy and neuronal loss. Loss of Pen-2 results in microgliosis and enhanced inflammatory responses in the cortex. Expression of NICD in Pen-2 cKO cortices ameliorates neither neurodegeneration nor neuroinflammation.

CONCLUSIONS: Pen-2 is required for neuronal survival in the adult cerebral cortex. The Notch signaling may not be involved in neurodegeneration caused by loss of Pen-2.

RevDate: 2020-09-22

Coughlan G, Puthusseryppady V, Lowry E, et al (2020)

Test-retest reliability of spatial navigation in adults at-risk of Alzheimer's disease.

PloS one, 15(9):e0239077 pii:PONE-D-20-14022.

The Virtual Supermarket Task (VST) and Sea Hero Quest detect high-genetic-risk Alzheimer`s disease (AD). We aimed to determine their test-retest reliability in a preclinical AD population. Over two time points, separated by an 18-month period, 59 cognitively healthy individuals underwent a neuropsychological and spatial navigation assessment. At baseline, participants were classified as low-genetic-risk of AD or high-genetic-risk of AD. We calculated two-way mixed effects intraclass correlation coefficients (ICC) for task parameters and used repeated measures ANOVAS to determine whether genetic risk or sex contributed to test-retest variability. The egocentric parameter of the VST measure showed the highest test-retest reliability (ICC = .72), followed by the SHQ distance travelled parameter (ICC = .50). Post hoc longitudinal analysis showed that boundary-based navigation predicts worsening episodic memory concerns in high-risk (F = 5.01, P = 0.03), but in not low-risk, AD candidates. The VST and the Sea Hero Quest produced parameters with acceptable test-retest reliability. Further research in larger sample sizes is desirable.

RevDate: 2020-09-22

Bardach SH, Kent S, GA Jicha (2020)

Alzheimer Disease Worries, Fears, and Stigma and Their Relationship to Genetic and Interventional Research Engagement.

Alzheimer disease and associated disorders [Epub ahead of print].

BACKGROUND: Alzheimer disease (AD) research increasingly requires healthy individuals willing to undergo genetic testing.

OBJECTIVE: This study seeks to: (1) describe older adults' beliefs about AD genetic testing, worry about AD, and fear of AD stigma, and (2) explore how these constructs relate to research participation.

METHODS: Surveys were sent to participants active in AD-observational research and those that were not. Three measures of research participation were explored: (1) being a current research participant, (2) self-report of clinical trial participation, and (3) expressing genetic registry interest.

RESULTS: The majority of the 502 respondents perceived greater benefit than the risk associated with AD genetic testing. AD worry and perceptions of AD stigma were low. Higher levels of AD worry and lower perceptions of AD stigma were associated with being a current AD research volunteer. AD worry and stigma were unrelated to clinical trial participation or genetic registry interest; these research participation measures were associated with AD genetic testing benefit.

CONCLUSIONS: Beliefs about AD genetic testing, AD worry, and AD stigma are related to research participation, but relationships vary based on the research participation investigated. Future work should identify how these findings can inform outreach and recruitment efforts.

RevDate: 2020-09-22

Carosi JM, Hein LK, van den Hurk M, et al (2020)

Retromer regulates the lysosomal clearance of MAPT/tau.

Autophagy [Epub ahead of print].

The macroautophagy/autophagy-lysosome axis enables the clearance and degradation of cytoplasmic components including protein aggregates, damaged organelles and invading pathogens. Protein aggregation and lysosomal system dysfunction in the brain are common features of several late-onset neurological disorders including Alzheimer disease. Spatial overlap between depletion of the endosomal-sorting complex retromer and MAPT/tau aggregation in the brain have been previously reported. However, whether retromer dysfunction plays a direct role in mediating MAPT aggregation remains unclear. Here, we demonstrate that the autophagy-lysosome axis is the primary mode for the clearance of aggregated species of MAPT using both chemical and genetic approaches in cell models of amyloid MAPT aggregation. We show that depletion of the central retromer component VPS35 causes a block in the resolution of autophagy. We establish that this defect underlies marked accumulation of cytoplasmic MAPT aggregates upon VPS35 depletion, and that VPS35 overexpression has the opposite effect. This work illustrates how retromer complex integrity regulates the autophagy-lysosome axis to suppress MAPT aggregation and spread.

RevDate: 2020-09-22

Ibrahim MA, Haleem M, AbdelWahab SA, et al (2020)

Sildenafil ameliorates Alzheimer disease via the modulation of vascular endothelial growth factor and vascular cell adhesion molecule-1 in rats.

Human & experimental toxicology [Epub ahead of print].

Alzheimer disease (AD) is a chronic neurodegenerative disease with multi-pathways pathogenesis. Sildenafil is a selective phosphodiesterase-5 inhibitor with a potential benefit in the treatment of AD. This study investigated the possible mechanisms underlying the effect of sildenafil in AD with emphasis on vascular endothelial growth factor (VEGF), and vascular cell adhesion molecule-1 (VCAM-1). Twenty-four adult male rats were classified into four groups; control group: received vehicles, sildenafil-control: received sildenafil (15 mg/kg/day, p.o.), AD group received Aluminum (25 mg/kg/day, p.o.), AD-treated group: received sildenafil (15 mg/kg/day, p.o.) for 6 weeks. AD was assessed by memory performance test and confirmed by histopathological examination and immunostaining of, neurogenesis marker nestin and α-synuclein. The levels of VEGF-A, VCAM-1, oxidative stress markers and TNF-α in brain tissue were evaluated. AD rats showed histopathological evidences of AD; along with increased latency time in the memory test. There was a decrease in VEGF-A, and an increase in VCAM-1, TNF-α, and oxidative stress markers. Immunohistochemical study showed a significant increase in α-synuclein and a significant decrease in nestin expressions in brain tissues. Sildenafil administration ameliorated the histopathological changes and decreased latency time. Such effect was associated with a decrease in VCAM-1, TNF-α and oxidative stress as well as an increase in VEGF-A. Sildenafil caused a significant increase in nestin and a decrease in α-synuclein immunostaining. These findings suggested a protective effect of sildenafil via modulation of VEGF-A, and VCAM-1.

RevDate: 2020-09-22

Wu B, Cai H, Tang S, et al (2020)

Methionine-Mediated Protein Phosphatase 2A Catalytic Subunit (PP2Ac) Methylation Ameliorates the Tauopathy Induced by Manganese in Cell and Animal Models.

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics pii:10.1007/s13311-020-00930-6 [Epub ahead of print].

The molecular mechanism of Alzheimer-like cognitive impairment induced by manganese (Mn) exposure has not yet been fully clarified, and there are currently no effective interventions to treat neurodegenerative lesions related to manganism. Protein phosphatase 2 A (PP2A) is a major tau phosphatase and was recently identified as a potential therapeutic target molecule for neurodegenerative diseases; its activity is directed by the methylation status of the catalytic C subunit. Methionine is an essential amino acid, and its downstream metabolite S-adenosylmethionine (SAM) participates in transmethylation pathways as a methyl donor. In this study, the neurotoxic mechanism of Mn and the protective effect of methionine were evaluated in Mn-exposed cell and rat models. We show that Mn-induced neurotoxicity is characterized by PP2Ac demethylation accompanied by abnormally decreased LCMT-1 and increased PME-1, which are associated with tau hyperphosphorylation and spatial learning and memory deficits, and that the poor availability of SAM in the hippocampus is likely to determine the loss of PP2Ac methylation. Importantly, maintenance of local SAM levels through continuous supplementation with exogenous methionine, or through specific inhibition of PP2Ac demethylation by ABL127 administration in vitro, can effectively prevent tau hyperphosphorylation to reduce cellular oxidative stress, apoptosis, damage to cell viability, and rat memory deficits in cell or animal Mn exposure models. In conclusion, our data suggest that SAM and PP2Ac methylation may be novel targets for the treatment of Mn poisoning and neurotoxic mechanism-related tauopathies.

RevDate: 2020-09-22

Mishra J, Kumar B, Pandey M, et al (2020)

Carbon Nano Tubes: Novel drug delivery system in amelioration of Alzheimer's disease.

Combinatorial chemistry & high throughput screening pii:CCHTS-EPUB-110064 [Epub ahead of print].

BACKGROUND: Alzheimer's disease is an irreversible, progressive brain disorder manifested with symptoms like loss of memory (known as dementia), personality changes, loss of cognition, impaired movement, confusion, deteriorated planning and thought process. Neurodegeneration in Alzheimer's disease is the result of deposition of protein beta-amyloid that forms plaques and another protein called tau, forming tangles that prevent proper functioning of nerve cells in the brain.

METHODS: The goal of the review was to comprehensively study the utilization of nanotechnology and the role that carbon nanotubes can play as a drug delivery system for amelioration of Alzheimer's disease.

RESULTS: Nanotechnology is one of the most researched domains of modern science. It contributes significantly to therapeutics by facilitating drug therapy to reach the target sites, which are otherwise difficult to reach with conventional drug delivery systems. Carbon nanotubes are the allotropes of carbon in which several carbon atoms bind with each other to form a cylindrical or a tube-like structure. The carbon nanotubes possess several unique qualities, which confers them with a high potential of being utilized as an efficient drug delivery system. They offer high drug loading, can readily cross the toughest biological barriers like BBB. Carbon nanotubes also facilitate the passage of drugs to the brain via the olfactory route, which further helps in restoring normal autophagy, thus preventing the elimination of autophagic chemicals. They can carry a vast range of cargos, including drugs, antigens, genetic materials, and biological macromolecules.

CONCLUSION: Carbon nanotubes are highly promising drug delivery system for anti-Alzheimer's drugs. They have potential of overcoming the various biological barriers like BBB. However, more extensive research is required so as to set up a firm base for development of advanced commercial products based on carbon nanotubes for treatment of Alzheimer's disease.

RevDate: 2020-09-22

Puente-González AS, Sánchez-González F, Hernández-Xumet JE, et al (2020)

Short and medium-term effects of a multicomponent physical exercise program with a Mediterranean diet on bone mineral density, gait, balance, and fall risk for patients with Alzheimer disease: Randomized controlled clinical trial study protocol.

Medicine, 99(38):e22385.

INTRODUCTION: Reduced bone mineral density and increased risk of falls are related with Alzheimer disease, and these increase likelihood of bone osteoporotic fractures causing serious complications such as disability, fear of falling, loss autonomy, decreased quality of life, and anticipated mortality in elderly patients. Gait and balance disturb are 2 factors to favor falls in elderly, and in patients with cognitive impairment, the risk of falls increases to double. Exercise and Mediterranean diet produce beneficial effects for aging, cognitive decline, and are widely recommended to reduce the effects of osteoporosis, fall risk, and related fragility fractures. The primary objective of this study is to evaluate the short and medium-term effects during 6 months, of a multicomponent physical exercise program with a Mediterranean diet on bone mineral density, fall risk, balance, and gait by a controlled clinical trial in patients with Alzheimer disease.

METHODS: The study is a 6-month, randomized controlled parallel-group, single-blinded clinical trial. Institutionalized patients with Alzheimer disease will be included. The intervention group will perform a multicomponent physical exercise program in reduced groups, with a frequency of 3 sessions per week, associated with a Mediterranean diet. This program includes strength, balance, and aerobic resistance exercises, and in the main part of the session, also ludic exercises to improve agility, coordination, and balance. The control group will receive usual care. The outcomes to assess are the change of physical functions, such as gait and balance, and the change of bone mineral density by calcaneal quantitative ultrasound, during the study follow-up at 1, 3, and 6 months. This clinical trial will generate more and new evidence on the effects of a multicomponent physical exercise program and Mediterranean diet in patients with Alzheimer disease on risk of falls and osteoporotic fractures, the relation of these with bone mineral density, gait and balance, and the correlations between them.

ETHICS AND DISSEMINATION: This study protocol has been approved by the Ethics Committee of the University of Salamanca. The results will be published in peer-reviewed journals and disseminated in national and international conferences, to the participants and their families, and the general public through the associations of people with AD.

TRIAL REGISTRATION ID: ClínicalTrials.gov ID: NCT04439097.

RevDate: 2020-09-22

Kainuma M, Funakoshi K, Ouma S, et al (2020)

The efficacy and safety of hachimijiogan for mild Alzheimer disease in an exploratory, open standard treatment controlled, randomized allocation, multicenter trial: A study protocol.

Medicine, 99(38):e22370.

BACKGROUND: Dementia among the Japanese aged 65 years or over population is estimated to approach about 700 million cases by 2025, and a corresponding rapid increase in Alzheimer disease (AD) can also be expected. The ballooning number of dementia patients, including AD, is creating major medical and social challenges. At present, only 3 drugs are recognized for the treatment of mild AD, and these are only used to alleviate symptoms. Although new therapies are needed to treat mild AD, insufficient development of disease-modifying drugs is being done.

METHODS/DESIGN: The aim of this exploratory, open standard, treatment-controlled, randomized allocation, multicenter trial is to determine the efficacy of the traditional Japanese Kampo medicine hachimijiogan (HJG) on the cognitive dysfunction of mild AD.Eighty-six patients with AD diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 and as mild AD according to the Mini Mental State Examination (MMSE ≥21) will be included. All will already have been taking the same dose of Donepezil, Galantamine, or Rivastigmine for more than 3 months. The patients will be randomly assigned to receive additional treatment with HJG or to continue mild AD treatment without additional HJG. The primary endpoint is the change from baseline of the Alzheimer's Disease Assessment Scale-cognitive component- Japanese version (ADAS-Jcog). ADAS-Jcog is a useful index for detecting change over time that investigates memory and visuospatial cognition injury from the early stage. The secondary endpoints are the changes from baseline of the Instrumental Activity of Daily Life, Apathy scale, and Nueropsychiatric Inventory scores. In this protocol, we will examine the Geriatric depression scale and do Metabolome analysis as exploratory endpoints. The recruitment period will be from August 2019 to July 2021.

DISCUSSION: This is the first trial of Kampo medicine designed to examine the efficacy of HJG for the cognitive dysfunction of patients with mild AD.

TRIAL REGISTRATION: This trial was registered on the Japan Registry of Clinical trials on 2 August 2, 2019 (jRCTs 071190018).

RevDate: 2020-09-22

Brenowitz WD, Besser LM, Kukull WA, et al (2020)

Clinician-judged hearing impairment and associations with neuropathologic burden.

Neurology, 95(12):e1640-e1649.

OBJECTIVE: To examine whether neuropathologic burden is associated with hearing impairment.

METHODS: We studied 2,755 autopsied participants ≥55 years of age from the National Alzheimer's Coordinating Center database. Participants had at least 1 clinical evaluation at US National Institute on Aging-funded Alzheimer's Disease Center no more than 2 years before death. Patients were classified as hearing impaired by clinician report at baseline. Common dementia neuropathologies included Alzheimer disease pathologic change (Consortium to Establish a Registry for Alzheimer's Disease neuritic plaque density, neurofibrillary degeneration Braak stage), Lewy body disease, gross infarcts, and microinfarcts. Logistic regression models predicted impaired hearing with adjustment for age at death, sex, race, education, center, and follow-up time. Relative risks were calculated with the use of marginal standardization.

RESULTS: Impaired hearing was common (32%). In participants who were cognitively normal at baseline (n = 580), impaired hearing was associated with higher Braak stage (relative risk [RR] 1.33 per 2-stage increase, 95% confidence interval [CI] 1.06-1.66) but not other pathologies. In participants with dementia (n = 2,175), impaired hearing was positively associated with microinfarcts (RR 1.18, 95% CI 1.00-1.39) and inversely associated with neuritic plaque density (RR 0.91 per score increase, 95% CI 0.85-0.99). Development of impaired hearing in those with cognitive impairment was associated with neocortical Lewy bodies (1.26, 95% CI 1.02-1.55).

CONCLUSIONS: Impaired hearing, reported before the onset of cognitive impairment, was associated with increased neurofibrillary tangle burden. Impaired hearing in those with cognitive impairment was associated with microinfarcts and neocortical Lewy bodies but not typical Alzheimer disease pathologic change. Functional hearing problems may be a preclinical marker of neurofibrillary neurodegeneration, although replication is needed.

RevDate: 2020-09-21

Blanken AE, DA Nation (2020)

Does Gender Influence the Relationship Between High Blood Pressure and Dementia? Highlighting Areas for Further Investigation.

Journal of Alzheimer's disease : JAD pii:JAD200245 [Epub ahead of print].

BACKGROUND: Gender differences have been noted in studies linking blood pressure to all-cause dementia, and the two most common forms of dementia: Alzheimer's disease (AD) and vascular dementia (VaD). However, how gender modifies the relationship between blood pressure and dementia remains unclear.

OBJECTIVE: To review evidence for a gender modifying effect on the link between blood pressure and all-cause dementia.

METHODS: A systematic review was conducted according to PRISMA guidelines. Sixteen out of 256 reviewed articles met inclusion criteria.

RESULTS: For women, higher midlife systolic blood pressure (SBP) and hypertension were both associated with greater risk of all-cause dementia, AD, and VaD, in six out of seven studies. Two of these studies reported higher midlife SBP/hypertension were associated with greater risk for all-cause dementia in women, but not men. One study reported higher midlife SBP associated with greater AD risk in women, but not men. However, another study reported that midlife hypertension associated with AD risk in men, but not women. No clear gender differences were reported in the relationship between late-life high blood pressure/hypertension with all-cause dementia or AD.

CONCLUSION: Studies rarely, and inconsistently, analyzed or reported gender effects. Therefore, interpretation of available evidence regarding the role of gender in blood pressure associated dementia was difficult. Several studies indicated higher midlife SBP was associated with greater risk of all-cause dementia for women, compared to men. Future studies should evaluate women-specific aging processes that occur in midlife when considering the association between blood pressure and dementia risk.

RevDate: 2020-09-21

Li J, Maharjan B, Xie B, et al (2020)

A Personalized Voice-Based Diet Assistant for Caregivers of Alzheimer Disease and Related Dementias: System Development and Validation.

Journal of medical Internet research, 22(9):e19897 pii:v22i9e19897.

BACKGROUND: The world's aging population is increasing, with an expected increase in the prevalence of Alzheimer disease and related dementias (ADRD). Proper nutrition and good eating behavior show promise for preventing and slowing the progression of ADRD and consequently improving patients with ADRD's health status and quality of life. Most ADRD care is provided by informal caregivers, so assisting caregivers to manage patients with ADRD's diet is important.

OBJECTIVE: This study aims to design, develop, and test an artificial intelligence-powered voice assistant to help informal caregivers manage the daily diet of patients with ADRD and learn food and nutrition-related knowledge.

METHODS: The voice assistant is being implemented in several steps: construction of a comprehensive knowledge base with ontologies that define ADRD diet care and user profiles, and is extended with external knowledge graphs; management of conversation between users and the voice assistant; personalized ADRD diet services provided through a semantics-based knowledge graph search and reasoning engine; and system evaluation in use cases with additional qualitative evaluations.

RESULTS: A prototype voice assistant was evaluated in the lab using various use cases. Preliminary qualitative test results demonstrate reasonable rates of dialogue success and recommendation correctness.

CONCLUSIONS: The voice assistant provides a natural, interactive interface for users, and it does not require the user to have a technical background, which may facilitate senior caregivers' use in their daily care tasks. This study suggests the feasibility of using the intelligent voice assistant to help caregivers manage patients with ADRD's diet.

RevDate: 2020-09-21

Tüshaus J, Müller SA, Kataka ES, et al (2020)

An optimized quantitative proteomics method establishes the cell type-resolved mouse brain secretome.

The EMBO journal [Epub ahead of print].

To understand how cells communicate in the nervous system, it is essential to define their secretome, which is challenging for primary cells because of large cell numbers being required. Here, we miniaturized secretome analysis by developing the "high-performance secretome protein enrichment with click sugars" (hiSPECS) method. To demonstrate its broad utility, hiSPECS was used to identify the secretory response of brain slices upon LPS-induced neuroinflammation and to establish the cell type-resolved mouse brain secretome resource using primary astrocytes, microglia, neurons, and oligodendrocytes. This resource allowed mapping the cellular origin of CSF proteins and revealed that an unexpectedly high number of secreted proteins in vitro and in vivo are proteolytically cleaved membrane protein ectodomains. Two examples are neuronally secreted ADAM22 and CD200, which we identified as substrates of the Alzheimer-linked protease BACE1. hiSPECS and the brain secretome resource can be widely exploited to systematically study protein secretion and brain function and to identify cell type-specific biomarkers for CNS diseases.

RevDate: 2020-09-21

Faridar A, Thome AD, Zhao W, et al (2020)

Restoring regulatory T-cell dysfunction in Alzheimer's disease through ex vivo expansion.

Brain communications, 2(2):fcaa112 pii:fcaa112.

Inflammation is a significant component of Alzheimer's disease pathology. While neuroprotective microglia are important for containment/clearance of Amyloid plaques and maintaining neuronal survival, Alzheimer inflammatory microglia may play a detrimental role by eliciting tau pathogenesis and accelerating neurotoxicity. Regulatory T cells have been shown to suppress microglia-mediated inflammation. However, the role of regulatory T cells in ameliorating the proinflammatory immune response in Alzheimer's disease requires further investigation. Forty-six patients with Alzheimer disease, 42 with mild cognitive impairment and 41 healthy controls were studied. The phenotypes of peripheral regulatory T cells were assessed with multicolour flow cytometry. Regulatory T cells were co-cultured with responder T cells and proliferation was determined by 3H-thymidine incorporation. In separate experiments, regulatory T cells were added to induced pluripotent stem cell-derived pro-inflammatory macrophages and changes in interleukin-6/tumour necrosis-alpha transcripts and protein levels were measured. Freshly isolated regulatory T cells were expanded ex vivo in the presence of CD3/CD28 expander beads, interleukin-2 and rapamycin to promote their suppressive function. We found that the suppressive function of regulatory T cells on responder T-cell proliferation was compromised at the Alzheimer disease stage, compared with mild cognitive impairment and healthy controls. CD25 mean fluorescence intensity in regulatory T-cell population was also reduced in Alzheimer dementia patients. Regulatory T cells did not suppress pro-inflammatory macrophages at baseline. Following ex vivo expansion, regulatory T-cell suppression of responder T-cell proliferation and pro-inflammatory macrophage activation increased in both patients and controls. Expanded regulatory T cells exerted their immunoregulatory function on pro-inflammatory macrophages through a contact-mediated mechanism. In conclusion, regulatory T-cell immunophenotype and function are compromised in Alzheimer's disease. Following ex vivo expansion, the immunomodulatory function of regulatory T cells is enhanced even at advanced stages of Alzheimer's disease. Restoration of regulatory T-cell function could be explored as a means to modulate the inflammatory status of Alzheimer's disease.

RevDate: 2020-09-21

Vermunt L, Dicks E, Wang G, et al (2020)

Single-subject grey matter network trajectories over the disease course of autosomal dominant Alzheimer's disease.

Brain communications, 2(2):fcaa102 pii:fcaa102.

Structural grey matter covariance networks provide an individual quantification of morphological patterns in the brain. The network integrity is disrupted in sporadic Alzheimer's disease, and network properties show associations with the level of amyloid pathology and cognitive decline. Therefore, these network properties might be disease progression markers. However, it remains unclear when and how grey matter network integrity changes with disease progression. We investigated these questions in autosomal dominant Alzheimer's disease mutation carriers, whose conserved age at dementia onset allows individual staging based upon their estimated years to symptom onset. From the Dominantly Inherited Alzheimer Network observational cohort, we selected T1-weighted MRI scans from 269 mutation carriers and 170 non-carriers (mean age 38 ± 15 years, mean estimated years to symptom onset -9 ± 11), of whom 237 had longitudinal scans with a mean follow-up of 3.0 years. Single-subject grey matter networks were extracted, and we calculated for each individual the network properties which describe the network topology, including the size, clustering, path length and small worldness. We determined at which time point mutation carriers and non-carriers diverged for global and regional grey matter network metrics, both cross-sectionally and for rate of change over time. Based on cross-sectional data, the earliest difference was observed in normalized path length, which was decreased for mutation carriers in the precuneus area at 13 years and on a global level 12 years before estimated symptom onset. Based on longitudinal data, we found the earliest difference between groups on a global level 6 years before symptom onset, with a greater rate of decline of network size for mutation carriers. We further compared grey matter network small worldness with established biomarkers for Alzheimer disease (i.e. amyloid accumulation, cortical thickness, brain metabolism and cognitive function). We found that greater amyloid accumulation at baseline was associated with faster decline of small worldness over time, and decline in grey matter network measures over time was accompanied by decline in brain metabolism, cortical thinning and cognitive decline. In summary, network measures decline in autosomal dominant Alzheimer's disease, which is alike sporadic Alzheimer's disease, and the properties show decline over time prior to estimated symptom onset. These data suggest that single-subject networks properties obtained from structural MRI scans form an additional non-invasive tool for understanding the substrate of cognitive decline and measuring progression from preclinical to severe clinical stages of Alzheimer's disease.

RevDate: 2020-09-21

Roth AR, Peng S, Coleman ME, et al (2021)

Network recall among older adults with cognitive impairments.

Social networks, 64:99-108.

Although it is widely accepted that personal networks influence health and illness, network recall remains a major concern. This concern is heightened when studying a population that is vulnerable to cognitive decline. Given these issues, we use data from the Social Network in Alzheimer Disease project to explore similarities and discrepancies between the network perceptions of focal participants and study partners. By leveraging data on a sample of older adults with normal cognition, mild cognitive impairment, and early stage dementia, we explore how cognitive impairment influences older adults' perceptions of their personal networks. We find that the average individual is more likely to omit weaker, peripheral ties from their self-reported networks than stronger, central ties. Despite observing only moderate levels of focal-partner corroboration across our sample, we find minimal evidence of perceptual differences across diagnostic groups. We offer two broad conclusions. First, self-reported network data, though imperfect, offer a reasonable account of the core people in one's life. Second, our findings assuage concerns that cognitively impaired older adults have skewed perceptions of their personal networks.

RevDate: 2020-09-21

Salmerón Ríos S, Lozoya Moreno S, Soler Moratalla I, et al (2020)

[Spanish tools of cognitive and behavior assessment of alzheimer´s disease in severe state.].

Revista espanola de salud publica, 94:.

BACKGROUND: There are different scales in Spanish for cognitive and behavioral assessment of patients with severe dementia. The objective of this study was to select those scales that are more accessible, useful and with better psychometric properties, both for clinical practice and for research.

METHODS: Literature review, by experts in the field, of scales of cognitive and behavioral assessment in dementia in the main scientific databases. Published in Spanish or English, excluding those not validated in Spanish.

RESULTS: 11 bibliographical references were selected. Cognitive scales: Severe Impairment Battery was the one with the most cognitive areas, its abbreviated version (SIB-s) had the best internal consistency (α=0.96), Baylor Profound Mental Status Examination had very good psychometric properties with 0.99 reliability and excellent concurrent validity with Mini-Mental State Examination (r=-0.91). Severe Cognitive Impairment Profile was the only one that allowed establishing subgroups of cognitive impairment. Behavioral scales: Neuropsychiatric Inventory was the gold standard in dementias, but there was only one specific scale for severe Alzheimer's disease, the Baylor Profound Mental Status Examination behavioral subscale.

CONCLUSIONS: In Spanish severe dementia, Severe Cognitive Impairment Profile and the Neuropsychiatric Inventory are the gold standard tool for cognitive assessment for research studies, and the Baylor Profound Mental Status Examination is the most useful for daily clinical practice.

RevDate: 2020-09-21

Carnevale L, Maffei A, Landolfi A, et al (2020)

Brain Functional Magnetic Resonance Imaging Highlights Altered Connections and Functional Networks in Patients With Hypertension.

Hypertension (Dallas, Tex. : 1979) [Epub ahead of print].

Hypertension is one of the main risk factors for vascular dementia and Alzheimer disease. To predict the onset of these diseases, it is necessary to develop tools to detect the early effects of vascular risk factors on the brain. Resting-state functional magnetic resonance imaging can investigate how the brain modulates its resting activity and analyze how hypertension impacts cerebral function. Here, we used resting-state functional magnetic resonance imaging to explore brain functional-hemodynamic coupling across different regions and their connectivity in patients with hypertension, as compared to subjects with normotension. In addition, we leveraged multimodal imaging to identify the signature of hypertension injury on the brain. Our study included 37 subjects (18 normotensives and 19 hypertensives), characterized by microstructural integrity by diffusion tensor imaging and cognitive profile, who were subjected to resting-state functional magnetic resonance imaging analysis. We mapped brain functional connectivity networks and evaluated the connectivity differences among regions, identifying the altered connections in patients with hypertension compared with subjects with normotension in the (1) dorsal attention network and sensorimotor network; (2) dorsal attention network and visual network; (3) dorsal attention network and frontoparietal network. Then we tested how diffusion tensor imaging fractional anisotropy of superior longitudinal fasciculus correlates with the connections between dorsal attention network and default mode network and Montreal Cognitive Assessment scores with a widespread network of functional connections. Finally, based on our correlation analysis, we applied a feature selection to highlight those most relevant to describing brain injury in patients with hypertension. Our multimodal imaging data showed that hypertensive brains present a network of functional connectivity alterations that correlate with cognitive dysfunction and microstructural integrity. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02310217.

RevDate: 2020-09-19

Kubick N, Flournoy PCH, Enciu AM, et al (2020)

Drugs Modulating CD4+ T Cells Blood-Brain Barrier Interaction in Alzheimer's Disease.

Pharmaceutics, 12(9): pii:pharmaceutics12090880.

The effect of Alzheimer's disease (AD) medications on CD4+ T cells homing has not been thoroughly investigated. CD4+ T cells could both exacerbate and reduce AD symptoms based on their infiltrating subpopulations. Proinflammatory subpopulations such as Th1 and Th17 constitute a major source of proinflammatory cytokines that reduce endothelial integrity and stimulate astrocytes, resulting in the production of amyloid β. Anti-inflammatory subpopulations such as Th2 and Tregs reduce inflammation and regulate the function of Th1 and Th17. Recently, pathogenic Th17 has been shown to have a superior infiltrating capacity compared to other major CD4+ T cell subpopulations. Alzheimer's drugs such as donepezil (Aricept), rivastigmine (Exelon), galantamine (Razadyne), and memantine (Namenda) are known to play an important part in regulating the mechanisms of the neurotransmitters. However, little is known about the effect of these drugs on CD4+ T cell subpopulations' infiltration of the brain during AD. In this review, we focus on understanding the influence of AD drugs on CD4+ T cell subpopulation interactions with the BBB in AD. While current AD therapies improve endothelial integrity and reduce astrocytes activations, they vary according to their influence on various CD4+ T cell subpopulations. Donepezil reduces the numbers of Th1 but not Th2, Rivastigmine inhibits Th1 and Th17 but not Th2, and memantine reduces Th1 but not Treg. However, none of the current AD drugs is specifically designed to target the dysregulated balance in the Th17/Treg axis. Future drug design approaches should specifically consider inhibiting CD4+ Th17 to improve AD prognosis.

RevDate: 2020-09-18

Lorettu L, Carpita B, Nivoli A, et al (2020)

Lithium Use During Pregnancy in a Patient With Bipolar Disorder and Multiple Sclerosis.

Clinical neuropharmacology, 43(5):158-161.

Although lithium is widely used as a first-line treatment for mood disorders, its mood-stabilizing effects remain not fully understood. A growing body of data are stressing that lithium seems to show broader properties, including neuroprotective effects. Lithium's ability to inhibit glycogen synthase kinase 3β, an enzyme that participates in the phosphorylation of τ, a microtubule-associated protein, stimulated interest in its possible therapeutic role in Alzheimer disease and other neurodegenerative disorders. Preliminary data also support exploration of lithium's potential therapeutic role in multiple sclerosis, an autoimmune disorder that is associated with co-occurring mood disorders. Lithium is associated with teratogenic risks to the developing fetus; however, recently revised downward estimates of its teratogenic risk of causing fetal cardiac malformation suggest that its potential therapeutic benefit to both mothers with bipolar disorder and their offspring should be considered in at least some cases. A 43-year-old woman previously diagnosed with bipolar disorder and MS was treated with lithium and thyroid hormone supplementation as her sole medications during her pregnancy. The patient remained euthymic throughout her pregnancy and over the course of her 5-year follow-up evaluations on this medication regimen. In addition to her stable mood, there has been no symptomatic progression or relapse of her MS, and her daughter continues to develop normally.The case supports consideration of balancing lithium's mood-stabilizing benefit with its known teratogenic risk during pregnancy. The case also supports exploration of possible additional benefit in the context of MS co-occurring with bipolar disorder.

RevDate: 2020-09-18

Huang Y, Jianfang M, Morales R, et al (2020)

Corticobasal manifestations of Creutzfeldt-Jakob disease with D178N-homozygous 129M genotype.

Prion, 14(1):232-237.

Creutzfeldt-Jakob disease (CJD) is a prion disease, usually presented with memory loss, ataxia, dementia, myoclonus, involuntary movements and psychiatric problems. D178N-homozygous 129M genotype has been recognized in the diagnosis of fatal familial insomnia (FFI) globally. Here we report a patient presented with progressive left upper limb stiffness, bradykinesia, hypomimia and weight loss (10 kg) initially. She progressed to dementia, dysphasia, dysphonia and be bedridden quickly but did not present insomnia. She was diagnosed with CJD corticobasal subtype carrying a classic D178N-129M mutation of PRNP in FFI. Remarkably, she has a strong family history of neurological degeneration diseases but the other members of this pedigree who do not carry D178N-homozygous 129M mutation in PRNP do not present any CJD or FFI symptoms. We conclude that this patient carrying D178N-homozygous 129M mutation in PRNP should be diagnosed as CJD. Thus, the clinicopathology should be considered as a crucial evidence in diagnosing some cases, but FFI could be evaluated as a differential diagnosis with a unique clinical profile. List of abbreviations AD: Alzheimer disease; ADL: Activities of Daily Living; CBD Cortical basal degeneration; CBS: Corticobasal syndrome; CJD: Creutzfeldt-Jakob disease; DWI: Diffusion-weighted image; EEG: Electroencephalograph, fCJD: familial Creutzfeld-Jakob disease; FFI: Fatal familial insomnia; FLAIR: Fluid-attenuated inversion recovery; MMSE: Mini-mental state examination; MoCA: Montreal Cognitive Assessment; MRI: Magnetic resonance imaging; PD: Parkinson disease; PrP: Prion protein; PSWC: Periodic sharp wave complexes; SWI: Susceptibility-weighted imaging.

RevDate: 2020-09-18

Raamana PR, Strother SC, Australian Imaging Biomarkers, Lifestyle flagship study of ageing, for The Alzheimer’s Disease Neuroimaging Initiative (2020)

Does size matter? The relationship between predictive power of single-subject morphometric networks to spatial scale and edge weight.

Brain structure & function pii:10.1007/s00429-020-02136-0 [Epub ahead of print].

Network-level analysis based on anatomical, pairwise similarities (e.g., cortical thickness) has been gaining increasing attention recently. However, there has not been a systematic study of the impact of spatial scale and edge definitions on predictive performance, which is necessary to obtain a clear understanding of their relative performance. In this study, we present a histogram-based approach to construct subject-wise weighted networks that enable a principled comparison across different methods of network analysis. We design several weighted networks based on three large publicly available datasets and perform a robust evaluation of their predictive power under four levels of separability. An interesting insight generated is that changes in nodal size (spatial scale) have no significant impact on predictive power among the three classification experiments and two disease cohorts studied, i.e., mild cognitive impairment and Alzheimer's disease from ADNI, and Autism from the ABIDE dataset. We also release an open source python package called graynet to enable others to leverage the novel network feature extraction algorithms presented here. These techniques and toolbox can also be applied to other modalities due to their domain- and feature-agnostic nature) in diverse applications of connectivity research. In addition, the findings from the ADNI dataset are replicated in the AIBL dataset using an open source machine learning tool called neuropredict.

RevDate: 2020-09-17

Vaz M, S Silvestre (2020)

Alzheimer's disease: Recent treatment strategies.

European journal of pharmacology pii:S0014-2999(20)30646-4 [Epub ahead of print].

Alzheimer Disease (AD) is a neurodegenerative disease characterized by two neuropathological hallmarks: extracellular deposition of amyloid plaques and intracellular neurofibrillary tangles. Current treatment for AD (donepezil, galantamine, rivastigmine and memantine) is only symptomatic and has modest benefits. Thus, the development of drugs with the potential to change the progression of the disease has been a priority. Therapies targeting amyloid β have been the focus for almost 30 years. However, highly promising drugs recently failed to show clinical benefits in phase III trials. Even the positive findings presented by Biogen on Aducanumab are not entirely clear and further data is necessary to confirm its validity. Therefore, researchers are turning their efforts around to tau-targeting therapies, since tau protein appears to be better correlated with the severity of cognitive decline than amyloid β. Currently, most anti-tau agents in clinical trials are immunotherapies and they are in the early stages of clinical research. Four monoclonal antibodies anti-tau (Gosuranemab, Tilavonemab, Semorinemab and Zagotenemab) and one anti-tau vaccine (AADvac1) have reached phase II, so far. In this review, we discuss the potential disease-modifying agents tested in clinical trials and update the information of drugs that are still under clinical evaluation.

RevDate: 2020-09-17

Mondal S, Vashi Y, Ghosh P, et al (2020)

Amyloid Targeting 'Artificial Chaperone' Impairs Oligomer Mediated Neuronal Damage and Mitochondrial Dysfunction Associated with Alzheimer Disease.

ACS chemical neuroscience [Epub ahead of print].

Alzheimer's Disease (AD) is an irreversible memory disorder associated with multiple neuropathological events includ-ing amyloid aggregation that triggers oxidative stress and mitochondrial dysfunction in humans. Herein, a new artificial chaperone PFBZ is reported to efficiently sequester toxic amyloid beta (Aβ) by binding at their 'Amyloidogenic domain (Aβ16-21)' with unprecedented selectivity and prevent amyloid mediated neuronal damage in a wild type (WT) mouse model. An accurate dose of PFBZ chaperone successfully attenuated amyloid triggered internal hemorrhage and pyknosis in cerebral cortex of WT mouse. The structural advantage of the polymer results in efficient Cu(II) chelation arresting a redox cycle to prevent ROS generation and protect mitochondria from ROS mediated damage. This was further evidenced by caspase activation and mitochondrial membrane potential (MMP) biomarkers and was complemented by brain histol-ogy and electron microscopy data which revealed that PFBZ chaperone gave a protective coating over amyloid surface and resists it from interacting with cell membrane and prevent inducing toxicity. This conjugated polymer artificial chap-erone based nano drug showed exceptional properties such as its multipotent and highly biocompatible nature, first of its kind specific amyloid (Aβ16-21) targeting behavior, bioimaging and BBB permeability with a potential to suppress amy-loid triggered neurotoxicity implicated in numerous human disorders through a rare synergistic mechanism.

RevDate: 2020-09-17

Ballard C, Aarsland D, Cummings J, et al (2020)

Drug repositioning and repurposing for Alzheimer disease.

Nature reviews. Neurology pii:10.1038/s41582-020-0397-4 [Epub ahead of print].

Drug repositioning and repurposing can enhance traditional drug development efforts and could accelerate the identification of new treatments for individuals with Alzheimer disease (AD) dementia and mild cognitive impairment. Transcriptional profiling offers a new and highly efficient approach to the identification of novel candidates for repositioning and repurposing. In the future, novel AD transcriptional signatures from cells isolated at early stages of disease, or from human neurons or microglia that carry mutations that increase the risk of AD, might be used as probes to identify additional candidate drugs. Phase II trials assessing repurposed agents must consider the best target population for a specific candidate therapy as well as the mechanism of action of the treatment. In this Review, we highlight promising compounds to prioritize for clinical trials in individuals with AD, and discuss the value of Delphi consensus methodology and evidence-based reviews to inform this prioritization process. We also describe emerging work, focusing on the potential value of transcript signatures as a cost-effective approach to the identification of novel candidates for repositioning.

RevDate: 2020-09-16

Raut P, Glass JB, RL Lieberman (2020)

Archaeal roots of intramembrane aspartyl protease siblings signal peptide peptidase and presenilin.

Proteins [Epub ahead of print].

Signal peptides help newly synthesized proteins reach the cell membrane or be secreted. As part of a biological process key to immune response and surveillance in humans, and associated with diseases, e.g. Alzheimer, remnant signal peptides and other transmembrane segments are proteolyzed by the intramembrane aspartyl protease (IAP) enzyme family. Here, we identified IAP orthologs throughout the tree of life. In addition to eukaryotes, IAPs are encoded in metabolically diverse archaea from a wide range of environments. We found three distinct clades of archaeal IAPs: (1) Euryarchaeota (e.g. halophilic Halobacteriales, methanogenic Methanosarcinales and Methanomicrobiales, marine Poseidoniales, acidophilic Thermoplasmatales, hyperthermophilic Archaeoglobus spp.), (2) DPANN, and (3) Bathyarchaeota, Crenarchaeota, and Asgard. IAPs were also present in bacterial genomes from uncultivated members of Candidate Phylum Radiation, perhaps due to horizontal gene transfer from DPANN archaeal lineages. Sequence analysis of the catalytic motif YD…GXGD (where X is any amino acid) in IAPs from archaea and bacteria reveals WD in Lokiarchaeota and many residue types in the X position. Gene neighborhood analysis in halophilic archaea shows IAP genes near corrinoid transporters (btuCDF genes). In marine Euryarchaeota, a putative BtuF-like domain is found in N-terminus of the IAP gene, suggesting a role for these IAPs in metal ion cofactor or other nutrient scavenging. Interestingly, eukaryotic IAP family members appear to have evolved either from Euryarchaeota or from Asgard archaea. Taken together, our phylogenetic and bioinformatics analysis should prompt experiments to probe the biological roles of IAPs in prokaryotic secretomes. This article is protected by copyright. All rights reserved.

RevDate: 2020-09-16

Aboelwafa HR, El-Kott AF, Abd-Ella EM, et al (2020)

The Possible Neuroprotective Effect of Silymarin against Aluminum Chloride-Prompted Alzheimer's-Like Disease in Rats.

Brain sciences, 10(9): pii:brainsci10090628.

Alzheimer's disease (AD) is a worldwide rapidly growing neurodegenerative disease. Here, we elucidated the neuroprotective effects of silymarin (SM) on the hippocampal tissues of aluminum chloride (AlCl3)-induced Alzheimer-like disease in rats using biochemical, histological, and ultrastructural approaches. Forty rats were divided into control, SM, AlCl3, and AlCl3 + SM groups. Biochemically, AlCl3 administration resulted in marked elevation in levels of lipid peroxidation (LPO) and nitric oxide (NO) and decrease in levels of reduced glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). Moreover, AlCl3 significantly increased tumor necrosis factor-α (TNF-α), interleukin-1beta (IL-1β), and acetylcholinesterase (AChE) activities. Furthermore, myriad histological and ultrastructural alterations were recorded in the hippocampal tissues of AlCl3-treated rats represented as marked degenerative changes of pyramidal neurons, astrocytes, and oligodendrocytes. Additionally, some myelinated nerve fibers exhibited irregular arrangement of their myelin coats, while the others revealed focal degranulation of their myelin sheaths. Severe defects in the blood-brain barrier (BBB) were also recorded. However, co-administration of SM with AlCl3 reversed most of the biochemical, histological, and ultrastructural changes triggered by AlCl3 in rats. The results of the current study indicate that SM can potentially mend most of the previously evoked neuronal damage in the hippocampal tissues of AlCl3-kindled rats.

RevDate: 2020-09-16

Semenov VE, Zueva IV, Mukhamedyarov MA, et al (2020)

Novel Acetylcholinesterase Inhibitors Based on Uracil Moiety for Possible Treatment of Alzheimer Disease.

Molecules (Basel, Switzerland), 25(18): pii:molecules25184191.

In this study, novel derivatives based on 6-methyluracil and condensed uracil were synthesized, namely, 2,4-quinazoline-2,4-dione with ω-(ortho-nitrilebenzylethylamino) alkyl chains at the N atoms of the pyrimidine ring. In this series of synthesized compounds, the polymethylene chains were varied from having tetra- to hexamethylene chains, and secondary NH, tertiary ethylamino, and quaternary ammonium groups were introduced into the chains. The molecular modeling of the compounds indicated that they could function as dual binding site acetylcholinesterase inhibitors, binding to both the peripheral anionic site and active site. The data from in vitro experiments show that the most active compounds exhibit affinity toward acetylcholinesterase within a nanomolar range, with selectivity for acetylcholinesterase over butyrylcholinesterase reaching four orders of magnitude. In vivo biological assays demonstrated the potency of these compounds in the treatment of memory impairment using an animal model of Alzheimer disease.

RevDate: 2020-09-18

Elzoghby AO, Abdelmoneem MA, Hassanin IA, et al (2020)

Lactoferrin, a multi-functional glycoprotein: Active therapeutic, drug nanocarrier & targeting ligand.

Biomaterials, 263:120355 pii:S0142-9612(20)30601-3 [Epub ahead of print].

Recent progress in protein-based nanomedicine, inspired by the success of Abraxane® albumin-paclitaxel nanoparticles, have resulted in novel therapeutics used for treatment of challenging diseases like cancer and viral infections. However, absence of specific drug targeting, poor pharmacokinetics, premature drug release, and off-target toxicity are still formidable challenges in the clinic. Therefore, alternative protein-based nanomedicines were developed to overcome those challenges. In this regard, lactoferrin (Lf), a glycoprotein of transferrin family, offers a promising biodegradable well tolerated material that could be exploited both as an active therapeutic and drug nanocarrier. This review highlights the major pharmacological actions of Lf including anti-cancer, antiviral, and immunomodulatory actions. Delivery technologies of Lf to improve its pries and enhance its efficacy were also reviewed. Moreover, different nano-engineering strategies used for fabrication of drug-loaded Lf nanocarriers were discussed. In addition, the use of Lf for functionalization of drug nanocarriers with emphasis on tumor-targeted drug delivery was illustrated. Besides its wide application in oncology nano-therapeutics, we discussed the recent advances of Lf-based nanocarriers as efficient platforms for delivery of anti-parkinsonian, anti-Alzheimer, anti-viral drugs, immunomodulatory and bone engineering applications.

RevDate: 2020-09-15

Aylanc V, Eskin B, Zengin G, et al (2020)

In vitro studies on different extracts of fenugreek (Trigonella spruneriana BOISS.): Phytochemical profile, antioxidant activity, and enzyme inhibition potential.

Journal of food biochemistry [Epub ahead of print].

The side effects of synthetic antioxidants make it necessary to find a natural alternative. Therefore, the current study investigates the potential of T. spruneriana as a new alternative in terms of natural bioactive components. In this context, antioxidant activity, enzyme inhibition, and phenolic compounds of different extracts including ethanol, methanol, ethyl acetate, and aqueous were identified. The results show that the ethyl acetate (113.59 ± 2.73 mg GAE/g) has the highest phenolic content, but ethanol extract has the highest scavenging activity for DPPH and TAC. The ethanol extract showed stronger inhibition on cholinesterase and α-amylase compared to other extracts. Besides, 12 bioactive compounds were characterized in T. spruneriana extracts by HPLC-DAD. Our findings support that T. spruneriana could be considered as a new source of active phytochemicals, as well as provide remarkable data on biological activities of some main enzymes playing role in the healing of hyperpigmentation, Alzheimer, and diabetes. PRACTICAL APPLICATIONS: This study reports the total content, types and amounts of bioactive compounds and potential beneficial bioactivities of the different extracts of T. spruneriana. Trigonella is abundant in nature and spread over a wide geographical area, and is used in making cheese, pastries, spices, and sausages in different countries, as well as for antidiabetic purposes. Trigonella leaves are a good source of bioactive compounds that contain compounds like quercetin, catechin, cinnamic acid, and coumaric acid, along with it have also a high content of soluble fibers and is suggested for body weight control. Apart from being the first study conducted to point out the potential of T. spruneriana as being a natural food additive, this study also demonstrated its medicinal importance by revealing the anti-hyperpigmentation, antidiabetic, neuroprotective, and antioxidant properties of T. spruneriana.

RevDate: 2020-09-15

Toubøl A, Moestrup L, Ryg J, et al (2020)

Stakeholder perspectives of the dementia-friendly hospital: A qualitative descriptive focus group study.

Dementia (London, England) [Epub ahead of print].

The term dementia-friendly hospital is increasingly used to describe a variety of initiatives and strategies that are implemented to meet the challenges faced by patients with dementia during hospitalization. However, no definition of the dementia-friendly hospital currently exists. This qualitative focus group study aimed to describe stakeholders' perspectives of the dementia-friendly hospital. Four stakeholder groups were included: people with dementia, relatives, hospital staff, and representatives from the Danish Alzheimer Association. The thematic analysis suggests that a person-centered approach is a key feature. This approach is described as a continuously reflexive awareness of how to see the person behind the dementia diagnosis. We discuss possible revision of the current dementia discourse and the implications of the findings for future practice and research.

RevDate: 2020-09-15

Xu F, Ono M, Ito T, et al (2020)

Remodeling of projections from ventral hippocampus to prefrontal cortex in Alzheimer's mice.

The Journal of comparative neurology [Epub ahead of print].

Emotional dysregulation often accompanies cognitive deficits in Alzheimer's disease (AD). The hippocampus, most notably damaged by AD pathology, is classified into the cognition-bound posterior and emotion-bound anterior hippocampi. Since the anterior hippocampus or its rodent counterpart, the ventral hippocampus (VH), sends dense afferents to the prefrontal cortex (PFC) and the basolateral amygdala (BLA), the two structures implicated in fear responses, we investigated whether these afferents are modified in 3xTg AD model mice. An anterograde dextrin tracer injected into VH revealed that axons in PFC were more ramified in 3xTg than wild-type (WT) mice, with the synaptic density reduced. The VH projections to BLA were not affected. Intracellular accumulation of amyloid β (Aβ) or Aβ-like immunoreactivity was found in PFC and BLA neurons alike. Behaviorally, in the 2-way active avoidance test, the frequency of chamber change was higher, with the test performance better, in 3xTg than WT mice, suggesting a distorted contextual fear in the 3xTg group. Given the essential involvement of parts of PFC in contextual fear responses and that of BLA in fear responses in general, the observed remodeling of VH-to-PFC afferents and the accumulation of intracellular Aβ in BLA and PFC pyramidal cells might exercise critical influences on enhanced avoidance behavior in 3xTg mice. This article is protected by copyright. All rights reserved.

RevDate: 2020-09-16

Leuzy A, Heurling K, De Santi S, et al (2020)

Validation of a spatial normalization method using a principal component derived adaptive template for [18F]florbetaben PET.

American journal of nuclear medicine and molecular imaging, 10(4):161-167.

Quantification may help in the context of amyloid-β positron emission tomography (PET). Quantification typically requires that PET images be spatially normalized, a process that can be subject to bias. We herein aimed to test whether a principal component approach (PCA) previously applied to [18F]flutemetamol PET extends to [18F]florbetaben. PCA was applied to [18F]florbetaben PET data for 132 subjects (70 Alzheimer dementia, 62 controls) and used to generate an adaptive synthetic template. Spatial normalization of [18F]florbetaben data using this approach was compared to that achieved using SPM12's magnetic resonance (MR) imaging driven algorithm. The two registration methods showed high agreement and minimal difference in standardized uptake value ratios (SUVR) (R2 = 0.997 using cerebellum as reference region and 0.996 using the pons). Our method allows for robust and accurate registration of [18F]florbetaben images to template space, without the need for an MR image, and may prove of value in clinical and research settings.

RevDate: 2020-09-15

San Lee J, Lee H, Park S, et al (2020)

Association between APOE ε2 and Aβ burden in patients with Alzheimer- and Vascular-Type Cognitive Impairment.

Neurology pii:WNL.0000000000010811 [Epub ahead of print].

OBJECTIVE: To investigate the association between apolipoprotein E (APOE) genotype and amyloid-β (Aβ) burden, as measured by PET in patients with subcortical vascular cognitive impairment (SVCI) and those with Alzheimer's disease-related cognitive impairment (ADCI).

METHODS: This was a cross-sectional study of 310 patients with SVCI and 999 with ADCI. To evaluate the effects of APOE genotype or diagnostic group on Aβ-positivity, we performed multivariate logistic regression analyses. Further distinctive underlying features of latent subgroups were examined by employing a latent class cluster analysis approach.

RESULTS: In comparison with ε3 homozygotes, in the ADCI group, ε2 carriers showed a lower frequency of Aβ-positivity (odds ratio [OR] 0.43, 95% CI 0.23-0.79) while in the SVCI group, ε2 carriers showed a higher frequency of Aβ-positivity (OR 2.26, 95% CI 1.02-5.01). In particular, we observed an interaction effect of ε2 carrier status and diagnostic group on Aβ-positivity (OR 5.12, 95% CI 1.93-13.56), in that relative to ε3 homozygotes, there were more Aβ-positive ε2 carriers in the SVCI group than in the ADCI group. We also identified latent subgroups of Aβ-positive APOE ε2 carriers with SVCI and Aβ-positive APOE ε4 carriers with ADCI.

CONCLUSIONS: Our findings suggest that APOE ε2 shows distinctly associated with Aβ deposition in patients with SVCI and those with ADCI. Our findings further suggest that there is a distinctive subgroup of Aβ-positive APOE ε2 carriers with SVCI among patients with cognitive impairments.

RevDate: 2020-09-15

Alarcón-Espósito J, Mallea M, J Rodríguez-Lavado (2020)

From hybrids to new scaffolds: the latest medicinal chemistry goals in multi-target directed ligands for Alzheimer's disease.

Current neuropharmacology pii:CN-EPUB-109921 [Epub ahead of print].

Alzheimer's disease (AD) is a chronic, progressive, and fatal neurodegenerative disorder affecting cognition, behavior, and function, being one of the most common causes of mental deterioration in elderly people. Once thought as being just developed because of β amyloid depositions or neurofibrillary Tau tangles, during the last decades, numerous ADrelated targets have been established, the multifactorial nature of AD became evident. In this context, the one drug-one target paradigm has resulted to be inefficient in facing AD and other disorders with complex etiology, opening the field for the emergence of the multitarget approach. In this review, we highlight the recent advances within this area, emphasizing in hybridization tools of well-known chemical scaffolds endowed with pharmacological properties concerning AD, such as curcumin-, resveratrol-, chromone- and indole-. We focus mainly on well stablished and incipient AD therapeutic targets, AChE, BuChE, MAOs, β-amyloid deposition, 5-HT4 and Serotonin transporter, with the aim to shed light about new insights in the AD multitarget therapy.

RevDate: 2020-09-15

Roda AR, Montoliu-Gaya L, Serra-Mir G, et al (2020)

Both Amyloid-β Peptide and Tau Protein Are Affected by an Anti-Amyloid-β Antibody Fragment in Elderly 3xTg-AD Mice.

International journal of molecular sciences, 21(18): pii:ijms21186630.

Alzheimer's disease (AD) is the most common dementia worldwide. According to the amyloid hypothesis, the early accumulation of the Aβ-peptide triggers tau phosphorylation, synaptic dysfunction, and eventually neuronal death leading to cognitive impairment, as well as behavioral and psychological symptoms of dementia. ScFv-h3D6 is a single-chain variable fragment that has already shown its ability to diminish the amyloid burden in 5-month-old 3xTg-AD mice. However, tau pathology is not evident at this early stage of the disease in this mouse model. In this study, the effects of scFv-h3D6 on Aβ and tau pathologies have been assessed in 22-month-old 3xTg-AD mice. Briefly, 3xTg-AD female mice were treated for 2 weeks with scFv-h3D6 and compared with 3xTg-AD and non-transgenic (NTg) mice treated with PBS. The treatment with scFv-h3D6 was unequivocally effective in reducing the area of Aβ staining. Furthermore, a tendency for a reduction in tau levels was also observed after treatment that points to the interplay between Aβ and tau pathologies. The pro-inflammatory state observed in the 3xTg-AD mice did not progress after scFv-h3D6 treatment. In addition, the treatment did not alter the levels of apolipoprotein E or apolipoprotein J. Thus, a 2-week treatment with scFv-h3D6 was able to reduce AD-like pathology in elderly 3xTg-AD female mice.

RevDate: 2020-09-14

Agnello L, Gambino CM, Lo Sasso B, et al (2020)

Neurogranin as a Novel Biomarker in Alzheimer's Disease.

Laboratory medicine pii:5905244 [Epub ahead of print].

BACKGROUND: In this study, we investigated the possible role of 2 novel biomarkers of synaptic damage, namely, neurogranin and α-synuclein, in Alzheimer disease (AD).

METHODS: The study was performed in a cohort consisting of patients with AD and those without AD, including individuals with other neurological diseases. Cerebrospinal fluid (CSF) neurogranin and α-synuclein levels were measured by sensitive enzyme-linked immunosorbent assays (ELISAs).

RESULTS: We found significantly increased levels of CSF neurogranin and α-synuclein in patients with AD than those without AD. Neurogranin was correlated with total tau (tTau) and phosphorylated tau (pTau), as well as with cognitive decline, in patients with AD. Receiver operating characteristic (ROC) curve analysis showed good diagnostic accuracy of neurogranin for AD at a cutoff point of 306 pg per mL with an area under the curve (AUC) of 0.872 and sensitivity and specificity of 84.2% and 78%, respectively.

CONCLUSIONS: Our findings support the use of CSF neurogranin as a biomarker of synapsis damage in patients with AD.

RevDate: 2020-09-14

Wang M, Peng H, Peng Z, et al (2020)

Efficacy and safety of ginkgo preparation in patients with vascular dementia: A protocol for systematic review and meta-analysis.

Medicine, 99(37):e22209.

BACKGROUND: Vascular dementia has become the second most common type of dementia after Alzheimer disease. At present, there is no uniform standard for VaD treatment guidelines among countries. The efficacy of ginkgo biloba in the treatment of vascular dementia is still controversial. The purpose of this study is to evaluate the effectiveness and safety of ginkgo biloba in the treatment of vascular dementia through meta-analysis.

METHODS: Six English databases (PubMed, Web of science, Medline, EBASE, Springer Cochrane Library, and WHO International Clinical Trials Registry Platform) and 4 Chinese databases (Wan fang Database, Chinese Scientific Journal Database, China National Knowledge Infrastructure Database(CNKI) and Chinese Biomedical Literature Database) will be searched normatively according to the rule of each database from the inception to August 1, 2020. Two reviewers will independently conduct article selection, data collection, and risk of bias evaluation. Any disagreement will be resolved by discussion with the third reviewer. Either the fixed-effects or random-effects model will be used for data synthesis based on the heterogeneity test. The change in the scores on mini-mental state examination, activity of daily living scale and Montreal cognitive assement will be used as the main outcome measure, Hamilton depression scale, Hastgawa dementia scale, blessed dementia scale, clinical dmentia rating scale as the secondary outcome. Treatment emergent symptom scale, general physical examination (temperature, pulse, respiration, blood pressure), Routine examination of blood, urine and stool, electrocardiogram, liver and kidney function examination as the security indexs. RevMan5.3.5 will be used for meta-analysis.

RESULTS: This study will provide high-quality evidence to assess the effectiveness and safety of ginkgo preparation for vascular dementia.

CONCLUSION: This systematic review will explore whether ginkgo preparation is an effective and safe intervention for vascular dementia.

ETHICS AND DISSEMINATION: Ethical approval are not required for this study. The systematic review will be published in a peer-reviewed journal, presented at conferences, and will be shared on social media platforms. This review will be disseminated in a peer-reviewed journal or conference presentation.


RevDate: 2020-09-14

Wang H, Yu H, Song K, et al (2020)

Traditional Chinese medicine for mild cognitive impairment: A protocol for systematic review and network meta-analysis.

Medicine, 99(37):e22187.

BACKGROUND: Mild cognitive impairment (MCI) is an intermediate stage between normal aging and Alzheimer disease, which is the most common form of dementia in the world. In clinical practice, traditional Chinese medicine (TCM) interventions have been administered for MCI, However, there is still uncertain about what strategy of TCM interventions treatment should be preferred in clinical practice. This study aims to evaluate the efficacy and acceptability of different TCM therapies through systematic review and network meta-analysis.

METHODS: According to the strategy, the authors will retrieve a total of 7 electronic databases by August 2020, including PubMed, the Cochrane Library, EMbase, China National Knowledge Infrastructure, China Biological Medicine, Chongqing VIP, and Wan-fang databases. After a series of screening, 2 researchers will use Aggregate Data Drug Information System and Stata software to analyze the data extracted from the randomized controlled trials of TCM therapies for MCI. The primary outcome of this study is the improvement of cognitive function and the secondary outcome is the activities of daily living, clinical efficacy, and adverse events, and the quality of the evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation instrument.

RESULTS: This study will provide a reliable evidence for the selection of TCM therapies in the treatment of MCI.

CONCLUSION: This study will generate evidence for different TCM therapies for MCI and provide a decision-making reference for clinical research.

ETHICS AND DISSEMINATION: This study does not require ethical approval. The results will be disseminated through a peer-reviewed publication.


RevDate: 2020-09-14

Nguyen XV, Candemir S, Erdal BS, et al (2020)

Predicting Mental Decline Rates in Mild Cognitive Impairment From Baseline MRI Volumetric Data.

Alzheimer disease and associated disorders [Epub ahead of print].

PURPOSE: In mild cognitive impairment (MCI), identifying individuals at high risk for progressive cognitive deterioration can be useful for prognostication and intervention. This study quantitatively characterizes cognitive decline rates in MCI and tests whether volumetric data from baseline magnetic resonance imaging (MRI) can predict accelerated cognitive decline.

METHODS: The authors retrospectively examined Alzheimer Disease Neuroimaging Initiative data to obtain serial Mini-Mental Status Exam (MMSE) scores, diagnoses, and the following baseline MRI volumes: total intracranial volume, whole-brain and ventricular volumes, and volumes of the hippocampus, entorhinal cortex, fusiform gyrus, and medial temporal lobe. Subjects with <24 months or <4 measurements of MMSE data were excluded. Predictive modeling of fast cognitive decline (defined as >0.6/year) from baseline volumetric data was performed on subjects with MCI using a single hidden layer neural network.

RESULTS: Among 698 baseline MCI subjects, the median annual decline in the MMSE score was 1.3 for converters to dementia versus 0.11 for stable MCI (P<0.001). A 0.6/year threshold captured dementia conversion with 82% accuracy (sensitivity 79%, specificity 85%, area under the receiver operating characteristic curve 0.88). Regional volumes on baseline MRI predicted fast cognitive decline with a test accuracy of 71%.

DISCUSSION: An MMSE score decrease of >0.6/year is associated with MCI-to-dementia conversion and can be predicted from baseline MRI.

RevDate: 2020-09-14

Yang D, AV Masurkar (2020)

Clinical Profiles of Arteriolosclerosis and Alzheimer Disease at Mild Cognitive Impairment and Mild Dementia in a National Neuropathology Cohort.

Alzheimer disease and associated disorders [Epub ahead of print].

OBJECTIVE: We sought to evaluate early clinical differences between cerebral arteriolosclerosis (pARTE), Alzheimer disease (pAD), and AD with arteriolosclerosis (ADARTE).

METHODS: Using National Alzheimer's Coordinating Center neuropathology diagnoses, we defined pARTE (n=21), pAD (n=203), and ADARTE (n=158) groups. We compared demographics, medical history, psychometrics, neuropsychiatric symptoms, and apolipoprotein E (APOE) allele variants across neuropathology groups. Retrospective timepoints were first evaluation with Global Clinical Dementia Rating (CDR) score of 0.5 and 1.0, via the CDR Dementia Staging Instrument, corresponding to mild cognitive impairment (MCI) and mild dementia, respectively.

RESULTS: In MCI, clinical differences were minimal but pARTE subjects were older, had later onset cognitive decline, and progressed less severely than pAD. In mild dementia, pAD subjects were younger and had earlier onset of decline. Neuropsychiatric (depression) and psychometric (Logical Memory Delayed Recall, Trails B) differences also emerged between the groups. In MCI, APOE4 associated with worse Logical Memory Delayed Recall in pAD and ADARTE. In mild dementia, APOE4 associated with better animal fluency in pAD, but with better Trails A performance and more neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire) in ADARTE.

CONCLUSIONS: Differences between pARTE, pAD, and ADARTE emerge at mild dementia rather than MCI. APOE4 has varied cognitive and psychiatric impact dependent on neuropathology group and stage.

RevDate: 2020-09-14

Sainani SR, Pansare PA, Rode K, et al (2020)

Emendation of Autophagic Dysfuction in Neurological Disorders: A Potential Therapeutic Target.

The International journal of neuroscience [Epub ahead of print].

Neurodegenerative disorders which have been continuously contributing to the global disease burden affect millions of people worldwide. Researchers strive hard to extract out the ultimate cure and serve for the betterment of the society. Aging and abnormal mutations seem to be the major culprits responsible for neurotoxicity and neuronal death. Another important cause for this neurodegeneration is autophagic dysfunction. Autophagy, which is the normal cleaning process of the cell, is a phenomenal process where a number of genes, proteins, receptors and transcription factors interplay for the ultimate cleaning. But due to abnormal mutations or decreased expression of certain important autophagic members, this efficient process is reported to be compromised in such disorders. This in-turn leads to accumulation of abnormal and unwanted protein aggregates and organelles thereby negatively affecting the neuronal function and survival. Hence, this review aims to understand the autophagic process, its impairment in various neurodegenerative and neuropsychiatric disorders along with certain molecules/compounds to fight those impairments.

RevDate: 2020-09-14

Wezynfeld NE, Tobolska A, Mital M, et al (2020)

Aβ5-x Peptides: N-Terminal Truncation Yields Tunable Cu(II) Complexes.

Inorganic chemistry [Epub ahead of print].

The Aβ5-x peptides (x = 38, 40, 42) are minor Aβ species in normal brains but elevated upon the application of inhibitors of Aβ processing enzymes. They are interesting from the point of view of coordination chemistry for the presence of an Arg-His metal binding sequence at their N-terminus capable of forming a 3-nitrogen (3N) three-coordinate chelate system. Similar sequences in other bioactive peptides were shown to bind Cu(II) ions in biological systems. Therefore, we investigated Cu(II) complex formation and reactivity of a series of truncated Aβ5-x peptide models comprising the metal binding site: Aβ5-9, Aβ5-12, Aβ5-12Y10F, and Aβ5-16. Using CD and UV-vis spectroscopies and potentiometry, we found that all peptides coordinated the Cu(II) ion with substantial affinities higher than 3 × 1012 M-1 at pH 7.4 for Aβ5-9 and Aβ5-12. This affinity was elevated 3-fold in Aβ5-16 by the formation of the internal macrochelate with the fourth coordination site occupied by the imidazole nitrogen of the His13 or His14 residue. A much higher boost of affinity could be achieved in Aβ5-9 and Aβ5-12 by adding appropriate amounts of the external imidazole ligand. The 3N Cu-Aβ5-x complexes could be irreversibly reduced to Cu(I) at about -0.6 V vs Ag/AgCl and oxidized to Cu(III) at about 1.2 V vs Ag/AgCl. The internal or external imidazole coordination to the 3N core resulted in a slight destabilization of the Cu(I) state and stabilization of the Cu(III) state. Taken together these results indicate that Aβ5-x peptides, which bind Cu(II) ions much more strongly than Aβ1-x peptides and only slightly weaker than Aβ4-x peptides could interfere with Cu(II) handling by these peptides, adding to copper dyshomeostasis in Alzheimer brains.

RevDate: 2020-09-14

Sorbara M, Graviotto HG, Lage-Ruiz GM, et al (2020)

COVID-19 and the forgotten pandemic: follow-up of neurocognitive disorders during lockdown in Argentina.

Neurologia (Barcelona, Spain) pii:S0213-4853(20)30247-4 [Epub ahead of print].

INTRODUCTION: Health systems in numerous countries around the world are suffering a serious burden as a consequence of the COVID-19 pandemic. As a result of this situation, the follow-up of such chronic diseases as dementia may be at risk. Similarly, neuropsychiatric complications related to lockdown measures may also be neglected; Argentina's lockdown has been the longest implemented in Latin America. This study aims to determine the frequency of the different types of medical consultations for neurocognitive disorders and the predictors for requiring consultation since the beginning of the lockdown.

METHODS: We performed a descriptive, observational, cross-sectional study based on data collected through an online survey.

RESULTS: Data were collected on 324 participants, with 165 (50.9%) having had at least one medical consultation. Consultations were held by telephone in 109 cases (33.6%), by e-mail in 62 (19.1%), by video conference in 30 (9.3%), and at the emergency department in 23 (7.1%). Predictors of requiring consultation were Clinical Dementia Rating scores ≥1 (P<.001) and diagnosis of Alzheimer disease (P=.017). Higher Neuropsychiatric Inventory scores were found in the group of respondents who did require medical consultation (P<.001), but no significant differences were found between groups for Zarit Burden Interview scores.

CONCLUSION: We identified a high prevalence of behavioural disorders and caregiver burden during lockdown. Nevertheless, only 50% of respondents had sought medical consultation (by telephone or email in 52.7% of cases). Care of people with dementia must be emphasised, guaranteeing follow-up of these patients.

RevDate: 2020-09-14

Vecchierini MF, Kilic-Huck U, Quera-Salva MA, et al (2020)

Melatonin (MEL) and its use in neurological diseases and insomnia: Recommendations of the French Medical and Research Sleep Society (SFRMS).

Revue neurologique pii:S0035-3787(20)30656-1 [Epub ahead of print].

The French Medicine and Research Sleep Society had organized a consensus conference about sleep/wake circadian rhythms and their disorders. During this conference a subgroup of 11 sleep doctors/researchers looked specifically at the use of MEL in different pathologies. This article gives a summary of the main results of MEL therapy in some neurological diseases and insomnia approved by this consensus group. Exogenous MEL, which crosses the blood-brain barrier, has been used as a treatment in its two available forms: an immediate release form that principally shows a chronobiotic action and a long release form that mimics the physiological MEL secretion rhythm and is used to replace reduced physiological secretion. MEL secretion decreases frequently with age, mostly in elderly insomniacs and dementia patients. Results of level A studies show that MEL therapy, used as an add-on treatment, has beneficial effects in mild cognitive impairment (MCI) and Alzheimer patients with sleep disorders in improving sleep quality and in regulating the sleep/wake rhythm. MEL has to be prescribed as early as possible and for a long period, at a dose of 2 to 5 or 10 mg. It may have a beneficial effect on cognitive function in MCI but shows no effect in moderate to severe Alzheimer's disease. It should be emphasized that there are no serious side effects with MEL treatment. In these diseases, light therapy used 12 hours before melatonin treatment has a positive synergic effect. In REM sleep behavior disorder, immediate release MEL should be prescribed first as its side effect profile is much better than clonazepam shortly before bedtime. MEL has a good efficacy on clinical symptoms and PSG REM sleep without atonia episodes and is well tolerated. In Parkinson disease with sleep disorders and without REM sleep behavior disorder, MEL seems to improve subjective sleep quality but no conclusions can be drawn. There is insufficient scientific proof for using MEL as a prophylactic treatment in primary headache, migraine and cluster headache. In epileptic patients, MEL can be safely used to regulate the sleep/wake rhythm and to improve insomnia but more randomized controlled studies are necessary. In primary or no-comorbid insomnia, only a 2 mg dose of slow release MEL, 1 to 2 hours before bedtime, over a period of 3 to 12 weeks, is recommended. It decreases sleep onset latency, improves quality of sleep, morning alertness and quality of life without serious side effects and without withdrawal symptoms.

RevDate: 2020-09-14

McGrath ER, Himali JJ, Levy D, et al (2020)

Growth Differentiation Factor 15 and NT-proBNP as Blood-Based Markers of Vascular Brain Injury and Dementia.

Journal of the American Heart Association [Epub ahead of print].

Background GDF15 (growth differentiation factor 15) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) may offer promise as biomarkers for cognitive outcomes, including dementia. We determined the association of these biomarkers with cognitive outcomes in a community-based cohort. Methods and Results Plasma GDF15 (n=1603) and NT-proBNP levels (n=1590) (53% women; mean age, 68.7 years) were measured in dementia-free Framingham Offspring cohort participants at examination 7 (1998-2001). Participants were followed up for incident dementia. Secondary outcomes included Alzheimer disease dementia, magnetic resonance imaging structural brain measures, and neurocognitive performance. During a median 11.8-year follow-up, 131 participants developed dementia. On multivariable Cox proportional-hazards analysis, higher circulating GDF15 was associated with an increased risk of incident all-cause and Alzheimer disease dementia (hazard ratio [HR] per SD increment in natural log-transformed biomarker value, 1.54 [95% CI, 1.22-1.95] and 1.37 [95% CI, 1.03-1.81], respectively), whereas higher plasma NT-proBNP was also associated with an increased risk of all-cause dementia (HR, 1.32; 95% CI, 1.05-1.65). Elevated GDF15 was associated with lower total brain and hippocampal volumes, greater white matter hyperintensity volume, and poorer cognitive performance. Elevated NT-proBNP was associated with greater white matter hyperintensity volume and poorer cognitive performance. Addition of both biomarkers to a conventional risk factor model improved dementia risk classification (net reclassification improvement index, 0.25; 95% CI, 0.05-0.45). Conclusions Elevated plasma GDF15 and NT-proBNP were associated with vascular brain injury on magnetic resonance imaging, poorer neurocognitive performance, and increased risk of incident dementia in individuals aged >60 years. Both biomarkers improved dementia risk classification beyond that of traditional clinical risk factors, indicating their potential value in predicting incident dementia.

RevDate: 2020-09-13

Walter S, Langford OG, Clanton TB, et al (2020)

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

The journal of prevention of Alzheimer's disease, 7(4):234-241.

BACKGROUND: The 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.

OBJECTIVES: To 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.

DESIGN: Participants 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.

SETTING: Both an online study and in-clinic non-interventional cohort study.

PARTICIPANTS: APT 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.

MEASUREMENTS: In 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).

RESULTS: During 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.

CONCLUSIONS: After 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.

RevDate: 2020-09-13

Walter S, Clanton TB, Langford OG, et al (2020)

Recruitment into the Alzheimer Prevention Trials (APT) Webstudy for a Trial-Ready Cohort for Preclinical and Prodromal Alzheimer's Disease (TRC-PAD).

The journal of prevention of Alzheimer's disease, 7(4):219-225.

BACKGROUND: The Alzheimer Prevention Trials (APT) Webstudy is the first stage in establishing a Trial-ready Cohort for Preclinical and Prodromal Alzheimer's disease (TRC-PAD). This paper describes recruitment approaches for the APT Webstudy.

OBJECTIVES: To remotely enroll a cohort of individuals into a web-based longitudinal observational study. Participants are followed quarterly with brief cognitive and functional assessments, and referred to Sites for in-clinic testing and biomarker confirmation prior to enrolling in the Trial-ready Cohort (TRC).

DESIGN: Participants are referred to the APT Webstudy from existing registries of individuals interested in brain health and Alzheimer's disease research, as well as through central and site recruitment efforts. The study team utilizes Urchin Tracking Modules (UTM) codes to better understand the impact of electronic recruitment methods.

SETTING: A remotely enrolled online study.

PARTICIPANTS: Volunteers who are at least 50 years old and interested in Alzheimer's research.

MEASUREMENTS: Demographics and recruitment source of participant where measured by UTM.

RESULTS: 30,650 participants consented to the APT Webstudy as of April 2020, with 69.7% resulting from referrals from online registries. Emails sent by the registry to participants were the most effective means of recruitment. Participants are distributed across the US, and the demographics of the APT Webstudy reflect the referral registries, with 73.1% female, 85.0% highly educated, and 92.5% Caucasian.

CONCLUSIONS: We have demonstrated the feasibility of enrolling a remote web-based study utilizing existing registries as a primary referral source. The next priority of the study team is to engage in recruitment initiatives that will improve the diversity of the cohort, towards the goal of clinical trials that better represent the US population.

RevDate: 2020-09-13

Danielyan L, Schwab M, Siegel G, et al (2020)

Cell motility and migration as determinants of stem cell efficacy.

EBioMedicine, 60:102989 pii:S2352-3964(20)30365-0 [Epub ahead of print].

BACKGROUND: Stem cells` (SC) functional heterogeneity and its poorly understood aetiology impedes clinical development of cell-based therapies in regenerative medicine and oncology. Recent studies suggest a strong correlation between the SC migration potential and their therapeutic efficacy in humans. Designating SC migration as a denominator of functional SC heterogeneity, we sought to identify highly migrating subpopulations within different SC classes and evaluate their therapeutic properties in comparison to the parental non-selected cells.

METHODS: We selected highly migrating subpopulations from mesenchymal and neural SC (sMSC and sNSC), characterized their features including but not limited to migratory potential, trophic factor release and transcriptomic signature. To assess lesion-targeted migration and therapeutic properties of isolated subpopulations in vivo, surgical transplantation and intranasal administration of MSCs in mouse models of glioblastoma and Alzheimer's disease respectively were performed.

FINDINGS: Comparison of parental non-selected cells with isolated subpopulations revealed superior motility and migratory potential of sMSC and sNSC in vitro. We identified podoplanin as a major regulator of migratory features of sMSC/sNSC. Podoplanin engineering improved oncovirolytic activity of virus-loaded NSC on distantly located glioblastoma cells. Finally, sMSC displayed more targeted migration to the tumour site in a mouse glioblastoma model and remarkably higher potency to reduce pathological hallmarks and memory deficits in transgenic Alzheimer's disease mice.

INTERPRETATION: Functional heterogeneity of SC is associated with their motility and migration potential which can serve as predictors of SC therapeutic efficacy.

FUNDING: This work was supported in part by the Robert Bosch Stiftung (Stuttgart, Germany) and by the IZEPHA grant.

RevDate: 2020-09-13

Elibol B, Beker M, Terzioglu-Usak S, et al (2020)

Thymoquinone administration ameliorates Alzheimer's disease-like phenotype by promoting cell survival in the hippocampus of amyloid beta1-42 infused rat model.

Phytomedicine : international journal of phytotherapy and phytopharmacology, 79:153324 pii:S0944-7113(20)30156-2 [Epub ahead of print].

BACKGROUND: Thymoquinone (TQ), a biologically active ingredient of Nigella sativa, has anti-inflammatory, anti-oxidative and neuroprotective properties. Therefore, it could be a good candidate in the recovery of Alzheimer`s disease (AD) pathology rather than current symptomatic reliefs.

PURPOSE: In the present study, we examined the molecular healing effects of TQ in amyloid beta 1-42 (Aβ1-42) peptide-infused AD rat hippocampus.

STUDY DESIGN: A micro-osmotic pump containing aggregated Aβ1-42 was cannulated into the hippocampus of adult female rats. After two weeks infusion, the dose of TQ (10 mg/kg or 20 mg/kg) was determined according to the HPLC results of cerebrospinal fluid and TQ was given to rats intragastrically for 15 days.

METHODS: The memory performance of rats was determined by Morris water maze test. Afterwards, the acetylcholinesterase (AChE) level were measured by ELISA. Histopathological examinations of hippocampal tissue were performed for cell survival by Nissl staining, for detection of amyloid plaque deposits by Congo red staining and for determination of degenerating neurons by Fluoro Jade C staining. MicroRNA/mRNA levels and protein expressions of AD-related genes and proteins were analyzed by Real-Time Polymerase Chain Reaction and Western Blotting, respectively.

RESULTS: Administration of TQ enhanced the memory performance of Aβ1-42 infused rats and it also ameliorated the neuronal loss in the cornu ammonis (CA1), but not in the dentate gyrus (DG). In addition, TQ treatment decreased the fibril deposition whose accumulation was significantly higher in the Aβ1-42-infused animals compared to that of the control group. The expression profiles of mir29c and Bax which significantly upregulated in the Aβ1-42-infused animals were attenuated by TQ. Furthermore, administration of TQ decreased the expressions of Aβ, phosphorylated-tau, and BACE-1 proteins. There was no significant therapeutic effect of TQ on the AKT/GSK3β or MAPK signaling pathways which were affected due to Aβ1-42 infusion.

CONCLUSION: TQ has the capacity to recover the neuropathology by removing Aβ plaques and by restoring neuron viability. All might have established the molecular basement of the consolidation in the memory observed by means of TQ treatment.

RevDate: 2020-09-12

Peña-Bautista C, Álvarez L, Baquero M, et al (2020)

Plasma isoprostanoids assessment as Alzheimer Disease progression biomarkers.

Journal of neurochemistry [Epub ahead of print].

Alzheimer Disease (AD) is the most common neurodegenerative disease worldwide. So, there is a need to identify AD early diagnosis and monitoring biomarkers in blood samples. The aim of the present study is to analyse the utility of lipid peroxidation biomarkers in AD progression evaluation. Participants (n= 19) were diagnosed with AD at early stages (Time 0, T0), and they were re-evaluated 2 years later (Time 1, T1). Plasma biomarkers from AD patients were determined at both times. Some analytes, such as dihomo-isoprostanes (17-epi-17-F2t-dihomo-IsoP, 17-F2t-dihomo-IsoP, Ent-7(RS)-7-F2t-dihomo-IsoP), and neuroprostanes (10-epi-10-F4t-NeuroP) showed very high probability of showing an increasing trend over time. Baseline values allowed to develop an affordable preliminary regression model to predict long-term cognitive status. So, some lipid peroxidation biomarkers would deserve consideration as useful progression AD biomarkers. The developed prediction model would constitute an important minimally invasive approach in AD personalized prognosis and perhaps could have some interest also in experimental treatments evaluation.

RevDate: 2020-09-14

Zuliani G, Trentini A, Rosta V, et al (2020)

Increased blood BACE1 activity as a potential common pathogenic factor of vascular dementia and late onset Alzheimer's disease.

Scientific reports, 10(1):14980 pii:10.1038/s41598-020-72168-3.

Late onset Alzheimer disease (LOAD) is traditionally considered as a separate disease from vascular dementia (VAD). However, growing evidence suggests that β-amyloid (Aβ) accumulation, that initiates LOAD-related neurodegeneration, is preceded by vascular events. Previous in vitro studies showed that β-secretase 1 (BACE1), the key-enzyme of amyloidogenesis, is upregulated by cerebrovascular insult; moreover, its activity is increased both in brain and serum of LOAD patients. We aimed to investigate whether BACE1 serum activity is altered also in dementias related, or not, to cerebrovascular disease. Thus, we evaluated serum BACE1 activity in a sample of individuals, including patients with LOAD (n. 175), VAD (n. 40), MIXED (LOAD/VAD) dementia (n. 123), other types of dementia (n. 56), and healthy Controls (n. 204). We found that BACE1 was significantly higher not only in LOAD (+ 30%), but also in VAD (+ 35%) and MIXED dementia (+ 22%) (p < 0.001 for all), but not in the other types of dementia (+ 10%). Diagnostic accuracy was 77% for LOAD, 83% for VAD, and 77% for MIXED dementia. In conclusion, we showed for the first time that the increase in peripheral BACE1 activity is a common feature of LOAD and VAD, thus underlying a further pathogenic link between these two forms of dementia.

RevDate: 2020-09-15

Flores J, Noël A, Foveau B, et al (2020)

Pre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging.

Nature communications, 11(1):4571 pii:10.1038/s41467-020-18405-9.

Early therapeutic interventions are essential to prevent Alzheimer Disease (AD). The association of several inflammation-related genetic markers with AD and the early activation of pro-inflammatory pathways in AD suggest inflammation as a plausible therapeutic target. Inflammatory Caspase-1 has a significant impact on AD-like pathophysiology and Caspase-1 inhibitor, VX-765, reverses cognitive deficits in AD mouse models. Here, a one-month pre-symptomatic treatment of Swedish/Indiana mutant amyloid precursor protein (APPSw/Ind) J20 and wild-type mice with VX-765 delays both APPSw/Ind- and age-induced episodic and spatial memory deficits. VX-765 delays inflammation without considerably affecting soluble and aggregated amyloid beta peptide (Aβ) levels. Episodic memory scores correlate negatively with microglial activation. These results suggest that Caspase-1-mediated inflammation occurs early in the disease and raise hope that VX-765, a previously Food and Drug Administration-approved drug for human CNS clinical trials, may be a useful drug to prevent the onset of cognitive deficits and brain inflammation in AD.

RevDate: 2020-09-14

Perrone F, Bjerke M, Hens E, et al (2020)

Amyloid-β1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations.

Alzheimer's research & therapy, 12(1):108 pii:10.1186/s13195-020-00676-5.

BACKGROUND: Alzheimer's disease (AD) mutations in amyloid precursor protein (APP) and presenilins (PSENs) could potentially lead to the production of longer amyloidogenic Aβ peptides. Amongst these, Aβ1-43 is more prone to aggregation and has higher toxic properties than the long-known Aβ1-42. However, a direct effect on Aβ1-43 in biomaterials of individuals carrying genetic mutations in the known AD genes is yet to be determined.

METHODS: N = 1431 AD patients (n = 280 early-onset (EO) and n = 1151 late-onset (LO) AD) and 809 control individuals were genetically screened for APP and PSENs. For the first time, Aβ1-43 levels were analysed in cerebrospinal fluid (CSF) of 38 individuals carrying pathogenic or unclear rare mutations or the common PSEN1 p.E318G variant and compared with Aβ1-42 and Aβ1-40 CSF levels. The soluble sAPPα and sAPPβ species were also measured for the first time in mutation carriers.

RESULTS: A known pathogenic mutation was identified in 5.7% of EOAD patients (4.6% PSEN1, 1.07% APP) and in 0.3% of LOAD patients. Furthermore, 12 known variants with unclear pathogenicity and 11 novel were identified. Pathogenic and unclear mutation carriers showed a significant reduction in CSF Aβ1-43 levels compared to controls (p = 0.037; < 0.001). CSF Aβ1-43 levels positively correlated with CSF Aβ1-42 in both pathogenic and unclear carriers and controls (all p < 0.001). The p.E318G carriers showed reduced Aβ1-43 levels (p < 0.001), though genetic association with AD was not detected. sAPPα and sAPPβ CSF levels were significantly reduced in the group of unclear (p = 0.006; 0.005) and p.E318G carriers (p = 0.004; 0.039), suggesting their possible involvement in AD. Finally, using Aβ1-43 and Aβ1-42 levels, we could re-classify as "likely pathogenic" 3 of the unclear mutations.

CONCLUSION: This is the first time that Aβ1-43 levels were analysed in CSF of AD patients with genetic mutations in the AD causal genes. The observed reduction of Aβ1-43 in APP and PSENs carriers highlights the pathogenic role of longer Aβ peptides in AD pathogenesis. Alterations in Aβ1-43 could prove useful in understanding the pathogenicity of unclear APP and PSENs variants, a critical step towards a more efficient genetic counselling.

RevDate: 2020-09-11

Guo J, Wang Z, Liu R, et al (2020)

Memantine, Donepezil, or Combination Therapy-What is the best therapy for Alzheimer's Disease? A Network Meta-Analysis.

Brain and behavior [Epub ahead of print].

INTRODUCTION: Alzheimer's disease (AD) is a degenerative brain disease that progresses over time, heavily burdening patients, families, and aging societies worldwide. Memantine and donepezil are frequently used in its treatment, both as monotherapy and in combination. This multiple treatment comparison meta-analysis assessed the efficacy of these regimens and placebo in the management of AD.

METHODS: We searched PubMed, Embase, the Cochrane Library, and Wanfang Med Online and China National Knowledge Infrastructure for English and Chinese publications from the first records to 17 April 2020. Two investigators scanned articles for placebo-controlled trials of memantine and donepezil alone and in combination. We extracted data on the following outcomes: cognition, global assessment, daily activities, neuropsychiatric symptoms, adverse events, and the acceptability and cost of these treatment regimens.

RESULTS: Of 936 records screened, we included 54 trials in this analysis. The combination therapy was more effective in improving cognition (mean difference (MD)-5.01, 95% credible interval (95% Crl) -10.73 to 0.86 in the Alzheimer's Disease Assessment Scale-Cognitive Subscale; MD 9.61, 95% Crl 2.29 to 16.97 in the Severe Impairment Battery), global assessment (MD -2.88, 95% Crl -6.04 to 0.40), daily activities (MD 13.06, 95% Crl -34.04 to 58.92), and neuropsychiatric symptoms (MD -6.84, 95% Crl -10.62 to -2.82) compared with placebo. Memantine was more acceptable than placebo (MD 0.93, 95% Crl 0.69 to 1.22).

CONCLUSIONS: Memantine plus donepezil showed superior outcomes for cognition, global assessment, daily activities, and neuropsychiatric symptoms, but lower acceptability than monotherapy and placebo. Combination therapy may be more cost-effective, because memantine slows the progression of AD.

RevDate: 2020-09-11

Stazi M, O Wirths (2020)

Chronic Memantine Treatment Ameliorates Behavioral Deficits, Neuron Loss, and Impaired Neurogenesis in a Model of Alzheimer's Disease.

Molecular neurobiology pii:10.1007/s12035-020-02120-z [Epub ahead of print].

Memantine, a non-competitive NMDA receptor antagonist possessing neuroprotective properties, belongs to the small group of drugs which have been approved for the treatment of Alzheimer's disease (AD). While several preclinical studies employing different transgenic AD mouse models have described beneficial effects with regard to rescued behavioral deficits or reduced amyloid plaque pathology, it is largely unknown whether memantine might have beneficial effects on neurodegeneration. In the current study, we assessed whether memantine treatment has an impact on hippocampal neuron loss and associated behavioral deficits in the Tg4-42 mouse model of AD. We demonstrate that a chronic oral memantine treatment for 4 months diminishes hippocampal CA1 neuron loss and rescues learning and memory performance in different behavioral paradigms, such as Morris water maze or a novel object recognition task. Cognitive benefits of chronic memantine treatment were accompanied by an amelioration of impaired adult hippocampal neurogenesis. Taken together, our results demonstrate that memantine successfully counteracts pathological alterations in a preclinical mouse model of AD.

RevDate: 2020-09-11

Mori T, Koyama N, Yokoo T, et al (2020)

Gallic Acid is a Dual α/β-Secretase Modulator that Reverses Cognitive Impairment and Remediates Pathology in Alzheimer Mice.

The Journal of biological chemistry pii:RA119.012330 [Epub ahead of print].

Several plant-derived compounds have demonstrated efficacy in pre-clinical Alzheimer's disease (AD) rodent models. Each of these compounds share a gallic acid (GA) moiety, and initial assays on this isolated molecule indicated that it might be responsible for the therapeutic benefits observed. To test this hypothesis in a more physiologically relevant setting, we investigated the effect of GA in the mutant human amyloid β-protein precursor/presenilin 1 (APP/PS1) transgenic AD mouse model. Beginning at 12 months, we orally administered GA (20 mg/kg) or vehicle once daily for 6 months to APP/PS1 mice that have accelerated Alzheimer-like pathology. At 18 months of age, GA therapy reversed impaired learning and memory as compared with vehicle and did not alter behavior in wild-type littermates. GA-treated APP/PS1 mice had mitigated cerebral amyloidosis, including brain parenchymal and cerebral vascular β-amyloid deposits, and decreased cerebral amyloid β-proteins. Beneficial effects co-occurred with reduced amyloidogenic and elevated nonamyloidogenic APP processing. Further, brain inflammation, gliosis, and oxidative stress were alleviated. We show that GA simultaneously elevates α- and reduces β-secretase activity, inhibits neuroinflammation and stabilizes brain oxidative stress in a pre-clinical mouse model of AD. We further demonstrate that GA increases abundance of the ADAM10 proprotein convertase furin and activates ADAM10, directly inhibits BACE1 activity but does not alter Adam10 or Bace1 transcription. Thus, our data reveal novel post-translational mechanisms for GA. We suggest further examination of GA supplementation in humans will shed light on the exciting therapeutic potential of this molecule.

RevDate: 2020-09-11

Cirrito JR, Wallace CE, Yan P, et al (2020)

Effect of Escitalopram on Aβ levels and plaque load in an Alzheimer mouse model.

Neurology pii:WNL.0000000000010733 [Epub ahead of print].

RATIONALE: Several neurotransmitter receptors activate signaling pathways that alter processing of the amyloid precursor protein (APP) into amyloid-β (Aβ). Serotonin signaling through a subset of serotonin receptors suppresses Aβ generation. We proposed that escitalopram, the most specific selective serotonin reuptake inhibitor (SSRI) that inhibits the serotonin transporter , SERT, would suppress Aβ levels in mice.

OBJECTIVES: We hypothesized that acute treatment with ESC would reduce Aβ generation which would be reflected chronically with a significant reduction in Aβ plaque load.

METHODS: We performed in vivo microdialysis and in vivo two-photon imaging to assess changes in brain interstitial fluid (ISF) Aβ and Aβ plaque size over time, respectively, in the APP/PS1 mouse model of Alzheimer's disease treated with vehicle or ESC. We also chronically treated mice with ESC to determine the effect on plaques histologically.

RESULTS: ESC acutely reduced ISF Aβ by 25% by increasing α-secretase cleavage of APP. Chronic administration of ESC significantly reduced plaque load by 28% and 34% at 2.5 mg/day and 5 mg/day, respectively. ESC at 5mg/kg did not remove existing plaques, but completely arrested individual plaque growth over time.

CONCLUSIONS: ESC significantly reduced Aβ in mice similar to previous findings in humans treated with acute dosing of an SSRI.

RevDate: 2020-09-15

Šmidlehner T, Bonnet H, Chierici S, et al (2020)

Fluorescently-labelled amyloid paired helical filaments (PHF) in monitoring its fibrillation kinetics.

Bioorganic chemistry, 104:104196 pii:S0045-2068(20)31493-0 [Epub ahead of print].

The core of the tau fibrils in Alzheimer disease is a hexapeptide sequence organized in paired helical filaments (PHF). This sequence AcPHF6 can be used as tau fibrils model for the fast screening of potential therapeutic inhibitors of fibril formation or their disruption. The assay is usually performed by monitoring the fluorescence increase of Thioflavin T (ThT), well-known reporter dye for fibrillation. However, the ThT assay is not faultless, and here we present novel fluorescent dye, cyanine attached to amino acid side-chain (Cy-aa) that shows several advantages over ThT. The fibrillation kinetics of AcPHF6 was monitored via Cy-aa at twenty times lower concentration compared to ThT and successfully reported the presence of fibrillation inhibitor by Cy-aa fluorescence decrease. Additionally, spectral properties of Cy-aa are red-shifted in comparison to ThT allowing screening of a wider range of potential fibrillation inhibitors. Moreover, in the mixture with the pre-formed fibrils, Cy-aa shows strong fluorescence light-up proportional to fibrils concentration. We also successfully coupled this fluorescent amino acid to PHF in order to completely avoid the possibility of dye displacement with screening compound, and this newly designed conjugate showed to be a reliable intrinsic fluorescent probe for monitoring fibrillation kinetics of amyloid peptides.

RevDate: 2020-09-10

Oh M, Oh SJ, Lee SJ, et al (2020)

Clinical Evaluation of 18F-PI-2620 as a Potent PET Radiotracer Imaging Tau Protein in Alzheimer Disease and Other Neurodegenerative Diseases Compared With 18F-THK-5351.

Clinical nuclear medicine [Epub ahead of print].

PURPOSE: PET is a useful tool for detecting the presence and extent of brain tau accumulation. However, most first-generation tau PET tracers are limited for high off-target binding and detection of tau in non-Alzheimer disease (AD). This study evaluated potential clinical applications of F-PI-2620 as a novel PET tracer with a high binding affinity for tau deposition in AD and non-AD tauopathies.

METHODS: Twenty-six participants diagnosed with either mild cognitive impairment, probable AD, frontotemporal dementia, or parkinsonism, as well as healthy controls underwent a 60- to 90-minute brain PET scan after 7 mci (259 MBq) injection of F-PI-2620. Some participants had previous PET scans using F-THK-5351 or F-FP-CIT for dopamine transporter imaging.

RESULTS: All participants showed no increase in off-target binding in basal ganglia on F-PI-2620 PET images, as noted for first-generation tau tracers. Aβ+ mild cognitive impairment or AD patients showed diverse cortical F-PI-2620 uptake in frontotemporoparietal cortex that correlated with Mini-Mental Status Examination (ρ = -0.692, P = 0.013). Aβ+ Parkinson disease with dementia and (Aβ unknown) primary progressive aphasia patients also showed increased F-PI-2620 uptakes in the frontotemporoparietal cortex. Patients with parkinsonism showed increased uptakes in the pallidum compared with Aβ- healthy controls (left: 1.41 ± 0.14 vs 1.04 ± 0.13, P = 0.014; right: 1.18 ± 0.16 vs 0.95 ± 0.07, P = 0.014).

CONCLUSIONS: F-PI-2620 PET might be a sensitive tool to detect cortical tau deposits in patients with Aβ+ AD and Aβ+ non-AD tauopathies. Furthermore, this study showed that "off-target" binding in the basal ganglia does not affect F-PI-2620.

RevDate: 2020-09-10

Belarbi S, Mostefaoui F, L Alipacha (2020)


Revue neurologique, 176S:S6-S7.

RevDate: 2020-09-10

Leroy M, Alleman A, Aziz AL, et al (2020)


Revue neurologique, 176S:S5.

RevDate: 2020-09-10

Sarazin M, Lagarde J, P Olivieri (2020)


Revue neurologique, 176S:S142.

RevDate: 2020-09-09

Smith EE, Couillard P, Fisk JD, et al (2020)

Pandemic Dementia Scarce Resource Allocation.

Canadian geriatrics journal : CGJ, 23(3):216-218.

Hospitals and intensive care units are straining to provide care for a large surge of patients with coronavirus disease 19 (Covid-19). Contingency plans are being made for the possibility that resources for lifesaving care, including mechanical ventilators, will be in short supply. Covid-19 is more severe and more likely to be fatal in older persons. Dementia is one of the commonest severe comorbidities of aging. Persons with dementia are vulnerable and often need the support of others to make their voices heard. This commentary, created by a task force commissioned by the Alzheimer Society of Canada, provides guidance for triaging persons with dementia to scarce medical resources during the Covid-19 pandemic.

RevDate: 2020-09-09

Kim JS, Lee HJ, Lee S, et al (2020)

Conductive Hearing Loss Aggravates Memory Decline in Alzheimer Model Mice.

Frontiers in neuroscience, 14:843.

The study of cognitive impairment associated with hearing loss has recently garnered considerable interest. Epidemiological data have demonstrated that hearing loss is a risk factor for cognitive decline as a result of aging. However, no previous study has examined the effect of hearing loss in patients with cognitive problems such as Alzheimer's disease. Therefore, we investigated the effect of conductive hearing loss in an Alzheimer's mouse model. Positron emission tomography (PET) and magnetic resonance imaging (MRI) were used to evaluate changes in glucose metabolism and gray matter concentrations in the 5xFAD Alzheimer's Disease (AD) transgenic mouse model with and without conductive hearing loss (HL). Conductive hearing loss was induced using chronic perforation of the tympanic membrane. Behavioral data from the Y-maze and passive avoidance tests revealed greater memory deficits in the AD with HL (AD-HL) group than in the AD group. Following induction of hearing loss, lower cerebral glucose metabolism in the frontal association cortex was observed in the AD-HL group than in the AD group. Although lower glucose metabolism in the hippocampus and cerebellum was found in the AD-HL group than in the AD group at 3 months, the gray matter concentrations in these regions were not significantly different between the groups. Furthermore, the gray matter concentrations in the simple lobule, cingulate/retrosplenial cortex, substantia nigra, retrosigmoid nucleus, medial geniculate nucleus, and anterior pretectal nucleus at 7 months were significantly lower in the AD-HL group than in the AD group. Taken together, these results indicate that even partial hearing loss can aggravate memory impairment in Alzheimer's disease.

RevDate: 2020-09-09

Chai X, Zhang W, Li L, et al (2020)

Profile of MIF in Developing Hippocampus: Association With Cell Proliferation and Neurite Outgrowth.

Frontiers in molecular neuroscience, 13:147.

Proinflammatory cytokine macrophage migration inhibitory factor (MIF) is a multifunctional cytokine and has been found involved in many neurological diseases such as Alzheimer disease (AD), epilepsy, and multiple sclerosis. Previous studies have shown that MIF is expressed in neocortex, hippocampus, hypothalamus, cerebellum, and spinal cord in adult mice. It is expressed by astrocytes and activates microglias in neuroinflammation. Further studies have shown that MIF is detected in moss fibers of dentate granule cells and in apical dendrites of pyramidal neurons in adult hippocampus. Only NeuroD-positive immature granule neurons but not NeuN-positive mature neurons express MIF. These findings led us eager to know the exact role of MIF in the development of hippocampus. Therefore, we systematically checked the spatial and temporal expression pattern of MIF and characterized MIF-positive cells in hippocampus from mice aged from postnatal day 0 (P0) to 3 months. Our results showed that the lowest level of MIF protein occurred at P7 and mif mRNA increased from P0, reached a peak at P7, and stably expressed until P30 before declining dramatically at 3 months. MIF was localized in fibers of GFAP- and BLBP-positive radial glial precursor cells in dentate gyrus (DG). DCX-expressing newly generated neurons were MIF-negative. Inhibition of MIF by MIF antagonist S, R-3-(4-hydroxyphenyl)-4, 5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) reduced BrdU-positive cells. Interestingly, MIF was expressed by NeuN-positive GABAergic interneurons including parvalbumin-and Reelin-expressing cells in the DG. Neither NeuN-positive granule cells nor NeuN-positive pyramidal neurons expressed MIF. In transgenic mice, POMC-EGFP-positive immature dentate granule cells and Thy1-EGFP-positive mature granule cells were MIF-negative. Treatment of neuronal cultures with ISO-1 inhibited neurite outgrowth. Therefore, we conclude that MIF might be important for feature maintenance of neural stem cells and neurite outgrowth during hippocampal development.

RevDate: 2020-09-10

Kivimäki M, Singh-Manoux A, Batty GD, et al (2020)

Association of Alcohol-Induced Loss of Consciousness and Overall Alcohol Consumption With Risk for Dementia.

JAMA network open, 3(9):e2016084 pii:2770285.

Importance: Evidence on alcohol consumption as a risk factor for dementia usually relates to overall consumption. The role of alcohol-induced loss of consciousness is uncertain.

Objective: To examine the risk of future dementia associated with overall alcohol consumption and alcohol-induced loss of consciousness in a population of current drinkers.

Seven cohort studies from the UK, France, Sweden, and Finland (IPD-Work consortium) including 131 415 participants were examined. At baseline (1986-2012), participants were aged 18 to 77 years, reported alcohol consumption, and were free of diagnosed dementia. Dementia was examined during a mean follow-up of 14.4 years (range, 12.3-30.1). Data analysis was conducted from November 17, 2019, to May 23, 2020.

Exposures: Self-reported overall consumption and loss of consciousness due to alcohol consumption were assessed at baseline. Two thresholds were used to define heavy overall consumption: greater than 14 units (U) (UK definition) and greater than 21 U (US definition) per week.

Main Outcomes and Measures: Dementia and alcohol-related disorders to 2016 were ascertained from linked electronic health records.

Results: Of the 131 415 participants (mean [SD] age, 43.0 [10.4] years; 80 344 [61.1%] women), 1081 individuals (0.8%) developed dementia. After adjustment for potential confounders, the hazard ratio (HR) was 1.16 (95% CI, 0.98-1.37) for consuming greater than 14 vs 1 to 14 U of alcohol per week and 1.22 (95% CI, 1.01-1.48) for greater than 21 vs 1 to 21 U/wk. Of the 96 591 participants with data on loss of consciousness, 10 004 individuals (10.4%) reported having lost consciousness due to alcohol consumption in the past 12 months. The association between loss of consciousness and dementia was observed in men (HR, 2.86; 95% CI, 1.77-4.63) and women (HR, 2.09; 95% CI, 1.34-3.25) during the first 10 years of follow-up (HR, 2.72; 95% CI, 1.78-4.15), after excluding the first 10 years of follow-up (HR, 1.86; 95% CI, 1.16-2.99), and for early-onset (<65 y: HR, 2.21; 95% CI, 1.46-3.34) and late-onset (≥65 y: HR, 2.25; 95% CI, 1.38-3.66) dementia, Alzheimer disease (HR, 1.98; 95% CI, 1.28-3.07), and dementia with features of atherosclerotic cardiovascular disease (HR, 4.18; 95% CI, 1.86-9.37). The association with dementia was not explained by 14 other alcohol-related conditions. With moderate drinkers (1-14 U/wk) who had not lost consciousness as the reference group, the HR for dementia was twice as high in participants who reported having lost consciousness, whether their mean weekly consumption was moderate (HR, 2.19; 95% CI, 1.42-3.37) or heavy (HR, 2.36; 95% CI, 1.57-3.54).

Conclusions and Relevance: The findings of this study suggest that alcohol-induced loss of consciousness, irrespective of overall alcohol consumption, is associated with a subsequent increase in the risk of dementia.

RevDate: 2020-09-08

Rasouli H, Hosseini Ghazvini SMB, Yarani R, et al (2020)

Deciphering inhibitory activity of flavonoids against tau protein kinases: a coupled molecular docking and quantum chemical study.

Journal of biomolecular structure & dynamics [Epub ahead of print].

Today, Alzheimer's disease (AD) is one of the most important neurodegenerative disorders that affected millions of people worldwide. Hundreds of academic investigations highlighted the potential roles of natural metabolites in the cornerstone of AD prevention. Nevertheless, alkaloids are only metabolites that successfully showed promising clinical therapeutic effects on the prevention of AD. In this regard, other plant metabolites such as flavonoids are also considered as promising substances in the improvement of AD complications. The lack of data on molecular mode of action of flavonoids inside brain tissues, and their potential to transport across the blood-brain barrier, a physical hindrance between bloodstream and brain tissues, limited the large-scale application of these compounds for AD therapy programs. Herein, a coupled docking and quantum study was applied to determine the binding mode of flavonoids and three protein kinases involved in the pathogenesis of AD. The results suggested that all docked metabolites showed considerable binding affinity to interact with target receptors, but some compounds possessed higher binding energy values. Because docking simulation cannot entirely reveal the potential roles of ligand substructures in the interaction with target residues, quantum chemical analyses (QCAs) were performed to cover this drawback. Accordingly, QCAs determined that distribution of molecular orbitals have a pivotal function in the determination of the type of reaction between ligands and receptors; therefore, using such quantum chemical descriptors may correct the results of virtual docking outcomes to highlight promising backbones for further developments. Communicated by Ramaswamy H. Sarma.

RevDate: 2020-09-18

Brosseron F, Kleemann K, Kolbe CC, et al (2020)

Interrelations of Alzheimer´s disease candidate biomarkers neurogranin, fatty acid-binding protein 3 and ferritin to neurodegeneration and neuroinflammation.

Journal of neurochemistry [Epub ahead of print].

There is growing evidence that promising biomarkers of inflammation in Alzheimer´s disease (AD) and other neurodegenerative diseases correlate strongest to levels of tau or neurofilament, indicating an inflammatory response to neuronal damage or death. To test this hypothesis, we investigated three AD candidate markers (ferritin, fatty acid binding protein 3 (FABP-3), and neurogranin) in interrelation to established AD and inflammatory protein markers. We further aimed to determine if such interrelations would be evident in pathological subjects only or also under non-pathological circumstances. Cerebrospinal fluid levels of the three proteins were quantified in samples from the University Clinic of Bonn (UKB) Department of Neurodegenerative Diseases & Geriatric Psychiatry, Germany. Data were analyzed based on clinical or biomarker-defined stratification of subjects with adjustment for covariates age, sex, and APOE status. Levels of ferritin, FABP-3 and neurogranin were elevated in subjects with pathological levels of t-tau independent of beta-amyloid status. The three markers correlated with each other, tau isoforms, age, and those inflammatory markers previously described as related to neurodegeneration, predominantly sTREM2, macrophage migration inhibitory factor, soluble vascular endothelial growth factor receptor, soluble vascular cell adhesion molecule 1 (sVCAM-1), and C1q. These interrelations existed in subjects with pathological and sub-pathological tau levels, in particular for FABP-3 and neurogranin. Relations to ferritin were independent of absolute levels of tau, too, but showed differing trajectories between pathological and non-pathological subjects. A specific set of inflammatory markers is highly related to markers of neuronal damage such as tau, neurogranin, or FABP-3. These proteins could be used as readouts of the inflammatory response during the neurodegeneration phase of AD.

RevDate: 2020-09-07

Mehta N, Zhu L, Lam K, et al (2020)

Health Forums and Twitter for Dementia Research: Opportunities and Considerations.

Journal of the American Geriatrics Society [Epub ahead of print].

BACKGROUND/OBJECTIVES: Social media platforms are promising sources for large quantities of participant-driven research data and circumvent some common challenges when conducting dementia research. This study provides a summary of key considerations and recommendations about using these platforms as research tools for dementia.

DESIGN: Mixed methods.

SETTING: Alzheimer's Society's online Dementia Talking Point forum from inception to April 17, 2018, and Twitter in February and March 2018.

PARTICIPANTS: All users of Dementia Talking Point who posted in subforums labeled "I have dementia" and "I care for a person with dementia," and Twitter users whose posts contained the keywords "dementia," "Alzheimer," or "Alzheimer's."

MEASUREMENTS: We quantified the average daily number of dementia-related posts on each platform and number of words per post. Guided by a codebook, we conducted thematic content analysis of 5% of the 15,513 posts collected from Dementia Talking Point, and 10% of the 25,948 comprehensible posts from Twitter containing "dementia," "Alzheimer," or "Alzheimer's." We also summarized research-relevant characteristics inherent to platforms and posts.

RESULTS: On average, Dementia Talking Point provided less than two new daily dementia-related posts with 213.5 to 241.5 words, compared with 7,883 new daily Twitter posts with 14.5 words. Persons with dementia (PWDs) commonly shared dementia-related concerns (75.7%), experiences (68.6%), and requests for, as well as offers of, information and support (44.3% and 38.6%, respectively). Caregivers commonly shared caregiving experience (67.0%) and requests for information and support (52.5%). Most common dementia-related Twitter posts were derogatory use of the term dementia (14.5%), advocacy, fundraising, and awareness (11.6%), and research dissemination (8.0%). Recommendations about these platforms' unique technical and ethical considerations are outlined.

CONCLUSIONS: Understanding the priorities of PWDs and their caregivers remains important to understand how clinicians can best support them. This study will help clinicians and researcher to better leverage online health forums and Twitter for such dementia-related information.

RevDate: 2020-09-07

Scarioni M, Arighi A, Fenoglio C, et al (2020)

Late-onset presentation and phenotypic heterogeneity of the rare R377W PSEN1 mutation.

European journal of neurology [Epub ahead of print].

BACKGROUND: Mutations in the PSEN1 gene are the most common cause of autosomal-dominant Alzheimer's disease and have been associated with the earliest disease onset. We describe an unusual presentation of the rare R377W PSEN1 mutation with a late age of onset, and we provide for the first time in vivo pathological evidence for this mutation.

METHODS: A 71-years old female patient with progressive cognitive decline in the past three years and positive family history for dementia underwent neurological evaluation, neuropsychological testing, lumbar puncture, conventional brain imaging, amyloid-PET and extensive genetic screening with a next generation sequencing technique.

RESULTS: The diagnostic work-up revealed mixed behavioural and amnestic disease features on neuropsychological tests, MRI, and FDG-PET. Amyloid-PET detected amyloid deposition in the frontal areas, in the parietal lobes and the precunei. The genetic screening unraveled the presence of the rare R377W mutation in the PSEN1 gene.

CONCLUSIONS: Extensive genetic screening is advisable also for late-onset presentations of Alzheimer's disease, especially in the presence of a positive family history or atypical clinical features.

RevDate: 2020-09-07

Holden E, Stoner CR, A Spector (2020)

Cognitive stimulation therapy for dementia: Provision in National Health Service settings in England, Scotland and Wales.

Dementia (London, England) [Epub ahead of print].

Objectives: Cognitive stimulation therapy (CST) is a brief, non-pharmacological intervention for people with dementia, with an established evidence base for improving cognition and quality of life. It is widely implemented in National Health Service (NHS) settings, but little is known about its naturalistic use. The aim of this survey was to identify and explore inclusion criteria, dose and quality of CST across services in Great Britain (England, Scotland and Wales).Methods: All NHS memory clinics and services for people with dementia were contacted and asked to complete a mixed methods online survey on CST delivery in their service. Questions were centred on who provided CST, who received CST, the dose of CST and any outcomes that were routinely measured.Results: A total of 57/186 services responded, giving a response rate of 30.7%. While the majority reported offering CST (87.7%), there was variability in how this was delivered. Differing inclusion criteria included the use of varying cognitive and behavioural outcome measures, and CST was reported as being offered once and twice weekly. Services also differed in how they evaluated the quality of CST and how this evidence was incorporated for future sessions.Conclusion: While there was a low response rate, this survey indicates that there is significant variability in how CST is used in clinical practice, with many trusts not adhering to the evidence base. To ensure that people with dementia are consistently offered evidence-based, high-quality CST across NHS settings, further standardisation of inclusion criteria, dose and outcomes is needed.

RevDate: 2020-09-06

Robinson-Lane SG, Zhang X, A Patel (2020)

Coping and adaptation to dementia family caregiving: A pilot study.

Geriatric nursing (New York, N.Y.) pii:S0197-4572(20)30252-4 [Epub ahead of print].

Family caregivers of Black older adults with dementia are at risk for cognitive decline and premature death. Reducing this risk and filling the void of culturally responsive interventions for caregivers requires the development of participant informed models of care that promote group strengths such as effective coping. In this pilot study, Black family caregivers (n=30) completed a survey comprised of a demographic questionnaire, various measures of function, self-efficacy, social support, and coping. Study findings point to a well-educated population with underlying health concerns such as obesity, hypertension, and diabetes that may be complicated by caregiving stress. Common coping strategies used by participants included spiritual coping (80%), use of past experiences (80%), and information gathering (75%). Clinicians can support dementia family caregivers by promoting spiritual coping and self-care, as well as providing reference resources about respite and managing challenging behaviors. Power analysis suggests a future sample size of 385.

RevDate: 2020-09-14

Ghotbi G, Mahdavi M, Najafi Z, et al (2020)

Design, synthesis, biological evaluation, and docking study of novel dual-acting thiazole-pyridiniums inhibiting acetylcholinesterase and β-amyloid aggregation for Alzheimer's disease.

Bioorganic chemistry, 103:104186 pii:S0045-2068(20)31483-8 [Epub ahead of print].

New compounds containing thiazole and pyridinium moieties were designed and synthesized. The potency of the synthesized compounds as selective inhibitors of acetylcholinesterase (AChE), and β-amyloid aggregation (Aβ) was evaluated. Compounds 7d and 7j showed the best AChE inhibitory activities at the submicromolar concentration range (IC50 values of 0.40 and 0.69 μM, respectively). Most of the novel compounds showed moderate to low inhibition of butyrylcholinesterase (BChE), which is indicative of their selective inhibitory effects towards AChE. Kinetic studies using the most potent compounds 7d and 7j confirmed a mixed-type of AChE inhibition mechanism in accordance with the docking results, which shows their interactions with both catalytic active (CAS) and peripheral anionic (PAS) sites. The specific binding of 7a, 7j, and 7m to PAS domain of AChE was also confirmed experimentally. In addition, 7d and 7j were able to show β-amyloid self-aggregation inhibitory effects (20.38 and 42.66% respectively) stronger than donepezil (14.70%) assayed at 10 μM concentration. Moreover, compounds 7j and 7m were shown to be effective neuroprotective agents in H2O2-induced oxidative stress on PC12 cells almost similar to those observed for donepezil. The ability of 7j to pass blood-brain barrier was demonstrated using the PAMPA method. The results presented in this work provide useful information about designing novel anti-Alzheimer agents.

RevDate: 2020-09-09

Calderón-Garcidueñas L, Torres-Solorio AK, Kulesza RJ, et al (2020)

Gait and balance disturbances are common in young urbanites and associated with cognitive impairment. Air pollution and the historical development of Alzheimer's disease in the young.

Environmental research [Epub ahead of print].

To determine whether gait and balance dysfunction are present in young urbanites exposed to fine particular matter PM2.5 ≥ annual USEPA standard, we tested gait and balance with Tinetti and Berg tests in 575 clinically healthy subjects, age 21.0±5.7y who were residents in Metropolitan Mexico City, Villahermosa and Reynosa. The Montreal Cognitive Assessment was also applied to an independent cohort n:76, age 23.3± 9.1y. In the 575 cohort, 75.4% and 34.4% had abnormal total Tinetti and Berg scores and high risk of falls in 17.2% and 5.7% respectively. BMI impacted negatively Tinetti and Berg performance. Gait dysfunction worsen with age and males performed worse than females. Gait and balance dysfunction were associated with mild cognitive impairment MCI (19.73%) and dementia (55.26%) in 57/76 and 19 cognitively intact subjects had gait and balance dysfunction. Seventy-five percent of urbanites exposed to PM2.5 had gait and balance dysfunction. For MMC residents-with historical documented Alzheimer disease (AD) and CSF abnormalities, these findings suggest Alzheimer Continuum is in progress. Early development of a Motoric Cognitive Risk Syndrome ought to be considered in city dwellers with normal cognition and gait dysfunction. The AD research frame in PM2.5 exposed young urbanites should include gait and balance measurements. Multicity teens and young adult cohorts are warranted for quantitative gait and balance measurements and neuropsychological and brain imaging studies in high vs low PM2.5 exposures. Early identification of gait and balance impairment in young air pollution-exposed urbanites would facilitate multidisciplinary prevention efforts for modifying the course of AD.

RevDate: 2020-09-05

Arruda F, Rosselli M, Greig MT, et al (2020)

The Association Between Functional Assessment and Structural Brain Biomarkers in an Ethnically Diverse Sample With Normal Cognition, Mild Cognitive Impairment, or Dementia.

Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists pii:5901620 [Epub ahead of print].

OBJECTIVE: To investigate the association between the functional activities questionnaire (FAQ) and brain biomarkers (bilateral hippocampal volume [HV], bilateral entorhinal volume [ERV], and entorhinal cortical thickness [ERT]) in cognitively normal (CN) individuals, mild cognitive impairment (MCI), or dementia.

METHOD: In total, 226 participants (137 females; mean age = 71.76, SD = 7.93; Hispanic Americans = 137; European Americans = 89) were assessed with a comprehensive clinical examination, a neuropsychological battery, a structural magnetic resonance imaging, and were classified as CN or diagnosed with MCI or dementia. Linear regression analyses examined the association between functional activities as measured by the FAQ on brain biomarkers, including HV, ERV, and ERT, controlling for age, education, global cognition, gender, and ethnicity.

RESULTS: The FAQ significantly predicted HV, ERV, and ERT for the entire sample. However, this association was not significant for ERV and ERT when excluding the dementia group. The FAQ score remained a significant predictor of HV for the non-dementia group. Age, education, gender, ethnicity, Montreal Cognitive Assessment score, and FAQ were also significant predictors of HV for the overall sample, suggesting that younger Hispanic females with fewer years of education, higher global mental status, and better functioning, were more likely to have larger HV.

CONCLUSION: FAQ scores were related to HV in older adults across clinical groups (CN, MCI, and dementia), but its association with the entorhinal cortex was driven by individuals with dementia. Demographic variables, including ethnicity, additionally influenced these associations.

RevDate: 2020-09-11

Didehbani N, Fields LM, Wilmoth K, et al (2020)

Mild Cognitive Impairment in Retired Professional Football Players With a History of Mild Traumatic Brain Injury: A Pilot Investigation.

Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology, 33(3):208-217.

BACKGROUND: Traumatic brain injury (TBI) is a known risk factor for neurodegenerative dementias such as Alzheimer disease (AD); however, the potential risk of mild cases of TBI, such as concussions, remains unclear.

OBJECTIVE: To explore whether a small sample of retired professional athletes with a diagnosis of mild cognitive impairment (MCI)-the prodromal stage of AD-and a history of multiple mild TBIs exhibit greater neuropsychological impairment than age-matched nonathletes with MCI and no history of TBI.

METHOD: Ten retired National Football League players diagnosed with MCI and reporting multiple mild TBIs, and 10 nonathletes, also diagnosed with MCI but with no history of TBI, completed a standard neurologic examination and neuropsychological testing. Independent samples t tests were conducted to examine differences in neuropsychological performance between the two groups.

RESULTS: The retired athletes with a history of mild TBI obtained generally similar scores to the nonathlete controls on measures of verbal learning and memory, verbal fluency, and processing speed. However, the retired athletes scored lower than the controls on tests of confrontation naming and speeded visual attention.

CONCLUSION: Retired athletes with MCI and a history of mild TBI demonstrated similar neuropsychological profiles as nonathlete controls despite lower scores on measures of confrontation naming and speeded visual attention. These findings suggest that a history of multiple mild TBIs does not significantly alter the overall neuropsychological profile of individuals with MCI; confirmation of this will require longitudinal research with larger sample sizes.

RevDate: 2020-09-05

Calderón-Garcidueñas L, González-Maciel A, Reynoso-Robles R, et al (2020)

Quadruple abnormal protein aggregates in brainstem pathology and exogenous metal-rich magnetic nanoparticles. The substantia nigrae is a very early target in young urbanites and the gastrointestinal tract likely a key brainstem portal.

Environmental research pii:S0013-9351(20)31036-7 [Epub ahead of print].

Fine particulate air pollution (PM2.5) exposures are linked with Alzheimer's and Parkinson's diseases. AD and PD neuropathological hallmarks are documented in children and young adults exposed lifelong to Metropolitan Mexico City air pollution; together with high frontal metal concentrations (especially iron)-rich nanoparticles (NP), matching air pollution combustion and friction-derived particles. Here, we identify aberrant hyperphosphorylated tau, ɑ synuclein and TDP-43 in the brainstem of 186 Mexico City 27.29±11.8y old residents. Critically, substantia nigrae (SN) pathology seen in mitochondria, endoplasmic reticulum and neuromelanin (NM) is co-associated with the abundant presence of exogenous, Fe-, Al- and Ti-rich NPs.The SN exhibits early and progressive neurovascular unit damage and mitochondria and NM exogenous engineered Ti-rich nanorods, also identified in neuroenteric neurons. Such reactive, cytotoxic and magnetic NPs may act as catalysts for reactive oxygen species formation, altered cell signaling, and protein misfolding, aggregation and fibril formation. Hence, pervasive, airborne and environmental, metal-rich and magnetic nanoparticles may be a common denominator for quadruple misfolded protein neurodegenerative pathologies affecting urbanites from earliest childhood. The substantia nigrae is a very early target and the gastrointestinal tract (and the neuroenteric system) likely key brainstem portals. The ultimate neural damage and neuropathology (Alzheimer's, Parkinson's and TDP-43 pathology included) could depend on NP characteristics and the differential access and targets achieved via their portals of entry,thus where you live, what air pollutants you are exposed to, what you are inhaling and swallowing from the air you breath, what you eat, how you travel, and your occupational longlife history are key. Control of NP sources becomes critical.

RevDate: 2020-09-07

Borja AJ, Hancin EC, Khosravi M, et al (2020)

Applications of Hybrid PET/Magnetic Resonance Imaging in Central Nervous System Disorders.

PET clinics, 15(4):497-508.

PET with 18F-fluorodeoxyglucose (FDG) is used to assess a wide array of inflammatory and neoplastic disorders. FDG-PET has shown particular utility in the evaluation of disorders of the central nervous system (CNS). Although fused PET/computed tomography (CT) is frequently used across the globe for these diseases, recent evidence has pointed to PET/magnetic resonance (MR) imaging as a more sensitive and specific molecular imaging modality. This article reviews the literature regarding the advantages of PET/MR imaging compared with PET/CT imaging, especially in CNS disease. It also introduces a new concept for PET-based evaluation of patients with neurodegenerative disorders: global disease assessment.

RevDate: 2020-09-17

Zhao L, Li Z, Vong JSL, et al (2020)

Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain.

Nature communications, 11(1):4413.

The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovascular dysfunction in neurodegenerative diseases remain elusive. Here, we report zonation-dependent transcriptomic changes in aged mouse brain endothelial cells (ECs), which prominently implicate altered immune/cytokine signaling in ECs of all vascular segments, and functional changes impacting the blood-brain barrier (BBB) and glucose/energy metabolism especially in capillary ECs (capECs). An overrepresentation of Alzheimer disease (AD) GWAS genes is evident among the human orthologs of the differentially expressed genes of aged capECs, while comparative analysis revealed a subset of concordantly downregulated, functionally important genes in human AD brains. Treatment with exenatide, a glucagon-like peptide-1 receptor agonist, strongly reverses aged mouse brain EC transcriptomic changes and BBB leakage, with associated attenuation of microglial priming. We thus revealed transcriptomic alterations underlying brain EC ageing that are complex yet pharmacologically reversible.

RevDate: 2020-09-09

El Alili M, Smaling HJA, Joling KJ, et al (2020)

Cost-effectiveness of the Namaste care family program for nursing home residents with advanced dementia in comparison with usual care: a cluster-randomized controlled trial.

BMC health services research, 20(1):831.

BACKGROUND: Dementia is a progressive disease that decreases quality of life of persons with dementia and is associated with high societal costs. The burden of caring for persons with dementia also decreases the quality of life of family caregivers. The objective of this study was to assess the societal cost-effectiveness of Namaste Care Family program in comparison with usual care in nursing home residents with advanced dementia.

METHODS: Nursing homes were randomized to either Namaste Care Family program or usual care. Outcome measures of the cluster-randomized trial in 231 residents included Quality of Life in Late-Stage Dementia (QUALID) and the Gain in Alzheimer Care Instrument (GAIN) for family caregivers over 12 months of follow-up. Health states were measured using the EQ-5D-3L questionnaire which were translated into utilities. QALYs were calculated by multiplying the amount of time a participant spent in a specific health state with the utility score associated with that health state. Healthcare utilization costs were estimated using standard unit costs, while intervention costs were estimated using a bottom-up approach. Missing cost and effect data were imputed using multiple imputation. Bootstrapped multilevel models were used after multiple imputation. Cost-effectiveness acceptability curves were estimated.

RESULTS: The Namaste Care Family program was more effective than usual care in terms of QUALID (- 0.062, 95%CI: - 0.40 to 0.28), QALY (0.0017, 95%CI: - 0.059 to 0.063) and GAIN (0.075, 95%CI: - 0.20 to 0.35). Total societal costs were lower for the Namaste Care Family program as compared to usual care (- 552 €, 95%CI: - 2920 to 1903). However, these differences were not statistically significant. The probability of cost-effectiveness at a ceiling ratio of 0 €/unit of effect extra was 0.70 for the QUALID, QALY and GAIN.

CONCLUSIONS: The Namaste Care Family program is dominant over usual care and, thus, cost-effective, although statistical uncertainty was considerable.

TRIAL REGISTRATION: Netherlands Trial Register (http://www.trialregister.nl/trialreg/index.asp , identifier: NL5570, date of registration: 2016/03/23).


RJR Experience and Expertise


Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.


Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.


Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.


Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.


While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.


Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.


Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.


Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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Bellingham, WA 98226


E-mail: RJR8222@gmail.com

Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

Research Gate page for R J Robbins

ResearchGate is a social networking site for scientists and researchers to share papers, ask and answer questions, and find collaborators. According to a study by Nature and an article in Times Higher Education , it is the largest academic social network in terms of active users.

Curriculum Vitae for R J Robbins

short personal version

Curriculum Vitae for R J Robbins

long standard version

RJR Picks from Around the Web (updated 11 MAY 2018 )