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Bibliography on: Alzheimer Disease — Current Literature

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Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 19 Apr 2021 at 01:31 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] OR 2021[PDAT]) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2021-04-17

Schreyer S, Berndt N, Eckstein J, et al (2021)

Dietary-challenged mice with Alzheimer-like pathology show increased energy expenditure and reduced adipocyte hypertrophy and steatosis.

Aging, 13: pii:202978 [Epub ahead of print].

Alzheimer's disease (AD) is frequently accompanied by progressing weight loss, correlating with mortality. Counter-intuitively, weight loss in old age might predict AD onset but obesity in midlife increases AD risk. Furthermore, AD is associated with diabetes-like alterations in glucose metabolism. Here, we investigated metabolic features of amyloid precursor protein overexpressing APP23 female mice modeling AD upon long-term challenge with high-sucrose (HSD) or high-fat diet (HFD). Compared to wild type littermates (WT), APP23 females were less prone to mild HSD-induced and considerable HFD-induced glucose tolerance deterioration, despite unaltered glucose tolerance during normal-control diet. Indirect calorimetry revealed increased energy expenditure and hyperactivity in APP23 females. Dietary interventions, especially HFD, had weaker effects on lean and fat mass gain, steatosis and adipocyte hypertrophy of APP23 than WT mice, as shown by 1H-magnetic-resonance-spectroscopy, histological and biochemical analyses. Proteome analysis revealed differentially regulated expression of mitochondrial proteins in APP23 livers and brains. In conclusion, hyperactivity, increased metabolic rate, and global mitochondrial dysfunction potentially add up to the development of AD-related body weight changes in APP23 females, becoming especially evident during diet-induced metabolic challenge. These findings emphasize the importance of translating this metabolic phenotyping into human research to decode the metabolic component in AD pathogenesis.

RevDate: 2021-04-16

Désormeaux-Moreau M, Michel CM, Vallières M, et al (2021)

Mobile Apps to Support Family Caregivers of People With Alzheimer Disease and Related Dementias in Managing Disruptive Behaviors: Qualitative Study With Users Embedded in a Scoping Review.

JMIR aging, 4(2):e21808 pii:v4i2e21808.

BACKGROUND: People with Alzheimer disease and related dementias often display disruptive behaviors (eg, aggression, wandering, and restlessness), which increase family caregivers' burden of care. However, there are few tools currently available to help these caregivers manage disruptive behaviors. Mobile apps could meet this need, but to date little is known about them.

OBJECTIVE: The aims of our study were to identify existing mobile apps designed to support family caregivers of people with Alzheimer disease and related dementias in managing disruptive behaviors; explore whether family caregivers view these mobile apps as relevant to meeting their needs and as useful in managing disruptive behaviors; and document the types of mobile apps that are of interest and appeal to most family caregivers (with regard to format, ergonomics, and clarity).

METHODS: A review of mobile apps initially conducted in February 2018 was updated in March 2019 with 2 platforms (App Store [Apple Inc.] and Google Play [Google]). The selected apps were first analyzed independently by 3 raters (2 students and 1 researcher) for each of the platforms. A focus group discussion was then held with 4 family caregivers to explore their perceptions of the apps according to their needs and interests. The content of the discussion was analyzed.

RESULTS: Initially, 7 of 118 apps identified met the inclusion criteria. An eighth app, recommended by one of the knowledge users, was added later. Four family caregivers (women aged between 58 and 78 years) participated in the discussion. Participants expressed a preference for easy-to-understand apps that provide concrete intervention strategies. They reported being most inclined to use two apps, Dementia Advisor and DTA Behaviours.

CONCLUSIONS: Few mobile apps on the market meet the needs of family caregivers in terms of content and usability. Our results could help to address this gap by identifying what family caregivers deem relevant in a mobile app to help them manage disruptive behaviors.

RevDate: 2021-04-16

K C S, Kakoty V, Krishna KV, et al (2021)

Neuroprotective Efficacy of Co-Encapsulated Rosiglitazone and Vorinostat Nanoparticle on Streptozotocin Induced Mice Model of Alzheimer Disease.

ACS chemical neuroscience [Epub ahead of print].

Anomalies in brain insulin signaling have been demonstrated to be involved in the pathology of Alzheimer disease (AD). In this context, the neuroprotective efficacy of an insulin sensitizer, rosiglitazone, has been confirmed in our previous study. In the present study, we hypothesize that a combination of an epigenetic modulator, vorinostat, along with rosiglitazone can impart improved gene expression of neurotrophic factors and attenuate biochemical and cellular alteration associated with AD mainly by loading these drugs in a surface modified nanocarrier system for enhanced bioavailability and enhanced therapeutic efficacy. Hence, in this study, rosiglitazone and vorinostat were loaded onto a poloxamer stabilized polymeric nanocarrier system and administered to mice in the intracerebroventricular streptozotocin (3 mg/kg) induced model of AD. Treatment with the free drug combination (rosiglitazone 5 mg/kg, vorinostat 25 mg/kg) for 3 weeks attenuated the behavioral, biochemical, and cellular alterations as compared to either treatment alone (rosiglitazone 10 mg/kg, vorinostat 50 mg/kg). Further, the coencapsulated nanoformulation (rosiglitazone 5 mg/kg, vorinostat 25 mg/kg) exerted better neuroprotective efficacy than the free drug combination as evidenced by improved behavioral outcome, reduced oxidative stress, and elevated levels of neurotrophic factors. In conclusion, the synergistic neuroprotective efficacy of rosiglitazone and vorinostat has been increased through the poloxamer stabilized polymeric nanocarrier system.

RevDate: 2021-04-16

Creekmore BC, Chang YW, EB Lee (2021)

The Cryo-EM Effect: Structural Biology of Neurodegenerative Disease Proteostasis Factors.

Journal of neuropathology and experimental neurology pii:6226995 [Epub ahead of print].

Neurodegenerative diseases are characterized by the accumulation of misfolded proteins. This protein aggregation suggests that abnormal proteostasis contributes to aging-related neurodegeneration. A better fundamental understanding of proteins that regulate proteostasis may provide insight into the pathophysiology of neurodegenerative disease and may perhaps reveal novel therapeutic opportunities. The 26S proteasome is the key effector of the ubiquitin-proteasome system responsible for degrading polyubiquitinated proteins. However, additional factors, such as valosin-containing protein (VCP/p97/Cdc48) and C9orf72, play a role in regulation and trafficking of substrates through the normal proteostasis systems of a cell. Nonhuman AAA+ ATPases, such as the disaggregase Hsp104, also provide insights into the biochemical processes that regulate protein aggregation. X-ray crystallography and cryo-electron microscopy (cryo-EM) structures not bound to substrate have provided meaningful information about the 26S proteasome, VCP, and Hsp104. However, recent cryo-EM structures bound to substrate have provided new information about the function and mechanism of these proteostasis factors. Cryo-EM and cryo-electron tomography data combined with biochemical data have also increased the understanding of C9orf72 and its role in maintaining proteostasis. These structural insights provide a foundation for understanding proteostasis mechanisms with near-atomic resolution upon which insights can be gleaned regarding the pathophysiology of neurodegenerative diseases.

RevDate: 2021-04-16

Walker JM, Fudym Y, Farrell K, et al (2021)

Asymmetry of Hippocampal Tau Pathology in Primary Age-Related Tauopathy and Alzheimer Disease.

Journal of neuropathology and experimental neurology pii:6226997 [Epub ahead of print].

Primary age-related tauopathy (PART) is a neurodegenerative entity defined as neurofibrillary degeneration generally restricted to the medial temporal region (Braak stage I-IV) with complete or near absence of diffuse and neuritic plaques. Symptoms range in severity but are generally milder and later in onset than in Alzheimer disease (AD). Recently, an early predilection for neurofibrillary degeneration in the hippocampal CA2 subregion has been demonstrated in PART, whereas AD neuropathologic change (ADNC) typically displays relative sparing of CA2 until later stages. In this study, we utilized a semiquantitative scoring system to evaluate asymmetry of neurofibrillary degeneration between left and right hippocampi in 67 PART cases and 17 ADNC cases. 49% of PART cases demonstrated asymmetric findings in at least one hippocampal subregion, and 79% of the asymmetric cases displayed some degree of CA2 asymmetry. Additionally, 19% of cases revealed a difference in Braak score between the right and left hippocampi. There was a significant difference in CA2 neurofibrillary degeneration (p = 0.0006) and CA2/CA1 ratio (p < 0.0001) when comparing the contralateral sides, but neither right nor left was more consistently affected. These data show the importance of analyzing bilateral hippocampi in the diagnostic evaluation of PART and potentially of other neurodegenerative diseases.

RevDate: 2021-04-16

Wang W, Zhou Q, Jiang T, et al (2021)

A novel small-molecule PROTAC selectively promotes tau clearance to improve cognitive functions in Alzheimer-like models.

Theranostics, 11(11):5279-5295 pii:thnov11p5279.

Intracellular accumulation of tau is a hallmark pathology in Alzheimer disease (AD) and the related tauopathies, thus targeting tau could be promising for drug development. Proteolysis Targeting Chimera (PROTAC) is a novel drug discovery strategy for selective protein degradation from within cells. Methods: A novel small-molecule PROTAC, named as C004019 with a molecular mass of 1,035.29 dalton, was designed to simultaneously recruite tau and E3-ligase (Vhl) and thus to selectively enhance ubiquitination and proteolysis of tau proteins. Western blotting, immunofluoresence and immunohistochemical staining were employed to verify the effects of C004019 in cell models (HEK293 and SH-SY5Y) and mouse models (hTau-transgenic and 3xTg-AD), respectively. The cognitive capacity of the mice was assessed by a suite of behavior experiments. Electrophysiology and Golgi staining were used to evaluate the synaptic plasticity. Results: C004019 induced a robust tau clearance via promoting its ubiquitination-proteasome-dependent proteolysis in HEK293 cells with stable or transient overexpression of human tau (hTau), and in SH-SY5Y that constitutively overexpress hTau. Furthermore, intracerebral ventricular infusion of C004019 induced a robust tau clearance in vivo. Most importantly, both single-dose and multiple-doses (once per 6 days for a total 5 times) subcutaneous administration of C004019 remarkably decreased tau levels in the brains of wild-type, hTau-transgenic and 3xTg-AD mice with improvement of synaptic and cognitive functions. Conclusions: The PROTAC (C004019) created in the current study can selectively and efficiently promote tau clearance both in vitro and in vivo, which provides a promising drug candidate for AD and the related tauopathies.

RevDate: 2021-04-16

Ramos-Zúñiga R, Guerrero-Cázares H, Gómez-Pinedo U, et al (2021)

Editorial: The Use of Biomaterials With Stem and Precursor Cells in Diseases of the Central Nervous System; A Step to Clinical Trials.

Frontiers in neurology, 12:654890.

RevDate: 2021-04-16

Main P, Tan WJ, Wheeler D, et al (2021)

Increased Abundance of Nuclear HDAC4 Impairs Neuronal Development and Long-Term Memory.

Frontiers in molecular neuroscience, 14:616642.

Dysregulation of the histone deacetylase HDAC4 is associated with both neurodevelopmental and neurodegenerative disorders, and a feature common to many of these disorders is impaired cognitive function. HDAC4 shuttles between the nucleus and cytoplasm in both vertebrates and invertebrates and alterations in the amounts of nuclear and/or cytoplasmic HDAC4 have been implicated in these diseases. In Drosophila, HDAC4 also plays a critical role in the regulation of memory, however, the mechanisms through which it acts are unknown. Nuclear and cytoplasmically-restricted HDAC4 mutants were expressed in the Drosophila brain to investigate a mechanistic link between HDAC4 subcellular distribution, transcriptional changes and neuronal dysfunction. Deficits in mushroom body morphogenesis, eye development and long-term memory correlated with increased abundance of nuclear HDAC4 but were associated with minimal transcriptional changes. Although HDAC4 sequesters MEF2 into punctate foci within neuronal nuclei, no alteration in MEF2 activity was observed on overexpression of HDAC4, and knockdown of MEF2 had no impact on long-term memory, indicating that HDAC4 is likely not acting through MEF2. In support of this, mutation of the MEF2 binding site within HDAC4 also had no impact on nuclear HDAC4-induced impairments in long-term memory or eye development. In contrast, the defects in mushroom body morphogenesis were ameliorated by mutation of the MEF2 binding site, as well as by co-expression of MEF2 RNAi, thus nuclear HDAC4 acts through MEF2 to disrupt mushroom body development. These data provide insight into the mechanisms through which dysregulation of HDAC4 subcellular distribution impairs neurological function and provides new avenues for further investigation.

RevDate: 2021-04-14

Zeinivand M, Nahavandi A, Baluchnejadmojarad T, et al (2020)

Dalteparin as a Novel Therapeutic Agent to Prevent Diabetic Encephalopathy by Targeting Oxidative Stress and Inflammation.

Basic and clinical neuroscience, 11(6):795-804.

Introduction: Hepcidin is the main modulator of systemic iron metabolism, and its role in the brain has been clarified recently. Studies have shown that hepcidin plays an important role in neuronal iron load and inflammation. This issue is of significance because neuronal iron load and inflammation are pathophysiological processes that are highly linked to neurodegeneration. Moreover, the activity of hepcidin has recently been manipulated to recover the neuronal impairment caused by brain inflammation in animal models.

Methods: Streptozotocin (STZ) was used to induce type 1 diabetes. Male Wistar rats (n = 40) with a weight range of 200-250 g were divided into control, diabetic, diabetic + insulin, and diabetic + dalteparin groups. Dalteparin (100 mg/kg IP) and insulin (100 mg/kg SC) were administered for 8 weeks. At the end of the experiment, Y-maze and passive avoidance tasks were carried out. The animals were perfused randomly and their hippocampal tissue was isolated for the analysis of markers such as lipid peroxidation like Malondialdehyde (MDA), hepcidin expression, iron, and ferritin. Blood samples were taken for the measurement of serum inflammatory cytokine Interleukin (IL)-6.

Results: The findings indicated that treatment with dalteparin reduced IL-6, MDA, ferritin, and hepcidin expression in diabetic rats compared to treatment with insulin (P<0.05). Moreover, treatment with dalteparin did not decrease the iron level or prevented its decline.

Conclusion: Treatment with dalteparin improved the cognitive dysfunctions and symptoms of Alzheimer disease in STZ-induced diabetic rats by appropriately modulating and reducing oxidative stress and neuroinflammation. This may enhance the existing knowledge of therapeutics to reduce cognitive impairment in diabetes and is suggested to be a potential therapeutic agent in diabetes.

RevDate: 2021-04-14

Cyprien F, Berr C, Maller JJ, et al (2021)

Late-life cynical hostility is associated with white matter alterations and the risk of Alzheimer's disease.

Psychological medicine pii:S0033291721000416 [Epub ahead of print].

BACKGROUND: Cynical hostility (CH), a specific dimension of hostility that consists of a mistrust of others, has been suggested as a high-risk trait for dementia. However, the influence of CH on the incidence of Alzheimer's disease (AD) remains poorly understood. This study investigated whether late-life CH is associated with AD risk and structural neuroimaging markers of AD.

METHODS: In community-dwelling older adults from the French ESPRIT cohort (n = 1388), incident dementia rate according to CH level was monitored during an 8-year follow-up and analyzed using Cox proportional hazards regression models. Brain magnetic resonance imaging volumes were measured at baseline (n = 508). Using automated segmentation procedures (Freesurfer 6.0), the authors assessed brain grey and white volumes on all magnetic resonance imaging scans. They also measured white matter hyperintensities volumes using semi-automated procedures. Mean volumes according to the level of CH were compared using ANOVA.

RESULTS: Eighty-four participants developed dementia (32 with AD). After controlling for potential confounders, high CH was predictive of AD (HR 2.74; 95% CI 1.10-6.85; p = 0.030) and all dementia types are taken together (HR 2.30; 95% CI 1.10-4.80; p = 0.027). High CH was associated with white matter alterations, particularly smaller anterior corpus callosum volume (p < 0.01) after False Discovery Rate correction, but not with grey matter volumes.

CONCLUSIONS: High CH in late life is associated with cerebral white matter alterations, designated as early markers of dementia, and higher AD risk. Identifying lifestyle and biological determinants related to CH could provide clues on AD physiopathology and avenues for prevention strategies.

RevDate: 2021-04-14

Cho Y, Han K, Kim DH, et al (2021)

Cumulative Exposure to Metabolic Syndrome Components and the Risk of Dementia: A Nationwide Population-Based Study.

Endocrinology and metabolism (Seoul, Korea) pii:EnM.2020.935 [Epub ahead of print].

Background: Metabolic disturbances are modifiable risk factors for dementia. Because the status of metabolic syndrome (MetS) and its components changes over time, we aimed to investigate the association of the cumulative exposure to MetS and its components with the risk of dementia.

Methods: Adults (n=1,492,776; ≥45-years-old) who received health examinations for 4 consecutive years were identified from a nationwide population-based cohort in Korea. Two exposure-weighted scores were calculated: cumulative number of MetS diagnoses (MetS exposure score, range of 0 to 4) and the composite of its five components (MetS component exposure score, range of 0 to 20). Hazard ratio (HR) and 95% confidence interval (CI) values for dementia were analyzed using the multivariable Cox proportional-hazards model.

Results: Overall, 47.1% of subjects were diagnosed with MetS at least once, and 11.5% had persistent MetS. During the mean 5.2 years of follow-up, there were 7,341 cases (0.5%) of incident dementia. There was a stepwise increase in the risk of all-cause dementia, Alzheimer's disease, and vascular dementia with increasing MetS exposure score and MetS component exposure score (each P for trend <0.0001). The HR of all-cause dementia was 2.62 (95% CI, 1.87 to 3.68) in subjects with a MetS component exposure score of 20 compared with those with a score of 0. People fulfilling only one MetS component out of 20 already had an approximately 40% increased risk of all-cause dementia and Alzheimer's disease.

Conclusion: More cumulative exposure to metabolic disturbances was associated with a higher risk of dementia. Of note, even minimal exposure to MetS components had a significant effect on the risk of dementia.

RevDate: 2021-04-15
CmpDate: 2021-04-15

Farkas MH, MM DeAngelis (2021)

Age-Related Macular Degeneration: From Epigenetics to Therapeutic Implications.

Advances in experimental medicine and biology, 1256:221-235.

Aberrant regulation of epigenetic mechanisms, including the two most common types; DNA methylation and histone modification have been implicated in common chronic progressive conditions, including Alzheimer disease, cardiovascular disease, and age-related macular degeneration (AMD). All these conditions are complex, meaning that environmental factors, genetic factors, and their interactions play a role in disease pathophysiology. Although genome wide association studies (GWAS), and studies on twins demonstrate the genetic/hereditary component to these complex diseases, including AMD, this contribution is much less than 100%. Moreover, the contribution of the hereditary component decreases in the advanced, later onset forms of these chronic diseases including AMD. This underscores the need to elucidate how the genetic and environmental factors function to exert their influence on disease pathophysiology. By teasing out epigenetic mechanisms and how they exert their influence on AMD, therapeutic targets can be tailored to prevent and/or slow down disease progression. Epigenetic studies that incorporate well-characterized patient tissue samples (including affected tissues and peripheral blood), similar to those relevant to gene expression studies, along with genetic and epidemiological information, can be the first step in developing appropriate functional assays to validate findings and identify potential therapies.

RevDate: 2021-04-14

Grunenwald A, LT Roumenina (2021)

The Benefits of Complement Measurements for the Clinical Practice.

Methods in molecular biology (Clifton, N.J.), 2227:1-20.

The complement cascade is an evolutionary ancient innate immune defense system, playing a major role in the defense against infections. Its function in maintaining host homeostasis on activated cells has been emphasized by the crucial role of its overactivation in ever growing number of diseases, such as atypical hemolytic uremic syndrome (aHUS), autoimmune diseases as systemic lupus erythematosus (SLE), C3 glomerulopathies (C3GN), age-related macular degeneration (AMD), graft rejection, Alzheimer disease, and cancer, to name just a few. The last decade of research on complement has extended its implication in many pathological processes, offering new insights to potential therapeutic targets and asserting the necessity of reliable, sensitive, specific, accurate, and reproducible biomarkers to decipher complement role in pathology. We need to evaluate accurately which pathway or role should be targeted pharmacologically, and optimize treatment efficacy versus toxicity. This chapter is an introduction to the role of complement in human diseases and the use of complement-related biomarkers in the clinical practice. It is a part of a book intending to give reliable and standardized methods to evaluate complement according to nowadays needs and knowledge.

RevDate: 2021-04-13

Lieberman RL, MT Ma (2021)

Molecular Insights into Myocilin and Its Glaucoma-Causing Misfolded Olfactomedin Domain Variants.

Accounts of chemical research [Epub ahead of print].

ConspectusNumerous human disorders arise due to the inability of a particular protein to adopt its correct three-dimensional structure in the context of the cell, leading to aggregation. A new addition to the list of such protein conformational disorders is the inherited subtype of glaucoma. Different and rare coding mutations in myocilin, found in families throughout the world, are causal for early onset ocular hypertension, a key glaucoma risk factor. Myocilin is expressed at high levels in the trabecular meshwork (TM) extracellular matrix. The TM is the anatomical region of the eye that regulates intraocular pressure, and its dysfunction is associated with most forms of glaucoma. Disease variants, distributed across the 30 kDa olfactomedin domain (mOLF), cause myocilin to be sequestered intracellularly instead of being secreted to the TM extracellular matrix. The working hypothesis is that the intracellular aggregates cause a toxic gain of function: TM cell death is thought to lead to TM matrix dysfunction, hastening elevated intraocular pressure and subsequent vision loss.Our lab has provided molecular underpinnings for myocilin structure and misfolding, placing myocilin-associated glaucoma within the context of amyloid diseases like Alzheimer and diabetes. We have dissected complexities of the modular wild-type (WT) myocilin structure and associated misfolded states. Our data support the model that full-length WT myocilin adopts a Y-shaped dimer-of-dimers conferred by two different coiled-coil regions, generating new hypotheses regarding its mysterious function. The mOLF β-propellers are paired at each tip of the Y. Disease-associated variants aggregate because mOLFs are less stable, leading to facile aggregation under physiological conditions (37 °C, pH 7.2). Mutant myocilin aggregates exhibit numerous characteristics of amyloid in vitro and in cells, and aggregation proceeds from a partially folded state accessed preferentially by disease variants at physiological conditions. Interestingly, destabilization is not a universal consequence of mutation. We identified counterintuitive, stabilizing point variants that adopt a non-native structure and do not aggregate; however, these variants have not been identified in glaucoma patients. An ongoing effort is predicting the consequence of any given mutation. This effort is relevant to interpreting data from large-scale sequencing projects where clinical and family history data are not available. Finally, our work suggests avenues to develop disease-modifying precision medicines for myocilin-associated glaucoma.

RevDate: 2021-04-13

Thomassen JQ, Tolstrup JS, Nordestgaard BG, et al (2021)

Plasma Concentrations of Magnesium and Risk of Dementia: A General Population Study of 102 648 Individuals.

Clinical chemistry pii:6224353 [Epub ahead of print].

BACKGROUND: Low and high concentrations of plasma magnesium are associated with increased risk of future all-cause dementia; however, the underlying reasons remain elusive. The magnesium ion is an important electrolyte serving as a cofactor in many enzymatic processes in the human organism. Magnesium affects both neuronal and vascular functions. We investigated the associations of plasma concentrations of magnesium associate with common subtypes of dementia as Alzheimer dementia and non-Alzheimer dementia, and potential pathways by which magnesium may affect risk of dementia.

METHODS: Plasma concentrations of magnesium were measured in 102 648 individuals from the Copenhagen General Population Study. Cox regression and natural effects mediation analyses evaluated associations with either Alzheimer dementia or non-Alzheimer dementia.

RESULTS: Multifactorially adjusted hazard ratios for non-Alzheimer dementia were 1.50(95% confidence interval (CI):1.21-1.87) for the lowest and 1.34(1.07-1.69) for the highest vs the fourth quintile (reference) of plasma magnesium concentrations. Diabetes, cumulated smoking, stroke, and systolic blood pressure mediated 10.4%(3.1-22.8%), 6.8%(1.2-14.0%), 1.3%(0.1-3.6%), and 1.0%(0.2-2.6%), respectively, in the lowest quintile, whereas stroke mediated 3.2%(0.4-11.9%) in the highest quintile. No associations were observed for Alzheimer dementia.

CONCLUSIONS: Low and high plasma magnesium concentrations were associated with high risk of vascular-related non-Alzheimer dementia, with the lowest risk observed at a concentration of 2.07 mg/dL (0.85 mmol/L). No association was observed for Alzheimer dementia. Mediation analysis suggested that diabetes may be in the causal pathway between low plasma magnesium concentrations and high risk of non-Alzheimer dementia, while cumulated smoking, stroke, and systolic blood pressure played minor mediating roles.

RevDate: 2021-04-13

Akdis CA (2021)

Does the epithelial barrier hypothesis explain the increase in allergy, autoimmunity and other chronic conditions?.

Nature reviews. Immunology [Epub ahead of print].

There has been a steep increase in allergic and autoimmune diseases, reaching epidemic proportions and now affecting more than one billion people worldwide. These diseases are more common in industrialized countries, and their prevalence continues to rise in developing countries in parallel to urbanization and industrialization. Intact skin and mucosal barriers are crucial for the maintenance of tissue homeostasis as they protect host tissues from infections, environmental toxins, pollutants and allergens. A defective epithelial barrier has been demonstrated in allergic and autoimmune conditions such as asthma, atopic dermatitis, allergic rhinitis, chronic rhinosinusitis, eosinophilic esophagitis, coeliac disease and inflammatory bowel disease. In addition, leakiness of the gut epithelium is also implicated in systemic autoimmune and metabolic conditions such as diabetes, obesity, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis and autoimmune hepatitis. Finally, distant inflammatory responses due to a 'leaky gut' and microbiome changes are suspected in Alzheimer disease, Parkinson disease, chronic depression and autism spectrum disorders. This article introduces an extended 'epithelial barrier hypothesis', which proposes that the increase in epithelial barrier-damaging agents linked to industrialization, urbanization and modern life underlies the rise in allergic, autoimmune and other chronic conditions. Furthermore, it discusses how the immune responses to dysbiotic microbiota that cross the damaged barrier may be involved in the development of these diseases.

RevDate: 2021-04-15

Saviano A, Casillo GM, Raucci F, et al (2021)

Supplementation with ribonucleotide-based ingredient (Ribodiet®) lessens oxidative stress, brain inflammation, and amyloid pathology in a murine model of Alzheimer.

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 139:111579 pii:S0753-3322(21)00364-4 [Epub ahead of print].

Alzheimer's disease (AD) is the most common type of dementia worldwide, characterized by the deposition of neurofibrillary tangles and amyloid-β (Aβ) peptides in the brain. Additionally, increasing evidence demonstrates that a neuroinflammatory state and oxidative stress, iron-dependent, play a crucial role in the onset and disease progression. Besides conventional therapies, the use of natural-based products represents a future medical option for AD treatment and/or prevention. We, therefore, evaluated the effects of a ribonucleotides-based ingredient (Ribodiet®) in a non-genetic mouse model of AD. To this aim, mice were injected intracerebroventricularly (i.c.v.) with Aβ1-42 peptide (3 µg/3 μl) and after with Ribodiet® (0.1-10 mg/mouse) orally (p.o.) 3 times weekly for 21 days following the induction of experimental AD. The mnemonic and cognitive decline was then evaluated, and, successively, we have assessed ex vivo the modulation of different cyto-chemokines on mice brain homogenates. Finally, the level of GFAP, S100β, and iron-related metabolic proteins were monitored as markers of reactive gliosis, neuro-inflammation, and oxidative stress. Results indicate that Ribodiet® lessens oxidative stress, brain inflammation, and amyloid pathology via modulation of iron-related metabolic proteins paving the way for its rationale use for the treatment of AD and other age-related diseases.

RevDate: 2021-04-12

Rouch L, De Souto Barreto P, Hanon O, et al (2021)

Visit-to-visit blood pressure variability and incident frailty in older adults.

The journals of gerontology. Series A, Biological sciences and medical sciences pii:6222275 [Epub ahead of print].

To determine whether visit-to-visit blood pressure (BP) variability (BPV) is associated with incident frailty. We included 1,394 non-frail community-dwelling participants aged ≥ 70 years from the Multidomain Alzheimer Preventive Trial (MAPT) who underwent repeated clinical examinations, including BP and frailty, over a 5-year follow-up period. Systolic BPV (SBPV), diastolic BPV (DBPV), mean arterial pressure variability (MAPV) and pulse pressure variability (PPV) were evaluated using standard deviation, coefficient of variation (CV), average real variability, successive variation, variation independent of mean and residual standard deviation. Incident frailty was assessed using the Fried phenotype. Cox proportional hazards models were used for the analyses. Higher SBPV was significantly associated with greater risk of frailty (1-sd increase of CV: HR = 1.18, 95% CI [1.02-1.36]) after adjustment for demographics, systolic BP, antihypertensive drugs, body mass index, diabetes, ischemic heart disease, congestive heart failure, stroke, atrial fibrillation, MAPT randomization group and frailty status. Similar results were observed with all indicators of variability. Higher PPV was associated with a greater risk of developing frailty over time (1-sd increase of CV: HR = 1.17, 95% CI [1.01-1.35]). DBPV and MAPV were not significantly associated with incident frailty. Higher SBPV and PPV were associated with greater risk of incident frailty. Our findings support the concept of BP physiological dysregulation underlying the frail state and suggest that BP instability could be an early marker of frailty.

RevDate: 2021-04-13

Müller P, Vellage AK, Schmicker M, et al (2021)

Structural MRI of the basal forebrain as predictor of cognitive response to galantamine in healthy older adults-A randomized controlled double-blinded crossover study.

Alzheimer's & dementia (New York, N. Y.), 7(1):e12153.

Introduction: Cholinesterase inhibitors can enhance cognitive functions in healthy elderly and delay cognitive decline in patients with Alzheimer`s disease (AD). However, not everyone benefits from this treatment (non-responders). Current studies show clinical meaningful improvements only in one third of AD patients treated with cholinesterase inhibitors.

Methods: Here we investigate structural magnetic resonance imaging of the basal forebrain cholinergic system volume (BFvol) as a potential predictor of cognitive response to a single dose of galantamine in healthy adults (n = 18; 59 to 75 years).

Results: We observed that the cognitive response to galantamine, more specifically the attention-dependent filtering performance in a delayed match-to-sample working memory task, correlated with BFvol: Only participants with high BFvol showed a significant positive effect of galantamine on the ability to filter out distracting information during the working memory encoding process.

Discussion: Future studies need to assess whether BFvol may serve as a predictor of the galantamine response in AD patients, too.

RevDate: 2021-04-13

Oizumi H, Yamasaki K, Suzuki H, et al (2021)

Fatty Acid-Binding Protein 3 Expression in the Brain and Skin in Human Synucleinopathies.

Frontiers in aging neuroscience, 13:648982.

Parkinson's disease (PD) and multiple system atrophy are types of adult-onset neurodegenerative disorders named synucleinopathies, which are characterized by prominent intracellular α-synuclein (αSyn) aggregates. We have previously found that αSyn aggregates and the vulnerability of dopaminergic neurons in the mouse brain are partly associated with the expression of fatty acid-binding protein 3 (FABP3, heart FABP). However, it remains to be elucidated whether FABP3 accumulation is associated with αSyn aggregates in human tissues. Here, we histologically studied FABP3 expression in human tissues obtained from patients with synucleinopathies, patients with Alzheimer disease (AD) and controls. We found that (1) a variety of neurons expressed the FABP3 protein in human brain tissues, (2) FABP3 was colocalized with αSyn aggregates in the brains of individuals with synucleinopathies but not with amyloid β or p-tau aggregates in the brains of individuals with AD, and (3) FABP3 was not present in p-αSyn deposits in biopsied skin tissues from individuals with PD. These findings suggest that FABP3 expression is associated with αSyn aggregation in synucleinopathies and provide new insights into the involvement of FABP3 in synucleinopathies.

RevDate: 2021-04-14

Duong MT, Nasrallah IM, Wolk DA, et al (2021)

Cholesterol, Atherosclerosis, and APOE in Vascular Contributions to Cognitive Impairment and Dementia (VCID): Potential Mechanisms and Therapy.

Frontiers in aging neuroscience, 13:647990.

Vascular contributions to cognitive impairment and dementia (VCID) are a common cause of cognitive decline, yet limited therapies exist. This cerebrovascular disease results in neurodegeneration via acute, chronic, local, and systemic mechanisms. The etiology of VCID is complex, with a significant impact from atherosclerosis. Risk factors including hypercholesterolemia and hypertension promote intracranial atherosclerotic disease and carotid artery stenosis (CAS), which disrupt cerebral blood flow and trigger ischemic strokes and VCID. Apolipoprotein E (APOE) is a cholesterol and phospholipid carrier present in plasma and various tissues. APOE is implicated in dyslipidemia and Alzheimer disease (AD); however, its connection with VCID is less understood. Few experimental models for VCID exist, so much of the present information has been drawn from clinical studies. Here, we review the literature with a focus on the clinical aspects of atherosclerotic cerebrovascular disease and build a working model for the pathogenesis of VCID. We describe potential intermediate steps in this model, linking cholesterol, atherosclerosis, and APOE with VCID. APOE4 is a minor isoform of APOE that promotes lipid dyshomeostasis in astrocytes and microglia, leading to chronic neuroinflammation. APOE4 disturbs lipid homeostasis in macrophages and smooth muscle cells, thus exacerbating systemic inflammation and promoting atherosclerotic plaque formation. Additionally, APOE4 may contribute to stromal activation of endothelial cells and pericytes that disturb the blood-brain barrier (BBB). These and other risk factors together lead to chronic inflammation, atherosclerosis, VCID, and neurodegeneration. Finally, we discuss potential cholesterol metabolism based approaches for future VCID treatment.

RevDate: 2021-04-13

Moraghebi M, Maleki R, Ahmadi M, et al (2021)

In silico Analysis of Polymorphisms in microRNAs Deregulated in Alzheimer Disease.

Frontiers in neuroscience, 15:631852.

Background: Alzheimer's disease (AD) is a degenerative condition characterized by progressive cognitive impairment and dementia. Findings have revolutionized current knowledge of miRNA in the neurological conditions. Two regulatory mechanisms determine the level of mature miRNA expression; one is miRNA precursor processing, and the other is gene expression regulation by transcription factors. This study is allocated to the in-silico investigation of miRNA's SNPs and their effect on other cell mechanisms.

Methods: We used databases which annotate the functional effect of SNPs on mRNA-miRNA and miRNA-RBP interaction. Also, we investigated SNPs which are located on the promoter or UTR region.

Results: miRNA SNP3.0 database indicated several SNPs in miR-339 and miR-34a in the upstream and downstream of pre-miRNA and mature miRNAs. While, for some miRNAs miR-124, and miR-125, no polymorphism was observed, and also miR-101 with ΔG -3.1 and mir-328 with ΔG 5.8 had the highest and lowest potencies to produce mature microRNA. SNP2TFBS web-server presented several SNPs which altered the Transcription Factor Binding Sites (TFBS) or generated novel TFBS in the promoter regions of related miRNA. At last, RBP-Var database provided a list of SNPs which alter miRNA-RBP interaction pattern and can also influence other miRNAs' expression.

Discussion: The results indicated that SNPs microRNA affects both miRNA function and miRNA expression. Our study expands molecular insight into how SNPs in different parts of miRNA, including the regulatory (promoter), the precursor (pre-miRNA), functional regions (seed region of mature miRNA), and RBP-binding motifs, which theoretically may be correlated to the Alzheimer's disease.

RevDate: 2021-04-13

Cochard LM, Levros LC, Joppé SE, et al (2021)

Manipulation of EGFR-Induced Signaling for the Recruitment of Quiescent Neural Stem Cells in the Adult Mouse Forebrain.

Frontiers in neuroscience, 15:621076.

The ventricular-subventricular zone (V-SVZ) is the principal neurogenic niche in the adult mammalian forebrain. Neural stem/progenitor cell (NSPC) activity within the V-SVZ is controlled by numerous of extrinsic factors, whose downstream effects on NSPC proliferation, survival and differentiation are transduced via a limited number of intracellular signaling pathways. Here, we investigated the relationship between age-related changes in NSPC output and activity of signaling pathways downstream of the epidermal growth factor receptor (EGFR), a major regulator of NSPC activity. Biochemical experiments indicated that age-related decline of NSPC activity in vivo is accompanied by selective deficits amongst various EGFR-induced signal pathways within the V-SVZ niche. Pharmacological loss-of-function signaling experiments with cultured NSPCs revealed both overlap and selectivity in the biological functions modulated by the EGFR-induced PI3K/AKT, MEK/ERK and mTOR signaling modules. Specifically, while all three modules promoted EGFR-mediated NSPC proliferation, only mTOR contributed to NSPC survival and only MEK/ERK repressed NSPC differentiation. Using a gain-of-function in vivo genetic approach, we electroporated a constitutively active EGFR construct into a subpopulation of quiescent, EGFR-negative neural stem cells (qNSCs); this ectopic activation of EGFR signaling enabled qNSCs to divide in 3-month-old early adult mice, but not in mice at middle-age or carrying familial Alzheimer disease mutations. Thus, (i) individual EGFR-induced signaling pathways have dissociable effects on NSPC proliferation, survival, and differentiation, (ii) activation of EGFR signaling is sufficient to stimulate qNSC cell cycle entry during early adulthood, and (iii) the proliferative effects of EGFR-induced signaling are dominantly overridden by anti-proliferative signals associated with aging and Alzheimer's disease.

RevDate: 2021-04-13

Choi SH, Lee NE, Cho HJ, et al (2021)

Gintonin facilitates brain delivery of donepezil, a therapeutic drug for Alzheimer disease, through lysophosphatidic acid 1/3 and vascular endothelial growth factor receptors.

Journal of ginseng research, 45(2):264-272.

Background: Gintonin is a ginseng-derived exogenous G-protein-coupled lysophosphatidic acid (LPA) receptor ligand, which exhibits in vitro and in vivo functions against Alzheimer disease (AD) through lysophosphatidic acid 1/3 receptors. A recent study demonstrated that systemic treatment with gintonin enhances paracellular permeability of the blood-brain barrier (BBB) through the LPA1/3 receptor. However, little is known about whether gintonin can enhance brain delivery of donepezil (DPZ) (Aricept), which is a representative cognition-improving drug used in AD clinics. In the present study, we examined whether systemic administration of gintonin can stimulate brain delivery of DPZ.

Methods: We administered gintonin and DPZ alone or coadministered gintonin with DPZ intravenously or orally to rats. Then we collected the cerebral spinal fluid (CSF) and serum and determined the DPZ concentration through liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis.

Results: Intravenous, but not oral, coadministration of gintonin with DPZ increased the CSF concentration of DPZ in a concentration- and time-dependent manner. Gintonin-mediated enhancement of brain delivery of DPZ was blocked by Ki16425, a LPA1/3 receptor antagonist. Coadministration of vascular endothelial growth factor (VEGF) + gintonin with DPZ similarly increased CSF DPZ concentration. However, gintonin-mediated enhancement of brain delivery of DPZ was blocked by axitinip, a VEGF receptor antagonist. Mannitol, a BBB disrupting agent that increases the BBB permeability, enhanced gintonin-mediated enhancement of brain delivery of DPZ.

Conclusions: We found that intravenous, but not oral, coadministration of gintonin facilitates brain delivery of DPZ from plasma via LPA1/3 and VEGF receptors. Gintonin is a potential candidate as a ginseng-derived novel agent for the brain delivery of DPZ for treatment of patients with AD.

RevDate: 2021-04-11

Tanay D, Bhaskar D, Gopal A, et al (2021)

Design, Synthesis And In-vitro Evaluation Of Fluorinated Triazoles as Multi-Target Directed Ligands for Alzheimer Disease.

Bioorganic & medicinal chemistry letters pii:S0960-894X(21)00225-0 [Epub ahead of print].

Alzheimer disease is multi-factorial and inflammation plays a major role in the disease progression and severity. Metals and reactive oxygen species (ROS) are the key mediators for inflammatory conditions associated with Alzheimer's. Along multi-factorial nature, major challenge for developing new drug is the ability of the molecule to cross blood brain barrier (BBB). We have designed and synthesized multi-target directed hexaflourocarbinol containing triazoles to inhibit Amyloid β aggregation and simultaneously chelate the excess metals present in the extracellular space and scavenge the ROS thus reduce the inflammatory condition. From the screened compound library, compound 1c found to be potent and safe. It has demonstrated inhibition of Amyloid β aggregation (IC50 of 4.6 μM) through selective binding with Amyloid β at the nucleation site (evidenced from the molecular docking). It also chelate metals (Cu+2, Zn+2 and Fe+3) and scavenges ROS significantly. Due to the presence of hexaflouro-carbinol moiety in the molecule it may assist to permeate BBB and improve the pharmacokinetic properties. The in-vitro results of compound 1c indicate the promiscuity for the development of hexaflourocarbinol containing triazoles amide scaffold as multi-target directed therapy against Alzheimer disease.

RevDate: 2021-04-11

Capone R, Tiwari A, Hadziselimovic A, et al (2021)

The C99 domain of the amyloid precursor protein resides in the disordered membrane phase.

The Journal of biological chemistry pii:S0021-9258(21)00438-5 [Epub ahead of print].

Processing of the amyloid precursor protein (APP) via the amyloidogenic pathway is associated with the etiology of Alzheimer's disease. The cleavage of APP by β-secretase to generate the transmembrane 99-residue C-terminal fragment (C99) and subsequent processing of C99 by γ-secretase to yield amyloid-β (Aβ) peptides are essential steps in this pathway. Biochemical evidence suggests amyloidogenic processing of C99 occurs in cholesterol- and sphingolipid-enriched liquid-ordered phase membrane rafts. However, direct evidence that C99 preferentially associates with these rafts has remained elusive. Here, we tested this by quantifying the affinity of C99-GFP for raft domains in cell-derived giant plasma membrane vesicles (GPMVs). We found that C99 was essentially excluded from ordered domains in vesicles from HeLa cells, undifferentiated SH-SY5Y cells, or SH-SY5Y-derived neurons; instead, ∼ 90% of C99 partitioned into disordered domains. The strong association of C99 with disordered domains occurred independently of its cholesterol-binding activity or homodimerization, or of the presence of the familial Alzheimer disease Arctic mutation (APP E693G). Finally, through biochemical studies we confirmed previous results which showed that C99 is processed in the plasma membrane by α-secretase, in addition to the well-known γ-secretase. These findings suggest that C99 itself lacks an intrinsic affinity for raft domains, implying that either i) amyloidogenic processing of the protein occurs in disordered regions of the membrane, ii) processing involves a marginal sub-population of C99 found in rafts, or iii) as-yet-unidentified protein-protein interactions with C99 in living cells drive the protein into membrane rafts to promote its cleavage therein.

RevDate: 2021-04-15

Pasieka A, Panek D, Jończyk J, et al (2021)

Discovery of multifunctional anti-Alzheimer's agents with a unique mechanism of action including inhibition of the enzyme butyrylcholinesterase and γ-aminobutyric acid transporters.

European journal of medicinal chemistry, 218:113397 pii:S0223-5234(21)00246-4 [Epub ahead of print].

Looking for an effective anti-Alzheimer's agent is very challenging; however, a multifunctional ligand strategy may be a promising solution for the treatment of this complex disease. We herein present the design, synthesis and biological evaluation of novel hydroxyethylamine derivatives displaying unique, multiple properties that have not been previously reported. The original mechanism of action combines inhibitory activity against disease-modifying targets: β-secretase enzyme (BACE1) and amyloid β (Aβ) aggregation, along with an effect on targets associated with symptom relief - inhibition of butyrylcholinesterase (BuChE) and γ-aminobutyric acid transporters (GATs). Among the obtained molecules, compound 36 exhibited the most balanced and broad activity profile (eeAChE IC50 = 2.86 μM; eqBuChE IC50 = 60 nM; hBuChE IC50 = 20 nM; hBACE1 IC50 = 5.9 μM; inhibition of Aβ aggregation = 57.9% at 10 μM; mGAT1 IC50 = 10.96 μM; and mGAT2 IC50 = 19.05 μM). Moreover, we also identified 31 as the most potent mGAT4 and hGAT3 inhibitor (IC50 = 5.01 μM and IC50 = 2.95 μM, respectively), with high selectivity over other subtypes. Compounds 36 and 31 represent new anti-Alzheimer agents that can ameliorate cognitive decline and modify the progress of disease.

RevDate: 2021-04-12

Flores J, Noël A, Foveau B, et al (2021)

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

Nature communications, 12(1):2271 pii:10.1038/s41467-021-22789-7.

RevDate: 2021-04-10

Donadio V, Wang Z, Incensi A, et al (2021)

In Vivo Diagnosis of Synucleinopathies: A Comparative Study of Skin Biopsy and RT-QuIC.

Neurology pii:WNL.0000000000011935 [Epub ahead of print].

OBJECTIVE: To determine whether: 1) the immunofluorescence (IF) is a reproducible technique in detecting misfolded α-synuclein (α-syn) in skin nerves; and subsequently 2) IF and RT-QuIC (both in skin and CSF) show a comparable in vivo diagnostic accuracy in distinguish synucleinopathies (SOPs) from non-synucleinopathies (non-SOPs) in a large cohort of patients.

METHODS: We prospectively recruited 90 patients fulfilling clinical and instrumental diagnostic criteria for all SOPs variants and non-SOPs (mainly including Alzheimer disease, tauopathies, and vascular parkinsonism or dementia). Twenty-four patients with mainly peripheral neuropathies were used as controls. Patients underwent skin biopsy for IF and RT-QuIC whereas CSF was performed in patients who underwent lumbar puncture for diagnostic purposes. IF and RT-QuIC analysis were made blinded to the clinical diagnosis.

RESULTS: IF showed reproducible results between two pairs of neighbouring skin samples. Furthermore, both IF and RT-QuIC showed high sensitivity and specificity in discriminating SOPs from non-SOPs and controls but IF presented the higher diagnostic accuracy. IF presented a good level of agreement with RT-QuIC both skin and CSF in SOPs.

CONCLUSIONS: 1) Both IF and RT-QuIC showed a high diagnostic accuracy although IF displayed the better value as well as an optimal reproducibility; 2) they presented a good level of agreement in SOPs supporting the use of a less invasive tests such as skin IF or RT-QuIC instead of CSF RT-QuIC as diagnostic tool for synucleinopathies.

CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that IF or RT-QuIC accurately distinguish SOPs from non-SOPs patients.

RevDate: 2021-04-13

Leinenga G, Koh WK, J Götz (2021)

A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease.

Alzheimer's research & therapy, 13(1):76.

BACKGROUND: Aducanumab is an anti-amyloid-β (Aβ) antibody that achieved reduced amyloid pathology in Alzheimer's disease (AD) trials; however, it is controversial whether it also improved cognition, which has been suggested would require a sufficiently high cumulative dose of the antibody in the brain. Therapeutic ultrasound, in contrast, has only begun to be investigated in human AD clinical trials. We have previously shown that scanning ultrasound in combination with intravenously injected microbubbles (SUS), which temporarily and safely opens the blood-brain barrier (BBB), removes amyloid and restores cognition in APP23 mice. However, there has been no direct testing of how the effects of SUS compare to immunotherapy or whether a combination therapy is more effective.

METHODS: In a study comprising four treatment arms, we tested the efficacy of an Aducanumab analog, Adu, both in comparison to SUS, and as a combination therapy, in APP23 mice (aged 13-22 months), using sham as a control. The active place avoidance (APA) test was used to test spatial memory, and histology and ELISA were used to measure amyloid. Brain antibody levels were also determined.

RESULTS: We found that both Adu and SUS reduced the total plaque area in the hippocampus with no additive effect observed with the combination treatment (SUS + Adu). Whereas in the cortex where there was a trend towards reducing the total plaque area from either Adu or SUS, only the combination treatment yielded a statistically significant decrease in total plaque area compared to sham. Only the SUS and SUS + Adu groups included animals that had their plaque load reduced to below 1% from above 10%. There was a robust improvement in spatial memory for the SUS + Adu group only, and in this group the level of Adu, when measured 3 days post-treatment, was 5-fold higher compared to those mice that received Adu on its own. Together, these findings suggest that SUS should be considered as a treatment option for AD. Alternatively, a combination trial using Aducanumab together with ultrasound to increase brain levels of the antibody may be warranted.

RevDate: 2021-04-09

Sheikh HK, Arshad T, Mohammad ZS, et al (2020)

Derivatives of diisopropyl phenoxyphosphate with controlled reactivity for enhancement of Acetylcholine (ACh) neurotransmitter.

Pakistan journal of pharmaceutical sciences, 33(5(Supplementary)):2239-2242.

Here, new phenoxide derivatives of diisopropyl flourophosphate for reaction with Lewis basic sites on acetyl cholinesterase (AChE) were designed. Such binding interaction or reaction inhibits the hydrolysis of the acetylcholine (ACh) neurotransmitter thus enhancing its concentration. This increased neurotransmitter concentration can enhance memory and cognition thus improving symptoms of neurodegenerative diseases such as Alzheimer disease and down syndrome. For docking analysis, we particularly targeted those reception sites on AChE that interacts with the ACh. This led to structural design of derivatives of diisopropyl phenoxyphosphate with controlled reactivity stemming from para substituted phenoxide leaving group. Impact of electron donating (CH3, OCH3) and withdrawing substituents (COCH3) on para position of phenol group on rate of acyl addition elimination reaction was modeled using QM DFT technique. Difference in activation energy between electron donating and withdrawing substituents on phenoxide was noted hence making the derivatives of diisopropyl phenoxyphosphate less reactive and more selective. Docking also confirmed binding of designed derivatives with AChE. Hence novel derivatives with high binding energy and controlled reactivity were designed for retrosynthesis.

RevDate: 2021-04-09

Chen J, Benjenk I, Barath D, et al (2021)

Disparities in Preventable Hospitalization Among Patients With Alzheimer Diseases.

American journal of preventive medicine pii:S0749-3797(21)00067-2 [Epub ahead of print].

INTRODUCTION: System-level care coordination strategies can be the most effective to promote continuity of care among people with Alzheimer's disease; however, the evidence is lacking. The objective of this study is to determine whether accountable care organizations are associated with lower rates of potentially preventable hospitalizations for people with Alzheimer's disease and whether hospital accountable care organization affiliation is associated with reduced racial and ethnic disparities in preventable hospitalizations among patients with Alzheimer's disease.

METHODS: This study employed a cross-sectional study design and used 2015 Healthcare Cost and Utilization Project inpatient claims data from 11 states and the 2015 American Hospital Association Annual Survey. Logistic regression and the Blinder-Oaxaca decomposition method were used.

RESULTS: African American patients with Alzheimer's disease were less likely to be hospitalized at accountable care organization‒affiliated hospitals than White patients. Among patients with Alzheimer's disease who were hospitalized, hospital accountable care organization affiliation was associated with lower odds of potentially preventable hospitalizations (OR=0.86, p=0.02; OR=0.66, p<0.001 with propensity score matching) after controlling for patient characteristics, hospital characteristics, and state indicators. Hospital accountable care organization affiliation explained 3.01% (p<0.01) of the disparity in potentially preventable hospitalizations between White and African American patients but could not explain disparities between White and Latinx patients.

CONCLUSIONS: Evidence suggests that accountable care organizations may be able to improve care coordination for people with Alzheimer's disease and to reduce disparities between Whites and African Americans. Further research is needed to determine whether this benefit can be attributed to accountable care organization formation or whether providers that participate in accountable care organizations tend to provide higher-quality care.

RevDate: 2021-04-15

Kim D, Lee JH, Kim HY, et al (2021)

Correction: Fluorescent indolizine derivative YI-13 detects amyloid-β monomers, dimers, and plaques in the brain of 5XFAD Alzheimer transgenic mouse model.

PloS one, 16(4):e0250194.

[This corrects the article DOI: 10.1371/journal.pone.0243041.].

RevDate: 2021-04-10

Cieri F, Zhuang X, Caldwell JZK, et al (2021)

Brain Entropy During Aging Through a Free Energy Principle Approach.

Frontiers in human neuroscience, 15:647513.

Neural complexity and brain entropy (BEN) have gained greater interest in recent years. The dynamics of neural signals and their relations with information processing continue to be investigated through different measures in a variety of noteworthy studies. The BEN of spontaneous neural activity decreases during states of reduced consciousness. This evidence has been showed in primary consciousness states, such as psychedelic states, under the name of "the entropic brain hypothesis." In this manuscript we propose an extension of this hypothesis to physiological and pathological aging. We review this particular facet of the complexity of the brain, mentioning studies that have investigated BEN in primary consciousness states, and extending this view to the field of neuroaging with a focus on resting-state functional Magnetic Resonance Imaging. We first introduce historic and conceptual ideas about entropy and neural complexity, treating the mindbrain as a complex nonlinear dynamic adaptive system, in light of the free energy principle. Then, we review the studies in this field, analyzing the idea that the aim of the neurocognitive system is to maintain a dynamic state of balance between order and chaos, both in terms of dynamics of neural signals and functional connectivity. In our exploration we will review studies both on acute psychedelic states and more chronic psychotic states and traits, such as those in schizophrenia, in order to show the increase of entropy in those states. Then we extend our exploration to physiological and pathological aging, where BEN is reduced. Finally, we propose an interpretation of these results, defining a general trend of BEN in primary states and cognitive aging.

RevDate: 2021-04-11

Eusebi PG, Sevane N, O'Rourke T, et al (2021)

Gene expression profiles underlying aggressive behavior in the prefrontal cortex of cattle.

BMC genomics, 22(1):245.

BACKGROUND: Aggressive behavior is an ancient and conserved trait, habitual for most animals in order to eat, protect themselves, compete for mating and defend their territories. Genetic factors have been shown to play an important role in the development of aggression both in animals and humans, displaying moderate to high heritability estimates. Although such types of behaviors have been studied in different animal models, the molecular architecture of aggressiveness remains poorly understood. This study compared gene expression profiles of 16 prefrontal cortex (PFC) samples from aggressive and non-aggressive cattle breeds: Lidia, selected for agonistic responses, and Wagyu, selected for tameness.

RESULTS: A total of 918 up-regulated and 278 down-regulated differentially expressed genes (DEG) were identified, representing above-chance overlap with genes previously identified in studies of aggression across species, as well as those implicated in recent human evolution. The functional interpretation of the up-regulated genes in the aggressive cohort revealed enrichment of pathways such as Alzheimer disease-presenilin, integrins and the ERK/MAPK signaling cascade, all implicated in the development of abnormal aggressive behaviors and neurophysiological disorders. Moreover, gonadotropins, are up-regulated as natural mechanisms enhancing aggression. Concomitantly, heterotrimeric G-protein pathways, associated with low reactivity mental states, and the GAD2 gene, a repressor of agonistic reactions associated with PFC activity, are down-regulated, promoting the development of the aggressive responses selected for in Lidia cattle. We also identified six upstream regulators, whose functional activity fits with the etiology of abnormal behavioral responses associated with aggression.

CONCLUSIONS: These transcriptional correlates of aggression, resulting, at least in part, from controlled artificial selection, can provide valuable insights into the complex architecture that underlies naturally developed agonistic behaviors. This analysis constitutes a first important step towards the identification of the genes and metabolic pathways that promote aggression in cattle and, providing a novel model species to disentangle the mechanisms underlying variability in aggressive behavior.

RevDate: 2021-04-07

Travers JL, Naylor MD, Coe NB, et al (2021)

Demographic Characteristics Driving Disparities in Receipt of Long-Term Services and Supports in the Community Setting.

Medical care pii:00005650-900000000-98167 [Epub ahead of print].

BACKGROUND: Research suggests that growth in Black and Hispanic (minority) older adults' nursing home (NH) use may be the result of disparities in access to community-based and alternative long-term services and supports (LTSS).

OBJECTIVE: We aimed to determine whether minority groups receiving care in NHs versus the community had fewer differences in their functional needs compared with the differences in nonminority older adults, suggesting a disparity.

METHODS: We identified respondents aged 65 years or above with a diagnosis of Alzheimer disease or dementia in the 2016 Health and Retirement Study who reported requiring LTSS help. We performed unadjusted analyses to assess the difference in functional need between community and NH care. Functional need was operationalized using a functional limitations score and 6 individual activities of daily living. We compared the LTSS setting for minority older adults to White older adults using difference-in-differences.

RESULTS: There were 186 minority older adults (community=75%, NH=25%) and 357 White older adults (community=50%, NH=50%). Between settings, minority older adults did not differ in education or marital status, but were younger and had greater income in the NH versus the community. The functional limitations score was higher in NHs than in the community for both groups. Functional needs for all 6 activities of daily living for the minority group were greater in NHs compared with the community.

CONCLUSION: Functional need for minority older adults differed by setting while demographics varied in unexpected ways. Factors such as familial and financial support are important to consider when implementing programs to keep older adults out of NHs.

RevDate: 2021-04-06

Eide PK, Mariussen E, Uggerud H, et al (2021)

Clinical application of intrathecal gadobutrol for assessment of cerebrospinal fluid tracer clearance to blood.

JCI insight pii:147063 [Epub ahead of print].

BACKGROUND: Methodology for estimation of cerebrospinal fluid (CSF) tracer clearance could have wide clinical application in predicting excretion of intrathecal drugs and metabolic solutes from brain metabolism, and for diagnostic work-up of cerebrospinal fluid disturbances.

METHODS: The magnetic resonance imaging (MRI) contrast agent gadobutrol (Gadovist) was utilized as CSF tracer and injected into the lumbar CSF. Gadobutrol is contained outside blood vessels of the central nervous system (CNS) and is thus eliminated along extra-vascular pathways, analogous to many CNS metabolites and intrathecal drugs. Tracer enrichment was verified and assessed in CSF by MRI at level of the cisterna magna in parallel with obtaining blood samples through 48 hours.

RESULTS: In a reference patient cohort (REF; n=29), both enrichment within CSF and blood coincided in time. Blood concentration profiles of gadobutrol through 48 hours varied between patients diagnosed with CSF leakage (n=4), idiopathic normal pressure hydrocephalus dementia (iNPH; n=7), pineal cysts (n=8), and idiopathic intracranial hypertension (IIH; n=4).

CONCLUSION: Assessment of CSF tracer clearance is clinically feasible and may provide a way to predict extra-vascular clearance of intrathecal drugs and endogenous metabolites from the CNS. The peak concentration in blood (at about 10 hrs) preceded by far peak tracer enhancement at MRI in extra-cranial lymphatic structures (at about 24 hrs) as shown in previous studies, indicating a major role of the spinal canal in CSF clearance capacity.

FUNDING: The work was supported by Department of Neurosurgery, Oslo university hospital, and Norwegian Institute for Air Research, Kjeller, Norway, and University of Oslo.

RevDate: 2021-04-06

Lingappa S, Shivakumar MS, Manivasagam T, et al (2021)

Neuroprotective effect of epalrestat on hydrogen peroxide induced neurodegeneration in SH-SY5Y cellular model.

Journal of microbiology and biotechnology pii:jmb.2101.01002 [Epub ahead of print].

Epalrestat (EPS) is a brain penetrant aldose reductase inhibitor, an approved drug currently used for the treatment of diabetic neuropathy. At near-plasma concentration, EPS induces glutathione biosynthesis, which in turn reduces oxidative stress in the neuronal cells. In this study we found that EPS reduces neurodegeneration by inhibiting reactive oxygen species (ROS) induced oxidative injury, mitochondrial membrane damage, apoptosis and tauopathy. EPS treatment up to 50 µM did not show any toxic effect on SH-SY5Y cell line (Neuroblastoma cells). However we observed toxic effect at a concentration of 100µM and above. At 50µM concentration, EPS showed better antioxidant activity against H2O2 (100µM) induced cytotoxicity, ROS formation and mitochondrial membrane damage in retinoic acid differentiated SH-SY5Y cell line. Furthermore, the study revealed that 50µM of EPS concentration reduced the glycogen synthase kinase-3 β (GSK3-β) expression and total tau protein level in H2O2 (100µM) treated cells. Findings from this study confirms the therapeutic efficacy of EPS on regulating alzheimer disease (AD) by regulating GSK3-β and total tau proteins phosphorylation, which helped to restore the cellular viability. This process could also reduce toxic fibrillary tangle formation and disease progression of AD. Therefore, it was conceived that an optimal concentration of EPS therapy could decrease AD pathology by reducing tau phosphorylation through regulating the expression level of GSK3-β.

RevDate: 2021-04-05

Pan Y, Zhang Y, Liu N, et al (2021)

Vitamin D Attenuates Alzheimer-like Pathology Induced by Okadaic Acid.

ACS chemical neuroscience [Epub ahead of print].

Many elderly individuals suffer from Alzheimer's disease (AD), which causes a growing concern. We investigated the mechanism underlying the effects of vitamin D (VD) as a prophylactic treatment. A mouse model of okadaic-acid-induced AD-like pathology was used in vivo and in vitro. Morris water maze and field trials were used to assess cognitive function. The expression levels of VDR, MTHFR, LCMT-1, PP2A, p-TAU (Thr396), and T-TAU and the methylation level of PP2A were measured by Western blotting, and a reversal of the increase in the levels of these proteins in an AD cell model was observed. We used MTHFR-knockdown SH-SY5Y cells to further test the effects of VD, treated these cells with cycloheximide and MG132, and used RT-PCR to explore the mechanism underlying MTHFR targeting. We found that the effects of VD on AD were impaired by MTHFR knockdown through a pretranscriptional mechanism. In addition, VD attenuated AD-induced cognitive impairment and significantly suppressed the expression of TAU. Our findings indicated that VD treatment alleviated TAU accumulation and rescued methylated PP2A by increasing the expression of LCMT-1 and MTHFR.

RevDate: 2021-04-06

Fani A, Sofia K, Theodora P, et al (2021)

Pseudoexfoliation syndrome in diabetic patients: transmission electron microscopy study of anterior lens epithelial cells.

Romanian journal of ophthalmology, 65(1):38-45.

Purpose: to examine the lens epithelial cells in diabetic patients with pseudoexfoliation to ultramicroscope and to compare the findings with those of patients without diabetes mellitus (DM) and/or without pseudoexfoliation (PEX). Materials and Methods: Forty patients aged 65-86 years were enrolled in the study. All patients had senile cataract and were divided into four groups of ten patients in each group. Group I: patients without pseudoexfoliation, without DM, Group II: without pseudoexfoliation, with DM, Group III: with pseudoexfoliation, without DM, Group IV (Pseudoexfoliation-Diabetic Group): with pseudoexfoliation, with DM. In all cases, part of the central portion of anterior lens capsule was removed during routine cataract surgery, and was properly prepared in order to be examined under a transmission electron microscope. Results: In the control group, mainly degenerative alterations to varying extents were observed. In all groups, intracellular and extracellular oedema, multilayering, apoptosis, completely destroyed cells adjacent to normal cellswere described. In the diabetic group, alterations were more severe with respect to group I. In PEX cases, the additionalirregularity of the epithelium surface, loose intercellular connection, as well as the loose connection between cells and basement membrane were described with the presence of PEX material free and within the basement membrane. In cases with PEX and DM, degenerative alterations and PEX material were observed as well, but the epithelium was better conserved compared to the PEX group. Conclusion: the observed lesions were more extended and more frequent in the pseudoexfoliation group, followed by the diabetic group. The pseudoexfoliation-diabetic group presented less intense modifications raising questions about the interaction of these different diseases. Abbreviations: DM = Diabetes Mellitus, PEX = Pseudoexfoliation, PXM = Pseudoexfoliative Material, AD = Alzheimer disease, TGF-β1 = Transforming Growth Factor beta 1, WHO = World Health Organization, LEC = Lens Epithelium Cells, BM = Basement Membrane, CM = Cytoplasmic Membrane.

RevDate: 2021-04-06

Forcano L, Fauria K, Soldevila-Domenech N, et al (2021)

Prevention of cognitive decline in subjective cognitive decline APOE ε4 carriers after EGCG and a multimodal intervention (PENSA): Study design.

Alzheimer's & dementia (New York, N. Y.), 7(1):e12155.

Introduction: Subjects exhibiting subjective cognitive decline (SCD) are at an increased risk for mild cognitive impairment and dementia. Given the delay between risk exposure and disease onset, SCD individuals are increasingly considered a good target population for cost-effective lifestyle-based Alzheimer's disease prevention trials.

Methods: The PENSA study is a randomized, double-blind, controlled clinical trial that aims to evaluate the efficacy of a personalized multimodal intervention in lifestyle (diet counseling, physical activity, cognitive training, and social engagement) combined with the use of epigallocatechin gallate (EGCG) over 12 months, in slowing down cognitive decline and improving brain connectivity. The study population includes 200 individuals meeting SCD criteria and carrying the apolipoprotein E ε4 allele, who will be randomized into four treatment arms (multimodal intervention + EGCG/placebo, or lifestyle recommendations + EGCG/placebo). The primary efficacy outcome is change in the composite score for cognitive performance measured with the Alzheimer's Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC-like) adding to the original version the Interference score from the Stroop Color and Word Test and the Five Digit Test. Secondary efficacy outcomes are (1) change in functional magnetic resonance imaging (fMRI) and structural neuronal connectivity (structural MRI) and (2) the safety assessment of the EGCG compound. This study is framed within the WW-FINGERS consortium.

Discussion: The use of new technologies (i.e., mobile ecological momentary assessments [EMAs], activity tracker) in the PENSA study allows the collection of continuous data on lifestyle behaviors (diet and physical activity) and mood, enabling a personalized design as well as an intensive follow-up of participants. These data will be used to give feedback to participants about their own performance along the intervention, promoting their involvement and adherence. The results of the study may aid researchers on the design of future clinical trials involving preventive lifestyle multicomponent interventions.

RevDate: 2021-04-06

Heine H, Adanitsch F, Peternelj TT, et al (2021)

Tailored Modulation of Cellular Pro-inflammatory Responses With Disaccharide Lipid A Mimetics.

Frontiers in immunology, 12:631797.

Pro-inflammatory signaling mediated by Toll-like receptor 4 (TLR4)/myeloid differentiation-2 (MD-2) complex plays a crucial role in the instantaneous protection against infectious challenge and largely contributes to recovery from Gram-negative infection. Activation of TLR4 also boosts the adaptive immunity which is implemented in the development of vaccine adjuvants by application of minimally toxic TLR4 activating ligands. The modulation of pro-inflammatory responses via the TLR4 signaling pathway was found beneficial for management of acute and chronic inflammatory disorders including asthma, allergy, arthritis, Alzheimer disease pathology, sepsis, and cancer. The TLR4/MD-2 complex can recognize the terminal motif of Gram-negative bacterial lipopolysaccharide (LPS)-a glycophospholipid lipid A. Although immense progress in understanding the molecular basis of LPS-induced TLR4-mediated signaling has been achieved, gradual, and predictable TLR4 activation by structurally defined ligands has not yet been attained. We report on controllable modulation of cellular pro-inflammatory responses by application of novel synthetic glycolipids-disaccharide-based lipid A mimetics (DLAMs) having picomolar affinity for TLR4/MD-2. Using crystal structure inspired design we have developed endotoxin mimetics where the inherently flexible β(1 → 6)-linked diglucosamine backbone of lipid A is replaced by a conformationally restricted α,α-(1↔1)-linked disaccharide scaffold. The tertiary structure of the disaccharide skeleton of DLAMs mirrors the 3-dimensional shape of TLR4/MD-2 bound E. coli lipid A. Due to exceptional conformational rigidity of the sugar scaffold, the specific 3D organization of DLAM must be preserved upon interaction with proteins. These structural factors along with specific acylation and phosphorylation pattern can ensure picomolar affinity for TLR4 and permit efficient dimerization of TLR4/MD-2/DLAM complexes. Since the binding pose of lipid A in the binding pocket of MD-2 (±180°) is crucial for the expression of biological activity, the chemical structure of DLAMs was designed to permit a predefined binding orientation in the binding groove of MD-2, which ensured tailored and species-independent (human and mice) TLR4 activation. Manipulating phosphorylation and acylation pattern at the sugar moiety facing the secondary dimerization interface allowed for adjustable modulation of the TLR4-mediated signaling. Tailored modulation of cellular pro-inflammatory responses by distinct modifications of the molecular structure of DLAMs was attained in primary human and mouse immune cells, lung epithelial cells and TLR4 transfected HEK293 cells.

RevDate: 2021-04-06

He Y, Wu J, Zhou L, et al (2021)

Quantification of Cognitive Function in Alzheimer's Disease Based on Deep Learning.

Frontiers in neuroscience, 15:651920.

Alzheimer disease (AD) is mainly manifested as insidious onset, chronic progressive cognitive decline and non-cognitive neuropsychiatric symptoms, which seriously affects the quality of life of the elderly and causes a very large burden on society and families. This paper uses graph theory to analyze the constructed brain network, and extracts the node degree, node efficiency, and node betweenness centrality parameters of the two modal brain networks. The T test method is used to analyze the difference of graph theory parameters between normal people and AD patients, and brain regions with significant differences in graph theory parameters are selected as brain network features. By analyzing the calculation principles of the conventional convolutional layer and the depth separable convolution unit, the computational complexity of them is compared. The depth separable convolution unit decomposes the traditional convolution process into spatial convolution for feature extraction and point convolution for feature combination, which greatly reduces the number of multiplication and addition operations in the convolution process, while still being able to obtain comparisons. Aiming at the special convolution structure of the depth separable convolution unit, this paper proposes a channel pruning method based on the convolution structure and explains its pruning process. Multimodal neuroimaging can provide complete information for the quantification of Alzheimer's disease. This paper proposes a cascaded three-dimensional neural network framework based on single-modal and multi-modal images, using MRI and PET images to distinguish AD and MCI from normal samples. Multiple three-dimensional CNN networks are used to extract recognizable information in local image blocks. The high-level two-dimensional CNN network fuses multi-modal features and selects the features of discriminative regions to perform quantitative predictions on samples. The algorithm proposed in this paper can automatically extract and fuse the features of multi-modality and multi-regions layer by layer, and the visual analysis results show that the abnormally changed regions affected by Alzheimer's disease provide important information for clinical quantification.

RevDate: 2021-04-15

Xu W, Tan CC, Cao XP, et al (2021)

Neuroinflammation modulates the association of PGRN with cerebral amyloid-β burden.

Neurobiology of aging, 103:52-59 pii:S0197-4580(21)00071-3 [Epub ahead of print].

Progranulin (PGRN) and neuroinflammatory markers increased over the course of Alzheimer's disease (AD). We aimed to determine whether neuroinflammation could modulate the association of PGRN with amyloid pathologies. Baseline cerebrospinal fluid (CSF) PGRN and AD pathologies were measured for 965 participants, among whom 228 had measurements of CSF neuroinflammatory markers. Causal mediation analyses with 10,000 bootstrapped iterations were conducted to explore the mediation effects within the framework of A/T/N biomarker profile. Increased levels of CSF PGRN and inflammatory markers (sTNFR1, sTNFR2, TGF-β1, ICAM1, and VCAM1) were associated with T- or N-positive (TN+) profile, irrespective of the amyloid pathology. In TN+ group, CSF PGRN was associated with increased levels of these inflammatory markers and CSF amyloid-β1-42 (p < 0.01). The neuroinflammatory markers significantly modulated (proportion: 20%~60%) the relationship of amyloid burden with CSF PGRN, which could predict slower cognitive decline and lower AD risk in the TN+ group. The abovementioned associations became non-significant in the TN- group. These findings revealed a close relationship between neuroinflammation and CSF PGRN in contributing to AD pathogenesis, and also highlighted the specific roles of PGRN in neurodegenerative conditions. Future experiments are warranted to verify the causal relationship.

RevDate: 2021-04-15

Cacciottolo M, Morgan TE, CE Finch (2021)

Age, sex, and cerebral microbleeds in EFAD Alzheimer disease mice.

Neurobiology of aging, 103:42-51 pii:S0197-4580(21)00075-0 [Epub ahead of print].

Cerebral microbleeds (MBs) increase at later ages in association with increased cognitive decline and Alzheimer Disease (AD). MB prevalence is also increased by APOE4 and hypertension. In EFAD mice (5XFAD+/-/human APOE+/+), cerebral cortex MBs are most prevalent in E4 females at 6 months, paralleling plaque amyloid. We evaluated MBs at 2, 4, and 6 months in relation to amyloid in plaques and cerebral amyloid angiopathy (CAA) by age, sex, APOE allele, and blood pressure. At 2 mo, MBs were 50% more numerous than plaques, followed by decreased ratio of MBs:Aβ plaques with female excess to 6 mo. The stable size of MBs suggests MBs arise as single events of extravasation, which may "seed" plaque formation. Blood pressure was normal from 2 to 6 months, minimizing a role of hypertension. Memory, assessed by fear conditioning, decreased with age in correlation with MBs and amyloid. Cortical layer analysis showed prevalent MBs and plaque in layers 4 and 5. Contrarily, CAA was prevalent in layers 1 and 2, discounting its contribution to MBs.

RevDate: 2021-04-08

Queda F, Calò S, Gwizdala K, et al (2021)

Novel Donepezil-Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer's Disease.

Molecules (Basel, Switzerland), 26(6):.

Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders, characterized by multiple pathological features. Therefore, multi-target drug discovery has been one of the most active fields searching for new effective anti-AD therapies. Herein, a series of hybrid compounds are reported which were designed and developed by combining an aryl-sulfonamide function with a benzyl-piperidine moiety, the pharmacophore of donepezil (a current anti-AD acetylcholinesterase AChE inhibitor drug) or its benzyl-piperazine analogue. The in vitro results indicate that some of these hybrids achieve optimized activity towards two main AD targets, by displaying excellent AChE inhibitory potencies, as well as the capability to prevent amyloid-β (Aβ) aggregation. Some of these hybrids also prevented Aβ-induced cell toxicity. Significantly, drug-like properties were predicted, including for blood-brain permeability. Compound 9 emerged as a promising multi-target lead compound (AChE inhibition (IC50 1.6 μM); Aβ aggregation inhibition 60.7%). Overall, this family of hybrids is worthy of further exploration, due to the wide biological activity of sulfonamides.

RevDate: 2021-04-08

Hugon J, C Paquet (2021)

The PKR/P38/RIPK1 Signaling Pathway as a Therapeutic Target in Alzheimer's Disease.

International journal of molecular sciences, 22(6):.

Neuropathological lesions in Alzheimer's disease (AD) include amyloid plaques formed by the accumulation of amyloid peptides, neurofibrillary tangles made of hyperphosphorylated tau protein, synaptic and neuronal degenerations, and neuroinflammation. The cause of AD is unknown, but according to the amyloid hypothesis, amyloid oligomers could lead to the activation of kinases such as eukaryotic translation initiation factor 2-alpha kinase 2 (PKR), p38, and receptor-interacting serine/threonine-protein kinase 1 (RIPK1), which all belong to the same stress-activated pathway. Many toxic kinase activations have been described in AD patients and in experimental models. A p38 mitogen-activated protein kinase inhibitor was recently tested in clinical trials but with unsuccessful results. The complex PKR/P38/RIPK1 (PKR/dual specificity mitogen-activated protein kinase kinase 6 (MKK6)/P38/MAP kinase-activated protein kinase 2 (MK2)/RIPK1) is highly activated in AD brains and in the brains of AD transgenic animals. To delineate the implication of this pathway in AD, we carried out a search on PubMed including PKR/MKK6/p38/MK2/RIPK1, Alzheimer, and therapeutics. The involvement of this signaling pathway in the genesis of AD lesions, including Aβ accumulations and tau phosphorylation as well as cognitive decline, is demonstrated by the reports described in this review. A future combination strategy with kinase inhibitors should be envisaged to modulate the consequences for neurons and other brain cells linked to the abnormal activation of this pathway.

RevDate: 2021-04-08

Rahimi F (2021)

Alzheimer Disease: Controversies in Basic Science Research, Different Theories, and Reasons for Failed Trials.

Biomedicines, 9(3):.

Dementia comprises a collection of cognitive and sensory symptoms, including memory loss, communication difficulties, difficulty in planning and problem solving, disorientation and confusion, compromised olfaction, loss of visual perception, agnosia; and psychological symptoms, including personality and behavioral changes, depression, anxiety, hallucination, mood swings, agitation, and apathy [...].

RevDate: 2021-04-13

Yonesi M, Garcia-Nieto M, Guinea GV, et al (2021)

Silk Fibroin: An Ancient Material for Repairing the Injured Nervous System.

Pharmaceutics, 13(3):.

Silk refers to a family of natural fibers spun by several species of invertebrates such as spiders and silkworms. In particular, silkworm silk, the silk spun by Bombyx mori larvae, has been primarily used in the textile industry and in clinical settings as a main component of sutures for tissue repairing and wound ligation. The biocompatibility, remarkable mechanical performance, controllable degradation, and the possibility of producing silk-based materials in several formats, have laid the basic principles that have triggered and extended the use of this material in regenerative medicine. The field of neural soft tissue engineering is not an exception, as it has taken advantage of the properties of silk to promote neuronal growth and nerve guidance. In addition, silk has notable intrinsic properties and the by-products derived from its degradation show anti-inflammatory and antioxidant properties. Finally, this material can be employed for the controlled release of factors and drugs, as well as for the encapsulation and implantation of exogenous stem and progenitor cells with therapeutic capacity. In this article, we review the state of the art on manufacturing methodologies and properties of fiber-based and non-fiber-based formats, as well as the application of silk-based biomaterials to neuroprotect and regenerate the damaged nervous system. We review previous studies that strategically have used silk to enhance therapeutics dealing with highly prevalent central and peripheral disorders such as stroke, Alzheimer's disease, Parkinson's disease, and peripheral trauma. Finally, we discuss previous research focused on the modification of this biomaterial, through biofunctionalization techniques and/or the creation of novel composite formulations, that aim to transform silk, beyond its natural performance, into more efficient silk-based-polymers towards the clinical arena of neuroprotection and regeneration in nervous system diseases.

RevDate: 2021-04-13

Preman P, Alfonso-Triguero M, Alberdi E, et al (2021)

Astrocytes in Alzheimer's Disease: Pathological Significance and Molecular Pathways.

Cells, 10(3):.

Astrocytes perform a wide variety of essential functions defining normal operation of the nervous system and are active contributors to the pathogenesis of neurodegenerative disorders such as Alzheimer's among others. Recent data provide compelling evidence that distinct astrocyte states are associated with specific stages of Alzheimer´s disease. The advent of transcriptomics technologies enables rapid progress in the characterisation of such pathological astrocyte states. In this review, we provide an overview of the origin, main functions, molecular and morphological features of astrocytes in physiological as well as pathological conditions related to Alzheimer´s disease. We will also explore the main roles of astrocytes in the pathogenesis of Alzheimer´s disease and summarize main transcriptional changes and altered molecular pathways observed in astrocytes during the course of the disease.

RevDate: 2021-04-13

Friedrich MG, Skora A, Hancock SE, et al (2021)

Tau Is Truncated in Five Regions of the Normal Adult Human Brain.

International journal of molecular sciences, 22(7):.

The truncation of Tau is thought to be important in promoting aggregation, with this feature characterising the pathology of dementias such as Alzheimer disease. Antibodies to the C-terminal and N-terminal regions of Tau were employed to examine Tau cleavage in five human brain regions: the entorhinal cortex, prefrontal cortex, motor cortex, hippocampus, and cerebellum. These were obtained from normal subjects ranging in age from 18 to 104 years. Tau fragments of approximately 40 kDa and 45 kDa with an intact N-terminus retained were found in soluble and insoluble brain fractions. In addition, smaller C-terminal Tau fragments ranging in mass from 17 kDa to 25 kDa were also detected. These findings are consistent with significant Tau cleavage taking place in brain regions from 18 years onwards. It appears that site-specific cleavage of Tau is widespread in the normal human brain, and that large Tau fragments that contain the N-terminus, as well as shorter C-terminal Tau fragments, are present in brain cells across the age range.

RevDate: 2021-04-13

Moelgg K, Jummun F, C Humpel (2021)

Spreading of Beta-Amyloid in Organotypic Mouse Brain Slices and Microglial Elimination and Effects on Cholinergic Neurons.

Biomolecules, 11(3):.

The extracellular deposition of β-amyloid (Aβ) is one of the major characteristics in Alzheimer´s disease (AD). The "spreading hypothesis" suggests that a pathological protein (similar to prions) spreads over the entire brain. The aim of the present study was to use organotypic brain slices of postnatal day 8-10 mice. Using collagen hydrogels, we applied different Aβ peptides onto brain slices and analyzed spreading as well as glial reactions after eight weeks of incubation. Our data showed that from all tested Aβ peptides, human Aβ42 had the most potent activity to spread over into adjacent "target" areas. This effect was potentiated when brain slices from transgenic AD mice (APP_SweDI) were cultured. When different brain areas were connected to the "target slice" the spreading activity was more intense, originating from ventral striatum and brain stem. Reactive glial-fibrillary acidic protein (GFAP) astrogliosis increased over time, but Aβ depositions co-localized only with Iba1+ microglia but not with astrocytes. Application of human Aβ42 did not cause a degeneration of cholinergic neurons. We concluded that human Aβ42 spreads over into other "target areas", causing activation of glial cells. Most of the spread Aβ42 was taken up by microglia, and thus toxic free Aβ could not damage cholinergic neurons.

RevDate: 2021-04-13

Patel D, Zhang X, Farrell JJ, et al (2021)

Set-Based Rare Variant Expression Quantitative Trait Loci in Blood and Brain from Alzheimer Disease Study Participants.

Genes, 12(3):.

Because studies of rare variant effects on gene expression have limited power, we investigated set-based methods to identify rare expression quantitative trait loci (eQTL) related to Alzheimer disease (AD). Gene-level and pathway-level cis rare-eQTL mapping was performed genome-wide using gene expression data derived from blood donated by 713 Alzheimer's Disease Neuroimaging Initiative participants and from brain tissues donated by 475 Religious Orders Study/Memory and Aging Project participants. The association of gene or pathway expression with a set of all cis potentially regulatory low-frequency and rare variants within 1 Mb of genes was evaluated using SKAT-O. A total of 65 genes expressed in the brain were significant targets for rare expression single nucleotide polymorphisms (eSNPs) among which 17% (11/65) included established AD genes HLA-DRB1 and HLA-DRB5. In the blood, 307 genes were significant targets for rare eSNPs. In the blood and the brain, GNMT, LDHC, RBPMS2, DUS2, and HP were targets for significant eSNPs. Pathway enrichment analysis revealed significant pathways in the brain (n = 9) and blood (n = 16). Pathways for apoptosis signaling, cholecystokinin receptor (CCKR) signaling, and inflammation mediated by chemokine and cytokine signaling were common to both tissues. Significant rare eQTLs in inflammation pathways included five genes in the blood (ALOX5AP, CXCR2, FPR2, GRB2, IFNAR1) that were previously linked to AD. This study identified several significant gene- and pathway-level rare eQTLs, which further confirmed the importance of the immune system and inflammation in AD and highlighted the advantages of using a set-based eQTL approach for evaluating the effect of low-frequency and rare variants on gene expression.

RevDate: 2021-04-13

Atrahimovich D, Avni D, S Khatib (2021)

Flavonoids-Macromolecules Interactions in Human Diseases with Focus on Alzheimer, Atherosclerosis and Cancer.

Antioxidants (Basel, Switzerland), 10(3):.

Flavonoids, a class of polyphenols, consumed daily in our diet, are associated with a reduced risk for oxidative stress (OS)-related chronic diseases, such as cardiovascular disease, neurodegenerative diseases, cancer, and inflammation. The involvement of flavonoids with OS-related chronic diseases have been traditionally attributed to their antioxidant activity. However, evidence from recent studies indicate that flavonoids' beneficial impact may be assigned to their interaction with cellular macromolecules, rather than exerting a direct antioxidant effect. This review provides an overview of the recent evolving research on interactions between the flavonoids and lipoproteins, proteins, chromatin, DNA, and cell-signaling molecules that are involved in the OS-related chronic diseases; it focuses on the mechanisms by which flavonoids attenuate the development of the aforementioned chronic diseases via direct and indirect effects on gene expression and cellular functions. The current review summarizes data from the literature and from our recent research and then compares specific flavonoids' interactions with their targets, focusing on flavonoid structure-activity relationships. In addition, the various methods of evaluating flavonoid-protein and flavonoid-DNA interactions are presented. Our aim is to shed light on flavonoids action in the body, beyond their well-established, direct antioxidant activity, and to provide insights into the mechanisms by which these small molecules, consumed daily, influence cellular functions.

RevDate: 2021-04-08

Jain AP, G Sathe (2021)

Proteomics Landscape of Alzheimer's Disease.

Proteomes, 9(1):.

Alzheimer's disease (AD) is the most prevalent form of dementia, and the numbers of AD patients are expected to increase as human life expectancy improves. Deposition of β-amyloid protein (Aβ) in the extracellular matrix and intracellular neurofibrillary tangles are molecular hallmarks of the disease. Since the precise pathophysiology of AD has not been elucidated yet, effective treatment is not available. Thus, understanding the disease pathology, as well as identification and development of valid biomarkers, is imperative for early diagnosis as well as for monitoring disease progression and therapeutic responses. Keeping this goal in mind several studies using quantitative proteomics platform have been carried out on both clinical specimens including the brain, cerebrospinal fluid (CSF), plasma and on animal models of AD. In this review, we summarize the mass spectrometry (MS)-based proteomics studies on AD and discuss the discovery as well as validation stages in brief to identify candidate biomarkers.

RevDate: 2021-04-13

Bivona G, Lo Sasso B, Gambino CM, et al (2021)

The Role of Vitamin D as a Biomarker in Alzheimer's Disease.

Brain sciences, 11(3):.

Vitamin D and cognition is a popular association, which led to a remarkable body of literature data in the past 50 years. The brain can synthesize, catabolize, and receive Vitamin D, which has been proved to regulate many cellular processes in neurons and microglia. Vitamin D helps synaptic plasticity and neurotransmission in dopaminergic neural circuits and exerts anti-inflammatory and neuroprotective activities within the brain by reducing the synthesis of pro-inflammatory cytokines and the oxidative stress load. Further, Vitamin D action in the brain has been related to the clearance of amyloid plaques, which represent a feature of Alzheimer Disease (AD), by the immune cell. Based on these considerations, many studies have investigated the role of circulating Vitamin D levels in patients affected by a cognitive decline to assess Vitamin D's eventual role as a biomarker or a risk factor in AD. An association between low Vitamin D levels and the onset and progression of AD has been reported, and some interventional studies to evaluate the role of Vitamin D in preventing AD onset have been performed. However, many pitfalls affected the studies available, including substantial discrepancies in the methods used and the lack of standardized data. Despite many studies, it remains unclear whether Vitamin D can have a role in cognitive decline and AD. This narrative review aims to answer two key questions: whether Vitamin D can be used as a reliable tool for diagnosing, predicting prognosis and response to treatment in AD patients, and whether it is a modifiable risk factor for preventing AD onset.

RevDate: 2021-04-13

Greco V, Neri C, Pieragostino D, et al (2021)

Investigating Different Forms of Hydrogen Sulfide in Cerebrospinal Fluid of Various Neurological Disorders.

Metabolites, 11(3):.

Over the past 30 years a considerable amount of data has accumulated on the multifaceted role of hydrogen sulfide (H2S) in the central nervous system. Depending on its concentrations, H2S has opposite actions, ranging from neuromodulator to neurotoxic. Nowadays, accurate determination of H2S is still an important challenge to understand its biochemistry and functions. In this perspective, this study aims to explore H2S levels in cerebrospinal fluid (CSF), key biofluid for neurological studies, and to assess alleged correlations with neuroinflammatory and neurodegenerative mechanisms. A validated analytical determination combining selective electrochemical detection with ion chromatography was developed to measure free and bound sulfur forms of H2S. A first cohort of CSF samples (n = 134) was analyzed from patients with inflammatory and demyelinating disorders (acute disseminated encephalomyelitis; multiple sclerosis), chronic neurodegenerative diseases (Alzheimer disease; Parkinson disease), and motor neuron disease (Amyotrophic lateral sclerosis). Given its analytical features, the chromatographic method resulted sensitive, reproducible and robust. We also explored low molecular weight-proteome linked to sulphydration by proteomics analysis on matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS). This study is a first clinical report on CSF H2S concentrations from neurological diseases and opens up new perspectives on the potential clinical relevance of H2S and its potential therapeutic application.

RevDate: 2021-04-15

de Souza IFF, Dos Santos TQ, Placido RV, et al (2021)

The liquid crystalline phase behaviour of a nasal formulation modifies the brain disposition of donepezil in rats in the treatment of Alzheimer's disease.

Colloids and surfaces. B, Biointerfaces, 203:111721 pii:S0927-7765(21)00165-X [Epub ahead of print].

Although nanoparticles, polymeric micelles, liposomes, nanoemulsions, and microemulsions were extensively evaluated as formulations for nasal administration of drugs, lyotropic liquid crystal (LLC) mesophases have been few studied. The phase transition from a low-viscosity microemulsion to a more viscous LLC may improve the mucoadhesion of the formulation. Donepezil is a drug administered orally in the treatment of Alzheimer's disease, and with gastrointestinal side effects that are typical of acetylcholinesterase inhibitors. Based on this, donepezil administration by nasal pathway using a mucoadhesive LLC may be a feasible alternative. A colloidal formulation was selected from a ternary diagram, combining CETETH-10, oleic acid, and water (40:45:15, w/w). Donepezil was incorporated into the formulation, and the characterisation included in vitro studies, such as mucoadhesion and drug release. Pharmacokinetics in Wistar rats included evaluations by the nasal pathway with donepezil incorporated into microemulsion. A phase transition from an isotropic to an anisotropic system was observed after the swelling of the microemulsion with artificial nasal fluid (12-20 %). The release of donepezil in vitro occurred in a sustained manner. Significant levels of donepezil were achieved in the brain after nasal administration of the microemulsion, as a promising strategy for the treatment of Alzheimer's disease.

RevDate: 2021-04-02

Süer C, Yıldız N, Barutçu Ö, et al (2021)

Long-term depression-related tau phosphorylation is enhanced by methylene blue in healthy rat hippocampus.

Pharmacological reports : PR [Epub ahead of print].

BACKGROUND: The present study examined whether inhibition of guanylate cyclase (GC) is associated with the plasticity-related microtubule-stabilizing protein tau phosphorylation in the dentate gyrus (DG) of hippocampal formation.

METHODS: To address this issue, methylene blue (MB 50 μM) or saline was infused into the DG starting from the induction of long-term potentiation (LTP) or depression (LTD) for 1 h. Then, protein phosphatase 1 alpha (PP1α), glycogen synthase kinase 3 beta (GSK3β), and tau total and phosphorylated protein levels were measured in these hippocampi using western blotting. LTP and LTD were induced by application of high- and low-frequency stimulation protocols (HFS and LFS), respectively. 5-min averages of the excitatory postsynaptic potential (EPSP) slopes and population spike amplitudes at the end of recording were averaged to measure the magnitude of LTP or LTD.

RESULTS: Low-frequency stimulation protocols was unable to phosphorylate thr181 and thr231epitopes of tau, but possessed kinase activity similar to the HFS in phosphorylation of ser396 and ser416 epitopes. MB infusion during LTD induction attenuated LTD, prevented EPSP/spike dissociation and increased tau phosphorylation at ser396 and ser416 epitopes, without changing tau phosphorylation at thr181 and thr231 epitopes. Neither LTP nor LTP-related tau phosphorylation state was changed by MB infusion.

CONCLUSION: Although MB can benefit to stabilize the balance between LTP and LTD, and to fix the increased spike wave discharges, it might trigger deregulation of tau phosphorylation, leading to the development of Alzheimer's disease by a mechanism that goes awry during induction of LTD. Thereby detailed studies to reveal more precise evidence for the use of MB in this disease are needed.

RevDate: 2021-04-02

Pachuta-Stec A (2021)

Antioxidant Activity of 1,2,4-Triazole and Its Derivatives: A Mini Review.

Mini reviews in medicinal chemistry pii:MRMC-EPUB-115130 [Epub ahead of print].

The information about the presence of free radicals in biological materials was given for the first time about 70 years ago. Since then, numerous scientific studies have been conducted and the science of free radicals was born. Today we know that free radicals are by-products of enzymatic reactions occurring in the organism. They are produced during endogenous processes such as: cell respiration, phagocytosis, biosynthesis, catalysis, and biotransformation. They can also be produced by exogenous processes (radiation, sunlight, heavy metals, bacteria, fungi, protozoa and viruses). The overproduction of free radicals affects the aging processes, oxidative stress (OS) and takes part in the pathogenesis of various diseases. Among them are cancer, rheumatoid arthritis, neurodegenerative diseases: Alzheimer and Parkinson, pulmonary diseases, atherosclerosis and DNA damage. Compounds with antioxidant activity are very important nowadays because they allow organisms to keep a balance between the production of free radicals and the speed of their neutralization in the body. Next to the natural antioxidants (flavonoids, carotenoids, vitamins, etc.), synthetic ones are also of great importance. Among synthetic compounds with antioxidant activity are 1,2,4-triazoles and its derivatives. 1,2,4-Triazoles are heterocyclic compounds with three nitrogen atoms. Due to a broad spectrum of biological activities, these derivatives have been of interest to scientists for many years. Some of them are also used as drugs. The finding of new synthetic compounds with antioxidant features in the triazole group has become important problem of medicinal chemistry.

RevDate: 2021-04-03

de Oliveira LG, Angelo YS, Iglesias AH, et al (2021)

Unraveling the Link Between Mitochondrial Dynamics and Neuroinflammation.

Frontiers in immunology, 12:624919.

Neuroinflammatory and neurodegenerative diseases are a major public health problem worldwide, especially with the increase of life-expectancy observed during the last decades. For many of these diseases, we still lack a full understanding of their etiology and pathophysiology. Nonetheless their association with mitochondrial dysfunction highlights this organelle as an important player during CNS homeostasis and disease. Markers of Parkinson (PD) and Alzheimer (AD) diseases are able to induce innate immune pathways induced by alterations in mitochondrial Ca2+ homeostasis leading to neuroinflammation. Additionally, exacerbated type I IFN responses triggered by mitochondrial DNA (mtDNA), failures in mitophagy, ER-mitochondria communication and mtROS production promote neurodegeneration. On the other hand, regulation of mitochondrial dynamics is essential for CNS health maintenance and leading to the induction of IL-10 and reduction of TNF-α secretion, increased cell viability and diminished cell injury in addition to reduced oxidative stress. Thus, although previously solely seen as power suppliers to organelles and molecular processes, it is now well established that mitochondria have many other important roles, including during immune responses. Here, we discuss the importance of these mitochondrial dynamics during neuroinflammation, and how they correlate either with the amelioration or worsening of CNS disease.

RevDate: 2021-04-03

Südkamp N, Shchyglo O, D Manahan-Vaughan (2021)

Absence of Pannexin 1 Stabilizes Hippocampal Excitability After Intracerebral Treatment With Aβ (1-42) and Prevents LTP Deficits in Middle-Aged Mice.

Frontiers in aging neuroscience, 13:591735.

Beta-amyloid protein [Aβ(1-42)] plays an important role in the disease progress and pathophysiology of Alzheimer's disease (AD). Membrane properties and neuronal excitability are altered in the hippocampus of transgenic AD mouse models that overexpress amyloid precursor protein. Although gap junction hemichannels have been implicated in the early pathogenesis of AD, to what extent Pannexin channels contribute to Aβ(1-42)-mediated brain changes is not yet known. In this study we, therefore, investigated the involvement of Pannexin1 (Panx1) channels in Aβ-mediated changes of neuronal membrane properties and long-term potentiation (LTP) in an animal model of AD. We conducted whole-cell patch-clamp recordings in CA1 pyramidal neurons 1 week after intracerebroventricular treatments of adult wildtype (wt) and Panx1 knockout (Panx1-ko) mice with either oligomeric Aβ(1-42), or control peptide. Panx1-ko hippocampi treated with control peptide exhibited increased neuronal excitability compared to wt. In addition, action potential (AP) firing frequency was higher in control Panx1-ko slices compared to wt. Aβ-treatment reduced AP firing frequency in both cohorts. But in Aβ-treated wt mice, spike frequency adaptation was significantly enhanced, when compared to control wt and to Aβ-treated Panx1-ko mice. Assessment of hippocampal LTP revealed deficits in Aβ-treated wt compared to control wt. By contrast, Panx1-ko exhibited LTP that was equivalent to LTP in control ko hippocampi. Taken together, our data show that in the absence of Pannexin1, hippocampi are more resistant to the debilitating effects of oligomeric Aβ. Both Aβ-mediated impairments in spike frequency adaptation and in LTP that occur in wt animals, are ameliorated in Panx1-ko mice. These results suggest that Panx1 contributes to early changes in hippocampal neuronal and synaptic function that are triggered by oligomeric Aβ.

RevDate: 2021-04-01

Sotoudegan F, Sotoudegan F, Talebkhan Garoosi Y, et al (2021)

Anti-Aβ-scFv-loaded polymeric nano-micelles with enhanced plasma stability.

The Journal of pharmacy and pharmacology, 73(4):460-472.

OBJECTIVES: Immunotherapy using recombinant monoclonal antibodies specifically Anti-amyloid-beta (Anti-Aβ) scFv is envisaged as an appropriate therapeutic for Alzheimer through reduction of amyloid-beta aggregation. The solubilization of therapeutics using polymeric micelles facilitates an improved bioavailability and extended blood half-life. In this study, the optimum production condition for Anti-amyloid-beta (Anti-Aβ) scFv was obtained. To increase the stability of plasma, Anti-Aβ-loaded polymeric micelles were synthesized.

METHODS: Escherichia coli SHuffle expression strain was used and purified by Ni-NTA. Pluronics P85 and F127 micelles were used for the Anti-Aβ delivery and were characterized in terms of morphology, drug loading and drug release in phosphate buffer and artificial cerebrospinal fluid. The stability profile was quantified at 4°C over a 30 days storage period. The stability in human plasma was also evaluated.

KEY FINDINGS: Proteins expressed in SHuffle resulted in increased levels of protein expression and solubility. Low critical micelle concentration value and high micelle encapsulation efficiency (<200 nm) achieved via direct dissolution method. Anti-Aβ-loaded micelles were around 2.2-fold more stable than Anti-Aβ in plasma solution. A sustained in-vitro release of Anti-Aβ from micelles was observed.

CONCLUSIONS: Results confirmed that Pluronic-micelles pose benefits as a nano-carrier to increase the stability of Anti-Aβ scFvin in the plasma.

RevDate: 2021-04-01

Üstün E, Çelebi MS, Ayvaz MÇ, et al (2021)

PEPPSI complexes as potential prodrugs: enzyme inhibition, antioxidant activity, electrochemical characterization, molecular docking analysis.

Zeitschrift fur Naturforschung. C, Journal of biosciences pii:znc-2020-0295 [Epub ahead of print].

In this study, enzyme inhibition and antioxidant activity analyzes of previously characterized pyridine-enhanced precatalyst preparation stabilization and initiation (PEPPSI)-type Palladium(II) complexes with benzimidazole-type ligands {dichloro[L]pyridine palladium(II), L1: 1-(2-methyl-2-propenyl)-3-[benzylbenzimidazole]-2-ylidene, L2: 1-(2-methyl-2-propenyl)-3-[4-chloro benzylbenzimidazole]-2-ylidene, L3: 1-(2-methyl-2-propenyl)-3-[3-methylbenzylbenzimidazole]-2-ylidene, L4: 1-(2-methyl-2-propenyl)-3-[3,4,5-thrimethoxybenzylbenzimidazole]-2-ylidene, L5: 1-(2-methyl-2-propenyl)-3-[3-naphthylbenzylbenzimidazole]-2-ylidene, L6: 1-(2-methyl-2-propenyl)-3-[anthracen-9-ylmethylbenzimidazole]-2-ylidene} were performed and evaluated as potential drugs for neurodegenerative disorders such as Alzheimer disease and Parkinson disease. Inhibition of tyrosinase enzyme of N-heterocyclic carbenes (NHC) complexes was determined for the first time in literature. Chelating activities of the complexes were determined and compared with EDTA. Electrochemical characterization was performed using cyclic voltammetry method. Moreover, global reactivity descriptors and electronic transitions were evaluated by DFT/TDDFT methods and molecular docking interactions with human acetylcholine esterase, human butyrylcholine esterase and oxidoreductase were studied.

RevDate: 2021-04-02

Trotti LM, Bliwise DL, Keating GL, et al (2021)

Cerebrospinal Fluid Hypocretin and Nightmares in Dementia Syndromes.

Dementia and geriatric cognitive disorders extra, 11(1):19-25.

Background/Aims: Hypocretin promotes wakefulness and modulates REM sleep. Alterations in the hypocretin system are increasingly implicated in dementia. We evaluated relationships among hypocretin, dementia biomarkers, and sleep symptoms in elderly participants, most of whom had dementia.

Methods: One-hundred twenty-six adults (mean age 66.2 ± 8.4 years) were recruited from the Emory Cognitive Clinic. Diagnoses were Alzheimer disease (AD; n = 60), frontotemporal dementia (FTD; n = 21), and dementia with Lewy bodies (DLB; n = 20). We also included cognitively normal controls (n = 25). Participants and/or caregivers completed sleep questionnaires and lumbar puncture was performed for cerebrospinal fluid (CSF) assessments.

Results: Except for sleepiness (worst in DLB) and nocturia (worse in DLB and FTD) sleep symptoms did not differ by diagnosis. CSF hypocretin concentrations were available for 87 participants and normal in 70, intermediate in 16, and low in 1. Hypocretin levels did not differ by diagnosis. Hypocretin levels correlated with CSF total τ levels only in men (r = 0.34; p = 0.02). Lower hypocretin levels were related to frequency of nightmares (203.9 ± 29.8 pg/mL in those with frequent nightmares vs. 240.4 ± 46.1 pg/mL in those without; p = 0.05) and vivid dreams (209.1 ± 28.3 vs. 239.5 ± 47.8 pg/mL; p = 0.014). Cholinesterase inhibitor use was not associated with nightmares or vivid dreaming.

Conclusion: Hypocretin levels did not distinguish between dementia syndromes. Disturbing dreams in dementia patients may be related to lower hypocretin concentrations in CSF.

RevDate: 2021-04-06

Nakamura Y, Yamamoto T, Xu X, et al (2021)

Enhancing calmodulin binding to ryanodine receptor is crucial to limit neuronal cell loss in Alzheimer disease.

Scientific reports, 11(1):7289.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive neuronal cell loss. Recently, dysregulation of intracellular Ca2+ homeostasis has been suggested as a common proximal cause of neural dysfunction in AD. Here, we investigated (1) the pathogenic role of destabilization of ryanodine receptor (RyR2) in endoplasmic reticulum (ER) upon development of AD phenotypes in AppNL-G-F mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic), and (2) the therapeutic effect of enhanced calmodulin (CaM) binding to RyR2. In the neuronal cells from AppNL-G-F mice, CaM dissociation from RyR2 was associated with AD-related phenotypes, i.e. Aβ accumulation, TAU phosphorylation, ER stress, neuronal cell loss, and cognitive dysfunction. Surprisingly, either genetic (by V3599K substitution in RyR2) or pharmacological (by dantrolene) enhancement of CaM binding to RyR2 reversed almost completely the aforementioned AD-related phenotypes, except for Aβ accumulation. Thus, destabilization of RyR2 due to CaM dissociation is most likely an early and fundamental pathogenic mechanism involved in the development of AD. The discovery that neuronal cell loss can be fully prevented simply by stabilizing RyR2 sheds new light on the treatment of AD.

RevDate: 2021-04-01

Nuebling GS, Prix C, Brendel M, et al (2021)

Low-degree trisomy 21 mosaicism promotes early-onset Alzheimer disease.

Neurobiology of aging pii:S0197-4580(21)00076-2 [Epub ahead of print].

Trisomy-21 mosaicism (mT21) with subclinical intellectual development disorder or physical phenotype has very rarely been associated with early-onset cognitive decline. Notably, early-onset Alzheimer's disease (EOAD) patients' family histories frequently suggest genetic causes other than autosomal-dominant APP/PSEN-1/2 mutations. We present an EOAD patient in his late fifties newly diagnosed with low-degree mT21 (13%/21% blood lymphocytes/ectodermal cells). We applied fluorescence in-situ hybridization to confirm a diagnosis of mT21. Multimodal positron-emission-tomography applying 18F-fluodesoxyglucose (metabolism), 18F-florbetaben (amyloid-β deposits) and 18F-PI-2620 (tau-deposits) tracers was used to confirm a diagnosis of EOAD according to the ATN-criteria of AD. Initial PET-studies revealed marked cerebral amyloid-β- and tau-pathology and parietotemporal hypometabolism, confirming EOAD according to the ATN-criteria of AD. A marked cognitive decline was accompanied by an increase in tau pathology in follow-up studies. This is the first case demonstrating that a low-degree APP gene-dose increase suffices to cause EOAD with prominent amyloid-β/tau pathology.

RevDate: 2021-04-10

Lin X, Wen X, Wei Z, et al (2021)

Vitamin K2 protects against Aβ42-induced neurotoxicity by activating autophagy and improving mitochondrial function in Drosophila.

Neuroreport, 32(6):431-437.

OBJECTIVE: Alzheimer disease is characterized by progressive decline in cognitive function due to neurodegeneration induced by accumulation of Aβ and hyperphosphorylated tau protein. This study was conducted to explore the protective effect of vitamin K2 against Aβ42-induced neurotoxicity.

METHODS: Alzheimer disease transgenic Drosophila model used in this study was amyloid beta with the arctic mutation expressed in neurons. Alzheimer disease flies were treated with vitamin K2 for 28 days after eclosion. Aβ42 level in brain was detected by ELISA. Autophagy-related genes and NDUFS3, the core subunit of mitochondrial complex I, were examined using real-Time PCR (RT-PCR) and western blot analysis.

RESULTS: Vitamin K2 improved climbing ability (P = 0.0105), prolonged lifespan (P < 0.0001) and decreased Aβ42 levels (P = 0.0267), upregulated the expression of LC3 and Beclin1(P = 0.0012 and P = 0.0175, respectively), increased the conversion of LC3I to LC3II (P = 0.0206) and decreased p62 level (P =0.0115) in Alzheimer disease flies. In addition, vitamin K2 upregulated the expression of NDUFS3 (P = 0.001) and increased ATP production (P = 0.0033) in Alzheimer disease flies.

CONCLUSION: It seems that vitamin K2 protect against Aβ42-induced neurotoxicity by activation of autophagy and rescue mitochondrial dysfunction, which suggests that it may be a potential valuable therapeutic approach for Alzheimer disease.

RevDate: 2021-04-14
CmpDate: 2021-04-14

Gu X, Shi Z, Liu S, et al (2021)

Incidence and risk factors of dementia and the primary subtypes in northern rural China.

Medicine, 100(13):e25343.

ABSTRACT: This study was carried out to estimate the incidence and to determine socio-demographic risk factors for dementia among individuals residing in rural northern China.The current prospective, population-based study was conducted between 2011 and 2016. Follow-up interviews were conducted annually from 2014 to 2016. The study involved 1511 dementia-free individuals aged 60 years or above from rural China. Standard criteria were used to make diagnoses for dementia and Alzheimer disease (AD).At least one follow up survey was completed with 1181 study participants. At the 5-year follow-up, 127 individuals had developed dementia, 75 had developed AD, and 32 had developed vascular dementia (VaD). With a total of 5649.2 risk years for the sample, the estimated incidence rates per 1000 person-years were 22.48 (95% CI: 18.62, 26.35) for dementia and 13.28 (95% CI: 10.29, 16.26) for AD. Incidence rates for dementia and AD increased with age across the 10-year age groups. Poor education (illiteracy) was an independent risk factor for both AD and VaD. Being engaged in social activities was an independent protective factor for VaD.The incidence of dementia in rural China was found to be higher than previously reported. Incidence of dementia increased with age, and AD was the most frequent type of dementia. Poor education was associated with a higher risk of VaD and AD. Engagement in social activities was an independent protective factor for VaD.

RevDate: 2021-04-12

Dërmaku-Sopjani M, Kurti F, Xuan NT, et al (2021)

Klotho-Dependent Role of 1,25(OH)2D3 in the Brain.

Neuro-Signals, 29(1):14-23.

The antiaging protein Klotho is encoded by the Klotho gene first identified as an 'aging suppressor', in mice. Klotho deficiency is involved in premature aging and early death, while its overexpression is related to longevity. Klotho is mostly expressed in the kidney, but also in the brain, and in other organs. Two forms of Klotho, the cell membrane and secreted form, have pleiotropic activities that include regulation of general metabolism, oxidative stress, and mineral metabolism that correlates with its effect on accelerating aging. Membrane Klotho serves as an obligate co-receptor for the fibroblast growth factor (FGF), while secreted Klotho plays its role as a humoral factor. Klotho protein participates in the regulation of several biological activities, including regulation of calcium-phosphate homeostasis and PTH as well as vitamin D metabolism. The active form of vitamin D, 1,25(OH)2D3 (1,25-dihydroxy-vitamin D3 = calcitriol), acts as a neurosteroid that participates in the regulation of multiple brain functions. It provides neuroprotection and suppresses oxidative stress, inhibits inflammation and inflammatory mediators, and stimulates various neurotrophins. Calcitriol is involved in many brain-related diseases, including multiple sclerosis, Alzheimer´s disease, Parkinson´s disease, and schizophrenia. This review covers the most recent advances in Klotho research and discusses Klotho-dependent roles of calcitriol in neuro-psycho-pathophysiology.

RevDate: 2021-03-30

Alexander GC, Emerson S, AS Kesselheim (2021)

Evaluation of Aducanumab for Alzheimer Disease: Scientific Evidence and Regulatory Review Involving Efficacy, Safety, and Futility.

JAMA pii:2778191 [Epub ahead of print].

RevDate: 2021-04-13

Pavarini G, Hamdi L, Lorimer J, et al (2021)

Young people's moral attitudes and motivations towards direct-to-consumer genetic testing for inherited risk of Alzheimer disease.

European journal of medical genetics, 64(6):104180 pii:S1769-7212(21)00046-X [Epub ahead of print].

PURPOSE: Since the U.S. Food and Drug Administration approved sales of genetic tests for late-onset Alzheimer's disease (LOAD) risk, a heated debate has arisen over whether these tests should indeed be offered online and direct-to-consumer (DTC). As this debate progresses, it is important to understand the ethical perspectives and motivations of young people, who are a key target group for DTC services.

METHODS: Thirty-one grandchildren of people with LOAD, aged 16-26, were interviewed about their moral attitudes and motivations with regards to DTC genetic testing for LOAD.

RESULTS: Even though most participants claimed that people should have the right to access these services, they also expressed concerns about potential distress in response to learning about risk, particularly for minors. About a third were interested in testing, primarily to gain self-knowledge regarding one's health; however, face-to-face services were vastly preferred over the online option.

CONCLUSION: While DTC genetic companies often market their services as a "fun consumer product", DTC testing for LOAD was largely understood as a serious health screening procedure and a vulnerable moment in the lives of young people in Alzheimer's families. This points to the importance of appropriate standards of information and support to young people pre- and post-testing.

RevDate: 2021-03-29

Peña-Quián Y, Sosa-Pérez S, Batista-Cuéllar JF, et al (2021)

Evaluating Cerebral Perfusion in Alzheimer Patients and First-Degree Relatives: Lessons from Artemisa Province, Cuba.

MEDICC review, 23(1):55-63.

INTRODUCTION: Alzheimer disease is related to several risk factors including aging, family history, high blood pressure and diabetes. Studies have shown specific regional cerebral perfusion changes in patients with Alzheimer disease. Some authors state that these changes could appear years before patient memory becomes impaired, enabling early diagnosis in high-risk persons who appear to be healthy.

OBJECTIVE: Determine the usefulness of cerebral perfusion studies in Alzheimer patients and first-degree relatives for obtaining additional diagnostic information and detecting functional changes that may suggest elevated disease risk.

METHODS: This study involved 128 persons (87 clinically diagnosed with Alzheimer disease and 41 of their first-degree relatives with normal cognition), all from Artemisa Province, Cuba. We performed clinical, laboratory, neuropsychological and genetic (apolipoprotein E-ApoE, e4 allele) tests, as well as cerebral perfusion studies using single photon emission computed tomography after administering 740-925 MBq of 99m Tc-ECD, following internationally standardized protocols.

RESULTS: In the Alzheimer disease group, the cerebral single photon emission computed tomography showed a typical Alzheimer pattern (bilateral posterior temporal-parietal hypoperfusion) in 77% (67/87) of participants; 35.9% (28/67) in stage 1; 51.3% (40/67) in stage 2; and 12.8% (10/67) in stage 3 of the disease. In this group, 12.7% (11/87) had mild or unilateral cerebral perfusion changes; 5.7% (5/87) vascular dementia; 3.4% (3/87) frontal dementia; and 1.2% (1/87) normal cerebral perfusion. Of the patients, 28.7% (25/87) received a different classification of stage and disease diagnosis after cerebral perfusion results were considered. In the relative group, 14.6% (6/41) had cerebral perfusion abnormalities. Among these, 7.1% (3/41) were mild bilateral temporal-parietal hypoperfusion; 4.8% (2/41) mild unilateral temporal-parietal hypoperfusion; and 2.4% (1/41) had perfusion defecits in their right frontal lobes. Of patients with typical Alzheimer disease patterns in the cerebral single photon emission computed tomography, 76.6% (52/67) had positive ApoE e4. All relatives with perfusion abnormalities (6/6) had positive ApoE e4.

CONCLUSIONS: Cerebral perfusion studies confirmed the Alzheimer disease diagnosis, classified disease stages, and differentiated between the types of dementia. The test showed perfusion changes in several asymptomatic first-degree relatives with positive ApoE e4, which could be predictors of disease. The technique was useful for evaluating patients and their relatives.

RevDate: 2021-03-29

Ashizawa T, Igarashi A, Sakata Y, et al (2021)

Impact of the Severity of Alzheimer's Disease on the Quality of Life, Activities of Daily Living, and Caregiving Costs for Institutionalized Patients on Anti-Alzheimer Medications in Japan.

Journal of Alzheimer's disease : JAD pii:JAD201514 [Epub ahead of print].

BACKGROUND: Alzheimer's disease (AD) increases societal costs and decreases the activities of daily living (ADL) and quality of life (QoL) of the affected individuals.

OBJECTIVE: We assess the impact of AD severity on ADL, QoL, and caregiving costs in Japanese facilities for the elderly.

METHODS: Patients with AD in facilities for the elderly were included (47 facilities, N = 3,461). The QoL, ADL, and disease severity of patients were assessed using Barthel Index (BI), EuroQoL-5D-5L (EQ-5D-5L), and Mini-Mental State Examination (MMSE), respectively. Annual caregiving costs were estimated using patients' claims data. The patients were subcategorized into the following three groups according to the MMSE score: mild (21≤MMSE≤30), moderate (11≤MMSE≤20), and severe (0≤MMSE≤10). Changes among the three groups were evaluated using the Jonckheere-Terpstra test.

RESULTS: Four hundred and one participants were on anti-AD medicines, of whom 287 (age: 86.1±6.4 years, 76.7% women) in the mild (n = 53, 84.0±6.9 years, 71.7%), moderate (n = 118, 86.6±5.9 years, 76.3%), and severe (n = 116, 86.6±6.5 years, 79.3%) groups completed the study questionnaires. The mean BI and EQ-5D-5L scores for each group were 83.6, 65.1, and 32.8 and 0.801, 0.662, and 0.436, respectively. The mean annual caregiving costs were 2.111, 2.470, and 2.809 million JPY, respectively. As AD worsened, the BI and EQ-5D-5L scores decreased and annual caregiving costs increased significantly.

CONCLUSION: AD severity has an impact on QoL, ADL, and caregiving costs.

RevDate: 2021-03-29

Pérez-López N, Martín C, García B, et al (2021)

Alterations in the Expression of the Genes Responsible for the Synthesis of Heparan Sulfate in Brains With Alzheimer Disease.

Journal of neuropathology and experimental neurology pii:6199418 [Epub ahead of print].

The saccharide chains of heparan sulfate appear to be involved in several aspects Alzheimer disease (AD) pathogenesis. Their structural complexity is due to the expression of different isoenzymes. We studied the differential transcription of heparan sulfate chain biosynthesis in AD brains, analyzing different brain regions in patients with different extents of AD pathology. The transcriptomic study was performed by RT-PCR using samples of amygdala, anterior hippocampus, posterior hippocampus, claustrum, calcarine fissure, globus pallidus and cerebellum from patients with mild, moderate, or severe AD, as well as healthy individuals. Certain heparan sulfate epitopes were also detected by immunohistochemistry. Several genes, across all stages of heparan sulfate synthesis, showed altered transcription in different brain regions of AD patients. The numbers of alterations were greater in in moderate versus mild AD patients. In severe patients, there were fewer alterations in genes related to early stages of biosynthesis, and overexpression of genes involved in late stages. The alterations correlated with progressive brain atrophy, although alterations were more common in the cerebellum. Detection of some heparan sulfate epitopes by immunohistochemistry was consistent with previous studies. In conclusion, transcriptional alterations in the biosynthetic genes of heparan sulfate depend on the brain region and the degree of AD pathology.

RevDate: 2021-04-05

Nobili A, La Barbera L, M D'Amelio (2021)

Targeting autophagy as a therapeutic strategy to prevent dopamine neuron loss in early stages of Alzheimer disease.

Autophagy [Epub ahead of print].

Alzheimer disease (AD) is a neurodegenerative disorder for which no approved medication exists. AD is characterized by worsening cognitive and non-cognitive symptoms, and research in the AD field strives to identify very precocious brain alterations leading to an irreversible condition. Recently it has been demonstrated that several early AD symptoms are paralleled with degeneration of neurons producing dopamine (DA), a neurotransmitter involved in the regulation of cognitive and non-cognitive functions. Actually, we found that ventral tegmental area (VTA) DA neurons degenerate early in a validated AD mouse model (Tg2576). Here, we summarize new data showing how macroautophagy/autophagy impairment - due to enhanced activity of the ABL/c-Abl kinase - might cause the DA neuron loss. We also proved that nilotinib, an ABL inhibitor, restores autophagy flux, thus preventing VTA neurodegeneration. Most notably, from a clinical point of view, nilotinib, by preventing DA neuronal loss, preserves DA outflow in VTA-projecting areas, improving Tg2576 behavioral phenotypes. Our findings shed light on the mechanism involved in DA neurodegeneration, revealing that autophagy represents a viable therapeutic target in early AD.

RevDate: 2021-03-29

Huq AJ, Sexton A, Lacaze P, et al (2021)

Genetic testing in dementia-A medical genetics perspective.

International journal of geriatric psychiatry [Epub ahead of print].

OBJECTIVE: When a genetic cause is suspected in a person with dementia, it creates unique diagnostic and management challenges to the treating clinician. Many clinicians may be unaware of the practicalities surrounding genetic testing for their patients, such as when to test and what tests to use and how to counsel patients and their families. This review was conducted to provide guidance to clinicians caring for patients with dementia regarding clinically relevant genetics.

METHODS: We searched PubMed for studies that involved genetics of dementia up to March 2020. Patient file reviews were also conducted to create composite cases.

RESULTS: In addition to families where a strong Mendelian pattern of family history is seen, people with younger age of onset, especially before the age of 65 years were found to be at an increased risk of harbouring a genetic cause for their dementia. This review discusses some of the most common genetic syndromes, including Alzheimer disease, frontotemporal dementia, vascular dementia, Parkinson disease dementia/dementia with Lewy bodies and some rarer types of genetic dementias, along with illustrative clinical case studies. This is followed by a brief review of the current genetic technologies and a discussion on the unique genetic counselling issues in dementia.

CONCLUSIONS: Inclusion of genetic testing in the diagnostic pathway in some patients with dementia could potentially reduce the time taken to diagnose the cause of their dementia. Although a definite advantage as an addition to the diagnostic repository, genetic testing has many pros and cons which need to be carefully considered first.

RevDate: 2021-03-30
CmpDate: 2021-03-30

Qiu C, Zhou W, Shi WT, et al (2020)

[Association between periodontitis and Alzheimer disease: a meta analysis].

Shanghai kou qiang yi xue = Shanghai journal of stomatology, 29(6):661-668.

PURPOSE: To evaluate the association between periodontitis and Alzheimer's disease.

METHODS: Databases of PubMed, Embase, CNKI, VIP and WanFang databases were searched for the relevant observational studies focusing on the association between periodontitis and Alzheimer's disease. The deadline was January 2019. Data quality evaluation and extraction were independently conducted by two authors. Meta analysis was performed using RevMan 5.2 software.

RESULTS: Four case-control, five cross-sectional and two cohort studies were included. One cohort study and four case-control studies treated periodontitis as the exposure factor, all five cross-sectional studies and the other cohort study treated Alzheimer's disease as the exposure factor. The results of meta analysis showed that patients with periodontitis had a higher risk of Alzheimer's disease (RR=1.22, 95%CI: 1.13-1.33, P<0.00001), and the risk was more higher in patients with severe periodontitis(RR=1.54, 95%CI:1.05-2.26, P=0.03<0.05); but there was no significant difference in the risk of Alzheimer's disease in patients with moderate periodontitis (RR=1.19, 95%CI: 0.98-1.44, P=0.07>0.05). The results of meta-analysis also showed that probing depth in patients with Alzheimer's disease was significantly higher than that of the control group (MD=2.58, 95%CI: 0.17-4.99, P=0.04<0.05), as well as clinical attachment loss (MD=1.27, 95%CI: 0.43-2.10, P=0.003<0.05), plaque index (MD=1.14, 95%CI: 0.85-1.44, P<0.00001) and the percentage of bleeding on probing (MD=21.11%, 95%CI: 18.23%-23.99%, P<0.00001). Furthermore, the number of present teeth in patients with Alzheimer's disease was significantly less than that of the control group (MD=-3.77, 95% CI: -6.89- -0.65, P=0.02<0.05).

CONCLUSIONS: The current evidence indicates that periodontitis is associated with Alzheimer's disease and patients with periodontitis (especially severe periodontitis) probably have a higher risk of developing Alzheimer's disease, and patients with Alzheimer's disease tend to have poorer periodontal health. However, the number of existing studies is limited and more clinical evidences are needed to support the correlation between these two diseases.

RevDate: 2021-04-01

Craig CE, Ray NJ, Müller MLTM, et al (2020)

New Developments in Cholinergic Imaging in Alzheimer and Lewy Body Disorders.

Current behavioral neuroscience reports, 7(4):278-286.

Purpose of Review: This paper aims to review novel trends in cholinergic neuroimaging in Alzheimer and Lewy body parkinsonian disorders.

Recent Findings: The spectrum of cholinergic imaging is expanding with the availability of spatially more precise radioligands that allow assessment of previously less recognized subcortical and cortical structures with more dense cholinergic innervation. In addition, advances in MRI techniques now allow quantitative structural or functional assessment of both the cholinergic forebrain and the pedunculopontine nucleus, which may serve as non-invasive prognostic predictors. Multimodal imaging approaches, such as PET-MRI or multiligand PET offer new insights into the dynamic and interactive roles of the cholinergic system at both local and larger-scale neural network levels.

Summary: Our understanding of the heterogeneous roles of the cholinergic system in age-related diseases is evolving. Multimodal imaging approaches that provide complimentary views of the cholinergic system will be necessary to shed light on the impact of cholinergic degeneration on regional and large-scale neural networks that underpin clinical symptom manifestation in neurodegeneration.

RevDate: 2021-03-29

Ophir K, Ran B, Felix B, et al (2021)

Ten year cumulative incidence of dementia after late onset epilepsy of unknown etiology.

Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia, 86:247-251.

Recent epidemiological studies suggest late life onset epilepsy of unknown etiology (LOEU) is a risk factor for future dementia. These studies rely on inclusion and exclusion of multiple diagnostic codes rather than structured data and neuroimaging findings, and thus challenging to interpret clinically. We assessed the cumulative incidence of dementia in patients with LOEU diagnosed through admission data and neuroimaging over a 10-year follow-up and compared baseline characteristics that distinguish group level incident dementia. We screened our hospital records for patients aged 55-69 with new epilepsy, admitted between 2000 and 2008, and excluded patients diagnosed with epilepsy from an underlying cause on medical records or neuroimaging. We used retrospective hospital data to follow patients for incident dementia or mortality at 10 years and compared baseline (demographics, depression or anxiety, vascular risk factors, results of electroencephalogram (EEG) studies, antidepressant use and type of ant seizure medication) and follow up (seizure recurrence, incident cerebrovascular disease) characteristics for patients with and without incident dementia. Fifty-four LOEU cases were screened, age at first seizure was 61 ± 5. The 10-year cumulative incidence of dementia was 22.20% (95% Confidence Interval 22.08-23.10%) and time to dementia diagnosis was 5.4 ± 3.9 years. Patients with incident dementia were more likely to be women (83% vs 38%, p = 0.002), have interictal epileptic form discharges (IED) on baseline EEG (70% vs 29%, p = 0.011) and depression or anxiety (50% vs 18%, p = 0.026). No differences were found in other baseline or follow up characteristics. Our results support recent findings of dementia incidence in LOEU. Prospective studies on LOEU should evaluate phenotypic determinants of individuals with late life epilepsy and the rate of progression to dementia.

RevDate: 2021-04-02

Cicognola C, Janelidze S, Hertze J, et al (2021)

Plasma glial fibrillary acidic protein detects Alzheimer pathology and predicts future conversion to Alzheimer dementia in patients with mild cognitive impairment.

Alzheimer's research & therapy, 13(1):68.

INTRODUCTION: Plasma glial fibrillary acidic protein (GFAP) is a marker of astroglial activation and astrocytosis. We assessed the ability of plasma GFAP to detect Alzheimer's disease (AD) pathology in the form of AD-related amyloid-β (Aβ) pathology and conversion to AD dementia in a mild cognitive impairment (MCI) cohort.

METHOD: One hundred sixty MCI patients were followed for 4.7 years (average). AD pathology was defined using cerebrospinal fluid (CSF) Aβ42/40 and Aβ42/total tau (T-tau). Plasma GFAP was measured at baseline and follow-up using Simoa technology.

RESULTS: Baseline plasma GFAP could detect abnormal CSF Aβ42/40 and CSF Aβ42/T-tau with an AUC of 0.79 (95% CI 0.72-0.86) and 0.80 (95% CI 0.72-0.86), respectively. When also including APOE ε4 status as a predictor, the accuracy of the model to detect abnormal CSF Aβ42/40 status improved (AUC = 0.86, p = 0.02). Plasma GFAP predicted subsequent conversion to AD dementia with an AUC of 0.84 (95% CI 0.77-0.91), which was not significantly improved when adding APOE ε4 or age as predictors to the model. Longitudinal GFAP slopes for Aβ-positive and MCI who progressed to dementia (AD or other) were significantly steeper than those for Aβ-negative (p = 0.007) and stable MCI (p < 0.0001), respectively.

CONCLUSION: Plasma GFAP can detect AD pathology in patients with MCI and predict conversion to AD dementia.

RevDate: 2021-03-29

Emran MY, Shenashen MA, El-Safty SA, et al (2021)

Microporous P-doped carbon spheres sensory electrode for voltammetry and amperometry adrenaline screening in human fluids.

Mikrochimica acta, 188(4):138.

An electrochemical sensor-based phosphorus-doped microporous carbon spheroidal structures (P-MCSs) has been designed for selective adrenaline (ADR) signaling in human blood serum. The P-MCS electrode sensor is built with heterogeneous surface alignments including multiple porous sizes with open holes and meso-/macro-grooves, rough surface curvatures, and integral morphology with interconnected and conjugated microspheres. In addition, the P atom-doped graphitic carbon forms highly active centers, increases charge mobility on the electrode surface, creates abundant active centers with facile functionalization, and induces binding to ADR molecules. The designed P-MCS electrode exhibits ultrasensitive monitoring of ADR with a low detection limit of 0.002 μM and high sensitivity of 4330 μA μM-1 cm-2. In addition, two electrochemical techniques, namely, square wave voltammetry (SWV) and chronoamperometry (CA), were used; these techniques achieve high stability, fast response, and a wide linear range from 0.01 to 6 μM. The sensing assays based on P-MCSs provide evidence of the formation of active interfacial surface-to-ADR binding sites, high electron diffusion, and heavy target loads along with/without a plane of spheroids. Thus, P-MCSs can be used for the routine monitoring of ADR in human blood serum, providing a fast response, and requiring highly economical materials at extremely low concentrations. Electrode surface modulation based on P-doped carbon spheres (P-MCS) exhibits high electrochemical activity with fast charge transport, multi-diffusible active centers, high loading of ADR, and facile molecular/electron diffusion at its surface. The P-MCS sensitively and selectively detects the ADR in human fluids and can be used for clinical investigation of some neuronal diseases such as Alzheimer diseases.

RevDate: 2021-03-27

Qian J, Betensky RA, Hyman BT, et al (2021)

Association of APOE Genotype With Heterogeneity of Cognitive Decline Rate in Alzheimer Disease.

Neurology pii:WNL.0000000000011883 [Epub ahead of print].

OBJECTIVE: To test the hypothesis that the APOE genotype is a significant driver of heterogeneity in Alzheimer's disease (AD) clinical progression, which could have important implications for clinical trial design and interpretation.

METHODS: We applied novel reverse-time longitudinal models to analyze the trajectories of CDR-SOB and MMSE scores -two common outcome measures in AD clinical trials- in 1,102 autopsy-proven AD subjects (moderate/frequent neuritic plaques and Braak tangle stage ≥III) from the National Alzheimer's Coordinating Center (NACC) Neuropathology database resembling mild-to-moderate AD participants in therapeutic clinical trials.

RESULTS: APOEε4 carriers exhibited ≈1.5 times faster CDR-SOB increase than APOEε3/ε3 carriers (2.12 points/year versus 1.44 points/year), and ≈1.3 times faster increase than APOEε2 carriers (1.65 points/year), whereas APOEε2 versus APOEε3/ε3 difference was not statistically significant. APOEε4 carriers had ≈1.1 times faster MMSE decline than APOEε3/ε3 subjects (-3.34 points/year versus -3.03 points/year) and ≈1.4 times faster decline than APOEε2 carriers (-2.43 points/year), whereas APOEε2 carriers had ≈1.2 times slower decline than APOEε3/ε3 subjects (-2.43 points/year versus -3.03 points/year). These findings remained largely unchanged after controlling for the effect of AD neuropathological changes on the rate of cognitive decline and for the presence and severity of comorbid pathologies.

CONCLUSIONS: compared to the APOEε3/ε3 reference genotype, the APOEε2 and ε4 alleles have opposite (slowing and accelerating, respectively) effects on the rate of cognitive decline, which are clinically relevant and largely independent of the differential APOE allele effects on AD and comorbid pathologies. Thus, APOE genotype contributes to the heterogeneity in rate of clinical progression in AD.

RevDate: 2021-04-10

Dhakal S, Wyant CE, George HE, et al (2021)

Prion-like C-Terminal Domain of TDP-43 and α-Synuclein Interact Synergistically to Generate Neurotoxic Hybrid Fibrils.

Journal of molecular biology, 433(10):166953 pii:S0022-2836(21)00154-6 [Epub ahead of print].

Aberrant aggregation and amyloid formation of tar DNA binding protein (TDP-43) and α-synuclein (αS) underlie frontotemporal dementia (FTD) and Parkinson's disease (PD), respectively. Amyloid inclusions of TDP-43 and αS are also commonly co-observed in amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB) and Alzheimer disease (AD). Emerging evidence from cellular and animal models show colocalization of the TDP-43 and αS aggregates, raising the possibility of direct interactions and co-aggregation between the two proteins. In this report, we set out to answer this question by investigating the interactions between αS and prion-like pathogenic C-terminal domain of TDP-43 (TDP-43 PrLD). PrLD is an aggregation-prone fragment generated both by alternative splicing as well as aberrant proteolytic cleavage of full length TDP-43. Our results indicate that two proteins interact in a synergistic manner to augment each other's aggregation towards hybrid fibrils. While monomers, oligomers and sonicated fibrils of αS seed TDP-43 PrLD monomers, TDP-43 PrLD fibrils failed to seed αS monomers indicating selectivity in interactions. Furthermore, αS modulates liquid droplets formed by TDP-43 PrLD and RNA to promote insoluble amyloid aggregates. Importantly, the cross-seeded hybrid aggregates show greater cytotoxicity as compared to the individual homotypic aggregates suggesting that the interactions between the two proteins have a discernable impact on cellular functions. Together, these results bring forth insights into TDP-43 PrLD - αS interactions that could help explain clinical and pathological presentations in patients with co-morbidities involving the two proteins.

RevDate: 2021-04-15

Ishioh M, Nozu T, Igarashi S, et al (2021)

Activation of central adenosine A2B receptors mediate brain ghrelin-induced improvement of intestinal barrier function through the vagus nerve in rats.

Experimental neurology, 341:113708 pii:S0014-4886(21)00114-X [Epub ahead of print].

Leaky gut that is a condition reflecting intestinal barrier dysfunction has been attracting attention for its relations with many diseases such as irritable bowel syndrome or Alzheimer dementia. We have recently demonstrated that ghrelin acts in the brain to improve leaky gut via the vagus nerve. In the present study, we tried to clarify the precise central mechanisms by which ghrelin improves intestinal barrier function through the vagus nerve. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), blocked the intracisternal ghrelin-induced improvement of intestinal hyperpermeability while dopamine, cannabinoid or opioid receptor antagonist failed to prevent it. Since DPCPX can block adenosine A1 and adenosine A2B receptors, we examined which subtype is involved in the mechanism. Intracisternal injection of adenosine A2B agonist but not adenosine A1 agonist improved colonic hyperpermeability, while peripheral injection of adenosine A2B agonist failed to improve it. Intracisternal adenosine A2B agonist-induced improvement of colonic hyperpermeability was blocked by vagotomy. Adenosine A2B specific antagonist, alloxazine blocked the ghrelin- or central vagal stimulation by 2-deoxy-d-glucose-induced improvement of intestinal hyperpermeability. These results suggest that activation of adenosine A2B receptors in the central nervous system is capable of improving intestinal barrier function through the vagal pathway, and the adenosine A2B receptors may mediate the ghrelin-induced improvement of leaky gut in a vagal dependent fashion. These findings may help us understand the pathophysiology in not only gastrointestinal diseases but also non-gastrointestinal diseases associated with the altered intestinal permeability.

RevDate: 2021-03-27

Navigatore Fonzo L, Alfaro M, Mazaferro P, et al (2021)

An intracerebroventricular injection of amyloid-beta peptide (1-42) aggregates modifies daily temporal organization of clock factors expression, protein carbonyls and antioxidant enzymes in the rat hippocampus.

Brain research pii:S0006-8993(21)00306-1 [Epub ahead of print].

Alzheimer disease (AD) is the most frequent form of dementia in the elderly. It is characterized by the deterioration of memory and learning. The histopathological hallmarks of AD include the presence of extracellular deposits of amyloid beta peptide, intracellular neurofibrillary tangles, neuron and synapse loss, in the brain, including the hippocampus. Accumulation of Aβ peptide causes an increase in intracellular reactive oxygen species (ROS) and free radicals associated to a deficient antioxidant defense system. Besides oxidative stress and cognitive deficit, AD patients show alterations in their circadian rhythms. The objective of this work was to investigate the effects of an intracerebroventricular injection of amyloid beta peptide Aβ(1-42) aggregates on temporal patterns of protein oxidation, antioxidant enzymes and clock factors in the rat hippocampus. Four-month-old male Holtzman rats divided into the groups control (CO) and Aβ-injected (Aβ), were maintained under 12h-light12h-dark conditions and received water and food ad-libitum. Hippocampus samples were isolated every 6 h during a 24h period. Our results showed daily patterns of protein carbonyls, catalase (CAT) and glutathione peroxidase (GPx) expression and activity, as well as Rorα and Rev-erbß mRNA, in the rat hippocampus. Interestingly, an intracerebroventricular injection of Aβ aggregates modified daily oscillation of protein carbonyls levels, phase-shifted daily rhythms of clock genes and had a differential effect on the daily expression and activity of CAT and GPx. Thus, Aβ aggregates might affect clock-mediated transcriptional regulation of antioxidant enzymes, by affecting the formation of BMAL1:CLOCK heterodimer, probably, as a consequence of the alteration of the redox state observed in rats injected with Aβ.

RevDate: 2021-03-27

Zhao J, Li T, J Wang (2021)

Association between psoriasis and dementia: A systematic review.

Neurologia (Barcelona, Spain) pii:S0213-4853(21)00027-X [Epub ahead of print].

INTRODUCTION: Risk factors for dementia include genetic factors, aging, environmental factors, certain diseases, and unhealthy lifestyle; most types of dementia share a common chronic systemic inflammatory phenotype. Psoriasis is also considered to be a chronic systemic inflammatory disease. It has been suggested that psoriasis may also contribute to the risk of dementia. The aim of this study was to systematically review the literature on the association between psoriasis and dementia.

DEVELOPMENT: Articles were selected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched the PubMed and Web of Science databases to identify articles published in peer-reviewed journals and studying the association between psoriasis and dementia. Studies meeting the inclusion criteria were reviewed. We used the Newcastle-Ottawa Scale to assess the quality of each study. After applying the inclusion and exclusion criteria, we included 8 studies for review, 3 of which were found to present a higher risk of bias. Six of the 8 studies supported the hypothesis that prior diagnosis of psoriasis increases the risk of dementia; one study including only a few cases reported that psoriasis decreased the risk of dementia, and one study including relatively young patients found no significant association between psoriasis and the risk of dementia.

CONCLUSION: Most studies included in this review supported the hypothesis that psoriasis constitutes a risk factor for dementia. However, well-designed stratified cohort studies assessing both psoriasis severity and treatment status are still required to determine the real effect of psoriasis on the risk of dementia and its subtypes.

RevDate: 2021-03-26

Al-Thani HF, Ahmad MN, Younes S, et al (2021)

Genetic Variants Associated With Alzheimer Disease in the 22 Arab Countries: A Systematic Review.

Alzheimer disease and associated disorders pii:00002093-900000000-99240 [Epub ahead of print].

BACKGROUND AND AIMS: Alzheimer disease (AD) is a progressive and complex neurodegenerative disease. Approximately 70% of AD risk is attributed to genetic risk factors, including variants in amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes. Several studies have revealed a considerable number of candidate loci and genes for AD among different ethnic populations. However, the outcomes of these studies have been inconsistent. In this study, we aimed to investigate the spectrum of variants that are associated with the onset and development of AD among 22 Arab countries.

METHODOLOGY: We systematically searched 4 literature databases (Science Direct, Scopus, PubMed, and Web of Science) from the date of inception until July 2020 using various search terms to obtain all the reported genetic data on Arab AD cases.

RESULTS: In total, 18 studies were included, comprising a total of 2173 individuals, of whom 888 were clinically diagnosed AD patients and were genetically tested for genes and variants associated with AD. A total of 27 variants in 8 genes were found to be associated with AD. Of these variants, 17 were unique to the Arab population and 10 were shared with other ethnic groups.

CONCLUSIONS: There is a dearth of studies on the genetics of AD in the Arab world. There seems to be distinctive genetic and clinical susceptibility profiles for Arab patients with AD.

RevDate: 2021-03-26

Eryilmaz IE, Bakar M, Egeli U, et al (2021)

Evaluation of the Clinical Features Accompanied by the Gene Mutations: The 2 Novel PSEN1 Variants in a Turkish Early-onset Alzheimer Disease Cohort.

Alzheimer disease and associated disorders pii:00002093-900000000-99239 [Epub ahead of print].

INTRODUCTION: Early-onset Alzheimer disease (EOAD) is an earlier Alzheimer disease form which is characterized by the mutations in the amyloid precursor protein, presenilin-1/2 (PSEN1/2), and triggering receptor expressed on myeloid cells 2 (TREM2). However, it is still necessary to report mutational screening in multiethnic groups to improve the genetic background of EOAD due to the variant classification challenge.

METHODS: We performed targeted sequencing for the amyloid precursor protein, PSEN1, PSEN2, and TREM2 genes in 74 patients and 1 family diagnosed with EOAD.

RESULTS: Among the detected variants, 8 were coding and 6 were noncoding in 15 of 74 patients. In PSEN1, 2 pathogenic coding variants (T274K and L364P) detected in 2 patients were novel and 3 coding variants (G183V, E318G, and L219P) detected in 2 patients were previously reported. We found 4 patients with the compound heterozygosity for the PSEN2 A23= and N43= and a family with the coexistence of them, and 1 patient with TREM2 Y38C. The coding variation frequency was 12.1%. In silico analysis indicated pathogenic potentials and clinical interpretations of the detected variants.

CONCLUSION: Our study reveals the rare gene variants including novel ones from the Turkish EOAD cohort and provides to clinicians the list of detected variants in the screened genes, which may also be useful for accurate genetic counseling.

RevDate: 2021-03-26

Claassen JAHR, Thijssen DHJ, Panerai RB, et al (2021)

REGULATION OF CEREBRAL BLOOD FLOW IN HUMANS: PHYSIOLOGY AND CLINICAL IMPLICATIONS OF AUTOREGULATION.

Physiological reviews [Epub ahead of print].

Brain function critically depends on a close matching between metabolic demands, appropriate delivery of oxygen and nutrients, and removal of cellular waste. This matching requires continuous regulation of cerebral blood flow (CBF), which can be categorized into four broad topics: 1) autoregulation, which describes the response of the cerebrovasculature to changes in perfusion pressure, 2) vascular reactivity to vasoactive stimuli [including carbon dioxide (CO2)], 3) neurovascular coupling (NVC), i.e., the CBF response to local changes in neural activity (often standardized cognitive stimuli in humans), and 4) endothelium-dependent responses. This review focuses primarily on autoregulation and its clinical implications. To place autoregulation in a more precise context, and to better understand integrated approaches in the cerebral circulation, we also briefly address reactivity to CO2 and NVC. In addition to our focus on effects of perfusion pressure (or blood pressure), we describe the impact of select stimuli on regulation of CBF (i.e., arterial blood gases, cerebral metabolism, neural mechanisms, and specific vascular cells), the inter-relationships between these stimuli, and implications for regulation of CBF at the level of large arteries and the microcirculation. We review clinical implications of autoregulation in aging, hypertension, stroke, mild cognitive impairment, anesthesia, and dementias. Finally, we discuss autoregulation in the context of common daily physiological challenges, including changes in posture (e.g., orthostatic hypotension, syncope) and physical activity.

RevDate: 2021-03-26

Bretland KA, Lin L, Bretland KM, et al (2021)

Irisin treatment lowers levels of phosphorylated tau in the hippocampus of pre-symptomatic female but not male htau mice.

Neuropathology and applied neurobiology [Epub ahead of print].

AIMS: Irisin is a hormone cleaved from fibronectin type-III domain-containing protein 5 in response to exercise and may be therapeutic in Alzheimer's disease (AD). Irisin is shown to repair damage caused by midlife cardiometabolic risk factors for AD (i.e., diabetes mellitus; hypertension), prevent neural amyloid beta aggregation, and reduce neuroinflammation. However, there are no investigations of irisin's effect on AD-associated tauopathy in the brain. This study begins to address this gap in knowledge.

METHODS: Transgenic htau mice that selectively develop age-related tauopathy were treated with recombinant irisin (100 ug/kg weekly i.p.) beginning at a pre-symptomatic age (4 months) to determine if irisin could prevent emergence of early neuropathology. One month later, mice were sacrificed to collect brain tissue and serum. Protein levels of ptau (serine 202), inflammatory cytokine tumour necrosis factor alpha (TNFα) and FNDC5 were quantified using capillary-based western blotting (Wes).

RESULTS: Our data show that irisin treatment significantly reduced ptau and TNFα in hippocampus and serum of female htau mice compared to vehicle-treated controls. Irisin treatment did not alter ptau levels in male htau hippocampus and appeared to enhance both neural and systemic TNFα levels.

CONCLUSIONS: This study provides the first evidence that enhancing the endogenous hormone irisin may be therapeutic against emerging neuropathology in a tauopathy-selective AD model. This is important because there are currently no disease-modifying therapeutics available for AD, and few agents in development address the multiple disease targets irisin appears to-making irisin an intriguing therapeutic candidate for further investigation.

RevDate: 2021-03-30

Butt OH, Long JM, Henson RL, et al (2021)

Cognitively normal APOE ε4 carriers have specific elevation of CSF SNAP-25.

Neurobiology of aging, 102:64-72 pii:S0197-4580(21)00058-0 [Epub ahead of print].

Cerebrospinal fluid (CSF) synaptosomal-associated protein 25 (SNAP-25) and neurogranin (Ng) are recently described biomarkers for pre- and postsynaptic integrity known to be elevated in symptomatic Alzheimer disease (AD). Their relationship with Apolipoprotein E (APOE) ε4 carrier status, the major genetic risk factor for AD, remains unclear. In this study, CSF SNAP-25 and Ng were compared in cognitively normal APOE ε4 carriers and noncarriers (n = 274, mean age 65 ± 9.0 years, 39% APOE ε4 carriers, 58% female). CSF SNAP-25, not CSF Ng, was specifically elevated in APOE ε4 carriers versus noncarriers (5.95 ± 1.72 pg/mL, 4.44 ± 1.40 pg/mL, p < 0.0001), even after adjusting for age, sex, years of education, and amyloid status (p < 0.0001). CSF total tau (t-tau), phosphorylated-tau-181 (ptau181), and neurofilament light chain (NfL) also did not vary by APOE ε4 status. Our findings suggest APOE ε4 carriers have amyloid-related and amyloid-independent presynaptic disruption as reflected by elevated CSF SNAP-25 levels. In contrast, postsynaptic disruption as reflected by elevations in CSF neurogranin is related to amyloid status.

RevDate: 2021-03-25

Byun MS, Park SW, Lee JH, et al (2021)

Association of Retinal Changes With Alzheimer Disease Neuroimaging Biomarkers in Cognitively Normal Individuals.

JAMA ophthalmology pii:2777826 [Epub ahead of print].

Importance: Retinal biomarkers reflecting in vivo brain Alzheimer disease (AD) pathologic abnormalities could be a useful tool for screening cognitively normal (CN) individuals at the preclinical stage of AD.

Objectives: To investigate the association of both functional and structural alterations of the retina with in vivo AD pathologic abnormalities in CN older adults and model a screening tool for detection of preclinical AD.

This cross-sectional study included a total of 49 CN individuals, and all assessment was done at the Seoul National University Hospital, Seoul, South Korea. All participants underwent complete ophthalmic examination, including swept-source optical coherence tomography (SS-OCT) and multifocal electroretinogram as well as amyloid-β (Aβ) positron emission tomography and magnetic resonance imaging. Data were collected from January 1, 2016, through October 31, 2017, and analyzed from February 1, 2018, through June 30, 2020.

Main Outcomes and Measures: For structural parameters of the retina, the thickness of the macula and layer-specific thicknesses, including peripapillary retinal nerve fiber layer and ganglion cell-inner plexiform layer measured by SS-OCT, were used for analysis. For functional parameters of the retina, implicit time and amplitude of rings 1 to 6 measured by multifocal electroretinogram were used.

Results: Of the 49 participants, 25 were women (51.0%); mean (SD) age was 70.6 (9.4) years. Compared with 33 CN individuals without Aβ deposition (Aβ-CN), the 16 participants with Aβ (Aβ+CN) showed reduced inner nasal macular thickness (mean [SD], 308.9 [18.4] vs 286.1 [22.5] μm; P = .007) and retinal nerve fiber layer thickness, particularly in the inferior quadrant (133.8 [17.9] vs 103.8 [43.5] μm; P = .003). In addition, the Aβ+CN group showed prolonged implicit time compared with the Aβ-CN group, particularly in ring 5 (41.3 [4.0] vs 38.2 [1.3] milliseconds; P = .002). AD-related neurodegeneration was correlated with the thickness of the ganglion cell-inner plexiform layer only (r = 0.41, P = .005). The model to differentiate the Aβ+CN vs Aβ-CN groups derived from the results showed 90% accuracy.

Conclusions and Relevance: The findings of this study showing both functional as well as structural changes of retina measured by multifocal electroretinogram and SS-OCT in preclinical AD suggest the potential use of retinal biomarkers as a tool for early detection of in vivo AD pathologic abnormalities in CN older adults.

RevDate: 2021-03-25

Grewal DS, S Fekrat (2021)

Structural and Functional Retinal Changes in Preclinical Alzheimer Disease.

JAMA ophthalmology pii:2777824 [Epub ahead of print].

RevDate: 2021-03-26

Liu CG, Zhao Y, Lu Y, et al (2021)

ABCA1-Labeled Exosomes in Serum Contain Higher MicroRNA-193b Levels in Alzheimer's Disease.

BioMed research international, 2021:5450397.

Objective: We aimed to establish a method to determine whether microRNA-193b (miR-193b) levels in ABCA1-labeled serum exosomes might serve as a marker for the diagnosis of Alzheimer's disease.

Methods: We used immunocapture methods to determine the levels of ABCA1-labeled exosomal miR-193b in cultures of white blood cells (WBCs), red blood cells (RBCs), mouse hippocampal neuron HT-22 cells, and primary mouse neuronal cells. ABCA1-labeled exosomal miR-193b levels were also evaluated in the cerebrospinal fluid (CSF) and serum of APP/PS1 double-transgenic mice, as well as control subjects (n = 60) and study participants with subjective cognitive decline (SCD, n = 89), stage and mild cognitive impairment (MCI, n = 92), and dementia of the Alzheimer type (DAT, n = 92).

Results: ABCA1 levels of exosomes harvested from the medium of HT-22 cells and neurons were significantly higher than those of RBCs and WBCs (P < 0.05). Exosomal ABCA1 from the CSF of APP/PS1 mice were transmitted to the serum of wild-type mice after injection, and high miR-193b levels were observed in both the serum and CSF after injection. The ABCA1-labeled exosomal miR-193b levels were higher in the CSF of MCI and DAT patients compared with the CSF of the control group (P < 0.05). The ABCA1-labeled exosomal miR-193b were also slightly higher (P > 0.05) in the serum of SCD patients and significantly higher in the serum of MCI and DAT patients compared with the serum of the control group (P < 0.05).

Conclusion: This study provides a method to capture specific exosomes. Detection of serum exosomes labeled with ABCA1 may facilitate the early diagnosis of AD.

RevDate: 2021-04-15

Benussi A, Cantoni V, Cotelli MS, et al (2021)

Exposure to gamma tACS in Alzheimer's disease: A randomized, double-blind, sham-controlled, crossover, pilot study.

Brain stimulation, 14(3):531-540 pii:S1935-861X(21)00058-9 [Epub ahead of print].

OBJECTIVE: To assess whether exposure to non-invasive brain stimulation with transcranial alternating current stimulation at γ frequency (γ-tACS) applied over Pz (an area overlying the medial parietal cortex and the precuneus) can improve memory and modulate cholinergic transmission in mild cognitive impairment due to Alzheimer's disease (MCI-AD).

METHODS: In this randomized, double-blind, sham controlled, crossover pilot study, participants were assigned to a single 60 min treatment with exposure to γ-tACS over Pz or sham tACS. Each subject underwent a clinical evaluation including assessment of episodic memory pre- and post-γ-tACS or sham stimulation. Indirect measures of cholinergic transmission evaluated using transcranial magnetic stimulation (TMS) pre- and post-γ-tACS or sham tACS were evaluated.

RESULTS: Twenty MCI-AD participants completed the study. No tACS-related side effects were observed, and the intervention was well tolerated in all participants. We observed a significant improvement at the Rey auditory verbal learning (RAVL) test total recall (5.7 [95% CI, 4.0 to 7.4], p < 0.001) and long delayed recall scores (1.3 [95% CI, 0.4 to 2.1], p = 0.007) after γ-tACS but not after sham tACS. Face-name associations scores improved during γ-tACS (4.3 [95% CI, 2.8 to 5.8], p < 0.001) but not after sham tACS. Short latency afferent inhibition, an indirect measure of cholinergic transmission evaluated with TMS, increased only after γ-tACS (0.31 [95% CI, 0.24 to 0.38], p < 0.001) but not after sham tACS.

CONCLUSIONS: exposure to γ-tACS over Pz showed a significant improvement of memory performances, along with restoration of intracortical connectivity measures of cholinergic neurotransmission, compared to sham tACS.

RevDate: 2021-04-01
CmpDate: 2021-04-01

Ferreira TR, Lopes LC, Motter FR, et al (2021)

Potentially inappropriate prescriptions to Brazilian older people with Alzheimer disease: A cross-sectional study.

Medicine, 100(12):e25015.

ABSTRACT: Older adults are the leading users of medications, where this can be associated with a high number of potentially inappropriate medications (PIMs) and of potentially inappropriate prescribing (PIP) and consequent harm to health. No Brazilian study evaluating potentially inappropriate prescribing in older patients with Alzheimer's disease (AD) was found. This study determined and analyzed the prevalence of PIP and PIM prescribed for older people with AD.A cross-sectional study was carried out at the Specialty Drugs Pharmacy in the city of Sorocaba, São Paulo State, Brazil. The MEDEX system provided the register in older people with AD and data were collected during interviews with patients and/or caregivers between June and September 2017. The PIMs were identified according to the 2019 Beers Criteria. The association between PIMs and independent variables was analyzed by Poisson regression.This study included 234 older patients with AD. The prevalence of PIP prescribed was 66.7% (n = 156). Of the 1073 medications prescribed, 30.5% (n = 327) were inappropriate with most affecting the central nervous system or cardiovascular, particularly quetiapine (12.8%) and acetylsalicylic acid (11.6%), respectively. Around 45.2% of the PIMs should be avoided in older people, especially sertraline (14.2%) and clonazepam (7.4%). After adjusted analysis, the PIMs were associated with the diagnosis of depression (P = 0.010) and the number of comorbidities (P = 0.005).There was a high number of PIMs among older people, a substantial number of which should have been avoided in this population. Health care professionals can apply these findings to improve safety in the use of medications for treating patients with AD.

RevDate: 2021-04-15

Han S, Zhang M, Jeong YY, et al (2021)

The role of mitophagy in the regulation of mitochondrial energetic status in neurons.

Autophagy [Epub ahead of print].

Mitochondria are the main cellular energy powerhouses and supply most of the energy in the form of ATP to fuel essential neuronal functions through oxidative phosphorylation (OXPHOS). In Alzheimer disease (AD), metabolic and mitochondrial disruptions are an early feature preceding any histopathological and clinical manifestations. Mitochondrial malfunction is also linked to synaptic defects in early AD. Mitophagy serves as a key cellular quality control mechanism involving sequestration of damaged mitochondria within autophagosomes and their subsequent degradation in lysosomes. However, it remains largely unknown whether mitophagy is involved in the regulation of energy metabolism in neurons, and if so, whether metabolic deficiency in AD is attributed to mitophagy dysfunction. Here we reveal that mitophagy is broadly activated in metabolically enhanced neurons upon OXPHOS stimulation, which sustains high energetic activity by increasing mitochondrial turnover and hence facilitating mitochondrial maintenance. Unexpectedly, in AD-related mutant HsAPP Tg mouse brains, early stimulation of OXPHOS activity fails to correct energy deficits but exacerbates synapse loss as a consequence of mitophagy failure. Excitingly, lysosomal enhancement in AD neurons restores impaired metabolic function by promoting elimination of damaged mitochondria, protecting against synaptic damage in AD mouse brains. Taken together, we propose a new mechanism by which mitophagy controls bioenergetic status in neurons, furthering our understanding of the direct impact of mitophagy defects on AD-linked metabolic deficits and shedding light on the development of novel therapeutic strategies to treat AD by the early stimulation of mitochondrial metabolism combined with elevation of lysosomal proteolytic activity.

RevDate: 2021-03-23

KÖylÜ A, Altunkaynak BZ, B DelİbaŞ (2021)

Effects of Tacrolimus on c-Fos in Hippocampus and Memory Performances in Streptozotocin Model of Alzheimer's Disease of Rats.

Turkish journal of medical sciences [Epub ahead of print].

BACKGROUND/AIM: Calcineurin, an inhibitor of calcium dependent phosphatase is highly presented in a brain of an Alzheimer?s disease. Aging brain gets more sensitive to hyperactivation of calcineurin and this event causes tau neurofibrillary plaque accumulation which is one of the outcomes of this disease. The regions of hippocampus are much effected from the results of this process. Our hypothesis is that a calcineurin inhibitor, tacrolimus, could prevent the accumulation and the decrease of the neuronal cells. Therefore, this immunosuppressive drug could be a candidate for an early treatment of Alzheimer disease.

MATERIALS AND METHODS: Fifteen male Wistar albino rats were divided to three groups; control, Alzheimer and Alzheimer+Tacrolimus. The Alzheimer group received an injection of streptozotocin intracerebroventricularly for the purpose of modelling the disease via generating free radicals leading a cognitive impairment. Alzheimer+Tacrolimus group first received an oral drug, a calcineurin inhibitor for 10 days afterwards prepared for the model as same as the Alzheimer group received. Finally, all groups performed the Morris water maze test for four days then sacrificed. For the aim of counting neurons in the hippocampus stereological methods, as well as for an evaluation of cellular response to stress in dentate gyrus a c-Fos immunohistochemistry was performed.

RESULTS: According to the probe trial of Morris water maze test, the latency time was dramatically higher at both Alzheimer and Alzheimer+Tacrolimus group (p < 0.01). We confirmed these results with our stereology data. The results from stereology technique indicate that there was a neuronal decrease at the hippocampus regions in Alzheimer and Alzheimer+Tacrolimus group. Our outcomes from immunohistochemical data showed a significant increase in the number of c-Fos-positive cells in Alzheimer group when comparing with Alzheimer+Tacrolimus group (p < 0.001).

CONCLUSION: There was none preventive effect for neuronal loss in the hippocampus under the effect of tacrolimus drug according to stereological results. However; tacrolimus administration may have reduced cellular stress and cell damage.

RevDate: 2021-03-29

van Oudenhoven FM, Swinkels SHN, Soininen H, et al (2021)

A competing risk joint model for dealing with different types of missing data in an intervention trial in prodromal Alzheimer's disease.

Alzheimer's research & therapy, 13(1):63.

BACKGROUND: Missing data can complicate the interpretability of a clinical trial, especially if the proportion is substantial and if there are different, potentially outcome-dependent causes.

METHODS: We aimed to obtain unbiased estimates, in the presence of a high level of missing data, for the intervention effects in a prodromal Alzheimer's disease trial: the LipiDiDiet study. We used a competing risk joint model that can simultaneously model each patient's longitudinal outcome trajectory in combination with the timing and type of missingness.

RESULTS: Using the competing risk joint model, we were able to provide unbiased estimates of the intervention effects in the presence of the different types of missingness. For the LipiDiDiet study, the intervention effects remained statistically significant after this correction for the timing and type of missingness.

CONCLUSION: Missing data is a common problem in (Alzheimer) clinical trials. It is important to realize that statistical techniques make specific assumptions about the missing data mechanisms. When there are different missing data sources, a competing risk joint model is a powerful method because it can explicitly model the association between the longitudinal data and each type of missingness.

TRIAL REGISTRATION: Dutch Trial Register, NTR1705 . Registered on 9 March 2009.

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RJR Experience and Expertise

Researcher

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.

Educator

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.

Administrator

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.

Technologist

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.

Publisher

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.

Speaker

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.

Facilitator

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.

Designer

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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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

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