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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 26 Jan 2022 at 01:30 Created: 

Alzheimer Disease — Current Literature

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

Created with PubMed® Query: alzheimer[TIAB] and (2017[PDAT] OR [2018[PDAT] OR 2019[PDAT] OR 2020[PDAT] OR 2021[PDAT]) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2022-01-17

Azzaz F, Yahi N, Di Scala C, et al (2022)

Ganglioside binding domains in proteins: Physiological and pathological mechanisms.

Advances in protein chemistry and structural biology, 128:289-324.

Gangliosides are anionic lipids that form condensed membrane clusters (lipid rafts) and exert major regulatory functions on a wide range of proteins. In this review, we propose a new view of the structural features of gangliosides with special emphasis on emerging properties associated with protein binding modes. We analyze the different possibilities of molecular associations of gangliosides in lipid rafts and the role of cholesterol in this organization. We are particularly interested in amide groups of N-acetylated sugars which make it possible to neutralize the negative charge of the carboxylate group of sialic acids. We refer to this effect as "NH trick" and we demonstrate that it is operative in GM1, GD1a, GD1b and GT1b gangliosides. The NH trick is key to understand the different topologies adopted by gangliosides (chalice-like at the edge of lipid rafts, condensed clusters in central areas) and their impact on protein binding. We define three major types of ganglioside-binding domains (GBDs): α-helical, loop shaped, and large flat surface. We describe the mode of interaction of each GBD with typical reference proteins: synaptotagmin, 5HT1A receptor, cholera and botulinum toxins, HIV-1 surface envelope glycoprotein gp120, SARS-CoV-2 spike protein, cellular prion protein, Alzheimer's β-amyloid peptide and Parkinson's disease associated α-synuclein. We discuss the common mechanisms and peculiarities of protein binding to gangliosides in the light of physiological and pathological conditions. We anticipate that innovative ganglioside-based therapies will soon show an exponential growth for the treatment of cancer, microbial infections, and neurodegenerative diseases.

RevDate: 2022-01-14
CmpDate: 2022-01-14

Ikeda T, Hori Y, Sohma Y, et al (2021)

Photo-Oxygenation: An Innovative New Therapeutic Approach Against Amyloidoses.

Advances in experimental medicine and biology, 1339:415-422.

Many types of amyloidoses are pathologically characterized by the deposition of amyloid, which is comprised of fibrils formed by abnormally aggregated proteins, in various peripheral tissues and the central nervous system (CNS). Neurodegenerative disorders, such as Alzheimer disease (AD), Parkinson disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), are well-known CNS amyloidoses that are characterized by amyloid deposition both inside and outside of cells. The amyloidogenic proteins of each disease have distinct primary sequences, and they normally function as soluble proteins. However, these proteins all aggregate and form amyloid with a common intermolecular tertiary structure, namely, a cross-β-sheet structure, finally leading to the onset of each disease. Therefore, inhibition of the aggregation of amyloid proteins or efficient clearance of the already formed amyloids are thought to be promising therapeutic strategies against amyloidoses.

RevDate: 2022-01-14
CmpDate: 2022-01-14

Athanasiadou E, Tsaloglidou A, Koukourikos K, et al (2021)

Care of Patients with Alzheimer's Disease.

Advances in experimental medicine and biology, 1339:9-20.

INTRODUCTION: Alzheimer's disease is one of the irreversible dementias and leads to death. About 10% of people over 60 years and 20% of people over 80 will have Alzheimer's sometime in their lives. In the case of Alzheimer's disease, care can turn into an extremely large and unevenly distributed burden. The burden that caregivers are called upon to lift is particularly high at the physical, psychological, and social levels.

PURPOSE: The purpose of this study was to describe the characteristics and needs of caregivers and even informal ones, that is, patients in the patient's family or friendly environment who voluntarily or unintentionally offer unpaid care to patients with Alzheimer's disease.

MATERIAL AND METHODS: The present study was conducted using the Carer Well-Being and Support Questionnaire (CWSv2) at Thessaloniki Psychiatric Hospital between October and December 2019. For the statistical analysis, the SPSS package 23 was used.

RESULTS: Alzheimer-type dementia is a condition with gradual, inevitable, and uncontrollable deterioration. So, it was expected that those involved in the care of these patients would be afraid of what their patient future care would be. Consequently, there is a high correlation coefficient between the two relevant variables (Fisher's Exact Test: 31,426; Sig: 0.007). Caregivers need to be alert at all times in order to fulfill their role and care for their loved one. There is a strong correlation index between the two variables (Fisher's Exact Test: 32,761; Sig: 0.003). The situation of a lack or distorted form of communication between patients and caregivers may also create or exacerbate caregivers' anxiety, causing them feelings of depression and deadlock that is also reflected in the relevant correlation index (Fisher's Exact Test: 30,053; Sig: 0.001). Women were more in need for additional help, with the two variables being marginally statistically significant (Fisher's Exact Test: 5.373; Sig: 0.05).

CONCLUSIONS: Taking into account the results, as reflected through the elaboration of the closed and open questions of this tool, new structures and services should be created in order to facilitate caregivers' job.

RevDate: 2022-01-14

Naomi R, Embong H, Othman F, et al (2021)

Probiotics for Alzheimer's Disease: A Systematic Review.

Nutrients, 14(1):.

Alzheimer's disease (AD) is the most common form of neurodegenerative disorders affecting mostly the elderly. It is characterized by the presence of Aβ and neurofibrillary tangles (NFT), resulting in cognitive and memory impairment. Research shows that alteration in gut microbial diversity and defects in gut brain axis are linked to AD. Probiotics are known to be one of the best preventative measures against cognitive decline in AD. Numerous in vivo trials and recent clinical trials have proven the effectiveness of selected bacterial strains in slowing down the progression of AD. It is proven that probiotics modulate the inflammatory process, counteract with oxidative stress, and modify gut microbiota. Thus, this review summarizes the current evidence, diversity of bacterial strains, defects of gut brain axis in AD, harmful bacterial for AD, and the mechanism of action of probiotics in preventing AD. A literature search on selected databases such as PubMed, Semantic Scholar, Nature, and Springer link have identified potentially relevant articles to this topic. However, upon consideration of inclusion criteria and the limitation of publication year, only 22 articles have been selected to be further reviewed. The search query includes few sets of keywords as follows. (1) Probiotics OR gut microbiome OR microbes AND (2) Alzheimer OR cognitive OR aging OR dementia AND (3) clinical trial OR in vivo OR animal study. The results evidenced in this study help to clearly illustrate the relationship between probiotic supplementation and AD. Thus, this systematic review will help identify novel therapeutic strategies in the future as probiotics are free from triggering any adverse effects in human body.

RevDate: 2022-01-14

Sierri G, Dal Magro R, Vergani B, et al (2021)

Reduced Levels of ABCA1 Transporter Are Responsible for the Cholesterol Efflux Impairment in β-Amyloid-Induced Reactive Astrocytes: Potential Rescue from Biomimetic HDLs.

International journal of molecular sciences, 23(1):.

The cerebral synthesis of cholesterol is mainly handled by astrocytes, which are also responsible for apoproteins' synthesis and lipoproteins' assembly required for the cholesterol transport in the brain parenchyma. In Alzheimer disease (AD), these processes are impaired, likely because of the astrogliosis, a process characterized by morphological and functional changes in astrocytes. Several ATP-binding cassette transporters expressed by brain cells are involved in the formation of nascent discoidal lipoproteins, but the effect of beta-amyloid (Aβ) assemblies on this process is not fully understood. In this study, we investigated how of Aβ1-42-induced astrogliosis affects the metabolism of cholesterol in vitro. We detected an impairment in the cholesterol efflux of reactive astrocytes attributable to reduced levels of ABCA1 transporters that could explain the decreased lipoproteins' levels detected in AD patients. To approach this issue, we designed biomimetic HDLs and evaluated their performance as cholesterol acceptors. The results demonstrated the ability of apoA-I nanodiscs to cross the blood-brain barrier in vitro and to promote the cholesterol efflux from astrocytes, making them suitable as a potential supportive treatment for AD to compensate the depletion of cerebral HDLs.

RevDate: 2022-01-11

Adhikari UK, Sakiz E, Habiba U, et al (2021)

Treatment of microglia with Anti-PrP monoclonal antibodies induces neuronal apoptosis in vitro.

Heliyon, 7(12):e08644.

Previous reports highlighted the neurotoxic effects caused by some motif-specific anti-PrPC antibodies in vivo and in vitro. In the current study, we investigated the detailed alterations of the proteome with liquid chromatography-mass spectrometry following direct application of anti-PrPC antibodies on mouse neuroblastoma cells (N2a) and mouse primary neuronal (MPN) cells or by cross-linking microglial PrPC with anti-PrPC antibodies prior to co-culture with the N2a/MPN cells. Here, we identified 4 (3 upregulated and 1 downregulated) and 17 (11 upregulated and 6 downregulated) neuronal apoptosis-related proteins following treatment of the N2a and N11 cell lines respectively when compared with untreated cells. In contrast, we identified 1 (upregulated) and 4 (2 upregulated and 2 downregulated) neuronal apoptosis-related proteins following treatment of MPN cells and N11 when compared with untreated cells. Furthermore, we also identified 3 (2 upregulated and 1 downregulated) and 2 (1 upregulated and 1 downregulated) neuronal apoptosis-related related proteins following treatment of MPN cells and N11 when compared to treatment with an anti-PrP antibody that lacks binding specificity for mouse PrP. The apoptotic effect of the anti-PrP antibodies was confirmed with flow cytometry following labelling of Annexin V-FITC. The toxic effects of the anti-PrP antibodies was more intense when antibody-treated N11 were co-cultured with the N2a and the identified apoptosis proteome was shown to be part of the PrPC-interactome. Our observations provide a new insight into the prominent role played by microglia in causing neurotoxic effects following treatment with anti-PrPC antibodies and might be relevant to explain the antibody mediated toxicity observed in other related neurodegenerative diseases such as Alzheimer.

RevDate: 2022-01-11

Chang TY, Yang CP, Chen YH, et al (2021)

Age-Stratified Risk of Dementia in Parkinson's Disease: A Nationwide, Population-Based, Retrospective Cohort Study in Taiwan.

Frontiers in neurology, 12:748096.

Introduction: Parkinson's disease (PD) manifests with dominant motor symptoms and a wide range of non-motor symptoms (NMS). Dementia is one of the most disabling and exhausting NMS throughout the clinical course. We conducted a population-based, age-stratified, retrospective cohort study to investigate the incidence rate and risk of dementia of patients with newly diagnosed PD, and linked to the clinicopathological PD subtypes. Methods: Patients with newly diagnosed PD (PD group, n = 760) and control subjects (non-PD group, n = 3,034) were selected from the Taiwan's National Health Insurance Research Database from January 2001 to December 2005. The dementia incidence rate and dementia-free survival rate were calculated. Results: The overall dementia incidence rate was 17.5 and 5.7 per 1,000 person-years in PD and non-PD groups, respectively. The PD group had a significantly higher overall risk of dementia than controls (p < 0.001). The younger PD patients had a lower dementia incidence rate than the older PD patients, but a higher dementia risk compared to the same age of controls (<60 years, adjusted HR 6.55, 95% CI 1.56-27.48, p = 0.010). The dementia-free survival rate was significantly lower in the PD group compared to the non-PD group during follow-up (p < 0.001). Conclusion: In our study, the older age of onset in PD patients resulted in a higher incidence rate of dementia. In the young age of PD patients, the incidence rate of dementia was lower than the older PD patients, but the dementia risk was higher than controls of the same age. These findings possibly implied that there were different pathogenesis and pathologies causing dementia in younger and older PD patients.

RevDate: 2022-01-11

Abanmy N, Alsabhan J, Gard P, et al (2021)

Association between the Val66Met polymorphism (rs6265/G196A) of the BDNF gene and cognitive performance with SSRI use in Arab Alzheimer's disease patients.

Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society, 29(12):1392-1398.

Brain derived neutrophic factor (BDNF) is a protein and a member of the neurotrophin family of growth factors, supports the survival of existing neurons and encourages the growth and differentiation of new neurons and synapses. The BDNF gene Val66Met polymorphism (rs6265/G196A) is responsible for BDNF synthesis that impact BDNF function that includes memory and cognition. This study investigated whether the BDNF gene Val66Met polymorphism (rs6265/G196A) is associated with cognitive function changes in both Alzheimer disease (AD) patients and elderly participants. In addition the impact of SSRI use on cognition improvement will be assessed. Healthy young, middle ages (25-59 years old) and elderly (more than 60 years old) participants (140) as well as 40 AD patients of whom are both of Saudi Arabian origin were recruited. The genotyping for the association study was performed by real-time PCR using Taqman chemistry in the ABI Prism 7900HT Sequence Detection System. Both Mini-Mental Status Examination (MMSE) and Clinical Dementia Rating (CDR) were used to assess cognitive function of healthy and AD participants, respectively. The findings showed that the BDNF Val66Met genotype distributions and allele frequencies have significant association with cognitive performance in both elderly control group and AD patients. The main findings showed that carriers of GG homozygotes (Val/Val) have superior cognitive performance among AD patients and elderly control subjects. In addition the use of SSRIs in 13 AD patients and 17 elderly participants positively improved cognitive function in elderly (p > 0.001) but not in AD patients (p = 0.1).

RevDate: 2022-01-11

Patel I, Patel J, Jindal SV, et al (2021)

Knowledge, Awareness, and Attitude Towards Dementia Amongst Medical Undergraduate Students: Can a Sensitization Program Help?.

Annals of Indian Academy of Neurology, 24(5):754-758.

Background: Current undergraduate medical academic curriculum does not emphasize on evaluation and management of dementia. The knowledge and attitude of medical students towards patients with dementia in India has not been ascertained previously.

Objective: We aimed to assess the knowledge and attitude of final year medical students about dementia and Alzheimer's disease. We also aimed to assess if a dedicated sensitization cum teaching session by a group of interns doctors guided by a neurologist could help improve students' knowledge and awareness towards dementia or not.

Methods and Materials: 82 consenting final year medical students answered questionnaires of Alzheimer Disease Knowledge Scale (ADKS) and Dementia Attitude Scale (DAS) at a baseline level. A sensitization cum teaching session by intern doctors was conducted to enhance students' knowledge about dementia. A post sensitization reassessment of students was done to assess impact of the session.

Results: The ADKS score was 57% at baseline which was increased to 71% post sensitization program. The mean DAS score was 3.2 at baseline which was reported to be 3.4 after sensitization program. Students reported significant improvement in their knowledge level but did not show the same improvement in their attitude and comfort level in caring for dementia after the sensitization program. Students were still not comfortable dealing with patients with dementia.

Conclusion: Medical students lack significant knowledge and training about dementia. Patient contact and practical training for basic assessment and care of dementia needs to be incorporated in the current academic curriculum. Dedicated sensitization sessions on dementia care can help improve the gap. Practical exposure to management of patients with dementia would be required to enhance the comfort level and attitude of students towards dementia.

RevDate: 2022-01-07

Brosseron F, Maass A, Kleineidam L, et al (2021)

Soluble TAM receptors sAXL and sTyro3 predict structural and functional protection in Alzheimer's disease.

Neuron pii:S0896-6273(21)01033-3 [Epub ahead of print].

There is an urgent need to improve the understanding of neuroinflammation in Alzheimer's disease (AD). We analyzed cerebrospinal fluid inflammatory biomarker correlations to brain structural volume and longitudinal cognitive outcomes in the DELCODE study and in a validation cohort of the F.ACE Alzheimer Center Barcelona. We investigated whether respective biomarker changes are evident before onset of cognitive impairment. YKL-40; sTREM2; sAXL; sTyro3; MIF; complement factors C1q, C4, and H; ferritin; and ApoE protein were elevated in pre-dementia subjects with pathological levels of tau or other neurodegeneration markers, demonstrating tight interactions between inflammation and accumulating neurodegeneration even before onset of symptoms. Intriguingly, higher levels of ApoE and soluble TAM receptors sAXL and sTyro3 were related to larger brain structure and stable cognitive outcome at follow-up. Our findings indicate a protective mechanism relevant for intervention strategies aiming to regulate neuroinflammation in subjects with no or subjective symptoms but underlying AD pathology profile.

RevDate: 2022-01-08

N'Go PK, Ahami OTA, El Hessni A, et al (2021)

Neuroprotective effects of the Chrysophyllum perpulchrum extract against an Alzheimer-like rat model of β amyloid1-40 intrahippocampal injection.

Translational neuroscience, 12(1):545-560.

Objective: Alzheimer's disease (AD) is a threatening disease for African populations in the upcoming years because of the increase in their expectancy of life. Here, we investigated whether natural products from Chrysophyllum perpulchrum as catechin and two dimeric procyanidins (catechin + hexose) could prevent progression of oxidative stress and cognitive changes using an AD-like rat model induced by Aβ1-40 injection into the hippocampal CA1 subfield.

Methodology: Adult male Wistar rats were either microinjected with 1% ammonia as a vehicle (10 µL) or aggregated Aβ1-40 at 10 µg bilateral hippocampus. On the 14th day of post-surgery, some Aβ rats were treated with melatonin (10 mg/kg i.p.) or with the Chrysophyllum perpulchrum extract (300 mg/kg p.o.), and some sham-operated rats received the extract alone. Cognitive abilities were tested with Y-maze, object recognition test and Morris Water Maze. Oxidative stress markers as well as the level of activated microglial cells were assayed in the brain.

Results: Aβ rats exhibited significant deficits of recognition memory and spatial learning. This was associated with an increase of microglia Iba 1 immunoreactivity as well as nitric oxide (NO), malondialdehyde and superoxide dismutase levels but not to the thiol content in the hippocampus, prefrontal cortex and septum of AD-like rats. The Chrysophyllum perpulchrum extract treatment mitigated Aβ-induced cognitive impairments and reversed microglia overactivation and subsequent generation of oxidative stress markers. Interestingly, the neuroprotective actions of the Chrysophyllum perpulchrum extract seem to be comparable to the control drug melatonin used albeit with some more beneficial effects.

Conclusion: These findings are preliminary and should be strengthened by more pharmacological studies of bioactive compounds of Chrysophyllum perpulchrum before being proposed as a promising drug against AD.

RevDate: 2022-01-11

Mohieldin AM, Alachkar A, Yates J, et al (2021)

Novel biomarkers of ciliary extracellular vesicles interact with ciliopathy and Alzheimer's associated proteins.

Communicative & integrative biology, 14(1):264-269.

Ciliary extracellular vesicles (ciEVs), released from primary cilia, contain functional proteins that play an important role in cilia structure and functions. We have recently shown that ciEVs and cytosolic extracellular vesicles (cyEVs) have unique and distinct biomarkers. While ciEV biomarkers have shown some interactions with known ciliary proteins, little is known about the interaction of ciEV proteins with proteins involved in ciliopathy and neurodegenerative disorders. Here, we reveal for the first time the protein-protein interaction (PPI) between the top five ciEVs biomarkers with ciliopathy and Alzheimer disease (AD) proteins. These results support the growing evidence of the critical physiological roles of cilia in neurodegenerative disorders.

RevDate: 2022-01-05

Yang H, Y Jeong (2021)

Correlation between Alteration of Sharp-wave Ripple Coupled Cortical Oscillation and Long-term Memory Deficit in Alzheimer Disease Model Mice.

Experimental neurobiology, 30(6):430-440.

Alzheimer's disease (AD) is the most common cause of dementia, characterized by prominent episodic memory dysfunction. Recent studies have suggested that there is a sequential mechanism in the memory deficit, with long-term ones preceding short-term ones. However, there is lack of explanation for these symptoms. Interaction between the hippocampus and retrosplenial cortex (RSC) during slow-wave sleep (SWS) is a crucial step for successful long-term memory formation. In particular, sharp-wave ripple (SWR) is a principal hippocampus oscillation that coordinates with RSC activity. To determine the relationship between memory dysfunction and SWR-related oscillation changes in AD, we implanted local field potential electrodes in the hippocampus and RSC of AD model mice (APP/PS1). We found that the SWR-coupled ripple wave increased in the RSC, while the amplitude of the SWR was preserved. In addition, the corresponding delta power in hippocampus and RSC was elevated, together with altered delta synchrony in AD mice. All these findings showed a significant correlation with long-term memory deficits measured in contextual fear conditions. Our study suggests that altered SWR-coupled oscillations are a possible underlying mechanism of episodic memory dysfunction in AD mice.

RevDate: 2022-01-05
CmpDate: 2022-01-05

Hedayati-Moghadam M, Hosseinian S, Paseban M, et al (2021)

The Role of Chemokines in Cardiovascular Diseases and the Therapeutic Effect of Curcumin on CXCL8 and CCL2 as Pathological Chemokines in Atherosclerosis.

Advances in experimental medicine and biology, 1328:155-170.

Curcumin, as a vegetative flavonoid, has a protective and therapeutic role in various adverse states such as oxidative stress and inflammation. Remedial properties of this component have been reported in the different chronic diseases including cancers (myeloma, pancreatic, breast, colorectal), vitiligo, psoriasis, neuropathic pains, inflammatory disorders (osteoarthritis, uveitis, ulcerative colitis, Alzheimer), cardiovascular conditions, and diabetes.Cardiovascular disorders include atherosclerosis and various manifestations of atherosclerosis such as stroke, and myocardial infarction (MI) is the leading cause of mortality globally. Studies have shown varying expressions of inflammatory and non-inflammatory chemokines and chemokine receptors in cardiovascular disease, which have been highlighted first in this review. The alteration in chemokines secretion and chemokine receptors has an essential role in the pathophysiology of cardiovascular disease. Chemokines as cytokines with low molecular weight (8-12 kDa) mediate white blood cell (WBC) chemotactic reactions, vascular cell migration, and proliferation that induce endothelial dysfunction, atherogenesis, and cardiac hypertrophy.Several studies reported that curcumin could be advantageous in the attenuation of cardiovascular diseases via anti-inflammatory effects and redress of chemokine secretion and chemokine receptors. We present these studies with a focus on two chemokines: CXCL8 (IL-8) and CCL2 (chemoattractant protein 1 or MCP-1). Future research will further elucidate the precise potential of curcumin on chemokines in the adjustment of cardiovascular system activity or curcumin chemokine-based therapies.

RevDate: 2022-01-04

Zeng P, Su HF, Ye CY, et al (2021)

Therapeutic Mechanism and Key Alkaloids of Uncaria rhynchophylla in Alzheimer's Disease From the Perspective of Pathophysiological Processes.

Frontiers in pharmacology, 12:806984.

Presently, there is a lack of effective disease-modifying drugs for the treatment of Alzheimer's disease (AD). Uncaria rhynchophylla (UR) and its predominant active phytochemicals alkaloids have been studied to treat AD. This study used a novel network pharmacology strategy to identify UR alkaloids against AD from the perspective of AD pathophysiological processes and identified the key alkaloids for specific pathological process. The analysis identified 10 alkaloids from UR based on high-performance liquid chromatography (HPLC) that corresponded to 127 targets correlated with amyloid-β (Aβ) pathology, tau pathology and Alzheimer disease pathway. Based on the number of targets correlated with AD pathophysiological processes, angustoline, angustidine, corynoxine and isocorynoxeine are highly likely to become key phytochemicals in AD treatment. Among the 127 targets, JUN, STAT3, MAPK3, CCND1, MMP2, MAPK8, GSK3B, JAK3, LCK, CCR5, CDK5 and GRIN2B were identified as core targets. Based on the pathological process of AD, angustoline, angustidine and isocorynoxeine were identified as the key UR alkaloids regulating Aβ production and corynoxine, isocorynoxeine, dihydrocorynatheine, isorhynchophylline and hirsutine were identified as key alkaloids that regulate tau phosphorylation. The findings of this study contribute to a more comprehensive understanding of the key alkaloids and mechanisms of UR in the treatment of AD, as well as provide candidate compounds for drug research and development for specific AD pathological processes.

RevDate: 2022-01-04
CmpDate: 2022-01-04

Ben Abdessalem H, Ai Y, Marulasidda Swamy KS, et al (2021)

Virtual Reality Zoo Therapy for Alzheimer's Disease Using Real-Time Gesture Recognition.

Advances in experimental medicine and biology, 1338:97-105.

Alzheimer's disease affects almost ten million people every year. Negative emotions such as frustration and anxiety can have impact on brain capability in terms of memory functions. Alzheimer's patients experience more negative emotions than healthy older adults. Non-pharmacological treatment such as animal therapy could help Alzheimer patient but has restrictions and requirements. We propose a Virtual Reality Zoo Therapy system in which the patients are immersed in a virtual environment and can interact with animals using their hands. With the immersive experience of virtual reality (VR), patients feel that they are in a real therapy room and can freely interact with animals. This system is controlled by an intelligent agent which tracks the patients' emotions using electroencephalography and commands the animals according to their hand gesture and emotions. Experiments have been done and preliminary results show that it is possible to predict patients' hand gesture and interpret them in order to interact with virtual animals and the Zoo Therapy system can reduce the negative emotions.

RevDate: 2022-01-10

Cecerska-Heryć E, Polikowska A, Serwin N, et al (2021)

Importance of oxidative stress in the pathogenesis, diagnosis, and monitoring of patients with neuropsychiatric disorders, a review.

Neurochemistry international, 153:105269 pii:S0197-0186(21)00315-6 [Epub ahead of print].

Oxidative stress is defined as the persistent imbalance between the activity of toxic reactive forms of both oxygen and nitrogen and the antioxidant defense. In low concentrations, they are essential for the proper functioning of the body. Still, their excessive amount contributes to the damage of the biomolecules, consequently leading to various pathologies of the organism. Due to the lipid-rich brain structure, enormous oxygen consumption, and the lack of a sufficient antioxidant barrier make it highly susceptible to oxidative imbalance. Hence, oxidative stress has been linked to various psychiatric disorders. These diseases include all behavioral, emotional, and cognitive abnormalities associated with a significant impediment to social life. Each of the diseases in question: Alzheimer's disease, schizophrenia, depression, and bipolar disorder, is characterized by excessive oxidative stress. Considerable damages to DNA, RNA, proteins, lipids, and mitochondrial dysfunction, are observed. All conditions show increased lipid peroxidation, which appears to be typical of psychiatric disorders because the brain contains large amounts of these types of molecules. In addition, numerous abnormalities in the antioxidant defense are noted, but the results of studies on the activity of antioxidant enzymes differ significantly. The most promising biomarkers seem to be GSH in Alzheimer's disease as an early-stage marker of the disease and thioredoxin in schizophrenia as a marker for therapy monitoring. Data from the literature are consistent with the decrease in antioxidants such as vitamin C, E, uric acid, albumin, etc. Despite these numerous inconsistencies, it seems that oxidative stress is present in the course of psychiatric diseases. Still, it cannot be conclusively determined whether it is the direct cause of development, a consequence of other abnormalities at the biochemical or molecular level, or the result of the disease itself.

RevDate: 2021-12-31

Rhodius-Meester HF, Leeuwis AE, Van Gils AM, et al (2021)

Young-onset dementia in memory clinics in the Netherlands: PRECODE-GP.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 17 Suppl 8:e053524.

BACKGROUND: The disease trajectory of patients with young onset dementia differs from older patients, as do healthcare requirements. To improve specialized care, more insight in young onset dementia is crucial. The aim of PRECODE-GP is therefore 1) to conduct an (annual) inventory of the diagnostic workup in all memory clinics in the Netherlands, and 2) to set up a prospective nationwide database including newly diagnosed younger patients with dementia.

METHODS: PRECODE-GP is part of the PRECODE project, a collaboration between four Dutch Alzheimer centers, Knowledgecenter Dementia at Young Age, Nivel and Alzheimer Nederland. Governance is embedded in the Dutch Memory Clinic Network. Memory clinics are asked annually to fill out a survey on their current diagnostic workup. Eligible patients (<70 years; any type of dementia) are identified by local specialists and recruited via an informed consent procedure providing consent for future linkage to other datasets. Demographics, test results and (etiological) diagnosis are collected in an online database.

RESULTS: PRECODE-GP was initiated in July 2019 and has been approved in 36 memory clinics, approval procedure is ongoing in additional 10 clinics. Based on the annual survey (filled out by 21 clinics), standard imaging of the brain occurs in almost half of memory clinics and neuropsychological examination in one third. CSF is performed when deemed necessary by the clinician. A median 250(141-396) new patients visited the memory clinics yearly, of whom 111(74-180)(48%) were diagnosed with dementia and 12(4-36)(6%) were <70 years. To date, 201 young onset dementia patients (age 62±8, 51% female, MMSE 22±5) are included in our prospective database, diagnosed with 140(69%) Alzheimer's dementia (AD), 29(14%) frontotemporal dementia (FTD), 14(7%) dementia with Lewy Bodies (DLB) and 18(9%) other dementia types. Patients with FTD were youngest (61±6 years), subjects with DLB were most often male (79%), in AD MMSE was lowest (21±5).

CONCLUSION: We took the first step to include patients with young onset dementia via all Dutch memory clinics. As a next step, we plan to link data to existing registries, to gain valuable knowledge on disease trajectories. All needed to improve quality of life for patients with young onset dementia.

RevDate: 2021-12-31

Sood G, Gawryluk J, Couture D, et al (2021)

Developing interdisciplinary participatory practices to disrupt the status quo in dementia research.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 17 Suppl 8:e057715.

BACKGROUND: In dementia research, there is a growing emphasis on generating meaningful research collaborations with people with lived experiences (PWLE). This brings attention to different participatory methods that have the ability to shift perspectives in research and deepen engagement with both PWLE and researchers. However, how participatory methods are realized in practice across the research process requires further investigation; as such, the purpose of this study was to: 1) Explore existing interdisciplinary practices, tools and strategies that promote partnership with PWLE to amplify lived experiences and foster inclusivity; and 2) Identify gaps and opportunity spaces to further develop person-centred and collaborative research tools and practices.

METHOD: The Alzheimer Society of B.C., Emily Carr University's Health Design Lab and researchers from the University of Victoria and the University of British Columbia partnered at the 2021 Dementia Lab conference to conduct two virtual participatory workshops. The workshops gathered 38 participants including researchers, interdisciplinary creatives, designers and PWLE. Participants were invited to share their experiences in dementia research and their vision of how to foster best-practices. Design methods such as envisioning, imagining, visualizing and drawing were adopted to facilitate dialogue and bring out tacit knowledge held by participants.

RESULTS: Inductive analysis of workshop data revealed that interdisciplinary practices are adopted in different dementia-related projects to foster collaboration with PWLE, which contributes to levelling out epistemological hierarchies. The following four overlapping themes emerged from the analysis: 1) Relationships of reciprocity: Translating research findings into community support and ensuring participants are invited to participate in knowledge making and sharing. 2) Pace: Developing research strategies, objectives and methods that allow for a slower pace to afford generative and person-centred outcomes. 3) Power dynamics: Shifting hierarchical power relations in research activities. 4) Generative and continuous practices: Embedding continuity of knowledge and ongoing relationships into research projects to ensure that acquired knowledge can be continually nourished, adopted and updated.

CONCLUSION: By centring perspectives of people with lived experiences of dementia and fostering interdisciplinary collaborations, generative and person-centred research practices can propel a shift in the status quo of dementia research, while empowering people living with dementia.

RevDate: 2021-12-31

Whate A, Kernoghan A, Elliott J, et al (2021)

The development of a national evaluation framework for the First Link® program across Canada.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 17 Suppl 8:e053838.

In Canada, the Alzheimer Society's First Link® program connects people living with dementia and their caregivers to the information, supports and services they need as early as possible and throughout the progression of the disease. Since its launch in 2002, First Link® has been implemented in all provincial societies across Canada. We have developed a national evaluation framework to guide the Alzheimer Society to gather data to assess First Link's® impact on the health system. This work has been conducted with active engagement and consultation with the Alzheimer Society, persons living with dementia and their caregivers and other health system stakeholders. We have also received guidance from a national project advisory committee of stakeholders. A contribution analysis lens was used to understand how the First Link® program may contribute to health system outcomes. First, we assessed the current state of the First Link® program across Canada and developed a theory of change. Key informant interviews with First Link® staff, clients and community referral partners, as well as those without direct experience with the First Link® program, were used to gather evidence to build upon and test the theory of change. We then mapped all available and potential data sources to the theory of change to develop a draft evaluation framework with indicators that show program impact. The draft evaluation framework will be presented to stakeholders for feedback and tested and revised in a rapid cycle evaluation at a representative group of Alzheimer Society pilot sites. The outcomes of this initiative will provide data to support the Alzheimer Societies' efforts to build a national case for ongoing, sustainable funding for First Link®.

RevDate: 2022-01-07

Sanchez CP (2021)

Efficacy of cognitive stimulation therapy virtual program for older adults with dementia in COVID-19 isolation.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 17 Suppl 8:e056213.

BACKGROUND: Cognitive stimulation virtual therapy (CSVT) is an evidence-based psychosocial intervention for people with mild-to-moderate dementia due to various etiological factors.

OBJECTIVE: The aim of the present study was to assess the efficacy of a cognitive stimulation virtual therapy CSVT program, in individuals who have vascular or Alzheimer dementia in COVID-19 isolation.

METHODS: Older adults with mild vascular or Alzheimer dementia (N = 20) were assigned to one of two programs: one group (N = 10) attended during six months, two sessions per week program of the cognitive stimulation virtual therapy CSVT program, while the other, active control group (N = 10) took part in alternative activities. The following tests were applied to their primary caregivers. A short form of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) and quality of life (Quality of Life (QoL) RESULTS: Compared with the active controls, the cognitive stimulation virtual therapy CSVT program showed a greater improvement in general cognitive functioning after the intervention (i.e. score increase on the IQCODE test). A trend towards improvement was also identified in short term/working memory and perceived quality of life (Quality of life (QoL) of elderly with dementia). The primary caregivers also perceived an improvement in mood, stress, anxiety and quality of sleep after the start of the virtual therapy during COVID-19 isolation.

CONCLUSION: The present results support the efficacy of cognitive stimulation virtual therapy CSVT program in people with dementia during COVID-19 isolation.

RevDate: 2021-12-31

Malvern R, Sivananthan S, N Christie (2021)

Piloting an innovative knowledge translation and exchange (KTE) approach on educational resources for caregivers.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 17 Suppl 8:e053895.

BACKGROUND: Knowledge translation and exchange (KTE) is about moving knowledge into practice, involving stakeholders in an ongoing iterative process. The Alzheimer Society of Canada (ASC) approaches KTE by emphasizing ongoing collaborations with our primary audiences: people with lived experience of dementia, healthcare providers, and researchers. Knowing that people have diverse learning styles and preferences for accessing information, ASC is diversifying the range of educational resources that are currently provided through a traditional medium (i.e., printed information sheets) to a multimedia range of KTE tools that can better meet the needs of our audiences. Beginning with a pilot project that explored the practical application of KTE to a key education resource, ASC has developed an operational process with the involvement of stakeholders to help our audiences access and benefit from the information they need in a manner that accommodates them.

METHOD: A resource for the KTE pilot project was chosen based on a data driven approach to assess need and impact (i.e., number of website views, downloads, printed resource orders and feedback from stakeholders). Using ASC's KTE framework and the results of an environmental scan that identified KTE approaches used by other organizations, the team operationalized the KTE framework through a focus on four dimensions: 1) audiences, 2) information channels, 3) feasibility and 4) accessibility of the resource. Key stakeholders, including Alzheimer Society support staff and family caregivers, collaborated with ASC on the development of the tools through focus groups.

RESULT: An infographic and a small video series on practical communication tips for caregivers were created. These KTE tools will support caregivers in staying connected to the person living with dementia at all stages of the disease; as the information is broad and digestible, it can be used by other audiences, such as healthcare providers.

CONCLUSION: The KTE pilot project is a stepping-stone to establish a more integrative KTE approach to ASC's educational resources. The process established through this project will ensure that those who turn to ASC for information can find reliable, up-to-date and evidence-based content through a variety of tools that are engaging, easy to understand and accessible.

RevDate: 2021-12-31

González A, Camila C, RB Maccioni (2021)

Alzheimer's disease: A potential diabetes type 3.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 17 Suppl 2:e058533.

BACKGROUND: Alzheimer's disease (AD) is the most prevalent cause of dementia in the elderly. Neuronal death and synaptic dysfunctions are considered the main hallmarks of this disease. The latter could be directly associated to an impaired metabolism. In particular, glucose metabolism dysregulation has demonstrated to be a key regulatory element in the onset and progression of AD, which is why nowadays AD is considered the type 3 diabetes.

METHODS: Within this revised topic, we provide an analysis regarding the influence of glucose metabolism in AD from three different perspectives: i) As a regulator of the energy source, ii) through several metabolic alterations, such as insulin resistance, that modify peripheral signaling pathways that influence the activation of the immune system (e.g., insulin resistance, diabetes, etc.) and iii) as modulators of various key post-translational modifications for protein aggregation.

RESULTS: During our research, it was demonstrated the relationship between glucose metabolism dysregulation and the onset and Alzheimer's disease: The latter is mediated by several metabolic alterations. Among those, included in our research, are metabolic dysregulation events (e.g insulin resistance), which in turn alters the proper ATP generation, and finally, post-translational modifications, e.g., glycosylation and phosphorylation that mediates protein aggregation (i.e tau hyperphosphorylation that leads to misfolding and pathological self-assembly).

CONCLUSIONS: Alzheimer's disease onset and development is related to a glucose metabolism impairment that affects energy source (ATP) regulation, several metabolic alterations such as insulin resistance, and mediator of post-translational modifications in key proteins (i.e tau) that promotes its self-assembly and aggregation. Thus, considering all the above mentioned, is it seems plausible to consider Alzheimer as the diabetes type 3.

RevDate: 2021-12-31

Kumar A, Doran E, Martini AC, et al (2021)

CAA and related co-morbidities in Down syndrome and Alzheimer disease.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 17 Suppl 2:e058726.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is a form of cerebrovascular pathology characterized by the deposition of beta-amyloid in the leptomeningeal and cortical blood vessels of the brain. CAA is a critical factor contributing to dementia in sporadic Alzheimer's disease (AD). Many individuals with Down syndrome (DS) develop CAA due to the overexpression of the amyloid precursor protein (APP) gene and the subsequent increase of beta-amyloid in the brain. However, little is known about the role of co-morbidities like seizures in the presence and severity of CAA, or the effect that CAA has on the course of AD in individuals with DS.

METHOD: Clinical and neuropathology data for 48 individuals were included in the study. The clinical data, including the presence or absence of seizures and APOE genotype, was collected prospectively as part of a longitudinal research protocol for AD in DS at UCI as well as through a retrospective chart review of the medical records of patients at the AD in DS Memory Care Clinic at UCI. The neuropathology data, including the presence and severity of CAA, was recorded using the guidelines of the National Alzheimer's Coordinating Committee (NACC).

RESULT: A greater percentage of individuals with seizures have CAA as compared to those who did not have seizures, although the presence of seizures does not appear to impact the severity of CAA. Regarding those individuals with the APOE e4 allele, the majority of these individuals experienced moderate or severe CAA, with relatively few individuals with mild CAA or none. The duration of AD course appeared to decrease as CAA severity increased, but the results were not conclusive.

CONCLUSION: Overall, we did not find a significant correlation between seizures and the presence or absence of CAA, or between the severity of CAA and the duration of AD course. Some limitations to our study included a limited number of individuals without CAA or seizures compared to those who presented these conditions. Continuing studies will reinforce the role of CAA in the development of AD and contribute to our understanding of the role of clinical co-morbidities in AD progression.

RevDate: 2021-12-31

Taliyan R, Kakoty V, Kc S, et al (2021)

Fibroblast Growth Factor 21 and Autophagy Modulation Ameliorates Amyloid β-Induced Alzheimer Disease Pathology in Rats.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 17 Suppl 2:e058695.

BACKGROUND: Alzheimer's disease (AD) is a multifactorial neurodegenerative condition and the most common cause of its initiation is accumulation of oligomeric amyloid beta1-42 (Aβ1-42). In recent past, several studies have shown autophagy deficits in AD may resulted accumulation of misfolded protein, Aβ1-42 and phosphorylated tau (ptau). Fibroblast growth factor 21 (FGF21), a metabolic hormone, has shown strong neuroprotective efficacy via increasing autophagic flux in AD. Therefore, this study was designed to investigate the synergistic neuroprotective efficacy of lentiviral FGF21 gene (LV-FGF21) delivery and rapamycin-autophagy modulator in Aβ1-42 induced AD in rats.

METHOD: LV-FGF21 was administered 4weeks before inducing AD by oligomeric Aβ1-42 into the lateral cerebral ventricles. Rats were divided into control, sham group administered with PBS intracerebroventricularly (ICV), ICV-Aβ1-42 group, ICV-Aβ1-42 group pre-treated with LV-FGF21, and pre-treated LV-FGF21 group combined with rapamycin. Morris water maze (MWM), ELISA assay for measuring protein levels of Aβ1-42 , ptau, soluble amyloid precursor protein (sAPP) and beta-site APP cleaving enzyme 1 (BACE1), oxidative stress measurement, mRNA expression and immunofluorescence analysis were performed after treatment completion.

RESULT: Aβ1-42 oligomer formation was confirmed by FESEM analysis. After 14 days, MWM analysis showed that the combination group considerably restored the cognitive ability while attenuated the level of Aβ1-42 , ptau, sAPP, and BACE1. Moreover, oxidative stress parameters considerably improved for the combined treated group as compared with ICV-Aβ1-42 group. Also, mRNA expression of main autophagy mediators (beclin-1, LAMP-2, LC3, ATF4, p62/SQSTM1) reflected positive outcome for the combination treatment group.

CONCLUSION: The findings of the present study confirmed the neuroprotective potential of FGF21 and rapamycin in debilitating AD pathology in rats.

RevDate: 2021-12-31

Tremblay JP, Tremblay G, Guyon A, et al (2021)

Insertion of the Icelandic mutation (A673T) in the APP gene using the CRISPR/Cas9 base editing and Prime editing technologies, a preventive treatment for Alzheimer?.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 17 Suppl 2:e058710.

BACKGROUND: There is currently no treatment for Alzheimer disease (AD). However, the Icelandic mutation in the APP gene (A673T) has been shown to confer a protection against the onset and development of AD (Jonsson et al. Nature 2012). This single nucleotide mutation in APP exon 16 reduces the cleavage of the APP protein by the beta-secretase by 40% thus preventing the development of AD even in persons more than 95 years old.

METHOD: Our research group has initially shown that the presence of the A673T mutation in an APP gene reduced the secretion of beta-amyloid peptides even if there is also a FAD mutation in the gene. This is the case for 14 different FAD mutations.We have also used the CRISPR/Cas9 base editing technology to insert the A673T mutation in the APP gene. We have compared several different cytidine base editor complexes to achieve the most effective and accurate genome modification possible in HEK293T cells and in SH-SY5Y neuroblastomas. The insertion of the A673T mutation in cells containing the London mutation reduced the secretion of beta-amyloid peptides.

RESULT: We have more recently used the Prime editing technology to insert only the A673T mutation without inducing the mutation of other nearby nucleotides. Repeated Prime editing treatment permitted to insert this mutation in up to 64% of the APP gene in HEK293T cells.

CONCLUSION: The insertion of the protective Icelandic mutation in the APP gene using these editing technologies opens a new potential preventive treatment for not only for Familial Alzheimer's diseases but also for sporadic Alzheimer's disease.

RevDate: 2021-12-31

Prater KE, Green KJ, Chiou KL, et al (2021)

Microglia subtype transcriptomes differ between Alzheimer Disease and control human postmortem brain samples.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 17 Suppl 2:e058474.

BACKGROUND: Microglia-mediated neuroinflammation is hypothesized to contribute to disease progression in neurodegenerative diseases such as Alzheimer's Disease (AD). Microglia subtypes are complex, with beneficial and harmful phenotypes. Understanding the gene expression networks which define the spectrum of microglia phenotypes is critical to identifying specific targets for neuroinflammation modulating therapies.

METHOD: Our study utilized post-mortem brain tissue from 22 total (7 male) participants; 12 (3 male) had significant AD neuropathic change. Nuclei isolated from prefrontal cortex were sorted for the myeloid marker PU.1 using fluorescence activated nucleus sorting (FANS). The FANS approach yields larger numbers of nuclei annotated as microglia with high quality sequence from each individual. We performed single-nucleus RNA-seq using the 10X Genomics Chromium platform.

RESULTS: We isolated more than 120,000 microglia nuclei, facilitating group comparisons based on disease state. Unbiased clustering revealed 10 microglia clusters and improved resolution of microglia heterogeneity compared to standard single-cell approaches. We identify clusters of microglia enriched for biological pathways implicating defined myeloid roles including interferon-stimulated, endo/lysosomal, neurodegenerative with a "disease-associated microglia" (DAM) signature, as well as a metabolically active and autophagic cluster. Interestingly, the cluster proportionately enriched for AD individuals' nuclei is not the DAM cluster but instead one of the clusters in which endo/lysosomal genes are highly upregulated. Furthermore, many of the genes in known AD risk loci are strongly differentially regulated in this AD associated cluster. We also identify a cluster of microglia that is proportionately enriched for control samples with upregulated cell cycle and proliferation genes. Trajectory analysis suggests that the paths AD and control nuclei take from unactivated "homeostatic" to various phenotypic states are also distinct.

CONCLUSION: Using human AD tissue collected with uniform protocols we characterize the transcriptomic profiles of microglia subtypes in human brain. By enriching for myeloid cells prior to analysis we can resolve microglia subtypes revealing the diversity of microglia which are "inflammatory" as well as other microglia subtypes responding with induction of metabolic and lysosomal pathways. Our data identifies subtypes of microglia that are unique to AD and control individuals. These results support the possibility of pharmacological targeting of specific subtypes of microglia to alter AD progression.

RevDate: 2021-12-31

Rishitha N, A Muthuraman (2021)

Therapeutic investigation of alpha napthoflavone in the intracerebroventricular injection of L-cysteine induced vascular dementia in rats.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 17 Suppl 12:e058344.

BACKGROUND: Alpha napthoflavone (ANF) is a flavonoid compound it is also know as Alpha- 7,8-benzoflavone, it is a natural flavone available in Russian knapweed in larger quantity. Pharmacologically, it is also reported to produce the cardioprotection, neuroprotection including anti-Alzheimer actions. It possesses multiple cellular actions like anti-oxidant, anti-inflammatory, and anti-apoptotic actions. However, the role of ANF in vascular dementia (VaD) not explored yet.

METHOD: VaD was induced by i.c.v. injection of L-Cys in rats. The test compounds i.e., ANF (40 and 80 mg/kg; p.o.) and reference drug i.e., donepezil (10 mg/kg; p.o.) were administered for 5 consecutive days. The behavioral assessment i.e., learning and memory functions were evaluated by Morris water maze (MWM) test. In addition, the biochemical markers i.e., acetylcholinesterase (AChE) activity; lipid peroxidation (LPO) and homocysteine (HCy) levels were estimated in hippocampal tissue samples RESULT: ANF shown ameliorative effect against i.c.v. injection of L-Cys induced VaD in rats via reduction of AChE activity, LPO and HCy levels CONCLUSION: ANF may be a newer candidate from herbal origin for the management of cerebrovascular disorders like stroke and vascular dementia.

RevDate: 2021-12-31

Vecchio F, Quaranta D, Miraglia F, et al (2021)

Neuronavigated Magnetic Stimulation combined with cognitive training for Alzheimer's patients: an EEG graph study.

GeroScience [Epub ahead of print].

Alzheimer's disease (AD) is the most common neurodegenerative disorder in elderly subjects. Recent studies verified the effects of cognitive training combined with repetitive transcranial magnetic stimulation (rTMS-COG) in AD patients. Here, we analyzed neuropsychological and neurophysiological data, derived from electroencephalography (EEG), to evaluate the effects of a 6-week protocol of rTMS-COG in 72 AD. We designed a randomized, double-blind, sham-controlled trial to evaluate efficacy of rTMS on 6 brain regions obtained by an individual MRI combined with COG related to brain areas to stimulate (i.e., syntax and grammar tasks, comprehension of lexical meaning and categorization tasks, action naming, object naming, spatial memory, spatial attention). Patients underwent neuropsychological and EEG examination before (T0), after treatment (T1), and after 40 weeks (T2), to evaluate the effects of rehabilitation therapy. "Small World" (SW) graph approach was introduced allowing us to model the architecture of brain connectivity in order to correlate it with cognitive improvements. We found that following 6 weeks of intensive daily treatment the immediate results showed an improvement in cognitive scales among AD patients. SW present no differences before and after the treatment, whereas a crucial SW modulation emerges at 40-week follow-up, emphasizing the importance of rTMS-COG rehabilitation treatment for AD. Additional results demonstrated that the delta and alpha1 SW seem to be diagnostic biomarkers of AD, whereas alpha2 SW might represent a prognostic biomarker of cognitive recovery. Derived EEG parameters can be awarded the role of diagnostic and predictive biomarkers of AD progression, and rTMS-COG can be regarded as a potentially useful treatment for AD.

RevDate: 2021-12-31

Yoo HS, Jeon S, Cavedo E, et al (2021)

Association of β-Amyloid and Basal Forebrain With Cortical Thickness and Cognition in Alzheimer and Lewy Body Disease Spectra.

Neurology pii:WNL.0000000000013277 [Epub ahead of print].

OBJECTIVE: Cholinergic degeneration and β-amyloid contribute to brain atrophy and cognitive dysfunction in Alzheimer's disease (AD) and Lewy body disease (LBD), but their relationship has not been comparatively evaluated.

METHODS: In this cross-sectional study, we recruited 28 normal controls (NC), 55 patients with AD mild cognitive impairment (MCI), 34 patients with AD dementia, 28 patients with LBD MCI, and 51 patients with LBD dementia. The subjects underwent cognitive evaluation, brain magnetic resonance imaging to measure the basal forebrain (BF) volume and global cortical thickness (CTh), and 18F-Florbetaben (FBB) positron emission tomography to measure the standardized uptake value ratio (SUVR). Using general linear models and path analyses, the association of FBB-SUVR and BF volume with the CTh and/or cognitive dysfunction were evaluated in AD spectrum (AD and NC) and LBD spectrum (LBD and NC), respectively. Covariates included age, sex, education, deep and periventricular white matter hyperintensities, intracranial volume, hypertension, diabetes mellitus, and hyperlipidemia.

RESULTS: BF volume mediated the association between FBB-SUVR and CTh both in AD and LBD spectra, while FBB-SUVR was associated with CTh independently of BF volume only in LBD spectrum. Significant correlation between voxel-wise FBB-SUVR and CTh was observed only in LBD group. FBB-SUVR was independently associated with widespread cognitive dysfunction both in AD and LBD spectra, especially in the memory domain [standardized beta (B) for AD spectrum = -0.60, B for LBD spectrum = -0.33]. In AD spectrum, BF volume was associated with memory dysfunction (B = 0.18), and CTh was associated with language (B = 0.21) and executive (B = 0.23) dysfunction. In LBD spectrum, however, BF volume and CTh were independently associated with widespread cognitive dysfunction.

CONCLUSIONS: There is a common β-amyloid-related degenerative mechanism with or without the mediation of BF in AD and LBD spectra, while the association of BF atrophy with cognitive dysfunction is more profound and there is localized β-amyloid-cortical atrophy interaction in LBD spectrum.

RevDate: 2022-01-01

Casciaro F, Persico G, Rusin M, et al (2021)

The Histone H3 K4me3, K27me3, and K27ac Genome-Wide Distributions Are Differently Influenced by Sex in Brain Cortexes and Gastrocnemius of the Alzheimer's Disease PSAPP Mouse Model.

Epigenomes, 5(4):.

BACKGROUND: Women represent the majority of Alzheimer's disease patients and show typical symptoms. Genetic, hormonal, and behavioral mechanisms have been proposed to explain sex differences in dementia prevalence. However, whether sex differences exist in the epigenetic landscape of neuronal tissue during the progression of the disease is still unknown.

METHODS: To investigate the differences of histone H3 modifications involved in transcription, we determined the genome-wide profiles of H3K4me3, H3K27ac, and H3K27me3 in brain cortexes of an Alzheimer mouse model (PSAPP). Gastrocnemius muscles were also tested since they are known to be different in the two sexes and are affected during the disease progression.

RESULTS: Correlation analysis distinguished the samples based on sex for H3K4me3 and H3K27me3 but not for H3K27ac. The analysis of transcription starting sites (TSS) signal distribution, and analysis of bounding sites revealed that gastrocnemius is more influenced than brain by sex for the three histone modifications considered, exception made for H3K27me3 distribution on the X chromosome which showed sex-related differences in promoters belonging to behavior and cellular or neuronal spheres in mice cortexes.

CONCLUSIONS: H3K4me3, H3K27ac, and H3K27me3 signals are slightly affected by sex in brain, with the exception of H3K27me3, while a higher number of differences can be found in gastrocnemius.

RevDate: 2022-01-04

Cheng X, Wang H, Zheng Z, et al (2021)

Alzheimer disease effects of different stages on intestinal flora: A protocol for systematic review and meta-analysis.

Medicine, 100(52):e28462.

BACKGROUND: Alzheimer disease (AD) is a common degenerative disease of the central nervous system that can be divided into 3 stages, according to the degree of cognitive impairment. The clinical manifestations are cognitive dysfunction and memory loss, impacting the daily activities of the affected individuals. In recent years, studies have demonstrated a relationship between intestinal flora and AD. However, no meta-analysis has documented the correlation between AD and intestinal flora, to the best of our knowledge. Herein, we sought to assess the correlation between different stages of AD and intestinal flora. A systematic and comprehensive understanding of this relationship is of great significance for developing prevention and treatment strategies against AD.

METHODS: A comprehensive search of the medical literature in Chinese and English language was performed in databases, such as PubMed, EBSCO, CNKI, web of science, WanFang, Cochrane Library, and CBM databases. Pre-defined search strategies were used to retrieve clinical studies of Alzheimer disease and gut microbiota. The included studies were independently analyzed by the 2 researchers who extracted the data. The quality of the data was evaluated according to the "Cochrane system evaluator manual." Finally, Endnote and RevMan software were used for systematic regression and meta-analysis of evidence.

RESULTS: We documented the intestinal flora changes in the 3 stages of Alzheimer disease, according to currently available clinical evidence, and revealed the correlation between the abundance and diversity of flora and treatment efficacy. These findings are essential for developing new strategies for the prevention and treatment of Alzheimer disease.

INPLASY REGISTRATION NUMBER: INPLASY2021100093.

ETHICS AND DISSEMINATION: Since all data utilized in this systematic review and meta-analysis are published, ethical approval was not needed.

RevDate: 2021-12-30

Sible IJ, Nation DA, Alzheimer’s Disease Neuroimaging Initiative (2021)

Visit-to-Visit Blood Pressure Variability and Longitudinal Tau Accumulation in Older Adults.

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

BACKGROUND: Elevated blood pressure variability (BPV) is predictive of dementia, independent of average blood pressure levels, but neuropathological mechanisms remain unclear. We examined whether BPV in older adults is related to tau accumulation in brain regions vulnerable to Alzheimer disease and whether relationships are modified by apoϵ4 carrier status.

METHODS: Two hundred eighty-six Alzheimer's Disease Neuroimaging Initiative participants without history of dementia underwent 3 to 4 blood pressure measurements over 12 months and ≥1 tau positron emission tomography thereafter. BPV was calculated as variability independent of mean. Each scan determined tau burden (standardized uptake value ratio) for a temporal meta-region of interest, including burden from entorhinal cortex, amygdala, parahippocampus, fusiform, inferior temporal, and middle temporal. Bayesian linear growth modeling examined the role of BPV, apolipoprotein ϵ4 carrier status, and time on regional tau accumulation after controlling for several variables, including baseline hypertension.

RESULTS: Elevated BPV was related to tau accumulation at follow-up in a temporal meta-region, independent of average blood pressure levels (ß, 0.89 [95% credible interval, 0.86-0.92]) and especially in entorhinal cortex (ß, 2.57 [95% credible interval, 2.15-2.99]). Apoϵ4 carriers with elevated BPV had the fastest tau accumulation at follow-up (ß, 1.73 [95% credible interval, 0.47-3.03]).

CONCLUSIONS: BPV is related to tau accumulation in brain regions vulnerable to Alzheimer disease, independent of average blood pressure. APOEϵ4 modified this relationship. Bidirectionality of findings is possible. BPV may represent a marker of vascular dysfunction related to early-stage tau pathology contributing to Alzheimer disease.

RevDate: 2021-12-30

Li S, Li Y, Wang Y, et al (2021)

Ionic-liquid-based ultrasound-assisted extraction combined with counter-current chromatography and semi-preparative-LC for the preparation of monoamine oxidase B inhibitors from Pueraria thomsonii.

Journal of separation science [Epub ahead of print].

A simple and efficient method was developed for the rapid screening and identification of ligands for monoamine oxidase B. A new ionic-liquid-based ultrasound-assisted extraction method for medicinal herbs was also developed and validated. In addition, the hyphenated technique of counter-current chromatography and semi-preparative-LC was developed and applied to the isolation of the chemical constituents for Pueraria thomsonii Benth. Three potent monoamine oxidase B inhibitors, viz. daidzein-4',7-diglucoside (42.2 mg), puerarin 6''-O-xyloside (88.3 mg), and 3'-hydroxypuerarin (48.5 mg) with purities of 98.2%, 96.3%, and 97.1%, respectively, were obtained from 500 g of P. thomsonii raw material using semi-HPLC, whereas 3'-methoxypuerarin (76.2 mg), daidzein-8-C-apiosyl (1→6) glucoside (84.2 mg), and tectorigenin (75.1 mg) with purities of 98.5%, 96.4%, and 96.8%, respectively, were obtained from 500 g raw material via counter-current chromatography using a two-phase solvent system comprising n-hexane-ethyl acetate-methanol-water at a volume ratio of 1.85:1.00:0.86:3.69 (v/v). Then, the anti-Alzheimer activity of the phytochemicals was assessed using a PC12 cell model. Treatment with tectorigenin, daidzein-4',7-diglucoside, puerarin 6''-O-xyloside, 3'-hydroxypuerarin, 3'-methoxypuerarin, and daidzein-8-C-apiosyl (1→6) glucoside (100 μg/mL), resulted in cell viabilities of 69.00%, 65.81%, 59.69%, 57.90%, 55.61%, and 54.59%, respectively (P < 0.001). The protocol was proved to be very accurate and efficient. This article is protected by copyright. All rights reserved.

RevDate: 2021-12-31

Khanal P, Zargari F, Far BF, et al (2021)

Integration of System Biology Tools to Investigate Huperzine A as an Anti-Alzheimer Agent.

Frontiers in pharmacology, 12:785964.

Aim: The present study aimed to investigate huperzine A as an anti-Alzheimer agent based on the principle that a single compound can regulate multiple proteins and associated pathways, using system biology tools. Methodology: The simplified molecular-input line-entry system of huperzine A was retrieved from the PubChem database, and its targets were predicted using SwissTargetPrediction. These targets were matched with the proteins deposited in DisGeNET for Alzheimer disease and enriched in STRING to identify the probably regulated pathways, cellular components, biological processes, and molecular function. Furthermore, huperzine A was docked against acetylcholinesterase using AutoDock Vina, and simulations were performed with the Gromacs package to take into account the dynamics of the system and its effect on the stability and function of the ligands. Results: A total of 100 targets were predicted to be targeted by huperzine A, of which 42 were regulated at a minimum probability of 0.05. Similarly, 101 Kyoto Encyclopedia of Genes and Genomes pathways were triggered, in which neuroactive ligand-receptor interactions scored the least false discovery rate. Also, huperzine A was predicted to modulate 54 cellular components, 120 molecular functions, and 873 biological processes. Furthermore, huperzine A possessed a binding affinity of -8.7 kcal/mol with AChE and interacted within the active site of AChE via H-bonds and hydrophobic interactions.

RevDate: 2021-12-30

de Guise E, Soucy B, Joubert S, et al (2021)

Risk Factors for Alzheimer Disease Development After Traumatic Brain Injury: A Preliminary Study.

Alzheimer disease and associated disorders pii:00002093-900000000-99208 [Epub ahead of print].

Traumatic brain injury (TBI) is increasingly recognized as a major risk factor for developing neurocognitive disorders, though this association remains controversial. Determination of risk factors for post-traumatic neurodegeneration in patients with TBI is critical given the high incidence of TBI. We hypothesized that cardiovascular and metabolic comorbidities, in addition to TBI severity, are associated with the risk of post-traumatic development of Alzheimer disease dementia (ADD). A case-controlled retrospective study was conducted using medical records and medical insurance data of 5642 patients with TBI admitted to a tertiary trauma center over a 12-year period, to assess risk factors of developing ADD after TBI. Logistic regression shows that presence of post-traumatic amnesia (P=0.03) and chronic vascular lesions (P=0.04) are significantly associated with development of ADD after TBI. This innovative preliminary study is the first to explore risk factors for post-traumatic ADD. Further association studies are essential to optimize care following TBI.

RevDate: 2022-01-07

Levine TF, Roe CM, Babulal GM, et al (2021)

Limited Longitudinal Change in Self-reported Spatial Navigation Ability in Preclinical Alzheimer Disease.

Alzheimer disease and associated disorders pii:00002093-900000000-99207 [Epub ahead of print].

Subtle changes in objective spatial navigation ability have been observed in the preclinical stage of Alzheimer disease (AD) cross-sectionally and have been found to predict clinical progression. However, longitudinal change in self-reported spatial navigation ability in preclinical AD has yet to be examined. The current study examined whether AD biomarkers suggestive of preclinical AD at baseline spatial navigation assessment and APOE genotype predicted decline in self-reported spatial navigation ability and whether APOE genotype moderated the association of AD biomarkers with change in self-reported spatial navigation. Clinically normal (Clinical Dementia Rating Scale=0) adults aged 56 to 90 completed the Santa Barbara Sense of Direction Scale (SBSOD) annually for an average of 2.73 years. Biomarker data was collected within +/-2 years of baseline (ie, cerebrospinal fluid Aβ42, p-tau181, p-tau181/Aβ42 ratio, positron emission tomography imaging with Florbetapir or Pittsburgh Compound-B, and hippocampal volume). APOE genotyping was obtained for all participants. SBSOD demonstrated a nonsignificant trend toward a decline over time (P=0.082). AD biomarkers did not predict change in self-reported spatial navigation (all Ps>0.163). APOE genotype did not moderate the relationship between AD biomarkers and self-reported spatial navigation in planned analyses (all Ps>0.222). Results suggest that self-reported spatial navigation ability, as estimated with the SBSOD, may be limited as a measure of subtle cognitive change in the preclinical stage of AD.

RevDate: 2021-12-30

Cothran FA, Alto R, Tomaszewski Farias S, et al (2021)

Caring for the Caregivers: An Alzheimer Disease Research Center Call to Action.

Alzheimer disease and associated disorders pii:00002093-900000000-99206 [Epub ahead of print].

Currently, over 16 million dementia caregivers in the US provide over 18 billion hours of care. As the number of persons living with dementia increases, so too will the number of family caregivers. Given the projected steady growth in caregivers and their health-related needs in caring for persons living with Alzheimer disease and related dementias, several initiatives are underway that focus on caregivers. One overlooked mechanism to meet caregiver needs is the National Institute on Aging's Alzheimer's Disease Research Centers (ADRCs). Through secondary analysis, we present a picture of dementia caregiving from the National Alzheimer's Coordinating Center's database and discuss a call to action for ADRCs to engage caregivers and further support the mission of the ADRC to advance the field of dementia research.

RevDate: 2022-01-03

Qurrat-Ul-Ain , Abid A, Lateef M, et al (2021)

Multi-activity tetracoordinated pallado-oxadiazole thiones as anti-inflammatory, anti-Alzheimer, and anti-microbial agents: Structure, stability and bioactivity comparison with pallado-hydrazides.

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 146:112561 pii:S0753-3322(21)01348-2 [Epub ahead of print].

Herein, we report a comparative study based on structure, thermal and solution stability, and biopotency against lipoxygenase (LOX), butyrylcholinesterase (BChE) and microbes for Pd(II) compounds of N,O,S bearing 5-(C5H4XR)-1,3,4-oxadiazole-2-thiones (L') of type [PdL'Cl2] (P'n) and N,O bearing respective hydrazides (L) of type trans-[PdL2Cl2] (Pn) {X = C, R = 4-I, 2-Br, 4-NO2, 3-NO2, 2-Cl, 3-Cl (n = 1-6, serially); X = N (n = 7)}. Spectral techniques (IR, EI-MS, NMR) and physicochemical evaluations successfully characterized the new compounds. The L' behaved as bidentate S-N donors bonded through exocyclic sulfur and N-3' nitrogen, while L acted as amino N donors. UV-vis (solution speciation) and thermal degradation profiles consistently confirmed the greater stability for P'n than Pn compounds. These compounds manifested varying degree in vitro potential to inhibit LOX, BChE and several bacteria and fungi, affected mainly by Pd(II) presence, M-L binding mode, nature and position of R, or halo groups electronegativity. Molecular docking with human 5-LOX and BChE further validated the respective experimental inhibition findings and explored several putative mechanistic interactions (H-bonding, π-stacking, π-alkyl, π-S, etc.) at the enzyme active sites. Pn generally offered superior antimicrobial and anti-LOX (anti-inflammatory) potential than respective P'n compounds, with P3/P'5, P(2,3,7)/P'3, and P6 being comparable, better and equivalent to ampicillin, nystatin and baicalein, the reference antibacterial, antifungal and anti-LOX drugs, respectively. Contrarily, the anti-BChE activity of P'n was found better than Pn compounds, showing P'2/P1 as the most promising anti-Alzheimer drug candidates. This study bares important structural and mechanistic aspects in optimizing antimicrobial, anti-inflammatory and anti-Alzheimer activities, highlighting some potential future pallado-drug candidates.

RevDate: 2021-12-29

Lee SH, Rezzonico MG, Friedman BA, et al (2021)

TREM2-independent oligodendrocyte, astrocyte, and T cell responses to tau and amyloid pathology in mouse models of Alzheimer disease.

Cell reports, 37(13):110158.

Non-neuronal responses in neurodegenerative disease have received increasing attention as important contributors to disease pathogenesis and progression. Here we utilize single-cell RNA sequencing to broadly profile 13 cell types in three different mouse models of Alzheimer disease (AD), capturing the effects of tau-only, amyloid-only, or combined tau-amyloid pathology. We highlight microglia, oligodendrocyte, astrocyte, and T cell responses and compare them across these models. Notably, we identify two distinct transcriptional states for oligodendrocytes emerging differentially across disease models, and we determine their spatial distribution. Furthermore, we explore the impact of Trem2 deletion in the context of combined pathology. Trem2 knockout mice exhibit severely blunted microglial responses to combined tau and amyloid pathology, but responses from non-microglial cell types (oligodendrocytes, astrocytes, and T cells) are relatively unchanged. These results delineate core transcriptional states that are engaged in response to AD pathology, and how they are influenced by a key AD risk gene, Trem2.

RevDate: 2021-12-29

Klein M, Kaleem A, Oetjen S, et al (2021)

Converging roles of PSENEN/PEN2 and CLN3 in the autophagy-lysosome system.

Autophagy [Epub ahead of print].

PSENEN/PEN2 is the smallest subunit of the γ-secretase complex, an intramembrane protease that cleaves proteins within their transmembrane domains. Mutations in components of the γ-secretase underlie familial Alzheimer disease. In addition to its proteolytic activity, supplementary, γ-secretase independent, functions in the macroautophagy/autophagy-lysosome system have been proposed. Here, we screened for PSENEN-interacting proteins and identified CLN3. Mutations in CLN3 are causative for juvenile neuronal ceroid lipofuscinosis, a rare lysosomal storage disorder considered the most common neurodegenerative disease in children. As mutations in the PSENEN and CLN3 genes cause different neurodegenerative diseases, understanding shared cellular functions of both proteins might be pertinent for understanding general cellular mechanisms underlying neurodegeneration. We hypothesized that CLN3 modulates γ-secretase activity and that PSENEN and CLN3 play associated roles in the autophagy-lysosome system. We applied CRISPR gene-editing and obtained independent isogenic HeLa knockout cell lines for PSENEN and CLN3. Following previous studies, we demonstrate that PSENEN is essential for forming a functional γ-secretase complex and is indispensable for γ-secretase activity. In contrast, CLN3 does not modulate γ-secretase activity to a significant degree. We observed in PSENEN- and CLN3-knockout cells corresponding alterations in the autophagy-lysosome system. These include reduced activity of lysosomal enzymes and lysosome number, an increased number of autophagosomes, increased lysosome-autophagosome fusion, and elevated levels of TFEB (transcription factor EB). Our study strongly suggests converging roles of PSENEN and CLN3 in the autophagy-lysosome system in a γ-secretase activity-independent manner, supporting the idea of common cytopathological processes underlying different neurodegenerative diseases.

RevDate: 2021-12-29

Alizadeh SR, MA Ebrahimzadeh (2021)

O-Glycoside quercetin derivatives: Biological activities, mechanisms of action, and structure-activity relationship for drug design, a review.

Phytotherapy research : PTR [Epub ahead of print].

Quercetin as a valuable natural flavonoid has shown extensive biological activities, including anticancer, antioxidant, antibacterial, antiinflammatory, anti-Alzheimer, antifungal, antiviral, antithalassemia, iron chelation, antiobesity, antidiabetic, antihypertension, and antiphospholipase A2 (PLA2) activities, by the modulation of various targets and signaling pathways that have attracted much attention. However, the low solubility and poor bioavailability of quercetin have limited its applications; therefore, the researchers have tried to design and synthesize many new derivatives of quercetin through different strategies to modify quercetin restrictions and improve its biological activities. This review categorized the O-glycoside derivatives of Quercetin into two main classes, 3-O-glycoside and other O-glycoside derivatives. Also, it studied biological activities, structure-activity relationship (SAR), and the action mechanism of O-glycoside quercetin derivatives. Overall, we summarized past and present research for discovering new potent lead compounds.

RevDate: 2021-12-29

Turkez H, Arslan ME, Barboza JN, et al (2021)

Therapeutic Potential of Ferulic Acid in Alzheimer's Disease.

Current drug delivery pii:CDD-EPUB-119739 [Epub ahead of print].

Alzheimer's Disease (AD) is one of the most important neurodegenerative diseases and it covers 60% of whole dementia cases. AD is a constantly progressing neurodegenerative disease as a result of the production of β-amyloid (Aβ) protein and the accumulation of hyper-phosphorylated Tau protein; it causes breakages in the synaptic bonds and neuronal deaths to a large extent. Millions of people worldwide suffer from AD because there is no definitive drug for disease prevention, treatment or slowdown. Over the last decade, multiple target applications have been developed for AD treatments. These targets include Aβ accumulations, hyper-phosphorylated Tau proteins, mitochondrial dysfunction, and oxidative stress resulting in toxicity. Various natural or semisynthetic antioxidant formulations have been shown to protect brain cells from Aβ induced toxicity and provide promising potentials for AD treatment. Ferulic acid (FA), a high-capacity antioxidant molecule, is naturally synthesized from certain plants. FA has been shown to have different substantial biological properties, such as anticancer, antidiabetic, antimicrobial, anti-inflammatory, hepatoprotective, and cardioprotective actions, etc. Furthermore, FA exerted neuroprotection via preventing Aβ-fibril formation, acting as an anti-inflammatory agent, and inhibiting free radical generation and acetylcholinesterase (AChE) enzyme activity. In this review, we present key biological roles of FA and several FA derivatives in Aβ-induced neurotoxicity, protection against free radical attacks, and enzyme inhibitions and describe them as possible therapeutic agents for the treatment of AD.

RevDate: 2021-12-28

Chandarana CV, S Roy (2021)

Comprehensive Review on Neuro-Degenerative Type 3DM.

Current diabetes reviews pii:CDR-EPUB-119366 [Epub ahead of print].

Alzheimer disease (AD) is thought to be the metabolic illness raised by defective insulin signaling, insulin resistance, and low insulin levels in the brain, according to a growing body of research. The "Type 3 diabetes" has been postulated for AD because reduced insulin signalling has molecular and physiological consequences that are comparable to Type I and Type 2 diabetes mellitus (Type 1 DM and Type 2 DM, respectively). The similarities between type 2 diabetes and Alzheimer's disease suggest that these clinical trials might yield therapeutic benefits. However, it's important to note that lowering your risk of Alzheimer's dementia, whether you have diabetes or not, is still a multidimensional process involving factors like exercise, smoking, alcohol, food, and mental challenge. The current aim is to show the relationship between T3D and AD being based on both the processing of amyloid-β (Aβ) precursor protein toxicity and the clearance of Aβ are the result of an impaired insulin signaling. The brain's metabolism with its high lipid content and energy needs, places excess demands on mitochondria and appears more susceptible to oxidative damage than the rest of the body. Current data suggests that increased oxidative stress relates to amyloid-β (Aβ) pathology and onset of AD.

RevDate: 2021-12-31

Viel C, Brandtner AT, Weißhaar A, et al (2021)

Effects of Magnesium Orotate, Benfotiamine and a Combination of Vitamins on Mitochondrial and Cholinergic Function in the TgF344-AD Rat Model of Alzheimer's Disease.

Pharmaceuticals (Basel, Switzerland), 14(12):.

Glucose hypometabolism, mitochondrial dysfunction, and cholinergic deficits have been reported in early stages of Alzheimer's disease (AD). Here, we examine these parameters in TgF344-AD rats, an Alzheimer model that carries amyloid precursor protein and presenilin-1 mutations, and of wild type F344 rats. In mitochondria isolated from rat hippocampi, we found reductions of complex I and oxidative phosphorylation in transgenic rats. Further impairments, also of complex II, were observed in aged (wild-type and transgenic) rats. Treatment with a "cocktail" containing magnesium orotate, benfotiamine, folic acid, cyanocobalamin, and cholecalciferol did not affect mitochondrial activities in wild-type rats but restored diminished activities in transgenic rats to wild-type levels. Glucose, lactate, and pyruvate levels were unchanged by age, genetic background, or treatment. Using microdialysis, we also investigated extracellular concentrations of acetylcholine that were strongly reduced in transgenic animals. Again, ACh levels in wild-type rats did not change upon treatment with nutrients, whereas the cocktail increased hippocampal acetylcholine levels under physiological stimulation. We conclude that TgF344-AD rats display a distinct mitochondrial and cholinergic dysfunction not unlike the findings in patients suffering from AD. This dysfunction can be partially corrected by the application of the "cocktail" which is particularly active in aged rats. We suggest that the TgF344-AD rat is a promising model to further investigate mitochondrial and cholinergic dysfunction and potential treatment approaches for AD.

RevDate: 2022-01-03

Ruganzu JB, Peng X, He Y, et al (2021)

Downregulation of TREM2 expression exacerbates neuroinflammatory responses through TLR4-mediated MAPK signaling pathway in a transgenic mouse model of Alzheimer's disease.

Molecular immunology, 142:22-36 pii:S0161-5890(21)00357-6 [Epub ahead of print].

Activation of glial cells and neuroinflammation play an important role in the onset and development of Alzheimer's disease (AD). Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor in the brain that is involved in regulating neuroinflammation. However, the precise effects of TREM2 on neuroinflammatory responses and its underlying molecular mechanisms in AD have not been studied in detail. Here, we employed a lentiviral-mediated strategy to downregulation of TREM2 expression on microglia in the brain of APPswe/PS1dE9 (APP/PS1) transgenic mice and BV2 cells. Our results showed that downregulation of TREM2 significantly aggravated AD-related neuropathology including Aβ accumulation, peri-plaque microgliosis and astrocytosis, as well as neuronal and synapse-associated proteins loss, which was accompanied by a decline in cognitive ability. The further mechanistic study revealed that downregulation of TREM2 expression initiated neuroinflammatory responses through toll-like receptor 4 (TLR4)-mediated mitogen-activated protein kinase (MAPK) signaling pathway and subsequent stimulating the production of pro-inflammatory cytokines in vivo and in vitro. Moreover, blockade of p38, JNK, and ERK1/2 inhibited the release of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) induced by Aβ1-42 in TREM2-knocked down BV2 cells. Taken together, these findings indicated that TREM2 might be a potential therapeutic target for AD and other neuroinflammation-related diseases.

RevDate: 2021-12-27

McGrath ER, Himali JJ, Levy D, et al (2021)

Plasma EFEMP1 Is Associated with Brain Aging and Dementia: The Framingham Heart Study.

Journal of Alzheimer's disease : JAD pii:JAD215053 [Epub ahead of print].

BACKGROUND: Epidermal growth factor containing fibulin extracellular matrix protein-1 (EFEMP1) has been associated with increased white matter hyperintensities (WMH) burden and disorders of premature aging and may have a shared pathophysiological role in the development of WMH and dementia.

OBJECTIVE: To determine the association between plasma EFEMP1 levels and MRI markers of vascular brain injury and incident all-cause and Alzheimer's disease (AD) dementia.

METHODS: We measured plasma EFEMP1 levels in 1597 [53% women, mean age 68.7 (SD 5.7) years] dementia-free Framingham Offspring cohort participants between 1998-2001 and subsequently followed them for incident dementia. Secondary outcomes included stroke, structural MRI brain measures and neurocognitive test performance.

RESULTS: During a median 11.8 [Q1, Q3 : 7.1, 13.3] year follow-up, 131 participants developed dementia. The highest quintile of plasma EFEMP1, compared to the bottom four quintiles, was associated with an increased risk of time to incident all-cause dementia (HR 1.77, 95% CI 1.18-2.64) and AD dementia (HR 1.76, 95% CI 1.11-2.81) but not with markers of vascular brain injury (WMH, covert brain infarcts or stroke). Higher circulating EFEMP1 concentrations were also cross-sectionally associated with lower total brain (β±SE, -0.28±0.11, p = 0.01) and hippocampal volumes (-0.006±0.003, p = 0.04) and impaired abstract reasoning (Similarities test, -0.18±0.08, p = 0.018 per standard deviation increment in EFEMP1).

CONCLUSION: Elevated circulating EFEMP1 is associated with an increased risk of all-cause and AD dementia, smaller hippocampal and total brain volumes, and poorer cognitive performance. EFEMP1 may play an important biological role in the development of AD dementia. Further studies to validate these findings are warranted.

RevDate: 2021-12-27

Salehi S, Nourbakhsh MS, Yousefpour M, et al (2021)

Chitosan-coated niosome as an efficient curcumin carrier to cross the blood-brain barrier: an animal study.

Journal of liposome research [Epub ahead of print].

This study aims to improve the curcumin bio-stability and brain permeability by loading in bare niosome (BN) and chitosan-coated niosome (ChN). Span 60, tween 60, and cholesterol were optimized as niosome shell components to attain the highest encapsulation efficiency (EE), besides the lowest particle size, using the mixture design method. The resulting optimized BN had a mean diameter of 80 ± 0.2 nm and surface charge of -31 ± 0.1 mv, which changed to 85 ± 0.15 nm and 35 ± 0.12 mv, respectively, after applying the chitosan layer. The EE% in bare niosome were about 80 ± 0.2, which changed to 82 ± 0.21 in ChN. The optimized formulation displayed sustained release, following the Hixson-Crowell model.Wistar rats were subjected to intraperitoneal injection (i.p.) of BN and ChN to evaluate the blood-brain barrier permeability of the curcumin. In this regard, ChN significantly increased curcumin concentration in different parts of the liver, plasma, and central nervous system (cerebral cortex, cerebellum, and stratum), compared with BN. Altogether, our results showed that ChN could be used as a promising delivery system for the treatment of some neurological diseases such as Alzheimer's.

RevDate: 2021-12-27

Ehrlich D, Dunzinger A, Malsiner-Walli G, et al (2021)

Lack of association between cortical amyloid deposition and glucose metabolism in early stage Alzheimer´s disease patients.

Radiology and oncology pii:raon-2021-0051 [Epub ahead of print].

BACKGROUND: Beta amyloid (Aβ) causes synaptic dysfunction leading to neuronal death. It is still controversial if the magnitude of Aβ deposition correlates with the degree of cognitive impairment. Diagnostic imaging may lead to a better understanding the role of Aβ in development of cognitive deficits. The aim of the present study was to investigate if Aβ deposition in the corresponding brain region of early stage Alzheimer´s disease (AD) patients, directly correlates to neuronal dysfunction and cognitive impairment indicated by reduced glucose metabolism.

PATIENTS AND METHODS: In 30 patients with a clinical phenotype of AD and amyloid positive brain imaging, 2-[18F] fluoro-2-deoxy-d-glucose (FDG) PET/CT was performed. We extracted the average [18F] flutemetamol (Vizamyl) uptake for each of the 16 regions of interest in both hemispheres and computed the standardized uptake value ratio (SUVR) by dividing the Vimazyl intensities by the mean signal of positive and negative control regions. Data were analysed using the R environment for statistical computing and graphics.

RESULTS: Any negative correlation between Aβ deposition and glucose metabolism in 32 dementia related and corresponding brain regions in AD patients was not found. None of the correlation coefficient values were statistically significant different from zero based on two-sided p- value.

CONCLUSIONS: Regional Aβ deposition did not correlate negatively with local glucose metabolism in early stage AD patients. Our findings support the role of Aβ as a valid biomarker, but does not permit to conclude that Aβ is a direct cause for an aberrant brain glucose metabolism and neuronal dysfunction.

RevDate: 2021-12-27

Jackson RJ, Meltzer JC, Nguyen H, et al (2021)

APOE4 derived from astrocytes leads to blood-brain barrier impairment.

Brain : a journal of neurology pii:6484505 [Epub ahead of print].

Apolipoprotein E (ApoE) is a multifaceted secreted molecule synthesized in the CNS by astrocytes and microglia, and in the periphery largely by the liver. ApoE has been shown to impact the integrity of the blood brain barrier, and, in humans, the APOE4 allele of the gene is reported to lead to a leaky blood brain barrier. We used allele specific knock-in mice expressing each of the common (human) ApoE alleles, and longitudinal multiphoton intravital microscopy, to directly monitor the impact of various ApoE isoforms on blood brain barrier integrity. We found that humanized APOE4, but not APOE2 or APOE3, mice show a leaky blood brain barrier, increased MMP9, impaired tight junctions, and reduced astrocyte end-foot coverage of blood vessels. Removal of astrocyte-produced ApoE4 led to the amelioration of all phenotypes while the removal of astrocyte-produced ApoE3 had no effect on blood brain barrier integrity. This work shows a cell specific gain of function effect of ApoE4 in the dysfunction of the BBB and implicates astrocyte production of ApoE4, possibly as a function of astrocytic end foot interactions with vessels, as a key regulator of the integrity of the blood brain barrier.

RevDate: 2022-01-11
CmpDate: 2022-01-11

Zeilinger EL, Zrnic Novakovic I, Komenda S, et al (2022)

Informant-based assessment instruments for dementia in people with intellectual disability: A systematic review and standardised evaluation.

Research in developmental disabilities, 121:104148.

BACKGROUND: Dementia in people with intellectual disability (ID) is frequent but hard to recognise. Evidence-based recommendations for suitable instruments are lacking.

AIMS: The present study set out to evaluate informant-based dementia assessment instruments and to provide evidence-based recommendations for instruments most suitable in clinical practice and research.

METHOD AND PROCEDURES: A systematic review was conducted across ten international electronic databases. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) guidelines, including a risk of bias assessment, was applied to extract information and to evaluate measurement properties and the quality of available evidence.

OUTCOMES AND RESULTS: In total, 42 studies evaluating 18 informant-based assessment instruments were analysed. For screening purposes, we recommend the Behavioral and Psychological Symptoms of Dementia in Down Syndrome Scale (BPSD-DS), the Cognitive Scale for Down Syndrome (CS-DS), and the Dementia Screening Questionnaire for Individuals with Intellectual Disabilities (DSQIID). For a more thorough dementia assessment, we recommend the Cambridge Examination for Mental Disorders of Older People with Down's Syndrome and Others with Intellectual Disabilities (CAMDEX-DS).

CONCLUSIONS AND IMPLICATIONS: Our study informs clinicians and researchers about adequate, well-evaluated dementia assessment instruments for people with ID, and highlights the need for high quality studies, especially regarding content validity.

RevDate: 2022-01-13

Lithgow BJ, Dastgheib Z, Z Moussavi (2021)

Baseline Prediction of rTMS efficacy in Alzheimer patients.

Psychiatry research, 308:114348 pii:S0165-1781(21)00642-9 [Epub ahead of print].

Repetitive transcranial magnetic stimulation (rTMS) with extensive 2-6-week protocols are applied to improve cognition and/or slow the cognitive decline seen in Alzheimer's Disease (AD). To date, there are no means to predict the response of a patient to rTMS treatment at baseline. Electrovestibulography (EVestG) biomarkers can be used to predict, at baseline, the efficacy of rTMS when applied to AD individuals. In a population of 27 AD patients (8 with significant cerebrovascular symptomatology, labelled ADcvd) EVestG signals were measured before and after rTMS treatment, and then compared with 16 age-matched healthy controls. MoCA was measured at baseline, whilst ADAS-Cog was the primary outcome measure. AD severity and comorbid cerebrovascular disease were treated as covariates. Using ADAS-Cog total score change, 13/27 AD/ADcvd patients improved with rTMS and 14/27 showed no-improvement. Leave-one-out-cross-validated linear-discriminant-analysis using two EVestG features yielded a blind accuracy of 75% for separating the improved and non-improved populations. Three-way separation of improved/non-improved/control accuracy was 91.9% using MoCA (67% alone) and one EVestG feature (66% alone). AD severity affects the rTMS treatment efficacy. The effect of existing significant cerebrovascular symptomatology on the efficacy of rTMS treatment remains unresolved. Baseline EVestG features can be predictive of the efficacy of rTMS treatment.

RevDate: 2022-01-05

Todri J, Lena O, Todri A, et al (2021)

Does the Global Postural Re-Education Affect the Psychological and Postural Aspects of Alzheimer Disease Patients? A Six Months Quasi-Experimental Study.

Current Alzheimer research, 18(13):1057-1065.

OBJECTIVE: To study the implementation of Global Postural Re-education as a rehabilitative alternative in residence facilities for seniors with Alzheimer, and to verify its effect on psychological and cognitive symptoms.

METHODS: A quasi-experimental design was employed using month-follow-up assessments at 1,3, and 6 months respectively. Ninety elderly people participated in the composition of the study sample: 69 women and 21 men aged from 67 to 89 years (80.2 ±5.5), grouped in two phases: mild and moderate, according to Alzheimer severity. Patients in both groups received the same treatment twice a week for consecutively 24 weeks. Three follow-up medium-long term assessments were performed at intervals of 1, 3, and 6 months. Outcome measures included Mini-Mental State Examination, Geriatric Depression Scale, Quality of Life in Alzheimer Disease, Barthel Index, and Tinetti Scale.

RESULTS: The severity of groups therapy interaction showed significant changes in four outcome measures as cognition [F(1,88)=60.26; p=.000; partial η2= 0.406], depression [F(1,88)=8.24; p=.005; partial η2= 0.086], life quality [F(1,88)= 10.45; p=.002; partial η2= 0.106] and equilibrium [F(1,88)= 6.96; p=.010; partial η2= 0.073]. No changes were found for autonomy [F(1,88)= 1.10; p=.297; partial η2= 0.012]. These changes between the two groups were observed at the sixth month follow-up assessment.

CONCLUSION: Global postural reeducation could be useful as a complementary rehabilitation treatment in Alzheimer patients.

RevDate: 2022-01-05

Peña-Bautista C, Álvarez-Sánchez L, García L, et al (2021)

Assessment of apolipoprotein E genotype for β-amyloid status prediction.

Current Alzheimer research, 18(13):1032-1040.

BACKGROUND: Apolipoprotein E (ApoE) is the major genetic risk factor for sporadic Alzheimer's Disease (AD). Some studies showed a relationship between ApoE4 genotype and the cerebrospinal fluid (CSF) biomarkers (β-amyloid42, p-Tau, t-Tau), as well as with cognitive status. In this sense, it could be interesting to develop an approach to establish amyloid status in a minimally invasive way.

METHODS: The present study assessed the ApoE genotype in different participant groups (mild cognitive impairment due to AD (MCI-AD), mild/moderate dementia due to AD, MCI not due to AD (MCI not AD), other neurological diseases, healthy participants) (n = 342).

RESULTS: As expected, the ApoE4 allele was more prevalent in AD patients, characterized by impairment in CSF β-amyloid42 levels (Aβ +), than in the other groups (Aβ -). In this sense, ApoE4-carrier subjects showed lower CSF levels for β-amyloid42 and higher CSF levels for t-Tau and p-Tau. From this, a multivariate model to predict Aβ status was developed by means of partial least square analysis (PLS) and predictive variables (ApoE genotype, cognitive score, sex, age). This model showed suitable AUC-ROC 0.792 (95% CI, 0.744-0.840) and predictive negative value (81.6%).

CONCLUSION: ApoE genotype could be useful in detecting CSF β-amyloid42 impairment associated with early AD development.

RevDate: 2021-12-25

Hainsworth AH, Elahi FM, RA Corriveau (2021)

An introduction to therapeutic approaches to vascular cognitive impairment.

Cerebral circulation - cognition and behavior, 2:100033.

Vascular cognitive impairment (VCI), encompassing vascular dementia, has been claimed as the "second-most common dementia" after Alzheimer Disease. Whether or not this is true, the clinical picture of most dementia in older people includes vascular disease. There are no validated pharmacological targets for prevention or treatment of VCI. This has inspired a multitude of potential treatment approaches, reflected by the articles in this Special Issue. These include in vitro testing of the novel oral anticoagulant dabigatran for protection against β-amyloid neurotoxicity, and an overview of neuroinflammation in VCI and the role of circulating markers (PIGF, VEGF-D) identified by the MarkVCID study. There are reviews of potential therapeutics, including adrenomedullin and nootropic preparations (exemplified by cerebrolysin). The role of sleep is reviewed, with possible therapeutic targets (5HT2A receptors). There is a clinical study protocol (INVESTIGATE-SVD) and a feasibility analysis for a secondary prevention trial in small vessel disease. Clinical data include secondary analyses of blood pressure and cerebral blood flow from a longitudinal clinical trial (NILVAD), differences between methylphenidate and galantamine responders and non-responders (STREAM-VCI), appraisal of treatment approaches in India, and primary outcomes from a randomised trial of Argentine tango dancing to preserve cognition in African American women (ACT). Treating vascular disease has great potential to improve global cognitive health, with public health impacts alongside individual benefit. Vascular disease burden varies across populations, offering the possibility of proactively addressing health inequity in dementia using vascular interventions. The next 5-10 years will witness cost-effective lifestyle interventions, repurposed drugs and novel therapeutics.

RevDate: 2021-12-25

Ruchoux MM, Kalaria RN, GC Román (2021)

The pericyte: A critical cell in the pathogenesis of CADASIL.

Cerebral circulation - cognition and behavior, 2:100031.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disease presenting with migraine, mood and cognitive disorders, focal neurological deficits, recurrent ischemic attacks, lacunar infarcts and brain white matter changes. As they age, CADASIL patients invariably develop cognitive impairment and subcortical dementia. CADASIL is caused by missense mutations in the NOTCH3 gene resulting in a profound cerebral vasculopathy affecting primarily arterial vascular smooth muscle cells, which target the microcirculation and perfusion. Based on a thorough review of morphological lesions in arteries, veins, and capillaries in CADASIL, we surmise that arteriolar and capillary pericyte damage or deficiency appears a key feature in the pathogenesis of the disease. This may affect critical pericyte-endothelial interactions causing stroke injury and vasomotor disturbances. Changes in microvascular permeability due to perhaps localized blood-brain barrier alterations and pericyte secretory dysfunction likely contribute to delayed neuronal as well as glial cell death. Moreover, pericyte-mediated cerebral venous insufficiency may explain white matter lesions and the dilatation of Virchow-Robin perivascular spaces typical of CADASIL. The postulated central role of the pericyte offers some novel approaches to the study and treatment of CADASIL and enable elucidation of other forms of cerebral small vessel diseases and subcortical vascular dementia.

RevDate: 2022-01-07

Vandenbark AA, Offner H, Matejuk S, et al (2021)

Microglia and astrocyte involvement in neurodegeneration and brain cancer.

Journal of neuroinflammation, 18(1):298.

The brain is unique and the most complex organ of the body, containing neurons and several types of glial cells of different origins and properties that protect and ensure normal brain structure and function. Neurological disorders are the result of a failure of the nervous system multifaceted cellular networks. Although great progress has been made in the understanding of glia involvement in neuropathology, therapeutic outcomes are still not satisfactory. Here, we discuss recent perspectives on the role of microglia and astrocytes in neurological disorders, including the two most common neurodegenerative conditions, Alzheimer disease and progranulin-related frontotemporal lobar dementia, as well as astrocytoma brain tumors. We emphasize key factors of microglia and astrocytic biology such as the highly heterogeneic glial nature strongly dependent on the environment, genetic factors that predispose to certain pathologies and glia senescence that inevitably changes the CNS landscape. Our understanding of diverse glial contributions to neurological diseases can lead advances in glial biology and their functional recovery after CNS malfunction.

RevDate: 2021-12-24

Shimada T, Uehara T, Nagasawa T, et al (2021)

A case report of late-onset schizophrenia differentiated from a dementing disorder.

Neurocase [Epub ahead of print].

We report a case of late-onset schizophrenia that required differentiation from a dementing disorder. The patient was an 83-year-old woman who had experienced auditory hallucinations since she was 67 years old. The patient had slightly elevated total tau and slightly decreased amyloid β1-42, cerebrospinal fluid biomarkers. This case was identified as late-onset schizophrenia. However, the results of cerebrospinal fluid biomarkers indicated that neurofibrillary tangles and neuronal death, which are characteristic of Alzheimer 's disease, may also have been present. Late-onset schizophrenia should be treated based on an appropriate differential diagnosis, including neuropathological consideration of dementing disorders.

RevDate: 2021-12-28

Kowalczyk P, Sulejczak D, Kleczkowska P, et al (2021)

Mitochondrial Oxidative Stress-A Causative Factor and Therapeutic Target in Many Diseases.

International journal of molecular sciences, 22(24):.

The excessive formation of reactive oxygen species (ROS) and impairment of defensive antioxidant systems leads to a condition known as oxidative stress. The main source of free radicals responsible for oxidative stress is mitochondrial respiration. The deleterious effects of ROS on cellular biomolecules, including DNA, is a well-known phenomenon that can disrupt mitochondrial function and contribute to cellular damage and death, and the subsequent development of various disease processes. In this review, we summarize the most important findings that implicated mitochondrial oxidative stress in a wide variety of pathologies from Alzheimer disease (AD) to autoimmune type 1 diabetes. This review also discusses attempts to affect oxidative stress as a therapeutic avenue.

RevDate: 2021-12-29

Le D, Brown L, Malik K, et al (2021)

Two Opposing Functions of Angiotensin-Converting Enzyme (ACE) That Links Hypertension, Dementia, and Aging.

International journal of molecular sciences, 22(24):.

A 2018 report from the American Heart Association shows that over 103 million American adults have hypertension. The angiotensin-converting enzyme (ACE) (EC 3.4.15.1) is a dipeptidyl carboxylase that, when inhibited, can reduce blood pressure through the renin-angiotensin system. ACE inhibitors are used as a first-line medication to be prescribed to treat hypertension, chronic kidney disease, and heart failure, among others. It has been suggested that ACE inhibitors can alleviate the symptoms in mouse models. Despite the benefits of ACE inhibitors, previous studies also have suggested that genetic variants of the ACE gene are risk factors for Alzheimer's disease (AD) and other neurological diseases, while other variants are associated with reduced risk of AD. In mice, ACE overexpression in the brain reduces symptoms of the AD model systems. Thus, we find two opposing effects of ACE on health. To clarify the effects, we dissect the functions of ACE as follows: (1) angiotensin-converting enzyme that hydrolyzes angiotensin I to make angiotensin II in the renin-angiotensin system; (2) amyloid-degrading enzyme that hydrolyzes beta-amyloid, reducing amyloid toxicity. The efficacy of the ACE inhibitors is well established in humans, while the knowledge specific to AD remains to be open for further research. We provide an overview of ACE and inhibitors that link a wide variety of age-related comorbidities from hypertension to AD to aging. ACE also serves as an example of the middle-life crisis theory that assumes deleterious events during midlife, leading to age-related later events.

RevDate: 2021-12-29

Azmat A, Tufail M, AD Chandio (2021)

Synthesis and Characterization of Ti-Sn Alloy for Orthopedic Application.

Materials (Basel, Switzerland), 14(24):.

Titanium (Ti)-based alloys (e.g., Ti6Al4V) are widely used in orthopedic implant applications owing to their excellent mechanical properties and biocompatibility. However, their corrosion resistance needs to be optimized. In addition, the presence of aluminum and vanadium cause alzheimer and cancer, respectively. Therefore, in this study, titanium-based alloys were developed via powder metallurgy route. In these alloys, the Al and V were replaced with tin (Sn) which was the main aim of this study. Four sets of samples were prepared by varying Sn contents, i.e., 5 to 20 wt. %. This was followed by characterization techniques including laser particle analyzer (LPA), X-ray diffractometer (XRD), scanning electron microscope (SEM), computerized potentiostate, vicker hardness tester, and nanoindenter. Results demonstrate the powder sizes between 50 and 55 µm exhibiting very good densification after sintering. The alloy contained alpha at all concentrations of Sn. However, as Sn content in the alloy exceeded from 10 wt. %, the formation of intermetallic compounds was significant. Thus, the presence of such intermetallic phases are attributed to enhanced elastic modulus. In particular, when Sn content was between 15 and 20 wt. % a drastic increase in elastic modulus was observed thereby surpassing the standard/reference alloy (Ti6Al4V). However, at 10 wt. % of Sn, the elastic modulus is more or less comparable to reference counterpart. Similarly, hardness was also increased in an ascending order upon Sn addition, i.e., 250 to 310 HV. Specifically, at 10 wt. % Sn, the hardness was observed to be 250 HV which is quite near to reference alloy, i.e., 210 HV. Moreover, tensile strength (TS) of the alloys were calculated using hardness values since it was very difficult to prepare the test coupons using powders. The TS values were in the range of 975 to 1524 MPa at all concentrations of Sn. In particular, the TS at 10 wt. % Sn is 1149 MPa which is comparable to reference counterpart (1168 MPa). The corrosion rate of Titanium-Sn alloys (as of this study) and reference alloy, i.e., Ti6Al4V were also compared. Incorporation of Sn reduced the corrosion rate at large than that of reference counterpart. In particular, the trend was in decreasing order as Sn content increased from 5 to 20 wt. %. The minimum corrosion rate of 3.65 × 10-9 mm/year was noticed at 20 wt. % than that of 0.03 mm/year of reference alloy. This shows the excellent corrosion resistance upon addition of Sn at all concentrations.

RevDate: 2021-12-28

Peña-Bautista C, Álvarez-Sánchez L, Cañada-Martínez AJ, et al (2021)

Epigenomics and Lipidomics Integration in Alzheimer Disease: Pathways Involved in Early Stages.

Biomedicines, 9(12):.

BACKGROUND: Alzheimer Disease (AD) is the most prevalent dementia. However, the physiopathological mechanisms involved in its development are unclear. In this sense, a multi-omics approach could provide some progress.

METHODS: Epigenomic and lipidomic analysis were carried out in plasma samples from patients with mild cognitive impairment (MCI) due to AD (n = 22), and healthy controls (n = 5). Then, omics integration between microRNAs (miRNAs) and lipids was performed by Sparse Partial Least Squares (s-PLS) regression and target genes for the selected miRNAs were identified.

RESULTS: 25 miRNAs and 25 lipids with higher loadings in the sPLS regression were selected. Lipids from phosphatidylethanolamines (PE), lysophosphatidylcholines (LPC), ceramides, phosphatidylcholines (PC), triglycerides (TG) and several long chain fatty acids families were identified as differentially expressed in AD. Among them, several fatty acids showed strong positive correlations with miRNAs studied. In fact, these miRNAs regulated genes implied in fatty acids metabolism, as elongation of very long-chain fatty acids (ELOVL), and fatty acid desaturases (FADs).

CONCLUSIONS: The lipidomic-epigenomic integration showed that several lipids and miRNAs were differentially expressed in AD, being the fatty acids mechanisms potentially involved in the disease development. However, further work about targeted analysis should be carried out in a larger cohort, in order to validate these preliminary results and study the proposed pathways in detail.

RevDate: 2022-01-13
CmpDate: 2022-01-13

Soto-Mercado V, Mendivil-Perez M, Velez-Pardo C, et al (2021)

(-)-Epigallocatechin-3-Gallate Diminishes Intra-and Extracellular Amyloid-Induced Cytotoxic Effects on Cholinergic-like Neurons from Familial Alzheimer's Disease PSEN1 E280A.

Biomolecules, 11(12):.

Alzheimer's disease (AD) is a complex neurodegenerative disease characterized by functional disruption, death of cholinergic neurons (ChNs) because of intracellular and extracellular Aβ aggregates, and hyperphosphorylation of protein TAU (p-TAU). To date, there are no efficient therapies against AD. Therefore, new therapies for its treatment are in need. The goal of this investigation was to evaluate the effect of the polyphenol epigallocatechin-3-gallate (EGCG) on cholinergic-like neurons (ChLNs) bearing the mutation E280A in PRESENILIN 1 (PSEN1 E280A). To this aim, wild-type (WT) and PSEN1 E280A ChLNs were exposed to EGCG (5-50 μM) for 4 days. Untreated or treated neurons were assessed for biochemical and functional analysis. We found that EGCG (50 μM) significantly inhibited the aggregation of (i)sAPPβf, blocked p-TAU, increased ∆Ψm, decreased oxidation of DJ-1 at residue Cys106-SH, and inhibited the activation of transcription factor c-JUN and P53, PUMA, and CASPASE-3 in mutant ChLNs compared to WT. Although EGCG did not reduce (e)Aβ42, the polyphenol reversed Ca2+ influx dysregulation as a response to acetylcholine (ACh) stimuli in PSEN1 E280A ChLNs, inhibited the activation of transcription factor NF-κB, and reduced the secretion of pro-inflammatory IL-6 in wild-type astrocyte-like cells (ALCs) when exposed to mutant ChLNs culture supernatant. Taken together, our findings suggest that the EGCG might be a promising therapeutic approach for the treatment of FAD.

RevDate: 2021-12-28

Mostafa NM, Mostafa AM, Ashour ML, et al (2021)

Neuroprotective Effects of Black Pepper Cold-Pressed Oil on Scopolamine-Induced Oxidative Stress and Memory Impairment in Rats.

Antioxidants (Basel, Switzerland), 10(12):.

Oxidative stress is usually associated with many neurodegenerative diseases. In this study, the gas chromatography-mass spectrometry (GC-MS) analysis of cold-pressed oil (CPO) from black pepper (Piper nigrum) fruits was performed and its neuroprotective effects were evaluated for the first time. The analysis of CPO revealed the presence of the lignan sesamin (39.78%), the alkaloid piperine (33.79%), the monoterpene hydrocarbons 3-carene (9.53%) and limonene (6.23%), and the sesquiterpene β-caryophyllene (10.67%). Black pepper hydrodistilled oil (HDO) was also comparatively analyzed by GC-MS to show the impact of oil isolation by two different methodologies on their components and class of compounds identified. HDO analysis revealed 35 compounds (99.64% of the total peak areas) mainly composed of monoterpene hydrocarbons (77.28%), such as limonene (26.50%), sabinene (21.36%), and β-pinene (15.53%), and sesquiterpene hydrocarbons (20.59%) represented mainly by β-caryophyllene (19.12%). Due to the low yield obtained for HDO (0.01% v/w), only CPO was chosen for the evaluation of its neuroprotective potential. Alzheimer-type dementia was induced in rats by scopolamine intraperitoneal injection (1.5 mg/kg/day) for seven days. CPO was administered orally (100 mg/kg) for a week before scopolamine administration and then concomitantly for another week. Donepezil (1 mg/kg, orally) was used as a reference drug. CPO administration significantly improved the rat behaviors as evaluated by the Morris water maze test, evident from prolongation in time spent in the platform quadrant (262.9%, compared to scopolamine) and increasing in the crossing time by 18.18% compared to the control group. The rat behavior tested by passive avoidance, showed prolongation in the step-through latency compared to control. Moreover, CPO significantly (p < 0.05) ameliorated the activities of antioxidant enzymes such as catalase, superoxide dismutase (SOD) and reduced malondialdehyde (MDA) equivalents by 22.48%, 45.41%, and 86.61%, respectively, compared to scopolamine. Furthermore, CPO administration decreased scopolamine-induced elevated acetylcholinesterase levels in rats' hippocampi by 51.30%. These results were supported by histopathological and in silico molecular docking studies. Black pepper oil may be a potential antioxidant and neuroprotective supplement.

RevDate: 2022-01-15

Yu ZY, Chen DW, Tan CR, et al (2022)

Physiological clearance of Aβ by spleen and splenectomy aggravates Alzheimer-type pathogenesis.

Aging cell, 21(1):e13533.

BACKGROUND: A previous study demonstrated that nearly 40%-60% of brain Aβ flows out into the peripheral system for clearance. However, where and how circulating Aβ is cleared in the periphery remains unclear. The spleen acts as a blood filter and an immune organ. The aim of the present study was to investigate the role of the spleen in the clearance of Aβ in the periphery.

METHODS: We investigated the physiological clearance of Aβ by the spleen and established a mouse model of AD and spleen excision by removing the spleens of APP/PS1 mice to investigate the effect of splenectomy on AD mice.

RESULTS: We found that Aβ levels in the splenic artery were higher than those in the splenic vein, suggesting that circulating Aβ is cleared when blood flows through the spleen. Next, we found that splenic monocytes/macrophages could take up Aβ directly in vivo and in vitro. Splenectomy aggravated behaviour deficits, brain Aβ burden and AD-related pathologies in AD mice.

CONCLUSION: Our study reveals for the first time that the spleen exerts a physiological function of clearing circulating Aβ in the periphery. Our study also suggests that splenectomy, which is a routine treatment for splenic rupture and hypersplenism, might accelerate the development of AD.

RevDate: 2021-12-23

Marotta G, Basagni F, Rosini M, et al (2021)

Role of Fyn Kinase Inhibitors in Switching Neuroinflammatory Pathways.

Current medicinal chemistry pii:CMC-EPUB-119579 [Epub ahead of print].

Fyn kinase is a member of the Src non-receptor tyrosine kinase family. Fyn is involved in multiple signaling pathways extending from cell proliferation and differentiation to cell adhesion and cell motility, and it has been found to be overexpressed in various types of cancers. In the central nervous system, Fyn exerts several different functions such as axon-glial signal transduction, oligodendrocyte maturation and myelination, and it is implicated in neuroinflammatory processes. Based on these premises, Fyn emerges as an attractive target in cancer and neurodegenerative disease therapy, particularly Alzheimer disease (AD), based on its activation by Aβ via cellular prion protein and its interaction with tau protein. However, Fyn is also a challenging target since the Fyn inhibitors discovered so far, due to the relevant homology of Fyn with other kinases, suffer from off-target effects. This review covers the efforts performed in the last decade to identify and optimize small molecules that effectively inhibit Fyn, both in enzymatic and in cell assays, including drug repositioning practices, as an opportunity of therapeutic intervention in neurodegeneration.

RevDate: 2021-12-23

Cullen N, Janelidze S, Palmqvist S, et al (2021)

Association of CSF Aβ38 Levels With Risk of Alzheimer Disease-Related Decline.

Neurology pii:WNL.0000000000013228 [Epub ahead of print].

OBJECTIVE: Experimental studies suggest that the balance between short and long Aβ species might modulate the toxic effects of Aβ in Alzheimer's disease (AD) but clinical evidence is lacking. We studied whether Aβ38 levels in cerebrospinal fluid (CSF) relate to risk of AD dementia and cognitive decline.

METHODS: CSF Aβ38 levels were measured in 656 individuals across two clinical cohorts - the Swedish BioFINDER study and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cox regression models were used to evaluate the association between baseline Aβ38 levels and risk of AD dementia in AD-biomarker positive individuals (AD+; determined by CSF P-tau/Aβ42 ratio) with subjective cognitive decline (SCD) or mild cognitive impairment (MCI). Linear mixed effects models were used to evaluate the association between baseline Aβ38 levels and cognitive decline as measured by the Mini-Mental State Examination (MMSE) in AD+ participants with SCD, MCI or AD dementia.

RESULTS: In the BioFINDER cohort, high Aβ38 levels were associated with slower decline in MMSE (β = 0.30 points / sd., P = 0.001) and with lower risk of conversion to AD dementia (HR = 0.83 per sd., P = 0.03). In the ADNI cohort, higher Aβ38 levels were associated with less decline in MMSE (β = 0.27, P = 0.01), but not risk of conversion to AD dementia (P = 0.66). Aβ38 levels in both cohorts were significantly associated with both cognitive and clinical outcomes when further adjusted for CSF P-tau or CSF Aβ42 levels.

INTERPRETATION: Higher CSF Aβ38 levels are associated with lower risk of AD-related changes in two independent clinical cohorts. These findings suggest that γ-secretase modulators could be effective as disease-altering therapy.

RevDate: 2021-12-23

Yu L, Boyle PA, Wingo AP, et al (2021)

Neuropathologic Correlates of Human Cortical Proteins in Alzheimer Disease and Related Dementias.

Neurology pii:WNL.0000000000013252 [Epub ahead of print].

BACKGROUND AND OBJECTIVES: Alzheimer's dementia is a complex clinical syndrome that can be defined broadly as an amnestic multidomain dementia. We previously reported human cortical proteins that are implicated in Alzheimer's dementia. To understand the pathologic correlates of these proteins for underlying disease mechanisms, we investigated cortical protein associations with common age-related neuropathologies.

METHODS: Participants were community-dwelling older adults from two cohort studies of aging and dementia. All underwent detailed annual clinical evaluations, and brain autopsies were performed after death. We refer Alzheimer's disease (AD) to pathologically defined disease, and refer Alzheimer's dementia to the clinical syndrome. Indices for AD, cortical Lewy bodies, limbic predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC), hippocampal sclerosis, macroscopic infarcts, microinfarcts, cerebral amyloid angiopathy, atherosclerosis and arteriolosclerosis were quantified during uniform structured neuropathologic evaluations. High-throughput protein abundances from frozen dorsolateral prefrontal cortex were quantified using mass spectrometry based tandem mass tag proteomics analysis. Eleven human cortical proteins implicated in Alzheimer's dementia, including ACE, CHSP1, CATH, DOC2A, ICA1L, LACTB, PKHA1, RTF2, SNX32, STX4, and STX6, were previously identified using an integrative approach. Logistic regression analysis examined the association of protein expression with each of the neuropathologic indices.

RESULTS: A total of 391 older adults were included. We did not observe associations of these protein targets with pathologic diagnosis of AD. By contrast, multiple proteins were associated with non-AD neurodegenerative and cerebrovascular conditions. In particular, higher CHSP1 expression was associated with cortical Lewy bodies and macroscopic infarcts, and higher CATH expression was associated with LATE-NC and arteriolosclerosis. Further, while higher STX6 expression increased the risk of Alzheimer's dementia, the protein was not associated with any of the neuropathologic indices investigated.

DISCUSSION: Cortical proteins implicated in Alzheimer's dementia do not necessarily work through AD pathogenesis; rather, non-AD neurodegenerative and vascular diseases, as well as other pathways are at play. Further, some proteins are pleiotrophic and associated with both neurodegenerative and cerebrovascular pathologies.

RevDate: 2021-12-22

de Oliveira MPB, Silva Serrão PRM, Medeiros Takahashi AC, et al (2021)

Reproducibility of Assessment Tests Addressing Body Structure and Function and Activity in Older Adults with Dementia: A Systematic Review.

Physical therapy pii:6427349 [Epub ahead of print].

OBJECTIVE: The purpose of this study was to analyze the relative and absolute reliability of assessment tests addressing body structure and function, and activity in older adults with dementia.

METHODS: Medline, Embase, Web of Science, The Cochrane Library, and Scielo were searched from inception until March 2021. Two independent reviewers performed the selection process based on titles, abstracts, and full text. Reliability studies of assessment tests in older adults with dementia were included. Methodological quality of the studies was evaluated using the COSMIN Risk of Bias checklist. Relative reliability was analyzed using the intraclass correlation coefficient (ICC) interpreted based on Munro classification. Absolute reliability was analyzed using the minimal detectable change (MDC) and standard error of measurement (SEM).

RESULTS: Fifteen studies involving a total of 560 older adults with dementia were included. Nineteen assessment tests were identified: 13 addressing body structure and function (muscle strength, postural balance, cardiorespiratory fitness) and 6 addressing activity (walking and mobility). Studies determined test-retest and interrater reliability. Fifteen studies evaluated relative reliability using the ICC, with values ranging from no or small correlation to very high correlations. Ten studies evaluated absolute reliability using the MDC or SEM or both.

CONCLUSION: Relative reliability of the assessment tests for body structure and function and activity was high to very high based on ICCs, demonstrating good reproducibility. Regarding absolute reliability, the analysis of the MDC values revealed the need for substantial change to determine that a real change had occurred. Future investigations should consider the type of dementia and standardization of verbal encouragement during the assessment.

IMPACT: This review identified the good reproducibility of assessment tests of body structure and function (muscle strength, postural balance, cardiorespiratory fitness) and activity (walking and mobility) domains in older adults with dementia. Clinically important values may differ when older adults with dementia of diverse etiologies are analyzed together and older adults specifically with Alzheimer disease. Identifying the type of dementia, analyzing types of dementia separately, and standardizing verbal commands during the execution of tests is of considerable clinical important for this population of older adults.

RevDate: 2022-01-15

Mahaman YAR, Embaye KS, Huang F, et al (2022)

Biomarkers used in Alzheimer's disease diagnosis, treatment, and prevention.

Ageing research reviews, 74:101544.

Alzheimer's disease (AD), being the number one in terms of dementia burden, is an insidious age-related neurodegenerative disease and is presently considered a global public health threat. Its main histological hallmarks are the Aβ senile plaques and the P-tau neurofibrillary tangles, while clinically it is marked by a progressive cognitive decline that reflects the underlying synaptic loss and neurodegeneration. Many of the drug therapies targeting the two pathological hallmarks namely Aβ and P-tau have been proven futile. This is probably attributed to the initiation of therapy at a stage where cognitive alterations are already obvious. In other words, the underlying neuropathological changes are at a stage where these drugs lack any therapeutic value in reversing the damage. Therefore, there is an urgent need to start treatment in the very early stage where these changes can be reversed, and hence, early diagnosis is of primordial importance. To this aim, the use of robust and informative biomarkers that could provide accurate diagnosis preferably at an earlier phase of the disease is of the essence. To date, several biomarkers have been established that, to a different extent, allow researchers and clinicians to evaluate, diagnose, and more specially exclude other related pathologies. In this study, we extensively reviewed data on the currently explored biomarkers in terms of AD pathology-specific and non-specific biomarkers and highlighted the recent developments in the diagnostic and theragnostic domains. In the end, we have presented a separate elaboration on aspects of future perspectives and concluding remarks.

RevDate: 2021-12-30
CmpDate: 2021-12-30

Schneider LS, Qiu Y, Thomas RG, et al (2021)

Impact of potential modifications to Alzheimer's disease clinical trials in response to disruption by COVID-19: a simulation study.

Alzheimer's research & therapy, 13(1):201.

BACKGROUND: The COVID-19 pandemic disrupted Alzheimer disease randomized clinical trials (RCTs), forcing investigators to make changes in the conduct of such trials while endeavoring to maintain their validity. Changing ongoing RCTs carries risks for biases and threats to validity. To understand the impact of exigent modifications due to COVID-19, we examined several scenarios in symptomatic and disease modification trials that could be made.

METHODS: We identified both symptomatic and disease modification Alzheimer disease RCTs as exemplars of those that would be affected by the pandemic and considered the types of changes that sponsors could make to each. We modeled three scenarios for each of the types of trials using existing datasets, adjusting enrollment, follow-ups, and dropouts to examine the potential effects COVID-19-related changes. Simulations were performed that accounted for completion and dropout patterns using linear mixed effects models, modeling time as continuous and categorical. The statistical power of the scenarios was determined.

RESULTS: Truncating both symptomatic and disease modification trials led to underpowered trials. By contrast, adapting the trials by extending the treatment period, temporarily stopping treatment, delaying outcomes assessments, and performing remote assessment allowed for increased statistical power nearly to the level originally planned.

DISCUSSION: These analyses support the idea that disrupted trials under common scenarios are better continued and extended even in the face of dropouts, treatment disruptions, missing outcomes, and other exigencies and that adaptations can be made that maintain the trials' validity. We suggest some adaptive methods to do this noting that some changes become under-powered to detect the original effect sizes and expected outcomes. These analyses provide insight to better plan trials that are resilient to unexpected changes to the medical, social, and political milieu.

RevDate: 2022-01-13

Arévalo B, Blázquez M, Serafín V, et al (2021)

Unraveling autoimmune and neurodegenerative diseases by amperometric serological detection of antibodies against aquaporin-4.

Bioelectrochemistry (Amsterdam, Netherlands), 144:108041 pii:S1567-5394(21)00304-2 [Epub ahead of print].

This work reports the first electroanalytical bioplatform to date for the determination of antibodies against aquaporin-4 (AQP4-Abs), whose serum level is considered as relevant biomarker for certain autoimmune diseases. The bioplatform relies on the use of magnetic microparticles modified with the biotinylated protein for the capture of specific antibodies. The captured IgGs are enzymatically labelled with a secondary antibody conjugated to the horseradish peroxidase (HRP) enzyme. Amperometric transduction is performed using the H2O2/hydroquinone (HQ) system, which results in a cathodic current variation directly proportional to the concentration of the target antibodies. The evaluation of the analytical and operational characteristics of the developed bioplatform shows that it is competitive in terms of sensitivity with the only biosensor reported to date as well as with the commercially available ELISA kits. The achieved limit of detection value is 8.8 pg mL-1. In addition, compared to ELISA kits, the developed bioplatform is advantageous in terms of cost and point of care operation ability. The bioplatform was applied to the analysis of control serum samples with known AQP4-Abs contents as well as of sera from healthy individuals and patients diagnosed with Systemic Lupus Erythematosus (SLE) and Alzheimer (AD) diseases, providing results in agreement with the ELISA methodology.

RevDate: 2021-12-20

Ahmed R, Huang J, Lifshitz R, et al (2021)

Structural determinants of the interactions of catechins with Aβ oligomers and lipid membranes.

The Journal of biological chemistry pii:S0021-9258(21)01312-0 [Epub ahead of print].

The aberrant self-assembly of intrinsically disordered proteins (IDPs) into soluble oligomers and their interactions with biological membranes underlies the pathogenesis of numerous neurodegenerative diseases, including Alzheimer's disease. Catechins have emerged as useful tools to reduce the toxicity of IDP oligomers by modulating their interactions with membranes. However, the structural determinants of catechin binding to IDP oligomers and membranes remain largely elusive. Here, we assemble a catechin library by combining several naturally occurring chemical modifications and, using a coupled NMR-statistical approach, we map at atomic resolution the interactions of such library with the Alzheimer's associated Aβ oligomers and model membranes. Our results reveal multiple catechin affinity drivers and show that the combination of affinity-reducing covalent changes may lead to unexpected net gains in affinity. Interestingly, we find that the positive cooperativity is more prevalent for Aβ oligomers than membrane binding, and that the determinants underlying catechin recognition by membranes are markedly different from those dissected for Aβ oligomers. Notably, we find that the unanticipated positive cooperativity arises from the critical regulatory role of the gallate catechin moiety, which recruits previously disengaged substituents into the binding interface and leads to an overall greater compaction of the receptor-bound conformation. Overall, the previously elusive structural attributes mapped here provide an unprecedented foundation to establish structure-activity relationships of catechins.

RevDate: 2021-12-20

Kuo PH (2021)

Cleaning the brain through turbulent glymphatic flow: The washing machine hypothesis.

Lymphology, 54(3):133-139.

In a thought experiment, a "washing machine" model is proposed based on turbulent flow from complex multi-dimensional forces to characterize fluid dynamics in the brain. The glymphatic system's hypothetical role in this system is illustrated in a series of diagrams. Implications of this model are discussed in terms of normal physiology and a variety of pathologic conditions such as brain atrophy and Alzheimer disease.

RevDate: 2022-01-07

Leuzy A, Smith R, Cullen NC, et al (2021)

Biomarker-Based Prediction of Longitudinal Tau Positron Emission Tomography in Alzheimer Disease.

JAMA neurology [Epub ahead of print].

Importance: There is currently no consensus as to which biomarkers best predict longitudinal tau accumulation at different clinical stages of Alzheimer disease (AD).

Objective: To describe longitudinal [18F]RO948 tau positron emission tomography (PET) findings across the clinical continuum of AD and determine which biomarker combinations showed the strongest associations with longitudinal tau PET and best optimized clinical trial enrichment.

This longitudinal cohort study consecutively enrolled amyloid-β (Aβ)-negative cognitively unimpaired (CU) participants, Aβ-positive CU individuals, Aβ-positive individuals with mild cognitive impairment (MCI), and individuals with AD dementia between September 2017 and November 2020 from the Swedish BioFINDER-2 (discovery cohort) and BioFINDER-1 (validation cohort) studies.

Exposures: Baseline plasma and cerebrospinal fluid Aβ42/Aβ40, tau phosphorylated at threonine-217 (p-tau217), p-tau181 and neurofilament light, magnetic resonance imaging, amyloid PET ([18F]flutemetamol), and tau PET ([18F]RO948 in the BioFINDER-2 study; [18F]flortaucipir in the BioFINDER-1 study).

Main Outcomes and Measures: Baseline tau PET standardized uptake value ratio (SUVR) and annual percent change in tau PET SUVR across regions of interest derived using a data-driven approach combining clustering and event-based modeling. Regression models were used to examine associations between individual biomarkers and longitudinal tau PET and to identify which combinations best predicted longitudinal tau PET. These combinations were then entered in a power analysis to examine how their use as an enrichment strategy would affect sample size in a simulated clinical trial.

Results: Of 343 participants, the mean (SD) age was 72.56 (7.24) years, and 157 (51.1%) were female. The clustering/event-based modeling-based approach identified 5 regions of interest (stages). In Aβ-positive CU individuals, the largest annual increase in tau PET SUVR was seen in stage I (entorhinal cortex, hippocampus, and amygdala; 4.04% [95% CI, 2.67%-5.32%]). In Aβ-positive individuals with MCI and with AD dementia, the greatest increases were seen in stages II (temporal cortical regions; 4.45% [95% CI, 3.41%-5.49%]) and IV (certain frontal regions; 5.22% [95% CI, 3.95%-6.49%]), respectively. In Aβ-negative CU individuals and those with MCI, modest change was seen in stage I (1.38% [95% CI, 0.78%-1.99%] and 1.80% [95% CI, 0.76%-2.84%], respectively). When looking at individual predictors and longitudinal tau PET in the stages that showed most change, plasma p-tau217 (R2 = 0.27, P < .005), tau PET (stage I baseline SUVR; R2 = 0.13, P < .05) and amyloid PET (R2 = 0.10, P < .05) were significantly associated with longitudinal tau PET in stage I in Aβ-positive CU individuals. In Aβ-positive individuals with MCI, plasma p-tau217 (R2 = 0.24, P < .005) and tau PET (stage II baseline SUVR; R2 = 0.44, P < .001) were significantly associated with longitudinal tau PET in stage II. Findings were replicated in BioFINDER-1 using longitudinal [18F]flortaucipir. For the power analysis component, plasma p-tau217 with tau PET resulted in sample size reductions of 43% (95% CI, 34%-46%; P < .005) in Aβ-positive CU individuals and of 68% (95% CI, 61%-73%; P < .001) in Aβ-positive individuals with MCI.

Conclusions and Relevance: In trials using tau PET as the outcome, plasma p-tau217 with tau PET may prove optimal for enrichment in preclinical and prodromal AD. However, plasma p-tau217 was most important in preclinical AD, while tau PET was more important in prodromal AD.

RevDate: 2021-12-21

Pérez MF, Saravia F, Castro MG, et al (2021)

Editorial: Targeting Neuroinflammation in Central Nervous System Disorders: Uncovering Mechanisms, Pharmacological Targets, and Neuropharmaceutical Developments.

Frontiers in pharmacology, 12:771610.

RevDate: 2021-12-20

Chaudhary S, Zhornitsky S, Chao HH, et al (2021)

Cerebral Volumetric Correlates of Apathy in Alzheimer's Disease and Cognitively Normal Older Adults: Meta-Analysis, Label-Based Review, and Study of an Independent Cohort.

Journal of Alzheimer's disease : JAD pii:JAD215316 [Epub ahead of print].

BACKGROUND: Affecting nearly half of the patients with Alzheimer's disease (AD), apathy is associated with higher morbidity and reduced quality of life. Basal ganglia and cortical atrophy have been implicated in apathy. However, the findings have varied across studies and left unclear whether subdomains of apathy may involve distinct neuroanatomical correlates.

OBJECTIVE: To identify neuroanatomical correlates of AD-associated apathy.

METHODS: We performed a meta-analysis and label-based review of the literature. Further, following published routines of voxel-based morphometry, we aimed to confirm the findings in an independent cohort of 19 patients with AD/mild cognitive impairment and 25 healthy controls evaluated with the Apathy Evaluation Scale.

RESULTS: Meta-analysis of 167 AD and 56 healthy controls showed convergence toward smaller basal ganglia gray matter volume (GMV) in apathy. Label-based review showed anterior cingulate, putamen, insula, inferior frontal gyrus (IFG) and middle temporal gyrus (MTG) atrophy in AD apathy. In independent cohort, with small-volume-correction, right putamen and MTG showed GMVs in negative correlation with Apathy Evaluation Scale total, behavioral, and emotional scores, and right IFG with emotional score (p < 0.05 family-wise error (FWE)-corrected), controlling for age, education, intracranial volume, and depression. With the Mini-Mental State Examination scores included as an additional covariate, the correlation of right putamen GMV with behavioral and emotional score, right MTG GMV with total and emotional score, and right IFG GMV with emotional score were significant.

CONCLUSION: The findings implicate putamen, MTG and IFG atrophy in AD associated apathy, potentially independent of cognitive impairment and depression, and suggest potentially distinct volumetric correlates of apathy.

RevDate: 2021-12-20

Haverkamp RA, Melis RJF, Claassen JAHR, et al (2021)

Day-To-Day Home Blood Pressure Variability and All-Cause Mortality in a Memory Clinic Population.

Journal of Alzheimer's disease : JAD pii:JAD215002 [Epub ahead of print].

BACKGROUND: High day-to-day blood pressure variability (BPV) has been associated with an increased risk for cognitive decline and mortality in the general population. Whether BPV is associated with increased all-cause mortality in older people with cognitive impairment is unknown.

OBJECTIVE: To investigate the association between day-to-day home BPV and all-cause mortality in older patients attending a memory clinic.

METHODS: We included 279 patients attending a memory clinic, who measured home blood pressure (BP) for 7 consecutive days in the morning and evening. Within-subject BPV was defined as the variation independent of the mean (VIM). Time-to-death was verified through the Dutch population registry. Cox proportional hazard regression was used. Separate analyses were performed for morning-to-morning and evening-to-evening BPV.

RESULTS: Mean age was 73±9 years, dementia and mild cognitive impairment were diagnosed in 35% and 34% respectively, and mean home BP was 139/79 mmHg. After a mean follow-up of 3.2 years, 52 patients had died. Neither day-to-day systolic nor diastolic VIM were associated with mortality (adjusted hazard ratio [HR] systolic VIM: 0.99, 95% -CI 0.92-1.06, p = 0.770, HR diastolic VIM: 1.04, 95% -CI 0.93-1.17, p = 0.517). When morning and evening measurements were analyzed separately, systolic morning-to-morning VIM was associated with mortality (adjusted HR: 1.09, 95% -CI 1.01-1.18, p = 0.033).

CONCLUSION: In this study, day-to-day BPV was not associated with all-cause mortality in patients attending a memory clinic. However, morning-to-morning BPV was. Due to the short assessment window, there is still a lack of clarity; hence future research is warranted to clarify the role of all BPV components in aging.

RevDate: 2022-01-12

Rovelet-Lecrux A, Feuillette S, Miguel L, et al (2021)

Impaired SorLA maturation and trafficking as a new mechanism for SORL1 missense variants in Alzheimer disease.

Acta neuropathologica communications, 9(1):196.

The SorLA protein, encoded by the SORL1 gene, is a major player in Alzheimer's disease (AD) pathophysiology. Functional and genetic studies demonstrated that SorLA deficiency results in increased production of Aβ peptides, and thus a higher risk of AD. A large number of SORL1 missense variants have been identified in AD patients, but their functional consequences remain largely undefined. Here, we identified a new pathophysiological mechanism, by which rare SORL1 missense variants identified in AD patients result in altered maturation and trafficking of the SorLA protein. An initial screening, based on the overexpression of 70 SorLA variants in HEK293 cells, revealed that 15 of them (S114R, R332W, G543E, S564G, S577P, R654W, R729W, D806N, Y934C, D1535N, D1545E, P1654L, Y1816C, W1862C, P1914S) induced a maturation and trafficking-deficient phenotype. Three of these variants (R332W, S577P, and R654W) and two maturation-competent variants (S124R and N371T) were further studied in details in CRISPR/Cas9-modified hiPSCs. When expressed at endogenous levels, the R332W, S577P, and R654W SorLA variants also showed a maturation defective profile. We further demonstrated that these variants were largely retained in the endoplasmic reticulum, resulting in a reduction in the delivery of SorLA mature protein to the plasma membrane and to the endosomal system. Importantly, expression of the R332W and R654W variants in hiPSCs was associated with a clear increase of Aβ secretion, demonstrating a loss-of-function effect of these SorLA variants regarding this ultimate readout, and a direct link with AD pathophysiology. Furthermore, structural analysis of the impact of missense variants on SorLA protein suggested that impaired cellular trafficking of SorLA protein could be due to subtle variations of the protein 3D structure resulting from changes in the interatomic interactions.

RevDate: 2022-01-14

Verheijen MCT, Krauskopf J, Caiment F, et al (2021)

iPSC-derived cortical neurons to study sporadic Alzheimer disease: A transcriptome comparison with post-mortem brain samples.

Toxicology letters, 356:89-99 pii:S0378-4274(21)00915-2 [Epub ahead of print].

Alzheimer's disease (AD) is the most common cause of dementia, characterized by the progressive impairment of cognition and memory loss. Sporadic AD (sAD) represents approximately 95 % of the AD cases and is induced by a complex interplay between genetic and environmental factors called "Alzheimerogens". Heavy metals (e.g. copper) and pesticides (e.g. fipronil) can affect many AD-related processes, including neuroinflammation (considered as AD-inducing factor). Research would benefit from in vitro models to investigate effects of Alzheimerogens. We compared transcriptomics changes in sAD induced pluripotent stem cell (iPSC) derived cortical neurons to differentially expressed genes (DEGs) identified in post-mortem AD brain tissue. These analyses showed that many AD-related processes could be identified in the sAD iPSC-derived neurons, and furthermore, could even identify more DEGs functioning in these processes than post-mortem AD-brain tissue. Thereafter, we exposed the iPSCs to AD-inducing factors (copper(II)chloride, fipronil sulfone and an inflammatory cytokine cocktail). Cytokine exposure induced expression of immune related genes while copper-exposure affected genes involved in lipid and cholesterol metabolism, which are known AD-related processes. Fipronil-exposure did not result in significant transcriptomic changes, although prolonged exposures or higher doses may be necessary. Overall, we show that iPSC-derived cortical neurons can be beneficial in vitro models to identify Alzheimerogens and AD-related molecular mechanisms.

RevDate: 2022-01-13

de Leeuw SM, Kirschner AWT, Lindner K, et al (2022)

APOE2, E3, and E4 differentially modulate cellular homeostasis, cholesterol metabolism, and inflammatory response in isogenic iPSC-derived astrocytes.

Stem cell reports, 17(1):110-126.

The apolipoprotein E4 (APOE4) variant is the strongest genetic risk factor for Alzheimer disease (AD), while the APOE2 allele is protective. A major question is how different APOE genotypes affect the physiology of astrocytes, the main APOE-producing brain cells. Here, we differentiated human APOE-isogenic induced pluripotent stem cells (iPSCs) (APOE4, E3, E2, and APOE knockout [APOE-KO]) to functional "iAstrocytes". Mass-spectrometry-based proteomic analysis showed genotype-dependent reductions of cholesterol and lipid metabolic and biosynthetic pathways (reduction: APOE4 >E3 >E2). Cholesterol efflux and biosynthesis were reduced in APOE4 iAstrocytes, while subcellular localization of cholesterol in lysosomes was elevated. An increase in immunoregulatory proteomic pathways (APOE4 >E3 >E2) was accompanied by elevated cytokine release in APOE4 cells (APOE4 >E3 >E2 >KO). Activation of iAstrocytes exacerbated proteomic changes and cytokine secretion mostly in APOE4 iAstrocytes, while APOE2 and APOE-KO iAstrocytes were least affected. Taken together, APOE4 iAstrocytes reveal a disease-relevant phenotype, causing dysregulated cholesterol/lipid homeostasis, increased inflammatory signaling, and reduced β-amyloid uptake, while APOE2 iAstrocytes show opposing effects.

RevDate: 2021-12-17

Kandimalla R, Manczak M, Pradeepkiran JA, et al (2021)

A partial reduction of Drp1 improves cognitive behavior and enhances mitophagy, autophagy and dendritic spines in a transgenic tau mouse model of Alzheimer disease.

Human molecular genetics pii:6464689 [Epub ahead of print].

The purpose of our study is to understand the impact of a partial dynamin-related protein 1 (Drp1) on cognitive behavior, mitophagy, autophagy, and mitochondrial and synaptic activities in transgenic Tau mice in Alzheimer's disease (ad). Our lab reported increased levels of Aβ and P-Tau, and abnormal interactions between Aβ and Drp1, P-Tau, and Drp1 induced increased mitochondrial fragmentation and reduced fusion and synaptic activities in ad. These abnormal interactions, result in the proliferation of dysfunctional mitochondria in ad neurons. Recent research on mitochondria revealed that fission protein Drp1 is largely implicated in mitochondrial dynamics in ad. To determine the impact of reduced Drp1 in ad, we recently crossed transgenic Tau mice with Drp1 heterozygote knockout (Drp1+/-) mice and generated double mutant (P301LDrp1+/-) mice. In the current study, we assessed cognitive behavior, mRNA and protein levels of mitophagy, autophagy, mitochondrial biogenesis, dynamics and synaptic genes, mitochondrial morphology & mitochondrial function, dendritic spines in Tau mice relative to double mutant mice. When compared to Tau mice, double mutant mice did better on Morris Maze (reduced latency to find hidden platform, increased swimming speed and time spent on quadrant) and rotarod (stayed a longer period of time) tests. Both mRNA and proteins levels autophagy, mitophagy, mitochondrial biogenesis and synaptic proteins were increased in double mutant mice compared to Tau (P301L) mice. Dendritic spines were significantly increased; mitochondrial number is reduced and length is increased in double mutant mice. Based on these observations, we conclude that reduced Drp1 is beneficial in a symptomatic-transgenic Tau (P301L) mice.

RevDate: 2021-12-17

Xhima K, Markham-Coultes K, Kofoed RH, et al (2021)

Ultrasound delivery of a TrkA agonist confers neuroprotection to Alzheimer-associated pathologies.

Brain : a journal of neurology pii:6469023 [Epub ahead of print].

Early degeneration of basal forebrain cholinergic neurons (BFCNs) contributes substantially to cognitive decline in Alzheimer's disease (AD). Evidence from preclinical models of neuronal injury and aging support a pivotal role for nerve growth factor (NGF) in neuroprotection, resilience, and cognitive function. However, whether NGF can provide therapeutic benefit in the presence of AD-related pathologies remains unresolved. Perturbations in the NGF signaling system in AD may render neurons unable to benefit from NGF administration. Additionally, challenges related to brain delivery remain for clinical translation of NGF-based therapies in AD. To be safe and efficient, NGF-related agents should stimulate the NGF receptor, tropomyosin receptor kinase A (TrkA), avoid activation through the p75 neurotrophin receptor (p75NTR), and be delivered non-invasively to targeted brain areas using real-time monitoring. We addressed these limitations using MRI-guided focused ultrasound (MRIgFUS) to increase blood-brain barrier (BBB) permeability locally and transiently, allowing an intravenously administered TrkA agonist that does not activate p75NTR, termed D3, to enter targeted brain areas. Here, we report the therapeutic potential of selective TrkA activation in a transgenic mouse model that recapitulates numerous AD-associated pathologies. Repeated MRIgFUS-mediated delivery of D3 (D3/FUS) improved cognitive function in the TgCRND8 model of AD. Mechanistically, D3/FUS treatment effectively attenuated cholinergic degeneration and promoted functional recovery. D3/FUS treatment also resulted in widespread reduction of brain amyloid pathology and dystrophic neurites surrounding amyloid plaques. Furthermore, D3/FUS markedly enhanced hippocampal neurogenesis in TgCRND8 mice, implicating TrkA agonism as a novel therapeutic target to promote neurogenesis in the context of AD-related pathology. Thus, this study provides evidence that selective TrkA agonism confers neuroprotection to effectively counteract AD-related vulnerability. Recent clinical trials demonstrate that non-invasive BBB modulation using MRIgFUS is safe, feasible and reversible in AD patients. TrkA receptor agonists coupled with MRIgFUS delivery constitute a promising disease-modifying strategy to foster brain health and counteract cognitive decline in AD.

RevDate: 2022-01-07

Jellinger KA (2022)

Recent update on the heterogeneity of the Alzheimer's disease spectrum.

Journal of neural transmission (Vienna, Austria : 1996), 129(1):1-24.

Alzheimer's disease (AD), the most common form of dementia worldwide, is a mixed proteinopathy (β-amyloid, tau and other proteins). Classically defined as a clinicopathological entity, AD is a heterogeneous, multifactorial disorder with various pathobiological subtypes showing different forms of cognitive presentation, currently referred to as the Alzheimer spectrum or continuum. Its morphological hallmarks are extracellular β-amyloid (amyloid plaques) and intraneuronal tau aggregates forming neurofibrillary tangles and neurites, vascular amyloid deposits (cerebral amyloid angiopathy), synapse and neuronal loss as well as neuroinflammation and reactive astrogliosis, leading to cerebral atrophy and progressive mental/cognitive impairment (dementia). In addition to "classical" AD, several subtypes with characteristic regional patterns of tau pathology have been segregated that are characterized by distinct clinical features, differences in age, sex distribution, disease duration, cognitive status, APOE genotype, and biomarker levels. In addition to four major subtypes based on the distribution of tau pathology and brain atrophy (typical, limbic predominant, hippocampal sparing, and minimal atrophy), several other clinical variants (non-amnestic, corticobasal, behavioral/dysexecutive, posterior cortical variants, etc.) have been identified. These heterogeneous AD variants are characterized by different patterns of key neuronal network destructions, in particular the default-mode network that is responsible for cognitive decline. Other frequent age-related co-pathologies, e.g., cerebrovascular lesions, Lewy and TDP-43 pathologies, hippocampal sclerosis, or argyrophilic grain disease, essentially influence the clinical picture and course of AD, and can challenge our understanding of this disorder including the threshold and causal relevance of each individual pathology. Unravelling the clinico-morphological heterogeneity among the AD spectrum entities is important for better elucidation of the pathogenic mechanisms affecting the aging brain that may enable a broader diagnostic coverage of AD as a basis for implementing precision medicine approaches and for developing preventive and ultimately disease-modifying therapies for this devastating disorder.

RevDate: 2021-12-18

Jameie SB, Pirasteh A, Naseri A, et al (2021)

β-Amyloid Formation, Memory, and Learning Decline Following Long-term Ovariectomy and Its Inhibition by Systemic Administration of Apigenin and β-Estradiol.

Basic and clinical neuroscience, 12(3):383-394.

Introduction: The increasing cases of Alzheimer Disease (AD) has caused numerous problems. The risk of developing AD increases in menopausal women, too. Apigenin and β-estradiol are effective antioxidant and neuroprotective agents. We conducted the present study to explore their combined effects on β-amyloid plaque formation, memory, and learning in ovariectomized rats.

Methods: Forty-two Wistar rats were randomly assigned into 6 groups: 1) ovariectomized (OVX), 2) OVX + apigenin, 3) OVX + β-estradiol, 4) OVX + apigenin + β-estradiol, 5 &6) vehicle shams for E2 and API, and 7) surgical sham. Treatment was done with apigenin and β-estradiol. Then, we studied the formation of β-amyloid plaques, neuronal density in the hippocampus area, apoptosis, memory, and learning.

Results: Findings showed the significant formation of β-amyloid plaques in the hippocampus of OVX animals and their memory impairment. Apigenin and β-estradiol significantly reduced the number of β-amyloid plaques, as well as the symptoms of memory impairment and learning, and decreased the expression of caspase-3 in treated animals.

Conclusion: Accordingly, β-estradiol and apigenin could have more potent therapeutic effects on AD.

RevDate: 2021-12-18

Jafarzadeh G, Shakerian S, Farbood Y, et al (2021)

Effects of Eight Weeks of Resistance Exercises on Neurotrophins and Trk Receptors in Alzheimer Model Male Wistar Rats.

Basic and clinical neuroscience, 12(3):349-359.

Introduction: This study evaluates the effects of 8 weeks of resistance exercises on the expression of neurotrophins and Trk receptors in Alzheimer model male Wistar rats.

Methods: For this purpose, 32 mature male Wistar rats with a mean weight of 230-280 g were chosen and divided into Alzheimer and Sham groups. The rats in the sham group received normal saline, while the ones in the Alzheimer group received streptomycin via intraventricular injection. These rats were then divided into the following four subgroups: 1) resting sham, 2) exercising sham, 3) resting Alzheimer, and 4) exercising Alzheimer. The two exercising rat subgroups exercised three times a week for 8 weeks. A weight was attached to their tails, and they had to carry it on a 26-step ladder in each cycle. Resting groups were handled every day to minimize the effects of stress. At the end of the eighth week and 24 hours after the last exercise session (to avoid the effects of the last exercise session), the rats were put under deep anesthesia and beheaded. Hippocampus tissues were precisely extracted, and samples were sent to the laboratory for molecular and cellular tests. To investigate gene expression, quantitative RTPCR was used.

Results: The tests for comparing the mean values of BDNF, NT3, NGF, TrkA, and TrkB in two rat groups showed that with error levels of less than 5%, there is a significant difference in the amounts of BDNF, NT3, NGF, TrkA, and TrkB between exercising rats and resting ones. These amounts were much higher in the exercising Alzheimer rats group.

Conclusion: Eight weeks of resistance exercises increased the expression of BDNF, NT3, and NGF genes and TrkA and TrkB receptors in Alzheimer model Wistar rats.

RevDate: 2021-12-18

Wu L, Wang W, Tian S, et al (2021)

Identification of Hub Genes in Patients with Alzheimer Disease and Obstructive Sleep Apnea Syndrome Using Integrated Bioinformatics Analysis.

International journal of general medicine, 14:9491-9502.

Background: Obstructive sleep apnea syndrome (OSA) is associated with an increased risk of Alzheimer's disease (AD). This study aimed to identify the key common genes in AD and OSA and explore molecular mechanism value in AD.

Methods: Expression profiles GSE5281 and GSE135917 were acquired from Gene Expression Omnibus (GEO) database, respectively. Weighted gene co-expression network analysis (WGCNA) and R 4.0.2 software were used for identifying differentially expressed genes (DEGs) related to AD and OSA. Function enrichment analyses using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and the protein-protein interaction network (PPI) using the STRING database were subsequently performed on the shared DEGs. Finally, the hub genes were screened from the PPI network using the MCC algorithm of CytoHubba plugin.

Results: Seven modules and four modules were the most significant with AD and OSA by WGCNA, respectively. A total of 33 common genes were screened in AD and OSA by VENN. Functional enrichment analysis indicated that DEGs were mainly involved in cellular response to oxidative stress, neuroinflammation. Among these DEGs, the top 10 hub genes (high scores in cytoHubba) were selected in the PPI network, including AREG, SPP1, CXCL2, ITGAX, DUSP1, COL1A1, SCD, ACTA2, CCND2, ATF3.

Conclusion: This study presented ten target genes on the basis of common genes to AD and OSA. These candidate genes may provide a novel perspective to explore the underlying mechanism that OSA leads to an increased risk of AD at the transcriptome level.

RevDate: 2022-01-10

Lai X, Hu J, Liu H, et al (2021)

A short peptide from sAPPα binding to BACE1-APP action site rescues Alzheimer-like pathology.

Neuroscience letters, 770:136397 pii:S0304-3940(21)00776-X [Epub ahead of print].

Amyloid β-peptide (Aβ) is the driven force of Alzheimer's disease (AD), and reducing Aβ production could be a potential therapeutic strategy for AD. sAPPα appears to have the ability to specifically inhibit β-cleavage of APP without inhibiting BACE1 completely, direct administration of sAPPα may not be clinically applicable due to the low permeability of blood-brain barrier (BBB). In this study, we investigated the neuroprotective effects of a short peptide generated from sAPPα, which could specifically bind to BACE1 at the BACE1-APP action site. We found that this peptide significantly reduced Aβ production both in vivo and in vitro, thus further attenuated Aβ deposition, Tau hyperphosphorylation, neuroinflammation et al. and rescued behavioral deficits. Therefore, this short peptide may hold promise for the treatment of AD due to its neuroprotective effects, low molecular weight to cross BBB, and less safety concerns. The anti-neurodegenerative capacity of sAPPα may not result solely from direct inhibition of BACE1.

RevDate: 2022-01-10

Badrikoohi M, Esmaeili-Bandboni A, P Babaei (2022)

Simultaneous administration of bromodomain and histone deacetylase I inhibitors alleviates cognition deficit in Alzheimer's model of rats.

Brain research bulletin, 179:49-56.

BACKGROUND: Histone deacetylases (HDACs) target various genes responsible for cognitive functions. However, chromatin readers, particularly bromodomain-containing protein 4 (BRD4), are capable to change the final products of genes. The objective of this study was to evaluate the simultaneous effects of inhibition of HDACs and BRD4 on spatial and aversive memories impaired by amyloid β (Aβ) in a rat model of Alzheimer's disease (AD) considering CREB and TNF-α signaling.

METHODS: Forty male Wistar rats aged 3 months were randomly divided into five groups: saline +DMSO, Aβ+saline+DMSO, Aβ+JQ1, Aβ+MS-275, Aβ+JQ1+MS-275, and received the related treatments. MS-275, is the second generation of HDACs inhibitor, and JQ1 is a potent inhibitor of the BET family of bromodomain proteins in mammals. After the treatments, cognitive function was assessed by Morris water maze (MWM) and passive avoidance learning (PAL). The hippocampal level of mRNA for CREB and TNF-α, and also phosphorylated CREB were measured using real-time PCR and western blotting respectively.

RESULTS: Administration of JQ1 and MS-275, either separately or simultaneously, improved acquisition and retrieval of spatial and aversive memories as it was evident by decreased escape latency and increased time spent in the target quadrant (TTS) in Morris water maze (MWM), together with increase in step-through latency, but reduced time spent in the dark zone time in passive avoidance learning (PAL) compared with Aβ+saline+DMSO. Furthermore, there was a significant rise in the hippocampal level of CREB mRNA and phosphorylated CREB, but a reduction in TNF-α expression in comparison with Aβ + Saline.

CONCLUSION: Simultaneous administration of JQ1 and MS-275 improves acquisition and retrieval of both spatial and aversive memories partly via CREB and TNF-α signaling with no superiority to monotherapy.

RevDate: 2022-01-03

Abdel-Aal RA, Hussein OA, Elsaady RG, et al (2022)

Naproxen as a potential candidate for promoting rivastigmine anti-Alzheimer activity against aluminum chloride-prompted Alzheimer's-like disease in rats; neurogenesis and apoptosis modulation as a possible underlying mechanism.

European journal of pharmacology, 915:174695.

BACKGROUND AND AIM: Alzheimer's disease (AD) is one of the leading causes of dependence and disability among the elderly worldwide. The traditional anti-Alzheimer medication, rivastigmine, one of the cholinesterase inhibitors (ChEIs), fails to achieve a definitive cure. We tested the hypothesis that naproxen administration to the rivastigmine-treated aluminum chloride (AlCl3) Alzheimer's rat model could provide an additive neuroprotective effect compared to rivastigmine alone.

MATERIALS AND METHODS: The studied groups were control (Cont), AlCl3 treated (Al), rivastigmine treated (RIVA), naproxen treated (Napro), and combined rivastigmine and naproxen treated (RIVA + Napro). Rats' memory, spatial learning, and cognitive behavior were assessed followed by evaluation of hippocampal acetylcholinesterase (AChE) activity. Hippocampal and cerebellar histopathology were thoroughly examined. Activated caspase-3 and the neuroepithelial stem cells marker; nestin expressions were immunohistochemically assayed.

RESULTS: AD rats displayed significantly impaired memory and cognitive function, augmented hippocampal AChE activity; massive neurodegeneration associated with enhanced astrogliosis, apoptosis, and impaired neurogenesis. Except for the enhancement of neurogenesis and suppression of apoptosis, the combination therapy had no additional neuroprotective benefit over rivastigmine-only therapy.

CONCLUSION: Naproxen's efficacy was established by its ability to function at the cellular level, improved neurogenesis, and decreased, apoptosis without having an additional mitigating impact on cognitive impairment in rivastigmine-treated AD rats.

RevDate: 2022-01-11
CmpDate: 2022-01-11

James C, Ranson JM, Everson R, et al (2021)

Performance of Machine Learning Algorithms for Predicting Progression to Dementia in Memory Clinic Patients.

JAMA network open, 4(12):e2136553.

Importance: Machine learning algorithms could be used as the basis for clinical decision-making aids to enhance clinical practice.

Objective: To assess the ability of machine learning algorithms to predict dementia incidence within 2 years compared with existing models and determine the optimal analytic approach and number of variables required.

This prognostic study used data from a prospective cohort of 15 307 participants without dementia at baseline to perform a secondary analysis of factors that could be used to predict dementia incidence. Participants attended National Alzheimer Coordinating Center memory clinics across the United States between 2005 and 2015. Analyses were conducted from March to May 2021.

Exposures: 258 variables spanning domains of dementia-related clinical measures and risk factors.

Main Outcomes and Measures: The main outcome was incident all-cause dementia diagnosed within 2 years of baseline assessment.

Results: In a sample of 15 307 participants (mean [SD] age, 72.3 [9.8] years; 9129 [60%] women and 6178 [40%] men) without dementia at baseline, 1568 (10%) received a diagnosis of dementia within 2 years of their initial assessment. Compared with 2 existing models for dementia risk prediction (ie, Cardiovascular Risk Factors, Aging, and Incidence of Dementia Risk Score, and the Brief Dementia Screening Indicator), machine learning algorithms were superior in predicting incident all-cause dementia within 2 years. The gradient-boosted trees algorithm had a mean (SD) overall accuracy of 92% (1%), sensitivity of 0.45 (0.05), specificity of 0.97 (0.01), and area under the curve of 0.92 (0.01) using all 258 variables. Analysis of variable importance showed that only 6 variables were required for machine learning algorithms to achieve an accuracy of 91% and area under the curve of at least 0.89. Machine learning algorithms also identified up to 84% of participants who received an initial dementia diagnosis that was subsequently reversed to mild cognitive impairment or cognitively unimpaired, suggesting possible misdiagnosis.

Conclusions and Relevance: These findings suggest that machine learning algorithms could accurately predict incident dementia within 2 years in patients receiving care at memory clinics using only 6 variables. These findings could be used to inform the development and validation of decision-making aids in memory clinics.

RevDate: 2022-01-07

Stazi M, Lehmann S, Sakib MS, et al (2021)

Long-term caffeine treatment of Alzheimer mouse models ameliorates behavioural deficits and neuron loss and promotes cellular and molecular markers of neurogenesis.

Cellular and molecular life sciences : CMLS, 79(1):55.

Epidemiological studies indicate that the consumption of caffeine, the most commonly ingested psychoactive substance found in coffee, tea or soft drinks, reduces the risk of developing Alzheimer's disease (AD). Previous treatment studies with transgenic AD mouse models reported a reduced amyloid plaque load and an amelioration of behavioral deficits. It has been further shown that moderate doses of caffeine have the potential to attenuate the health burden in preclinical mouse models of a variety of brain disorders (reviewed in Cunha in J Neurochem 139:1019-1055, 2016). In the current study, we assessed whether long-term caffeine consumption affected hippocampal neuron loss and associated behavioral deficits in the Tg4-42 mouse model of AD. Treatment over a 4-month period reduced hippocampal neuron loss, rescued learning and memory deficits, and ameliorated impaired neurogenesis. Neuron-specific RNA sequencing analysis in the hippocampus revealed an altered expression profile distinguished by the up-regulation of genes linked to synaptic function and processes, and to neural progenitor proliferation. Treatment of 5xFAD mice, which develop prominent amyloid pathology, with the same paradigm also rescued behavioral deficits but did not affect extracellular amyloid-β (Aβ) levels or amyloid precursor protein (APP) processing. These findings challenge previous assumptions that caffeine is anti-amyloidogenic and indicate that the promotion of neurogenesis might play a role in its beneficial effects.

RevDate: 2022-01-11
CmpDate: 2022-01-11

Farfel JM, Leurgans SE, Capuano AW, et al (2021)

Dementia and autopsy-verified causes of death in racially-diverse older Brazilians.

PloS one, 16(12):e0261036.

BACKGROUND: While dementia has been associated with specific causes of death, previous studies were relatively small autopsy series or population-based studies lacking autopsy confirmation and were restricted to Non-Latinx Whites. Here, we examine the association of dementia with autopsy-verified causes of death in racially-diverse older Brazilians.

METHODS: As part of the Pathology, Alzheimer´s and Related Dementias Study (PARDoS), a community-based study in Brazil, we included 1941 racially-diverse deceased, 65 years or older at death. We conducted a structured interview with legal informants including the Clinical Dementia Rating (CDR) Scale for dementia proximate to death. Causes of death were assessed after full-body autopsy and macroscopic examination of the brain, thoracic and abdominal/pelvic organs. Up to four causes of death were reported for each decedent. Causes of death were classified as circulatory, infectious, cancer and other. Logistic regression was used to determine associations of dementia with cause of death, controlling for age, sex, race, and education.

RESULTS: Dementia was associated with a higher odds of an infectious cause of death (OR = 1.81, 95%CI:1.45-2.25), and with a lower odds of a circulatory disease as cause of death (OR = 0.69, 95%CI:0.54-0.86) and cancer as cause of death (OR = 0.41, 95%CI:0.24-0.71). Dementia was associated with a higher odds of pneumonia (OR = 1.92, 95%CI:1.53-2.40) and pulmonary embolism (OR = 2.31, 95%CI:1.75-3.05) as causes of death and with a lower odds of acute myocardial infarction (OR = 0.42, 95%CI:0.31-0.56) and arterial disease (OR = 0.76, 95%CI:0.61-0.94) as causes of death.

CONCLUSION: Racially-diverse older Brazilians with dementia had a higher odds of an infectious cause of death and a lower odds of cancer and circulatory disease as causes of death than those without dementia.

RevDate: 2021-12-17

Bhat A, Dalvi H, Jain H, et al (2021)

Perspective insights of repurposing the pleiotropic efficacy of statins in neurodegenerative disorders: An expository appraisal.

Current research in pharmacology and drug discovery, 2:100012.

Neurodegenerative disorders which affects a larger population pose a great clinical challenge. These disorders impact the quality of life of an individual by damaging the neurons, which are the unit cells of the brain. Clinicians are faced with the grave challenge of inhibiting the progression of these diseases as available treatment options fail to meet the clinical demand. Thus, treating the disease/disorder symptomatically is the Hobson's choice. The goal of the researchers is to introduce newer therapies in this segment and introducing a new molecule will take long years of development. Hence, drug repurposing/repositioning can be a better substitute in comparison to time consuming and expensive drug discovery and development cycle. Presently, a paradigm shift towards the re-purposing of drugs can be witnessed. Statins which have been previously approved as anti-hyperlipidemic agents are in the limelight of research for re-purposed drugs. Owing to their anti-inflammatory and antioxidant nature, statins act as neuroprotective in several brain disorders. Further they attenuate the amyloid plaques and protein aggregation which are the triggering factors in the Alzheimer's and Parkinson's respectively. In case of Huntington disease and Multiple sclerosis they help in improving the psychomotor symptoms and stimulate remyelination thus acting as neuroprotective. This article reviews the potential of statins in treating neurodegenerative disorders along with a brief discussion on the safety concerns associated with use of statins and human clinical trial data linked with re-tasking statins for neurodegenerative disorders along with the regulatory perspectives involved with the drug repositioning.

RevDate: 2021-12-15

Lu WH, Giudici KV, Guyonnet S, et al (2021)

Associations of plasma neurofilament light chain and progranulin with frailty in older adults.

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

BACKGROUND: In previous studies, plasma neurofilament light chain (NfL) and progranulin (PGRN) levels are associated with cognitive and physical impairment in older individuals. However, evidence of their relationships with frailty is lacking. This study aims to explore the associations of plasma NfL and PGRN levels with frailty in community-dwelling older adults.

METHODS: We included 507 older adults (mean [standard deviation] age, 76.7 [4.5] years) with plasma NfL and PGRN measurements from the Multidomain Alzheimer Preventive Trial (MAPT). The timepoint of biomarker measurements, either 12 or 24 months after study enrollment, was defined as the baseline for each participant. Frailty phenotype (robust, pre-frail, and frail) was assessed at 12, 24, 36, 48, and 60 months by Fried's frailty criteria. The cross-sectional associations between plasma neurodegenerative biomarkers and frailty severity were examined using logistic regressions. We further used Cox proportional hazard models to evaluate the associations between plasma biomarkers and incident frailty among robust or pre-frail participants at baseline (n = 403).

RESULTS: At baseline, participants with high plasma NfL levels (>93.11 pg/ml [the upper quartile]) had a higher likelihood of pre-frailty or frailty compared to their normal NfL counterparts (odds ratio = 1.68; 95% confidence interval = 1.10-2.57); however, this association did not remain significant after controlling for covariates. Neither NfL nor PGRN levels showed prospective associations with incident frailty over 4 years.

CONCLUSIONS: This study failed to find associations of circulating NfL and PGRN levels with frailty among community-dwelling older adults in adjusted analyses. Whether plasma neurodegenerative markers serve as potential biomarkers of frailty requires further investigation.

RevDate: 2021-12-15

Li Y, Schindler SE, Bollinger JG, et al (2021)

Validation of Plasma Amyloid-β 42/40 for Detecting Alzheimer Disease Amyloid Plaques.

Neurology pii:WNL.0000000000013211 [Epub ahead of print].

OBJECTIVE: To determine the diagnostic accuracy of a plasma Aβ42/Aβ40 assay in classifying amyloid PET status across global research studies using samples collected by multiple centers that utilize different blood collection and processing protocols. METHODS: Plasma samples (n=465) were obtained from three large Alzheimer's Disease (AD) research cohorts in the US (n=182), Australia (n=183), and Sweden (n=100). Plasma Aβ42/Aβ40 was measured by a high precision immunoprecipitation mass spectrometry (IPMS) assay and compared to the reference standards of amyloid PET and CSF Aβ42/Aβ40. RESULTS: In the combined cohort of 465 participants, plasma Aβ42/Aβ40 had good concordance with amyloid PET status (Receiver Operating Characteristic Area Under the Curve [AUC] of 0.84, 95% confidence interval [CI] 0.80-0.87); concordance improved with the inclusion of APOE ε4 status (AUC 0.88, 95% CI 0.85-0.91). The AUC of plasma Aβ42/Aβ40 with CSF amyloid status was 0.85 (95% CI 0.78-0.91) and improved to 0.93 (95% CI 0.89-0.97) with APOE ε4 status. These findings were consistent across the three cohorts, despite differences in protocols. Further, the assay performed similarly in both cognitively unimpaired and impaired individuals. CONCLUSIONS: Plasma Aβ42/Aβ40 is a robust measure for detecting amyloid plaques and can be utilized to aid in the diagnosis of AD, identify those at risk for future dementia due to AD, and improve the diversity of populations enrolled in AD research and clinical trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that plasma Aβ42/Aβ40, as measured by a high precision IPMS assay, accurately diagnoses brain amyloidosis in both cognitively unimpaired and impaired research participants.

RevDate: 2022-01-14

Chauhan BS, Kumar R, Kumar P, et al (2022)

Neuroprotective potential of flavonoid rich Ascophyllum nodosum (FRAN) fraction from the brown seaweed on an Aβ42 induced Alzheimer's model of Drosophila.

Phytomedicine : international journal of phytotherapy and phytopharmacology, 95:153872.

BACKGROUND: In Alzheimer Disease (AD) pathogenesis, aggregation of Aβ42 fibrils strongly correlates with memory dysfunction and neurotoxicity. Till date, no promising cures for AD. Report shows that flavonoids contributed anti-oxidant, anti-cancer and neuroprotection activity by regulating the mitochondrial machinery. Here, we first report the identification of flavonoids from Ascophyllum nodosum as having the ability to dissolve Aβ42 fibrils in an AD model of Drosophila. FRAN could be superior anti-AD agents for neuroprotection, their underlying mechanism and how they collectively halted amyloidogenesis is currently being investigated.

PURPOSE: This study aimed to investigate the neuroprotective role of FRAN in the Aβ42 expressing AD model of Drosophila.

METHODS: Drosophila stocks: OregonR+, ey-GAL4/CyO, elavc155-GAL4, UAS-mitoGFP, UAS-mcherry.mito.OMM, UAS-Aβ42/CyO were used, cultured at 28±1 °C in a BOD incubator. Ascophyllum extract rich in flavonoids as revealed by LC-MS study and employed against the AD flies. The validation of Aβ42 expression was done by immunostaining and q-RT PCR. The eye roughness of AD flies was scored in a dose-dependent manner. Further, In vivo and in silico studies of FRAN extract was executed against Aβ42 induced neurotoxicity.

RESULTS: In order to determine the most effective lethal dose of FRAN extract concentration 1, 2, 5, 10 mg/ml were screened using OregonR+flies. Extract 1 and 2 mg/ml did not show any lethality. Hence, extract 2 mg/ml was employed on AD flies and a ≥ 50% rescue in the eye phenotype was observed using SEM images. This dose had a strong effect on cell apoptosis, viability, longevity, mitochondrial dysfunction and oxidative stress by regulating mitochondrial dynamic markers in comparable to control. Extract also scavenging free radicals in order to maintain in situ cellular ROS and prevent Aβ42-induced neurotoxicity in vivo and in silico. Hence, we suggest its great potential as a future therapeutic agent for AD treatment.

CONCLUSION: In conclusion, FRAN extract rich in flavonoids as having largest neuroprotective activity against Aβ42 aggregation in eye tissue of Drosophila. Extract shows strong effect against Aβ42-induced neurotoxicity by altering the various cellular and molecular events. So, it could be considered as strong anti-AD agents for neuroprotection.

RevDate: 2021-12-28

Sveikata L, Charidimou A, A Viswanathan (2022)

Vessels Sing Their ARIAs: The Role of Vascular Amyloid in the Age of Aducanumab.

Stroke, 53(1):298-302.

We review the implications of the recently approved aducanumab amyloid-β immunotherapy for treating Alzheimer disease with comorbid cerebral amyloid angiopathy. In clinical trials, amyloid-β immunotherapy has been associated with a high rate of amyloid-related imaging abnormalities, potentially driven by coexisting cerebral amyloid angiopathy. Therefore, immunotherapy's efficacy in patients may be modified by coexisting cerebrovascular pathology. We discuss the contributions of cerebral amyloid angiopathy on the development of amyloid-related imaging abnormalities and propose strategies to identify cerebral amyloid angiopathy in patients considered for immunotherapy.

RevDate: 2021-12-27

Yoshimura M, Arizono E, Takase K, et al (2021)

Usefulness of texture analysis in 123I-FP-CIT for the differentiation of AD and DLB subtypes.

Hellenic journal of nuclear medicine, 24(3):206-213.

OBJECTIVE: I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) is well known to be a useful tracer for differentiating dementia with Lewy bodies (DLB) and Alzheimer disease (AD). However, clinically, there are some cases in which these diseases cannot be differentiated by ordinary quantitative methods. Therefore, in this study, we established an index that reflects not only the total count but also the distribution and heterogeneity of tracer uptake. We investigated whether assessment of the heterogeneous depletion of 123I-FP-CIT is useful for the differentiation of various types of dementia, i.e., probable DLB, possible DLB, and AD, using texture analysis.

MATERIALS AND METHODS: A total of 122 patients with either probable DLB (n=35), possible DLB (n=23), AD (n=44), and normal controls (n=20) were analyzed. Summated single photon emission computed tomography (SPECT) images (7 to 10 slices) of the patients, including the bilateral striatum, were analyzed using the gray-level histogram method (GLHM) of texture analysis. Mean, variance, skewness, and kurtosis of GLHM were compared with the specific binding ratio by Livia Tossici-Bolt's method (SBR).

RESULTS: The sensitivity and specificity for differentiating probable DLB from possible DLB, AD, and normal controls were 97.1% and 77.0%, respectively, for skewness, using a cut-off point of 6.8%, and 97.1% and 81.6%, respectively, for kurtosis, using a cut-off point of 53.4%. The sensitivity and specificity for differentiating probable and possible DLB from AD and normal controls was 65.5% and 98.4%, respectively, for skewness, using a cut-off point of 6.4%, and 79.3% and 93.8%, respectively, for kurtosis, using a cut-off point of 53.4%.

CONCLUSION: In the assessment of the efficacy of 123I-FP-CIT to differentiate AD and DLB subtypes, mean, variance, skewness, and kurtosis by GLHM was as useful as the SBR method. Moreover, possible DLB and probable DLB could be differentiated by skewness and kurtosis. Our results demonstrate that texture analysis is more useful than conventional quantitative methods for obtaining valuable information of the brain. Textural features as such may have considerable potential as imaging biomarkers of DLB progression.

RevDate: 2021-12-15

Eger SJ, Le Guen Y, Khan RR, et al (2022)

Confirming Pathogenicity of the F386L PSEN1 Variant in a South Asian Family With Early-Onset Alzheimer Disease.

Neurology. Genetics, 8(1):e647.

Objectives: The F386L PSEN1 variant has been reported in 1 Japanese family with limited clinical information. We aimed to prove that F386L is pathogenic by demonstrating that it segregates with early-onset Alzheimer disease (AD).

Methods: Eight individuals in a South Asian family provided DNA for genetic testing and underwent a neurologic examination.

Results: The female proband was diagnosed with AD at age 45 years and died at age 49 years. She had a CSF biomarker profile consistent with AD, and her florbetaben PET scan was amyloid positive with high uptake in the striatum. Her MRI showed no prominent white matter disease. Her affected relatives had an age at onset range of 38-57 years and had imaging and biomarker profiles similar to hers.

Discussion: The results presented here, in conjunction with the prior report, confirm the pathogenicity of F386L. Furthermore, our study highlights the importance of studying families from underrepresented populations to identify or confirm the pathogenicity of rare variants that may be specific to certain genetic ancestries.

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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

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Curriculum Vitae for R J Robbins

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Curriculum Vitae for R J Robbins

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